Inhibitors of influenza virus replication

文档序号：1780012 发布日期：2019-12-06 浏览：27次中文

阅读说明：本技术 流感病毒复制抑制剂 (Inhibitors of influenza virus replication ) 是由 P·查理弗森 M·P·克拉克 U·K·本达拉格 R·S·贝西埃尔 J·J·库特邓红波于 2010-06-17 设计创作，主要内容包括：本发明涉及流感病毒复制抑制剂。具体地,抑制流感病毒在生物样品或患者中复制、减少生物样品或患者中流感病毒的量和治疗患者流感的方法包括向所述生物样品或患者施用有效量的用结构式(I)表示的化合物或其药学上可接受的盐：<Image he="669" wi="561" file="DDA0002142614910000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中结构式(IA)的值如本文所述。一种化合物用结构式(IA)或其药学上可接受的盐表示,其中结构式(IA)的值如本文所述。一种药物组合物,包含有效量的这种化合物或其药学上可接受的盐、和药学上可接受的载体、佐剂或媒介物。(The present invention relates to inhibitors of influenza virus replication. Specifically, the methods of inhibiting the replication of influenza virus in a biological sample or patient, reducing the amount of influenza virus in a biological sample or patient, and treating influenza in a patient comprise administering to the biological sample or patient an effective amount of a compound represented by structural formula (I): wherein the values of structural formula (IA) are as described herein. A compound is represented by structural formula (IA) or a pharmaceutically acceptable salt thereof, wherein the values of structural formula (IA) are as described herein. A pharmaceutical composition comprising an effective amount of such a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.)

1. A compound of structural formula (IA) or a pharmaceutically acceptable salt thereof,

Wherein the content of the first and second substances,

Z1 is-R, -F, -Cl, -CN, -OR, -CO2R, -NO2, OR-CON (R) 2;

Z2 is-R, -OR, -CO2R, -NR 2, OR-CON (R) 2;

Z3 is-H, -OH, halogen, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -O (C1-C4 alkyl), or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy and-O (C1-C4 alkyl);

R1 is-H, C1-C6 alkyl, -S (O)2-R ", OR-C (O) OR";

R3 is-H, -Cl, -F, -Br, -OH, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -CN, or a C1-C4 aliphatic group optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy;

R4 is:

Wherein the content of the first and second substances,

Ring A is a C3-C10 non-aromatic carbocyclic ring optionally further substituted by one or more JAs, or a 3-10 membered non-aromatic heterocyclic ring optionally further substituted by one or more JBs,

Rings B and C are each independently a 4-10 membered non-aromatic heterocyclic ring optionally and independently further substituted with one or more JBs;

Ring D is a 4-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JD 1; or

Ring a and R8 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R9 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R11 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, wherein each carbocyclic ring is optionally further substituted by one or more JA, and wherein each heterocyclic ring is optionally further substituted by one or more JB;

Each of JA and JB is independently selected from halogen, cyano, oxo, -NCO, and Q1-R5; or optionally two JAs and two JB's each independently form, together with the atoms to which they are attached, a 4-8 membered ring optionally substituted by one or more JE 1;

Q1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (NR) NR-, -NRC (NR) NR-, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO2-, -NRSO2 NR' -, -P (O) (OR) O-, -OP (O) (ORa) O-, -SO2, -P (O)2O-, -CO2SO2-, or- (CR6R7) p-Y1-;

Q2 is independently a bond, -O-, -S-, -NR-, -C (O) -, -C (NR) NR-, -NRC (NR) NR-, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2NR-, -P (O) (OR) O-, -OP (ORa) O-, -P (O)2O-, -CO2SO2-, or- (CR6R7) p-Y1-;

Q3 is independently a bond, -C (O) -, -C (═ NR) NR-, -NRC (═ NR) NR-, -CO2-, -C (O) NR-, -SO2-, -SO2N (R) -, -C (O) NRC (O) O-, or- (CR6R7) p-Y1-;

R5 is: i) -H; ii) a C1-C6 aliphatic group optionally substituted with one or more JC 1; iii) C3-C10 non-aromatic carbocyclic, or 6-10 membered carbocyclic aryl, each optionally and independently substituted with one or more JC 1; or iv) a 4-10 membered non-aromatic heterocycle, or a 5-10 membered heteroaryl, each optionally and independently substituted with one or more JD 1; or

R5 and each of Q1, Q2, Q3 together optionally and independently form a 4-8 membered non-aromatic ring optionally substituted with one or more JE 1; and is

R6 and R7 are each independently-H, or C1-C6 alkyl optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy, or optionally R6 and R7 together with the carbon atoms to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups;

R8 and R9 are each independently-H, halogen, cyano, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, or C2-C6 alkoxyalkoxy; or R8 together with Q2 and R5 optionally and independently form a 5-7 membered non-aromatic ring optionally substituted with one or more JE 1;

R10 is independently-H, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, C2-C6 alkoxyalkoxy, C3-C8 non-aromatic carbocyclic ring, phenyl, 4-8 membered non-aromatic heterocyclic ring, and 5-6 membered heteroaryl; wherein each of said carbocycle, phenyl, heterocycle and heteroaryl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;

R11, R12, R13 and R14 are each independently-H, halogen, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;

optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups;

R and R' are each independently-H, or C1-C6 alkyl optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or optionally, R' together with R5 and the nitrogen atom to which it is attached forms a 5-7 membered non-aromatic heterocyclic ring optionally substituted with one or more JD 1;

r "is independently: i) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or ii) C3-C6 carbocyclyl, 5-6 membered heteroaryl, or phenyl, each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C1-C6-hydroxyalkyl, C2-C6-alkoxyalkyl, C1-C6-aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6-hydroxyalkoxy, and C2-C6 alkoxyalkoxy;

R independently is: i) -H; ii) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, amino, carboxy, a C3-C8 non-aromatic carbocyclic ring, a 5-6 membered non-aromatic heterocyclic ring, phenyl, a 5-6 membered heteroaryl, -O (C1-C6 alkyl), and-C (O) (C1-C6-alkyl); wherein each of said alkyl groups in-O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl and heteroaryl is independently and optionally substituted with one or more JE 1; or iii) each independently and optionally substituted with one or more JE 1C 3-C8 non-aromatic carbocyclic ring, or 4-8 membered non-aromatic heterocyclic ring; and is

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -s (o) Ra, -SO2Ra, -NRbRc, -C (o) Rb, -C (NR) Rc, -C (NR) NRbRc, -NRC (NR) NRbRc, -C (o) ORb, -oc (o) Rb, -NRC (o) Rb, -C (o) NRbRc, -NRC (o) ORb, -OCONRbRc, -C (o) NRCO2Rb, -NRC (o) ORb, -C (o) NR ORb, -SO2 nrcrrb, -NRSO2Rb, -NRSO2 nrcrrb, -p (o) (ORa)2, -o (ORa)2, -p (o)2(ORa), and-CO 2SO2Rb, or optionally, two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 4-8 membered ring optionally substituted with one or more JE 1;

Each JE1 is independently selected from halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C1-C6 alkyl, -O (C1-C6 alkyl), and-C (O) (C1-C6-alkyl), wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and is

Each Ra is independently:

i) A C1-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O (C1-C6 alkyl), -C (O) (C1-C6-alkyl), C3-C8 non-aromatic carbocyclic ring, 4-8 membered non-aromatic heterocyclic ring, 5-10 membered heteroaryl and 6-10 membered carbocyclic aryl; wherein each said alkyl group of substituents of the C1-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocyclic rings, heterocyclic rings, heteroaryl groups and carbocyclic aryl groups that are substituents of the C1-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more JE 1;

ii) a C3-C8 non-aromatic carbocyclic ring, or a 4-8 membered non-aromatic heterocyclic ring, each of which is optionally and independently substituted with one or more JE 1; or

iii) a 5-10 membered heteroaryl, or a 6-10 membered carbocyclic aryl, each of which is optionally and independently substituted with one or more JE 1; and is

Rb and Rc are each independently Ra or-H; or optionally, Rb and Rc, together with the nitrogen atom to which they are attached, each independently form a 5-7 membered non-aromatic heterocyclic ring optionally substituted by one or more JE 1;

p is independently 1,2, 3 or 4;

When rings A and B are 3-6 membered, n and m are each independently 0 or 1; or when rings A and B are 7-10 membered, n and m are each independently 0, 1 or 2;

k is 0, 1 or 2;

x and y are each independently 0,1 or 2;

z is 1 or 2; and is

Provided that, if Y1 is a bond, then R5 is neither-H nor a C1-C6 aliphatic group; and is

if Q2 and Q3 are each independently a bond, then R5 is neither-H nor a C1-C6 aliphatic group.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (VI),

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (II), (III), (IV) or (V),

wherein the content of the first and second substances,

R3 is-H, -F, -Cl, -CF3, -NH2, -NH (CH3), or-N (CH3) 2;

Z1 is-H, -F, -Cl, -CF3, C1-C4 alkyl, -CH2NH2, -C (O) NH2, -C (O) NH (CH3), -C (O) N (CH3)2, -O (C1-C4 alkyl), or-CN;

R and R' are each independently-H or C1-C6 alkyl;

Ring A is an optionally substituted C4-C7 non-aromatic carbocyclic ring;

Rings B and C are each independently an optionally substituted 4-7 membered non-aromatic heterocyclic ring;

Ring D is an optionally substituted 4-7 membered non-aromatic heterocyclic ring;

Each of JA and JB is independently selected from halogen, cyano, oxo, and Q1-R5; or optionally two JA and two JB are each independently taken together with the atoms to which they are attached to form a 5-7 membered ring optionally substituted with one or more JE1 and fused to the ring to which it is attached;

JC1 and JD1 are each independently selected from: halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb, and-NRSO 2NRcRb, or optionally, two JC1 and two JD1, respectively, independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with and fused to the respective rings to which they are attached, JC 1;

Q1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO2-, -NRSO2 NR' -, or- (CR6R7) p-Y1-;

Q2 is independently a bond, -O-, -S-, -NR-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2NR '-, -NRSO2 NR' -, or- (CR6R7) p-Y1-; and is

Q3 is independently a bond, -C (O) -, -CO2-, -C (O) NR '-, -SO2-, -SO2 NR' -, -C (O) NRC (O) O-, or- (CR6R7) p-Y1-;

Provided that, if Q2-R5 is-OR 5 OR-NR' R5, ring A is further substituted with one OR more JAs other than-H, and

provided that, if Q3 is-C (o) -, R5 is a substituted C1-C6 aliphatic group, an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl group, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl group.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (XIA) or (XIB),

Wherein the content of the first and second substances,

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (XIIA) or (XIIB),

Wherein the content of the first and second substances,

Ring B is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (XIII),

wherein the content of the first and second substances,

Ring C is a 5-6 membered non-aromatic heterocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (IA) is a compound of formula (XIV),

Wherein the content of the first and second substances,

Ring D is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy.

8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R4 is

Wherein the content of the first and second substances,

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocyclic ring optionally further substituted by one or more JA;

Ring G5 is a 5-10 membered non-aromatic bridged heterocyclic ring optionally further substituted with one or more JBs;

X is-O-, -S-, or-NRg-;

R13 and R14 are each independently-H, halogen, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;

Optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups;

R21, R22, R23, R24, and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;

Rg is-H, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;

q is 0, 1 or 2;

x is 0,1 or 2; and is

r is 1 or 2.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R4 is

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof,

Each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2;

R21, R22, R23, and R24 are each independently-H, halogen, -OH, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.

11. The compound of claim 1, or a pharmaceutically acceptable salt thereof,

R4 is

Ring a is a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R8 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R9 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R11 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, wherein each said carbocyclic ring is independently and optionally substituted with one or more JA and wherein each carbocyclic ring is independently and optionally substituted with one or more JB;

R1 is-H;

R2 is-H, -CH3, -CH2OH, or-NH 2;

R3 is-H, -F, -Cl, C1-4 alkyl, or C1-4 haloalkyl;

Z1 is-H, -F, or-Cl;

Z2 is-H, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and-O (C1-C4 alkyl);

z3 is-H, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and-O (C1-C4 alkyl);

Q2 is independently-O-, -CO2-, -OC (O) -, -C (O) NR ' -, -C (O) NRC (O) O-, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O)2O-, -CO2SO2-, or- (CR6R7) p-Y1-;

Y1 is-O-, -CO2-, -OC (O) -, -C (O) NR ' -, -C (O) NRC (O) O-, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O)2O-, or-CO 2SO 2-;

R5 is: i) -H; ii) an optionally substituted C1-C6 alkyl group; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; iv) an optionally substituted 4-7 membered non-aromatic heterocyclic ring; v) optionally substituted phenyl; vi) an optionally substituted 5-6 membered heteroaromatic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring; and is

Said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, -NRCO (C1-C4 alkyl), -CONR (C1-C4 alkyl), -NRCO2(C1-C4 alkyl), a C3-C7 non-aromatic carbocyclic ring optionally substituted with one or more JE1, a 4-7 membered non-aromatic heterocyclic ring optionally substituted with one or more JE1, and a phenyl group optionally substituted with one or more JE 1;

Wherein each of said carbocycle, heterocycle, phenyl and heteroaryl represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy;

Each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2;

r11, R12, R13 and R14 are each independently-H, halogen, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C6 alkoxy;

Each of JA and JB is independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2 Rb; wherein each said alkyl group is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and is

n is 0 or 1;

x is 0 or 1.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof,

R1 is-H;

R2 is-H;

R3 is-H, -F, or-Cl;

Z1 is-H, -F, or-Cl;

Z2 is-H;

Z3 is-H;

x is-O-;

R5 is-H, optionally substituted C1-C6 alkyl, or optionally substituted phenyl;

Each R8 is independently-H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or-O (C1-C4 alkyl);

Each of R9, R13, and R14 is independently-H or C1-C4 alkyl;

Each ring G1-G5 is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), C1-C4 alkyl optionally substituted with one or more substituents selected from halogen, hydroxy and C1-C4 alkoxy.

13. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

14. the pharmaceutical composition of claim 13, further comprising a therapeutic agent selected from an antiviral agent or a vaccine.

15. A method of reducing the amount of influenza virus in a biological sample or patient comprising administering to the biological sample or patient an effective amount of a compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, or a combination of said compounds or pharmaceutically acceptable salts thereof.

16. the method of claim 15, further comprising administering to the biological sample or patient an additional agent comprising oseltamivir.

17. The method of claim 16, wherein the additional agent is administered prior to, concurrently with, or after the administration of the compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.

Background

Influenza spreads worldwide in seasonal epidemics, causing hundreds of thousands of deaths per year-millions in pandemic. For example, 3 influenza pandemics occurred in the 20 th century, resulting in the death of tens of millions of people, each pandemic arising from the emergence of new viral strains in humans. Often, these new strains result from the transmission of existing influenza viruses from other animal species to humans.

influenza is transmitted from person to person mainly by large virus-laden droplets produced when an infected person coughs or sneezes; these large droplets may then settle on mucosal surfaces in the upper respiratory tract of susceptible individuals who are close to (e.g., within about 6 feet) the infected person. Transmission may also occur by direct or indirect contact with respiratory secretions, such as touching a surface contaminated with influenza virus, then touching the eyes, nose or mouth. An adult may be able to transmit influenza to others 1 day before symptoms appear or about 5 days after symptoms begin. Children and immunocompromised people may be contagious 10 days or more after the onset of the symptoms.

Influenza viruses are RNA viruses of the Orthomyxoviridae (Orthomyxoviridae) family, which include 5 genera: influenza a virus, influenza B virus, influenza C virus, salmon anemia virus (isavus) and torulo virus (thogo virus).

influenza a virus belongs to 1 species, influenza a virus. Wild waterfowl is a natural host for a large number of influenza types a. Sometimes, the virus spreads to other species and can then cause devastating outbreaks in poultry or cause pandemics of human influenza. Of the 3 influenza types, influenza a is the most virulent human pathogen and causes the most serious disease. Influenza a viruses can be subdivided into different serotypes based on antibody responses to these viruses. The confirmed human serotypes, ordered by the number of known human pandemic deaths, are: H1N1 (causing spanish flu in 1918), H2N2 (causing asian flu in 1957), H3N2 (causing hong kong flu in 1968), H5N1 (pandemic threat in the 2007-08 flu season), H7N7 (with rare potential for animal infections), H1N2 (endemic epidemics in humans and pigs), H9N2, H7N2, H7N3 and H10N 7.

Influenza B virus belongs to 1 species, influenza B virus. Influenza B infects humans almost exclusively and is less common than influenza a. The only other animal known to be susceptible to influenza B infection is seal. This type of influenza mutates at a rate 2-3 times slower than type a and is therefore of low genetic diversity, with only one influenza B serotype. Due to this lack of antigenic diversity, a certain degree of influenza B immunity is usually acquired in the early years. However, influenza B mutations are sufficient to make durable immunization impossible. This reduces the rate of antigen change, incorporates its restricted host changes (inhibits cross-species antigen conversion), and ensures that no major influenza B epidemics occur.

Influenza C virus belongs to 1 species, influenza C virus, which infects humans and pigs and can cause severe disease and endemic epidemics. However, influenza C is less common than other types of influenza and often appears to cause mild disease in children.

A. influenza B and C viruses are very similar in structure. Viral particles are 80-120nm in diameter and generally approximate spheres, but filamentous forms may occur. Unusual for viruses, nucleic acids whose genomes are not single fragments; in contrast, the genome contains segmented negative-sense RNAs of 7 or 8 segments. The influenza a genome encodes 11 proteins: hemagglutinin (HA), Neuraminidase (NA), Nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2, and PB 2.

HA and NA are macromolecular glycoproteins outside the virion. HA is a lectin that mediates binding of the virus to the target cell and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells by cleaving sugars that bind to mature viral particles. Thus, these proteins have been the target of antiviral drugs. Moreover, these proteins are antigens of antibodies that can be produced. Influenza a viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of H and N discrimination in, for example, H5N1 (see above).

influenza incurs direct costs due to lost productivity and associated medical care as well as indirect costs of preventative measures. In the united states, influenza is responsible for over 100 billion dollars of total costs per year, and it is estimated that future pandemics can cause billions of dollars of direct and indirect costs. The prevention cost is also high. Governments around the world have spent billions of dollars in preparing and planning for a possible H5N1 avian influenza pandemic, costs associated with purchasing medications and vaccines and developing strategies for disaster development and increased border controls.

Current influenza treatment options include vaccination and chemotherapy or chemoprevention with antiviral drugs. Vaccination against influenza is often recommended for high-risk groups, such as children and the elderly, or people with asthma, diabetes or heart disease. However, it is possible to vaccinate but still obtain influenza. Some vaccines for specific influenza strains are reformulated each season, but it is unlikely that all strains actively infecting humans in the world of the season will be included. Factories formulate and produce millions of doses needed to treat seasonal epidemics in about 6 months; sometimes new or overlooked strains become prominent during this period and infect people, even though these people have been vaccinated (e.g. 2003-2004 flu season H3N2 Fujian flu). It is also possible to infect just before vaccination and the strain for which the vaccine is supposed to prevent, since it takes about two weeks for the vaccine to become effective.

In addition, the efficacy of these influenza vaccines can vary. Because of the high mutation rate of viruses, certain influenza vaccines typically confer protection for no more than a few years. Since the virus changes rapidly over time and different strains become dominant, a vaccine formulated for one year may not be effective in the next year.

also, the RNA-dependent RNA polymerase of influenza vRNA produces a nucleotide insertion error approximately every 1 ten thousand nucleotides (which is the approximate length of influenza vRNA) due to the lack of RNA proofreading enzyme. Thus, almost every new influenza virus is mutated-antigenic drifted. If more than one virus line infects a single cell, the genome is separated into 8 individual vRNA fragments to allow for vRNA mixing or reassortment. The rapid changes in the genetics of the generated viruses produce antigenic shifts and allow the viruses to infect new host species and quickly overcome protective immunity.

Antiviral drugs may also be used to treat influenza, where neuraminidase inhibitors are particularly effective, but the virus may develop resistance to standard antiviral drugs.

Thus, there remains a need for agents for treating influenza infection, for example agents with an expanded therapeutic window and/or reduced sensitivity to viral titers.

disclosure of Invention

The present invention relates generally to methods of treating influenza, methods of inhibiting replication of influenza virus, methods of reducing the amount of influenza virus, compounds and compositions useful in these methods.

In one aspect, the invention relates to a method of inhibiting replication of influenza virus in a biological sample or patient. In one embodiment, the method comprises the step of administering to the biological sample or patient an effective amount of a compound represented by structural formula (IA):

Wherein:

Z1 is-R, -F, -Cl, -CN, -OR, -CO2R, -NO2 OR-CON (R) 2;

Z2 is-R, -OR, -CO2R, -NR 2 OR-CON (R) 2;

Z3 is-H, -OH, halo (e.g., -Cl or-Br), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -O (C1-C4 alkyl), or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halo, cyano, hydroxy and-O (C1-C4 alkyl);

R1 is-H or C1-C6 alkyl;

R2 is-H, -F, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C ═ N-OH, cyclopropyl optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, -OCH3 and-CH 3, or C1-C4 alkyl optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy and-O (C1-C4 alkyl); and is

r3 is-H, -Cl, -F, -OH, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -Br, -CN or a C1-C4 aliphatic optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy;

R4 is:

i) Wherein ring T is a C3-C10 non-aromatic carbocyclic ring optionally substituted with one or more JA or a 3-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JB, or ring T and R9 optionally form a non-aromatic C5-C10 membered carbocyclic ring optionally substituted with one or more JA or a 5-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JB;

ii) wherein ring J is a 3-10 membered non-aromatic heterocyclic ring optionally substituted by one or more JBs; or

iii) wherein ring D is a 4-10 membered non-aromatic heterocyclic ring optionally substituted by one or more JD 1; and is

q1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (NR) NR-, -NRC (NR) NR-, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO 2-or NRSO 2NR' -, -P O (OR) O-, -OP (O) (ORa) O-, -O (O), -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1-;

Y1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (NR) NR-, -NRC (NR) NR-, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO2-, -NRSO 2NR' -, -P (O) (OR) O-, -OP (O) (ORa) O-, -O (O-), -P (O) 2O-or-CO 2SO 2-;

R5 and Q1 together optionally form a 4-8 membered non-aromatic ring optionally substituted with one or more JE 1; and is

R9 is independently-H, halogen, cyano, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy;

Optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups;

R and R' are each independently-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or optionally, R' together with R5 and the nitrogen atom to which it is attached forms a 5-7 membered non-aromatic heterocyclic ring optionally substituted with one or more JD 1;

r independently is: i) -H; ii) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, amino, carboxy, a C3-C8 nonaromatic carbocyclic ring, a 5-6 membered nonaromatic heterocyclic ring, phenyl, a 5-6 membered heteroaryl, -O (C1-C6 alkyl), and-C (O) (C1-C6 alkyl); wherein each said alkyl group in-O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycle, heterocycle, phenyl and heteroaryl is independently and optionally substituted with one or more JE 1; or iii) each independently and optionally substituted with one or more JE 1C 3-C8 non-aromatic carbocyclic ring or 4-8 membered non-aromatic heterocyclic ring; and is

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -s (o) Ra, -SO2Ra, -NRbRc, -C (o) Rb, -C (NR) Rc, -C (NR) NRbRc, -NRC (NR) NRbRc, -C (o) ORb, -oc (o) Rb, -NRC (o) Rb, -C (o) NRbRc, -NRC (o) ORb, -OCONRbRc, -C (o) NRCO2Rb, -NRC (o) ORb, -C (o) NR ORb, -SO2 nrcrrb, -NRSO2Rb, -NRSO2 nrcrrb, -p (o) (ORa)2, -op (ORa)2, -p (o)2ORa and-CO 2SO2Rb, or optionally, two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 4-8 membered ring optionally substituted with one or more JE 1;

Ra is independently: i) a C1-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O (C1-C6 alkyl), -C (O) (C1-C6-alkyl), C3-C8 non-aromatic carbocyclic ring, 4-8 membered non-aromatic heterocyclic ring, 5-10 membered heteroaryl and 6-10 membered carbocyclic aryl; wherein each said alkyl of the substituents of the C1-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocyclic rings, heterocyclic rings, heteroaryl groups and carbocyclic aryl groups that are substituents of the C1-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more JE 1;

ii) a C3-C8 non-aromatic carbocyclic ring or a 4-8 membered non-aromatic heterocyclic ring, each of which is optionally and independently substituted with one or more JE 1; or

iii) a 5-10 membered heteroaryl or a 6-10 membered carbocyclic aryl, each of which is optionally and independently substituted with one or more JE 1; and is

Rb and Rc are each independently Ra or-H; or optionally, Rb and Rc together with the nitrogen atom to which they are attached each independently form a 5-7 membered non-aromatic heterocyclic ring optionally substituted by one or more JE 1;

p is independently 1,2, 3 or 4;

t is 0,1 or 2;

j is 1 or 2; and is

z is 1 or 2.

In another embodiment, the method comprises administering to the biological sample or patient an effective amount of a compound represented by structural formula (I):

wherein:

R1 is-H;

R2 is-H, -CH3, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2;

R4 is: i) a C3-C10 non-aromatic carbocyclic ring optionally substituted with one or more JA; ii) a 4-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JBs; or iii) a C1-C6 aliphatic group optionally substituted with one or more substituents independently selected from JC, a C3-C8 non-aromatic carbocyclic ring or a 6-10 membered carbocyclic aryl group each optionally and independently substituted with one or more JAs, a 5-10 membered heteroaryl group or a 4-10 membered non-aromatic heterocyclic ring each optionally and independently substituted with one or more JB;

each of JA and JB is independently selected from halogen, cyano, oxo, -NCO, and Q1-R5; or optionally two JAs and two JB's each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted by one or more JE 1;

JC is independently selected from: halogen, cyano, oxo, -OR5, -SR5, -NR 'R5, -C (O) R5, -CO2R5, -OC (O) R5, -C (O) NR' R5, -C (O) NRC (O) OR5, -NRC (O) OR5, -NRC (O) R5, -NRC (O) NR 'R5, -NRCO2R5, -OC (O) NR' R5, -S (O) R5, -SO2R5, -SO2NR 'R5, -NRSO2R5 and-NRSO 2NR' R5;

Q1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (═ NR) -, -CO2-, -oc (O) -, -C (O) NR' -, -C (O) nrc (O) O-, -nrc (O) NR '-, -NRCO2-, -oc (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -n (R) SO 2-or-NRSO 2 NR' -or- (CR6R7) p-Y1-;

Y1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (═ NR) -, -CO2-, -oc (O) -, -C (O) NR' -, -C (O) nrc (O) O-, -nrc (O) NR '-, -NRCO2-, -oc (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO2-, or-NRSO 2NR' -;

R5 is: i) -H; ii) a C1-C6 aliphatic group optionally substituted with one or more JC 1; iii) C3-C8 non-aromatic carbocyclic or 6-10 membered carbocyclic aryl each optionally and independently substituted by one or more JC 1; or iv) a 4-8 membered non-aromatic heterocycle or 5-10 membered heteroaryl each optionally and independently substituted with one or more JD 1. Optionally, R5 and Q1 together optionally form a 5-7 membered non-aromatic ring optionally substituted with one or more JE 1;

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb, -NRSO2NRcRb and-P (O) ORa)2-, or optionally, two JC1 and two JD1 together with the atoms to which they are attached, independently form a 5-7 membered ring optionally substituted with one or more JE1 and fused to the respective ring to which it is attached;

Each of Z1, Z2, R3, R6, R7, R, R', R, JE1, Ra, Rb, Rc and p is independently as described above for structural formula (IA).

in another embodiment, the invention relates to a method of reducing the amount of influenza virus in a biological sample or patient. The method comprises administering to the biological sample or patient an effective amount of a compound represented by structural formula (I) or structural formula (IA), each independently as described above.

In yet another embodiment, the invention relates to a method of treating or preventing influenza in a patient, comprising administering to the patient an effective amount of a compound represented by structural formula (I) or structural formula (IA), each independently as described above.

In yet another embodiment, the present invention relates to a compound represented by structural formula (IA) or a pharmaceutically acceptable salt thereof:

Or a pharmaceutically acceptable salt thereof, wherein:

R1 is-H, C1-C6 alkyl, -S (O)2-R 'OR-C (O) OR', OR R1 is-H OR C1-C6 alkyl;

R4 is:

Wherein:

Ring a is a C3-C10 non-aromatic carbocyclic ring optionally further substituted by one or more JA or a heterocyclic ring optionally further substituted by one or more JB;

Rings B and C are each independently a 4-10 membered non-aromatic heterocyclic ring optionally and independently further substituted with one or more JBs;

Ring D is a 4-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JD 1; or

Q3 is independently a bond, -C (O) -, -C (═ NR) NR-, -NRC (═ NR) NR-, -CO2-, -C (O) NR-, -SO2-, -SO2N (R) -, -C (O) NRC (O) O-, or- (CR6R7) p-Y1-;

R "is independently: i) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy; or ii) C3-C6 carbocyclyl, 5-6 membered heteroaryl, or phenyl, each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6-hydroxyalkoxy and C2-C6 alkoxyalkoxy;

Each of Z1, Z2, Z3, Q1, Q2, Q3, Y1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R, R', R x, JA, JB, JC1, JD1, JE1, Ra, Rb, Rc and p is independently as described above for structural formula (IA) of the method of inhibiting influenza virus replication;

When rings A and BETA are 3-6-membered, n and m are each independently 0 or 1; or when rings A and BETA are 7-10 members, n and m are each independently 0, 1 or 2;

k is 0, 1 or 2;

x and y are each independently 0,1 or 2;

z is 1 or 2; and is

If Y1 is a bond, then R5 is neither-H nor a C1-C6 aliphatic group; and is

If Q2 and Q3 are each independently a bond, then R5 is neither-H nor a C1-C6 aliphatic group.

in yet another embodiment, the invention relates to a compound represented by structural formula (I), or a pharmaceutically acceptable salt thereof, wherein the values of the variables of structural formula (I) are as follows:

R1 is-H, C1-C6 alkyl, -S (O)2-R 'OR-C (O) OR', OR R1 is-H OR C1-C6 alkyl;

R4 is:

Ring a is a C3-C8 non-aromatic carbocyclic ring optionally further substituted by one or more JA or a heterocyclic ring optionally further substituted by one or more JB;

Rings B and C are each independently a 4-8 membered non-aromatic heterocyclic ring optionally and independently further substituted with one or more JBs;

Ring D is a 4-8 membered non-aromatic heterocyclic ring optionally substituted with one or more JD 1;

each of Z1, Z2, Z3, Q1, Q2, Q3, Y1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R, R', R x, JC1, JD1, JE1, Ra, Rb, Rc and p is independently as described above for structural formula (I) of the method of inhibiting influenza virus replication;

when rings A and BETA are 4-6-membered, n and m are each independently 0 or 1; or when rings A and BETA are 7-8 members, n and m are each independently 0,1 or 2;

k is 0,1 or 2;

x and y are each independently 0,1 or 2;

z is 1 or 2;

If Y1 is a bond, then R5 is neither-H nor a C1-C6 aliphatic group; and is

If Q2 and Q3 are each independently a bond, then R5 is neither-H nor a C1-C6 aliphatic group.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a compound represented by structural formula (I) or structural formula (IA) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, wherein the values of the variables of structural formulae (I) and (IA) are each independently as described above for the compounds of the present invention.

The invention also provides the use of a compound described herein to inhibit replication of influenza virus in a biological sample or patient, to reduce the amount of influenza virus in a biological sample or patient, or to treat influenza in a patient.

Also provided herein is the use of a compound described herein for the manufacture of a medicament for treating influenza in a patient, reducing the amount of influenza virus in a biological sample or patient, or inhibiting replication of influenza virus in a biological sample or patient.

Drawings

Figure 1 is a graph showing the percent survival of Balb/c mice (4-5 weeks old) over time in a prophylactic study in which 2h prior to infection was administered orally gavage (10mL/kg) with compound 514(100mg/kg) or vehicle alone (0.5% methylcellulose 0.5% Tween 80) as an initial dose and for 5 days, 2 times daily.

Figure 2 is a graph showing the percent survival of Balb/c mice (4-5 weeks old) over time in a treatment study in which compound 588(200mg/kg) or vehicle alone was administered orally gavage 24h post infection and continued for 10 days, 2 times daily.

figures 3-8 are tables showing some specific compounds of the invention.

Detailed Description

Use of the disclosed compounds

One aspect of the present invention generally relates to the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition comprising such a compound or a pharmaceutically acceptable salt thereof, to inhibit influenza virus replication in a biological sample or patient, to reduce the amount of influenza virus in a biological sample or patient (reduce viral titer), and to treat influenza in a patient.

in one embodiment, the present invention relates generally to the use of a compound represented by structural formula (I) or structural formula (IA) or a pharmaceutically acceptable salt thereof for any of the applications specified above:

the 1 st set of variables for structural formulae (I) and (IA) are independently as follows:

Z1 is-R, -F, -Cl, -CN, -OR, -CO2R, -NO2 OR-CON (R) 2. In particular, Z1 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH (C1-C6 alkyl), or-CON (C1-C6 alkyl) 2, wherein each said alkyl (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -CO2(C1-C6 alkyl), -CONH (C1-C6 alkyl), and-CON (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, Z1 is-H, -F, -Cl, C1-C4 haloalkyl (e.g., -CF3), C1-C4 alkyl, -CH2NH2, -C (O) NH2, -C (O) NH (CH3), -C (O) N (CH3)2, -O (C1-C4 alkyl), or-CN. In particular, Z1 is-H, -F, -Cl, -CF3, C1-C4 alkyl or-CN. In particular, Z1 is-H, -F, -Cl, -CF3, -CH3 or-CN. In particular, Z1 is-H, -F or-CN. In particular, Z1 is-H or-F.

Z2 is-R, -OR, -CO2R, -NR 2 OR-CON (R) 2. In particular, Z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each of said alkyl (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -NH (C1-C6 alkyl), and-N (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, Z2 is-H, C1-C6 alkyl or-O (C1-C6 alkyl), wherein each alkyl is optionally and independently substituted. In particular, Z2 is-H or optionally substituted C1-C6 alkyl.

z3 in formula (IA) is-H, -OH, halogen, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -O (C1-C4 alkyl), or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy and-O (C1-C4 alkyl). In particular, Z3 is-H, -O (C1-C4 alkyl) or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy and-O (C1-C4 alkyl). In particular, Z3 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, and-O (C1-C4 alkyl). In particular, Z3 is-H.

R1 is-H or C1-6 alkyl. In particular, R1 is-H.

R2 is-H, -F, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C ═ N-OH, cyclopropyl optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, -OCH3 and CH3, or C1-C4 alkyl optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy and-O (C1-C4 alkyl). In particular, R2 is-H, -CH3, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2. In particular, R2 is-H, -F, -CH3, -CH2OH or-NH 2. In particular, R2 is-H or-CH 3.

R3 is-H, -Cl, -F, -OH, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -Br, -CN or a C1-C4 aliphatic optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, R3 is-H, -Cl, -F, -CF3, -OCH3, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -Br, -O (C1-C4 alkyl), -CN, -C1-C4 haloalkyl, -OH or-C1-C4 aliphatic. In particular, R3 is-H, -Cl, -F, -CF3, -OCH3, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -Br, -O (C1-C4 alkyl), -CHCH (CH3), -CHCH2, -CN, -CH2CF3, -CH2F, -CHF2, -OH or-C1-C4 alkyl. In particular, R3 is-H, -Cl, -F, -Br, -CN, -CF3, -O (C1-C4 alkyl), -OH, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2. In particular, R3 is-H, -F, -Cl, -CF3, -NH2, -NH (CH3) or-N (CH3) 2. In particular, R3 is-H, -Cl or-F. In particular, R3 is-Cl. In particular, R3 is-H, -Cl, -F, -Br, -CN, -CF3, -CH3, -C2H5, -O (C1-C4 alkyl), -OH, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2. In particular, R3 is-H, -F, -Cl, -CF3, -CH3, -C2H5, -NH2, -NH (CH3) or-N (CH3) 2. In particular, R3 is-F or-Cl.

R4 is: i) a C3-C10 non-aromatic carbocyclic ring optionally substituted with one or more JA; ii) a C1-C6 aliphatic group (e.g., C1-C6 alkyl or C2-C6 alkenyl) optionally substituted with one or more substituents independently selected from JC, a C3-C8 non-aromatic carbocyclic ring or 6-10 membered carbocyclic aryl group each optionally and independently substituted with one or more JA, and a 5-10 membered heteroaryl or 4-10 membered non-aromatic heterocyclic ring each optionally and independently substituted with one or more JB; or iii) a 4-10 membered non-aromatic heterocycle optionally substituted with one or more JB. In particular, R4 is i) an optionally substituted C3-C10 carbocyclic ring; ii) a C1-C6 aliphatic (e.g., C1-C6 alkyl or C2-C6 alkenyl) substituted with one or more substituents independently selected from JC, an optionally substituted C3-C8 non-aromatic carbocyclic ring and an optionally substituted 4-10 membered non-aromatic heterocyclic ring; or iii) an optionally substituted 4-10 membered non-aromatic heterocyclic ring. In particular, the C1-C6 aliphatic group represented by R4 is substituted with: -OR5, -SR5, -NR 'R5, -C (O) R5, -CO2R5, -OC (O) R5, -C (O) NR' R5, -C (O) NRC (O) OR5, -NRC (O) OR5, -NRC (O) R5, -NRC (O) NR 'R5, -NRCO2R5, -OC (O) NR' R5, -SOR5, -SO2R5, -SO2NR 'R5-, N R) SO2R5, -NRSO2 NR' R5, optionally substituted C3-C8 nonaromatic carbocyclic rings and optionally substituted 4-10 membered nonaromatic heterocyclic rings. More particularly, R4 is:

i) Wherein ring T (including rings A, B and C described below) is a C3-C10 non-aromatic carbocyclic ring optionally substituted with one or more JA or a 3-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JB, or ring T and R9 optionally form a non-aromatic C5-C10 membered carbocyclic ring optionally substituted with one or more JA or a 5-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JB;

ii) wherein ring J is a 3-10 membered non-aromatic heterocyclic ring optionally substituted by one or more JBs; or

iii) wherein ring D is a 4-10 membered non-aromatic heterocyclic ring optionally substituted by one or more JD 1. More particularly, R4 is:

R5 is: i) -H; ii) a C1-C6 aliphatic group optionally substituted with one or more JC 1; iii) C3-C10 non-aromatic carbocyclic or 6-10 membered carbocyclic aryl each optionally and independently substituted by one or more JC 1; or iv) a 4-10 membered non-aromatic heterocycle or 5-10 membered heteroaryl each optionally and independently substituted with one or more JD 1. In particular, R5 is: i) -H; ii) a C1-C6 aliphatic (e.g., C1-C6 alkyl or C2-C6 alkenyl) optionally substituted with one or more JC 1; iii) C3-C8 non-aromatic carbocyclic or 6-10 membered carbocyclic aryl each optionally and independently substituted by one or more JC 1; or iv) a 4-8 membered non-aromatic heterocycle or 5-10 membered heteroaryl each optionally and independently substituted with one or more JD 1. Optionally, R5 together with each of Q1, Q2 and Q3 optionally and independently form a 4-8 membered non-aromatic ring optionally substituted with one or more JE 1. It is understood that the non-aromatic ring formed by R5 and Q1 may be employed as part of Q1. In some embodiments, R5 together with Q2 and R8 optionally and independently form a 5-7 membered non-aromatic ring optionally substituted with one or more JE 1.

In particular, R5 is independently i) -H; ii) C1-C6-alkyl or C2-C6-alkenyl optionally substituted with one or more JC 1; iii) a C3-C8 non-aromatic carbocyclic ring optionally substituted by one or more JC 1; iv) phenyl optionally substituted by one or more JC 1; v) a 4-8 membered non-aromatic heterocycle optionally substituted by one or more JD 1; or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more JD 1. In particular, R5 is independently i) -H; ii) C1-C6-alkyl or C2-C6-alkenyl optionally and independently substituted with one or more JC 1; or iii) a 4-8 membered non-aromatic heterocycle optionally substituted by one or more JD 1. In particular, R5 is independently i) -H; ii) C1-C6-alkyl or C2-C6-alkenyl optionally and independently substituted with one or more JC 1.

R6 and R7 are each independently-H or C1-C6 alkyl optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy, or optionally R6 and R7 together with the carbon atoms to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups. Alternatively, R6 and R7 are each independently-H or C1-C4 alkyl optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) OH, - (CO) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy, or optionally R6 and R7 together with the carbon atoms to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups. In particular, R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or R8 together with Q2 and R5 optionally and independently form a 5-7 membered non-aromatic ring optionally substituted with one or more JE 1.

Each R9 is independently-H, halogen, cyano, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or R8 together with Q2 and R5 optionally and independently form a 5-7 membered non-aromatic ring optionally substituted with one or more JE 1. Specifically, each R9 is independently-H, halogen, cyano, hydroxy, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or R8 together with Q2 and R5 optionally and independently form a 5-7 membered non-aromatic ring optionally substituted with one or more JE 1.

Optionally, R9 and ring T form a non-aromatic C5-C10 membered carbocyclic ring optionally substituted by one or more JA or a 5-10 membered non-aromatic heterocyclic ring optionally substituted by one or more JB.

Specifically, each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2; and each R9 is independently-H or C1-C4 alkyl, more specifically, -H, -CH3, or-CH 2CH 3.

R10 is independently-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, C2-C6 alkoxyalkoxy, C3-C8 non-aromatic carbocyclic ring, phenyl, 4-8 membered non-aromatic heterocyclic ring and 5-6 membered heteroaryl; wherein each of said carbocyclic ring, phenyl ring, heterocyclic ring and heteroaryl of the substituents of C1-C6 alkyl represented by R10 is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy. In particular, R10 is independently-H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6-alkoxyalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 cyanoalkyl. In particular, R10 is-H or C1-C6-alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, R10 is-H or C1-C6-alkyl.

r11, R12, R13 and R14 are each independently-H, halogen or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups. In particular, R11 and R12 are each independently-H or C1-C4 alkyl; and R13 and R14 are each independently-H or C1-C4 alkyl, or together with the carbon atom to which they are attached form a cyclopropane ring. In particular, R11 and R12 are each independently-H or-CH 3; and R13 and R14 are each independently-H, -CH3, or-CH 2CH3, or together with the carbon atom to which they are attached form a cyclopropane ring.

optionally R11 and ring a form a bridged ring optionally further substituted by one or more JA.

Ring a is a C3-C10 non-aromatic carbocyclic ring optionally further substituted by one or more JA, or a 3-10 membered non-aromatic heterocyclic ring optionally further substituted by one or more JB. In particular, ring A is an optionally substituted C3-C8 non-aromatic carbocyclic or heterocyclic ring. In particular, ring a is a C3-C8 non-aromatic carbocyclic ring optionally further substituted by one or more JA. In particular, ring a is a non-aromatic 4-7 or 5-7 membered carbocyclic ring optionally further substituted by one or more JA. Specific examples of ring a are optionally substituted cyclohexyl or cyclopentyl rings.

Optionally, rings a and R8 form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or rings a and R9 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, and rings a and R11 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, wherein each carbocyclic ring is optionally further substituted by one or more JA, and wherein each heterocyclic ring is optionally further substituted by one or more JB. In some embodiments, the bridged rings are each independently 6-10 membered. Exemplary bridged rings include:

Wherein each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocyclic ring optionally further substituted by one or more JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocyclic ring optionally further substituted by one or more JB; r21, R22, R23, R24, and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; x is-O-, -S-or-NRg-; rg is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; q is 0, 1 or 2; x is 0, 1 or 2; r is 1 or 2. Additional examples of bridged rings include adamantyl rings.

ring B is a 4-10 membered non-aromatic heterocyclic ring optionally further substituted with one or more JBs. In particular, ring B is 4-8 membered. In particular, ring B is 4-7 or 5-7 membered. Specific examples of ring B include:

Wherein each of rings B1-B9 is optionally substituted.

Ring C is a 4-10 membered non-aromatic heterocyclic ring optionally further substituted with one or more JBs. In particular, ring C is 4-8 membered. In particular, ring C is 4-7 or 5-7 membered. Specific examples of ring C include:

Wherein each of ring C1-C5 is optionally and independently substituted.

Ring D is a 4-10 membered non-aromatic heterocyclic ring optionally substituted with one or more JD 1. In particular, ring D is 4-8 membered. In particular, ring D is 4-7 or 5-7 membered. Specific examples of the ring D include:

Wherein each of ring D1-D7 is optionally substituted.

In particular, each of rings A-D is an independent and optionally substituted 4-8 or 4-7 membered ring.

Each Q1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (NR) NR-, -NRC (NR) NR-, -CO2-, -oc- (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O), O-, -NRC (O) NR '-, -NRCO2-, -oc (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO2-, or-NRSO 2NR' -, -p (O), (or) O-, -op (O), (ora) O-, -O, -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1-. Specifically, each Q1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (═ NR) -, -CO2-, -oc- (O) -, -C (O) NR' -, -C (O) nrc (O) O-, -nrc (O) NR '-, -NRCO2-, -oc- (O) NR' -, -S (O) -, -SO2-, -NRSO2-, -SO2NR '-, NRSO 2NR' -or- (CR6R7) p-Y1-. Specifically, each Q1 is independently a bond, -O-, -S-, -NR ' -, -C (O) -, -CO2-, -OC (O) -, -C (O) NR ' -, -C (O) NHC (O) O-, -C (O) N (CH3) C (O) O, -NHC (O) O-, -N (CH3) C (O) NHC (O) O-, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR ' -, -N (CH3) C O NR ' -, -NHCO2-, -N (CH3) CO2-, -OC (O) NR ' -, -S (O) -, -SO2- -NHSO2-, -N (CH3) SO2-, -SO2NR' -or- (CR6R7) p-Y1-.

Each Q2 is independently a bond, -O-, -S-, -NR-, -C (O) -, -C (NR) NR-, -NRC (NR) NR-, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2NR-, -P (O) (OR) O-, -OP O (ORa) O-, -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1. Specifically, each Q2 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (═ NR) -, -CO2-, -oc- (O) -, -C (O) NR' -, -C (O) nrc (O) O-, -nrc (O) NR '-, -NRCO2-, -oc- (O) NR' -, -S (O) -, -SO2-, -NRSO2-, -SO2NR '-, NRSO 2NR' -or- (CR6R7) p-Y1-. Specifically, each Q2 is independently-O-, -NR ' -, -C (O) -, -CO2-, -C (O) NR ' -, -NRC (O) -, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -NRSO2-, -SO2NR ' -or- (CR6R7) p-Y1-. Specifically, each Q2 is independently-CO 2-, -C (O) NR ' -, -NRC (O) -, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -NRSO2-, or- (CR6R7) p-Y1-. Specifically, each Q2 is independently-NR ' -, -C (O) NR ' -, -NRC (O) -, -SO2NR ' -, -NRC (O) NR ' -, -NRCO2-, -OCONR ' -or- (CR6R7) p-Y1-. Specifically, each Q2 is independently- -C (O) NR ' - -, - -NRC (O) NR ' - -, - -NRCO2- -OCONR ' - -or- - (CR6R7) p-Y1- -. Specifically, each Q2 is independently-O-, -NR '-, -C (O) -, -CO2-, -C (O) NR' -, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR '-, -N (CH3) C (O) NR' -, -NHCO2-, -N (CH3) CO2-, -OC (O) NR '-, -NHSO2-, -N (CH3) SO2-, -SO2NR' -or- (CR6R7) p-Y1-. Specifically, each Q2 is independently-CO 2-, -C (O) NR '-, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR' -, -N (CH3) C (O) NR '-, -NHCO2-, -N (CH3) CO2-, -OC (O) NR' -, -NHSO2-, -N (CH3) SO2-, -SO2NH-, -SO2N (CH3) -or- (CR6R7) p-Y1-. Specifically, each Q2 is independently-NR ' -, -C (O) NR ' -, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR ' -, -N (CH3) C (O) NR ' -, -NHCO2-, -N (CH3) CO2-, -OCONR ' -or- (CR6R7) p-Y1-. Specifically, each Q2 is independently-C (O) NR '-, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR' -, -N (CH3) C (O) NR '-, -NHCO2-, -N (CH3) CO2-, -OCONR' -or- (CR6R7) p-Y1-.

each Q3 is independently a bond, -C (O) -, -C (═ NR) NR-, -NRC (═ NR) NR-, -CO2-, -C (O) NR-, -SO2-, -SO2N (R) -, -C (O) NRC (O) O-, or- (CR6R7) p-Y1-. In particular, each Q3 is independently a bond, -C (O) -, -C (═ NR) -, -CO2-, -C (O) NR '-, -SO2-, -SO2 NR' -, -C (O) nrc (O) O-, or- (CR6R7) p-Y1-. Specifically, each Q3 is independently-C (O) -, -CO2-, -C (O) NR '-, -SO2-, -SO2 NR' -, -C (O) NRC (O) O-or- (CR6R7) p-Y1-. Specifically, each Q3 is independently-C (O) -, -CO2-, -C (O) NH-, -C (O) N (CH3) -, -SO2-, -SO2NH-, -SO2N (CH3) -, -C (O) NHC (O) O-, -C (O) N (CH3) C (O) O-or- (CR6R7) p-Y1-. Specifically, each Q3 is independently-C (O) -, -CO2-, -C (O) NR' -, -C (O) NHC (O) O-or- (CR6R7) p-Y1-. In particular, each Q3 is independently-C (O) -, -CO2-, -C (O) NR' -, or- (CR6R7) p-Y1-.

optionally, Q2 and Q3 can each independently form together with R5 a non-aromatic ring optionally exemplified by one or more JE1 members from 5-7. It is understood that the non-aromatic ring formed by R5 and Q2 may be employed as part of Q2. It is understood that the non-aromatic ring formed by R5 and Q3 may be employed as part of Q3.

Each Y1 is independently a bond, -O-, -S-, -NR-, -C (O) -, -C (NR) NR-, -NRC (NR) NR-, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2NR-, -P (O) (OR) O-, -OP O (ORa) O-, -P (O) 2O-or-CO 2SO 2-. In particular, each Y1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (═ NR) -, -CO2-, -oc- (O) -, -C (O) NR' -, -nrc (O) NR '-, -NRCO2-, -oc (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO2-, -NRSO2 NR' -, -nrc (O) -or-C (O) nrc (O) O-. Specifically, each Y1 is independently a bond, -O-, -NR '-, -C (O) NR' -, -NRC (O) -, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -NRC (O) NHC (O) O-or-C (O) NHC (O) O-. Specifically, each Y1 is independently a bond, -O-, -S-, -NR ' -, -C (O) -, -CO2-, -OC (O) -, -C (O) NR ' -, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR ' -, -N (CH3) C (O) NR ' -, -NHCO2-, -N (CH3) CO2-, -OC (O) NR ' -, -S (O) -, -SO2-, -NHSO2-, -N (CH3) SO2-, -SO2NH-, SO2N (CH3) -, -NHSO2NH-, -N (CH3) SO2NH-, -N (CH3) SO2N (CH3) -, -C (O) NHC (O) O-, -C (O) N (CH3) C (O) O-, -NHC (O) O-or-N (CH3) C (O) NHC (O) O-. Specifically, each Y1 is independently a bond, -O-, -NR ' -, -C (O) NR ' -, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR ' -, -N (CH3) C (O) NR ' -, -NHCO2-, -N (CH3) CO2-, -OC (O) NR ' -, -C (O) NHC (O) O-or-NHC (O) O-.

Each of JA and JB is independently selected from halogen, cyano, oxo, -NCO, and Q1-R5; or optionally two JAs and two JBs each independently form, together with the atoms to which they are attached, a 4-8 membered ring (e.g., a spiro ring or fused ring) optionally substituted with one or more JE 1. Specifically, each of JA and JB is independently selected from halogen, cyano, oxo, -NCO, and Q1-R5; or optionally two JAs and two JB's each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted by one or more JE 1. The 5-7 membered ring formed by JA or JB may be aromatic or non-aromatic. The 5-7 membered ring formed by JA or JB may optionally be fused to the ring to which it is attached. In some embodiments, the 5-7 membered ring may optionally be a spiro ring formed from two twinned sites JA and two twinned sites JB, respectively.

JC is independently selected from the group consisting of halogen, cyano, oxo, -OR5, -SR5, -NR 'R5, -C (O) R5, -CO2R5, -OC (O) R5, -C (O) NR' R5, -C (O) NRC (O) OR5, -NRC (O) OR5, -NRC (O) R5, -NRC (O) NR 'R5, -NRCO2R5, -OC (O) NR' R5, -S (O) R5, -SO2R5, -SO2NR 'R5, -NRSO2R5, -NRSO2 NR' R5, and-P (O) 2-. Specifically, JC is independently selected from-OR 5, -SR5, -NR 'R5, -C (O) R5, -CO2R5, -OC (O) R5, -C (O) NR' R5, -C (O) NRC (O) OR5, -NRC (O) OR5, -NRC (O) R5, -NRC (O) NR 'R5, -NRCO2R5, -OC (O) NR' R5, -S (O) R5, -SO2R5, -SO2NR 'R5, -NRSO2R5 and-NRSO 2 NR' R5. In particular, JC is selected from halogen, cyano, oxo, -OR5, -NR 'R5, -C (O) R5, -CO2R5, -OC (O) R5, -C (O) NR' R5, -C (O) NRC (O) OR5, -NRC (O) R5, -NRC (O) NR 'R5, -NRCO2R5 and-OC (O) NR' R5. In particular, JC is selected from halogen, cyano, oxo, -OR5, -NR 'R5, -C (O) R5, -CO2R5, -OC (O) R5, -C (O) NR' R5 and-NRC (O) R5. In particular, JC is selected from halogen, cyano, oxo, -OR5, -NR 'R5, -C (O) NR' R5 and-NRC (O) R5. In particular, JC is selected from-OR 5, -NR 'R5, -C (O) NR' R5 and-NRC (O) R5.

JC1 and JD1 are each independently selected from: halogen, cyano, oxo, Ra, -ORb, -SRb, -s (o) Ra, -SO2Ra, -NRbRc, -C (o) Rb, -C (NR) Rc, -C (NR) NRbRc, -NRC (NR) NRbRc, -C (o) ORb, -oc (o) Rb, -NRC (o) Rb, -C (o) NRbRc, -NRC (o) ORb, -OCONRbRc, -C (o) NRCO2Rb, -NRC (o) ORb, -C (o) NR ORb, -SO2 nrcrrb, -NRSO2Rb, -NRSO2 nrcrrb, -p (o) (ORa)2, -op (ORa)2, -p (o)2ORa and-CO 2SO2Rb, or optionally, two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 4-8 membered ring optionally substituted with one or more JE 1. In particular, JC1 and JD1 are each independently selected from halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and-NRSO 2 NRcRb.

Optionally, two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which they are attached. It will be appreciated that the choice of the value of each of JC1 and JD1 is a choice that results in the formation of stable or chemically feasible compounds. For example, suitable values for each of JC1 and JD1 on a carbon atom independently include halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and-NRSO 2 NRcRb; and suitable values of JD1 on the nitrogen atom include Ra, -SO2Ra, -SO2N (R) Rb, -C (O) ORb, -C (O) NRbRc, -C (O) NRCO2Rb and-C (O) NR (ORb). Specific examples of JC1 and JD1 independently include halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NHRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NHC (O) Rb, -C (O) NHRc, -NHC (O) ORb and-OCONHRc, -N (CH3) Rc, -N (CH3) C (O) Rb, -C (O) N (CH3) Rc, -N (CH3) C (O) NHRc, -N (CH3) C (O) ORb, -OCON (CH3) Rc, -C (O) NHCO2Rb, -C (O) N (CH3) CO2Rb, -NHC (O) (ORb), (N (CH3) C) O) ORb, -NHC (O) ORb) (NH) C (CH3) O) ORb, -NHSO2Rb, -SO2NHRb, -SO2N (CH3) Rb and-N (CH3) SO2 Rb. Specific examples of each JD1 at the nitrogen atom independently include Ra, -SO2Ra, -C (O) Rb, -C (O) ORb, -C (O) NHRc, -C (O) N (CH3) Rc, -C (O) NHCO2Rb, -C (O) N (CH3) CO2Rb, -C (O) NH (ORb) -and-C (O) N (CH3) (ORb). More specific examples of each of JC1 and JD1 on carbon atoms independently include halogen, cyano, hydroxy, oxo, C1-C1 alkyl, -O (C1-C1 alkyl), -NH 1, -NH (C1-C1 alkyl), -N (C1-C1 alkyl) 2, -C (O) (C1-C1 alkyl), -OC (O) (C1-C1 alkyl), -C (O) O (C1-C1 alkyl), C1-C1 cycloalkyl, and-CO 21, wherein each of said alkyl (e.g., C1-C1 alkyl, -O (C1-C1 alkyl), -NH 1, -NH (C1-C1 alkyl), -N (C1-C1 alkyl) 2, -C (O) (C1-C1 alkyl), -OC 1-C1 alkyl) (C1-C1 alkyl), -OC 1 alkyl) (C1-C1 alkyl) (C1 alkyl), -C (O) O (C1-C4 alkyl) and alkyl represented by C3-C6 cycloalkyl) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OCO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. More specific examples of each JD1 on the nitrogen atom independently include halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -C (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and C3-C6 cyclo (alkyl), wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OCO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

each JE1 is independently selected from halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C1-C6 alkyl, -O (C1-C6 alkyl), and-C (O) (C1-C6-alkyl), wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, each JE1 is independently selected from halogen, cyano, hydroxy, oxo, C1-C6 alkyl, - - -O (C1-C6 alkyl), - -C (O) (C1-C6-alkyl), - -NH2, - -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -C (O) O (C1-C6 alkyl), -oc (O) (C1-C6 alkyl), -nhc (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. It will be appreciated that selection of a suitable JE1 is one that results in the formation of a stable or chemically viable compound. For example, suitable substituents on a carbon atom independently include halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -O (C1-C6 alkyl), -C (O) (C1-C6-alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) NH2, -C (O) NH (C1-C1 alkyl), -C (O) N (C1-C1 alkyl) 2, -C (O) (C1-C1 alkyl), -C (O) O (C1-C1 alkyl), -OC (O) (C1-C1 alkyl), -NHC (C1-C1 alkyl), -N (C1-C1 alkyl) C (C1O) (C1 alkyl), and wherein each of said alkyl, C1-C1 alkyl, and CO2 is optionally substituted by one or more substituents independently selected from each of C5972-C1 alkyl, optionally : halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. For example, suitable substituents on the nitrogen atom independently include C1-C6 alkyl, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), and-C (O) O (C1-C6 alkyl), wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

r and R' are each independently-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy. In particular, R and R' are each independently-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -CO2H, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy and C1-C6 alkoxyalkoxy. In particular, R and R' are each independently-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2 and-O (C1-C6 alkyl). Specifically, R and R' are each independently-H or C1-C6 alkyl (e.g., -CH3 or-CH 2CH 3).

Optionally, R' together with R5 and the nitrogen atom to which it is attached forms a 5-7 membered non-aromatic heterocyclic ring optionally substituted with one or more JD 1. In particular, the non-aromatic heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -C (O) (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, the non-aromatic heterocycle is optionally substituted with one or more substituents independently selected from: halogen, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Each R is independently: i) -H; ii) a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, a C3-C8 nonaromatic carbocyclic ring, a 5-6 membered nonaromatic heterocyclic ring, phenyl, a 5-6 membered heteroaryl, -O (C1-C6 alkyl), and-C (O) (C1-C6 alkyl); wherein each of said alkyl groups (e.g., -O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl) is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said C3-C8 non-aromatic carbocyclic ring, 5-6 membered non-aromatic heterocyclic ring, phenyl and 5-6 membered heteroaryl is independently and optionally substituted with one or more JE 1; or iii) each C3-C8 non-aromatic carbocyclic ring or 4-8 membered non-aromatic heterocyclic ring independently and optionally substituted by one or more JE 1. In particular, each R is independently: i) -H; ii) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 aminoalkoxy, C1-C4 cyanoalkoxy, C1-C4 hydroxyalkoxy, and C2-C4 alkoxyalkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C2-C4 alkoxyalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 aminoalkoxy, C1-C4 cyanoalkoxy, C1-C4 hydroxyalkoxy, and C2-C4 alkoxyalkoxy. In particular, each R is: i) -H; ii) C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy and C1-C6 alkyl, wherein each alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Each Ra is independently: i) a C1-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, amino, carboxy, amido, -O (C1-C6 alkyl), -C (O) (C1-C6 alkyl), C3-C8 non-aromatic carbocyclic ring, 4-8 membered non-aromatic heterocyclic ring, 5-10 membered heteroaryl and 6-10 membered carbocyclic aryl; wherein each said alkyl of a substituent of a C1-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocycles, heterocycles, heteroaryls and carbocyclic aryls that are substituents of the C1-C6 aliphatic group represented by Ra are optionally and independently substituted with one or more JE 1; ii) each C3-C8 non-aromatic carbocyclic or 4-8 membered non-aromatic heterocyclic ring optionally and independently substituted with one or more JE 1; or iii) a 5-10 membered heteroaryl or 6-10 membered carbocyclic aryl each optionally and independently substituted with one or more JE 1.

alternatively, each Ra is independently: i) a C1-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6-alkyl), -OC (O) (C1-C6-alkyl), -CO2H, -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -O (C1-C6 alkyl), -C (O) (C1-C6-alkyl), C3-C8 non-aromatic carbocyclic ring, 6-10 membered carbocyclic aryl, 4-8 membered non-aromatic heterocyclic ring and 5-10 membered heteroaryl; wherein each said alkyl group of substituents of the C1-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocyclic ring, phenyl, non-aromatic heterocyclic ring and heteroaryl of substituents of the C1-C6 aliphatic group represented by Ra is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6-alkyl), -oc (O) (C1-C6-alkyl), -CO2H, -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -nhc (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -O (C1-C6 alkyl) and-C (O) (C1-C6-alkyl), each of said alkyl groups being optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; ii) a C3-C8 non-aromatic carbocyclic group or a 4-8 membered non-aromatic heterocyclic group, each of which is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6-alkyl), -oc (O) (C1-C6-alkyl), -CO2H, -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -nhc (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -O (C1-C6 alkyl), and-C (O) (C1-C6-alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; or iii) a 5-10 membered heteroaryl or a 6-10 membered carbocyclic aryl, each of which is optionally and independently substituted with one or more of: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -CO2H, -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -NHC O (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl), wherein each said alkyl group is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

In particular, Ra is independently: i) a C1-C6 aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6-alkyl), -OC (O) (C1-C6-alkyl), -CO2H, -O (C1-C6 alkyl), -C (O) (C1-C6-alkyl), and C3-C7 non-aromatic carbocyclic group, phenyl, 4-7 membered non-aromatic heterocyclic group or 5-6 membered heteroaryl, each of which is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -CO2H, -O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl); ii) a C3-C7 non-aromatic carbocyclic group optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -CO2H, -O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl); iii) a 4-7 membered non-aromatic heterocyclic group optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -CO2H, -O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl); iv) 5-6 membered heteroaryl or phenyl each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -CO2H, -O (C1-C6 alkyl) and-C (O) (C1-C6 alkyl). Each alkyl group, including substituents thereof, referred to in the value of Ra is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

in particular, an optionally substituted C1-C6 aliphatic group represented by Ra is an optionally substituted C1-C6 alkyl group.

Rb and Rc are each independently Ra or-H; or optionally, Rb and Rc and the nitrogen atom to which they are attached (e.g., represented by-NRbRc, -C (O) NRbRc, -NRC (O) NRbRc, or-OCONRbRc) each independently form a non-aromatic 5-7 membered heterocyclic ring optionally substituted with one or more JE 1. Suitable specific substituents for the heterocycle formed by Rb and Rc independently include halogen, cyano, hydroxy, oxo, amino, carboxy, amido, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6-alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, C2-C6 alkoxyalkoxy, and (O) (C1-C6-alkyl). Suitable specific substituents for the heterocycle formed by Rb and Rc independently include halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 hydroxyalkoxy, C2-C4 alkoxyalkoxy, -CO2(C1-C4 alkyl), -OC (O) (C1-C4 alkyl), and-CO 2H.

it will be appreciated that the selection of suitable substituents for the heterocyclic ring formed by Rb and Rc is one that results in the formation of stable or chemically feasible compounds. Suitable substituents on carbon atoms include, for example, independently halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6-aminoalkoxy, C1-C6-cyanoalkoxy, C1-C6 hydroxyalkoxy, C2-C6-alkoxyalkoxy, -C (O) (C1-C6-alkyl), -C (O) O (C1-C6-alkyl), -OC 1-C6 alkyl), -CO2H, -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -NHC (O) (C1-C6 alkyl) and-N (C1-C6 alkyl) C (O) (C1-C6 alkyl). In another example, suitable substituents on carbon atoms independently include halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 hydroxyalkoxy, C2-C4 alkoxyalkoxy, -CO (C1-C4 alkyl), -CO2(C1-C4 alkyl), and-CO 2H. For example, suitable substituents on the nitrogen atom independently include C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 cyanoalkyl, -C (O) (C1-C6 alkyl), -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -CO2H, -C (O) NH2, -C (O) NH (C1-C6 alkyl), and-C (O) N (C1-C6 alkyl) 2. In another example, suitable substituents on the nitrogen atom independently include C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 hydroxyalkoxy, -CO (C1-C4 alkyl), -CO2(C1-C4 alkyl), and-CO 2H.

each Rd is independently-H, C1-C6 alkyl or-C (o) (C1-C6 alkyl), wherein each said alkyl moiety is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, each Rd is independently-H or C1-C6 alkyl optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

p is independently 1,2,3 or 4. In particular, p is independently 1 or 2.

k. n and m are each independently 0, 1 or 2. Or, when rings A and B are 3-6 membered, n and m are each independently 0 or 1; and k is independently 0, 1 or 2; when rings A and B are 7-8 membered, n and m are each independently 0, 1 or 2; and k is independently 0, 1 or 2.

x and y are each independently 0,1 or 2.

z is 1 or 2.

The set of variables 2 for structural formulae (I) and (IA) is as follows:

R2 is-H or-CH 3.

R3 is-H, -Cl, -F, -Br, -CN, -CF3, -O (C1-C4 alkyl), -OH, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2.

The values (including specific values) and provisos for the remaining variables of structural formulae (I) and (IA) are each independently as described above for the 1 st set of variables of structural formulae (I) and (IA).

the 3 rd set of variables for structural formulae (I) and (IA) are as follows:

R2 is-H or-CH 3.

R4 is i) an optionally substituted C3-C10 carbocycle; ii) a C1-C6 aliphatic group (e.g., C1-C6 alkyl or C2-C6 alkenyl) substituted with one or more substituents independently selected from: JC. An optionally substituted C3-C8 non-aromatic carbocyclic ring and an optionally substituted 4-10 membered non-aromatic heterocyclic ring; or iii) an optionally substituted 4-10 membered non-aromatic heterocyclic ring.

the values (including specific values) and provisos for the remaining variables of structural formulae (I) and (IA) are each independently as described above for the 1 st set of variables of structural formulae (I) and (IA).

The 4 th set of variables for structural formulae (I) and (IA) are as follows:

R2 is-H or-CH 3.

R3 is-H, -Cl, -F, -Br, -CN, -CF3, -O (C1-C4 alkyl), -OH, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2.

r4 is selected from the formulas A-D depicted above.

The values of the remaining variables of structural formulae (I) and (IA), including specific values, are each independently as described above for the 1 st set of variables of structural formulae (I) and (IA).

The set of 5 th variables for structural formulae (I) and (IA) are as follows:

R2 is-H or-CH 3.

R3 is-H, -F, -Cl, -CF3, -NH2, -NHMe or-NMe 2.

R4 is i) an optionally substituted C3-C10 carbocycle; ii) a C1-C6 aliphatic group (e.g., C1-C6 alkyl or C2-C6 alkenyl) optionally substituted with one or more substituents independently selected from the group consisting of: JC. An optionally substituted C3-C8 non-aromatic carbocyclic ring and an optionally substituted 4-10 membered non-aromatic heterocyclic ring; or iii) an optionally substituted 4-10 membered non-aromatic heterocyclic ring.

The 6 th set of variables for structural formulae (I) and (IA) are as follows:

R2 is-H or-CH 3.

R3 is-H, -F, -Cl, -CF3, -NH2, -NH (CH3) or-N (CH3) 2.

R4 is selected from the formulas A-D depicted above.

The values of the remaining variables of structural formulae (I) and (IA), including the specific values, are each independently as described above for the 1 st set of variables of structural formulae (I) and (IA).

The 7 th set of variables for structural formulae (I) and (IA) are as follows:

r2 is-H or-CH 3.

R3 is-H, -F or-Cl.

The 8 th set of variables for structural formula I are as follows:

R2 is-H or-CH 3.

R3 is-H, -F or-Cl.

R4 is selected from the formulas A-D depicted above.

The 9 th set of variables for structural formulae (I) and (IA) are as follows:

R2 is-H.

R3 is-H or-Cl.

The 10 th set of variables for structural formulae (I) and (IA) are as follows:

R2 is-H.

R3 is-H or-Cl.

R4 is selected from the formulas A-D depicted above.

The 11 th set of variables for structural formulae (I) and (IA) are as follows:

Each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, or 10 th variables of structural formulae (I) and (IA).

z1 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH (C1-C6 alkyl) or-CON (C1-C6 alkyl) 2; and Z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2; wherein each of said alkyl groups (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -CO2(C1-C6 alkyl), -NH (C1-C6 alkyl), and-N (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The 12 th set of variables for structural formulae (I) and (IA) are as follows:

Each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, or 10 th variables of structural formulae (I) and (IA).

Z1 is-H, -F, -Cl, C1-C4 haloalkyl (e.g., -CF3), C1-C4 alkyl, -O (C1-C4 alkyl), or-CN.

Z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl) or-N (C1-C6 alkyl) 2; wherein each of said alkyl groups (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -NH (C1-C6 alkyl), and-N (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

the 13 th set of variables for structural formulae (I) and (IA) are as follows:

Each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, or 10 th variables of structural formulae (I) and (IA).

Z1 is-H, -F, -Cl, C1-C4 haloalkyl (e.g., -CF3), C1-C4 alkyl, -O (C1-C4 alkyl), or-CN.

z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The 14 th set of variables for structural formulae (I) and (IA) are as follows:

Each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, or 10 th variables of structural formulae (I) and (IA).

Z1 is-H, -F, -Cl, -CF3, -CH3 or-CN.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

In the 15 th variable set of structural formulae (I) and (IA), the values (including specific values) and provisos of the variables (except R, and R') of structural formulae (I) and (IA) are each independently as described in the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, 10 th, 11 th, 12 th, 13 th, or 14 th variable set of structural formulae (I) and (IA) above; and where applicable:

Each R is independently: i) -H; ii) a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy and C1-C6 alkyl, wherein each alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and is

R and R' are each independently-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, and-O (C1-C6 alkyl); or optionally R' together with R5 and the nitrogen atom to which it is attached form a 5-7 membered non-aromatic heterocycle optionally substituted with one or more JD 1.

The 16 th set of variables for structural formulae (I) and (IA) are as follows:

Q1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO 2-or-NRSO 2 NR' -or- (CR6R7) p-Y1-.

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and-NRSO 2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7 membered ring optionally substituted with and fused to the respective ring to which they are attached, or one or more JE 1.

The values (including specific values) and provisos for the remaining variables of structural formulae (I) and (IA) are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th,10 th, 11 th, 12 th, 13 th or 14 th variable set of structural formulae (I) and (IA).

the 17 th set of variables for structural formulae (I) and (IA) are as follows:

R1 is-H.

r2 is-H, -CH3, -CH2OH or-NH 2. Alternatively, R2 is-H or-CH 2 OH.

R3 is-H, -F, -Cl, C1-4 alkyl or C1-4 haloalkyl. Alternatively, R3 is-H, -F or-Cl.

z1 is-H, -F or-Cl.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

Z3 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

Where applicable, the remaining variables are as described in any of the variable sets of structural formulae (IA) and (I) above.

The 18 th set of variables for structural formulae (I) and (IA) are as follows:

R1 is-H.

R2 is-H or-CH 2 OH.

R3 is-H, -F or-Cl. Alternatively, R3 is-F or-Cl.

Z1 is-H, -F or-Cl.

Z2 and Z3 are-H.

The remaining variables are each independently as described in any one of the variable sets of structural formulae (IA) and (I) above.

The 19 th set of variables for structural formulae (I) and (IA) are as follows:

R5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; iv) an optionally substituted 4-7 membered non-aromatic heterocycle; v) optionally substituted phenyl; vi) an optionally substituted 5-6 membered heteroaromatic ring, or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring; and is

Said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, -NRCO (C1-C4 alkyl), -CONR (C1-C4 alkyl), -NRCO2(C1-C4 alkyl), C3-C7 non-aromatic carbon ring optionally substituted by one or more JE1, 4-7 membered non-aromatic heterocyclic ring optionally substituted by one or more JE1, and phenyl optionally substituted by one or more JE 1; and is

Wherein each of said carbocycle, heterocycle, phenyl and heteroaryl represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

R1, R2, R3, Z1, Z2 and Z3 are each independently as described above in the 17 th or 18 th set of variables.

The remaining variables are each independently as described in any one of the variable sets of structural formulae (IA) and (I) above.

In some embodiments, the variables of structural formulae (IA) and (I) are each independently as described in any of the variable sets above, with the proviso that: r4 is:

When rings A and B are 3-6 membered, n and m are each independently 0 or 1; or when rings A and B are 7-10 membered, n and m are each independently 0,1 or 2; and is

If Y1 is a bond, then R5 is neither-H nor a C1-C6 aliphatic group; and is

If Q2 and Q3 are each independently a bond, then R5 is neither-H nor a C1-C6 aliphatic group.

In some embodiments, the present invention relates to the use of a compound represented by any one of structural formulae II, III, IV, and V depicted below, or a pharmaceutically acceptable salt thereof, for any of the applications described above:

The 1 st set of variables for structures II-V are as follows:

Z1 is-H, -F, -Cl, C1-C4 haloalkyl (e.g., -CF3), C1-C4 alkyl, -O (C1-C4 alkyl), or-CN.

z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

R3 is-H, -Cl, -F, -Br, -CN, -CF3, -O (C1-C4 alkyl), -OH, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2. In particular, R3 is-H, -F, -Cl, -CF3, -NH2, -NH (CH3) or-N (CH3) 2. In particular, R3 is-H, -Cl or-F. In particular, R3 is-Cl.

Each R and R' is independently-H or C1-C6 alkyl.

The definition of ring A-D of formulas II-V, including the specific variables each independently as set forth above for variables 1 of structural formulas (I) and (IA), wherein each of rings A-D is an independent and optionally substituted 4-7 membered ring.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st set of variables of formulae (I) and (IA).

The set of variables 2 for structures II, III, IV and V are as follows:

Z1 is-H, -F, -Cl, -CF3, -CH3 or-CN.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st set of variables of formulae II-V.

The 3 rd set of variables for structures II, III, IV and V are as follows:

z1 is-H, -F or-CN.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st set of variables of formulae II-V.

The 4 th set of variables for structures II, III, IV and V are as follows:

Z1 is-H, -F or-CN.

R3 is-H, -Cl or-F.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st set of variables of formulae II-V.

The 5 th set of variables for structures II, III, IV and V are as follows:

Z1 is-H, -F or-CN.

R3 is-H, -Cl, -F, -CF3, -NH2, -NH (CH3) or-N (CH3) 2.

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Each R9 is independently-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st set of variables of formulae II-V.

The 6 th set of variables for structures II, III, IV and V are as follows:

z1 is-H, -F or-CN.

Z2 is-H or optionally substituted C1-C6 alkyl.

R3 is-H, -Cl or-F.

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Each R9 is independently-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st set of variables of formulae II-V.

In the 7 th variable set of structural formulae II-V, the values (including specific values) of the variables of structural formulae II-V (except for R6, R7, R8, R9, R11, R12, R13, and R14) are each independently as described above in the 1 st, 2 nd, 3 rd, or 4 th variable set of structural formulae II-V; and is

R6 and R7 are each independently-H or-C1-C4 alkyl, or together with the carbon atom to which they are attached form a cyclopropane ring.

each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

each R9 is independently-H or-C1-C4 alkyl.

R11 and R12 are each independently-H or-C1-C4 alkyl.

R13 and R14 are each independently-H or-C1-C4 alkyl, or together with the carbon atom to which they are attached form a cyclopropane ring.

In the 8 th variable set of structural formulae II-V, the values (including specific values) of the variables of structural formulae II-V are each independently as described above for the 1 st variable set of structural formulae II-V.

Provided that when Q2-R5 is-OR 5 OR-NR' R5, ring A is further substituted with one OR more JAs other than-H.

provided that, if Q3 is-C (o) -, R5 is a substituted C1-C6 aliphatic (e.g., C1-C6 alkyl or C2-C6 alkenyl), an optionally substituted C3-C8 nonaromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl, an optionally substituted 4-8 membered nonaromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl. In one embodiment, the C1-C6 aliphatic group is substituted with one or more JC1, wherein JC1 is independently selected from: optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring or optionally substituted 5-10 membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and NRSO2 cNRRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

In the 9 th variable set of structural formulae II-V, the values of the variables of structural formulae II-V (including specific values) are each independently as described above for the 1 st variable set of structural formulae (I) and (IA).

The 10 th set of variables for structures II-V are as follows:

JA and JB are independently selected from halogen, cyano, oxo, and Q1-R5; or optionally two JA and two JB are each independently taken together with the atoms to which they are attached to form a 5-7 membered ring optionally substituted with one or more JE1 and fused to the ring to which it is attached.

Q1 is independently a bond, -O-, -S-, -NR-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2 NR-or- (CR6R7) p-Y1-.

Q2 is independently a bond, -O-, -S-, -NR-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2 NR-or- (CR6R7) p-Y1-.

Q3 is independently a bond, -C (O) -, -CO2-, -C (O) NR-, -SO2-, -SO2N (R) -, -C (O) NRC (O) -or- (CR6R7) p-Y1-.

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and-NRSO 2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7 membered ring optionally substituted with and fused to the respective ring to which they are attached, or one or more JE 1.

Ring a is a C3-C8 non-aromatic carbocyclic ring optionally and independently further substituted with one or more JA.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, or 9 th variable set of formulae II-V.

In another embodiment, the present invention relates to the use of a compound represented by structural formula xi (a) or xi (b), or a pharmaceutically acceptable salt thereof, for any of the applications described above.

The 1 st set of variables for structures XI (A) and XI (B) are as follows:

Ring a is a 5-7 membered non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl), (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring a is a 5-7 membered non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring a is a 5-7 membered carbocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Each R9 is independently-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

each R and R' is independently-H or C1-C6 alkyl.

the values (including specific values) and provisos for the remaining variables of structures XI (A) and XI (B) are each independently as described above for the 1 st set of variables of structures (I) and (IA).

The set of variables 2 for structures XI (A) and XI (B) is as follows:

The values of ring A, R, R', R6, R7, R8, R9, R11, R12, R13, and R14 (including particular values) are each independently as set forth above for variables 1 of formulas xi (a) and xi (b).

The variable x is 0 or 1 and the variable n is 0 or 1.

The values (including specific values) and provisos for the remaining variables of structures XI (A) and XI (B) are each independently as described above for the 1 st set of variables of structures (I) and (IA).

The set of variables 3 for structures XI (A) and XI (B) is as follows:

Values (including specific values) for ring A, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the variable set 2 of formulae xi (a) and xi (b).

Q2 is-O-, -NR '-, -CO-, -CO2-, -C (O) NR' -, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OCONR '-, -NRSO2-, -SO2 NR' -or- (CR6R7) p-Y1-. Specifically, Q2 is-O-, -NH-, -N (CH3) -, -C (O) -, -CO2-, -C (O) NH-, -C (O) N (CH3) -, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR ' -, -N (CH3) C (O) NR ' -, -NHCO2-, -N (CH3) CO2-, -OC (O) NR ' -, -NHSO2-, -N (CH3) SO2-, -SO2NH-, -SO2N (CH3) -or- (CR6R7) p-Y1-.

The 4 th set of variables for structures XI (A) and XI (B) are as follows:

The values (including specific values) for rings A, Q2, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above in the 3 rd set of variables of formulas XI (A) and XI (B).

R5 is independently i) -H; ii) a C1-C6-aliphatic (e.g., C1-C6-alkyl or C2-C6-alkenyl) optionally substituted with one or more JC 1; iii) a C3-C8 non-aromatic carbocyclic ring optionally substituted by one or more JC 1; iv) phenyl optionally substituted by one or more JC 1; v) a 4-8 membered non-aromatic heterocycle optionally substituted by one or more JD 1; or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more JD 1.

JC1 and JD1 are each independently selected from halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra-, -SO2Ra, -NHRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NHC (O) Rb, -C (O) NHRc, -NHC (O) NHRc, -NHC (O) ORb, -OCONHRc, -NHC (O) ORb, -N (CH3) Rc, -N (CH3) C (O) Rb, -C (O) N (CH3) Rc, -N (CH3) C (O) NHRc, -N (CH3) C (O) ORb, -OCON (CH3) Rc, -C (O) NHCO2Rb, -C (O) N (CH3) CO2Rb, -N (CH3) C (O) NHCO) ORb, -NHSO 2(2 Rb, -SO2NHRb, -SO2N (CH3) Rb and-N (CH3) SO2 Rb.

the 5 th set of variables for structures XI (A) and XI (B) are as follows:

The values (including specific values) for Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above in the 4 th set of variables of formulas XI (A) and XI (B).

Ring a is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The 6 th set of variables for structures XI (A) and XI (B) are as follows:

The values (including specific values) for Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above in the 5 th set of variations of structures XI (A) and XI (B).

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions:

Wherein each of rings a1-a27 is independently and optionally further substituted with one or more substituents. Suitable substituents are as described in ring A of the 1 st variable set of structural formulae XI (A) and XI (B).

The 7 th set of variables for structures XI (A) and XI (B) are as follows:

The values (including specific values) for the groups- [ CR13R14] x-Ring A-Q2-R5, Q2, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as set forth in the 6 th set of variables of formulae XI (A) and XI (B) above.

Each R5 is independently: i) -H; ii) a C1-C6-aliphatic group optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), -CO2H, C3-C8 non-aromatic carbocyclic ring, phenyl, 4-8 membered non-aromatic heterocyclic ring and 5-6 membered heteroaryl; or iii) a C3-C7 non-aromatic carbocyclic ring, a 4-7 membered non-aromatic heterocyclic ring, a phenyl group, or a 5-6 membered heteroaromatic ring, each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl) and-CO 2H; wherein each of said alkyl groups of the substituents of aliphatic, carbocyclic, heterocyclic, phenyl and heteroaryl groups represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and wherein each of said carbocyclic ring, phenyl ring, heterocyclic ring and heteroaryl of the substituent of the C1-C6-aliphatic group represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The 8 th set of variables for structures XI (A) and XI (B) are as follows:

The values (including specific values) for Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above in the 7 th set of variables of formulas XI (A) and XI (B).

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions:

Wherein each of ring a6, A8, a11, a14, and a15 is optionally and independently further substituted.

R8 is independently halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

The set of 9 th variables for structures XI (A) and XI (B) are as follows:

the values (including specific values) for the groups- [ CR13R14] x-Ring A-Q2-R5, Q2, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as set forth in the 8 th set of variables of formulae XI (A) and XI (B) above.

R5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; or iv) an optionally substituted 4-7 membered non-aromatic heterocyclic ring. Each of said alkyl groups represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, an optionally substituted C3-C7 nonaromatic carbocyclic ring and an optionally substituted 4-7 membered nonaromatic heterocyclic ring. Each of the carbocyclic and heterocyclic rings represented by R5 and mentioned for substituents of C1-C6 alkyl represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl) and-CO 2H, wherein each said alkyl (e.g., represented by C1-C4 alkyl, -O (C1-C4 alkyl), -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), and-C (O) O (C1-C4 alkyl)) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The 10 th set of variables for structures XI (A) and XI (B) are as follows:

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions:

Wherein each of ring A1-A4, A7-A20, A22, A23, A25, and A27 is independently and optionally further substituted. Suitable substituents are as described in ring A in the 1 st variables of formulae XI (A) and XI (B).

The 11 th set of variables for structures XI (A) and XI (B) are as follows:

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions:

Wherein each of ring a5-a7, a21, a24, and a26 is independently and optionally further substituted. Suitable substituents are as described in ring A of the 1 st variable set of structural formulae XI (A) and XI (B).

In the 12 th set of variables of structural formulae XI (A) and XI (B), the values (including particular values) and provisos for the variables of structural formulae XI (A) and XI (B) are each independently as described above in the 1 st set of variables of structural formulae (I) and (IA).

In the 13 th variable set of structural formulae XI (A) and XI (B), the values (including particular values) and provisos for the variables of structural formulae XI (A) and XI (B) are each independently as described above for the 16 th variable set of structural formulae (I) and (IA) or the 10 th variable set of structural formulae II-V.

In another embodiment, the present invention relates to the use of a compound represented by structural formula xii (a) or xii (b) below, or a pharmaceutically acceptable salt thereof, for any of the uses described above:

The 1 st set of variables for structures XII (A) and XII (B) are as follows:

Ring B is a 4-7 membered non-aromatic heterocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl), (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring B is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring B is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

R9 is-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R and R' is independently-H or C1-C6 alkyl.

The values of the remaining variables (including specific values) and additional conditions of structures xii (a) and xii (b) are each independently as described in the 1 st set of variables of structures (I) and (IA) above.

The set of variables 2 for structures XII (A) and XII (B) is as follows:

The values (including specific values) for ring B, R, R', R6, R7, R9, R11, R12, R13, and R14 are each independently as described above for the 1 st set of variables of structural formulae xii (a) and xii (b).

The variable y is 0 or 1.

The 3 rd set of variables for structures XII (A) and XII (B) are as follows:

The values (including specific values) for ring B, R, R', R6, R7, R9, R11, R12, R13, and R14 are each independently as described above for the 2 nd set of variables of formulas xii (a) and xii (b).

q3 is independently-C (O) -, -CO2-, -C (O) NH-, -C (O) N (CH3) -, -C (O) NHC (O) O-, -C (O) N (CH3) C (O) O-, -SO2-, -SO2NH-, -SO2N (CH3) -or- (CR6R7) p-Y1-.

The 4 th set of variables for structures XII (A) and XII (B) is as follows:

The values of ring B, Q3, R, R', R6, R7, R9, R11, R12, R13, and R14 (including specific values) are each independently as described above for the 3 rd set of variables of formulas xii (a) and xii (b).

JC1 and JD1 are each independently selected from halogen, cyano, oxo, Ra, -ORb, -SRb, -SORa, -SO2Ra, -NHRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NHC (O) Rb, -C (O) NHRc, -NHC (O) NHRc, -NHC (O) ORb, -OCONHRc, -NHC (O) ORb, -N (CH3) Rc, -N (CH3) C (O) Rb, -C (O) N (CH3) Rc, -N (CH3) C (O) NHRc, -N (CH3) C (O) ORb, -OCON (CH3) Rc, -C (O) NHCO2Rb, -C (O) N (CH3) CO2Rb, -N (CH3) C (O) NHCO) ORb, -NHSO 2(2 Rb, -SO2NHRb, -SO2N (CH3) Rb and-N (CH3) SO2 Rb.

the values of the remaining variables (including specific values) and additional conditions of structures xii (a) and xii (b) are each independently as described in the 1 st set of variables of structures (I) and (IA) above.

The 5 th set of variables for structures XII (A) and XII (B) is as follows:

values (including specific values) for rings B, Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 4 th variable set of structural formulae xii (a) and xii (b).

Ring B is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The 6 th set of variables for structures XII (A) and XII (B) is as follows:

The values of Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y (including particular values) are each independently as described above in the 5 th set of variables of structural formulae xii (a) and xii (b).

Ring B is independently selected from one of the structures depicted below:

Wherein each of rings B1-B9 is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, each of rings B1-B9 is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

The 7 th set of variables for structures XII (A) and XII (B) is as follows:

Values (including specific values) for rings B, Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 6 th set of variables of structural formulae xii (a) and xii (b).

The 8 th set of variables for structures XII (A) and XII (B) is as follows:

the values of Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y (including particular values) are each independently as described above in the 7 th set of variables of structural formulae xii (a) and xii (b).

the group (ring B) -Q3-R5 is:

Wherein ring B2 is optionally and independently further substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

the 9 th set of variables for structures XII (A) and XII (B) is as follows:

The values (including specific values) for the groups (ring B) -Q3-R5, Q3, R, R', R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above in the 8 th set of variables of formulas XII (A) and XII (B).

r5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; or iv) an optionally substituted 4-7 membered non-aromatic heterocyclic ring, wherein said alkyl represented by R5 is optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, an optionally substituted C3-C7 nonaromatic carbocyclic ring and an optionally substituted 4-7 membered nonaromatic heterocyclic ring. Each of the carbocyclic and heterocyclic rings represented by R5 and mentioned for substituents of C1-C6 alkyl represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

in the 10 th variable set of structural formulae xii (a) and xii (b), the values of the variables of structural formulae xii (a) and xii (b), including the specific values, are each independently as described above in the 1 st variable set of structural formulae (I) and (IA).

In the 11 th variable set of structural formulae xii (a) and xii (b), the values of the variables of structural formulae xii (a) and xii (b), including the specific values, are each independently as described in the 16 th variable set of structural formulae (I) and (IA) or the 10 th variable set of structural formulae II-V above.

In another embodiment, the present invention is directed generally to the use of a compound represented by structural formula XIII, below, or a pharmaceutically acceptable salt thereof, for any of the applications described above.

The 1 st set of variables for formula XIII are as follows:

Ring C is a 5-7 membered non-aromatic heterocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring C is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring C is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

R9 is-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

Each R and R' is independently-H or C1-C6 alkyl.

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st set of variables of formulae (I) and (IA).

The set of variables 2 for formula XIII are as follows:

the values (including specific values) for ring C, R, R', R6, R7, R9, R11, and R12 are each independently as described above for the 1 st set of variables of formula XIII.

R10 is-H or C1-C6-alkyl.

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st set of variables of formulae (I) and (IA).

The 3 rd set of variables for formula XIII are as follows:

The values (including specific values) of R, R', R6, R7, R9, R10, R11, and R12 are each independently as described above for the 1 st set of variables of formula XIII.

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st set of variables of formulae (I) and (IA).

The 4 th set of variables for formula XIII are as follows:

The values (including specific values) of R, R', R6, R7, R9, R10, R11, and R12 are each independently as described above for the 2 nd variable set of formula XIII.

Ring C is independently selected from:

Wherein each of ring C1-C5 is optionally and independently substituted. Suitable substituents are as described in ring C of the 1 st variable set of formula XIV.

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st set of variables of formulae (I) and (IA).

In the 5 th variable set of formula XIII, the values (including the specified values) and the provisos for the variables of formula XIII are each independently as described above for the 1 st variable set of formulae (I) and (IA).

In another embodiment, the present invention is directed generally to the use of a compound represented by structural formula XIV below or a pharmaceutically acceptable salt thereof for any of the applications described above.

The 1 st set of variables for structure XIV are as follows:

Ring D is a 4-7 membered non-aromatic heterocyclic ring optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring D is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring D is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each of R and R' is independently-H or C1-C6 alkyl.

The values (including specific values) and provisos for the remaining variables of structure XIV are each independently as described above for the 1 st set of variables of structures (I) and (IA).

The set of variables 2 for structure XIV are as follows:

The values (including specific values) for ring D, R, R', R6, R7, R13, and R14 are each independently as described above for the 1 st variation set for formula XIV.

The value z is 1.

the values (including specific values) and provisos for the remaining variables of structure XIV are each independently as described above for the 1 st set of variables of structures (I) and (IA).

The 3 rd set of variables for structure XIV are as follows:

The values of z, R', R6, R7, R13, and R14 (including specific values) are each independently as described above for the variation set 2 of Structure XIV.

Ring D is independently selected from:

Wherein each of rings D1-D7 is optionally and independently substituted. Suitable substituents are as described in ring D of the 1 st variable set of formula XIV.

Each Rd is independently-H, C1-C6 alkyl or-C (o) (C1-C6 alkyl), wherein each said alkyl moiety is optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, each Rd is independently-H or C1-C6 alkyl optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The values (including specific values) and provisos for the remaining variables of structure XIV are each independently as described above for the 1 st set of variables of structures (I) and (IA).

In the 4 th variable set of formula XIV, the values (including the specified values) and provisos of the variables of formula XIV are each independently as described above for the 1 st variable set of formulae (I) and (IA).

In another embodiment, the compounds of structural formulae I-IV and XI-XIV and pharmaceutically acceptable salts thereof are independently as described above; and with the proviso that, where applicable, if Y1 is a bond, then R5 is neither-H nor an unsubstituted C1-C6 aliphatic group. In particular, if Y1 is a bond, then R5 is a substituted C1-C6 aliphatic, an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, and an optionally substituted 5-10 membered heteroaryl. In particular, the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1, wherein JC1 is independently selected from: optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring, optionally substituted 5-10 membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and-NRSO 2 cRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

In yet another embodiment, the compounds of structural formulae IA-IV and XI-XIV and pharmaceutically acceptable salts thereof are independently as described above; and with the proviso that, where applicable, if Q2 is a bond, then R5 is neither-H nor a C1-C6 aliphatic; and with the proviso that if Q3 is a bond, then R5 is neither-H nor a C1-C6 aliphatic group. In particular, if Q2 and Q3 are each independently a bond, R5 is an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl group, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl group. In particular, if Q2 and Q3 are each independently a bond, then R5 is an optionally substituted C3-C8 non-aromatic carbocyclic ring or an optionally substituted 4-8 membered non-aromatic heterocyclic ring.

in yet another embodiment, the compounds are represented by structural formula (I) or a pharmaceutically acceptable salt thereof, wherein each variable in the formula is independently as described above, and wherein:

R4 is:

Ring E is a C4-C8 non-aromatic carbocyclic ring optionally further substituted by one or more JA.

Ring F is a 4-8 membered non-aromatic heterocyclic ring optionally substituted with one or more JE 1.

Each of rings G1 and G2 is independently a 5-10 membered non-aromatic bridged carbocyclic ring optionally substituted with one or more JA.

r5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; or iv) an optionally substituted 4-7 membered non-aromatic heterocyclic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring. The alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, an optionally substituted C3-C7 non-aromatic carbocyclic ring and an optionally substituted 4-7 membered non-aromatic heterocyclic ring; wherein the carbocyclic and heterocyclic rings represented by R5 and mentioned for substituents of C1-C6 alkyl represented by R5 are independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

R11, R12, R13 and R14 are each independently-H, halogen or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy; or optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups.

R21, R22, R23 and R24 are each independently-H, halogen, -OH, or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.

p and q are each independently 0, 1 or 2.

x is 0, 1 or 2.

r is 1 or 2.

the values (including specific values) and provisos for the remaining variables of structural formula I are each independently as described in any of the variable sets 1-15 of structural formula I above.

In yet another embodiment, the compounds represented by structural formula (I) or pharmaceutically acceptable salts thereof are independently as described in the preceding paragraph; and ring F is selected from any one of rings F1-F6:

Each of rings F1-F6 is optionally and independently substituted; and is

Each Rf is independently-H or C1-C6 alkyl halo, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy, optionally and independently substituted with one or more substituents independently selected from the group consisting of.

In yet another embodiment, the compound represented by structural formula (XIA) or (XIB), or a pharmaceutically acceptable salt thereof, is as described above; and is

the group- [ C (R13R14) ] x-ring a-Q2-R5 is independently:

Wherein:

each of ring a14 and a28 is optionally and independently further substituted; and is

The values (including specific values) and provisos of the remaining variables of formulae (XIA) and (XIB) are each independently as described in any of the 1 st to 11 th variable sets of formulae (XIA) and (XIB) above.

In yet another embodiment, the compounds represented by structural formula (XIA) or (XIB), or a pharmaceutically acceptable salt thereof, are independently as described in the preceding paragraph; and R5 is optionally substituted C1-C6 alkyl, an optionally substituted C3-C7 nonaromatic carbocyclic ring, or an optionally substituted 4-7 membered nonaromatic heterocyclic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring. In particular, R5 is an optionally substituted 4-7 membered non-aromatic heterocyclic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring.

In another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

R4 is:

Ring E is a C4-C10 non-aromatic carbocyclic ring optionally further substituted by one or more JA.

Ring F is a 4-8 membered non-aromatic heterocyclic ring optionally further substituted by one or more JE 1. Specific examples of the ring F include:

Additional examples include each of rings F1-F7 being optionally and independently substituted. Exemplary substituents for ring F (including rings F1-F7) include halogen, cyano, hydroxy, C1-C4 alkoxy, and C1-C4 alkyl optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, and-O (C1-C4 alkyl).

Rf is independently-H or C1-C6 alkyl optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.

Optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups.

s is 0,1 or 2.

x is 0, 1 or 2.

the remaining variables are each independently as described above for any one of the sets of variables of structural formulae (IA) and (I).

In another embodiment, the compounds are represented by structural formula (I) or (IA) or a pharmaceutically acceptable salt thereof, wherein:

Ring E is a C4-C8 non-aromatic carbocyclic ring optionally further substituted by one or more JA.

R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

The other variables are each independently as described in the preceding paragraph.

In yet another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

R4 is:

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more JA.

Ring G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more JBs.

X is-O-, -S-or-NRg-.

Optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups.

r21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy. In particular, R21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C36 6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl).

Rg is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.

q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.

The remaining variables are each independently as described above for any one of the sets of variables of structural formulae (IA) and (I).

In yet another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

R4 is:

Wherein rings G1 and G2 are each independently a 5-10 membered non-aromatic bridged ring optionally further substituted by one or more JA.

each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Q2 is independently a bond, -O-, -S-, -NR-, -C (O) -, -C (═ NR) -, -CO2-, -oc (O) -, -C (O) NR-, -C (O) nrc (O) O-, -nrc (O) NR-, -NRCO2-, -oc (O) NR-, -S (O) -, -SO2-, -n (R) SO2-, -SO2NR '-, -NRSO 2NR' -or- (CR6R7) p-Y1-. Alternatively, Q2 is independently-O-, -CO2-, -OC (O) -, -C (O) NR-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -CO2SO2-, -P (O) 2O-or- (CR6R7) p-Y1-. Alternatively, Q2 is independently-O-or-CO 2-.

in some embodiments, rings E and G (including G1-G5) are optionally and independently further substituted with one or more JA (for carbocyclic rings) or JB (for heterocyclic rings), wherein each of JA and JB is independently selected from halogen, cyano, oxo, -NCO, and Q1-R5, and wherein:

Q1 is independently a bond, -O-, -S-, -NR-, -C (O) -, -C (═ NR) -, -CO2-, -oc (O) -, -C (O) NR-, -C (O) nrc (O) O-, -nrc (O) NR-, -NRCO2-, -oc (O) NR-, -S (O) -, -SO2-, -n (R) SO2-, -SO2NR '-, -NRSO 2NR' -or- (CR6R7) p-Y1-; and Y1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (═ NR) -, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO 2-or-NRSO 2NR' -.

Or: q1 is independently a bond, -O-, -S-, -NR-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2NR '-, -NRSO2 NR' -or- (CR6R7) p-Y1-; and Y1 is independently-O-, -CO2-, -OC (O) -, -C (O) NR-, -NRC (O) NR-, -NRCO 2-or-OC (O) NR-.

In yet another embodiment, Q1 and Y1 are each independently as described in the preceding paragraph and:

R5 is independently: i) -H; ii) a C1-C6-aliphatic optionally substituted by one or more JC 1; iii) a C3-C8 non-aromatic carbocyclic ring optionally substituted by one or more JC 1; iv) phenyl optionally substituted by one or more JC 1; v) a 4-8 membered non-aromatic heterocycle optionally substituted by one or more JD 1; or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more JD 1; and is

JC1 and JD1 are each independently selected from halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NHRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NHC (O) Rb, -C (O) NHRc, -NHC (O) NHRc, -NHC (O) ORb, -OCONHRc, -NHC (O) ORb, -N (CH3) Rc, -N (CH3) C (O) Rb, -C (O) N (CH3) Rc, -N (CH3) C (O) NHRc, -N (CH3) C (O) ORb, -OCON (CH3) Rc, -C (O) NHCO2Rb, -C (O) N (CH3) CO2Rb, -N (CH3) C (O) NHCO) ORb, -NHSO 2(2 Rb, -SO2NHRb, -SO2N (CH3) Rb and-N (CH3) SO2 Rb.

In some particular embodiments, the compounds are represented by structural formula (IA) or (I), wherein:

R1 is-H.

R2 is-H, -CH3, -CH2OH or-NH 2. In particular, R2 is-H or-CH 2 OH.

R3 is-H, -F, -Cl, C1-4 alkyl or C1-4 haloalkyl. Alternatively, R3 is-H, -F or-Cl.

Z1 is-H, -F or-Cl.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

z3 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

R5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; iv) an optionally substituted 4-7 membered non-aromatic heterocycle; v) optionally substituted phenyl; vi) an optionally substituted 5-6 membered heteroaromatic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring; and is

said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, -NRCO (C1-C4 alkyl), -CONR (C1-C4 alkyl), -NRCO2(C1-C4 alkyl), C3-C7 non-aromatic carbon ring optionally substituted by one or more JE1, 4-7 membered non-aromatic heterocyclic ring optionally substituted by one or more JE1, and phenyl optionally substituted by one or more JE 1; and is

Wherein each of said carbocycle, heterocycle, phenyl and heteroaryl represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The remaining variables, including R4, comprising the spiro ring represented by rings E and F or the bridged ring represented by rings G1-G5 are each independently as described in any of the 4 embodiments above.

In yet another embodiment, the compounds are represented by structural formula (IA) or (I), wherein the values of the variables are each independently as described in the previous embodiment, except:

Z2 is-H;

Z3 is-H;

R5 is independently: i) -H; or ii) C1-C6-alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), -CO2H, C3-C8 non-aromatic carbon ring, 4-8 membered non-aromatic heterocyclic ring, phenyl and 5-6 membered heteroaryl;

Wherein each of said alkyl groups involved in the substituents of the C1-C6-alkyl group represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and is

Wherein each of said carbocyclic rings, phenyl rings, heterocyclic rings and heteroaryl groups involved in the substituents of C1-C6-alkyl represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

In yet another embodiment, each of rings E, G1-G5 is independently and optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C35 6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2 Rb; wherein each said alkyl group is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, each of rings E, G1-G5 is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy and C1-C4 alkyl optionally substituted by one or more substituents selected from halogen, cyano, hydroxy and-O (C1-C4 alkyl).

In another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

R4 is:

Ring a is a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R8 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R9 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R11 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, wherein each said carbocyclic ring is independently and optionally substituted by one or more JA and wherein each carbocyclic ring is independently and optionally substituted by one or more JB.

r1 is-H.

R2 is-H, -CH3, -CH2OH or-NH 2. In particular, R2 is-H or-CH 2 OH.

R3 is-H, -F, -Cl, C1-4 alkyl (e.g., -CH3 or-C2H 5), or C1-4 haloalkyl (e.g., -CF 3). Alternatively, R3 is-H, -F or-Cl.

Z1 is-H, -F or-Cl.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

z3 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

Q2 is independently-O-, -CO2-, -OC (O) -, -C (O) NR ' -, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1-.

Y1 is-O-, -CO2-, -OC (O) -, -C (O) NR ' -, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O) 2O-or-CO 2SO 2-.

R5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; iv) an optionally substituted 4-7 membered non-aromatic heterocycle; v) optionally substituted phenyl; vi) an optionally substituted 5-6 membered heteroaromatic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring; and is

Said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, -NRCO (C1-C4 alkyl), -CONR (C1-C4 alkyl), -NRCO2(C1-C4 alkyl), C3-C7 non-aromatic carbon ring optionally substituted by one or more JE1, 4-7 membered non-aromatic heterocyclic ring optionally substituted by one or more JE1, and phenyl optionally substituted by one or more JE 1;

Wherein each of said carbocycle, heterocycle, phenyl and heteroaryl represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

r11, R12, R13 and R14 are each independently-H, halogen or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C6 alkoxy.

Each of JA and JB is independently selected from halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C63 6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2 Rb; wherein each said alkyl group is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

n is 0 or 1.

x is 0 or 1.

the remaining variables are each independently as described above for any one of the sets of variables for structural formulae (IA) and (I).

in another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocyclic ring optionally further substituted by one or more JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocyclic ring optionally further substituted by one or more JB.

X is-O-, -S-or-NRg-.

R21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl).

rg is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy, and C2-C6 alkoxyalkoxy.

q is 0,1 or 2.

r is 1 or 2.

The remaining variables are each independently as described in the preceding paragraph.

In yet another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein the variables are each independently as described in the preceding paragraph, except as described below:

R1 is-H.

R2 is-H.

R3 is-H, -F, -Cl, C1-4 alkyl or C1-4 haloalkyl. Alternatively, R3 is-H, -F or-Cl.

Z1 is-H, -F or-Cl.

Z2 is-H.

Z3 is-H.

X is-O-.

R5 is-H, optionally substituted C1-C6 alkyl, or optionally substituted phenyl.

Each R8 is independently-H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or-O (C1-C4 alkyl).

each of R9, R13, and R14 is independently-H or C1-C4 alkyl.

R21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C6 alkyl and-O (C1-C6 alkyl). In particular, R21, R22, R23, R24 and R25 are each independently-H, C1-6 alkyl or C16 haloalkyl.

In yet another embodiment, the compounds are represented by any of formulae I-V (hereinafter reference formulae I-IV, including formulae I, IA, II, III, IV, V, and VI) and XI (A) -XIV (hereinafter reference formulae XI (A) -XIV, including formulae XIA, XIB, XIIA, XIIB, XIII, and XIV), wherein the values of the variables are independently as described in any of the embodiments above, except that R3 is C1-6 alkyl, e.g., methyl or ethyl.

In yet another embodiment, the compound is represented by any of structural formulas I-V and XI (A) -XIV, wherein the values of the variables are independently as described in any of the embodiments above, except that x is 0.

In yet another embodiment, the compounds are represented by any of structural formulas I, IA, II, VI, XI (a), and XI (b), wherein the values of the variables are independently as described in any of the embodiments above, except that ring a is bridged.

In yet another embodiment, the compounds are represented by any one of structural formulae I, IA, II, VI, XI (a), and XI (b), wherein the values of the variables are independently as described in any of the embodiments above, except that Q2 is independently: -C (═ NR) -, -C (═ NR) NR-, -NRC (═ NR) NR-, -CO2-, -oc (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2NR-, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1-; alternatively, Q2 is independently-CO 2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2NR-, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1-.

In yet another embodiment, the compounds are represented by any of structural formulas I-V and XI (A) -XIV, wherein the values of the variables are independently as described in any of the embodiments above, provided that when Q2 is-O-or-NR-, then ring A is further substituted with JA instead of-H; and with the proviso that if Q3 is-C (o) -, then R5 is substituted C1-C6 aliphatic, optionally substituted C3-C8 nonaromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered nonaromatic heterocyclic ring, or optionally substituted 5-10 membered heteroaryl. In a particular embodiment, when Q2 is-O-or-NR-, then Ring A is further substituted in the twin of-Q2R 5 by JA rather than-H.

In a further embodiment, the present invention relates to the use of any compound selected from the group described in figures 3,4, 5,6,7 and 8, or a pharmaceutically acceptable salt thereof, for any of the applications described above.

In some embodiments, the compounds are represented by any one of structural formulae I-V and xi (a) -XIV, and the variables are each independently as described for the compounds of figures 1-8.

In a further embodiment, the invention relates to the use of a compound of any one of the embodiments or a pharmaceutically acceptable salt thereof for any of the applications described above, including the sets of variables for structures I-V and XI (A) -XIV described above, provided that when R3 is-Cl, Z1 is-F, and Z2 is-H, then R4 is not 2-NH 2-cyclohexyl.

In yet another embodiment, the compounds described herein, or pharmaceutically acceptable salts thereof, can be used to reduce viral titer in a biological sample (e.g., infected cell culture) or a human (e.g., viral titer in the lungs of a patient).

The terms "influenza virus mediated condition," "influenza infection," or "influenza" as used herein are used interchangeably to refer to a disease caused by infection with an influenza virus.

Influenza is an infectious disease caused by influenza viruses that affects birds and mammals. Influenza viruses are RNA viruses of the orthomyxoviridae family, which includes 5 genera: influenza a virus, influenza B virus, influenza C virus, salmon anemia virus and torpedo soil virus. Influenza a viruses, which are subdivided into different serotypes H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2, H7N2, H7N3 and H10N7, can be classified according to antibody responses to these viruses. Influenza B virus belongs to 1 species, and influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza a. Influenza C virus belongs to 1 species, influenza C virus, which infects humans and pigs and can cause severe disease and endemic epidemics. However, influenza C is less common than other types and often appears to cause mild disease in children.

In some embodiments of the invention, the influenza or influenza virus is associated with an influenza a or B virus. In some embodiments of the invention, the influenza or influenza virus is associated with influenza a virus. In some particular embodiments of the invention, the influenza a virus is H1N1, H2N2, H3N 2or H5N 1.

in humans, the common symptoms of influenza are chills, fever, pharyngitis, myalgia, severe headache, cough, weakness and general malaise. In more severe cases, influenza causes life-threatening pneumonia, especially in young children and the elderly. Although often confused with the common cold, influenza is a more serious disease and is caused by different types of viruses. Particularly in children, influenza can cause nausea and vomiting, but these symptoms are more characterized by unrelated gastroenteritis, sometimes referred to as "gastrointestinal cold" or "24 hour flu".

Influenza symptoms can begin quite suddenly 1-2 days after infection. The first symptom is usually the chill fight or intolerance of cold, but fever in infection is also a common early symptom, with body temperatures ranging from 38-39 ℃ (about 100-. Many people are seriously ill for several days in bed, have general pain and are more serious in the back and legs. Influenza symptoms may include: physical pain, especially in joints and throat, extreme cold and fever, fatigue, headache, irritative tearing, redness of the eyes, skin (especially the face), mouth, throat and nose, abdominal pain (in children with influenza B). Influenza symptoms are non-specifically complicated by many pathogens ("influenza-like"). Often, laboratory data is required to facilitate a diagnosis.

The terms "disease," "disorder," and "condition" are used interchangeably herein to refer to an influenza virus-mediated medical or pathological condition.

The terms "subject" and "patient" as used herein are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails or turkeys, or lactating animals), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a "human".

The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof, biopsy material or extracts thereof obtained from mammals, blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

The term "multiplicity of infection" or "MOI" as used herein is the ratio of infectious agent (e.g., phage or virus) to infected subject (e.g., cell). For example, when referring to a population of cells inoculated with infectious viral particles, the multiplicity of infection or MOI is the ratio determined by the number of infectious viral particles precipitated in a well divided by the number of target cells present in the well.

The term "inhibiting replication of influenza virus" as used herein includes reducing the amount of virus replication (e.g., by at least 10%) and completely preventing virus replication (i.e., 100% reducing the amount of virus replication). In some embodiments, influenza virus replication is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

Influenza virus replication can be measured by any suitable method known in the art. For example, influenza virus titers can be measured in a biological sample (e.g., infected cell culture) or in humans (e.g., lung virus titers in patients). More particularly, for cell-based assays, cells are cultured in vitro in each case, the virus is added to the culture in the presence or absence of test agents, and the virus-dependent endpoint is assessed after an appropriate time. For a typical assay, suitable influenza strain A/Puerto Rico/8/34 can be cultured using Madin Darby canine kidney cells (MDCK) and standard tissue culture. The first type of cell detection that can be used in the present invention relies on the death of infected target cells, a process known as cytopathic effect (CPE), in which viral infection causes depletion of cellular resources and eventual lysis of the cells. In the first type of cell assay, a small fraction of cells (typically 1/10 to 1/1000) in a well of a microtiter plate are infected, the virus is allowed to replicate several times over 48-72h, and the number of cell deaths is then measured using the decrease in cellular ATP compared to uninfected controls. A second type of cellular assay that can be employed in the present invention relies on the proliferation of virus-specific RNA molecules in infected cells, and the RNA content is measured directly using the branched-chain DNA hybridization method (bDNA). In the second type of cell assay, a small number of cells are initially infected in the wells of a microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional cells, the cells are then lysed and the viral RNA content is measured. This assay is usually stopped early after 18-36h, while all target cells remain viable. Viral RNA is quantified by hybridization to specific oligonucleotide probes immobilized on the wells of the detection plate, followed by amplification of the signal by hybridization to additional probes linked to a reporter enzyme.

As used herein, "viral titer" is a measure of viral concentration. Titer testing can employ serial dilutions to obtain approximate quantitative information from assays that essentially only evaluate as positive or negative. Titer corresponds to the highest dilution factor that still produces a positive reading; for example, a positive reading in the first 8 consecutive two-fold dilutions translates to a titer of 1: 256. A specific example is virus titer. To determine titres, several dilutions were made, e.g., 10-1, 10-2, 10-3, … …, 10-8. The lowest virus concentration that still infects cells is the virus titer.

The term "treatment" as used herein refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity, and/or duration of an influenza virus-mediated condition, or ameliorating one or more symptoms (particularly, one or more discernible symptoms) of an influenza virus-mediated condition as a result of administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the invention)). In particular embodiments, the therapeutic treatment comprises ameliorating at least one measurable physical parameter of an influenza virus-mediated condition. In other embodiments, the therapeutic treatment comprises inhibiting the progression of an influenza virus-mediated condition, either physically, by, for example, stabilizing discernible symptoms, or physiologically, by, for example, stabilizing physical parameters, or both. In other embodiments, the therapeutic treatment comprises reducing or stabilizing an influenza virus-mediated infection. Antiviral drugs can be used in the community to treat people already suffering from influenza to reduce the severity of the symptoms and reduce their number of days of illness.

The term "chemotherapy" refers to the use of drugs, such as small molecule drugs (rather than "vaccines"), to treat a disorder or disease.

The terms "prevention", "prophylactic use" and "prophylactic treatment" as used herein refer to any medical or public health procedure aimed at preventing, rather than treating or curing, a disease. The term "preventing" as used herein refers to reducing the risk of acquiring or developing a specified condition, or reducing or inhibiting a relapse or disease-free condition in a subject who has or may be in close proximity to a patient. The term "chemoprevention" refers to the use of drugs, such as small molecule drugs (rather than "vaccines"), to prevent a disorder or disease.

Prophylactic use as used herein includes use in situations where outbreaks have been detected to prevent infection or spread in places of close contact (e.g., in hospital wards, day care centers, prisons, nursing homes, etc.) by many people at high risk of serious influenza complications. It is also included in populations where influenza protection is required but protection is not obtained after vaccination (e.g. due to weak immune system) or for which the vaccine is not available, or when they cannot be vaccinated due to side effects. Also included is use within 2 weeks after vaccination, as the vaccine is still ineffective during this period. Prophylactic use may also include treating a person who is not flu or is not considered to be at high risk of complications to reduce the chance of contracting the flu and transmitting the flow to a high risk person (e.g., a health care worker, nursing home staff, etc.) in close proximity to him.

According to the US CDC, an influenza "outbreak" is defined as a sudden increase in acute fever respiratory disease (AFRI) within 48-72h in a population of people in close proximity to each other above the normal background rate or when any subject in the analyzed population tests positive for influenza. Influenza cases determined by any test method are considered outbreaks.

"clustering" is defined as a combination of 3 or more AFRI cases occurring within 48-72h in a group of people in close proximity to each other (e.g., in the same area, same household of a supporting sexual life facility, etc.).

As used herein, an "indicated case," "primary case," or "patient zero (patient zero)" is the initial patient in the demographic sample of the epidemiological survey. The term is not capitalized when used to refer to such patients, usually in epidemiological surveys. When the term is used in a report on a particular survey to refer to a particular person rather than the name of that person, the term capitalized on a Patient Zero (Patient Zero). Scientists often look for prescription cases to determine how the disease spreads and what etiology will control the disease during the outbreak. Note that the indicated case is the first patient to indicate the presence of an outbreak. Earlier cases can be found and labeled as first, second, third, etc.

In one embodiment, the method of the invention is a prophylactic or "preemptive" treatment for a patient, particularly a person predisposed to complications caused by an influenza virus infection. The term "priority," as used herein, for example in priority usage, "priority," etc., is prophylactic use in situations where "indicated cases" or "outbreaks" have been confirmed to prevent spread of infection in the rest of the community or population.

In another embodiment, the methods of the invention may be used as a "priority" measure for members of a community or group, particularly humans, to prevent the spread of infection.

An "effective amount" as used herein refers to an amount that elicits the desired biological response. In the present invention, the biological response is expected to be inhibition of influenza virus replication, reduction in the amount of influenza virus or reduction or amelioration of the severity, duration, progression or onset of influenza virus infection, prevention of spread of influenza virus infection, prevention of recurrence, evolution, onset or progression of symptoms associated with influenza virus infection, or enhancement of the prophylactic or therapeutic effect of another anti-influenza infection therapy used. The exact amount of compound administered to a subject will depend on the mode of administration, the type and severity of the infection and the characteristics of the subject, such as health, age, sex, weight and tolerance to drugs. The skilled artisan will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other antiviral agents, such as anti-influenza drugs, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages of approved agents are known and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition being treated, and the amount of the compound described herein being used. In the case where amounts are not explicitly specified, an effective amount should be taken. For example, a compound described herein may be administered to a subject at a dosage in the range of about 0.01-100 mg/body weight/day for therapeutic or prophylactic treatment.

In general, the dosage regimen will be selected in accordance with a variety of factors including the condition being treated and the severity of the condition, the activity of the particular compound employed, the particular composition employed, the age, weight, health, sex and diet of the patient, the time of administration, route of administration and rate of excretion of the particular compound employed, the renal and hepatic function of the subject, the particular compound or salt thereof employed, the duration of the treatment, the drug employed in conjunction or concomitantly with the particular compound employed, and like factors well known in medicine. The skilled artisan can readily determine and specify an effective amount of a compound described herein that is required to treat, prevent, inhibit (in whole or in part), or arrest the progression of a disease.

The dosage range of the compounds described herein is about 0.01-100 mg/body weight/day, 0.01-50 mg/body weight/day, 0.1-50 mg/body weight/day, or 1-25 mg/body weight/day. It is understood that the total amount per day may be administered in a single dose or may be administered in multiple doses, for example 2 times daily (e.g., every 12h), 3 times daily (e.g., every 8h), or 4 times daily (e.g., every 6 h).

for therapeutic treatment, a compound described herein can be administered to a patient, for example, within 48h (or within 40h or less than 2 days or less than 1.5 days or 24 h) of symptomatic attack (e.g., nasal congestion, sore throat, cough, pain, fatigue, headache, and chills/sweating). Therapeutic treatment may continue for any suitable period of time, e.g., 5 days, 7 days, 10 days, 14 days, etc. For prophylactic treatment during a community outbreak, a compound described herein can be administered to a patient, for example, within 2 days of the onset of indicated case symptoms, and can continue for any suitable time, e.g., 7 days, 10 days, 14 days, 20 days, 28 days, 35 days, 42 days, etc.

Various methods of administration can be employed in the present invention and are described in detail below under the heading "methods of administration".

Combination therapy

An effective amount can be achieved in a method or pharmaceutical composition of the invention using structures I-V (e.g., structures I, IA, II, III, IV, and V) and XI (A) -XIV (e.g., structures XIA, XIB, XIIA, XIIB, and XIV) or a pharmaceutically acceptable salt or solvate thereof (e.g., hydroxide) alone or in combination with another suitable therapeutic agent, such as an antiviral agent or vaccine. When "combination therapy" is employed, an effective amount can be achieved using a first amount of a compound of any one of structural formulae I-V and XI (A) -XIV, or a pharmaceutically acceptable salt or solvate thereof (e.g., a hydroxide), and a second amount of an additional suitable therapeutic agent (e.g., an antiviral agent or a vaccine).

In another embodiment of the invention, the compound of any one of structural formulae I-V and XI (A) -XIV and the additional therapeutic agent are each administered in an effective amount (i.e., each in a therapeutically effective amount if administered alone). In another embodiment, the compound of any of structural formulae I-V and XI (A) -XIV and the additional therapeutic agent are each administered in an amount that alone does not provide a therapeutic effect (sub-therapeutic dose). In yet another embodiment, a compound of any one of structures I-V and XI (A) -XIV can be administered in an effective amount, while an additional therapeutic agent is administered in a sub-therapeutic dose. In yet another embodiment, a compound of any of structural formulae I-V and XI (A) -XIV can be administered in a subtherapeutic dose, while an additional therapeutic agent, such as a suitable cancer therapeutic agent, is administered in an effective amount.

The terms "combination" or "administration in combination" as used herein are used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not limit the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

Co-administration encompasses administration of the first and second amounts of the compound in combination in a substantially simultaneous manner, e.g., administration in a single pharmaceutical composition, e.g., a capsule or tablet with a fixed ratio of the first and second amounts, or administration in multiple separate capsules or tablets. In addition, such combined administration also encompasses the sequential use of each compound in either order.

In one embodiment, the present invention relates to combination therapies for inhibiting influenza virus replication or treating or preventing influenza virus infection in a patient using a compound or pharmaceutical composition of the present invention of any one of structural formulae I-V and XI (A) -XIV in a biological sample or patient. Accordingly, the pharmaceutical compositions of the present invention also include those comprising an influenza virus replication inhibitor of the present invention in combination with an antiviral compound that exhibits anti-influenza virus activity.

Methods of use of the compounds and compositions of the invention also include combinations of chemotherapy and compounds or compositions of any one of structural formulae I-V and xi (a) -XIV, or combinations of the compounds or compositions of the invention and another antiviral agent and vaccination against influenza.

When co-administration comprises administering a first amount of a compound of any one of formulae I-V and xi (a) -XIV alone and a second amount of an additional therapeutic agent, the compounds are administered at a time sufficient to approximate the expected therapeutic effect. For example, the interval between administrations that can produce the desired therapeutic effect at a time can range from a few minutes to a few hours, and the properties of each compound, such as potency, solubility, bioavailability, plasma half-life, and kinetic profile, can be considered. For example, the compound of any one of structural formulae I-V and XI (A) -XIV, and the second therapeutic agent can be administered within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other, or within about 30 minutes of each other, in any order.

more particularly, a first therapy (e.g., a prophylactic or therapeutic agent (e.g., a compound of the invention)) can be administered to the subject prior to (e.g., 5min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 12h, 24h, 48h, 72h, 96h, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with or after (e.g., 5min, 15min, 30min, 45min, 1h, 2h, 4h, 6h, 12h, 24h, 48h, 72h, 96h, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy (e.g., a prophylactic or therapeutic agent (e.g., a compound of the invention)).

It is understood that a combination of a first amount of a compound of any one of formulae I-V and xi (a) -XIV and a second amount of an additional therapeutic agent produces an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect produced by administering the first amount of a compound of any one of formulae I-V and xi (a) -XIV and the second amount of the additional therapeutic agent alone.

The term "synergistic" as used herein refers to a combination of a compound of the invention and another therapy (e.g., prophylactic or therapeutic agent) that is more effective than the additive effects of the therapy. The synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) may allow for the use of lower doses of one or more therapies and/or less frequent administration of the therapies to a subject. Being able to utilize lower doses of a therapy (e.g., a prophylactic or therapeutic agent) and/or to administer the therapy less frequently can reduce toxicity associated with administration of the therapy to a subject without reducing the efficacy of the therapy in the prevention, management, or treatment of a disorder. In addition, synergistic effects may result in an increase in the efficacy of the agent in the prevention, management or treatment of a disorder. Finally, the synergistic effect of a combination of therapies (e.g., a combination of prophylactic or therapeutic agents) can avoid or reduce the deleterious or adverse side effects associated with either therapy alone.

When combination therapy with a compound of the invention of any of structural formulae I-V and xi (a) -XIV is combined with an influenza vaccine, both therapeutic agents can be administered such that the interval between each administration can be longer (e.g., days, weeks, or months).

The presence of a synergistic effect can be determined using suitable methods for assessing drug interactions. Suitable methods include, for example, the Sigmoid-Emax formula (Holford, N.H.G., and Scheiner, L.B., Clin.Pharmacokinet.6:429-453(1981)), the Loewe addition formula (Loewe, S. and Muischnek, H., Arch.Exp.Pathol Pharmacol.114:313-326(1926)), and the efficiency formula (Chou, T.C.and Talalay, P., adv.enzyme Regul.22:27-55 (1984)). Each of the above mentioned formulas can be applied with experimental data to generate a corresponding graph to help assess the effect of a drug combination. The corresponding figures mentioned above in relation to the formula are the concentration-effect curve, the isobologram curve and the combined index curve, respectively.

Specific examples of agents that may be administered in combination with the compounds described herein include neuraminidase inhibitors (e.g., oseltamivir and zanamivir), viral ion channel (M2 protein) blockers (e.g., amantadine and rimantadine), and Antiviral drugs described in WO 2003/015798, including T-705 (see also ruuta et al, Antiviral read, 82:95-102(2009), "T-705 (flaviviral) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections.") developed by Toyama Chemical, japan. In some embodiments, the compounds described herein may be administered in combination with a conventional influenza vaccine.

compounds of the invention

Another aspect of the invention relates generally to compounds. In one embodiment, the present invention is generally directed to compounds represented by structural formula (IA) or (I):

the 1 st variable subset of structural formulae (I) and (IA) for the compounds of the present invention is as follows:

R1 is-H, C1-C6 alkyl, -S (O)2-R ", OR-C (O) OR". In particular, R1 is-H or S (O)2-R ". In particular, R1 is-H or-S (O)2- (phenyl), wherein the phenyl is optionally substituted with one or more substituents selected from C1-C6 alkyl and C1-C6 haloalkyl. More particularly, the phenyl group is optionally substituted with one or more substituents selected from-CH 3 and-CF 3 (e.g., at the para-position thereof). In particular, R1 is-H or C1-6 alkyl. In particular, R1 is-H.

r4 is:

R "is independently: i) C1-C6-alkyl optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy; or ii) a C3-C6 carbocyclic group, a 5-6 membered heteroaryl group, or a phenyl group, each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, nitro, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy. In particular, R "is independently optionally substituted 5-6 membered heteroaryl or optionally substituted phenyl. In particular, R "is independently phenyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

The values of Z1, Z2, Z3, Q1, Q2, Q3, Y1, ring a-D, R, R, R', R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, Ra, Rb, Rc, Rd, JA, JB, JC1, JD1 and JE1, including their specific values and substituents, are each independently as set forth above for the 1 st variables of formulae (IA) and (I) of the process of the present invention.

The value p is independently 1,2, 3 or 4. In particular, p is independently 1 or 2.

Rings A and B are 3-6 membered, n and m are each independently 0 or 1; and k is independently 0, 1 or 2. Alternatively, rings A and B are 7-10 membered, n and m are each independently 0, 1 or 2; and k is independently 0, 1 or 2.

The values x and y are each independently 0, 1 or 2.

The value z is 1 or 2.

provided that if Y1 is a bond, then R5 is neither-H nor an unsubstituted C1-C6 aliphatic group. In particular, if Y1 is a bond, R5 is a substituted C1-C6 aliphatic, an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl. In particular, the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1, wherein JC1 is independently selected from: optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring, optionally substituted 5-10 membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2N (R) Rb, -NRSO2Rb, and-NRSO 2 NRRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

Provided that, if Q2 and Q3 are each independently a bond, R5 is an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl group, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl group. In particular, if Q2 and Q3 are each independently a bond, then R5 is an optionally substituted C3-C8 nonaromatic carbocyclic ring or an optionally substituted 4-8 membered nonaromatic heterocyclic ring.

Alternatively, with the proviso that if rings a and B are each independently 5 or 6 membered, R1 and R2 are both-H, R3 is-Cl, Z2 is-H and Z1 is-F, then Q2-R5 and Q3-R5 are not-H, respectively; and with the proviso that the ring B-Q3-R5 moiety is not N-methyl-3-pyrrolidinyl

the subset of variables 2 of structural formulae (IA) and (I) for the compounds of the present invention are as follows:

R2 is-H or-CH 3.

R3 is-H, -Cl, -F, -Br, -CN, -CF3, -O (C1-C4 alkyl), -OH, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2.

R4 is selected from the formulas A-D depicted above.

The values (including specific values) and provisos for the remaining variables of structural formulae (IA) and (I) are each independently as described above for the 1 st subset of variables of structural formulae (IA) and (I).

a subset of variables 3 of structural formula I for the compounds of the present invention are as follows:

R2 is-H or-CH 3.

R3 is-H, -F, -Cl, -CF3, -NH2, -NH (CH3) or-N (CH3) 2.

R4 is selected from the formulas A-D depicted above.

a subset of variables 4 of structural formulae (IA) and (I) for the compounds of the present invention are as follows:

R2 is-H or-CH 3.

R3 is-H, -F or-Cl.

r4 is selected from the formulas A-D depicted above.

The 5 th variable subset of structural formulae (IA) and (I) for the compounds of the present invention is as follows:

R2 is-H.

R3 is-H or-Cl.

R4 is selected from the formulas A-D depicted above.

The 6 th variable subset of structural formulae (IA) and (I) for the compounds of the present invention is as follows:

Each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, or5 th variable subsets of structural formulae (IA) and (I).

Z1 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH (C1-C6 alkyl) or-CON (C1-C6 alkyl) 2; and Z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2; wherein each of said alkyl groups (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -CO2(C1-C6 alkyl), -NH (C1-C6 alkyl), and-N (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The 7 th variable subset of structural formulae (IA) and (I) for the compounds of the present invention is as follows:

each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, or5 th variable subsets of structural formulae (IA) and (I).

Z1 is-H, -F, -Cl, -CF3, C1-C4 alkyl, -O (C1-C4 alkyl) or-CN; and Z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each of said alkyl (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -NH (C1-C6 alkyl), and-N (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

the values (including specific values) and provisos of the remaining variables of structural formulae (IA) and (I) are each independently as described above in the 1 st subset of variables.

The 8 th variable subset of structural formulae (IA) and (I) for the compounds of the present invention is as follows:

Each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, or5 th variable subsets of structural formulae (IA) and (I).

Z1 is-H, -F, -Cl, C1-C4 haloalkyl (e.g., -CF3), C1-C4 alkyl, -O (C1-C4 alkyl), or-CN.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The values (including specific values) and provisos of the remaining variables of structural formulae (IA) and (I) are each independently as described above in the 1 st subset of variables.

The 9 th variable subset of structural formulae (IA) and (I) for the compounds of the present invention is as follows:

Each of R2, R3, and R4 is independently as described in the 1 st, 2 nd, 3 rd, 4 th, or5 th variable subsets of structural formulae (IA) and (I).

Z1 is-H, -F, -Cl, -CF3, -CH3 or-CN.

the values (including specific values) and provisos for the remaining variables of structural formulae (IA) and (I) are each independently as described above for the 1 st subset of variables of structural formulae (IA) and (I).

in the 10 th variable subset of structural formulae (IA) and (I) of the compounds of the present invention, the variables of structural formulae (IA) and (I), including the particular values, are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th or 9 th variable subset of structural formulae (IA) and (I); and when applicable:

Each R is independently: i) -H; ii) a C1-C6 alkyl group optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; or iii) a 3-7 membered carbocyclic ring optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy and C1-C6 alkyl, wherein each alkyl is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; and is

R' is independently phenyl optionally substituted with one or more substituents independently selected from C1-C6 alkyl and C1-C6 haloalkyl.

In the 11 th variable subset of structural formulae (IA) and (I) of the compounds of the present invention, the variables of structural formulae (IA) and (I), including the particular values, are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th or 10 th variable subset of structural formulae (IA) and (I); and when applicable:

Provided that, if Y1 is a bond, R5 is a substituted C1-C6 aliphatic, an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl; and is

In the 12 th variable subset of structural formulae (IA) and (I) of the compounds of the present invention, the variables of structural formulae (IA) and (I), including the particular values, are each independently as described above for the 11 th variable subset of structural formulae (IA) and (I); and when Y1 is a bond, the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1 wherein JC1 is independently selected from: optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring, optionally substituted 5-10 membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2N (R) Rb, -NRSO2Rb and-NRSO 2 NRcRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

A 13 th subset of variables of structural formulae (IA) and (I) are as follows:

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and-NRSO 2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7 membered ring optionally substituted with and fused to the respective ring to which they are attached, or one or more JE 1.

The values (including specific values) and provisos for the remaining variables of structural formulae (IA) and (I) are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, 10 th, 11 th or 12 th subset of variables of structural formulae (IA) and (I).

in the 14 th variable subset of structural formulae (IA) and (I), the values of the variables are independently as described above for the 17 th variable set of structural formulae (IA) and (I).

In the 15 th variable subset of structural formulae (IA) and (I), the values of the variables are independently as described above for the 18 th variable set of structural formulae (IA) and (I).

in the 16 th variable subset of structural formulae (IA) and (I), the values of the variables are independently as described above for the 19 th variable set of structural formulae (IA) and (I).

In some embodiments, the compounds are represented by structural formulae (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein R1 is-H or C1-6 alkyl, and wherein the values of the remaining variables are independently as described above for any subset of variables of structural formulae (IA) and (I).

in another embodiment, the present invention relates generally to compounds represented by structural formula VI or a pharmaceutically acceptable salt thereof.

The 1 st subset of variables of structural formula VI for the compounds of the present invention are as follows:

Z1 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH (C1-C6 alkyl), or-CON (C1-C6 alkyl) 2, wherein each of said alkyl (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -CO2(C1-C6 alkyl), -CONH (C1-C6 alkyl), and-CON (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each of said alkyl (e.g., represented by C1-C6 alkyl, -O (C1-C6 alkyl), -NH (C1-C6 alkyl), and-N (C1-C6 alkyl) 2) is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The values (including specific values) and provisos for the remaining variables of structural formula VI are each independently as described above for the 1 st subset of variables of structural formulae (IA) and (I).

A subset of variables 2 of structural formula VI for the compounds of the present invention are as follows:

Z1 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH (C1-C6 alkyl), or-CON (C1-C6 alkyl) 2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

R3 is-H, -Cl, -F, -Br, -CN, -CF3, -O (C1-C4 alkyl), -OH, -NH2, -NH (C1-C4 alkyl) or-N (C1-C4 alkyl) 2.

A subset of variables 3 of structural formula VI for the compounds of the present invention are as follows:

z1 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -F, -Cl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH (C1-C6 alkyl), or-CON (C1-C6 alkyl) 2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Z2 is-H, C1-C6 alkyl, -O (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

R3 is-H, -F, -Cl, -CF3, -NH2, -NH (CH3) or-N (CH3) 2. In particular, R3 is-H, -Cl or-F. In particular, R3 is-Cl.

In the 4 th variable subset of structural formula VI for the compounds of the present invention, the values (including particular values) and provisos for the variables of structural formula VI are each independently as described above for the 1 st variable subset of structural formulae (IA) and (I).

in the 5 th variable subset of structural formula VI of the compounds of the present invention, the values (including particular values) and provisos for the variables of structural formula VI are each independently as described above for the 1 st, 2 nd, 3 th, or 4 th variable subsets of structural formulae (IA) and (I); and when applicable:

Provided that if Q2-R5 is-OR 5 OR-NR' R5, ring a is further substituted with one OR more JA other than-H; and is

Provided that, if Q3 is-C (o) -, R5 is a substituted C1-C6 aliphatic, an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl.

In the 6 th variable subset of structural formula VI of the compounds of the present invention, the values (including particular values) and provisos of the variables of structural formula VI are each independently as described in sub-set 5 above; and when Q3 is-C (o) -the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1 wherein JC1 is independently selected from: optionally substituted C3-C8 nonaromatic carbocyclic ring, optionally substituted 6-to 10-membered carbocyclic aryl, optionally substituted 4-to 8-membered nonaromatic heterocyclic ring, optionally substituted 5-to 10-membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2N (R) Rb, -NRSO2Rb and-NRSO 2 NRcRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

In the 7 th variable subset of structural formula VI for the compounds of the invention, the values (including particular values) and provisos for the variables of structural formula VI are each independently as described above for the 1 st, 2 nd, 3 th, or 4 th variable subsets of structural formulae (IA) and (I); and when applicable:

In the 8 th variable subset of structural formula VI for the compounds of the invention, the values (including particular values) and provisos for the variables of structural formula VI are each independently as described above for the 7 th variable subset of structural formulae (IA) and (I); and is

When Y1 is a bond, the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1, wherein JC1 is independently selected from: optionally substituted C3-C8 nonaromatic carbocyclic ring, optionally substituted 6-to 10-membered carbocyclic aryl, optionally substituted 4-to 8-membered nonaromatic heterocyclic ring, optionally substituted 5-to 10-membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2N (R) Rb, -NRSO2Rb and-NRSO 2 NRcRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

In the 9 th variable subset of structural formula VI of the compounds of the present invention, the values (including particular values) and provisos for the variables of structural formula VI are each independently as described above for the 1 st, 2 nd, 3 th, or 4 th variable subsets of structural formulae (IA) and (I); and when applicable:

Provided that if Q2-R5 is-OR 5 OR-NR' R5, ring a is further substituted with one OR more JA other than-H;

Provided that, if Q3 is-C (o) -, R5 is substituted C1-C6 aliphatic, optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring, or optionally substituted 5-10 membered heteroaryl;

In the 10 th variable subset of structural formula VI for the compounds of the present invention, the values (including particular values) and provisos for the variables of structural formula VI are each independently as described above for the 9 th variable subset of structural formulae (IA) and (I); and is

when Q3 is-C (o) -, or Y1 is a bond, the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1, wherein JC1 is independently selected from: optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring, optionally substituted 5-10 membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2N (R) Rb, -NRSO2Rb and-NRSO 2 NRcRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

In the 11 th variable subset of structural formula VI of the compounds of the present invention, the values of the variables of structural formula VI (including specific values) are each independently as described above for the 13 th variable subset of structural formulae (IA) and (I).

In another embodiment, the present invention relates generally to compounds represented by any one of structural formulae II, III, IV, and V:

The 1 st subset of variables for structural formulae II, III, IV and V of the compounds of the present invention are as follows:

Each Q2 is independently-O-, -S-, -NR '-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -N (R) SO2-, -SO2NR '-, -NRSO 2NR' -, or- (CR6R7) p-Y1-.

Each Q3 is independently-C (O) -, -CO2-, -C (O) NR '-, -SO2-, -SO2 NR' -, -C (O) NRC (O) O-or- (CR6R7) p-Y1-.

Z1 is-H, -F, -Cl, C1-C4 haloalkyl (e.g., -CF3), C1-C4 alkyl, -O (C1-C4 alkyl), or-CN.

Each R and R' is independently-H or C1-C6 alkyl.

the definition of ring A-D of formulas II-V, including the specific variables each independently as described above for the 1 st set of variables of structural formulas (IA) and (I), wherein each of rings A-D is an independent and optionally substituted 4-7 membered ring.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st set of variables of formulae (IA) and (I).

The subset of variables 2 of structural formulae II, III, IV and V for the compounds of the present invention is as follows:

z1 is-H, -F, -Cl, -CF3, -CH3 or-CN.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st subset of variables of formulae II-V.

The 3 rd variable subset of structural formulae II, III, IV and V for the compounds of the present invention is as follows:

z1 is-H, -F or-CN.

the values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st subset of variables of formulae II-V.

The 4 th variable subset of structural formulae II, III, IV and V for the compounds of the present invention is as follows:

Z1 is-H, -F or-CN.

R3 is-H, -Cl or-F.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st subset of variables of formulae II-V.

the 5 th variable subset of structural formulae II, III, IV and V for the compounds of the present invention is as follows:

Z1 is-H, -F or-CN.

r3 is-H, -Cl, -F, -CF3, -NH2, -NH (CH3), -N (CH3) 2.

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Each R9 is independently-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st subset of variables of formulae II-V.

The 6 th variable subset of structural formulae II, III, IV and V for the compounds of the present invention is as follows:

Z1 is-H, -F or-CN.

R3 is-H, -Cl or-F.

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Each R9 is independently-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

The values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st subset of variables of formulae II-V.

In the 7 th variable subset of structural formulae II-V of the compounds of the present invention, the values (including specific values) and provisos for the variables of structural formulae II-V other than R6, R7, R8, R9, R11, R12, R13, and R14 are each independently as described above for the 1 st, 2 nd, 3 rd, or 4 th subset of variables of structural formulae (IA) and (I).

R6 and R7 are each independently-H or-C1-C4 alkyl, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

each R9 is independently-H or-C1-C4 alkyl.

r11 and R12 are each independently-H or-C1-C4 alkyl.

R13 and R14 are each independently-H or-C1-C4 alkyl, or together with the carbon atom to which they are attached form a cyclopropane ring.

In the 8 th variable subset of structural formulae II-V of the compounds of the present invention, the values (including specific values) and provisos for the variables of structural formulae II-V are each independently as described above for the 1 st variable subset of structural formulae (IA) and (I).

In the 9 th variable subset of structural formulae II-V of the compounds of the present invention, the values of the variables of structural formulae II-V (including specific values) are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th or 8 th variable subset of structural formulae (IA) and (I).

Provided that if Q2-R5 is-OR 5 OR-NR' R5, ring A is further substituted with one OR more JAs other than-H; and is

In the 10 th variable subset of structural formulae II-V of the compounds of the present invention, the values (including specific values) of the variables of structural formulae II-V are each independently as described above for the 9 th variable subset of structural formulae II-V; and when applicable:

When Q3 is-C (o) -the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1 wherein JC1 is independently selected from: optionally substituted C3-C8 nonaromatic carbocyclic ring, optionally substituted 6-to 10-membered carbocyclic aryl, optionally substituted 4-to 8-membered nonaromatic heterocyclic ring, optionally substituted 5-to 10-membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2N (R) Rb, -NRSO2Rb and-NRSO 2 NRcRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

In the 11 th variable subset of structural formulae II-V of the compounds of the present invention, the values (including specific values) of the variables of structural formulae II-V are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th or 8 th subset of variables of structural formulae II-V; and when applicable:

provided that, if Y1 is a bond, R5 is a substituted C1-C6 aliphatic, an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl; and is

In the 12 th variable subset of structural formulae II-V of the compounds of the present invention, the values (including specific values) of the variables of structural formulae II-V are each independently as described above for the 11 th variable subset of structural formulae II-V; and when applicable:

In the 13 th variable subset of structural formulae II-V of the compounds of the present invention, the values (including specific values) of the variables of structural formulae II-V are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th or 8 th subset of variables of structural formulae II-V; and when applicable:

Provided that if Q2-R5 is-OR 5 OR-NR' R5, ring a is further substituted with one OR more JA other than-H;

in the 14 th variable subset of structural formulae II-V of the compounds of the present invention, the values (including specific values) of the variables of structural formulae II-V are each independently as described above for the 13 th variable subset of structural formulae II-V; and when applicable:

When Q3 is-C (o) -, or Y1 is a bond, the C1-C6 aliphatic group represented by R5 is substituted with one or more JC1, wherein JC1 is independently selected from: optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring, optionally substituted 5-10 membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2N (R) Rb, -NRSO2Rb and-NRSO 2 NRcRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

A subset of the 15 th variables of structural formulae II-V are as follows:

Q3 is independently a bond, -C (O) -, -CO2-, -C (O) NR-, -SO2-, -SO2N (R) -, -C (O) NRC (O) -or- (CR6R7) p-Y1-.

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) ORb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and-NRSO 2NRcRb, or optionally, two JC1 and two JD1, respectively, together with the atoms to which they are attached, independently form a 5-7 membered ring optionally substituted with and fused to the respective ring to which they are attached, or one or more JE 1.

Ring a is a C3-C8 non-aromatic carbocyclic ring optionally and independently further substituted with one or more JA.

the values (including specific values) and provisos for the remaining variables of formulae II-V are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, 10 th, 11 th, 12 th, 13 th or 14 th subset of variables of formulae II-V.

in another embodiment, the present invention relates generally to compounds represented by structural formula XI (A) or XI (B), or a pharmaceutically acceptable salt thereof.

A subset of variables 1 of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

each Q2 is independently-O-, -S-, -NR ' -, -C (O) -, -CO2-, -OC (O) -, -C (O) NR ' -, -C (O) NRC (O) O-, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -SO2-, -N (R) SO2-, -SO2NR ' -or- (CR6R7) p-Y1-.

Ring a is a 5-7 membered non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl), (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring a is a 5-7 membered non-aromatic carbocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring a is a 5-7 membered carbocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R8 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Each R9 is independently-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

each R and R' is independently-H or C1-C6 alkyl.

Provided that if Q2-R5 is-OR 5 OR-NR' R5, ring a is further substituted with one OR more JA other than-H.

The values (including specific values) and provisos for the remaining variables of structures XI (A) and XI (B) are each independently as described above for the 1 st subset of variables of structures (IA) and (I).

A subset of variables 2 of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

The values (including particular values) and provisos for rings A, Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, and R14 are each independently as described above for the 1 st subset of variables of structural formulae xi (a) and xi (b).

The variable x is 0 or 1 and the variable n is 0 or 1.

The values (including specific values) and provisos for the remaining variables of formulas XI (A) or XI (B) are each independently as described above for the 1 st subset of variables of formulas XI (A) and XI (B).

A subset of variables 3 of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

The values (including specific values) and provisos for ring A, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the subset 2 variables of structural formulae xi (a) and xi (b).

Q2 is-O-, -NR '-, -CO-, -CO2-, -C (O) NR' -, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OCONR '-, -NRSO2-, -SO2NR' -or- (CR6R7) p-Y1-. Specifically, Q2 is-O-, -NH-, -N (CH3) -, -C (O) -, -CO2-, -C (O) NH-, -C (O) N (CH3) -, -NHC (O) -, -N (CH3) C (O) -, -NHC (O) NR ' -, -N (CH3) C (O) NR ' -, -NHCO2-, -N (CH3) CO2-, -OC (O) NR ' -, -NHSO2-, -N (CH3) SO2-, -SO2NH-, -SO2N (CH3) -or- (CR6R7) p-Y1-.

a subset of variables 4 of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

the values (including specific values) and provisos for rings A, Q2, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the 3 rd subset of variables of structural formulae xi (a) and xi (b).

R5 is independently: i) -H; ii) a C1-C6 aliphatic (e.g., C1-C6-alkyl or C2-C6 alkenyl) optionally substituted with one or more JC 1; iii) a C3-C8 non-aromatic carbocyclic ring optionally substituted by one or more JC 1; iv) phenyl optionally substituted by one or more JC 1; v) a 4-8 membered non-aromatic heterocycle optionally substituted by one or more JD 1; or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more JD 1.

JC1 and JD1 are each independently selected from the following: halogen, cyano, oxo, Ra, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NHRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NHC (O) Rb, -C (O) NHRc, -NHC (O) NHRc, -NHC (O) ORb, -OCONHRc, -NHC (O) ORb, -N (CH3) Rc, -N (CH3) C (O) Rb, -C (O) N (CH3) Rc, -N (CH3) C (O) NHRc, -N (CH3) C (O) ORb, -OCON (CH3) Rc, -C (O) NHCO2Rb, -C (O) N (CH3) CO2Rb, -N (CH3) C (O) NHCO) ORb, -NHSO 2(2 Rb, -SO2NHRb, -SO2N (CH3) Rb and-N (CH3) SO2 Rb.

A subset of the 5 th variables of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

The values (including specific values) and provisos for Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the 4 th subset of variables of structural formulae xi (a) and xi (b).

Ring a is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Provided that if Q2-R5 is-OR 5 OR-NR' R5, ring a is further substituted with one OR more JA other than-H.

A subset of the 6 th variables of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

The values (including specific values) and provisos for Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the 5 th subset of variables of structural formulae xi (a) and xi (b).

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions:

Wherein each of rings a1-a27 is independently and optionally further substituted with one or more substituents. In particular, rings a5, a6, a21, a24, and a26 are each independently further substituted with one or more substituents other than-H. Suitable substituents are as described for ring A in the 1 st subset of variables of formulae XI (A) and XI (B).

A subset of the 7 th variables of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

the values (including specific values) and provisos for the group- [ CR13R14] x-Ring A-Q2-R5, Ring A, Q2, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the 6 th subset of variables of formulas XI (A) and XI (B).

A subset of the 8 th variables of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

The values (including specific values) and provisos for Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the 7 th subset of variables of structural formulae xi (a) and xi (b).

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions: wherein each of ring a6, A8, a11, a14, and a15 is optionally and independently further substituted. Suitable substituents are as described for ring A in the 1 st subset of variables of formulae XI (A) and XI (B) above.

Each R8 is independently halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

the values (including specific values) and provisos for the remaining variables of structures XI (A) and XI (B) are each independently as described above for the 1 st subset of variables of structures (IA) and (I).

A subset of the 9 th variables of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

the values (including specific values) for the groups- [ CR13R14] x-ring a-Q2-R5, ring A, Q2, R, R', R6, R7, R8, R9, R11, R12, R13, R14, x, and n, and the provisos are each independently as described above for the 8 th subset of variables of structural formulae xi (a) and xi (b).

Each R5 is independently: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring, or iv) an optionally substituted 4-7 membered non-aromatic heterocyclic ring; wherein said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, an optionally substituted C3-C7 nonaromatic carbocyclic ring and an optionally substituted 4-7 membered nonaromatic heterocyclic ring. Each of the carbocyclic and heterocyclic rings represented by R5 and mentioned for substituents of C1-C6 alkyl represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -CO (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

a10 th subset of variables of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions:

Wherein each of ring A1-A4, A7-A20, A22, A23, A25, and A27 is independently and optionally further substituted. Suitable substituents are described in 1 st variable quantum focusing ring A of formulae XI (A) and XI (B).

a11 th subset of variables of structural formulae XI (A) and XI (B) for the compounds of the present invention are as follows:

the values (including specific values) and provisos for Q2, R, R', R5, R6, R7, R8, R9, R11, R12, R13, R14, x, and n are each independently as described above for the 7 th subset of variables of structural formulae xi (a) and xi (b).

The group- [ (C)0-1R13R14] -Ring A-Q2-R5 is independently selected from one of the following depictions:

Wherein each of ring a5-a7, a21, a24, and a26 is independently and optionally further substituted. Suitable substituents are as described for ring A in the 1 st subset of variables of formulae XI (A) and XI (B).

Each R8 is independently halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

In the 12 th variable subsets of structural formulae xi (a) and xi (b) of the compounds of the invention, the values (including specific values) and provisos for the variables of structural formulae xi (a) and xi (b) are each independently as described above for the 1 st variable subset of structural formulae (IA) and (I).

In the 13 th variable subsets of the structural formulae xi (a) and xi (b) of the compounds of the invention, the values (including particular values) and provisos for the variables of structural formulae xi (a) and xi (b) are each independently as described above in the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th, 10 th or 11 th subset of variables of structural formulae xi (a) and xi (b); and when applicable:

Provided that, if Q2 is a bond, R5 is an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl group, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl group.

In the 14 th variable subsets of the structural formulae xi (a) and xi (b) of the compounds of the invention, the values (including specific values) and provisos of the variables of structural formulae xi (a) and xi (b) are each independently as described above in the 13 th variable subset of structural formulae xi (a) and xi (b); and when applicable:

In the 15 th variable subsets of structural formulae xi (a) and xi (b) for the compounds of the invention, the values (including specific values) of the variables of structural formulae xi (a) and xi (b) are each independently as described above for the 13 th variable subset of structural formulae (IA) and (I), the 11 th variable subset of structural formula (VI), or the 15 th variable subset of structural formulae (II) - (V).

In another embodiment, the present invention is generally directed to a compound of structural formula XII (A) or XII (B), or a pharmaceutically acceptable salt thereof.

The 1 st variable subset of structural formulae XII (A) and XII (B) of the compounds of the invention is as follows:

Each Q3 is independently-C (O) -, -CO2-, -C (O) NR '-, -SO2-, -SO2 NR' -, -C (O) NRC (O) O-or- (CR6R7) p-Y1-.

Ring B is a 4-7 membered non-aromatic heterocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl), (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring B is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring B is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

r9 is-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

Each R and R' is independently-H or C1-C6 alkyl.

provided that, if Q3 is-C (o) -, R5 is a substituted C1-C6 aliphatic, an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl. In particular, the C1-C6 aliphatic group is substituted with one or more JC1, wherein JC1 is independently selected from: optionally substituted C3-C8 non-aromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered non-aromatic heterocyclic ring, optionally substituted 5-10 membered heteroaryl, -ORb, -SRb, -S (O) Ra, -SO2Ra, -NRbRc, -C (O) Rb, -C (O) ORb, -OC (O) Rb, -NRC (O) Rb, -C (O) NRbRc, -NRC (O) ORb, -OCONRbRc, -C (O) NRCO2Rb, -NRC (O) NRCO2Rb, -C (O) NR (ORb), -SO2NRcRb, -NRSO2Rb and NRSO2 cNRRb; or optionally two JC1 and two JD1 each independently form, together with the atoms to which they are attached, a 5-7 membered ring optionally substituted with one or more JE1 and fused to each ring to which it is attached.

Structural formulae xii (a) and xii (b) the values of the remaining variables (including specific values) and accompanying conditions are each independently as described above for the 1 st subset of variables of structural formulae (IA) and (I).

The sub-set of variables 2 of structural formulae XII (A) and XII (B) of the compounds of the invention are as follows:

The values (including specific values) and provisos for rings B, Q3, R, R', R6, R7, R9, R11, R12, R13, and R14 are each independently as described above for the 1 st subset of variables of structural formulae xii (a) and xii (b).

The variable y is 0 or 1.

The 3 rd variable subset of structural formulae XII (A) and XII (B) of the compounds of the invention is as follows:

The values (including specific values) and provisos for ring B, R, R', R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 2 nd subset of variables of formulas xii (a) and xii (b).

Q3 is independently-C (O) -, -CO2-, -C (O) NH-, -C (O) N (CH3) -, -C (O) NHC (O) O-, -C (O) N (CH3) C (O) O-, -SO2-, -SO2NH-, -SO2N (CH3) -or- (CR6R7) p-Y1-.

The 4 th variable subset of structural formulae XII (A) and XII (B) for the compounds of the invention is as follows:

The values (including specific values) and provisos for rings B, Q3, R, R', R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 3 rd variable subset of structural formulae xii (a) and xii (b).

R5 is independently: i) -H; ii) a C1-C6 aliphatic (e.g., C1-C6-alkyl or C2-C6-alkenyl) optionally substituted with one or more JC 1; iii) a C3-C8 non-aromatic carbocyclic ring optionally substituted by one or more JC 1; iv) phenyl optionally substituted by one or more JC 1; v) a 4-8 membered non-aromatic heterocycle optionally substituted by one or more JD 1; or vi) a 5-6 membered heteroaryl ring optionally substituted with one or more JD 1.

The 5 th variable subset of structural formulae XII (A) and XII (B) for the compounds of the invention is as follows:

The values (including specific values) and provisos for Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 4 th variable subset of structural formulae xii (a) and xii (b).

Ring B is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

structural formulae xii (a) and xii (b) the values of the remaining variables (including specific values) and accompanying conditions are each independently as described above for the 1 st subset of variables of structural formulae (IA) and (I).

The 6 th variable subset of structural formulae XII (A) and XII (B) for the compounds of the invention is as follows:

the values (including specific values) and provisos for Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 5 th subset of variables of structural formulae xii (a) and xii (b).

Ring B is independently selected from one of the structures depicted below:

each of rings B1, B2, and B4-B9 is optionally and independently substituted. Suitable substituents are independently as described for ring B in the 1 st subset of variables of structural formulae (IA) and (I) above.

The 7 th variable subset of structural formulae XII (A) and XII (B) for the compounds of the invention is as follows:

The values (including specific values) and provisos for rings B, Q3, R, R', R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 6 th subset of variables of structural formulae xii (a) and xii (b).

The 8 th variable subset of structural formulae XII (A) and XII (B) for the compounds of the invention is as follows:

the values (including specific values) and provisos for Q3, R, R', R5, R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 7 th subset of variables of structural formulae xii (a) and xii (b).

Group- [ C (R13R14) ] x-Ring B-Q2-R5:

The 9 th variable subset of structural formulae XII (A) and XII (B) for the compounds of the invention is as follows:

The values (including specific values) and provisos for rings B, Q3, R, R', R6, R7, R9, R11, R12, R13, R14, and y are each independently as described above for the 8 th subset of variables of structural formulae xii (a) and xii (b).

Each R5 is independently: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring, or iv) an optionally substituted 4-7 membered non-aromatic heterocyclic ring, wherein the alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, an optionally substituted C3-C7 nonaromatic carbocyclic ring and an optionally substituted 4-7 membered nonaromatic heterocyclic ring. Each of the carbocyclic and heterocyclic rings represented by R5 and mentioned for substituents of C1-C6 alkyl represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -CO (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

in the 10 th variable subset of structural formulae xii (a) and xii (b) for the compounds of the invention, the values (including specific values) and provisos for the variables of structural formulae xii (a) and xii (b) are each independently as described above for the 1 st variable subset of structural formulae (IA) and (I).

In the 11 th variable subset of structural formulae xii (a) and xii (b) of the compounds of the invention, the values (including specific values) and provisos for the variables of structural formulae xii (a) and xii (b) are each independently as described above for the 1 st, 2 nd, 3 rd, 4 th, 5 th, 6 th, 7 th, 8 th, 9 th,10 th or 11 th variable subset of structural formulae xii (a) and xii (b); and when applicable:

Provided that, if Q3 is a bond, R5 is an optionally substituted C3-C8 non-aromatic carbocyclic ring, an optionally substituted 6-10 membered carbocyclic aryl group, an optionally substituted 4-8 membered non-aromatic heterocyclic ring, or an optionally substituted 5-10 membered heteroaryl group.

In the 12 th variable subset of structural formulae xii (a) and xii (b) of the compounds of the invention, the values (including specific values) and provisos of the variables of structural formulae xii (a) and xii (b) are each independently as described above for the 11 th variable subset of structural formulae xii (a) and xii (b); and when applicable:

In the 13 th variable subset of structural formulae xii (a) and xii (b) of the compounds of the invention, the values (including specific values) of the variables of structural formulae xii (a) and xii (b) are each independently as described above for the 13 th variable subset of structural formulae (IA) and (I), the 11 th variable subset of structural formula VI, or the 15 th variable subset of structural formulae II-V.

In another embodiment, the present invention relates generally to compounds of structural formula XIII:

A subset of variables 1 of structural formula XIII for compounds of the invention are as follows:

Ring C is a 5-7 membered non-aromatic heterocyclic ring optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and-C1-C4 alkoxy. In particular, ring C is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring C is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

r9 is-H or-CH 3.

R11 and R12 are each independently-H or-CH 3.

Each R and R' is independently-H or C1-C6 alkyl.

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st subset of variables of formulae (IA) and (I).

A subset of variables 2 of structural formula XIII for compounds of the invention are as follows:

The values (including specific values) for ring C, R, R', R6, R7, R9, R11, and R12 are each independently as described above for the 1 st subset of variables of formula XIII.

r10 is-H or C1-C6-alkyl.

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st subset of variables of formulae (IA) and (I).

A subset of variables 3 of structural formula XIII for compounds of the invention are as follows:

The values (including specific values) of R, R', R6, R7, R9, R10, R11, and R12 are each independently as described above for the subset 2 variables of formula XIII.

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st subset of variables of formulae (IA) and (I).

A subset of variables 4 of structural formula XIII for compounds of the invention are as follows:

The values (including specific values) of R, R', R6, R7, R9, R10, R11, and R12 are each independently as described above for the 3 rd subset of variables of formula XIII.

Ring C is independently selected from:

Wherein each of rings C1-C5 is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO 2H-and-CO 2(C1-C4 alkyl), wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

In particular, each of rings C1-C5 is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

The values (including specific values) and provisos for the remaining variables of formula XIII are each independently as described above for the 1 st subset of variables of formulae (IA) and (I).

In the 5 th variable subset of formula XIII, the values of the variables of formula XIII, including the particular values, are each independently as described above for the 1 st subset of variables of formulae (IA) and (I).

In another embodiment, the present invention relates generally to compounds represented by structural formula XIV below or a pharmaceutically acceptable salt thereof:

the 1 st subset of variables of structural formula XIV for the compounds of the present invention are as follows:

Ring D is a 4-7 membered non-aromatic heterocyclic ring optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C6 alkyl, C2-C6 alkenyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6-alkyl), -OC O (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl) and-CO 2 Rb; wherein each of said alkyl and alkenyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring D is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, ring D is optionally further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

R6 and R7 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

R13 and R14 are each independently-H or-CH 3, or together with the carbon atom to which they are attached form a cyclopropane ring.

each of R and R' is independently-H or C1-C6 alkyl.

The values (including specific values) and provisos for the remaining variables of structure (XIV) are each independently as described above for the 1 st subset of variables of structures (IA) and (I).

A subset of variables 2 of structural formula XIV for compounds of the present invention are as follows:

The values (including specific values) for ring D, R, R', R6, R7, R13, and R14 are each independently as described above for the variable subset 1 of structural formula XIV.

The variable z is 1.

all other variables, including specific values and provisos, of structural formula XIV are each independently as described above for the 1 st subset of variables of structural formulae (IA) and (I).

A subset of variables 3 of structural formula XIV for the compounds of the present invention are as follows:

The values of z, R', R6, R7, R13, and R14 (including specific values) are each independently as described above for the subset of variables 2 of structural formula XIV.

Ring D is independently selected from:

Wherein each of rings D1-D7 is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -CO2H, and-CO 2(C1-C4 alkyl), wherein each of said alkyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

In particular, each of rings D1-D7 is optionally and independently further substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C2 alkyl), -NH (C1-C2 alkyl) 2, C1-C2 alkyl, C1-C2 haloalkyl, C1-C2 hydroxyalkyl, C2-C4 alkoxyalkyl, C1-C2 alkoxy, C1-C2 hydroxyalkoxy, C1-C2 haloalkoxy, C2-C4 alkoxyalkoxy, -CO2H and-CO 2(C1-C4 alkyl).

each Rd is independently-H, C1-C6 alkyl or-C (o) (C1-C6 alkyl), wherein each said alkyl moiety is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, each Rd is independently-H or C1-C6 alkyl optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

in the 4 th variable subset of structural formula XIV of the compounds of the present invention, the values (including specific values) and provisos for the variables of structural formula XIV are each independently as described above for the 1 st variable subset of structural formulae (IA) and (I).

In yet another embodiment, the compounds are represented by structural formula (I) or a pharmaceutically acceptable salt thereof, wherein each variable in the formula is independently as described above, and wherein:

R4 is:

Ring E is a C4-C8 non-aromatic carbocyclic ring optionally further substituted by one or more JA.

Ring F is a 4-8 membered non-aromatic heterocyclic ring optionally substituted with one or more JE 1.

each of rings G1 and G2 is independently a 5-10 membered non-aromatic bridged carbocyclic ring optionally substituted with one or more JA.

r5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; or iv) an optionally substituted 4-7 membered non-aromatic heterocyclic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring. The alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, an optionally substituted C3-C7 non-aromatic carbocyclic ring and an optionally substituted 4-7 membered non-aromatic heterocyclic ring; wherein each of said carbocyclic and heterocyclic rings represented by R5 and mentioned for substituents of C1-C6 alkyl represented by R5 is independently and optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

p and q are each independently 0, 1 or 2.

x is 0, 1 or 2.

r is 1 or 2.

The values (including specific values) and provisos for the remaining variables of structural formula I are each independently as described above for any one of the 1 st to 15 th variable sets of structural formula I.

In yet another embodiment, the compounds represented by structural formula (I) or a pharmaceutically acceptable salt thereof are independently as described in the preceding paragraph; and ring F is selected from any one of rings F1-F6:

Each of rings F1-F6 is optionally and independently substituted; and is

In yet another embodiment, the compound represented by structural formula (XIA) or (XIB) or a pharmaceutically acceptable salt thereof is as described above; and is

The group- [ C (R13R14) ] x-ring a-Q2-R5 is independently:

Wherein:

Each of ring a14 and a28 is optionally and independently further substituted; and is

The values (including specific values) and provisos of the remaining variables of formulae (XIA) and (XIB) are each independently as described above for any of the 1 st to 11 th variable sets of formulae (XIA) and (XIB).

In yet another embodiment, the compounds represented by structural formula (XIA) or (XIB) or a pharmaceutically acceptable salt thereof are independently as described in the previous paragraph; and R5 is optionally substituted C1-C6 alkyl, optionally substituted C3-C7 nonaromatic carbocyclic ring, or optionally substituted 4-7 membered nonaromatic heterocyclic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring. In particular, R5 is an optionally substituted 4-7 membered non-aromatic heterocyclic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring.

In another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

R4 is:

Ring E is a C4-C10 non-aromatic carbocyclic ring optionally further substituted by one or more JA.

Ring F is a 4-8 membered non-aromatic heterocyclic ring optionally substituted with one or more JE 1. Specific examples of the ring F include:

Exemplary substituents for ring F (including rings F1-F7) include halogen, cyano, hydroxy, C1-C4 alkoxy, and C1-C4 alkyl optionally substituted with one or more substituents selected from halogen, cyano, hydroxy, and-O (C1-C4 alkyl).

Optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups.

s is 0, 1 or 2.

x is 0, 1 or 2.

The remaining variables are each independently as described in any one of the variable sets of structural formulae (IA) and (I).

In another embodiment, the compounds are represented by structural formula (I) or (IA) or a pharmaceutically acceptable salt thereof, wherein:

Ring E is a C4-C8 non-aromatic carbocyclic ring optionally further substituted by one or more JA.

R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

The other variables are each independently as described in the preceding paragraph.

In another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

r4 is:

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more JA.

ring G5 is a 5-10 membered non-aromatic bridged ring optionally further substituted with one or more JBs.

X is-O-, -S-or-NRg-.

R8 and R9 are each independently-H, halogen, cyano, hydroxyl, amino, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 cyanoalkyl, C2-C6 alkoxyalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 carboxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy or C2-C6 alkoxyalkoxy.

Optionally, R13 and R14 together with the carbon atom to which they are attached form a cyclopropane ring optionally substituted with one or more methyl groups.

R21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, oxo, hydroxy, oxo, amino, carboxy, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 aminoalkoxy, C1-C6 cyanoalkoxy, C1-C6 hydroxyalkoxy and C2-C6 alkoxyalkoxy. In particular, R21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C36 6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl).

q is 0, 1 or 2; x is 0, 1 or 2; and r is 1 or 2.

the remaining variables are each independently as described in any of the sets of variables for structural formulae (IA) and (I)

In another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

R4 is:

Wherein rings G1 and G2 are each independently a 5-10 membered non-aromatic bridged ring optionally further substituted by one or more JA.

Each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

Q2 is independently a bond, -O-, -S-, -NR-, -C (O) -, -C (═ NR) -, -CO2-, -oc (O) -, -C (O) NR-, -C (O) nrc (O) O-, -nrc (O) NR-, -NRCO2-, -oc (O) NR-, -S (O) -, -SO2-, -n (R) SO2-, -SO2NR '-, -NRSO2 NR' -or- (CR6R7) p-Y1-. Alternatively, Q2 is independently-O-, -CO2-, -OC (O) -, -C (O) NR-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -CO2SO2-, -P (O) 2O-or- (CR6R7) p-Y1-. Alternatively, Q2 is independently-O-or-CO 2-.

In some embodiments, rings E and G (including G1-G5) are optionally and independently further substituted with one or more JA (for carbocyclic rings) or JB (for heterocyclic rings), wherein each of JA and JB is independently selected from halogen, cyano, oxo, -NCO, and Q1-R5, and wherein:

Q1 is independently a bond, -O-, -S-, -NR-, -C (O) -, -C (═ NR) -, -CO2-, -oc (O) -, -C (O) NR-, -C (O) nrc (O) O-, -nrc (O) NR-, -NRCO2-, -oc (O) NR-, -S (O) -, -SO2-, -n (R) SO2-, -SO2NR '-, -NRSO2 NR' -or- (CR6R7) p-Y1-; and Y1 is independently a bond, -O-, -S-, -NR '-, -C (O) -, -C (═ NR) -, -CO2-, -OC (O) -, -C (O) NR' -, -C (O) NRC (O) O-, -NRC (O) NR '-, -NRCO2-, -OC (O) NR' -, -S (O) -, -SO2-, -SO2NR '-, -NRSO 2-or-NRSO 2 NR' -.

or: q1 is independently a bond, -O-, -S-, -NR-, -C (O) -, -CO2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2NR '-, -NRSO2 NR' -or- (CR6R7) p-Y1-; and Y1 is independently-O-, -CO2-, -OC (O) -, -C (O) NR-, -NRC (O) NR-, -NRCO 2-or-OC (O) NR-.

In yet another embodiment, Q1 and Y1 are each independently as described in the preceding paragraph and:

In some particular embodiments, the compounds are represented by structural formula (IA) or (I), wherein:

r1 is-H.

R2 is-H, -CH3, -CH2OH or-NH 2. In particular, R2 is-H or-CH 2 OH.

r3 is-H, -F, -Cl, C1-4 alkyl or C1-4 haloalkyl. Alternatively, R3 is-H, -F or-Cl.

Z1 is-H, -F or-Cl.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

Z3 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

R5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; iv) an optionally substituted 4-7 membered non-aromatic heterocycle; v) optionally substituted phenyl; vi) an optionally substituted 5-6 membered heteroaromatic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring; and is

Said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, -NRCO (C1-C4 alkyl), -CONR (C1-C4 alkyl), -NRCO2(C1-C4 alkyl), C3-C7 non-aromatic carbon ring optionally substituted by one or more JE1, 4-7 membered non-aromatic heterocyclic ring optionally substituted by one or more JE1, and phenyl optionally substituted by one or more JE 1; and is

Wherein each of said carbocycle, heterocycle, phenyl and heteroaryl represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

the remaining variables, including R4, comprising the spiro ring represented by rings E and F or the bridged ring represented by rings G1-G5 are each independently as described in any of the 4 embodiments above.

In yet another embodiment, the compounds are represented by structural formula (IA) or (I), wherein the values of the variables are each independently as described in the previous embodiment, except:

Z2 is-H;

z3 is-H;

in yet another embodiment, each of rings E, G1-G5 is independently and optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C35 6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), and-CO 2 Rb; wherein each said alkyl group is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In particular, each of rings E, G1-G5 is independently and optionally substituted with one or more substituents selected from: halogen, cyano, hydroxy, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy and C1-C4 alkyl optionally substituted by one or more substituents selected from halogen, cyano, hydroxy and-O (C1-C4 alkyl).

In another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

r4 is:

Ring a is a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R8 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R9 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, or ring a and R11 optionally form a non-aromatic 5-10 membered bridged carbocyclic or heterocyclic ring, wherein each said carbocyclic ring is independently and optionally substituted by one or more JA and wherein each carbocyclic ring is independently and optionally substituted by one or more JB.

R1 is-H.

R2 is-H, -CH3, -CH2OH or-NH 2. In particular, R2 is-H or-CH 2 OH.

R3 is-H, -F, -Cl, C1-4 alkyl (e.g., -CH3 or-C2H 5), or C1-4 haloalkyl (e.g., -CF 3). Alternatively, R3 is-H, -F or-Cl.

Z1 is-H, -F or-Cl.

Z2 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

Z3 is-H or C1-C6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy and-O (C1-C4 alkyl).

Y1 is-O-, -CO2-, -OC (O) -, -C (O) NR ' -, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR ' -, -NRCO2-, -OC (O) NR ' -, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O) 2O-or-CO 2SO 2-.

R5 is: i) -H; ii) optionally substituted C1-C6 alkyl; iii) an optionally substituted C3-C7 non-aromatic carbocyclic ring; iv) an optionally substituted 4-7 membered non-aromatic heterocycle; v) optionally substituted phenyl; vi) an optionally substituted 5-6 membered heteroaromatic ring; or optionally, together with R and the nitrogen atom to which it is attached, form a 5-7 membered optionally substituted non-aromatic heterocyclic ring; and is

Said alkyl group represented by R5 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), C1-C4 alkoxy, -NRCO (C1-C4 alkyl), -CONR (C1-C4 alkyl), -NRCO2(C1-C4 alkyl), C3-C7 non-aromatic carbon ring optionally substituted by one or more JE1, 4-7 membered non-aromatic heterocyclic ring optionally substituted by one or more JE1, and phenyl optionally substituted by one or more JE 1;

Wherein each of said carbocycle, heterocycle, phenyl and heteroaryl represented by R5 is independently and optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, C1-C4 alkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -C (O) (C1-C4 alkyl), -OC (O) (C1-C4 alkyl), -C (O) O (C1-C4 alkyl), and-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

Each of R8 and R9 is independently-H, halogen, cyano, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, -O (C1-C4 alkyl), -NH2, -NH (C1-C4 alkyl), or-N (C1-C4 alkyl) 2.

R11, R12, R13 and R14 are each independently-H, halogen or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy and C1-C6 alkoxy.

n is 0 or 1.

x is 0 or 1.

The remaining variables are each independently as described above for any one of the sets of variables for structural formulae (IA) and (I).

In another embodiment, the compound is represented by structural formula (IA) or (I) or a pharmaceutically acceptable salt thereof, wherein:

R4 is:

Each of rings G1-G4 is independently a 5-10 membered non-aromatic bridged carbocyclic ring optionally further substituted by one or more JA, and ring G5 is a 5-10 membered non-aromatic bridged heterocyclic ring optionally further substituted by one or more JB.

X is-O-, -S-or-NRg-.

R21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, C1-C6 alkyl, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -C (O) (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl).

q is 0,1 or 2.

r is 1 or 2.

The remaining variables are each independently as described in the preceding paragraph.

R1 is-H.

R2 is-H.

R3 is-H, -F, -Cl, C1-4 alkyl or C1-4 haloalkyl. Alternatively, R3 is-H, -F or-Cl.

Z1 is-H, -F or-Cl.

Z2 is-H.

Z3 is-H.

x is-O-.

R5 is-H, optionally substituted C1-C6 alkyl, or optionally substituted phenyl.

each R8 is independently-H, halogen, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C2-C4 alkoxyalkyl, or-O (C1-C4 alkyl).

Each of R9, R13, and R14 is independently-H or C1-C4 alkyl.

r21, R22, R23, R24 and R25 are each independently-H, halogen, -OH, C1-C6 alkoxy or C1-C6 alkyl optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C6 alkyl and-O (C1-C6 alkyl). In particular, R21, R22, R23, R24 and R25 are each independently-H, C1-6 alkyl or C1-6 haloalkyl.

In yet another embodiment, the compounds are represented by any of formulae I-VI (hereinafter reference formulae I-VI, including formulae I, IA, II, III, IV, V, VI) and XI (A) (hereinafter reference formulae XI (A) -XIV, including formulae XIA, XIB, XIIA, XIIB, XIII and XIV), wherein the values of the variables are independently as described above for any embodiment of the compounds of the invention, except that R3 is C1-6 alkyl, e.g., methyl or ethyl.

in yet another embodiment, the compounds are represented by any of structural formulas I-VI and XI (A) -XIV, wherein the values of the variables are independently as described above for any embodiment of the compounds of the invention, except that x is 0.

In yet another embodiment, the compounds are represented by any of structural formulae I, IA, II, VI, XI (a), and XI (b), wherein the values of the variables are independently as described above for any embodiment of the compounds of the invention, except that ring a is bridged.

In yet another embodiment, the compounds are represented by any one of structural formulae I, IA, II, VI, XI (a), and XI (b), wherein the values of the variables are independently as described above for any embodiment of the compounds of the present invention, except that Q2 is independently the following: -C (═ NR) -, -C (═ NR) NR-, -NRC (═ NR) NR-, -CO2-, -oc (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2NR-, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1-; alternatively, Q2 is independently-CO 2-, -OC (O) -, -C (O) NR-, -C (O) NRC (O) O-, -NRC (O) -, -NRC (O) NR-, -NRCO2-, -OC (O) NR-, -S (O) -, -SO2-, -N (R) SO2-, -SO2N (R) -, -NRSO2NR-, -P (O) (OR) O-, -OP (O) (ORa) O-, -P (O)2O-, -CO2SO 2-or- (CR6R7) p-Y1-.

In yet another embodiment, the compounds are represented by any of structural formulae I-VI and XI (A) -XIV, wherein the values of the variables are independently as described above for any embodiment of the compounds of the invention, provided that when Q2 is-O-or-NR-, then ring A is further substituted with JA instead of-H; and with the proviso that if Q3 is-C (o) -, then R5 is substituted C1-C6 aliphatic, optionally substituted C3-C8 nonaromatic carbocyclic ring, optionally substituted 6-10 membered carbocyclic aryl, optionally substituted 4-8 membered nonaromatic heterocyclic ring, or optionally substituted 5-10 membered heteroaryl. In a particular embodiment, when Q2 is-O-or-NR-, then Ring A is further substituted in the twin of-Q2R 5 with JA instead of-H.

In yet another embodiment, the present invention relates to a compound selected from any one of the compounds depicted in figures 3-5, or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention relates to a compound selected from any one of the compounds depicted in figure 6, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the present invention relates to a compound selected from any one of the compounds depicted in figure 7, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the present invention relates to a compound selected from any one of the compounds depicted in figure 8, or a pharmaceutically acceptable salt thereof.

In some embodiments, the variables of structural formulae I-VI and xi (a) -XIV are each independently as described in the compounds of figures 3-8.

Each independently as described above for the methods of the invention, the aforementioned compounds of the invention are useful as inhibitors of replication of influenza virus in a biological sample or patient. These compounds may also be used to reduce the amount of influenza virus (virus titer) in a biological sample or patient. They may also be used for the therapeutic and prophylactic treatment of infections caused by influenza viruses in biological samples or patients.

The invention also provides methods of making the compounds of the invention. In one embodiment, the method is directed to the preparation of a compound represented by structural formula (IA) or a pharmaceutically acceptable salt thereof. The method comprises reacting compound a as shown in scheme a below: with compound B: a step of reacting to form a compound represented by structural formula (XX):

Scheme A

The variables for structural formulae (IA) and (XX) and compounds (a) and (B) are independently as defined in any of the embodiments above. Ts is tosyl. Any suitable reaction conditions known in the art for coupling a dioxaborolan and a chloropyrimidine can be used for the reaction between compounds (a) and (B), for example in WO 2005/095400 and WO 2007/084557. For example, the reaction between the compounds (a) and (B) may be carried out in the presence of Pd (PPh3) 4. Specific exemplary conditions are as described in the following examples (e.g., general schemes 5A, 6A, 7, 11, 14, 16, 31, 32, 33, 40, 44, 49, 51, 52, 58, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 76).

in another embodiment, the method comprises the step of reacting compound C1 or C2 with NH2R4 as shown in scheme B below to form a compound represented by structural formula (XX):

Scheme B

The variables for structural formulae (IA) and (XX), compounds (C1) and (C2), and R4 of NH2R4 are independently defined as in any of the embodiments above. Ts is tosyl. Any suitable reaction conditions for coupling the amine and the sulfinyl group are known in the art, for example, in WO 2005/095400 and WO 2007/084557, to be useful for the reaction of compounds (C1) and (C2) and NH2R 4. Specific exemplary conditions are as described in the following examples (e.g., general schemes 13, 15, 19, 20, 23, 30, 39, 41, 42, 44, 45, 50, 53, 54, 65, 72, 73, 74, and 77).

The methods described above according to schemes a and B optionally and independently further comprise deprotecting the Ts group of the compound of structural formula (XX) to form the compound of structural formula (IA). Any suitable conditions known in the art for deprotecting the Ts group may be employed in the present invention. Certain exemplary conditions are described in the following examples. Demethylated benzenesulfonylation can result in compounds of formula (IA) wherein R1 is-H. If desired, the R1 position may be alkylated by any suitable method known in the art to form a compound of formula (IA) wherein R1 is C1-6 alkyl.

Compounds (a), (B), (C1), (C2) and NH2R4 may be prepared by any suitable method known in the art. Certain exemplary synthetic methods are described in the following examples. For example, compound (C1) can be prepared as described in scheme C: for example, the reaction between compounds (D) and (E) in the presence of Pd (PPh3)4 can produce compound (F). Compound (F) can then be oxidized under suitable conditions, for example, by treatment with m-chloroperoxybenzoic acid to form compound (C). (see, e.g., the detailed experimental details set forth in the example of general protocol 44)

scheme C

definitions and general terms

for the purposes of the present invention, chemical elements are identified according to the periodic Table of the elements of the CAS version of the handbook of Physics, 75 th edition. In addition, in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausolinto: 1999 and "March's Advanced Organic Chemistry", 5 th edition, ed: a general rule of organic chemistry is described in Smith, M.B. and March, J., John Wiley & Sons, New York:2001, the entire contents of which are hereby incorporated by reference.

As described herein, the compounds of the invention may be optionally substituted with one or more substituents, for example as generally set forth below or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" may be used interchangeably with the phrase "substituted or unsubstituted. In general, the term "substituted," with or without the term "optional" preceding it, refers to the replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent. Unless otherwise noted, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure may be substituted with one or more substituents selected from a specified group, the substituents at each position may be the same or different. When the term "optionally substituted" precedes a listed item, the term refers to the group that all substituents in the listed item can replace. A substituent radical or structure is unsubstituted if it is not identified or defined as "optionally substituted". For example, if X is optionally substituted C1-C3 alkyl or phenyl; x may be an optionally substituted C1-C3 alkyl group or an optionally substituted phenyl group. Likewise, if the term "optionally substituted" follows an item in the list, unless otherwise noted, the term also refers to all substitutable groups in the preceding list. For example: if X is C1-C3 alkyl or phenyl, wherein X is optionally and independently substituted with JX, then both C1-C3 alkyl and phenyl may be optionally substituted with JX. It will be apparent to one of ordinary skill in the art that groups such as H, halogen, NO2, CN, NH2, OH or OCF3 are not substitutable groups.

The phrase "to" as used herein refers to 0 or any integer equal to or less than the number following the phrase. For example, "to 3" means any of 0, 1,2, and 3. As described herein, a specified range of numbers of atoms includes any integer therein. For example, a group having 1-4 atoms can have 1,2, 3, or 4 atoms.

The choice of substituents and combinations of substituents contemplated by the present invention are those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein relates to compounds that do not substantially change when subjected to conditions that allow their production, detection and, in particular, their recovery, purification and use for one or more of the uses disclosed herein. In some embodiments, a stabilizing compound or chemically feasible compound is one that does not substantially change when stored at 40 ℃ or less for at least 1 week in the absence of moisture or other chemical reaction conditions. Only those options and combinations of substituents that result in stable structures are contemplated. These options and combinations will be readily apparent to those of ordinary skill in the art and can be determined without undue experimentation.

The term "aliphatic" or "aliphatic group" as used herein refers to a straight (i.e., unbranched) or branched hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, but which is non-aromatic. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1 to 6 aliphatic carbon atoms, and in other embodiments, aliphatic groups contain 1 to 4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl or alkynyl groups. Collective examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and tert-butyl, and acetylene.

The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon. The term "alkenyl" as used herein refers to a straight or branched chain hydrocarbon containing one or more double bonds. The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon containing one or more triple bonds. Each of "alkyl", "alkenyl", or "alkynyl" as used herein is optionally substituted as described below. In some embodiments, "alkyl" is C1-C6 alkyl or C1-C4 alkyl. In some embodiments, "alkenyl" is C2-C6 alkenyl or C2-C4 alkenyl. In some embodiments, "alkynyl" is C2-C6 alkynyl or C2-C4 alkynyl.

The term "alicyclic" (or "carbocycle" or "carbocyclyl" or "carbocyclic") refers to a non-aromatic carbon that contains only ring systems having 3 to 14 ring carbon atoms that may be saturated or contain one or more units of unsaturation. In some embodiments, the number of carbon atoms is 3 to 10. In other embodiments, the number of carbon atoms is from 4 to 7. In other embodiments, the number of carbon atoms is 5 or 6. The term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged carbocyclic ring systems. The term also includes polycyclic ring systems in which the carbocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the carbocyclic ring. A "fused" bicyclic ring system includes two rings that share 2 contiguous ring atoms. The bridged bicyclic group includes two rings that share 3 or 4 adjacent ring atoms. Spiro ring systems share 1 ring atom. Examples of alicyclic groups include, but are not limited to, cycloalkyl and cycloalkenyl. Specific examples include, but are not limited to, cyclohexyl, cyclopropenyl, and cyclobutyl.

The term "heterocycle" (or "heterocyclyl" or "heterocyclic" or "non-aromatic heterocycle") as used herein relates to a non-aromatic ring system having 3 to 14 ring atoms that may be saturated or contain one or more units of unsaturation, wherein one or more ring carbons are replaced with a heteroatom such as N, S or O and each ring in the system contains 3 to 7 members. In some embodiments, the non-aromatic heterocycle contains up to 3 heteroatoms selected from N, S and O within the ring. In other embodiments, the non-aromatic heterocycle contains up to 2 heteroatoms selected from N, S and O within the ring system. In other embodiments, the non-aromatic heterocycle contains up to 2 heteroatoms selected from N and O within the ring system. The term includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. The term also includes polycyclic ring systems in which the heterocyclic ring may be fused to one or more non-aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combinations thereof, wherein the radical or point of attachment is on the heterocyclic ring. Examples of heterocycles include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazacycloheptanyl, azocyclooctyl, diazocyclooctyl, azidocyclooctyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolocyclooctanyl, oxazepanyl, thiazolocyclooctanyl, thiazolidinonyl, benzimidazolonyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, including, for example: 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-tetrahydropyriperazinyl, 2-tetrahydropyriperazinyl, 3-tetrahydropyrazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, and the like, Indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiophenyl, benzodithietanyl, 3- (1-alkyl) -benzimidazol-2-one, and 1, 3-dihydro-imidazol-2-one.

The term "aryl" (or "aromatic ring" or "aryl group") used alone or as a larger moiety in "aralkyl", "arylalkoxy", "aryloxyalkyl", or "heteroaryl" refers to an aromatic carbocyclic or heterocyclic ring system. The term "aryl" is used interchangeably with the terms "aromatic ring" or "aryl group".

An "aromatic carbocyclic" group has only carbon ring atoms (typically 6 to 14) and includes aromatic monocyclic rings, such as phenyl, and aromatic fused polycyclic ring systems in which two or more aromatic carbocyclic rings are fused to each other. Examples include 1-naphthyl, 2-naphthyl, 1-anthryl and 2-anthryl. Also included within the scope of the term "aromatic carbocyclic ring" or "aromatic carbocyclic" as used herein are groups in which an aromatic ring is "fused" to one or more non-aromatic rings (carbocyclic or heterocyclic), for example in indanyl, phthalimidyl, naphthalimide, phenanthridinyl or tetrahydronaphthyl groups, wherein the groups or points of attachment are on aromatic rings.

The terms "heteroaryl", "heteroaromatic ring", "heteroaryl group", "aromatic heterocycle" or "heteroaromatic group", used alone or as a larger moiety in "heteroaralkyl", "heteroarylalkoxy", refer to a heteroaromatic ring group having 5-14 members, including heteroaromatic monocycles and aromatic polycycles, wherein the aromatic monocycle is fused to one or more other aromatic rings. Heteroaryl groups have one or more heterocyclic atoms. The term "heteroaryl" as used herein also includes within its scope groups in which an aromatic ring is "fused" to one or more non-aromatic rings (carbocyclic or heterocyclic), wherein the radical or point of attachment is on an aromatic ring. For example, a bicyclic 6,5 heteroaromatic ring as used herein is a 6-membered heteroaromatic ring fused to a second 5-membered ring, wherein the radical or point of attachment is on the 6-membered ring. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, or thiadiazolyl, including for example: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5-triazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-oxazolyl, 3-pyrazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, Tetrazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl, benzisoxazolyl, isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, purinyl, pyrazinyl, 1,3, 5-triazinyl, quinazolinyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl) and isoquinolyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

As used herein, "ring," "cyclic group," or "cyclic moiety" includes mono-, bi-, and tricyclic ring systems, including every one of the previously defined alicyclic, heterocyclic aliphatic, carbocyclic aryl, or heteroaryl groups.

As used herein, a "bicyclic ring system" includes 8-12 (e.g., 9, 10, or 11) membered structures forming 2 rings, wherein there is at least one atom in common (e.g., 2 atoms in common). Bicyclic ring systems include bicycloaliphatic (e.g., bicycloalkyl or bicycloalkenyl), bicycloaliphatic, bicycloaromatic, and bicycloheteroaryl.

As used herein, "bridged bicyclic ring system" refers to a bis-heterocyclic aliphatic ring system or a bicyclic aliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, bicyclo [3.2.3] nonyl, 2-oxa-bicyclo [2.2.2] octyl, 1-aza-bicyclo [2.2.2] octyl, 3-aza-bicyclo [3.2.1] octyl and 2, 6-dioxa-tricyclo [3.3.1.03,7] nonyl. The bridged bicyclic ring system may be optionally substituted with one or more substituents, such as alkyl (including carboxyalkyl, hydroxyalkyl and haloalkyl (e.g., trifluoromethyl)), alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, carbocyclic aryl, heteroaryl, alkoxy, cycloalkoxy, heterocycloalkoxy, (carbocyclic aryl) oxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, aroyl, heteroaroyl, nitro, carboxyl, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl) carbonylamino, (carbocyclic aryl) carbonylamino, aralkylcarbonylamino, (heterocycloalkyl) carbonylamino, (heterocycloalkylalkyl) carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, heteroarylcarbonylamino, etc, Cyano, halo, hydroxy, acyl, mercapto, alkylsulfonyl, sulfoxy, urea, thiourea, sulfamoyl, sulfonamide, oxo, or carbamoyl.

The term "bridge" as used herein refers to a bond, atom, or unbranched chain of atoms connecting two different parts of a molecule. Two atoms (usually, but not always, two tertiary carbon atoms) connected by a bridge are denoted as "bridgeheads".

The term "spiro" as used herein refers to a ring system having one atom (typically a quaternary carbon atom) as the only common atom between two rings.

The term "ring atom" is an atom in an aromatic, cycloalkyl or non-aromatic heterocycle, such as C, N, O or S.

The "substitutable ring atom" in an aromatic group is a ring carbon or nitrogen atom bonded to a hydrogen atom. The hydrogen may optionally be replaced by a suitable substituent group. Thus, the term "substitutable ring atom" does not include a ring nitrogen or carbon atom that is common when two rings are fused. In addition, "substitutable ring atoms" do not include ring carbon or nitrogen atoms when the structures depict that they are already attached to a moiety other than hydrogen.

The term "heteroatom" refers to one or more of hydrogen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; quaternized forms of any basic nitrogen or heterocyclic substitutable nitrogen, such as N (as in 3, 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

Optionally substituted aralkyl groups as used herein may be substituted in the alkyl and aryl moieties. Unless otherwise noted, an optionally substituted aralkyl group as used herein is optionally substituted at the aryl moiety.

in some embodiments, aliphatic or heteroaliphatic or non-aromatic heterocycles may contain one or more substituents. Suitable substituents on the saturated carbon of the aliphatic or heteroaliphatic or non-aromatic heterocyclic ring are selected from those listed above, for example, in the definitions of JA, JB, JC1, JD1 and JE 1. Other suitable substituents include those listed as suitable for the unsaturated carbon of the carbocyclic aryl or heteroaryl group and additionally include the following: -O, ═ S, ═ NNHR, ═ NN (R) 2, ═ nnhc (O) R, ═ NNHCO2 (alkyl), ═ NNHSO2 (alkyl), or ═ NR, wherein each R is independently selected from hydrogen or optionally substituted C1-6 aliphatic. Optional substituents on the aliphatic group of R are selected from NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, halogen, C1-4 aliphatic, OH, O (C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O (haloC 1-4 aliphatic), or halo (C1-4 aliphatic), wherein each of the C1-4 aliphatic groups of the aforementioned R is unsubstituted.

In some embodiments, optional substituents on the nitrogen of the non-aromatic heterocycle include, for example, those used in the definition of JB, JD1 and JE 1. Other suitable substituents include-R +, -N (R +)2, -C (O) R +, -CO2R +, -C (O) R +, -C (O) CH2C (O) R +, -SO2R +, -SO2N (R +)2, -C (═ S) N (R +)2, -C (═ NH) -N (R +)2, or-NR + SO2R +; wherein R + is hydrogen, optionally substituted C1-6 aliphatic, optionally substituted phenyl, optionally substituted-O (Ph), optionally substituted-CH 2(Ph), optionally substituted- (CH2)1-2(Ph), optionally substituted-CH ═ CH (Ph), or unsubstituted 5-6 membered heteroaryl or a heterocyclic ring having 1-4 heteroatoms independently selected from oxygen, nitrogen or sulfur, or, on the same or different substituents, two separate occurrences of R + and the atoms to which each R + group is bonded together form a 5-8 membered heterocyclic, carbocyclic aromatic or heteroaromatic ring or a 3-8 membered cycloalkyl ring, wherein said heteroaryl or heterocyclic ring has 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. The aliphatic group of R + or the optional substituent on the phenyl ring is selected from NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, halogen, C1-4 aliphatic, OH, O (C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O (haloC 1-4 aliphatic), or halo (C1-4 aliphatic), wherein each of the aforementioned C1-4 aliphatic groups of R + is unsubstituted.

In some embodiments, carbocyclic aryl (including aralkyl, arylalkoxy, aryloxyalkyl, and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy, and the like) groups may contain one or more substituents. Suitable substituents on the unsaturated carbon atom of the carbocyclic aryl or heteroaryl group are selected from, for example, the substituents listed in the definitions of JA, JB, JC1, JD1 and JE 1. Other suitable substituents include: halogen, -R °, -OR °, -SR °,1, 2-methylenedioxy, 1, 2-ethylenedioxy, phenyl (Ph) optionally substituted by R °, O (Ph) optionally substituted by R °, CH2 (1-2 (Ph) optionally substituted by R °, CH (CH) (Ph) optionally substituted by R °, -NO2, -CN, -N (R °)2, -NR ° C (O) R °, -NR ° C (S) R °, -NR ° C (O) N (R °)2, -NR ° C (S) N (R °)2, -NR ° CO2R °, -NR ° NR ° C (O) R °, -NR ° NR ° C (O) N (R °)2, -NR ° CO2R °, (O) C (O), -C (O) CH2C (O) R °, -CO2R °, -C (O) R °, -C(s) R °, -C (O) N (R °)2, -C(s) N (R °)2, -oc (O) R °, -C (O) N (OR °) R °, -C (NOR °) R °, -s (O)2R °, -s (O)3R °, -SO2N (R °)2, -s (O) R °, -NR ° SO2N (R °)2, -NR ° SO2R °, -N (OR °) R °, -C (═ NH) -N (R °)2 OR- (CH2)0-2nhc (O) () R °; wherein each independently occurring R ° is selected from hydrogen, an optionally substituted C1-C6 aliphatic, unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O (Ph), or-CH 2(Ph), or, on the same or different substituents, two independently occurring R ° together with the atoms to which each R ° group is bonded form a 5-8 membered heterocyclyl, carbocyclic aryl or heteroaryl ring or a 3-8 membered cycloalkyl ring, wherein the heteroaryl or heterocyclyl ring has 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Optional substituents on the aliphatic group of R ° are selected from NH2, NH (C1-4 aliphatic), N (C1-4 aliphatic) 2, halogen, C1-4 aliphatic, OH, O (C1-4 aliphatic), NO2, CN, CO2H, CO2(C1-4 aliphatic), O (haloC 1-4 aliphatic) or halo (C1-4 aliphatic), CHO, N (CO) (C1-4 aliphatic), C (O) N (C1-4 aliphatic), wherein each of the aforementioned C1-4 aliphatic groups of R ° is unsubstituted.

Non-aromatic nitrogen-containing heterocycles that are substituted on the ring nitrogen and attached to the rest of the molecule at a ring carbon atom are referred to as N-substituted. For example, an N-alkylpiperidinyl group is attached to the remainder of the molecule at the 2,3 or 4 position of the piperidine ring and is substituted with an alkyl group at the ring nitrogen. A non-aromatic nitrogen-containing heterocycle substituted on the ring nitrogen and attached to the rest of the molecule at the second ring nitrogen atom, such as pyrazinyl, is referred to as an N' substituted-N-heterocycle. For example, the N' acyl N-pyrazinyl group is attached to the rest of the molecule at a ring nitrogen atom and is substituted with an acyl group at a second ring nitrogen atom.

The term "unsaturated" as used herein refers to a moiety having one or more units of unsaturation.

As detailed above, in some embodiments, two independently occurring R ° (or R +, or any other variable similarly defined herein) can be taken together with the atom to which each variable is attached to form a 5-8 membered heterocyclyl, carbocyclic aryl or heteroaryl ring, or a 3-8 membered cycloalkyl ring. Exemplary rings formed when two independently occurring R ° (or R +, or any other variable similarly defined herein) and the atoms to which each variable is attached are taken together include, but are not limited to, the following: a) two independently occurring R ° (or R +, or any other variable similarly defined herein) that connect the same atom and that are joined together to form a ring, such as N (R °)2, wherein the two occurrences of R ° and the nitrogen atom are joined together to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independently occurring R ° (OR R +, OR any other variable similarly defined herein) attached to different atoms and joined together with those two atoms to form a ring, for example, two occurrences of R ° where a phenyl group is substituted with two occurrences of OR °, and the oxygen atom attached thereto are joined together to form an oxygen-containing fused 6-membered ring: it will be appreciated that the various other rings formed when two separately occurring R ° (or R +, or any other variable similarly defined herein) and the atoms to which each variable is attached are taken together and the examples detailed above are not intended to be limiting.

In some embodiments, the alkyl or aliphatic chain may be optionally interrupted by another atom or group. This means that the methylene units of the alkyl or aliphatic chain are optionally replaced by said other atoms or groups. Examples of such atoms or groups include, but are not limited to, those listed in the definitions of Q1, Y1, Q2, and Q3. Further examples include-NR-, -O-, -S-, -CO2-, -OC (O) -, -C (O) CO-, -C (O) NR-, -C (═ N-CN) -, -NRCO-, -NRC (O) O-, -SO2NR-, -NRSO2-, -NRC (O) NR-, -OC (O) NR-, -NRSO2NR-, -SO-or-SO 2-, wherein R is as defined above.

An "amino" group as used herein refers to-NRXRY, wherein each of RX and RY is independently-H, C1-C6 aliphatic, C3-7 non-aromatic carbocyclic ring, 5-6 membered carbocyclic aryl or heteroaryl group, or 4-7 membered non-aromatic heterocyclic ring, each independently as defined herein and optionally substituted. Suitable substituents for carbocycle, carbocycle aryl, heteroaryl and heterocyclyl each independently include halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, C1-C6 alkyl, -O (C1-C6 alkyl), -C (O) OH, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHC (O) O (C1-C6 alkyl), -C (O) NH (C1-C6 alkyl) and-C (O) N (C1-C6 alkyl) 2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl) and-N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. Suitable substituents of C1-C6 aliphatic (including C1-C6 alkyl) include halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -O (C1-C6 alkyl), -C (O) OH, -C (O) O (C1-C6 alkyl), -OC (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHC (O) O (C1-C6 alkyl), -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, phenyl, 5-6 membered heteroaryl, 5-6 membered non-aromatic heterocyclic ring and C3-C7 carbocyclic ring, wherein each said alkyl is optionally and independently substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy, and wherein each of said phenyl, heteroaryl, heterocycle, and carbocycle is optionally and independently substituted with one or more substituents described above for the carbocycle, carbocycle aryl, heteroaryl, and heterocycle represented by RX and RY. In some embodiments, each of RX and RY is independently-H, an optionally substituted C1-6 aliphatic group, or an optionally substituted C3-8 non-aromatic carbocyclic ring. In some embodiments, each of RX and RY is independently-H or an optionally substituted C1-6 aliphatic group. In some embodiments, each of RX and RY is independently-H or C1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. Examples of amino groups include-NH 2, aliphatic amino, alkylamino, dialkylamino, or arylamino. An "aliphatic amino" group as used herein refers to-NRXRY, wherein RX is an optionally substituted C1-6 aliphatic group as described above; and RY is-H or an optionally substituted C1-6 aliphatic group as described above. An "alkylamino" group as used herein refers to-NHRX, wherein RX is an optionally substituted C1-6 alkyl group as described above. A "dialkylamino" group, as used herein, refers to-NRXRY, wherein each of RX and RY is independently optionally substituted C1-6 alkyl as described above. An "arylalkyl" group, as used herein, refers to-NRXRY, wherein RX is a 5-6 membered carbocyclic aryl or heteroaryl and RY is-H or a 5-6 membered carbocyclic aryl or heteroaryl, wherein each of said carbocyclic aryl and heteroaryl is independently and optionally substituted as described above. When the term "amino" is not a terminal group (e.g., alkylcarbonylamino), it is represented by — NRX-. RX has the same meaning as defined above. In one embodiment, the amino group is-NH 2 or an aliphatic amino group. In another embodiment, the amino group is-NH 2, an alkylamino group, or a dialkylamino group. In yet another embodiment, the amino group is-NH 2 or an arylamino group. In yet another embodiment, amino is-NH 2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each alkyl is optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

"amido" as used herein encompasses "aminocarbonyl" and "carbonylamino". These terms, used alone or in conjunction with another group, refer to an amido group, such as n (rxry) -c (o) -or ryc (o) -n (RX) - (when used terminally) and-c (o) -n (RX) -or-n (RX) -c (o) - (when used internally), wherein RX and RY are defined above. Examples of acylamino groups include alkylamido (e.g. alkylcarbonylamino or alkylaminocarbonyl), (heterocycloaliphatic) acylamino, (heteroaralkyl) acylamino, (heteroaryl) acylamino, (heterocycloalkyl) alkylamido, arylamido, aralkylamido, (cycloalkyl) alkylamido or cycloalkylamido. In some embodiments, acylamino is-nhc (o) (C1-C6 alkyl), -N (C1-C6 alkyl) C (o) (C1-C6 alkyl), -C (o) NH2, -C (o) NH (C1-C6 alkyl) or-C (o) NH (C1-C6 alkyl) 2, wherein each of said alkyl is optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy. In some embodiments, amido is-nhc (o) (C1-C6 alkyl), -N (C1-C6 alkyl) C (o) (C1-C6 alkyl), -C (o) NH2, -C (o) NH (C1-C6 alkyl), or-C (o) NH (C1-C6 alkyl) 2, wherein each alkyl is optionally and independently substituted with one or more substituents selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl) and C1-C4 alkoxy.

The term "urea" group as used herein refers to the structure-NRX-CO-NRYRZ and the "thiourea" group refers to the structures-NRX-CS-NRYRZ (when used terminally) and-NRX-CO-NRY-or-NRX-CS-NRY (when used internally), wherein RX, RY and RZ are each independently as defined above.

As used herein, an "acyl" group refers to acyl or RX-c (o) - (e.g., -alkyl-c (o) -, also referred to as "alkylcarbonyl"), wherein RX and "alkyl" are previously defined. Acetyl and pivaloyl are examples of acyl groups.

As used herein, a "carboxy" group refers to-COOH, -COORX, -OC (O) H, -OC (O) RX (when used as a terminal group) or-OC (O) -or-C (O) O- (when used as an internal group), wherein RX is as defined above

The term "hydroxyl" or "hydroxy" or "alcohol moiety" refers to — OH.

the term "alkoxycarbonyl", as used herein, encompassed by carboxy, used alone or in conjunction with another group, refers to a group such as (alkyl-O) -c (O) -and the like.

"carbonyl" as used herein refers to-C (O) -.

As used herein, "oxo" refers to ═ O.

The term "alkoxy" as used herein or "alkylthio" as used herein refers to an alkyl group as previously defined attached to the molecule through an oxygen ("alkoxy", e.g. -O-alkyl) or sulfur ("alkylthio", e.g. -S-alkyl) atom.

The terms "halogen", "halo" and "halo" as used herein refer to F, Cl, Br or I.

The term "cyano" or "nitrile" as used herein refers to-CN or-C ≡ N.

The terms "alkoxyalkyl", "alkoxyalkenyl", "alkoxyaliphatic", and "alkoxyalkoxy" refer to an alkyl, alkenyl, aliphatic, or alkoxy group that may be substituted, as the case may be, with one or more alkoxy groups.

the terms "haloalkyl", "haloalkenyl", "haloaliphatic" and "haloalkoxy" refer to alkyl, alkenyl, aliphatic or alkoxy groups which may be substituted as the case may be with one or more halogen atoms, for example-CF 3 and-CF 2CF 3.

the terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic" and "cyanoalkoxy" refer to alkyl, alkenyl, aliphatic or alkoxy groups which may be substituted as the case may be by one or more cyano groups. In some embodiments, cyanoalkyl is (NC) -alkyl-.

The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic" and "aminoalkoxy" refer to an alkyl, alkenyl, aliphatic or alkoxy group, as the case may be, substituted with one or more amino groups, wherein the amino group is as defined above. In some embodiments, the aminoaliphatic is a C1-C6 aliphatic group substituted with one or more-NH 2 groups. In some embodiments, aminoalkyl refers to the structure (RXRY) N-alkyl-, wherein each of RX and RY is independently as defined above. In some particular embodiments, aminoalkyl is C1-C6 alkyl substituted with one or more-NH 2 groups. In some particular embodiments, aminoalkenyl is C1-C6 alkenyl substituted with one or more-NH 2 groups. In some embodiments, the aminoalkoxy group is-O (C1-C6 alkyl), wherein the alkyl is substituted with one or more-NH 2 groups.

The terms "hydroxyalkyl", "hydroxyalkanoyl" and "hydroxyalkoxy" refer to an alkyl, aliphatic or alkoxy group, as the case may be, which may be substituted with one or more-OH groups.

The terms "alkoxyalkyl", "alkoxyaliphatic" and "alkoxyalkoxy" refer to an alkyl, aliphatic or alkoxy group which may be substituted as the case may be by one or more alkoxy groups. For example, "alkoxyalkyl" refers to an alkyl group, such as (alkyl-O) -alkyl-, where alkyl is as defined above.

The term "carboxyalkyl" refers to an alkyl group substituted with one or more carboxy groups, wherein alkyl and carboxy are as defined above.

In some embodiments, each amino group involved in the above description of variables (e.g., R6, R7, JE1, R, R', R ", R, Ra, Rb, and Rc) of structural formulae I-VI and xi (a) -XIV is independently-NH 2, -NH (C1-C6 alkyl), -NH (C3-C6 carbocycle), -N (C1-C6 alkyl) 2, or-N (C1-C6 alkyl) (C3-C35 6), wherein the alkyl and carbocycle groups are each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; each carboxy group involved in the above description of variables (e.g., R6, R7, JE1, R, R', R ", R, Ra, Rb, and Rc) of structural formulae I-VI and xi (a) -XIV is independently-C (O) O (C1-C6 alkyl), -oc (O) (C1-C6 alkyl), -C (O) O (C3-C6 carbocycle), -oc (O) (C3-C6 carbocycle), or-CO 2H, wherein the alkyl and carbocycle groups are each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; each amido group involved in the above description of variables of formulae I-VI and XI (A) -XIV (e.g., R6, R7, JE1, R, R', R ", Ra, Rb and Rc) is independently-NHC (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -C (O) NH (C1-C6 alkyl), -C O) N (C1-C6 alkyl) 2, -NHC (O) (C3-C6 carbocycle), -N (C1-C6 alkyl) C (O) (C3-C3 carbocycle), -C (C3-C3 carbocycle) (C3-C3) or NH (C3) C3 (3) carbocycle, wherein the alkyl and carbocyclic groups are each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; each aminoalkyl group referred to in the above description of variables (e.g., R8, R9, and R ") of structural formulae I-VI and xi (a) -XIV is independently a C1-C6 alkyl group substituted with one or more amino groups independently selected from: -NH2, -NH (C1-C4 alkyl), and-N (C1-C4 alkyl) 2; each aminoalkoxy group referred to in the above description of the variables (e.g., R6, R7, R8, R9, R10, R11, R12, R13, R14, R, R' and R ") of structural formulae I-VI and xi (a) -XIV is independently an-O (C1-C6 alkyl) group, wherein the alkyl group is substituted with one or more amino groups independently selected from-NH 2, -NH (C1-C4 alkyl), and-N (C1-C4 alkyl) 2.

In some embodiments, each amino group involved in the above description of variables (e.g., R6, R7, JE1, R, R', R ", R, Ra, Rb, and Rc) of structural formulae I-VI and xi (a) -XIV is independently-NH 2, -NH (C1-C6 alkyl), or-N (C1-C6 alkyl) 2, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; each carboxy group involved in the above description of variables (e.g., R6, R7, JE1, R, R', R ", R, Ra, Rb, and Rc) of structural formulae I-VI and xi (a) -XIV is independently-C (O) O (C1-C6 alkyl), -oc (O) (C1-C6 alkyl), or-CO 2H, wherein each of said alkyl groups is optionally and independently substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; each amido group involved in the above description of variables (e.g., R6, R7, JE1, R, R', R ", R, Ra, Rb, and Rc) of structural formulae I-VI and xi (a) -XIV is independently-nhc (o), (C1-C6 alkyl), -N (C1-C6 alkyl) C (o), (C1-C6 alkyl), -C (o) NH (C1-C6 alkyl), -C (o) N (C1-C6 alkyl) 2, or-C (o) NH2, wherein said alkyl groups are each optionally and independently substituted with one or more substituents independently selected from: halogen, cyano, hydroxy, oxo, -NH2, -NH (C1-C4 alkyl), -N (C1-C4 alkyl) 2, -OCO (C1-C4 alkyl), -CO (C1-C4 alkyl), -CO2H, -CO2(C1-C4 alkyl), and C1-C4 alkoxy; each aminoalkyl group referred to in the description above for the variables (e.g., R8, R9, and R ") of structural formulae I-VI and xi (a) -XIV is independently a C1-C6 alkyl group substituted with one or more amino groups independently selected from: NH2, -NH (C1-C4 alkyl), and-N (C1-C4 alkyl) 2; each aminoalkoxy group referred to in the above description of the variables (e.g., R6, R7, R8, R9, R10, R11, R12, R13, R14, R, R' and R ") of structural formulae I-VI and xi (a) -XIV is independently an-O (C1-C6 alkyl) group, wherein the alkyl group is substituted with one or more amino groups independently selected from-NH 2, -NH (C1-C4 alkyl), and-N (C1-C4 alkyl) 2.

The terms "protecting group" and "protecting group" as used herein are used interchangeably and refer to a reagent used to temporarily block one or more desired functional groups in a compound having multiple reactive sites. In certain embodiments, the protecting group has one or more, or in particular all, of the following characteristics: a) selectively adding functional groups in good yield to produce a protective matrix; b) stable to reactions occurring at one or more other reaction sites; and c) can be selectively removed in good yield with reagents that do not attack the regenerated deprotected functional group. One skilled in the art will appreciate that in some cases the agent does not attack other reactive groups in the compound. In other cases, the reagent may also react with other reactive groups in the compound. Examples of protecting Groups are detailed in Greene, T.W., Wuts, P.G, "Protective Groups in Organic Synthesis", 3 rd edition, John Wiley & Sons, New York:1999 (and other versions of the present document), the entire contents of which are hereby incorporated by reference. The term "nitrogen protecting group" as used herein refers to a reagent used to temporarily block one or more desired nitrogen reaction sites in a polyfunctional compound. Preferred nitrogen protecting Groups also have the characteristics exemplified above for protecting Groups, and certain exemplary nitrogen protecting Groups are also detailed by Greene, T.W., Wuts, P.G in "Protective Groups in Organic Synthesis" (3 rd edition, John Wiley & Sons, New York:1999) Chapter 7, the entire contents of which are hereby incorporated by reference.

The term "displaceable moiety" or "leaving group" as used herein refers to a group that associates with an aliphatic or aromatic group as defined herein and will be displaced by nucleophilic attack by a nucleophile.

unless otherwise noted, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, cis-trans, conformational and rotational) forms of the structures. For example, the R and S configurations, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers of each asymmetric center are included in the present invention unless only one isomer is specifically drawn. As will be appreciated by those skilled in the art, substituents may be free to rotate about any rotatable bond. For example, the substituents depicted also represent

Thus, individual stereochemical isomers as well as enantiomeric, diastereomeric, cis/trans, conformational and rotameric mixtures of the compounds of the invention are within the scope of the invention.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In addition, unless otherwise noted, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having existing structures, except for replacement of hydrogen with deuterium or tritium or replacement of carbon with 13C-or 14C-rich carbon, are within the scope of the invention. For example, compounds of formulae I-VI (e.g., formulae I, IA, II, III, IV, V, and VI) and XI (A) -XIV (e.g., formulae XIA, XIB, XIIA, XIIB, XIII, and XIV) having a position-D relative to R2 are also within the scope of the present invention. Such compounds are useful, for example, as analytical tools or probes in biological assays. Such compounds, and in particular deuterium analogues, are also useful therapeutically.

The terms "bond" and "absent" are used interchangeably to mean that the group is absent.

The compounds of the present invention are defined herein by their chemical structures and/or chemical names. When a compound is referred to by chemical structure and chemical name, and the chemical structure and chemical name conflict, the identity of the compound is determined by the chemical structure.

Pharmaceutically acceptable salts, solvates, clathrates, prodrugs and other derivatives

The compounds described herein may exist in the free state or, where appropriate, as salts. Those pharmaceutically acceptable salts are of particular interest because they can be used to administer the compounds described below for medical purposes. Pharmaceutically unacceptable salts are used in the manufacturing process for isolation and purification, and in some cases, for isolation of stereoisomeric forms of the compounds of the invention or intermediates thereof.

The term "pharmaceutically acceptable salt" as used herein, means a compound which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without adverse side effects, such as toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, s.m. berge et al describe in detail pharmaceutically acceptable salts in j.pharmaceutical Sciences,1977,66,1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds described herein include salts derived from suitable inorganic and organic acids and bases. These salts can be prepared in situ during the final isolation and purification of the compounds.

Where the compounds described herein contain a basic group or bioisostere of sufficient basicity, acid addition salts can be prepared by: 1) reacting the purified compound in free base form with a suitable organic or inorganic acid and 2) isolating the salt thus formed. In practice, acid addition salts may be in a more convenient form to use, and the use of a salt is equivalent to the use of the free base form.

Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, boronates, butyrates, camphorates, camphorsulfonates, citrates, estradiol 17-cyclopentanepropionates, gluconic acid di-salts, lauryl sulfate, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, glycolates, gluconates, glycolates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, benzoates, bisulfates, salts of boron, butyrates, camphorates, camphor, Palmitate, naphthenate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

when the compounds described herein contain a carboxy group or sufficient acidity of a bioisostere, base addition salts can be prepared by: 1) reacting the purified compound in free acid form with a suitable organic or inorganic base and 2) isolating the salt thus formed. In practice, the use of base addition salts may be more convenient and the use of the salt form essentially corresponds to the use of the free acid form. Salts derived from suitable bases include alkali metal (e.g., sodium, lithium and potassium), alkaline earth metal (e.g., magnesium and calcium), ammonium and N + (C1-4 alkyl) 4 salts. The present invention also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water-or oil-soluble or dispersible products can be obtained by this quaternization.

Base addition salts include pharmaceutically acceptable metal and amine salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum. Sodium and potassium salts are generally preferred. Further pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, and the like. Suitable amine base addition salts can be prepared from amines which are frequently used in pharmaceutical chemistry because of their low toxicity and medical acceptability. Ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N' -dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, diphenylmethylamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, dicyclohexylamine, and the like.

Although other acids and bases are not pharmaceutically acceptable per se, they may be used to prepare salts as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid or base addition salts.

It will be appreciated that the present invention includes mixtures/combinations of different pharmaceutically acceptable salts and also includes mixtures/combinations of the free compound and the pharmaceutically acceptable salt.

in addition to the compounds described herein, pharmaceutically acceptable solvates (e.g., hydroxides) and clathrates of these compounds can also be employed in compositions for the treatment or prevention of the conditions identified herein.

The term "pharmaceutically acceptable solvate" as used herein is a solvate formed by combining one or more pharmaceutically acceptable solvent molecules with one of the compounds described herein. The term solvate includes hydroxides (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).

The term "hydroxide" as used herein refers to a compound described herein, or a salt thereof, that further includes stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.

The term "clathrate," as used herein, refers to a compound described herein in a lattice form that contains spaces (e.g., channels) in which guest molecules (e.g., solvents or water) are entrapped, or a salt thereof.

In addition to the compounds described herein, pharmaceutically acceptable derivatives or prodrugs of these compounds may also be employed in compositions for the treatment or prevention of the conditions identified herein.

"pharmaceutically acceptable derivative or prodrug" includes any pharmaceutically acceptable ester, salt of an ester, or other derivative or salt thereof of a compound described herein, which upon administration to a subject is capable of providing, directly or indirectly, a compound described herein, or an inhibitory active metabolite or residue thereof. Particularly popular derivatives or prodrugs are those that increase the bioavailability of the compounds when administered to a patient (e.g., by making the orally administered compounds more readily absorbed into the blood) or that increase the delivery of the parent compound to a biological cavity (e.g., the brain or lymphatic system) relative to the parent species.

As used herein and unless otherwise noted, the term "prodrug" refers to a compound derivative that can hydrolyze, oxidize, or react under biological conditions (in vitro or in vivo) to provide a compound described herein. Once so reacted under biological conditions, the prodrugs may become active, or they may be active in their unreacted form. Examples of prodrugs contemplated in the present invention include, but are not limited to, analogs or derivatives of the compounds of the present invention, including biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogs. Other examples of prodrugs include derivatives of the compounds described herein, including the-NO, -NO2, -ONO, or-ONO 2 moiety. Prodrugs can generally be prepared using well known methods, for example, as described in BURGER' S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995)172-178,949-982 (Manfred E.Wolff ed., 5 th edition).

A "pharmaceutically acceptable derivative" is an adduct or derivative that is capable of providing, directly or indirectly, a compound as described herein, or a metabolite or residue thereof, upon administration to a patient. Examples of pharmaceutically acceptable derivatives include, but are not limited to, esters and salts of such esters.

Pharmaceutically acceptable prodrugs of the compounds described herein include, but are not limited to, esters, amino acid esters, phosphate esters, metal salts, and sulfonate esters.

Pharmaceutical composition

The compounds described herein can be formulated as pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present invention relates to a pharmaceutical composition comprising a compound of the invention as described above and a pharmaceutically acceptable carrier, diluent, adjuvant or vehicle. In one embodiment, the invention is a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitable for convenient pharmaceutical practice suitably selected with respect to the intended form of administration.

An "effective amount" includes both a "therapeutically effective amount" and a "prophylactically effective amount". The term "therapeutically effective amount" refers to an amount effective to treat and/or ameliorate influenza virus infection in a patient infected with influenza. The term "prophylactically effective amount" refers to an amount effective to prevent and/or substantially reduce the chance or extent of an outbreak of an influenza virus infection. Specific examples of effective amounts are described above in the section entitled use of the disclosed compounds.

Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or free of other adverse or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.

Pharmaceutically acceptable carriers, adjuvants or vehicles as used herein include any solvent, diluent or other liquid vehicle, dispersing or suspending co-adjuvant, surfactant, isotonic agent, thickening or emulsifying agent, preservative, solid binder, lubricant, and the like, all as appropriate for the particular dosage form desired. Pharmaceutical Sciences 16 th edition, e.w. Martin (Mack Publishing co., Easton, Pa.,1980) by Remington discloses various carriers for use in formulating pharmaceutically acceptable compositions and known techniques for their preparation. Except insofar as any conventional carrier is concerned, the use of a medium incompatible with the compounds described herein, e.g., by producing any undesirable biological effect or interacting in a deleterious manner with any other component of a pharmaceutically acceptable salt, is contemplated to be within the scope of the present invention. The phrase "side effects" as used herein encompasses detrimental adverse effects of a therapy (e.g., prophylactic or therapeutic agents). Side effects are always detrimental, but detrimental effects are not necessarily detrimental. Adverse effects of therapy (e.g., prophylactic or therapeutic agents) can be harmful or uncomfortable or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosion), nausea, vomiting, neurotoxicity, toxic kidney damage, renal toxicity (including conditions like renal papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including leukopenia, myelosuppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, somnolence, pain (including myalgia, osteodynia, and headache), hair loss, weakness, dizziness, extrapyramidal symptoms, akathisia, cardiovascular disorders, and sexual dysfunction.

Some examples of substances that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., twin 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium, Ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers, as well as other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), and coloring agents, anti-adhesion agents, coating agents, sweetening and flavoring agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.

Application method

The above-described compounds and pharmaceutically acceptable compositions can be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally as an oral or nasal spray, and the like, depending on the severity of the infection being treated.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections.

For example, injectable formulations can be sterilized by filtration through a bacterial-retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

To prolong the effect of the compounds described herein, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming microcapsule matrices of the compounds in biodegradable polymers such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are in particular suppositories which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers, for example cocoa butter, polyethylene glycol or a suppository wax, which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, for example sodium citrate or dicalcium phosphate and/or a) fillers or extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, for example carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose and acacia, c) humectants, for example glycerol, d) disintegrating agents, for example agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents, for example paraffin, f) absorption accelerators, for example quaternary ammonium compounds, g) wetting agents, for example cetyl alcohol and glycerol monostearate, h) absorbents, for example kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

Solid compositions of similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols.

the active compound may also be in the form of a microencapsulated form with one or more of the above-mentioned excipients. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings, and other coatings well known in the pharmaceutical art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to the inert diluent, for example tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.

Dosage forms for topical or transdermal administration of the compounds described herein include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of a skin patch that has the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The compositions described herein can also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally, or intravenously.

The sterile injectable form of the compositions described herein can be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids, such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the production of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

The pharmaceutical compositions described herein may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers which are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions described herein may be administered in the form of suppositories for rectal use. These pharmaceutical compositions can be prepared by mixing the agent with a non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions described herein may also be administered topically, particularly when the target of treatment includes topical application to an easily accessible area or organ, including the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Local instillation to the lower intestinal tract may be achieved with rectal suppository formulations (see above) or suitable enema formulations. Topical skin patches may also be used.

For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or solutions in isotonic pH adjusted sterile saline in particular, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.

The pharmaceutical compositions may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.

The compounds for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be administered in a single daily dose or in multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.

Examples of the use of

preparation of the Compounds

The compounds disclosed herein can be prepared by any suitable method known in the art, for example, WO 2005/095400 and WO 2007/084557, including those of formulae I-VI (e.g., formulae I, IA, II, III, IV, V, and VI) and xi (a) -XIV (e.g., formulae XIA, XIB, XIIA, XIII, and XIV). For example, the compounds depicted in FIGS. 3-8 can be prepared by any suitable method known in the art, e.g., WO 2005/095400 and WO 2007/084557, and by the exemplary syntheses described below. In particular, the compounds depicted in figure 8 can be prepared as described in WO 2005/095400 and WO 2007/084557. The synthesis of certain exemplary compounds of structural formulae I-VI and XI (A) -XIV is described below. In general, the compounds of formulae I-VI and XI (A) -XIV can be prepared as shown in those syntheses, optionally with any suitable modification desired.

General analytical methods

the term rt (min) as used herein refers to LCMS retention time in minutes associated with a compound. Unless otherwise noted, the methods used to obtain the reported retention times are as follows:

Column: YMC-Pack Pro Cig 50mm by 4.6mm inner diameter

Gradient: 10-95% methanol/H2O. Flow rate: 1.5 ml/min. Ultraviolet-visible detection.

methods for the synthesis and characterization of compounds

The synthesis of certain exemplary compounds of structural formulae I-VI (e.g., formulae I, IA, II, III, IV, V, and VI) and XI (A) -XIV (e.g., formulae XIA, XIB, XIIA, XIIB, XIII, and XIV) is described below. NMR and mass spectrometry data for certain specific compounds are summarized in tables 1-5.

General scheme 1

(a) (S) -1-Boc-3-aminopiperidine, iPr2NEt, DMF, 90 ℃; (b) TFA, CH2Cl 2; (c) 2- (methoxymethyl) oxirane, ethanol, microwave, 140 ℃; (d)1N LiOH, THF, microwave, 120 deg.C

formation of tert-butyl (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxylate (1b)

To a solution of 5-chloro-3- (5-fluoro-4-methanesulfonyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 1a (3.5g, 7.5mmol) and tert-butyl (3S) -3-aminopiperidine-1-carboxylate (1.8g, 9.0mmol) in DMF (32mL) was added diisopropylethylamine (2.6mL, 15.1 mmol). The reaction mixture was heated at 90 ℃ for 75 min. The mixture was cooled to room temperature and diluted into saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with brine (3 times), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0% to 10% MeOH in CH2Cl2) to afford the desired product 1b as a white solid.

LCMS RT＝4.6(M+1)601.5,(M-1)599.6。

Formation of (S) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine (1c)

To a solution of tert-butyl (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] piperidine-1-carboxylate 1b (2.1g, 3.5mmol) in CH2Cl2(30mL) was added trifluoroacetic acid (20 mL). After stirring the reaction mixture at room temperature for 75min, the mixture was concentrated in vacuo. The crude residue was diluted with EtOAc and neutralized with 1N sodium hydroxide solution. The liquid phase was separated and re-extracted with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford the desired product (1c) as a pale yellow solid.

1H NMR (300MHz, d6-DMSO) δ 8.76(d, J ═ 2.5, Hz,1H),8.50(d, J ═ 2.5Hz,1H),8.44(s,1H),8.27(d, J ═ 4.0Hz,1H),8.06(d, J ═ 8.5Hz,2H), 7.66(d, J ═ 6.9Hz,1H),7.45(d, J ═ 8.2Hz,2H),4.17(m,1H),3.17 (dd, J ═ 3.1,11.8Hz,1H),2.99-2.94(m,1H),2.67-2.60(m,1H), 2.38-2.34 (m,1H),2.06-2.02(m,1H), 1.63-1H, 1.77(m, 1H) and 1.50 ppm. LCMS RT ═ 2.1(M +1)501.5, (M-1) 499.5.

Formation of 1- ((S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-methoxypropan-2-ol (1d)

To 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -3-piperidinyl ] pyrimidin-4-amine 1c (0.20g, 0.40mmol) in ethanol was added 2- (methoxymethyl) oxirane (0.04mL, 0.40 mmol). The reaction mixture was heated in a microwave reactor at 140 ℃ for 5 min. The reaction was evaporated to dryness and the resulting residue was purified by silica gel chromatography (0-10% MeOH: CH2Cl2) to afford the desired product (1 d).

1H NMR (300MHz, d6-DMSO) δ 8.78(d, J ═ 2.5Hz,1H),8.49(d, J ═ 2.4Hz,1H),8.43(d, J ═ 1.2Hz,1H),8.26(d, J ═ 3.9Hz,1H),8.07 (d, J ═ 8.4Hz,2H),7.60(d, J ═ 7.5Hz,1H),7.45(d, J ═ 8.2Hz,2H), 4.54-4.50(m,1H),4.20(m,1H),3.35-3.17(m,1H),3.33(s,3H),3.25 (m,1H),3.19(d,2H),3.00(m,1H),2.75(d, 8.11H), 11.33 (s,3H),3.25 (m,1H),3.19(d,2H),3.00(m,1H), 2H), 3.75(d, 11.75 (m,1H), 3.3.73 (m,1H), 3.3.3.3.3.3, 3.3.3H), and 93(m, 3.3.3.3.3.3.3.3.

LCMS RT＝2.4(M+1)589.6。

Formation of 1- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-methoxypropan-2-ol (537)

To a solution of 1- [ (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-piperidinyl ] -3-methoxy-propan-2-ol 1d (0.15g, 0.24mmol) in THF was added a 1N LiOH solution. The reaction mixture was heated in a microwave reactor at 120 ℃ for 5 min. The reaction mixture was diluted with water and the liquid phase was extracted with EtOAc (twice). The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was purified by silica gel chromatography (5-20% MeOH: CH2Cl2) to afford the desired product (537) as a white solid.

1H NMR (300MHz, d6-DMSO) δ 12.35(s,1H),8.73(d, J ═ 2.4Hz,1H),8.29(d, J ═ 2.4Hz,1H),8.19-8.09(m,2H),7.36(d, J ═ 7.5Hz,1H), 4.53(dd, J ═ 4.5,8.0Hz,1H),4.27(s,1H),3.77-3.72(m,1H), 3.36-3.20(m,3H),3.22(s,3H),3.03-2.97(m,1H),2.76(d, J ═ 10.6 Hz,1H),2.44-2.14(m,2H),2.08(m,2H),1.99-1.94(m,1H), 1.63-1H, 1H), 1.71-15 (m,1H),1.7 (m,1H) and 1.15 ppm.

LCMS RT＝1.6(M+1)435.5。

Other analogs that can be prepared in the same manner as 537 are described below:

3- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) propane-1, 2-diol (525)

1H NMR (300MHz, d6-DMSO) δ 12.31(s,1H),8.72(d, J ═ 2.4Hz,1H),8.28(d, J ═ 2.4Hz,1H),8.20(s,1H),8.17(d, J ═ 4.0Hz,1H), 7.33(d, J ═ 7.6Hz,1H),4.51(m,1H),4.37(s,1H),4.25(m,1H),3.64 (m,1H),3.35(s,2H),3.08-2.95(m,1H),2.80-2.70(m,1H),2.47-2.25 (m,2H),2.22-2.12(m,2H),1.99-1.90(m,1H),1.70-1.60(m, 1H) and 1H (m, 1H).

LCMS RT＝1.5(M+1)421.5。

1- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-isopropoxypropan-2-ol (551)

1H NMR (300MHz, d6-DMSO) δ 12.32(s,1H),8.72(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.19-8.16(M,2H),7.32(d, J ═ 8.0Hz, 1H),4.42-4.37(M,2H),3.70(s,1H),3.52-3.42(M,1H),3.35-3.25(M, 1H),2.99(M,1H),2.73(M,1H),2.43-2.11(M,4H),1.94(M,1H), 1.75-1.60 (M,2H),1.52-1.40(M,1H) and 1.10-0.99(M, 6H).

LCMS RT＝1.7(M+1)463.4,(M-1)461.5。

(S) -1- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) butan-2-ol (538)

1H NMR (300MHz, d6-DMSO) δ 12.53(s,1H),10.32(s,1H),8.69 (dd, J ═ 2.5,5.2Hz,1H),8.56(d, J ═ 2.4Hz,1H),8.31(m,2H),7.97(s, 1H),4.76(m,1H),3.92(m,2H),3.84-3.55(m,2H),3.40-2.80(m,3H), 2.14-1.90(m,3H),1.80-1.74(m,2H),1.65(m,1H),1.43-1.23(m,2H) and 0.96-0.85(m,3H) ppm.

LCMS RT＝1.6(M+1)419.6。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -2-methylpropan-2-ol (546)

1H NMR (300MHz, CDCl3) δ 9.60(s,1H),8.87(d, J ═ 2.3Hz,1H), 8.33(d, J ═ 2.3Hz,1H),8.17(d, J ═ 2.7Hz,1H),8.09(d, J ═ 3.3Hz, 1H),5.34(d, J ═ 11.5Hz,1H),4.45-4.42(m,1H),3.09(d, J ═ 11.3Hz, 1H),2.75-2.59(m,4H),2.40(s,2H),1.94-1.70(m,4H) and 1.27(s,6H) ppm.

LCMS RT＝1.6(M+1)419.5。

(R) -3- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) propane-1, 2-diol (588)

1H NMR (300MHz, DMSO) δ 12.31(s,1H),8.72(d, J ═ 2.4Hz,1H), 8.27(d, J ═ 2.4Hz,1H),8.19(s,1H),8.16(d, J ═ 4.0Hz,1H),7.33 (d, J ═ 7.8Hz,1H),4.47-4.44(m,1H),4.35(d, J ═ 4.0Hz,1H), 4.28-4.17 (m,1H),3.64-3.62(m,1H),3.17(d, J ═ 5.2Hz,1H),3.02-2.98 (m,1H),2.78-2.73(m,1H),2.37(d, J ═ 12.8,5.2, 2, 5.3, 2H), 2.02-2.98 (m,1H),2.78-2.73(m,1H),2.37(dd, 12.8, 5.8, 2.5, 2.43, 2.73(m,1H), 1H, 1, 1.46-4 (m,1H), and 1H). LCMS RT ═ 1.5(M +1) 421.4. LCMS RT ═ 1.6(M +1)419.3

(S) -3- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) propane-1, 2-diol (587)

1H NMR (300MHz, DMSO) δ 12.31(s,1H),8.72(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.20(s,1H),8.16(d, J ═ 4.0Hz,1H),7.33 (d, J ═ 7.5Hz,1H),4.34(s,1H),4.27-4.23(m,1H),3.62(s,1H),3.35 (d, J ═ 5.5Hz,1H), 3.06-3.03 (m,1H),2.78-2.74(m,1H),2.44(d, J ═ 5.0Hz,1H),2.27(dd, J ═ 12.9,6.9, 1H), 2.20-2.20 (m,1H), 2.27(dd, 1.9, 1H), 1H, and 1.49-1H.

1- ((3S,4S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -4-methylpiperidin-1-yl) -3-methoxypropan-2-ol (550)

1H NMR (300MHz, d6-DMSO) δ 12.33(s,1H),8.72(d, J ═ 2.5Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.22-8.20(m,2H),6.72-6.62(m,1H), 4.61(dd, J ═ 4.2,10.0Hz,1H),4.54(m,1H),3.75-3.71(m,1H), 3.34-3.22 (m,1H),3.22(d,3H),2.88-2.42(m,4H),2.41-2.25(m,4H),1.93 (m,1H),1.56(m,2H) and 0.90(d, J ═ 6.7Hz, 3H). LCMS RT ═ 1.6(M +1) 449.5.

3- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -2-hydroxypropionamide (603)

1H NMR (300MHz, DMSO) δ 12.31(s,1H),8.71(d, J ═ 2.4Hz,1H), 8.28-8.25(m,1H),8.19-8.16(m,2H),7.34-7.30(m,1H),7.19(s, 1H),7.11(s,1H),4.24(s,1H),3.99(dd, J ═ 3.5,7.6Hz,1H),3.01(d, J ═ 10.3Hz,1H),2.81-2.63(m,2H),2.36-2.29(m,2H),1.71(s,3H) and 1.51-1.44(m,2H) ppm.

General scheme 2

(a) Tert-butyl bromoacetate, Na2CO3, DMF; (b)1N LiOH, THF, microwave, 120 deg.C, 10 min; (c) TFA, CH2Cl2

Formation of tert-butyl (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxylate (2a)

To a solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -3-piperidinyl ] pyrimidin-4-amine 1c (0.25g, 0.50mmol) in DMF was added tert-butyl bromoacetate (0.08mL, 0.55mmol) and Na2CO3(0.11g, 0.99 mmol). The reaction mixture was stirred at room temperature for 6 h. The resulting viscous white precipitate was diluted with saturated aqueous NaCl solution and washed with water. The white solid was dissolved in CH2Cl2 and the solution was dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0% to 5% MeOH in CH2Cl2) to afford the desired product 2a as a white solid.

1H NMR (300MHz, d6-DMSO) δ 8.76(d, J ═ 2.4Hz,1H),8.48(d, J ═ 3.6Hz,1H),8.44(s,1H),8.26(d, J ═ 3.9Hz,2H),8.07(d, J ═ 8.4Hz,2H), 7.59(d, J ═ 8.2Hz,1H),7.44(d, J ═ 8.1Hz,2H),4.18(m,1H),3.19 (s,2H),3.03-2.99(m,1H),2.78-2.73(m,1H),2.45-2.30(m,2H), 2.37(s,3H),1.99-1.93(m,1H),1.80-1.60(m,2H), 1.46-1H (m,1H), and 1H (m, 1H).

LCMS RT＝2.8(M+1)615.6,(M-1)613.6。

Formation of tert-butyl (S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) acetate (2b)

To a solution of tert-butyl 2- [ (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-piperidinyl ] acetate 2a (0.27g, 0.44mmol) in THF was added a 1N LiOH solution. The reaction mixture was heated in a microwave at 120 ℃ for 10 min. The reaction mixture was diluted with brine, extracted with EtOAc and then extracted with 20% isopropanol/CH 2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting product 2b was used without further purification.

LCMS RT＝2.0(M+1)461.5。

Formation of (S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) acetic acid (577)

To a solution of tert-butyl 2- [ (3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-piperidinyl ] acetate 2b (0.12g, 0.26mmol) in CH2Cl2(4mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at room temperature for 18h and concentrated in vacuo. The crude residue was diluted with 5% MeOH/CH2Cl2, and the resulting white precipitate was filtered and washed with CH2Cl2 to obtain the desired product 577 as the trifluoroacetate salt.

1H NMR (300MHz, d6-DMSO) δ 12.46(s,1H),8.70(d, J ═ 2.4Hz,1H), 8.36(d, J ═ 2.3Hz,1H),8.31(d, J ═ 2.4Hz,1H),8.29(d, J ═ 3.9Hz,1H), 7.79(d, J ═ 7.0Hz,1H),4.70-4.50(m,1H),4.21(s,2H), 3.80-3.70 (m,1H),3.55-3.47(m,1H),3.20-2.90(m,2H),2.10-1.95(m,3H) and 1.69-1.60(m,1H) ppm. LCMS RT ═ 1.9(M +1) 405.4.

Other analogs that can be prepared in the same manner as 577:

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) acetamide (567)

1H NMR (300MHz, d6-DMSO) δ 12.29(s,1H),8.72(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.21(s,1H),8.17(d, J ═ 4.0Hz,1H),7.41 (d, J ═ 7.7Hz,1H),7.29(s,1H),7.10(s,1H),4.35-4.29(m,1H), 2.98-2.75 (m,1H),2.92(d, J ═ 6.8Hz,2H),2.68(d, J ═ 10.8Hz,1H), 2.29-2.19 (m,2H),1.96-1.92(m,1H),1.80-1.65(m,2H) and 1.53-1H). LCMS RT ═ 2.1(M +1)404.4, (M-1) 402.5.

2- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) propionamide (583)

1H NMR (300MHz, d6-DMSO) δ 8.70(d, J ═ 2.3Hz,1H),8.52(d, J ═ 8.7Hz,1H),8.35(dd, J ═ 5.0,6.5Hz,2H),4.10(dd, J ═ 2.7,7.0Hz, 1H),3.80-3.90(m,1H),3.60-3.80(m,1H),2.35-2.45(m,1H), 2.15-2.35 (m,1H),1.80-1.95(m,1H) and 1.60-1.65(m,3H) ppm.

LCMS(M+1)418.4。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-cyanopyrimidin-4-ylamino) piperidin-1-yl) acetamide (654)

LCMS RT＝2.9(M+1)411.4,(M-1)409.4。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-methylpyrimidin-4-ylamino) piperidin-1-yl) acetamide (620)

LCMS RT＝1.9(M+1)400.4,(M-1)398.3。

2- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) propionic acid (573).

1H NMR (300MHz, d6-DMSO) δ 12.51(s,1H),10.28-10.00(m, 1H),8.70(s,1H),8.38(s,1H),8.31(d, J ═ 2.4Hz,1H),8.30(d, J ═ 4.2 Hz,1H),7.89-7.75(m,1H),4.70-4.50(m,1H),4.33-4.29(m,1H), 3.79-3.45(m,2H),3.20-2.80(m,2H),2.12-1.95(m,3H),1.72-1.60 (m,1H) and 1.52(d, J ═ 5.5Hz,3H) ppm.

2- ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -N-methylpropanamide (606)

1H NMR (300MHz, d6-DMSO) δ 8.69(d, J ═ 12.7Hz,1H), 8.54-8.49 (m,1H),8.32(dd, J ═ 4.8,7.2Hz,2H),4.83-4.76(m,1H),4.02(m, 1H),3.95-3.71(m,2H),3.31-3.10(m,1H),2.86(s,3H),2.33(d, J ═ 9.9Hz,1H),2.40-2.14(m,3H),1.94(s,1H),1.66-1.58(m,3H) and 1.10 (d, J ═ 6.5Hz,3H) ppm.

LCMS(M+1)432.2。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -2-methylpropionic acid (590)

H NMR(300MHz,MeOD)δ8.81(d,J＝2.3Hz,1H),8.19(t,J＝ 2.5Hz,2H),7.98(d,J ＝4.2Hz,1H),4.48(s,1H),2.90(d,J＝10.1Hz, 1H),2.74-2.66(m,2H),2.60(d,J＝5.7Hz, 1H),1.89-1.83(m,2H), 1.67(s,1H),1.25(d,J＝4.9Hz,6H)ppm。LCMS(M+1)433.4。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -2-methylpropanamide (598)

LCMS RT＝1.8(M+1)432.4。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -N, 2-dimethylpropanamide (599)

1H NMR (300MHz, MeOD) δ 8.86(d, J ═ 2.4Hz,1H),8.23(d, J ═ 2.3Hz,1H),8.17(s,1H),8.03(d, J ═ 4.1Hz,1H),4.46(dd, J ═ 4.7,8.8 Hz,1H),4.10(q, J ═ 7.2Hz,1H),3.05(d, J ═ 12.8Hz,1H),2.66(s,3H), 2.34(dd, J ═ 11.3,20.6Hz,2H),2.08(d, J ═ 12.3Hz,1H),1.89-1.71(m, 2H),1.66-1.54(m,1H) and 1.19(s, 6H).

LCMS(M+1)433.4。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -N, N, 2-trimethylpropanamide (600)

1H NMR (300MHz, MeOD) δ 8.81(d, J ═ 2.4Hz,1H),8.22(d, J ═ 2.4Hz,1H),8.14(s,1H),8.02(d, J ═ 4.0Hz,1H),4.45-4.37(m,1H), 3.61(s,3H),2.97(d, J ═ 8.8Hz,1H),2.80(s,3H),2.72(s,1H),2.39(t, J ═ 10.0Hz,2H),2.15(dd, J ═ 3.6,12.7Hz,1H),1.91-1.79(m,2H), 1.53-1.47 (m,1H) and 1.28(s, 6H).

LCMS(M+1)460.5。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -N- (2-methoxyethyl) -2-methylpropanamide (601)

1H NMR (300MHz, MeOD) δ 8.88(d, J ═ 2.3Hz,1H),8.23(d, J ═ 2.3Hz,1H),8.17(s,1H),8.02(d, J ═ 4.1Hz,1H),4.47-4.41(m,1H), 3.38(dd, J ═ 1.6,4.8Hz,4H), 3.12-3.07 (m,1H),2.73(d, J ═ 10.8Hz,1H), 2.35-2.29 (m,2H), 2.19-2.15 (m,1H), 1.91-1.80 (m,2H),1.55 (s,1H),1.37(s,1H) and 1.20(s,6H) ppm.

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -N-cyclopropyl-2-methylpropanamide (602)

1H NMR (300MHz, MeOD) δ 8.82(d, J ═ 2.3Hz,1H),8.23(d, J ═ 2.3Hz,1H),8.15(s,1H),8.01(d, J ═ 4.0Hz,1H),4.41(m,1H),3.02(d, J ═ 10.0Hz,1H), 2.59-2.47 (m,1H), 2.40-2.30 (m,2H), 2.09-2.01 (m,1H), 1.89-1.85(m,1H), 1.78-1.66 (m,1H), 1.61-1.55 (m,1H), 1.26-1.16 (m,1H),1.10(d, J ═ 6.6H), 0.68-0.63 (m,2H) and 0.44-2H (m, 1H).

LCMS(M+1)472.4。

General scheme 3

(a) CF3CH2SO2CCl3, iPr2NEt, DMF; (b)1N LiOH, THF, microwave, 120 deg.C, 10min

Formation of (S) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (2,2, 2-trifluoroethyl) piperidin-3-yl) pyrimidin-4-amine (3a)

To a solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -3-piperidinyl ] pyrimidin-4-amine 1c (0.17g, 0.34mmol) in DMF (1.5mL) was added 2,2, 2-trifluoroethyl trichloromethanesulfonate (0.19g, 0.68mmol) followed by iPr2NEt (0.24mL, 1.36 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was poured into brine and extracted twice with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford the desired product 3a as a white solid.

1H NMR (300MHz, d6-DMSO) δ 8.77(d, J ═ 2.4Hz,1H),8.48(d, J ═ 2.4Hz,1H),8.42(s,1H),8.27(d, J ═ 3.9Hz,1H),8.05(d, J ═ 8.4Hz,2H), 7.62(d, J ═ 7.5Hz,1H),7.44(d, J ═ 8.2Hz,2H),4.17(m,1H), 3.30-3.18 (m,3H),2.90(m,1H),2.44-2.32(m,2H),2.35(s,3H),1.95(m, 1H),1.72-1.57(m,2H) and 1.51-1.40 ppm (m, 1H).

LCMS RT＝4.6(M+1)583.4,(M-1)581.4。

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (2,2, 2-trifluoroethyl) piperidin-3-yl) pyrimidin-4-amine (668)

To a solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -1- (2,2, 2-trifluoroethyl) -3-piperidinyl ] pyrimidin-4-amine 3a (0.10g, 0.18mmol) in THF was added a solution of 1M LiOH (0.90mL, 0.90 mmol). The reaction mixture was heated in a microwave at 120 ℃ for 10 min. The reaction mixture was diluted with brine, extracted with EtOAc and then extracted with 20% isopropanol/CH 2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-10% MeOH: CH2Cl2) to afford the desired product 1339 as a white solid.

1H NMR (300MHz, d6-DMSO) δ 12.32(s,1H),8.71(d, J ═ 2.4Hz,1H),8.28(d, J ═ 2.4Hz,1H),8.18-8.16(m,2H),7.38(d, J ═ 7.7Hz,1H), 4.22-4.17(m,1H),3.31-3.16(m,3H),2.90(m,1H),2.40(t, J ═ 10.2Hz,2H),2.00-1.95(m,1H),1.77-1.60(m,2H) and 1.50-1.38(m, 1H) ppm.

LCMS RT＝3.5(M+1)429.4,(M-1)427.4。

Other analogs can be prepared in the same manner as 668:

Synthesis of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (2, 2-difluoroethyl) piperidin-3-yl) -5-fluoropyrimidin-4-amine (1)

1H NMR (300MHz, d6-DMSO) δ 12.31(s,1H),8.72(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.20(s,1H),8.17(d, J ═ 4.0Hz,1H), 7.33(d, J ═ 7.6Hz,1H),4.51(m,1H),4.37(s,1H),4.25(m,1H),3.64 (m,1H),3.35(s,2H),3.08-2.95(m,1H),2.80-2.70(m,1H),2.47-2.25 (m,2H),2.22-2.12(m,2H),1.99-1.90(m,1H),1.70-1.60(m, 1H) and 1H (m, 1H).

LCMS RT＝2.7(M+1)411.4,(M-1)409.4。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (2, 2-difluoroethyl) piperidin-3-yl) -5-fluoropyrimidin-4-amine (595)

1H NMR (300MHz, d6-DMSO) δ 12.32(s,1H),8.71(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.18-8.15(m,2H),7.32(d, J ═ 7.1Hz,1H), 4.20(d, J ═ 7.1Hz,1H),3.46(t, J ═ 5.8Hz,2H),3.19(s,3H), 3.10-3.06 (m,1H),2.82-2.78(m,1H),2.57-2.50(m,2H),2.11-1.95(m, 3H),1.71-1.63(m,2H) and 1.48-1.35(m,1H) ppm.

LCMS RT＝1.7(M+1)405.4,(M-1)403.4。

(S) -2- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) acetonitrile (669)

1H NMR (300MHz, d6-DMSO) δ 12.31(s,1H),8.69(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H), 8.19-8.17 (m,2H),7.47(d, J ═ 7.7Hz,1H), 4.30-4.20 (m,1H),3.80(s,2H), 3.07-3.03 (m,1H), 2.82-2.73 (m,1H), 2.29-2.10 (m,2H), 2.05-1.96 (m,1H), 1.87-1.65 (m,2H) and 1.49-1.40 (m,1H) ppm; LCMS RT ═ 2.3(M +1)386.1, (M-1) 384.2.

General scheme 4

(a) 1H-imidazole-2-carbaldehyde, Na (OAc)3BH, HOAc, 1, 2-dichloroethane, 60 ℃; (b)1N LiOH, THF, microwave, 120 deg.C, 10min

Formation of (S) -N- (1- ((1H-imidazol-2-yl) methyl) piperidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (4a)

To a solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -3-piperidinyl ] pyrimidin-4-amine 1c (0.16g, 0.32mmol) in 1, 2-dichloroethane (2mL) was added 1H-imidazole-2-carbaldehyde (0.03g, 0.36mmol) followed by 2 drops of acetic acid and Na (OAc)3BH (0.10g, 0.49 mmol). The reaction mixture was heated at 60 ℃ for 18 h. The mixture was cooled to room temperature and diluted with saturated aqueous NaHCO 3. The phases were extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2) to afford product 4 a.

1H NMR (300MHz, d6-DMSO) δ 11.83(s,1H),8.75(d, J ═ 2.4Hz,1H), 8.48(d, J ═ 2.4Hz,1H),8.41(s,1H),8.25(d, J ═ 3.8Hz,1H),8.07 (d, J ═ 8.3Hz,2H),7.56(d, J ═ 8.2Hz,1H),7.44(d, J ═ 8.2Hz,2H), 7.00-6.80(m,2H),4.22(m,1H),3.58(dd, J ═ 18.9,13.8Hz,2H),2.95 (m,1H),2.75-2.72(m,1H),2.36(s,3H), 2.04-2.04 (m,1H), 1.45-1H, 1-1.55-1H, and 1.93(m, 1H).

Formation of (S) -N- (1- ((1H-imidazol-2-yl) methyl) piperidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (589)

To a solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -1- (1H-imidazol-2-ylmethyl) -3-piperidinyl ] pyrimidin-4-amine 4a (0.08g, 0.13mmol) in THF (2.5mL) was added a solution of 1M LiOH (0.67mL, 0.65 mmol). The reaction mixture was heated at 120 ℃ for 10min in a microwave. The mixture was cooled to room temperature and diluted with brine. The liquid phase was extracted with CH2Cl2 and then twice with 20% isopropanol/CH 2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to afford the desired product 589 as a white solid.

1H NMR (300MHz, d6-DMSO) δ 8.77(d, J ═ 2.4Hz,1H),8.48(d, J ═ 2.4Hz,1H),8.42(s,1H),8.27(d, J ═ 3.9Hz,1H),8.05(d, J ═ 8.4Hz, 2H),7.62(d, J ═ 7.5Hz,1H),7.44(d, J ═ 8.2Hz,2H),4.17(m,1H), 3.30-3.18 (m,3H),2.90(m,1H),2.44-2.32(m,2H),2.35(s,3H),1.95(m, 1H),1.72-1.57(m,2H) and 1.51-1.40 ppm (m, 1H).

LCMS RT＝1.6(M+1)427.4。

Other analogs that can be prepared in the same manner as 589:

N- (1- ((1H-imidazol-5-yl) methyl) piperidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (594)

1H NMR (300MHz, d6-DMSO) δ 12.31(s,1H),11.86-11.77(m, 1H),8.70(d, J ═ 2.2Hz,1H),8.28(d, J ═ 2.4Hz,1H),8.15(d, J ═ 3.9Hz,1H), 8.10(d, J ═ 2.5Hz,1H),7.54(s,1H),7.31(d, J ═ 7.6Hz,1H), 6.87(s,1H),4.19(m,1H),3.57(d, J ═ 13.8Hz,1H),3.48(d, J ═ 13.8Hz,1H), 3.04(d, J ═ 8.3Hz,1H),2.80(d, J ═ 10.4, 10.10H), 1.48 (d, J ═ 13.8Hz,1H), 1H, 62-1H, 1m, 1H, and 1.35 ppm; LCMS RT ═ 1.6(M +1)427.4, (M-1) 425.4.

general scheme 5A

(a) (3S) -3-aminopiperidine-1-carboxylic acid tert-butyl ester, iPr2NEt base, 2-propanol, 80 ℃; (b) 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine, DME/H2O, K2CO3, tetrakis (triphenylphosphine) palladium (0), 90 ℃; (c) NaOMe/MeOH; (d) isopropanol/HCl; (e) methanesulfonyl chloride, iPr2NEt, CH2Cl2/DMF

formation of tert-butyl (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] piperidine-1-carboxylate (5a)

To a solution of tert-butyl (3S) -3-aminopiperidine-1-carboxylate (8.1g, 40.4mmol) and 2, 4-dichloro-5-fluoro-pyrimidine (6.6g, 39.8mmol) in isopropanol (80mL) was added N, N-diisopropyl-N-ethylamine (9.0mL, 51.7 mmol). The reaction mixture was warmed to 80 ℃ and stirred for 17 h. All volatiles were removed under reduced pressure and the residue was dissolved in EtOAc. The organic layer was partitioned with water and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the desired product 5 a.

LCMS RT＝3.3(M+1)331.1。

Formation of tert-butyl (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] piperidine-1-carboxylate (1b)

To a solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (1.8g, 4.2mmol) and tert-butyl (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] piperidine-1-carboxylate 5a (1.2g, 3.7mmol) in DME (15mL) and H2O (5mL) was added K2CO3(1.7g, 12.1 mmol). The mixture was purged with nitrogen for 15 min. Tetrakis (triphenylphosphine) palladium (0) (0.2g, 0.2mmol) was added to the mixture and the reaction mixture was heated at 90 ℃ for 3 days. The reaction was cooled to room temperature and then diluted with EtOAc/H2O. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The resulting residue was dissolved in CH2Cl2 and purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford the desired product 1 b.

LCMS RT＝4.6(M+1)601.2。

Formation of tert-butyl (3S) -3- [ [2- (5-chloro-1H-pyrrolo [5,4-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] piperidine-1-carboxylate (2b)

To tert-butyl (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] piperidine-1-carboxylate 1b (0.93g, 1.55mmol) in methanol (10mL) was added sodium methoxide (10mL of 1M solution). The reaction mixture was warmed to 45 ℃. After stirring for 30min, the reaction was cooled to room temperature and quenched by addition of water. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the desired product 2 b.

LCMS RT＝2.8(M+1)447.2。

Formation of S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine (5b)

to a suspension of (3S) -3- [ [2- (5-chloro-1H-pyrrolo [5,4-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester 2b (0.45g, 1.01mmol) in isopropanol (3mL) was added propan-2-ol hydrochloride (1.5mL of a 5M solution, 7.500 mmol). The reaction mixture was warmed to 80 ℃ and stirred for 3 hours. The mixture was cooled to room temperature and all volatiles were removed under reduced pressure. The resulting crude product 5b was used without further purification.

LCMS RT＝1.5(M+1)347.1。

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (methylsulfonyl) piperidin-3-yl) pyrimidin-4-amine (389)

To a solution of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine hydrochloride 5b (0.04g, 0.11mmol) in CH2Cl2(1.4mL) and DMF (0.30mL) was added N, N-diisopropyl-N-ethylamine (0.30mL, 1.70mmol) followed by methanesulfonyl chloride (0.02g, 0.20 mmol). The reaction mixture was stirred at room temperature for 17 h. The mixture was concentrated in vacuo, dissolved in 1mL of DMSO and purified by preparative HPLC (0.1% ammonium formate-H2O/acetonitrile) to obtain the desired product 389.

LCMS RT＝1.8(M+1)425.3。

Other analogs that can be prepared in the same manner as 389:

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (ethylsulfonyl) piperidin-3-yl) -5-fluoropyrimidin-4-amine (393)

LCMS RT＝1.8(M+1)439.3。

(S) -N- (1- (butylsulfonyl) piperidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (390)

LCMS RT＝2.1(M+1)467.3。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (cyclopropylsulfonyl) piperidin-3-yl) -5-fluoropyrimidin-4-amine (391)

LCMS RT＝1.9(M+1)451.3。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (isopropylsulfonyl) -piperidin-3-yl) pyrimidin-4-amine (394)

LCMS RT＝1.9(M+1)453.3。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (cyclopentylmethylsulfonyl) piperidin-3-yl) -5-fluoropyrimidin-4-amine (392)

LCMS RT＝2.3(M+1)493.5。

General scheme 5B

Formation of (R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) piperidin-3-yl) pyrimidin-4-amine (316)

To a solution of 2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine 5c (0.40g, 1.15mmol) in a 10:1 mixture of CH2Cl2/DMF (8mL) was added iPr2NEt (0.60mL, 3.46mmol) followed by 1-propanesulfonyl chloride (0.13mL, 1.15 mmol). The reaction mixture was stirred at room temperature for 5 h. The resulting residue was purified by preparative HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 316.

LCMS RT＝2.5(M+1)453.3。

Other analogs that can be prepared in the same manner as 316:

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (ethylsulfonyl) piperidin-3-yl) -5-fluoropyrimidin-4-amine (321)

LCMS RT＝2.7(M+1)439.1。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (isopropylsulfonyl) -piperidin-3-yl) pyrimidin-4-amine (322)

LCMS RT＝2.9(M+1)453.1。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) -piperidin-3-yl) pyrimidin-4-amine (306)

LCMS RT＝2.9(M+1)453.2。

General scheme 5C

(a) Cyclobutylformyl chloride, iPr2NEt, CH2Cl2/DMF

Formation of (S) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) (cyclobutyl) methanone (395)

To a solution of CH2Cl2(1.40mL) and DMF (300 μ of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine hydrochloride 5b (0.04g, 0.11mmol) was added N, N-diisopropyl-N-ethylamine (0.30mL, 1.70mmol) followed by cyclobutanecarbonyl chloride (0.01g, 0.12 mmol). the reaction mixture was stirred at room temperature for 17H.

LCMS RT＝1.9(M+1)429.3。

Other analogs that can be prepared in the same manner as 395:

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) propan-1-one (435)

LCMS RT＝1.8(M+1)403.4。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -2-methylpropan-1-one (436)

LCMS RT＝1.9(M+1)417.4。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -2, 2-dimethylpropan-1-one (437)

LCMS RT＝2.0(M+1)431.4。

(S) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) (cyclopropyl) methanone (451)

LCMS RT＝1.8(M+1)415.4。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-methoxypropan-1-one (396)

LCMS RT＝1.7(M+1)433.3。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) ethanone (434)

LCMS RT＝1.6(M+1)389.4。

(R) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-methylbutan-1-one (318)

LCMS RT＝2.9(M+1)431.1。

(R) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) (cyclopropyl) methanone (317)

LCMS RT＝2.7(M+1)415.1。

(R) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-methoxypropan-1-one (320)

LCMS RT＝2.5(M+1)433.1。

(R) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) (cyclobutyl) methanone (319)

LCMS RT＝2.8(M+1)429.1。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-methylbutan-1-one (332)

LCMS RT＝2.0(M+1)431.2。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) piperidin-1-yl) ethanone (485)

LCMS RT＝1.9(M+1)371.5。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -2-methoxyethanone (486)

LCMS RT＝1.9(M+1)401.5。

(S) -methyl 4- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) piperidin-1-yl) -4-oxobutanoate (487)

LCMS RT＝2.0(M+1)443.9。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) -3-methoxypropan-1-one (488)

LCMS RT＝1.9(M+1)415.5。

(S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) piperidin-1-yl) -3-methylbutan-1-one (489)

LCMS RT＝2.1(M+1)413.5。

general scheme 5D

(a) 1-methylcyclopropane-1-carboxylic acid, EDAC-HCl, HOBt, iPr2NEt, CH2Cl2/DMF

Formation of (S) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) (1-methylcyclopropyl) methanone (445)

To a solution of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine hydrochloride 5b (0.04g, 0.10mmol) in CH2Cl2(1.4mL) and DMF (0.3mL) was added N, N-diisopropyl-N-ethylamine (0.3mL, 1.72mmol), followed by 3- (ethyliminomethyleneamino) -N, N-dimethyl-propan-1-amine hydrochloride (0.02g, 0.12mmol), 1-hydroxybenzotriazole hydrate (0.02g, 0.12mmol), and 1-methylcyclopropane-1-carboxylic acid (0.01g, 0.12 mmol). The mixture was concentrated in vacuo, dissolved in 1mL of DMSO and purified by preparative HPLC (0.1% ammonium formate-H2O/acetonitrile) to obtain the desired product 445.

LCMS RT＝2.1(M+1)429.5。

An analog that can be prepared in the same manner as 445:

(S) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) (3-methyloxetan-3-yl) methanone (444)

LCMS RT＝1.7(M+1)445.4。

General scheme 5E

(a) Isopropyl isocyanate, iPr2NEt, CH2Cl2/DMF

Formation of (S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-isopropylpiperidine-1-carboxamide (439)

To a solution of CH2Cl2(1.4mL) and DMF (0.3mL) in (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine hydrochloride 5b (0.042g, 0.100mmol) was added N, N-diisopropyl-N-ethylamine (0.300mL, 1.720mmol) followed by isopropyl isocyanate (0.120 mmol). The reaction mixture was stirred at room temperature for 17 h. The mixture was concentrated in vacuo, dissolved in 1mL of DMSO and purified by preparative HPLC (0.1% ammonium formate-H2O/acetonitrile) to obtain the desired product 439.

LCMS RT＝1.8(M+1)432.4。

Other analogs can be prepared in the same manner as 439:

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-ethylpiperidine-1-carboxamide (438)

LCMS RT＝1.7(M+1)418.4。

Formation of 3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-propylpiperidine-1-carboxamide (196)

to a solution of 2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine 5b (0.020g, 0.058mmol) in a 1:1 mixture of CH2Cl 2/pyridine (2mL) was added propyl isocyanate (0.005mL, 0.058 mmol). The reaction mixture was stirred at room temperature for 12 h. The resulting residue was purified by HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 196.

LCMS RT＝2.6(M+1)432.1,(M-1)430.1。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-propylpiperidine-1-carboxamide (324)

LCMS RT＝2.6(M+1)432.2。

(S) -N-butyl-3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxamide (323)

LCMS RT＝2.7(M+1)446.2。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxamide (507)

LCMS (TFA buffer): room temperature 1.69min, ES + 390.

General scheme 5F

(a) methyl chloroformate, iPr2NEt, CH2Cl2/DMF

Formation of methyl (S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxylate (440)

To a solution of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine hydrochloride 5b (0.042g, 0.100mmol) in CH2Cl2(1.4mL) and DMF (0.3mL) was added N, N-diisopropyl-N-ethylamine (0.300mL, 1.720mmol) followed by methyl chloroformate (0.009g, 0.120 mmol). The reaction mixture was stirred at room temperature for 17 h. The mixture was concentrated in vacuo, dissolved in 1mL of DMSO and purified by preparative HPLC (0.1% ammonium formate-H2O/acetonitrile) to obtain the desired product 440.

LCMS RT＝1.8(M+1)405.4。

An analog that can be prepared in the same manner as 440:

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxylic acid ethyl ester (441)

LCMS RT＝1.9(M+1)419.4。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxylic acid isopropyl ester (442)

LCMS RT＝2.1(M+1)433.4。

General scheme 5G

(a) (2, 5-dioxopyrrolidin-1-yl) [ (3S) -tetrahydrofuran-3-yl ] carbonate, iPr2NEt, CH2Cl2/DMF

Formation of ((S) -tetrahydrofuran-3-yl) ester of (S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxylic acid (443)

to a solution of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-yl) pyrimidin-4-amine hydrochloride 5b (0.042g, 0.100mmol) in CH2Cl2(1.4mL) and DMF (0.3mL) was added N, N-diisopropyl-N-ethylamine (0.300mL, 1.720mmol) followed by (2, 5-dioxopyrrolidin-1-yl) [ (3S) -tetrahydrofuran-3-yl ] carbonate (0.028g, 0.120 mmol). The reaction mixture was stirred at room temperature for 17 h. The mixture was concentrated in vacuo, dissolved in 1mL of DMSO and purified by preparative HPLC (0.1% ammonium formate-H2O/acetonitrile) to obtain the desired product 443.

LCMS RT＝1.8(M+1)463.3。

General scheme 6A

(a) iPr2NEt, THF; (b) pd (PPh3)4, 2M Na2CO3, 80 ℃; (c)4N HCl/dioxane, MeOH, 80 ℃; (d) (S) -2, 5-dioxopyrrolidin-1-yltetrahydrofuran-3-yl carbonate, iPr2NEt, THF; (e) 25% NaOMe/MeOH or 1M LiOH, 150 ℃ microwave, 10min

formation of 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -cyclobutylcarbamic acid tert-butyl ester (6a)

A mixture of 2, 4-dichloro-5-fluoro-pyrimidine (0.97g, 5.81mmol) and iPr2NEt (2.53mL, 14.50mmol) in THF (50mL) was treated with tert-butyl 3-aminoacridine-1-carboxylate (1.00g, 5.81mmol) and stirred at room temperature until LCMS indicated completion. The mixture was concentrated to dryness, then diluted in water and extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give an oil, which was purified by silica gel chromatography (0-100% petroleum ether/EtOAc gradient). The solvent was removed under reduced pressure and dried under vacuum to yield 3.36g (89% yield) of a white solid.

LCMS:RT＝3.2min,ES303。

Formation of tert-butyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxylate (6b)

A gas of a solution of 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -cyclobutyl carbamic acid tert-butyl ester 6a (0.39g, 1.28mmol) and 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (0.60g, 1.39mmol) in DME (10mL) and 2M Na2CO3(5mL) was degassed with argon (3X vacuum and backfill), then treated with catalytic Pd (PPh3)4 and the mixture was heated in argon at 80 ℃. After 3h, the solvent was concentrated to a reduced volume, then diluted with EtOAc and filtered through florisil (40mL pad) and washed with EtOAc. The solvent was concentrated in vacuo and the resulting dark residue was purified by silica gel chromatography (0-100% petroleum ether/EtOAc gradient) to give 230mg (32% yield) of 6b as a white solid.

LCMS:RT＝4.7min,ES573。

Formation of N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine hydrochloride (6c)

A solution of tert-butyl 3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxylate 6b (0.23g, 0.40mmol) in methanol (10mL) was treated with 4N HCl/dioxane (5mL, 20mmol) and then heated at 80 ℃ for 30 min. The solvent was removed and the residue was dried under vacuum to obtain 240mg of a solid which was used without purification.

LCMS RT＝2.4min,ES473。

Formation of tetrahydrofuran-3-yl (S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxylate (422)

A suspension of N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine hydrochloride 6c (0.06g, 0.11mmol) in THF (1mL) was treated with iPr2NEt (0.30mL, 1.70mmol) and solid (S) -2, 5-dioxopyrrolidin-1-yltetrahydrofuran-3-yl carbonate (0.03g, 0.11mmol) was added. The resulting mixture was stirred at room temperature for 2H, then quenched with 200 μ L morpholine and evaporated to dryness to obtain tetrahydrofuran-3-yl (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxylic acid tetrahydrofuran-3-yl ester 6d using no purification.

LCMS RT＝3.8min,ES588。

Tetrahydrofuran-3-yl (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxylate 6d was dissolved in methanol (2mL), then treated with 25% sodium methoxide/methanol (0.5mL) and heated in a sealed tube at 60 ℃. LCMS showed complete reaction after 10 min. The resulting solution was quenched with saturated aqueous NH4Cl solution (0.5mL), then evaporated to dryness and the residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to obtain 25.9mg (55% yield) of the desired product 422 as a solid.

LCMS RT＝1.8min,ES433。

General scheme 6B

formation of 2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) azetidin-3-yl) pyrimidin-4-amine (423)

to a stirred suspension of N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine hydrochloride 6c (0.055g, 0.110mmol) in THF (1mL) was added iPr2NEt (0.300mL, 1.720mmol) followed by propane-1-sulfonyl chloride (0.012mL, 0.108 mmol). The resulting homogeneous pale yellow solution mixture was heated at 50 ℃ for 1h, at which time LCMS showed complete reaction. Morpholine (0.20mL) was added and the solution was evaporated to dryness. The resulting residue was dissolved in methanol (2mL), then treated with 25% sodium methoxide/methanol (0.5mL) and heated in a sealed tube at 60 ℃ for 10 min. The resulting solution was quenched with saturated aqueous NH4Cl solution (0.5mL) and then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to obtain 19.8mg (43% yield) of the desired product 423 as a solid.

LCMS RT＝2.6min,ES425。

other analogs that can be prepared in the same manner as 423:

2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (cyclopentyl-methanesulfonyl) azetidin-3-yl) -5-fluoropyrimidin-4-amine (469)

To a stirred solution of N- (azetidin-3-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine hydrochloride 6c (0.03g, 0.06mmol) in dichloromethane (1mL) was added iPr2NEt (0.33. mu.L, 1.90mmol) followed by cyclopentylmethanesulfonyl chloride (0.01g, 0.06 mmol). The resulting mixture was stirred at room temperature for 30min, at which time LCMS showed complete reaction. Morpholine (0.20mL) was added and the solution was evaporated to dryness. The resulting residue was dissolved in methanol (2mL), then treated with 25% sodium methoxide/methanol (0.5mL) and heated in a sealed tube at 60 ℃ for 10 min. The solution was quenched with saturated aqueous NH4Cl solution (0.5mL) and then evaporated to dryness. The resulting residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to obtain 27.4mg (88% yield) of the desired product 469 as a solid. LCMS RT 3.1min, ES + 465.

1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidin-1-yl) -2-methoxyethanone (468)

According to the procedure for compound 469, methoxyacetyl chloride was used to obtain 11.7mg (51% yield) of 468 as a white solid.

LCMS RT＝1.6min,ES390。

formation of 3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) azetidine-1-carboxamide (512)

According to the procedure for compound 469, using 61mg (0.11mmol) of 6c and trimethylsilyl isocyanate (15.14. mu.L, 0.11mmol) gives 87mg (79% yield) of 512 as a white solid:

LCMS RT＝2.4min,ES362。

General scheme 7

(a)2, 4-dichloro-5-fluoropyrimidine, iPr2NEt, THF; (b) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, Pd (PPh3)4, 2M Na2CO3, 90 ℃; (c)4N HCl/dioxane, MeOH, 80 ℃; (d) methanesulfonyl chloride, iPr2NEt, THF, room temperature; (e) 25% NaOMe/MeOH or 1M LiOH, 150 ℃ microwave, 10min

Formation of tert-butyl (S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) pyrrolidine-1-carboxylate (7a)

To a mixture of 2, 4-dichloro-5-fluoro-pyrimidine (1.75g, 10.48mmol) and iPr2NEt (3.27mL, 18.78mmol) in THF (50mL) was added tert-butyl (3S) -3-aminopyrrolidine-1-carboxylate (1.83mL, 10.48mmol) in THF (2 mL). The resulting solution was stirred at room temperature for 2 h. The mixture was concentrated to dryness, diluted with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo to give 3.41g of 7a as a white foamy solid.

LCMS RT＝3.0min.ES317。

Formation of tert-butyl (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1-carboxylate (7b)

A solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (2.41g, 5.60mmol) and tert-butyl (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] pyrrolidine-1-carboxylate 7a (1.69g, 5.30mmol) in DME (34mL) and 2M Na2CO3(8.5mL) was degassed with nitrogen (5min), treated with Pd (PPh3)4(0.31g, 0.27mmol), and then heated at 90 ℃ overnight. The resulting dark solution was filtered through florisil, washed with EtOAc, then concentrated in vacuo. The resulting residue was purified by silica gel chromatography ((0-100%) petroleum ether: EtOAc gradient). The solvent was removed under reduced pressure and dried under vacuum to give 1.33g (42% yield) of a white solid.

LCMS RT＝4.4min.ES588。

Formation of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -pyrrolidin-3-yl ] pyrimidin-4-amine (7c)

A solution of tert-butyl (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] pyrrolidine-1-carboxylate 7b (1.33g, 2.27mmol) in THF (25mL) is treated with hydrochloric acid (12mL of a 4M solution in dioxane, 48.00mmol) at room temperature. The reaction was then heated at 90 ℃ until LCMS showed completion. The mixture was concentrated to dryness and then dried under vacuum to give 1.04g (88% yield) of 7c as a tan solid.

LCMS RT＝2.3min.ES487。

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (methylsulfonyl) pyrrolidin-3-yl) pyrimidin-4-amine (398)

To a stirred solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -pyrrolidin-3-yl ] pyrimidin-4-amine hydrochloride 7c (0.05g, 0.10mmol) in THF (1mL) was added iPr2NEt (0.10mL, 0.57mmol) followed by methanesulfonyl chloride (0.04mL, 0.57 mmol). The resulting homogeneous pale yellow mixture was heated at 50 ℃ for 1h, at which time LCMS showed complete reaction. Morpholine (0.20mL) was added and the solution was evaporated to dryness. The resulting residue was dissolved in methanol (2mL), then treated with 25% sodium methoxide/methanol (0.5mL) and heated in a sealed tube at 60 ℃ until LCMS showed the reaction was complete. The resulting solution was quenched with saturated aqueous NH4Cl solution (0.5mL) and then evaporated to dryness. The residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to obtain 15.8mg (37% yield) of 398 as a solid.

LCMS RT＝1.7min.ES411。

other analogs that can be prepared in a similar manner to 398:

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (ethanesulfonyl) pyrrolidin-3-yl) -5-fluoropyrimidin-4-amine (399)

According to the procedure for compound 398, using 50mg (0.10mmol) of 7c and ethanesulfonyl chloride (54 μ L, 0.57mmol) 21.7mg (49% yield) as a solid 399 is obtained.

LCMS RT＝1.8min.ES425。

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (isopropylsulfonyl) pyrrolidin-3-yl) pyrimidin-4-amine (400)

According to the procedure for compound 398, using 2-propanesulfonyl chloride (82mg, 0.57mmol) gives 17.9mg (39% yield) of 400 as a solid.

LCMS RT＝1.9min.ES439。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (cyclopropylsulfonyl) pyrrolidin-3-yl) -5-fluoropyrimidin-4-amine (401)

Following the procedure for compound 398, using cyclopropylsulfonyl chloride (81mg, 0.57mmol) gave 17.1mg (37% yield) of 401 as a solid.

LCMS RT＝1.9min.ES437。

(S) -N- (1- (butylsulfonyl) pyrrolidin-3-yl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (402)

according to the procedure for compound 398, using butylsulfonyl chloride (90mg, 0.57mmol) 21mg (45% yield) of 402 as a solid was obtained.

LCMS RT＝2.1min.ES453。

formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (cyclopentylsulfonyl) pyrrolidin-3-yl) -5-fluoropyrimidin-4-amine (403)

following the procedure for compound 398, using cyclopentanesulfonyl chloride (97mg, 0.57mmol) gives 403 as a solid, 9.7mg (20% yield).

LCMS RT＝2.1min.ES465。

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (1- (propylsulfonyl) pyrrolidin-3-yl) pyrimidin-4-amine (410)

According to the procedure for compound 398, using propanesulfonyl chloride (20mg, 0.14mmol) gave 15.5mg (36% yield) of 410 as a solid.

LCMS RT＝2.0min.ES439。

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (cyclopentylmethylsulfonyl) pyrrolidin-3-yl) -5-fluoropyrimidin-4-amine (479)

following the procedure for compound 398, using cyclopentylmethylsulfonyl chloride (30mg, 0.16mmol) gave 26.7mg (58% yield) of 479 as a solid.

LCMS RT＝2.3min.ES479。

Formation of methyl (S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1-carboxylate (476)

According to the procedure for compound 398, using methyl chloroformate (20mg, 0.21mmol), 13.6mg (52% yield) was obtained as trifluoroacetate salt 476 after purification by preparative HPLC.

LCMS (ammonium formate buffer) RT ═ 2.6min. es + 391.

Formation of isopropyl (S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1-carboxylate (477)

According to the procedure 476, 11.3mg (42% yield) of 477 was obtained as the trifluoroacetate salt after purification by preparative HPLC using isopropyl chloride (20mg, 0.21 mmol).

LCMS (ammonium formate buffer) RT ═ 2.0min. es +419

(3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1-carboxylic acid (tetrahydrofuran-3-yl) methyl ester (484)

According to the procedure for compound 398, after preparative HPLC purification using methyl 2, 5-dioxopyrrolidin-1-yl (tetrahydrofuran-3-yl) carbonate (0.023g, 0.096mmol) gave 5.7mg (10% yield) of 484 as the trifluoroacetate salt.

LCMS (ammonium formate buffer) RT ═ 2.6min. es + 461.

formation of ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-1-yl) (tetrahydrofuran-3-yl) methanone (478)

Using tetrahydrofuran-3-carboxylic acid (35mg, 0.30mmol) according to the procedure for compound 398, 22.2mg (52% yield) of 478 as a solid was obtained.

LCMS (TFA buffer) RT ═ 1.6min. es + 431.

Formation of (S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-1-yl) ethanone (480)

According to the procedure for compound 398, acetyl chloride (45 μ L, 0.64mmol) was used to obtain 4.2mg (18% yield) of 480 as a solid.

LCMS (TFA buffer) RT ═ 1.6min, ES + 375.

Formation of (S) -1- (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-1-yl) -2-methoxyethanone (481)

Using methoxyacetyl chloride (50mg, 0.46mmol), 8.6mg (33% yield) of 481 as solid was obtained according to the procedure for compound 398.

LCMS (TFA buffer) RT ═ 1.6min, ES + 405.

Formation of (S) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-1-yl) (3-methyloxetan-3-yl) methanone (482)

According to the procedure for compound 398, using 3-methyloxetane-3-carboxylic acid (15mg, 0.13mmol), 17.7mg (42% yield) of 482 as a solid was obtained.

LCMS (TFA buffer) RT ═ 1.6min, ES + 431.

Formation of ((S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-1-yl) (morpholin-2-yl) methanone (483)

According to the procedure for compound 398, morpholine-2-carboxylic acid (25mg, 0.11mmol) was used to obtain 3.6mg (8% yield) 483 as a solid.

LCMS (TFA buffer): rt 1.4min, ES + 446.

The other enantiomer (8a) was obtained using the procedure equivalent to preparation 7 c.

Analogs that can be prepared from compound 8 a.

General scheme 8

(a) (S) -2, 5-dioxopyrrolidin-1-yltetrahydrofuran-3-yl carbonate, iPr2NEt, THF, RT; (b) 25% NaOMe/MeOH or 1M LiOH, 150 ℃ microwave, 10min

Formation of ((S) -tetrahydrofuran-3-yl) ester of (R) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidine-1-carboxylic acid (424)

According to the procedure for Compound 398, using tert-butyl (R) -3-aminopyrrolidine-1-carboxylate and (S) -2, 5-dioxopyrrolidin-1-yltetrahydrofuran-3-ylcarbonate, 19.8mg (47% yield) of 424 as a solid was obtained.

LCMS (TFA buffer) RT ═ 1.8min, ES + 447.

formation of (R) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-1-yl) (3-methyloxetan-3-yl) methanone (473)

According to the procedure for compound 482, (R) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (pyrrolidin-3-yl) pyrimidin-4-amine hydrochloride 8a and 3-methyloxetane-3-carboxylic acid (50mg, 0.46mmol) were used to obtain 18.6mg (44% yield) of 473 as a solid.

LCMS (TFA buffer) RT ═ 1.6min, ES + 431.

Formation of (S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- (1- (cyclopropylmethyl) pyrrolidin-3-yl) -5-fluoropyrimidin-4-amine (415)

A solution of (S) -2- (5-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (pyrrolidin-3-yl) pyrimidin-4-amine hydrochloride 7c (0.05g, 0.10mmol) in methanol (3mL) was treated with cyclopropanecarboxaldehyde (0.30mmol), sodium cyanoborohydride (0.30mmol) and potassium acetate (0.04g, 0.30mmol) and then stirred at 60 ℃ until the reaction was complete. Treatment with aqueous solution gave an oil which was dissolved in methanol (2mL) and then treated with 25% sodium methoxide/methanol (0.5mL) and heated at 60 ℃ in a sealed tube. LCMS showed complete reaction. The resulting solution was quenched with saturated aqueous NH4Cl solution (0.5mL), then evaporated to dryness and the residue was dissolved in DMSO and purified by reverse phase HPLC (ammonium formate buffer) to obtain 6.2mg (17% yield) of 415 as a solid.

LCMS RT＝1.5min,ES387。

Formation of N- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -1- (methylsulfonyl) cycloheximide-4-amine (496)

the desired product 496 was obtained as a solid using methanesulfonyl chloride according to the procedure for compound 398.

LCMS RT＝1.8min,ES439。

Formation of 1- (4- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cycloheximide-1-yl) ethanone (497)

The desired product 497 was obtained as a solid using acetyl chloride according to the procedure for compound 398.

LCMS RT＝1.7min,ES403。

formation of methyl 4- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cycloheximide-1-carboxylate (498)

the desired product 498 was obtained as a solid using methyl chloroformate according to the procedure for compound 398.

LCMS RT＝1.9min,ES419。

Formation of 4- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N-dimethylcycloheximide-1-carboxamide (499)

The desired product 499 is obtained as a solid using dimethylcarbamoyl chloride according to the procedure of compound 398.

LCMS RT＝1.8min,ES432。

Formation of 4- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cycloheximide-1-carboxamide (509)

the desired product 509 is obtained as a solid using trimethylsilyl isocyanate according to the procedure for compound 398.

LCMS RT＝1.6min,ES404。

Formation of 4- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-methylcyclo-hexylimine-1-carboxamide (506)

The desired product 506 was obtained as the hydrochloride salt after treatment with HCl/dioxane using methyl isocyanate according to the procedure for compound 398.

LCMS RT＝2.1min,ES418。

General scheme 11

(a) iPr2NEt, THF; (b) 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine, Pd (Ph3P)4, Na2CO3, DME, 130 ℃; (c) HCl/dioxane, CH2Cl 2; (d) 3-Methoxypropionyl chloride, iPr2NEt, CH2Cl2/DMF

Formation of (R) -3- ((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) -piperidine-1-carboxylic acid tert-butyl ester (11a)

To a solution of 2, 4-dichloro-5-fluoropyrimidine (0.43g, 2.59mmol) and tert-butyl (R) -3- (aminomethyl) piperidine-1-carboxylate (0.56g, 2.59mmol) in THF (50mL) was added iPr2NEt (0.45mL, 2.59 mmol). The reaction mixture was heated at 80 ℃ for 8 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (5-30% EtOAc/hexanes) to afford the desired product 11 a.

LCMS(M+1)345.1。

Formation of tert-butyl (R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (11b)

to a solution of degassed 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.71g, 1.65mmol), (R) -3- ((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) -piperidine-1-carboxylic acid tert-butyl ester 11a (1.19g, 3.60mmol) and aqueous K2CO3(2.48mL of a 2M solution, 4.97mmol) in THF (30mL) was added bis (tri-tert-butylphosphine) palladium (0) (0.17g, 0.33 mmol). The reaction mixture was degassed again for 15 min. The mixture was stirred at room temperature for 4h, concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (10% -80% EtOAc/hexanes) to afford the desired product 11 b.

LCMS(M+1)461.4,(M-1)460.7。

Formation of 2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-ylmethyl) pyrimidin-4-amine (11c)

To a solution of (R) -tert-butyl 3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate 11b (0.13g, 2.8mmol) in 5% MeOH/CH2Cl2 was added 0.7ml of 4N HCl/dioxane solution. The reaction mixture was stirred at room temperature for 12 h. The resulting precipitate was filtered and used without further purification.

LCMS(M+1)361.1。

Formation of (R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3-methoxypropan-1-one (327)

to a solution of 2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-ylmethyl) pyrimidin-4-amine 11c (0.04g, 0.11mmol) in a 10:1 mixture of CH2Cl2/DMF (1mL) was added iPr2NEt (0.058mL, 0.33mmol) and 3-methoxypropionyl chloride (0.02g, 0.17 mmol). After 12H, the solvent was concentrated in vacuo and the resulting crude product was purified by preparative HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 327.

LCMS(M+1)447.3。

other analogs that can be prepared by the same procedure as 327:

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-methoxyphenyl) methanone (113)

LCMS RT＝2.9(M+1)479.4,(M-1)477.6。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2- (thiophen-2-yl) ethanone (104)

LCMS RT＝2.8(M+1)485.3,(M-1)483.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (3, 5-difluorophenyl) methanone (108)

LCMS RT＝2.1(M+1)501.3。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanone (111)

LCMS RT＝2.5(M+1)403.4。

(R) -benzo [ b ] thiophen-2-yl (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) methanone (107)

LCMS RT＝3.2(M+1)521.3。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanone (37)

LCMS RT＝2.5(M+1)403.3。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (furan-2-yl) methanone (102)

LCMS RT＝2.7(M+1)455.3,(M-1)453.3。

(R) -2- (benzyloxy) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanone (106)

LCMS RT＝3.0(M+1)509.3,(M-1)507.5。

(R) -fluoroethyl 2-3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (126)

LCMS RT＝2.1(M+1)451.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (thiophen-2-yl) methanone (97)

LCMS RT＝2.9(M+1)471.2,(M-1)469.6。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2, 2-dimethylpropan-1-one (105)

LCMS RT＝3.0(M+1)445.3,(M-1)443.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2, 3-dimethylphenyl) methanone (157)

LCMS RT＝2.0(M+1)493.1。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-phenoxyethanone (94)

LCMS RT＝2.9(M+1)495.3,(M-1)493.5。

(R) -ethyl 2- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-oxoacetate (110)

LCMS RT＝2.5(M+1)461.3,(M-1)459.4。

(S) -ethyl 3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (33)

LCMS RT＝3.0(M+1)433.3,(M-1)431.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid prop-1-en-2-yl ester (74)

LCMS RT＝3.1(M+1)445.2,(M-1)443.4。

(R) -3- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonyl) pyrazine-2-carboxylic acid (82)

LCMS RT＝1.6(M+1)511.3。

(1S,2R) -2- ((R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonyl) cyclopropanecarboxylic acid (83)

LCMS RT＝1.6(M+1)473.4。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-methoxyethanone (45)

LCMS RT＝2.4(M+1)433.3,(M-1)431.4。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid allyl ester (17)

LCMS RT＝3.1(M+1)445.3,(M-1)443.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid prop-2-ynyl ester (122)

LCMS RT＝2.9(M+1)443.3,(M-1)441.5。

(S) -5- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -5-oxopentanoic acid ethyl ester (19)

LCMS RT＝2.8(M+1)503.4,(M-1)501.5。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid but-2-ynyl ester (127)

LCMS RT＝3.1(M+1)457.3,(M-1)455.6。

(S) -methyl 3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (23)

LCMS RT＝2.8(M+1)419.3,(M-1)417.3。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid allyl ester (119)

LCMS RT＝3.1(M+1)445.4,(M-1)443.5。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid but-2-ynyl ester (30)

LCMS RT＝3.1(M+1)457.3,(M-1)455.6。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid tert-butyl ester (15)

LCMS RT＝2.7(M+1)461.3。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid isobutyl ester (28)

LCMS RT＝3.3(M+1)461.4。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) propan-1-one (32)

LCMS RT＝1.9(M+1)417.2。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-methylpropan-1-one (34)

LCMS RT＝3.2(M+1)447.4,(M-1)445.5。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid isopropyl ester (35)

LCMS RT＝3.0(M+1)447.3,(M-1)445.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (cyclopentyl) methanone (99)

LCMS RT＝3.1(M+1)457.3,(M-1)455.4。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) but-2-en-1-one (41)

LCMS RT＝2.7(M+1)429.3,(M-1)427.4。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3, 3-dimethylbut-1-one (42)

LCMS RT＝3.1(M+1)459.3,(M-1)457.4。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3,3, 3-trifluoropropan-1-one (44)

LCMS RT＝2.8(M+1)471.3,(M-1)469.4。

(S) -2- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -N, N, N-trimethyl-2-oxoethylammonium (43)

LCMS RT＝2.4(M+1)460.3,(M-1)458.5。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2- (dimethylamino) ethanone (46)

LCMS RT＝2.2(M+1)446.4,(M-1)444.5。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2- (pyridin-3-yl) ethanone (47)

LCMS RT＝2.4(M+1)480.3,(M-1)478.6。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) but-3-en-1-one (49)

LCMS RT＝2.7(M+1)429.3,(M-1)427.4。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2- (1H-tetrazol-1-yl) ethanone (48)

LCMS RT＝2.4(M+1)471.3,(M-1)469.4。

(R) -5- ((S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonyl) dihydrofuran-2 (3H) -one (51)

LCMS RT＝1.7(M+1)472.9。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4 ylamino) methyl) piperidin-1-yl) -2- (1H-imidazol-1-yl) ethanone (50)

LCMS RT＝2.3(M+1)469.3,(M-1)467.4。

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) pent-4-yn-1-one (52)

LCMS RT＝1.9(M+1)441.3。

(R) -5- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -5-oxopentanoic acid (53)

LCMS RT＝1.8(M+1)475.3,(M-1)473.4。

(R) -2- (2- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-oxoethoxy) acetic acid (54)

LCMS RT＝1.7(M+1)477.3,(M-1)475.4。

(1S,3R) -3- ((R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonyl) cyclopentanecarboxylic acid (55)

LCMS RT＝2.5(M+1)501.3,(M-1)499.6。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-fluorophenyl) methanone (58)

LCMS RT＝2.9(M+1)483.3,(M-1)481.5。

(R) -5- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3, 3-dimethyl-5-oxopentanoic acid (80)

LCMS RT＝1.9(M+1)503.3。

2-chloro-1- ((R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) propan-1-one (93)

LCMS RT＝2.9(M+1)451.2,(M-1)449.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (cyclohexyl) methanone (95)

LCMS RT＝3.2(M+1)471.3,(M-1)449.4。

(R) -3- ((2- (5-amino-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid tert-butyl ester (114)

LCMS RT＝2.7(M+1)461.3。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid ethyl ester (495)

LCMS RT＝1.7(M+1)385.4。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-methoxyethanone (491)

LCMS RT＝1.7(M+1)415.4。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methylpiperidin-1-yl) -3-methoxypropan-1-one (493)

LCMS RT＝1.7(M+1)429.5。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) -3-methylbutan-1-one (494)

LCMS RT＝1.9(M+1)427.5。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid 2-methoxyethyl ester (24)

LCMS RT＝2.8(M+1)463.2,(M-1)461.3。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-acetophenone (56)

LCMS RT＝2.9(M+1)479.3,(M-1)477.4。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3-methyl-2-buten-1-one (57)

LCMS RT＝2.8(M+1)443.3,(M-1)441.4。

(R) -4- (methoxycarbonyl) phenyl 3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (63)

LCMS RT＝3.2(M+1)539.3,(M-1)537.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid phenyl ester (68)

LCMS RT＝3.2(M+1)481.4,(M-1)479.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid 2-chlorophenyl ester (70)

LCMS RT＝3.3(M+1)515.3,(M-1)513.3。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid 2-methoxyphenyl ester (69)

LCMS RT＝3.2(M+1)511.3。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid p-tolyl ester (71)

LCMS RT＝3.4(M+1)495.3,(M-1)493.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid 3- (trifluoromethyl) phenyl ester (72)

LCMS RT＝3.5(M+1)549.3,(M-1)547.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid 4-fluorophenyl ester (73)

LCMS RT＝3.3(M+1)499.3,(M-1)497.4。

(R) -2- (1- (2- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-oxoethyl) cyclopentyl) acetic acid (81)

LCMS RT＝2.0(M+1)529.3。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-chlorophenyl) methanone (84)

LCMS RT＝2.0(M+1)499.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (3, 4-difluorophenyl) methanone (85)

LCMS RT＝2.1(M+1)501.3。

(R) -2-chloro-1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanone (92)

LCMS RT＝2.7(M+1)437.2,(M-1)435.3。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2, 6-dichlorophenyl) methanone (96)

LCMS RT＝2.9(M+1)535.2,(M-1)533.2。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2- (4-fluorophenyl) ethanone (98)

LCMS RT＝2.9(M+1)497.3,(M-1)495.4。

(R) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-cyclopentylethanone (100)

LCMS RT＝3.1(M+1)471.3,(M-1)469.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (pyrazin-2-yl) methanone (111)

LCMS RT＝2.5(M+1)467.2,(M-1)465.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (furan-2-yl) methanone (186)

LCMS RT＝2.7(M+1)455.3,(M-1)453.3。

(R) -benzo [ d ] [1,3] dioxol-5-yl (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) methanone (103)

LCMS RT＝2.8(M+1)509.3,(M-1)507.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2, 4-difluorophenyl) methanone (152)

LCMS RT＝2.8(M+1)501.3,(M-1)499.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2- (methylamino) phenyl) methanone (112)

LCMS RT＝3.0(M+1)494.3,(M-1)492.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (3, 4-dimethoxyphenyl) methanone (109)

LCMS RT＝2.7(M+1)525.3,(M-1)523.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (3, 5-difluorophenyl) methanone (86)

LCMS RT＝2.8(M+1)501,(M-1)499。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (6-fluoro-4H-benzo [ d ] [1,3] dioxin-8-yl) methanone (142)

LCMS RT＝2.8(M+1)541.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (o-tolyl) methanone (143)

LCMS RT＝2.9(M+1)479.4,(M-1)477.6。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2- (trifluoromethyl) phenyl) methanone (146)

LCMS RT＝3.0(M+1)533.3,(M-1)531.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2, 3-dihydroxybenzofuran-6-yl) methanone (145)

LCMS RT＝2.9(M+1)507.3,(M-1)505.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2, 4-dichlorophenyl) methanone (147)

LCMS RT＝3.2(M+1)533.3,(M-1)531.4。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-ethoxyphenyl) methanone (158)

LCMS RT＝3.0(M+1)509.4,(M-1)507.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-methoxy-3-methylphenyl) methanone (148)

LCMS RT＝3.0(M+1)509.3,(M-1)507.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2, 5-difluorophenyl) methanone (151)

LCMS RT＝2.9(M+1)501.2,(M-1)499.5。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-phenoxyphenyl) methanone (150)

LCMS RT＝3.2(M+1)557.3,(M-1)555.6。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2, 4-diethoxyphenyl) methanone (154)

LCMS RT＝2.3(M+1)525.3,(M-1)523.2。

(R) - (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (cyclopropyl) methanone (325)

LCMS RT＝2.7(M+1)429.2。

(R) - (3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-methoxyphenyl) methanone (272)

LCMS RT＝2.5(M+1)461.3。

(R) -1- (3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanone (268)

LCMS RT＝2.1(M+1)369.3。

(R) - (3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) (phenyl) methanone (271)

LCMS RT＝2.5(M+1)431.4。

(R) -1- (3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) butan-1-one (270)

LCMS RT＝2.4(M+1)397.3。

(R) - (3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) (phenyl) -1-propanone (269)

LCMS RT＝2.3(M+1)383.3。

(S) -1- (3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) -1-butanone (225)

LCMS RT＝2.4(M+1)397.4。

In a similar manner to the preparation of compound 327, a compound having an absolute stereochemistry opposite was prepared as follows:

General scheme 12A

(a) Tert-butyl isocyanate, pyridine, CH2Cl2

Formation of (S) -N-tert-butyl-3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxamide (20)

To a solution of (R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-ylmethyl) pyrimidin-4-amine 12a (0.013g, 0.036mmol) in a mixture of pyridine/CH 2Cl2(1mL of 1:1 mixture) was added tert-butyl isocyanate (0.005mL, 0.046 mmol). The reaction mixture was stirred at 40 ℃ for 12 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 20.

LCMS RT＝3.0(M+1)460.4,(M-1)458.4。

Other analogs that can be prepared in the same manner as 20:

(R) -N-tert-butyl-3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxamide (128)

LCMS RT＝3.0(M+1)460.4,(M-1)458.4。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (thiophen-3-yl) piperidine-1-carboxamide (22)

LCMS RT＝2.9(M+1)486.3,(M-1)484.6。

(S) -ethyl 2- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonamido) acetate (25)

LCMS RT＝2.6(M+1)490.3,(M-1)488.4。

(S) -ethyl 3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonyl carbamate (26)

LCMS RT＝2.5(M+1)476.3,(M-1)474.5。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-isopropylpiperidine-1-carboxamide (27)

LCMS RT＝2.7(M+1)446.4,(M-1)444.5。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-methylpiperidine-1-carboxamide (29)

LCMS RT＝2.4(M+1)418.3,(M-1)416.1。

(S) -N-allyl-3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxamide (39)

LCMS RT＝2.6(M+1)444.4,(M-1)442.4。

(S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (pyridin-3-yl) piperidine-1-carboxamide (40)

LCMS RT＝2.5(M+1)481.3,(M-1)479.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3-fluorophenyl) piperidine-1-carboxamide (75)

LCMS RT＝3.0(M+1)498.3,(M-1)496.5。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3-methoxyphenyl) piperidine-1-carboxamide (76)

LCMS RT＝2.9(M+1)510.3,(M-1)508.5。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3-acetylphenyl) piperidine-1-carboxamide (77)

LCMS RT＝2.8(M+1)522.3,(M-1)520.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-m-tolylpiperidine-1-carboxamide (78)

LCMS RT＝3.0(M+1)494.3,(M-1)492.4。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (3- (trifluoromethyl) phenyl) piperidine-1-carboxamide (79)

LCMS RT＝3.3(M+1)548.3,(M-1)546.4。

(R) -ethyl 3- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonamido) propionate (118)

LCMS RT＝2.6(M+1)504.2,(M-1)502.5。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (5-methyl-2- (trifluoromethyl) furan-3-yl) piperidine-1-carboxamide (120)

LCMS RT＝3.2(M+1)552.4,(M-1)550.5。

(R) -methyl 2- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonamido) acetate (125)

LCMS RT＝2.6(M+1)490.4,(M-1)488.6。

(R) -N-tert-butyl-3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxamide (117)

LCMS RT＝2.8(M+1)486.3,(M-1)484.5。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (thiophen-2-yl) piperidine-1-carboxamide (129)

LCMS RT＝2.8(M+1)486.3,(M-1)484.5。

(R) -methyl 3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carbonyl carbamate (131)

LCMS RT＝1.6(M+1)462.7。

(R) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N- (4-methylthiophen-2-yl) piperidine-1-carboxamide (130)

LCMS RT＝2.0(M+1)500.6。

(S) -3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N, N-dimethylpiperidine-1-carboxamide (228)

LCMS RT＝2.3(M+1)398.3。

(R) -3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-methylpiperidine-1-carboxamide (274)

LCMS RT＝2.1(M+1)384.3。

(R) -N-ethyl-3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidine-1-carboxamide (275)

LCMS RT＝2.2(M+1)398.4。

(R) -3- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-propylpiperidine-1-carboxamide (276)

LCMS RT＝2.3(M+1)412.4。

general scheme 12B

(b) Propyl isocyanate, iPr2NEt, pyridine, CH2Cl2

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (methylsulfonyl) -piperidin-3-yl) methyl) pyrimidin-4-amine (36)

To a solution of (R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-ylmethyl) pyrimidin-4-amine 12a (0.018g, 0.050mmol) and pyridine (0.7mL) in CH2Cl2(0.7mL) was added methanesulfonyl chloride (0.004mL, 0.050 mmol). The reaction mixture was stirred at room temperature for 24 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 36.

LCMS RT＝2.7(M+1)439.3,(M-1)437.3。

Other analogs that can be prepared in the same manner as 36:

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((1- (cyclopropylsulfonyl) piperidin-3-yl) methyl) -5-fluoropyrimidin-4-amine (61)

LCMS RT＝2.8(M+1)465.3,(M-1)463.3。

(R, E) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (styrylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (60)

LCMS RT＝3.2(M+1)525.3。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (3-methoxyphenylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (62)

LCMS RT＝3.1(M+1)531.3,(M-1)529.4。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (4-fluorophenylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (64)

LCMS RT＝3.1(M+1)519.3,(M-1)517.4。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (3-fluorophenylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (65)

LCMS RT＝3.1(M+1)519.2,(M-1)517.4。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (m-tolylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (66)

LCMS RT＝3.2(M+1)515.3,(M-1)513.4

(R) -N- ((1- (3-bromophenylsulfonyl) piperidin-3-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (67)

LCMS RT＝3.3(M+1)579.2,(M-1)577.2。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (phenylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (87)

LCMS RT＝2.1(M+1)501.3。

(R) -N- ((1- (3-bromophenylsulfonyl) piperidin-3-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (88)

LCMS RT＝2.0(M+1)561.3。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (phenylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (89)

LCMS RT＝2.1(M+1)507.2。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (2-fluorophenylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (90)

LCMS RT＝2.1(M+1)519.2。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (1-methyl-1H-imidazol-4-ylsulfonyl) piperidin-3-yl) methyl) pyrimidin-4-amine (91)

LCMS RT＝1.8(M+1)505.3。

General scheme 12C

(a) (R) -3-bromo-2-methylpropan-1-ol, iPr2NEt, THF

Formation of (S) -3- ((S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-methylpropan-1-ol (135)

To a solution of (R) -3-bromo-2-methylpropan-1-ol (0.006mL, 0.055mmol) and (R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (piperidin-3-ylmethyl) -pyrimidin-4-amine 12a (0.020g, 0.055mmol) in CH3CN (2mL) was added K2CO3(0.023g, 0.165 mmol). The reaction mixture was heated at 80 ℃ for 24 h. The solvent was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 135.

LCMS RT＝2.5(M+1)433.4,(M-1)431.6。

Other analogs that can be prepared in the same manner as 135:

(S) -1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3, 3-dimethyl-2-butanone (140)

LCMS RT＝2.9(M+1)459.3,(M-1)457.5。

(R) -3- ((S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-methylpropan-1-ol (141)

LCMS RT＝1.4(M+1)433.5。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (2-methylbenzyl) piperidin-3-yl) methyl) pyrimidin-4-amine (139)

LCMS RT＝3.2(M+1)465.3,(M-1)463.4。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (3-methylbenzyl) piperidin-3-yl) methyl) pyrimidin-4-amine (137)

LCMS RT＝3.1(M+1)465.4,(M-1)463.6。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((1- (cyclohexylmethyl) piperidin-3-yl) methyl) -5-fluoropyrimidin-4-amine (134)

LCMS RT＝3.1(M+1)457.3,(M-1)455.5。

(S) -2- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanol (133)

LCMS RT＝2.3(M+1)405.3,(M-1)403.6。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((1- (2, 2-dimethoxyethyl) piperidin-3-yl) methyl) -5-fluoropyrimidin-4-amine (132)

LCMS RT＝2.2(M+1)449.7。

(S, E) -4- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) 2-butenoic acid methyl ester (138)

LCMS RT＝2.8(M+1)459.3,(M-1)457.7。

(S) -4- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) butyronitrile (666)

LCMS RT＝2.6(M+1)428.3,(M-1)426.5。

(S) -3- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) propionitrile (667)

LCMS RT＝1.4(M+1)414.5。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (pyrimidin-2-yl) piperidin-3-yl) methyl) pyrimidin-4-amine (124)

LCMS RT＝3.1(M+1)439.3(M-H)437.4。

General scheme 13

(a) Benzyl chloroformate, triethylamine, CH2Cl 2; (b) dimethyl sulfoxide, oxalyl chloride, triethylamine, CH2Cl 2; (c) DAST, THF; (d) 10% Pd/C, MeOH, H2, di-tert-butyl dicarbonate; (e) LiOH, THF/MeOH/water; (f) pyridine, di-tert-butyl dicarbonate, NH4HCO3, 1, 4-dioxane; (g) triethylamine, TFAA, CH2Cl 2; (h) raney Ni, MeOH, H2; (i) 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, iPr2NEt, THF, microwave, 130 ℃,15 min; (j) NaOMe, MeOH; (k) isopropanol/HCl, 45 ℃; (l) 3-methoxy chloropropionyl, iPr2NEt, CH2Cl2, DMF

Formation of 1-benzyl 2-methyl 4-hydroxypiperidine-1, 2-dicarboxylate (13b)

Benzyl chloroformate (6.20mL, 43.43mmol) was added dropwise over 10min to a cold solution (5 ℃) of methyl 4-hydroxypiperidine-2-carboxylate 13a (5.17g, 32.48mmol) and triethylamine (6.00mL, 43.05mmol) in CH2Cl2(135 mL). The resulting solution was stirred at 5 ℃ for 1h, and then allowed to warm to room temperature. The reaction mixture was diluted with water and the layers were separated. The aqueous solution was re-extracted with CH2Cl2 and the combined organics were dried over MgSO4, filtered and evaporated to dryness. The crude product was passed through a silica gel packed column, eluting with 30-80% EtOAc in hexanes to afford the desired product 13 b.

1H NMR (300MHz, CDCl3) Δ 7.36-7.33(m,5H),5.17(s,2H), 4.89-4.78(m,1H),4.18-4.09(m,1H),3.96(s,1H),3.76-3.70(m,3H), 3.53-3.41(m,2H),2.44(s,1H),1.96-1.91(m,1H) and 1.71(s,2H) ppm.

4-Oxopiperidine-1, 2-dicarboxylic acid 1-benzyl 2-methyl ester (13c)

To a 500mL flask flame dried under N2 was added CH2Cl2(65mL), followed by oxalyl chloride (5.2mL, 59.6 mmol). After cooling the reaction mixture to-78 deg.C, dimethyl sulfoxide (8.4mL, 118.4mmol) was added followed by 1-benzyl 2-methyl 4-hydroxypiperidine-1, 2-dicarboxylate 13b (8.6g, 29.2mmol) in CH2Cl2(65 mL). The reaction was stirred at-78 ℃ for 45 min. Triethylamine (24.4mL, 175.1mmol) was added to the mixture and the mixture was allowed to warm to room temperature. The reaction mixture was diluted with CH2Cl2 and 1N HCl. The layers were separated and the liquid phase was re-extracted with CH2Cl 2. The combined organic phases were washed with water, dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by silica gel chromatography (30-50% EtOAc/hexanes) to give the desired product 13 c.

1H NMR (300MHz, CDCl3) δ 7.37(s,5H),5.24-5.18(m,3H), 5.02(s,1H),4.12(q, J ═ 7.1Hz,1H),3.74-3.65(m,3H),2.79(d, J ═ 7.0Hz,2H) and 2.53(s,2H) ppm.

Formation of 1-benzyl 2-methyl 4, 4-difluoropiperidine-1, 2-dicarboxylate (13d)

To a cold solution (0 ℃ C.) of 1-benzyl 2-methyl 4-oxopiperidine-1, 2-dicarboxylate 13c (7.4g, 25.4mmol) in THF (75mL) was added (diethylamino) sulfur trifluoride (25.0mL, 189.2 mmol). After 2h at 0 ℃ the reaction was quenched carefully with water. The mixture was diluted with EtOAc and water. Solid NaHCO3 was added to adjust the pH to neutral. The layers were separated and the organics were washed with water, brine, dried over MgSO4, filtered and evaporated to dryness. The crude product was passed through a silica gel packed column eluting with 15-20% EtOAc in hexanes to afford the desired product 13 d.

1H NMR (300MHz, CDCl3) δ 7.37-7.31(m,5H),5.30-5.06(m, 3H),4.45-4.22(m,1H),3.76-3.52(m,3H),3.45(d, J ═ 9.0Hz,1H), 2.76(s,1H) and 2.23-1.93(m,3H) ppm.

Formation of 1-tert-butyl 2-methyl 4, 4-difluoropiperidine-1, 2-dicarboxylate (13e)

A Parr flask (1L) was charged with 10% palladium on carbon (0.57g) and di-tert-butyl dicarbonate (4.47g, 20.49 mmol). 1-benzyl 2-methyl-4, 4-difluoropiperidine-1, 2-dicarboxylate 13d (4.28g, 13.66mmol) in methanol (150mL) was added and hydrogen was introduced via a shaker (46 PSI). The reaction mixture was shaken at room temperature for one week. The mixture was filtered through celite and washed thoroughly with CH2Cl 2. The filtrate was concentrated to dryness and redissolved in 10% EtOAc/hexanes. The crude product was purified by silica gel chromatography (10-20% EtOAc/hexanes) to obtain 5.1g of the desired product as a mixture 13e and about 840mg of contaminating product. The crude mixture obtained was used directly in the next step without further purification.

1H NMR (300MHz, CDCl3) δ 5.08(s,1H),4.89(s,1H),4.12(q, J ═ 7.2Hz,1H),3.76(s, H),3.74(s,3H),3.34(s,1H),3.29(t, J ═ 7.2Hz,1H), 2.77(s,1H),2.04(m,1H) and 1.53(s,9H) ppm.

Formation of 1- (tert-butoxycarbonyl) -4, 4-difluoropiperidine-2-carboxylic acid (13f)

To a solution of 1-tert-butyl 2-methyl 4, 4-difluoropiperidine-1, 2-dicarboxylate 13e (4.6g, 16.5mmol) in THF (18mL), methanol (18mL) and H2O (9mL) was added lithium hydroxide (3.45g, 82.22 mmol). The reaction mixture was stirred at room temperature for 1 h. All volatiles were removed under reduced pressure. The residue was diluted with a small amount of water and ether. The layers were separated and the organic phase was discarded. The liquid phase was acidified to pH3 by addition of saturated aqueous KHSO4 solution. The product was extracted with EtOAc. The organic phase was washed with water, dried over MgSO4, filtered and evaporated to dryness. The resulting product was used without further purification.

1H NMR (300MHz, CDCl3) δ 5.14(s,1H),4.93(s,1H),4.12(q, J ═ 7.1Hz,1H),3.28(d, J ═ 6.3Hz,1H),2.75(d, J ═ 8.7Hz,1H),2.06(d, J ═ 8.5Hz,1H),1.99-1.81(m,1H) and 1.47(s,9H) ppm.

Formation of tert-butyl 2-carboxamido-4, 4-difluoropiperidine-1-carboxylate (13g)

To a solution of 13f (1.67g, 6.30mmol) of 1-tert-butoxycarbonyl-4, 4-difluoro-piperidine-2-carboxylic acid in 1, 4-dioxane (12mL) was added pyridine (0.35mL, 4.33mmol), followed by di-tert-butyl dicarbonate (1.78g, 8.17mmol) and ammonium bicarbonate (0.63g, 7.86 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with water, saturated aqueous KHSO4 solution, brine, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was used without further purification.

formation of tert-butyl 2-cyano-4, 4-difluoropiperidine-1-carboxylate (13h)

To a solution of 13g (1.72g, 6.51mmol) of tert-butyl 2-carboxamido-4, 4-difluoro-piperidine-1-carboxylate in CH2Cl2(50mL) was added N, N-triethylamine (2.03mL, 14.61mmol), followed by dropwise addition of (2,2, 2-trifluoroacetyl) -2,2, 2-trifluoroacetate (1.02mL, 7.32 mmol). After 15min, the mixture was diluted with saturated aqueous NaHCO3 and the layers were separated. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The crude residue was passed through a silica gel packed column and eluted with 10-30% EtOAc/hexanes to give the desired product for 13 h.

1H NMR (300MHz, CDCl 3). delta.5.43 (s,1H),4.19(s,1H),3.25(s, 1H),2.36(m,1H),2.23-2.12(m,1H),1.83(s,1H),1.70(s,1H) and 1.53-1.46 (m,9H) ppm.

Formation of tert-butyl 2- (aminomethyl) -4, 4-difluoropiperidine-1-carboxylate (13i)

raney nickel (0.36mL, 5.40mmol) was washed with MeOH (2X) and loaded into a parr shaker. A solution of tert-butyl 2-cyano-4, 4-difluoro-piperidine-1-carboxylate in methanol (50mL) for 13h (1.33g, 5.40 mmol). The reaction mixture was subjected to hydrogenation conditions overnight on a parr shaker (46 PSI). The mixture was filtered through celite and washed thoroughly with CH2Cl 2. All volatiles were removed under reduced pressure and the crude material was used without further purification.

2- ((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -4, 4-difluoropiperidine-1-carboxylic acid tert-butyl ester (13j)

To a solution of tert-butyl 2- (aminomethyl) -4, 4-difluoro-piperidine-1-carboxylate 13i (0.10g, 0.41mmol) and 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine (0.18g, 0.38mmol) in THF (2mL) was added iPr2NEt (0.20mL, 1.15 mmol). The reaction mixture was heated in a microwave at 130 ℃ for 15 min. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The crude residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford the desired product 13 j.

LCMS(M-1)649.52。

Formation of tert-butyl 2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -4, 4-difluoropiperidine-1-carboxylate (13k)

To a solution of 2- [ [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] methyl ] -4, 4-difluoro-piperidine-1-carboxylic acid tert-butyl ester 13j (0.23g, 0.35mmol) in methanol (4mL) was added sodium methoxide (4mL of 25% w/v, 18.51 mmol). The reaction mixture was stirred at room temperature for 15 min. All volatiles were removed under reduced pressure and the residue was quenched with water. EtOAc was added and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The crude residue was pure enough to be used without further purification.

LCMS(M+1)497.44,(M-1)495.52。

Formation of 2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((4, 4-difluoropiperidin-2-yl) methyl) -5-fluoropyrimidin-4-amine (13m)

to a solution of tert-butyl 2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -4, 4-difluoropiperidine-1-carboxylate 13k (0.09g, 0.18mmol) in 2-propanol (2mL) was added propan-2-ol hydrochloride (2mL, 6M, 12.00 mmol). After stirring the reaction mixture at room temperature for 17h, 1mL of IPA/HCl was added and the reaction mixture was heated at 45 deg.C for 1 h. All volatiles were removed under reduced pressure and the residue was used directly in the next step without further purification.

LCMS(M+1)397.40,(M–1)395.44。

Formation of 1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -4, 4-difluoropiperidin-1-yl) -3-methoxypropan-1-one (584)

To a solution of 2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- [ (4, 4-difluoro-2-piperidinyl) methyl ] -5-fluoro-pyrimidin-4-amine 13k (0.086g, 0.198mmol) in CH2Cl2(1mL), DMF (0.5mL), and iPr2NEt (0.10mL, 0.57mmol) was added 3-methoxypropionyl chloride (2.43g, 0.20 mmol). The reaction mixture was stirred at room temperature for 17 h. All volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography to yield a mixture enriched in the desired product 13, which was purified by preparative HPLC.

1H NMR (300MHz, d6-DMSO) δ 12.45(M,1H),8.71(d, J ═ 8.5Hz, 1H),8.31(M,2H),8.01(M,1H),5.33(s,1H),4.62-4.43(M,2H), 4.39-3.72(M,5H),3.68(s,2H),3.43-3.40(M,1H),3.15(s,1H),3.07 (s,1H),2.33(s,2H) and 2.08(s,2H) ppm LCMS (M +1)483.44, (M-1) 481.52.

Other analogs that can be prepared in the same manner as 584 are described below:

N- ((4-benzylmorpholin-2-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (388)

1H NMR (300MHz, CDCl3) δ 9.14-9.09(m,1H),8.81-8.71(m, 1H),8.29(d, J ═ 2.3Hz,1H),8.07(d, J ═ 2.5Hz,1H),7.34(s,5H), 5.58-5.41 (m,1H),3.92-3.43(m,4H),2.83-2.72(m,2H),2.38-2.28(m, 2H) and 1.62(m,2H) ppm.

LCMS RT＝1.8(M+1)453.4。

2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-isopropylmorpholine-4-carboxamide (446)

LCMS RT＝1.7(M+1)448.4

2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxylic acid isopropyl ester (447)

LCMS RT＝2.0(M+1)449.3

2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((4- (isopropylsulfonyl) morpholin-2-yl) methyl) pyrimidin-4-amine (448)

LCMS RT＝1.9(M+1)469.3

1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) propan-1-one (449)

LCMS RT＝1.7(M+1)419.4

(2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) (cyclopropyl) methanone (450)

LCMS RT＝1.7(M+1)431.4

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxylic acid tert-butyl ester (515)

1H NMR (300MHz, CDCl3) δ 10.38(s,1H),8.81(d, J ═ 2.0Hz,1H), 8.49(d, J ═ 2.3Hz,1H),8.38(s,1H),8.08(d, J ═ 3.4Hz,1H),6.11(d, J ═ 5.0Hz,1H),4.44(d, J ═ 9.4Hz,1H),4.02-3.62(m,6H),3.55(dd, J ═ 2.4,12.1Hz,1H),3.35-3.27(m,1H) and 1.40-1.22(m,9H) ppm

LCMS RT＝2.5(M+1)463.5。

1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) propan-1-one (516)

LCMS RT＝1.9(M+1)419.4

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-propylmorpholine-4-carboxamide (517)

1H NMR (300MHz, d6-DMSO) δ 12.54(s,1H),8.76(d, J ═ 2.0Hz,1H), 8.46(s,1H),8.32(d, J ═ 2.1Hz,1H),8.26(d, J ═ 3.9Hz,1H),8.08 (d, J ═ 7.5Hz,1H),6.30(s,1H),4.28(s,1H),3.93-3.74(m,3H), 3.51-3.47 (m,2H),3.39-3.20(m,2H),2.95(dd, J ═ 6.2,13.1Hz,3H), 1.35-1.25 (m,2H) and 0.76(t, J ═ 7.3, 3H) Hz.

LCMS RT＝2.3(M+1)448.54。

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxylic acid methyl ester (526)

LCMS RT＝2.4(M+1)421.0。

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxylic acid ethyl ester (527)

LCMS RT＝2.5(M+1)435.1。

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxylic acid allyl ester (528)

LCMS RT＝2.6(M+1)447.1。

1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) -2-methylpropan-1-one (529)

LCMS RT＝2.5(M+1)433.1。

1- (3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) -2, 2-dimethylpropan-1-one (530)

LCMS RT＝1.9(M+1)447.1。

(3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholino) (cyclobutyl) methanone (531)

LCMS RT＝2.6(M+1)445.1。

2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((4- (methylsulfonyl) morpholin-3-yl) methyl) pyrimidin-4-amine (532)

LCMS RT＝2.4(M+1)441.0。

2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((4- (cyclopropylsulfonyl) morpholin-3-yl) methyl) -5-fluoropyrimidin-4-amine (533)

LCMS RT＝2.4(M+1)467.0。

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) morpholine-4-carboxamide (534)

LCMS RT＝2.0(M+1)406.0。

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-ethylmorpholine-4-carboxamide (535)

LCMS RT＝2.2(M+1)434.1。

3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) -N-isopropylmorpholine-4-carboxamide (536)

LCMS RT＝2.3(M+1)448.1。

(R) -fluoroethyl 2-2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (180)

LCMS RT＝2.1(M+1)451.4。

(S) -2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid 2-methoxyethyl ester (161)

LCMS RT＝2.8(M+1)463.4。

(S) -2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid 2-chloroethyl ester (163)

LCMS RT＝3.1(M+1)467.4。

(S) -2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylic acid prop-2-ynyl ester (164)

LCMS RT＝3.0(M+1)443.5。

(S) - (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (thiazol-2-yl) methanone (165)

LCMS RT＝2.8(M+1)472.5。

(S) - (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (3-methoxyphenyl) methanone (174)

LCMS RT＝2.8(M+1)495.6。

(S) -methyl 2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (166)

LCMS RT＝2.9(M+1)419.5。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanone (179)

LCMS RT＝2.5(M+1)403.4。

(S) -ethyl 2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidine-1-carboxylate (171)

LCMS RT＝3.0(M+1)433.3。

(R) - (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (3-methoxyphenyl) methanone (184)

LCMS RT＝2.7(M+1)495.5。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) propan-1-one (208)

LCMS RT＝1.9(M+1)417.2。

(R) - (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-methoxyphenyl) methanone (190)

LCMS RT＝2.9(M+1)495.4。

(R) - (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (4-fluorophenyl) methanone (209)

LCMS RT＝2.0(M+1)483.1。

(R) - (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) (3- (trifluoromethyl) phenyl) methanone (210)

LCMS RT＝2.2(M+1)533.1。

(R) -4-chloro-1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) butan-1-one (278)

LCMS RT＝2.4(M+1)465.1。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) pent-4-en-1-one (279)

LCMS RT＝2.1(M+1)443.2。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3,3, 3-trifluoropropan-1-one (280)

LCMS RT＝2.1(M+1)471.2。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) hex-5-yn-1-one (281)

LCMS(M+1)454.2。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -3-phenylpropan-1-one (293)

LCMS RT＝3.1(M+1)493.2。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) -2-cyclohexylethanone (294)

LCMS RT＝3.3(M+1)485.2。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) butan-1-one (295)

LCMS RT＝2.9(M+1)431.2。

(R) -1- (2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) piperidin-1-yl) pentan-1-one (326)

LCMS RT＝3.0(M+1)445.2。

(S) -1- (2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) ethanone (256)

LCMS RT＝2.2(M+1)369.3。

(S) -1- (2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) propan-1-one (257)

LCMS RT＝2.3(M+1)383.3。

(S) -1- (2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) butan-1-one (258)

LCMS RT＝2.5(M+1)397.3。

(S) - (2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) (phenyl) methanone (259)

LCMS RT＝2.4(M+1)431.3。

(S) - (2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) piperidin-1-yl) (2-methoxyphenyl) methanone (260)

LCMS RT＝2.4(M+1)461.3。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (methylsulfonyl) -piperidin-2-yl) methyl) pyrimidin-4-amine (381)

LCMS RT＝2.7min,(M+H)439.3。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (ethanesulfonyl) -piperidin-2-yl) methyl) pyrimidin-4-amine (382)

LCMS RT＝2.9min,(M+H)453.3。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (propylsulfonyl) piperidin-2-yl) methyl) pyrimidin-4-amine (328)

LCMS RT＝2.2min,(M+H)467.1。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (2,2, 2-trifluoro-ethanesulfonyl) -piperidin-2-yl) methyl) pyrimidin-4-amine (383)

LCMS RT＝3.0min,(M+H)507.3。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (methylsulfonyl) -piperidin-2-yl) methyl) pyrimidin-4-amine (384)

LCMS RT＝2.7min,(M+H)439.3。

(R) -N- ((1- (butylsulfonyl) piperidin-2-yl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (329)

LCMS RT＝2.3min,(M+H)481.2。

(S) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1- (cyclopropylsulfonyl) -piperidin-2-yl) methyl) pyrimidin-4-amine (386)

LCMS RT＝2.9min,(M+H)465.3。

(R) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -N- ((1- (3-chloropropylsulfonyl) piperidin-2-yl) methyl) -5-fluoropyrimidin-4-amine (330)

LCMS RT＝2.2min,(M+H)501.1。

(R) -2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-isopropylpiperidine-1-carboxamide (371)

LCMS RT＝1.8min,(M+H)412.2。

(R) -N-cyclopropyl-2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -methyl) piperidine-1-carboxamide (372)

LCMS RT＝1.9min,(M+H)424.2。

(R) -N-ethyl-2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -methyl) piperidine-1-carboxamide (373)

LCMS RT＝1.7min,(M+H)398.2。

(R) -2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -N-methylpiperidine-1-carboxamide (374)

LCMS RT＝1.6min,(M+H)384.2。

(R) -2- ((5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) methyl) -n-propylpiperidine-1-carboxamide (375)

LCMS RT＝1.8min,(M+H)412.2。

General scheme 14

(a) iPr2NEt, isopropanol, 80 ℃; (b) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, Pd (Ph3P)4, Na2CO3, DME, 130 ℃; (c) HCl/dioxane, CH2Cl 2; (d) propyl isocyanate, pyridine, CH2Cl2

formation of 1- ((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol (14a)

To a solution of 2- (aminomethyl) cyclohexanol hydrochloride (0.09g, 0.54mmol) and 2, 4-dichloro-5-fluoro-pyrimidine (0.10g, 0.60mmol) in isopropanol (2mL) was added iPr2NEt (0.21mL, 1.20 mmol). The reaction mixture was heated at 80 ℃ for 12 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (25% -75% EtOAc/hexanes) to afford the desired product 14 a.

LCMS(M+1)260.1,(M-1)258.3。

Formation of 2- ((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol (14b)

To a solution of degassed 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.15g, 0.35mmol), 1- ((2-chloro-5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol 14a (0.09g, 0.35mmol) and aqueous KOAc (1.04mL of 1M solution, 1.04mmol) in dimethylacetamide was added triphenylphosphine palladium (0.04g, 0.03 mmol). The reaction mixture was heated in a microwave at 140 ℃ for 15min and then cooled to room temperature. The reaction mixture was filtered through celite, concentrated in vacuo, and the resulting crude residue was purified by preparative HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 14 b: LCMS RT ═ 2.6(M +1) 530.3.

Formation of (2R) -2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol (12)

to a solution of 14b (0.10g, 0.19mmol) of 2- ((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexanol in THF (3mL) was added aqueous lithium hydroxide (1mL of 1N solution). The reaction mixture was stirred at room temperature for 12 h. The resulting residue was purified by preparative HPLC (0.1% TFA-H2O/acetonitrile) to afford the desired product 12.

LCMS FIA RT＝1.9(M+1)376.2。

2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanol (13)

LCMS FIA RT＝1.8(M+1)362.2。

2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanol (14)

LCMS FIA RT＝1.0(M+1)348.3。

(1R,2S,3R,5R) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -5- (hydroxymethyl) cyclopentane-1, 2-diol (657)

1H NMR (300MHz, DMSO) δ 12.41(s,1H),8.80(d, J ═ 2.3Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.25(s,1H),8.17(d, J ═ 4.0Hz,1H),7.64 (s,1H),4.80-4.50(m,3H),4.47(dd, J ═ 7.5,14.8Hz,1H),3.89(dd, J ═ 5.3,6.3Hz,1H),3.77(dd, J ═ 5.1,5.0Hz,1H),3.50-3.37(m,2H), 2.36-2.24 (m,1H),2.04(dd, J ═ 8.3,13.5, 1H),1.99 (m,1H), 1.27.27H (td, 1H), and 1.21H.

LCMS RT＝3.0(M+1)399.4。

General scheme 14B

(a)Raney-Ni、H(50PSI)、EtOH；(b)15a、THF，70℃；(c)TFA、CHCl； (d)1N LiOH、 THF，120℃

Formation of trans-tert-butyl 2- (aminomethyl) cyclohexylcarbamate (14d)

The solution of tert-butyl trans-2-cyanocyclohexylcarbamate and Raney-Ni in anhydrous EtOH was stirred for 24H under H2 gas (50 PSI). After filtration and evaporation of the solvent, flash chromatography (SiO2, 0-20% MeOH-CH2Cl2, gradient elution) afforded the title compound 14d as a racemic mixture of trans isomers (286mg, 66% yield): FIA (M + H) 229.33.

Formation of trans-2- ((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl-amino) methyl) cyclohexylcarbamic acid tert-butyl ester (14e)

A solution of 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine 15a (0.42g, 0.90mmol) and tert-butyl trans-2- (aminomethyl) cyclohexylcarbamate (0.24g, 1.06mmol) in THF (10mL) was heated to 70 ℃. After 1.3h, the mixture was concentrated in vacuo. Flash chromatography (SiO2, 0-60% EA/Hex, gradient elution) provided the desired intermediate tert-butyl trans-2- ((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexanecarboxylate 14e as a racemic mixture of the trans isomer, which was subjected to the next reaction without further purification (0.52g, 92% yield).

Formation of N- ((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (14f)

A solution of tert-butyl trans-2- ((2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexylcarbamate 14e (0.52g) in CH2Cl2(5mL) was treated with TFA (2.5mL) for 30 min. The solution was concentrated in vacuo and the resulting crude material was taken up in CH3CN and concentrated several times in vacuo to remove excess TFA and provide the desired amine 14f as a racemic mixture of the trans isomers as a TFA salt, which is sufficiently pure for use in the next reaction.

LCMS RT＝1.93min,(M+H)529.0

Formation of N- ((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (555)

a solution of N- ((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine 14f (0.050g, 0.077mmol) in THF was treated with LiOH (0.5mL, 1.0M) at 60 ℃. After 5min, the solution was diluted with EtOAc and washed with brine at 120 ℃, filtered and concentrated in vacuo. Preparative HPLC provided the desired compound 555 as a racemic mixture of trans isomers (12mg, 33% yield).

1H NMR (300MHz, MeOD) δ 8.75(d, J ═ 2.4Hz,1H),8.31(d, J ═ 2.4Hz,1H),8.29(s,1H),8.24(d, J ═ 4.4Hz,1H),3.96(dd, J ═ 5.8,14.4 Hz,1H),3.73(dd, J ═ 4.3,14.3Hz,1H),3.08-3.00(m,1H),2.05-1.87 (m,3H),1.80(m,3H) and 1.48-1.39(m,4H) ppm; LCMS RT 1.9min, (M + H) 375.0.

General scheme 14C

(a)i：RCOCl、DIEA、CHCl；ii：1N LiOH、THF，120℃

n- (trans-2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexyl) -2-methoxyacetamide (556)

To a cooled mixture of N- ((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (0.060g, 0.093mmol) and iPr2NEt (0.057mL, 0.330mmol) in CH2Cl2(2mL) was added 2-methoxyacetyl chloride (0.010g, 0.098mmol) at 0 ℃. After 5min, the solution was allowed to warm to room temperature. After 3h, the mixture was concentrated in vacuo, taken up in THF (1mL) and treated with LiOH (0.326mL, 1.0M solution) at 120 ℃ for 10 min. The resulting mixture was cooled to room temperature and partitioned, and the aqueous layer was extracted with EtOAc and the combined organics were concentrated in vacuo. Preparative HPLC provided the desired product 556(8.6mg, 17% yield) as a racemic mixture of TFA salts.

1H NMR (300MHz, MeOD) δ 8.74(d, J ═ 2.3Hz,1H),8.42(s,1H), 8.38(d, J ═ 2.3Hz,1H),8.27(d, J ═ 5.4Hz,1H),3.85-3.81(m,2H), 3.75(d, J ═ 8.5Hz,2H),3.26(s,3H),1.97-1.77(m,5H) and 1.43-1.35 (m,4H) ppm; LCMS RT 2.8min, (M + H) 446.8.

The following analogs can be prepared in the same manner as 556.

formation of N- (trans-2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexyl) methanesulfonamide (557)

Sulfonamide 557 was prepared according to the procedure for compound 36 (scheme 12B) using N- ((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-B ] pyridin-3-yl) -5-fluoropyrimidin-4-amine 14f and methanesulfonyl chloride to afford the desired product 557 as a racemic mixture of the trans isomers.

1H NMR (300.0MHz, MeOD) δ 8.78(d, J ═ 2.4Hz,1H),8.45(d, J ═ 4.2Hz,1H),8.37(d, J ═ 2.3Hz,1H),8.26(d, J ═ 5.4Hz,1H),4.12(dd, J ═ 4.5,13.7Hz,1H),3.89(dd, J ═ 7.1,13.8Hz,1H),3.26-3.16(m,1H), 3.00(s,3H),2.18-1.90(m,2H),1.79-1.74(m,2H) and 1.50-1.25(m, 4H) ppm; LCMS RT 2.8min, (M + H) 452.6.

Formation of 3- (trans-2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) cyclohexyl) -1, 1-dimethylurea (564)

Urea 564 was prepared according to the procedure for compound 20 (scheme 12A) using N- ((trans-2-aminocyclohexyl) methyl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine 14f and dimethylcarbamoyl chloride to give the desired product 564 as a racemic mixture of the trans isomers.

General scheme 15

(a) (1S,2S) -cyclohexane-1, 2-diamine, THF, 140 ℃; (b) AcCl, iPr2NEt, CH2Cl 2; (c)1M LiOH, DCE, 150 ℃ and microwave for 20min

Formation of (1S,2S) -N1- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1, 2-diamine (15b)

5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 15a (0.25g, 0.53mmol) and (1S,2S) -cyclohexane-1, 2-diamine (0.12g, 1.08mmol) were dissolved in THF (3.0mL) and heated in a small sealed bottle for 20min to 140 ℃. The solvent was evaporated in vacuo and the residue was purified by silica gel chromatography (0% -15% MeOH/CH2Cl2) to afford product 15b as a white foamy solid (220mg, 79% yield).

1H NMR (300MHz, CDCl3) δ 8.85(d, J ═ 2.4Hz,1H),8.52(s,1H), 8.40(d, J ═ 2.4Hz,1H),8.13-8.09(m,3H),7.31-7.28(m,2H),5.14(d, J ═ 6.6Hz,1H),3.96-3.85(m,1H),2.69(td, J ═ 10.2,4.7Hz,1H),2.40 (s,3H),2.33(d, J ═ 5.6Hz,1H),2.12-2.06(m,1H),1.88-1.84(m,2H) and 1.60-1.21(m,4H) ppm; LCMS RT ═ 2.33(M +1) 515.2.

formation of N- [ (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] acetamide (433)

(1S,2S) -N- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 2-diamine 15b (0.100g, 0.194mmol) was dissolved in dichloromethane (2mL) and treated with iPr2NEt (0.075g, 0.101mL, 0.583 mmol). Acetyl chloride (0.021mL, 0.291mmol) was added and the reaction stirred at room temperature for 30 min. The volatiles were evaporated under reduced pressure and the residue was dissolved in dichloroethane (2mL) and treated with LiOH (0.097mL of a 1M solution, 0.971 mmol). The reaction mixture was heated in a microwave at 150 ℃ for 10 min. The reaction mixture was diluted with EtOAc (5mL) and water (5mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 5mL) and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography (0% -15% MeOH/CH2Cl2) to afford N- [ (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] acetamide 433(34mg, 44% yield).

1H NMR (300MHz, d6-DMSO) δ 13.03(s,1H),9.10(s,1H),9.05 (s,1H),8.67(d, J ═ 2.1Hz,1H),8.48(d, J ═ 5.4Hz,1H),8.43(d, J ═ 2.3Hz,1H), 7.97(d, J ═ 7.7Hz,1H),4.15-4.07(m,1H),3.93-3.87(m,1H), 2.20-2.15(m,1H),1.99-1.92(m,1H),1.85-1.79(m,2H),1.74(s,3H) and 1.52-1.36(m,4H) ppm; LCMS RT ═ 2.41(M +1) 403.4.

General scheme 16

(a) cyclohexane-cis-1, 2-diamine, isopropanol, iPr2 NEt; (b)3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine, Pd (PPh3)4, Na2CO3, DME DCE, microwave at 150 ℃; (c)1M LiOH, 150 ℃, microwave; (d) MeSO2Cl, iPr2NEt, DMF DCM

Formation of N1- (2-chloro-5-fluoropyrimidin-4-yl) cyclohexane-cis-1, 2-diamine (16a)

2, 4-dichloro-5-fluoropyrimidine (0.50g, 2.99mmol) was dissolved in isopropanol (7mL) and treated with iPr2NEt (1.50mL, 8.98 mmol). Cyclohexane-cis-1, 2-diamine (0.46g, 4.03mmol) was added and the reaction stirred at room temperature overnight. The solvent was evaporated and the reaction mixture was diluted in EtOAc (15mL) and washed with saturated NaHCO3 water. The aqueous layer was extracted with EtOAc (15mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the crude product. The resulting crude product was purified by silica gel chromatography (5% -30% MeOH/CH2Cl2) to provide 16a as a white solid (370mg, 50% yield).

1H NMR (300MHz, CDCl3) δ 7.83(d, J ═ 2.8Hz,1H),6.16(s,1H), 4.08(s,1H),3.13(d, J ═ 3.9Hz,1H) and 1.84-1.44(m,8H) ppm; LCMS RT ═ 0.8(M +1) 245.1.

Formation of N1- (5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1, 2-diamine (16b)

3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-b ] pyridine (0.26g, 0.65mmol) was dissolved in DME (8mL) and treated with N1- (2-chloro-5-fluoropyrimidin-4-yl) cyclohexane-cis-1, 2-diamine 16a (0.16g, 0.65 mmol). Pd (PPh3)4(0.10mg, 0.08mmol) and 2M aqueous Na2CO3(3.25mL) were added and the suspension was heated in a microwave for 20min to 150 ℃.1M aqueous LiOH (5mL) was added and the reaction was heated to 150 ℃ under microwave for an additional 15 min. The organic solvent was evaporated under reduced pressure and the liquid phase extracted with CH2Cl2(2 × 20 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0% -100% CH2Cl2/EtOAc) to provide product 16b as a brown foam (140mg, 66% yield).

1H NMR (300MHz, d6-DMSO) δ 12.14(s,1H),8.66(d, J ═ 8.0Hz, 1H),8.29-8.22(m,3H),7.81(s,2H),7.28-7.19(m,2H),4.55(s,1H), 3.74(s,1H) and 1.92-1.49(m,8H) ppm; LCMS RT ═ 1.8(M +1) 327.2.

formation of N- [ cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] methanesulfonamide (337)

N1- (5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1, 2-diamine 16b (0.009g, 0.027mmol) was dissolved in a 8:2 mixture of CH2Cl2/DMF (1mL) and treated with iPr2NEt (0.019mL, 0.110mmol) and methanesulfonyl chloride (0.006mL, 0.083 mmol). The reaction was stirred at room temperature overnight, concentrated in vacuo and the residue was purified by HPLC with 10% -90% acetonitrile/water and 0.03% TFA to provide compound 337.

1H NMR (300MHz, d6-DMSO) δ 12.47(s,1H),8.64(d, J ═ 7.8Hz,1H), 8.45-8.34(m,3H),7.29(dd, J ═ 4.8,7.8Hz,1H),7.06(d, J ═ 7.5Hz,1H), 4.47-4.25(m,1H),4.05-3.89(m,1H),2.80(s,3H), 1.95-1.62 (m,6H) and 1.49-1.24(m,2H) ppm; LCMS RT ═ 2.3(M +1) 405.3.

The following compounds may be prepared in a manner similar to that described in scheme 15 or scheme 16:

N- [ cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] -cyclohexyl ] propanamide (341)

1H NMR (300MHz, d6-DMSO) δ 12.47(s,1H),8.65(d, J ═ 8.1Hz, 1H),8.49-8.23(m,3H),7.61(d, J ═ 7.8Hz,1H),7.29(dd, J ═ 4.7,8.0 Hz,1H),4.39(d, J ═ 19.5Hz,2H),2.10(q, J ═ 7.6Hz,2H),1.79-1.64 (m,6H),1.48(d, J ═ 6.4Hz,2H) and 0.91(t, J ═ 7.6Hz,3H) ppm; LCMS RT ═ 2.3(M +1) 383.4.

N- [ cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] butanamide (342)

LCMS RT＝2.5(M+1)397.4。

N- [ cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] cyclopentanecarboxamide (343)

LCMS RT＝2.7(M+1)423.4。

n- [ cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] benzamide (344)

LCMS RT＝2.7(M+1)431.4。

N- [ cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] propan-1-sulfonamide (346)

1H NMR (300MHz, d6-DMSO) δ 12.41(s,1H),8.65(d, J ═ 7.8Hz, 1H),8.38-8.33(m,3H),7.28(dd, J ═ 4.7,7.9Hz,1H),7.06(d, J ═ 8.1Hz, 1H),4.36(s,1H),3.88(s,1H),2.83(t, J ═ 7.7Hz,2H),1.85-1.70 (m,6H),1.59(q, J ═ 7.8Hz,2H),1.47-1.24(m,2H) and 0.82(t, J ═ 7.4Hz,3H) ppm; LCMS RT ═ 2.6(M +1) 433.3.

1- [ cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] -3-propyl-urea (347)

N- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] acetamide (348)

1H NMR (300MHz, d6-DMSO) δ 12.53(s,1H),8.66(d, J ═ 7.6Hz,1H), 8.43(s,1H),8.39-8.36(m,2H),7.91(d, J ═ 7.9Hz,1H),7.32(dd, J ═ 4.7,7.9Hz,1H),4.08-3.94(m,1H),3.86(d, J ═ 8.4Hz,1H),2.13(d, J ═ 24.3Hz,1H),1.95(d, J ═ 10.2Hz,1H),1.81-1.73(m,2H),1.73(s, 3H) and 1.43-1.14(m,4H) ppm; LCMS RT ═ 2.2(M +1) 369.4.

N- [ trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] propionamide (349)

LCMS RT＝2.7(M+1)417.3。

N- [ (1R,2R) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] cyclopentanecarboxamide (351)

LCMS RT＝3.1(M+1)457.3。

N- [ (1R,2R) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] benzamide (352)

LCMS RT＝3.0(M+1)465.3。

N- [ (1R,2R) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] methanesulfonamide (353)

LCMS RT＝2.7(M+1)439.4。

N- [ (1R,2R) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] propane-1-sulfonamide (354)

LCMS RT＝3.0(M+1)467.3。

1- [ (1R,2R) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-propyl-urea (355)

LCMS RT＝2.8(M+1)446.3。

N- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] butanamide (358)

LCMS RT＝2.5(M+1)397.4。

N- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] cyclopentanecarboxamide (359)

LCMS RT＝2.7(M+1)423.4。

N- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] benzamide (360)

LCMS RT＝2.63(M+1)431.4。

N- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] methanesulfonamide (361)

1H NMR (300MHz, d6-DMSO) δ 12.54(s,1H),8.66(d, J ═ 8.0Hz, 1H),8.43-8.36(m,3H),7.32(dd, J ═ 4.7,7.9Hz,1H),7.21(d, J ═ 8.3Hz, 1H),4.16(d, J ═ 9.3Hz,1H),3.35(d, J ═ 9.8Hz,1H),2.91(d, J ═ 8.9 Hz,3H),2.12-2.02(m,2H),1.79-1.73(m,2H) and 1.64-1.15(m,4H) ppm; LCMS RT ═ 2.4(M +1) 405.3.

N- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] propan-1-sulfonamide (362)

1H NMR (300MHz, d6-DMSO) δ 12.43(s,1H),8.68(d, J ═ 7.9Hz, 1H),8.38-8.33(m,3H),7.29(dd, J ═ 4.7,7.8Hz,1H),7.17(d, J ═ 8.6Hz,1H), 4.14(d, J ═ 6.9Hz,1H),3.33-3.26(m,1H),3.07-2.89(m,2H), 2.07(d, J ═ 12.6Hz,2H),1.76(d, J ═ 7.9Hz,2H),1.61-1.33(m,6H) and 0.90(t, J ═ 7.4Hz,3H) ppm; LCMS RT ═ 2.6(M +1) 433.3.

N- [ trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] butanamide (363)

LCMS RT＝2.9(M+1)431.3。

N- [ (trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] cyclopentanecarboxamide (364)

LCMS RT＝3.1(M+1)457.3。

N- [ trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] benzamide (365)

LCMS RT＝3.0(M+1)465.3。

N- [ trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] propane-1-sulfonamide (367)

LCMS RT＝3.0(M+1)467.3。

1- [ trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-propyl-urea (368)

LCMS RT＝2.8(M+1)446.3。

Methyl N- [ (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (425)

1H NMR (300MHz, d6-DMSO) δ 13.02(s,1H),9.10(s,2H),8.67 (s,1H),8.44-8.40(m,2H),7.26(d, J ═ 6.5Hz,1H),4.19(s,1H),3.66(d, J ═ 9.8Hz,1H),3.48(s,3H),2.13(s,1H),2.02(d, J ═ 9.2Hz,1H),1.78 (d, J ═ 9.6Hz,2H) and 1.47-1.34(m,4H) ppm; LCMS RT ═ 2.1(M +1) 419.2.

1- [ (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-methyl-urea (426)

1H NMR (300MHz, d6-DMSO) δ 12.56(s,1H),8.70(d, J ═ 2.2Hz, 1H),8.35(dd, J ═ 2.4,6.8Hz,2H),8.28(d, J ═ 4.2Hz,1H),5.99(d, J ═ 7.0Hz,1H),5.80-5.63(m,1H),3.91-3.87(m,1H),3.66-3.45(m, 1H),2.54(s,3H),2.30(d, J ═ 13.0Hz,1H),2.04(d, J ═ 46.9Hz,1H), 1.78(d, J ═ 8.5Hz,2H) and 1.56-1.23(m,4H) ppm; LCMS RT ═ 2.5 (M +1) 419.5.

3- [ (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -1, 1-dimethyl-urea (427)

1H NMR (300MHz, d6-DMSO) δ 12.59(s,1H),8.72(d, J ═ 2.3Hz,1H), 8.41(d, J ═ 2.7Hz,1H),8.35(d, J ═ 2.3Hz,1H),8.29(d, J ═ 4.4Hz,1H), 8.23(s,1H),6.19(d, J ═ 7.8Hz,1H),4.04-3.97(m,1H), 3.78-3.69 (m,1H),2.68(s,6H),2.31(d, J ═ 11.6Hz,1H),1.95(d, J ═ 9.8Hz,1H), 1.79(d, J ═ 10.4Hz,2H) and 1.60-1.32 ppm (m, 4H); LCMS RT ═ 2.7(M +1) 432.4.

N- [ (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] methanesulfonamide (428)

1H NMR (300MHz, d6-DMSO) δ 12.54(s,1H),8.72(d, J ═ 2.3Hz,1H), 8.38-8.29(m,3H),7.82(s,1H),7.21(d, J ═ 8.3Hz,1H),4.52(brs, 1H),4.12-4.05(m,1H),2.92(s,3H),2.09(d, J ═ 12.8Hz,2H),1.78(brs, 2H) and 1.49-1.39(m,4H) ppm; LCMS RT ═ 2.7(M +1) 439.4.

1- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-methyl-urea (430)

1H NMR (300MHz, d6-DMSO) δ 12.61(s,1H),8.68(d, J ═ 2.2Hz,1H), 8.39-8.31(m,4H),6.12(d, J ═ 6.7Hz,1H),5.91-5.83(m,1H), 4.29-4.13(m,1H),4.02-3.91(m,1H),2.55(s,3H),1.93(d, J ═ 12.8Hz, 1H) and 1.74-1.53(m,7H) ppm; LCMS RT ═ 2.6(M +1) 418.5.

3- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -1, 1-dimethyl-urea (431)

1H NMR (300MHz, d6-DMSO) δ 12.54(s,1H),8.68(d, J ═ 2.3Hz, 1H),8.33-8.29(m,3H),7.96(s,1H),5.72(d, J ═ 6.9Hz,1H),4.36(s, 1H),4.10(s,1H),2.76(s,6H),1.96-1.87(m,2H),1.74-1.63(m,4H) and 1.55-1.45(m,2H) ppm; LCMS RT ═ 2.8(M +1) 432.4.

Methyl N- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (432)

1H NMR (300MHz, d6-DMSO) δ 12.54(s,1H),8.67(d, J ═ 2.2Hz,1H), 8.35-8.29(m,3H),7.62(s,1H),7.05(d, J ═ 7.2Hz,1H), 4.50-4.40 (m,1H),4.20-4.10(m,1H),3.46(s,3H),1.87(d, J ═ 10.9Hz,2H), 1.71-1.65(m,4H) and 1.43(d, J ═ 7.4Hz,2H) ppm; LCMS RT ═ 2.9 (M +1)419.

N- [ 5-fluoro-2- (1H-pyrrolo [5,4-b ] pyridin-3-yl) pyrimidin-4-yl ] cyclohexane-cis-1, 2-diamine (206)

LCMS RT＝1.9(M+1)327.2.。

Trans-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexanol (207)

LCMS RT＝2.2(M+1)328.2。

Cis-2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexanol (277)

LCMS RT＝1.6(M+1)328.2。

N- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] propanamide (333)

LCMS RT＝2.7(M+1)417.4。

N- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] butanamide (334)

LCMS RT＝2.9(M+1)431.4。

N- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] cyclopentanecarboxamide (335)

LCMS RT＝3.1(M+1)457.3。

N- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] benzamide (336)

LCMS RT＝3.0(M+1)465.4。

N- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] propane-1-sulfonamide (338)

LCMS RT＝2.9(M+1)467.3。

1- [ cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-propyl-urea (339)

LCMS RT＝2.9(M+1)446.3。

1- [ trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-propyl-urea (350)

LCMS RT＝2.6(M+1)403.3。

N- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] propionamide (356)

LCMS RT＝2.3(M+1)383.4。

(1R,2R) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5- (trifluoromethyl) pyrimidin-4-yl) cyclohexane-1, 2-diamine (31)

LCMS RT＝2.2(M+1)411.2。

N1- (5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1, 2-diamine (4)

LCMS RT＝2.2(M+1)327.2。

(1R,2R) -N1- (5-chloro-2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) cyclohexane-1, 2-diamine (115)

LCMS RT＝1.3(M+1)377.2。

N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-methylpyrimidin-4-yl) cyclohexane-1, 2-diamine (116)

LCMS RT＝3.3(M+1)357.2。

N- [ (1R,2R) -2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] butanamide (369)

LCMS RT＝2.9(M+1)431.3。

1- [ (1R,2R) -2- [ [ 5-fluoro-2- (1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] -3-propyl-urea (370)

LCMS RT＝2.4(M+1)412.4。

2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- (2-methoxycyclohexyl) -pyrimidin-4-amine (412)

LCMS RT＝3.5(M+1)376.4。

General scheme 18

Dppa, Et3N, toluene, 110 ℃; ii BnOH, 85 ℃; (b) LiOH, THF H2O (c) Boc2O, pyridine, NH4HCO3, dioxane; (d) BTIB, CH3CN H2O

Formation of (1S,3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid (18a)

(1S,3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid can be prepared according to the procedures of the references described in Barnett, C.J., Gu, R.L., Kobierski, M.E., WO-2002024705, Stereoselective process for purifying cyclohexamide derivatives.

Formation of ethyl (1R,3S) -3-benzyloxycarbonylaminocyclohexanecarboxylate (18b)

(1S,3R) -3- (ethoxycarbonyl) cyclohexanecarboxylic acid 18a (10.0g, 49.9mmol) was dissolved in toluene (100mL) and treated with triethylamine (7.6mL, 54.9mmol) and DPPA (12.2mL, 54.9 mmol). The resulting solution was heated to 110 ℃ and stirred for 1 h. After cooling to 70 ℃, benzyl alcohol (7.7mL, 74.9mmol) was added and the mixture was heated to 85 ℃ overnight. The resulting solution was cooled to room temperature, poured into EtOAc (150mL) and water (150mL) and the layers separated. The aqueous layer was extracted with EtOAc (2 × 75mL) and the combined organic extracts were washed with water (100mL) and brine (100mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel chromatography (0% -50% EtOAc/hexanes) to afford 18b (15.3g, containing-25% benzyl alcohol) for the next step without further purification.

Formation of (1R,3S) -3-benzyloxycarbonylaminocyclohexanecarboxylic acid (18c)

(1R,3S) -3-benzyloxycarbonylaminocyclohexanecarboxylic acid ethyl ester 18b (36g, 117.9mmol) was dissolved in THF (144.0mL) and treated with a solution of LiOH (5.647g, 235.8mmol) in water (216.0 mL). After stirring overnight, the reaction mixture was diluted with water (100mL), washed with methyl tert-butyl ether (150mL) and adjusted to pH3 by the addition of 3N HCl. The acidic solution was extracted with EtOAc (3 × 100mL) and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo.

The crude product was triturated with methyl tert-butyl ether (30mL) and filtered to provide a first crop of crystals. The filtrate was treated with heptane (20mL), concentrated to 30mL and allowed to stand at room temperature for 3h to provide a second crop of crystals 18c collected by filtration, totaling 14.4g (44% yield).

1H NMR (300MHz, CDCl3) δ 7.38-7.33(m,5H),5.11(s,2H),4.68 (s,1H),3.55(s,1H),2.44(d, J ═ 11.0Hz,1H),2.32(d, J ═ 11.7Hz,1H), 2.03-1.86(m,3H) and 1.48-0.88(m,4H) ppm.

Formation of benzyl N- [ (1S,3R) -3-carboxamidocyclohexyl ] carbamate (18d)

To a solution of (1R,3S) -3-benzyloxycarbonylaminocyclohexanecarboxylic acid 18c (10.0g, 36.1mmol) in 1, 4-dioxane (300mL) was added pyridine (2.9mL, 36.1mmol), followed by di-tert-butyl dicarbonate (10.7mL, 46.9mmol) and ammonium bicarbonate (10.1g, 126.2 mmol). After 3h, another portion of di-tert-butyl dicarbonate (1.5g, 6.8mmol) and ammonium bicarbonate (1.5g, 6.8mmol) was added and stirring was continued overnight. The reaction was quenched by addition of 2N HCl (400mL) and stirred for 1 h. The resulting suspension was filtered under reduced pressure, washed with 2N HCl (50mL), water (8x50mL) and hexane (3x50mL) and dried in vacuo to provide benzyl N- [ (1S,3R) -3-formylaminocyclohexyl ] carbamate 18d (9.1g, 91%) as a white solid.

H NMR(300MHz,CDCl)δ7.40–7.24(m,5H),5.08(s,2H), 3.58–3.44(m,1H),2.38– 2.21(m,1H),2.17(d,J＝12.7,1H),2.05– 1.78(m,8H),1.54–0.97(m,5H)。

N- [ (1S,3R) -3-Aminocyclohexyl ] carbamic acid benzyl ester (18e)

Benzyl N- [ (1S,3R) -3-carboxamidocyclohexyl ] carbamate 18d (9.1g, 32.9mmol) was suspended in a mixture of acetonitrile (100mL) and water (100mL) and treated with bis (trifluoroacetoxy) iodobenzene (15.5g, 36.1 mmol). The suspension was stirred at room temperature overnight and then quenched with 1N HCl (100 mL). After evaporation of acetonitrile, the acidic aqueous solution was washed with EtOAc (2 × 150 mL). The pH was adjusted to basic by addition of solid KOH and the resulting emulsion was extracted with EtOAc (3x200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford product 18e (6.2g, 75% yield).

H NMR(300MHz,CDCl)δ7.31-7.45(m,5H),5.11(s,2H), 4.90(br.s.,1H),3.58 (br.s.,1H),2.72-2.97(m,1H),2.14(d,J＝11.90 Hz,1H),1.87-2.02(m,1H),1.73-1.87 (m,2H),1.21-1.46(m,1H), 0.89-1.18(m,3H)。

general scheme 19

(a) MeOCOCl, Et3N, THF; (b) h2, Pd/C, EtOH; (c) 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine, THF, 130 ℃, microwave; (d) LiOH, 130 ℃, microwave

Formation of methyl N- [ (1R,3S) -3-benzyloxycarbonyl-aminocyclohexyl ] carbamate (19a)

Benzyl N- [ (1S,3R) -3-aminocyclohexyl ] carbamate 18e (0.99g, 3.99mmol) was dissolved in THF (20mL) and treated with methyl chloroformate (0.62mL, 7.97mmol) followed by triethylamine (1.67mL, 11.96 mmol). After stirring at room temperature for 1h, the solvent was evaporated under reduced pressure and the residue was diluted in a 1:3 mixture of CH2Cl2: EtOAc (130mL) and washed with 1N HCl (50mL) and 2N Na2CO3(50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the desired product 19a as a white solid (1.09g, 89% yield).

H NMR(300MHz,CDCl)δ7.21-7.37(m,5H),5.02(s,2H), 4.26-4.62(m,1H),3.58 (s,3H),3.34-3.54(m,2H),2.24(d,J＝11.71 Hz,1H),1.82-2.03(m,2H),1.72(dt,J＝ 3.14,13.93Hz,1H),1.23-1.44 (m,1H),0.79-1.02(m,3H)。

Formation of methyl N- [ (1R,3S) -3-aminocyclohexyl ] carbamate (19b)

Methyl N- [ (1R,3S) -3-benzyloxycarbonylaminocyclohexyl ] carbamate 19a (1.09g, 3.56mmol) was dissolved in ethanol (100mL) and treated with 10% Pd/C (0.38g, 0.36 mmol). The flask was capped, degassed and equipped with a hydrogen balloon and stirred overnight. The reaction mixture was filtered under nitrogen and concentrated in vacuo to afford product 19b as a white solid.

H NMR(300MHz,CDCl)δ3.31-3.56(m,1H),3.03(s,4H), 2.81(t,J＝10.67Hz, 1H),2.03-2.20(m,1H),1.71-2.01(m,3H),1.27- 1.49(m,1H),0.92-1.14(m,3H)。

Methyl N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (570)

5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridine 19b (2.04g, 4.39mmol) and methyl N- [ (1R,3S) -3-amino-cyclohexyl ] carbamate (0.60g, 3.14mmol) were dissolved in THF (16mL) and heated in a microwave for 20min to 130 ℃. Lithium hydroxide (15.67mL of a 1M solution, 15.67mmol) was added and the resulting mixture was heated in a microwave at 130 ℃ for 20 min. The resulting solution was diluted in water (150mL) and ethyl acetate (200mL) and the layers were separated. The aqueous layer was extracted with EtOAc (100mL) and the organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (40-100% EtOAc/hexanes) and the pure fraction was then treated with 4N HCl in dioxane to provide compound hydrochloride 570 as an off-white solid.

1H NMR (300MHz, MeOD) δ 8.81(d, J ═ 2.1Hz,1H),8.20(d, J ═ 2.3Hz,1H),8.15(s,1H),7.97(d, J ═ 4.1Hz,1H),4.26 to 4.18(m,1H), 3.71 to 3.52(m,1H),3.59(s,3H),2.36(d, J ═ 10.5Hz,1H),2.18(d, J ═ 10.7Hz,1H),2.04 to 1.86(m,2H),1.57(s,1H) and 1.43 to 1.15(m,3H) ppm; LCMS RT ═ 2.0(M +1)419.4(M-1) 417.3.

General scheme 20

(a) 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine, THF; (b) CH2Cl2, trifluoroacetic acid; (c) acetyl chloride, Et3N, THF; and (d) LiOH, 130 ℃ and microwave.

Formation of tert-butyl N- [ (1R,3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (20b)

N- [ (1R,3S) -3-Aminocyclohexyl ] carbamic acid tert-butyl ester 20a (0.15g, 0.70mmol) and 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 1a (0.49g, 1.05mmol) were dissolved in THF (30mL) and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was purified by two silica gel chromatographies, first with (0% -10% MeOH/CH2Cl2) and second with (10% -50% EtOAc/hexanes) to afford tert-butyl N- [ (1R,3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (20b) (330mg, 38%).

1H NMR (300MHz, CDCl3) δ 8.74(d, J ═ 2.4Hz,1H),8.58(s,1H), 8.38(d, J ═ 2.4Hz,1H),8.13(s,1H),8.09(t, J ═ 3.3Hz,2H),7.29(d, J ═ 8.1Hz,2H),5.02(d, J ═ 7.1Hz,1H),4.47(d, J ═ 7.7Hz,1H), 4.25-4.16 (m,1H),3.68(d, J ═ 2.0Hz,1H),2.48(d, J ═ 11.7Hz,1H),2.38(s, 3H),2.26(d, J ═ 12.8, 1H),2.11(d, J ═ 11.56H), 1.95(d, 1H), 1H, 9.6 (m ═ 1H), 1H, and 1H).

formation of (1R,3S) -N1- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine (20c)

Tert-butyl N- [ (1R,3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (20b) (0.33g, 0.53mmol) was dissolved in CH2Cl2(10mL) and treated with trifluoroacetic acid (2 mL). After stirring for 2h, the solvent was evaporated under reduced pressure and the resulting residue was passed through a polymer-supported carbonate column to provide the free base of (1R,3S) -N1- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine 20c (0.25g, 0.43mmol, 81%).

1H NMR (300MHz, CDCl3) δ 8.76(dd, J ═ 2.4,6.3Hz,1H),8.52 to 8.49(m,1H),8.39(d, J ═ 2.4Hz,1H),8.14 to 8.04(m,3H),7.29(d, J ═ 7.5Hz,2H),5.61(s,1H),4.28 to 4.16(m,1H),3.19 to 3.10(m,1H),2.39 (s,3H),2.39 to 2.31(m,1H),2.08 to 1.90(m,3H),1.63 to 1.50(m,1H) and 1.40 to 1.17(m,3H) ppm.

Formation of N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] acetamide (547)

(1R,3S) -N1- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine 20c (0.050g, 0.097mmol) was dissolved in THF (1.0mL) and treated with triethylamine (0.041mL, 0.290mmol) and acetyl chloride (0.013mL, 0.190 mmol). After stirring overnight, the solvent was evaporated and the residue was taken up in THF (1.0mL) and treated with 1M LiOH (1.0mL, 1.0 mmol). The reaction mixture was heated in a microwave for 10min to 130 ℃. The solvent was evaporated under reduced pressure and the residue was purified by HPLC using 5% -70% H2O/acetonitrile and 0.1% TFA. The purified fractions were concentrated to dryness to provide the TFA salt of the product, which was dissolved in MeOH and passed through a polymer-bound carbonate cartridge to provide the free base of product 547.

H NMR(300MHz,MeOD)δ8.81(s,1H),8.20(s,1H),8.15(s, 1H),7.99(d,J＝4.1, 1H),4.23(t,J＝11.4,1H),3.90(t,J＝11.4,1H), 2.35(d,J＝11.6,1H),2.20(d,J＝12.5, 1H),2.00(d,J＝15.9,2H),1.92 (s,3H),1.67(dd,J＝26.3,13.2,1H),1.53-1.06(m,3H) ppm LCMS RT ＝2.1(M+1)403.2。

The following compounds can be prepared by methods similar to those described in scheme 19 and scheme 20:

(1R,3S) -N1- [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine (542)

LCMS RT＝1.4(M+1)361.4。

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] acetamide (576)

Methyl N- [ (1S,3R) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (548)

LCMS RT＝2.8(M+1)419.5。

3- [ (1S,3R) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -1, 1-dimethyl-urea (549)

LCMS RT＝2.6(M+1)432.5。

n- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -2-methoxy-acetamide (591)

1H NMR (300MHz, MeOD) δ 8.82(d, J ═ 2.4Hz,1H),8.21(d, J ═ 2.3Hz,1H),8.16(s,1H),7.99(d, J ═ 4.1Hz,1H),4.29 to 4.21(m,1H), 4.04 to 3.96(m,1H),3.87(s,2H),3.40(s,3H),2.34(d, J ═ 11.6Hz,1H), 2.21(d, J ═ 12.5Hz,1H),2.02 to 1.93(m,2H),1.74 to 1.62(m,1H) and 1.54 to 1.28(m,3H) ppm.

LCMS RT＝2.6(M+1)433.4。

2-methoxyethyl N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (592)

H NMR(300MHz,MeOD)δ8.84(s,1H),8.21(s,1H),8.16(s, 1H),7.99(d,J＝ 3.97Hz,1H),4.18-4.34(m,1H),4.14(br.s.,2H),3.49 -3.74(m,3H),3.3(s,3H)2.38(d,J ＝9.06Hz,1H),2.19(d,J＝13.41Hz, 1H),1.84-2.11(m,2H),1.51-1.78(m,1H),1.12-1.47 (m,3H)ppm。

LCMS RT＝2.5(M+1)463.4。

General scheme 21:

(a) tetrahydrofuran-2-carboxylic acid, EDC, HOBt, DIPEA, CH2Cl2, room temperature; (b) LiOH, 130 ℃, microwave

Formation of N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] tetrahydrofuran-2-carboxamide hydrochloride (638)

To a solution of (1S,3R) -N1- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine 20c (60mg, 0.12mmol) in CH2Cl2(3mL) was added tetrahydrofuran-2-carboxylic acid (20.3mg, 0.17mmol), EDC (26.8mg, 0.14mmol), HOBt (17.8mg, 0.12mmol) and DIPEA (60.2mg, 0.47mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in THF (4mL) and treated with 1M aqueous lithium hydroxide (3.0mL, 3.0 mmol). The reaction mixture was heated in a microwave for 20min to 130 ℃. The solvent was evaporated under reduced pressure and the residue was purified by HPLC using 5-70% MeOH// H2O and 6mM HCl for 15 min. The purified fraction was concentrated to provide N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] tetrahydrofuran-2-carboxamide hydrochloride 638.

1H NMR (300MHz, MeOD) δ 8.55(d, J ═ 1.0Hz,1H),8.46-8.45 (m,1H),8.29-8.27(m,2H),4.28(d, J ═ 6.1Hz,2H),4.00-3.87(m, 3H),2.36-2.16(m,3H),2.00-1.91(m,5H) and 1.75-1.41(m,4H) ppm.

LCMS RT＝3.77(M+1)459.37,(M-1)457.35。

The following compounds may be prepared according to methods similar to those described in scheme 19, scheme 20 and scheme 21:

(1R,3S) -N1- [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine (542)

LCMS RT＝1.4(M+1)361.4。

n- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] acetamide (576)

Methyl N- [ (1S,3R) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (548)

LCMS RT＝2.8(M+1)419.5。

3- [ (1S,3R) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -1, 1-dimethyl-urea (549)

LCMS RT＝2.6(M+1)432.5。

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -2-methoxy-acetamide (591)

LCMS RT＝2.6(M+1)433.4。

2-methoxyethyl N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (592)

LCMS RT＝2.5(M+1)463.4。

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-hydroxy-2, 2-dimethyl-propionamide hydrochloride (650)

1H NMR (300MHz, MeOD) δ 8.56-8.54(m,2H),8.34(s,1H), 8.30(t, J ═ 5.4Hz,1H),4.29(t, J ═ 11.4Hz,1H),3.93(t, J ═ 11.6Hz,1H), 3.54(s,2H),2.34(d, J ═ 10.8Hz,1H),2.18(d, J ═ 11.4Hz,1H), 2.01(d, J ═ 11.3Hz,2H),1.73-1.37(m,4H) and 1.15(s,6H) ppm.

LCMS RT＝3.79(M+1)461.38,(M-1)459.4。

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] tetrahydropyran-3-carboxamide hydrochloride (633)

1H NMR (300MHz, MeOD) δ 8.64(d, J ═ 2.2Hz,1H),8.51(s,1H), 8.36(d, J ═ 2.2Hz,1H),8.29(d, J ═ 5.5Hz,1H),4.39(t, J ═ 11.9Hz,1H), 3.93-3.82(m,3H),3.54-3.30(m,2H),2.52-2.43(m,1H), 2.37-2.33 (m,1H),2.20(d, J ═ 11.6Hz,1H),2.01(d, J ═ 11.3Hz,2H), 1.90-1.88 (m,1H),1.83-1.63(m,4H) and 1.59-1.26(m, 3H).

LCMS RT＝3.25(M+1)473.42,(M-1)471.1。

n- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-hydroxy-propionamide hydrochloride (634)

1H NMR (300MHz, MeOD) δ 8.61(d, J ═ 2.1Hz,1H),8.53(s,1H), 8.35(d, J ═ 2.0Hz,1H),8.29(d, J ═ 5.5Hz,1H),4.37(t, J ═ 11.2Hz,1H), 3.95(s,1H),3.80(s,2H),2.42(t, J ═ 5.5Hz,3H),2.20(d, J ═ 11.5Hz,1H), 2.03(d, J ═ 11.0Hz,2H) and 1.76 to 1.29(m,4H) ppm.

LCMS RT＝3.47(M+1)433.21,(M-1)431.3。

n- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-methyl-oxetane-3-carboxamide hydrochloride (635)

1H NMR (300MHz, MeOD) δ 8.48-8.45(m,2H),8.29-8.23(m, 2H),4.84(d, J ═ 6.0Hz,1H),4.38(d, J ═ 6.0Hz,1H),4.26-4.23(m, 1H),3.96(s,1H),3.77-3.62(m,2H),2.36(s,1H),2.18(d, J ═ 11.5Hz, 1H),2.02(d, J ═ 12.3Hz,2H),1.70-1.25(m,4H) and 1.59(s,3H) ppm.

LCMS RT＝3.12(M+1)459.38,(M-1)457.4。

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] tetrahydropyran-4-carboxamide hydrochloride (636)

1H NMR (300MHz, MeOD) δ 8.64(d, J ═ 2.3Hz,1H),8.51(s,1H), 8.36(d, J ═ 2.3Hz,1H),8.29(d, J ═ 5.6Hz,1H),4.44-4.36(m,1H), 3.96-3.87(m,3H),3.47-3.37(m,2H),2.49-2.35(m,2H),2.21(d, J ═ 12.4Hz,1H),2.02(d, J ═ 11.9Hz,2H) and 1.83-1.23(m,8H) ppm. LCMS RT ═ 3.12(M +1)473.4, (M-1) 471.4.

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-hydroxy-butanamide hydrochloride (640)

1H NMR (300MHz, MeOD) δ 8.69(d, J ═ 2.3Hz,1H),8.51(s,1H), 8.37(d, J ═ 2.2Hz,1H),8.29(d, J ═ 5.6Hz,1H),4.43(t, J ═ 11.9Hz,1H), 4.14(q, J ═ 6.1Hz,1H),3.94(t, J ═ 11.9Hz,1H),2.40-2.19(m, 4H),2.03(d, J ═ 8.2Hz,2H),1.78-1.69(m,1H),1.59-1.44(m,3H) and 1.18(d, J ═ 6.1Hz,3H) ppm.

LCMS RT＝3.37(M+1)447.41,(M-1)445.1。

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -2-hydroxy-propionamide hydrochloride (642)

1H NMR (300MHz, MeOD) δ 8.68(s,1H),8.56(s,1H),8.39(d, J ═ 1.5Hz,1H),8.31(d, J ═ 5.3Hz,1H),4.47-4.40(m,1H),4.15(s,1H), 3.98(m,1H),2.41(s,1H),2.23(d, J ═ 10.6Hz,1H),2.04(d, J ═ 11.0Hz, 2H) and 1.77-1.36(m,7H) ppm.

LCMS RT＝3.52(M+1)433.58,(M-1)431.3。

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] tetrahydropyran-2-carboxamide hydrochloride (651)

1H NMR (300MHz, MeOD) δ 8.56-8.51(m,2H),8.33-8.29(m, 2H),4.30(d, J ═ 3.0Hz,1H),3.98(dd, J ═ 11.5,23.4Hz,2H), 3.83-3.79 (m,1H),3.55(t, J ═ 8.9Hz,1H),2.35(d, J ═ 11.1Hz,1H),2.19(d, J ═ 11.2Hz,1H),2.03-1.90(m,4H) and 1.73-1.37(m,8H) ppm. LCMS RT ═ 4.1(M +1)473.41, (M-1)471.4

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] tetrahydrofuran-3-carboxamide hydrochloride (652)

1H NMR (300MHz, MeOD) δ 8.72(d, J ═ 2.3Hz,1H),8.56(s,1H), 8.42(d, J ═ 2.2Hz,1H),8.34(d, J ═ 5.6Hz,1H),4.51-4.43(m,1H), 4.02-3.88(m,3H),3.86-3.78(m,2H),3.07-3.02(m,1H),2.42(d, J ═ 7.5Hz,1H),2.25(d, J ═ 12.0Hz,1H),2.19-2.06(m,4H) and 1.79-1.35 (m,4H) ppm.

LCMS RT＝3.9(M+1)459.41,(M-1)457.4。

(S) -tetrahydrofuran-3-yl (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl carbamate (649)

LCMS RT＝3.3(M+1)475.37,(M-1)473.35。

N- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl) -3-methoxypropionamide (611)

LCMS RT＝2.0(M+1)447.4,(M-1)445.4。

N- [2- (5-chloro-1H-pyrrolo [5,4-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] cyclohexane-cis-1, 3-diamine (540)

LCMS RT＝1.4(M+1)361.5。

N- [ cis-3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl ] amino ] cyclohexyl ] acetamide (452)

(prepared from cis/trans-1, 3-diaminocyclohexane; separation of the trans diastereoisomer by HPLC)

LCMS RT＝1.3(M+1)403.1(M-1)401.1。

N- [ trans-3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] acetamide (457) (separated from the cis diastereoisomer by HPLC)

LCMS RT＝1.6(M+1)403.2(M-1)401.1。

1- [ cis-3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-methyl-urea (455)

(prepared from cis/trans-1, 3-diaminocyclohexane; separation of the trans diastereoisomer by HPLC)

LCMS RT＝1.7(M+1)416.2。

1- [ trans-3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -3-methyl-urea (458)

(prepared from cis/trans-1, 3-diaminocyclohexane; separated from the cis diastereomer by HPLC)

LCMS RT＝0.8(M+1)418.2(M-1)416.1。

3- [ cis-3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -1, 1-dimethyl-urea (456)

(prepared from cis/trans-1, 3-diaminocyclohexane; separation of the trans diastereoisomer by HPLC)

LCMS RT＝1.5(M+1)432.2(M-1)430.2。

3- [ trans-3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] -1, 1-dimethyl-urea (459)

(prepared from cis/trans-1, 3-diaminocyclohexane; separated from the cis diastereomer by HPLC)

LCMS RT＝1.5(M+1)432.2(M-1)430.2。

Cis-3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexylcarbamic acid methyl ester (514) - (racemic cis mixture-prepared from cis-1, 3-diaminocyclohexane)

LCMS RT＝1.3(M+1)418.8。

N- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl) morpholine-4-carboxamide (647)

LCMS RT＝3.6(M+1)474.4(M-1)472.5。

N- [3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] methanesulfonamide (454)

LCMS RT＝1.6(M+1)439.1(M-1)437.1。

(tetrahydrofuran-3-yl) (1R,3S) -methyl 3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexylcarbamate (648)

LCMS RT＝3.7(M+1)489.38,(M-1)487.49。

General scheme 22

(a) 4-tert-butoxycarbonylmorpholine-2-carboxylic acid, EDC, HOBt, iPr2NEt, CH2Cl2, room temperature; (b) CH2Cl2, TFA; (c) LiOH, 130 ℃, microwave

Formation of N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] morpholine-2-carboxamide dihydrochloride (637)

To a solution of (1S,3R) -N1- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine (0.06g, 0.12mmol) in CH2Cl2(3mL) was added 4-tert-butoxycarbonylmorpholine-2-carboxylic acid (40.4mg, 0.17mmol), EDC (0.03g, 0.14mmol), HOBt (0.02g, 0.12mmol) and iPr2NEt (0.06g, 0.47mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2(2mL) and TFA (2mL) and stirred at room temperature for 2 h. The resulting solution was concentrated in vacuo, dissolved in THF (4mL) and treated with 1N aqueous lithium hydroxide (3.0mL, 3.0 mmol). The reaction mixture was heated in a microwave for 20min to 130 ℃. The solvent was evaporated under reduced pressure and the residue was purified by HPLC using 5-70% MeOH/H2O and 6mM HCl for 15 min. The purified fraction was concentrated to provide the dihydrochloride salt of N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] morpholine-2-carboxamide.

1H NMR (300MHz, MeOD) δ 8.68(s,1H),8.62(s,1H),8.40(s, 1H),8.33(d, J ═ 4.7Hz,1H),4.44-4.35(m,2H),4.21(d, J ═ 12.2Hz, 1H),4.04-3.92(m,2H),3.58(d, J ═ 12.3Hz,1H),3.23-3.08(m,2H), 2.37(d, J ═ 8.1Hz,1H),2.23(d, J ═ 11.1Hz,1H),2.05(d, J ═ 9.7Hz, 2H),1.72(m,2H) and 1.59-1.44(m,2H) ppm; LCMS RT ═ 2.4(M +1) 474.43, (M-1) 472.4.

Other analogs that can be prepared in the same manner as 637 are described below:

N- [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] piperidine-4-carboxamide dihydrochloride (639)

1H NMR (300MHz, MeOD) δ 8.66(s,1H),8.60(s,1H),8.38(s, 1H),8.31(d, J ═ 4.7Hz,1H),4.43 to 4.36(m,1H),3.98 to 3.91(m,1H), 3.43(d, J ═ 10.3Hz,2H),3.03(t, J ═ 10.6Hz,2H),2.60(s,1H),2.38(d, J ═ 10.2Hz,1H),2.21(d, J ═ 10.6Hz,1H),2.07 to 1.92(m,6H) and 1.74 to 1.30(m,4H) ppm.

LCMS RT＝2.4(M+1)472.46,(M-1)470.4。

General scheme 23

(a) (1S,2S) -cyclohexane-1, 2-diamine, THF, microwave at 120 ℃; (b) methyl chloroformate, iPr2NEt, CH2Cl 2; (c) LiAlH4, THF

Formation of (1S,2S) -N1- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1, 2-diamine (23b)

A solution of 5-chloro-3- (5-fluoro-4-methylsulphinyloxy-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 23a (0.50g, 1.08mmol) in THF (4mL) was treated with (1S,2S) -cyclohexane-1, 2-diamine (0.27g, 2.37mmol) and iPr2NEt (2.15mmol) at 120 deg.C for 10 min. The mixture was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH-CH2Cl2) to provide the desired intermediate as a white solid (410 mg).

LCMS RT＝2.2(M+1)515.5。

Formation of methyl (1S,2S) -2- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) cyclohexylcarbamate (23c)

To a mixture of (1S,2S) -N1- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1, 2-diamine 23b (0.18g, 0.35mmol) in dichloromethane (4mL) at room temperature was added iPr2NEt (0.12mL, 0.70mmol) followed by methyl chloroformate (0.03mL, 0.37 mmol). After 35min, the mixture was diluted with EtOAc, then washed with saturated aqueous NH4Cl solution, saturated aqueous NaHCO3 solution, and brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide a crude product that was sufficiently pure for the next reaction.

LCMS RT＝4.1(M+1)573.4。

Formation of (1S,2S) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N2-methylcyclohexane-1, 2-diamine (522)

To a stirred solution of methyl (1S,2S) -2- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexylcarbamate 23c (0.09g, 0.16mmol) in THF (3mL) at room temperature was added LiAlH4(0.06g, 1.66mmol) and the mixture was stirred at room temperature for a further 2H. The reaction was quenched with 0.06mL KOH (5% aq) followed by water (3 X0.06mL). Then, Et2O (6mL) was added and stirring was continued for 20 min. The milky white suspension was filtered and washed with EtOAc, and the residue was washed with EtOAc. The combined organic phases were concentrated in vacuo and purified by preparative HPLC followed by preparative TLC to afford the desired product as the free base, which was then converted to the HCl salt by treatment with HCl (4N in dioxane).

LCMS RT＝1.7(M+1)375.5。

General scheme 24:

(a)NaCNBH、(CHO)、HOAc、CHCN

Formation of (1S,2S) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N2, N2-dimethylcyclohexane-1, 2-diamine (523)

To a mixture of (1S,2S) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1, 2-diamine 23b (0.08g, 0.22mmol) in acetonitrile (1.6mL) at room temperature was added formaldehyde (0.09mL of 37% w/v, 1.11mmol), followed by NaCNBH3(0.04g, 0.56 mmol). A gel-like mixture was formed and after 4min the mixture became liquid again. After 4h, quench the reaction with 5mL of 2N NaOH and stir the mixture overnight. The mixture was diluted with EtOAc and stirred until all solids dissolved. The layer was extracted several times with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (0-15% MeOH-CH2Cl2) followed by preparative HPLC afforded the desired product, which was converted to the corresponding HCl salt with HCl (4N in dioxane).

1H NMR (300MHz, MeOD) δ 8.65(d, J ═ 2.3Hz,1H),8.54(s,1H), 8.43(d, J ═ 5.1Hz,1H),8.40(d, J ═ 2.3Hz,1H),4.82-4.72(m,1H), 3.66-3.53(m,1H),2.96(s,3H),2.77(s,3H),2.33(d, J ═ 12.3Hz,2H), 2.10-1.97(m,2H) and 1.75-1.48(m,4H) ppm; LCMS RT ═ 1.7(M +1) 389.5.

General scheme 25:

(a)2- (methoxymethyl) oxirane, methanol, and microwave at 130 ℃; (b) LiOH, 130 ℃, microwave

Formation of 1- [ [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] amino ] -3-methoxy-propan-2-ol (610)

To a solution of (1S,3R) -N1- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine 20c (50mg, 0.09mmol) in methanol (2mL) was added 2- (methoxymethyl) oxirane (9.4mg, 0.11mmol) and the reaction mixture was heated in a microwave for 10min to 140 ℃.1M aqueous LiOH (1.0mL, 1.0mmol) was added and the reaction mixture was heated to 130 ℃ in a microwave for 10 min. The solvent was evaporated under reduced pressure and the residue was purified by HPLC for more than 15min using 5-70% CH3CN// H2O and 0.1% TFA. The purified fraction was concentrated and redissolved in MeOH and passed through a carbonate-PS column to provide the free base of the desired product, 1- [ [ (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexyl ] amino ] -3-methoxy-propan-2-ol 610.

1H NMR (300MHz, MeOD) δ 8.85(d, J ═ 2.3Hz,1H),8.22(d, J ═ 2.2Hz,1H),8.15(s,1H),7.98(d, J ═ 4.1Hz,1H),4.20(m,1H),3.82(dd, J ═ 3.9,8.2Hz,1H),3.55-3.45(m,1H),3.30(s,3H),3.23-3.07(m, 1H),2.86-2.77(m,2H),2.68-2.59(m,1H),2.44(d, J ═ 10.9Hz,1H), 2.15(d, J ═ 9.8, 1H),2.07-1.94(m,2H),1.65 (m, 56.56, 1.42H), and 1H (m, 1H); LCMS RT ═ 1.52(M +1) 449.42.

General scheme 26:

(a) 2-bromoacetamide, Na2CO3, DMF, room temperature; (b) LiOH, 130 ℃, microwave

formation of 2- [ [1R,3S) -3- [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl ] amino ] cyclohexylamino ] -acetamide (593)

To a solution of (1S,3R) -N1- [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] cyclohexane-1, 3-diamine 20c (0.050g, 0.100mmol) in DMF (2mL) was added 2-bromoacetamide (0.015g, 0.100mmol) and Na2CO3(0.021g, 0.190 mmol). The reaction mixture was stirred at room temperature overnight. 1M aqueous lithium hydroxide (2.0mL, 2.0mmol) was added and the reaction mixture was heated in a microwave for 10min to 130 ℃. The solvent was evaporated under reduced pressure and the residue was purified by HPLC using 5-70% CH3CN// H2O and 0.1% TFA for more than 15 min. The purified fraction was concentrated, redissolved in MeOH and passed through a carbonate-PS column to provide the free base of the desired product, 2- [ [1R,3S) -3- [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl ] amino ] cyclohexylamino ] -acetamide 593.

1H NMR (300MHz, MeOD) δ 8.85(d, J ═ 2.3Hz,1H),8.22(d, J ═ 2.2Hz,1H),8.15(s,1H),7.99(d, J ═ 4.1Hz,1H),4.28 to 4.20(m,1H), 2.82 to 2.73(m,1H),2.65(s,2H),2.40(d, J ═ 10.2Hz,1H),2.15(d, J ═ 8.5Hz,1H),2.05 to 1.92(m,2H),1.64 to 1.55(m,1H) and 1.44 to 1.12(m, 3H) ppm; LCMS RT ═ 1.47(M +1) 418.21.

General scheme 27:

a) 3-aminocyclohexanol, iPr2NEt, THF, MW 130 ℃; b) ag2O, CaSO4, CH3I, room temperature; c) sodium methoxide, THF

Formation of (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanol (27a)

to a solution of 5-chloro-3- (5-fluoro-4- (methylsulfonyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine 1a (1.09g, 2.34mmol) and 3-aminocyclohexanol (0.32g, 2.82mmol) in THF was added DIEA (0.60g, 4.69 mmol). The reaction mixture was heated in a microwave at 130 ℃ for 10 min. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel chromatography to obtain 550mg of the desired product 27 a.

H NMR(300MHz,CDCl)δ8.88(s,1H),8.56(s,1H),8.40(d,J ＝2.4Hz,1H),8.12– 8.07(m,3H),7.32–7.28(m,2H),5.70(m,1H), 4.35(m,1H),4.10(m,1H),2.40(s,3H),2.32 (d,J＝12.3Hz,1H),2.0– 1.95(m,2H),1.70-1.45(m 4H)。

Formation of 2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S) -3-methoxycyclohexyl) pyrimidin-4-amine (27b)

To a suspension of iodomethane (0.20g, 0.41mmol) and 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -cyclohexanol 27a (0.47g, 2.04mmol) was added silver oxide (0.578g, 4.07mmol) and calcium sulfate (0.28g, 2.04 mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo. The resulting crude mixture was purified by silica gel chromatography to obtain 120mg of the desired product 27 b.

H NMR(300MHz,CDCl)δ8.88(s,1H),8.56(s,1H),8.4(d,J＝ 2.4Hz,1H),8.13– 8.06(m,3H),7.30(d,J＝8.7Hz,2H),6.00(s,1H), 4.42-4.32(m,1H),3.60-3.50(m,1H), 3.4(s,3H),2.4(s,3H),2.25(dd,J ＝3.4,9.7Hz,1H),2.00-1.84(m 3H),1.75-1.60(m, 3H),1.60-1.50(m, 1H)。

Formation of 2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S) -3-methoxycyclohexyl) pyrimidin-4-amine (552)

to a solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-N- (3-methoxycyclohexyl) pyrimidin-4-amine 27b (0.08g, 0.15mmol) in THF was added a few drops of NaOMe. The reaction mixture was stirred at room temperature for 20 min. Ethyl acetate and brine were added to the reaction mixture. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in CH3CN/H2O and the mixture was purified by preparative HPLC to obtain 23mg of the desired product 552.

H NMR(300MHz,CDOD)δ8.70(d,J＝2.3Hz,1H),8.45(s, 1H),8.35(d,J＝2.3Hz, 1H),8.25(d,J＝5.4Hz,1H),4.35(m,1H),3.52 (m,1H),3.4(s,3H),2.53(d,J＝12.1Hz, 1H),2.18(d,J＝11.4Hz,2H), 2.05-1.95(m,1H),1.65-1.4(m,3H),1.38-1.25(m,1H)；LCMS RT＝ 2.22min(M+1)376.23。

(3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanol (524)

LCMS RT＝2.0(M+1)362.48。

3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexylcarbamic acid ethyl ester (608)

LCMS RT＝2.9(M+1)433.4。

General scheme 28:

a) Dess-Martin periodinane (Dess-Martin periodinane), CH2Cl 2; b) CH3MgBr, THF; c) sodium methoxide, THF

formation of 3- (2- (5-chloro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanone (28a)

To a solution of 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanol 27a (0.54g, 1.05mmol) in 20ml CH2Cl2 was added desmesartan oxidant (0.62g, 1.47 mmol). The suspension was stirred at room temperature for 6 h. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The resulting residue was purified by silica gel chromatography (45% ethyl acetate/hexanes gradient) to afford 430mg of the desired product.

H NMR(300MHz,CDCl3)δ8.66(d,J＝2.4Hz,1H),8.42(s1H), 8.31(d,J＝2.3Hz, 1H),8.05-8.02(m,3H),7.24-7.19(m,2H),2.99(d,J ＝5.2Hz,1H),4.56(s,1H),2.85(dd,J ＝4.7,13.9Hz,1H),2.50-2.40(m, 3H),2.40(s,3H),1.95-1.80(m,2H),1.70-1.50(m,2H)。

Formation of 3- (2- (5-chloro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (28b)

To a cold (0 ℃) solution of 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanone 28a (0.47g, 0.92mmol) in THF (5mL) was added methylmagnesium bromide (3.30mL of a 1.4M solution, 4.58 mmol). The reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was diluted with ethyl acetate and saturated aqueous NH4Cl solution. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by silica chromatography with DCM and methanol, eluting both products with 95% DCM and 5% methanol without separation. The two diastereomers were used as a mixture without further purification.

LCMS (10-90% 3/5min (gradient/run) w/FA) showed 2 peaks of the desired product. Peak 1: retention time 4.04min (M +1: 530.42); peak 2: retention time 4.18min (M +1: 530.45).

Formation of (3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (571 and 572)

To a solution of 3- (2- (5-chloro-1- (benzenesulfonyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol 28b in THF was added a few drops of 25% sodium methoxide at room temperature. The reaction mixture was stirred at room temperature for 5 min. The reaction mixture was diluted with ethyl acetate and brine. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The product was purified by preparative HPLC to obtain two diastereomers.

Diastereomer 1-571

H NMR(300MHz,CDOD)δ8.78(d,J＝2.2Hz,1H),8.60(s,1H), 8.36(s,1H),8.30 (dd,J＝5.6,9.9Hz,1H),4.85(m,1H)2.25-1.95(m, 3H),1.86-1.6(m 4H),1.40-1.3(m 2H),1.3(s,3H)；LCMS RT 2.39(M+1) 376.42。

Diastereoisomers 2-572

H NMR(300MHz,CDOD)8.66(d,J＝2.1Hz,1H),8.55(d,J＝ 2.7Hz,1H),8.38(s, 1H),8.258(dd,J＝5.6,9.5Hz,1H),4.6(s,1H), 2.00-1.50(m,9H),1.30(s,3H)；

LCMS RT 1.97(M+1)376.41。

3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethynylcyclohexanol (617 and 618)

diastereomer 1-617: LCMS RT ═ 3.6(M +1) 386.4.

diastereomer 2-618: LCMS RT ═ 3.2(M +1) 386.3.

3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-vinylcyclohexanol (627 and 628)

Diastereomer 1-627: LCMS RT ═ 4.0(M +1) 388.4.

Diastereomer 2-628: LCMS RT ═ 3.7(M +1) 388.4.

3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- (hydroxymethyl) cyclohexanol (646)

LCMS RT＝3.4(M+1)392.4。

3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylcyclohexanol (626)

LCMS RT＝4.1(M+1)390.4。

General scheme 29

Formation of (3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (29a)

The starting racemic alcohol (3S) -3-aminocyclohexanol was prepared according to the procedure described in Bernardelli, P., Bladon, M., Lorthiois, E., Manage, A., Vergne, F.and Wrigglesworth, R., Tetrahedron Asymmetry 2004,15, 1451-.

(3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol was prepared using (3S) -3-aminocyclohexanol according to the procedure for compound 16a, affording the desired product 29a as a solid.

formation of (S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanone (29b)

To 700mL of a solution of 7.9g (32.16mmol) (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanol 29a (7.90g, 32.16mmol) in CH2Cl2(700mL) was added desselin reagent (17.73g, 41.81 mmol). The reaction mixture was stirred at room temperature for 20h until TLC chromatography indicated completion of the reaction. The reaction mixture was filtered through a pad of celite, and the resulting filtrate was washed with 200mL of saturated aqueous NaHCO3 solution and 200mL of brine. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (50% EtOAc/hexanes) to afford 7.3g of the desired product 29b (93% yield).

H NMR(300MHz,CDOD)δH NMR(300MHz,CDCl3)δ7.96- 7.93(m,1H),7.28(s,1H), 5.12(s,1H),4.57-4.48(m,1H),2.87(dd,J＝ 4.8,14.0Hz,1H),2.51-2.23(m,4H),2.12- 2.02(m,1H)；LCMS RT＝ 2.97(M+1)244.26。

Formation of (3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (29c, 29d)

To a solution of (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone (1.83g, 7.49mmol) in THF (100mL) was added methylmagnesium bromide (21.4mL of a 1.4M solution, 29.96mmol) at room temperature. The reaction mixture was stirred at room temperature for 5 min. To the reaction mixture was added saturated aqueous NH4Cl solution and EtOAc. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The two spots were separated by silica gel chromatography (120g silica gel column).

Fraction-1 (29 c): 1H NMR (300MHz, CD3OD) δ δ 7.81(d, J ═ 2.8Hz, 1H),7.28(d, J ═ 0.5Hz, H),4.47(q, J ═ 3.8Hz,1H),1.92-1.87(m,2H), 1.82-1.77(m,1H),1.69(dd, J ═ 4.2,14.0Hz,2H) and 1.56-1.48(m,4H) ppm; LCMS RT ═ 3.43(M +1) 260.3.

Fraction-2 (29 d): 1H NMR (300MHz, CD3OD) δ 7.87(d, J ═ 2.8Hz, H),7.28 (s, H),4.95(d, J ═ 5.0Hz,1H),4.45-4.33(m,1H),2.17(s, H),2.12-2.06(m,1H), 1.93-1.78(m,1H),1.71(dd, J ═ 3.1,5.6Hz,2H), 1.39-1.25 (m,4H) and 1.19-1.05(m,1H) ppm; LCMS RT ═ 3.10(M +1)260.29

Formation of (3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (29e, 29f)

A solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (1.46g, 3.37mmol), (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] -1-methyl-cyclohexanol 29c (0.72g, 2.81mmol), and Na2CO3(4.21mL of a 2M solution, 8.433mmol) in dimethoxyethane (15mL) was degassed with nitrogen for 30 min. Tetrakis (triphenylphosphine) palladium (0.16g, 0.14mmol) was added to the reaction mixture. The reaction mixture was heated at 130 ℃ for 45min in a Q-tube apparatus. The reaction mixture was filtered through a pad of 1cm silica gel and 2cm celite. The product was purified by silica gel chromatography (hexanes/EtOAc) to afford the desired product 29e (63% yield).

1H NMR (300MHz, CD3OD) δ 8.81(d, J ═ 2.4Hz,1H),8.50(s,1H), 8.38(d, J ═ 2.4Hz,1H),8.10(d, J ═ 8.3Hz,2H),8.04(d, J ═ 3.3Hz, 1H),7.29(d, J ═ 8.1Hz,2H),6.85(d, J ═ 5.7Hz, H),4.58(t, J ═ 3.7Hz,1H), 2.39(s, H),1.98-1.93(m,2H),1.86(d, J ═ 4.0Hz,2H),1.72-1.56 (m,5H),1.36(d, J ═ 3.8, 3H) and 1.30H (m, 26 ppm).

LCMS RT＝4.62(M+1)530.4。

diastereomer 29f was prepared according to the same procedure as 29e, substituting 29d as starting material for the suzuki coupling process.

1H NMR (300MHz, CD3OD) δ 8.89(d, J ═ 2.4Hz,1H),8.55(s,1H), 8.39(d, J ═ 2.4Hz,1H),8.09(t, J ═ 8.4Hz,2H),8.08(s,1H),7.29(d, J ═ 8.2Hz,2H),4.89(d, J ═ 6.6Hz,1H),4.55(m,1H),2.39(s,3H),2.24(t, J ═ 1.8Hz,2H),2.02 to 1.93(m,1H),1.77(t, J ═ 3.3Hz,2H),1.46 to 1.33 (m,5H) and 1.29 to 1.15(m,1H) ppm.

LCMS RT＝4.36(M+1)530.3。

Formation of (3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (655, 656)

To a solution of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanol 29f (2.85g, 5.38mmol) in THF (200mL) at room temperature was added 1.5mL of a 25% W/W sodium methoxide solution. The reaction mixture was immediately injected into the LC/MS. LC/MS showed the reaction was complete. The reaction mixture was diluted with 200ml EtOAc and the organic phase was washed with saturated aqueous NaHCO3 solution and then twice with brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (80g silica, 5% MeOH in CH2Cl2) to yield 1.7g of the desired product. The resulting product was dissolved in 70ml THF, to which was added 1.8ml 5M HCl/IPA. The resulting suspension was stirred at room temperature for 1 h. The solvent was removed under reduced pressure to obtain 1.7g of the desired product 655 as the HCl salt.

1H NMR (300MHz, CD3OD) δ 9.54(s,1H),8.86(d, J ═ 2.3Hz,1H), 8.31(d, J ═ 2.4Hz,1H),8.15(d, J ═ 2.7Hz,1H),8.04(d, J ═ 3.5Hz, 1H),7.28(s, H),6.66(s,1H),4.62-4.59(m,1H),1.96-1.88(m, 4H),1.81(dd, J ═ 4.5,14.9Hz,1H) and 1.68-1.57(m,6H) ppm; LCMS RT ═ 4.01(M +1) 376.4.

the corresponding diastereomer 656 may be prepared in the same manner.

General scheme 30

(a) mCPBA, CH2Cl 2; (b) NH4OH and water at 50 ℃ for 72 h; (c) 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, iPr2NEt, DMF, 90 ℃, 17H; (d)1N LiOH, THF, microwave 120 deg.C, 10min

Formation of 1-methyl-7-oxabicyclo [4.1.0] heptane (30a)

To a cold (0 ℃ C.) solution of 1-methylcyclohexene (3.0g, 31.2mmol) in CH2Cl2(150mL) was added mCPBA (8.4g, 48.7 mmol). The reaction mixture was stirred at 0 ℃ for 1 h. The reaction mixture was diluted in saturated aqueous NaHCO3 and extracted with ether. The organic phase was washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford the desired compound as an oil which was used without further purification.

Formation of 2-amino-1-methylcyclohexanol (30b)

To a solution of 1-methyl-7-oxabicyclo [4.1.0] heptane 30a (1.0g, 7.1mmol) in water was added ammonium hydroxide (6.0mL, 154.1 mmol). The mixture was heated for 48h to 50 ℃. The mixture was diluted with water, extracted with EtOAc and then extracted twice with 20% MeOH/CHCl 3. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to provide the desired product 30b as an amorphous white solid.

1H NMR (300.0MHz, DMSO) δ 2.44(dd, J ═ 3.4,10.8Hz,1H), 1.64-1.45(m,4H),1.28-1.01(m,4H) and 0.97(s,3H) ppm.

Formation of 2- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (30c)

To a solution of 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 1a (0.97g, 2.09mmol) and 2-amino-1-methylcyclohexanol 30b (0.40g, 3.13mmol) in DMF (10mL) was added iPr2NEt (0.73mL, 4.17 mmol). The reaction mixture was heated at 90 ℃ for 17 h. The reaction mixture was cooled to room temperature and diluted in saturated aqueous NaCl. The liquid phase was extracted twice with EtOAc. The organic phase was washed twice with saturated aqueous NaCl solution, dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography (0-50% EtOAc/hexanes loaded with CH2Cl2) afforded the desired product 30c as a white solid.

1H NMR (300.0MHz, DMSO) δ 9.00(d, J ═ 2.4Hz,1H),8.49(dd, J ═ 2.4,10.3Hz,1H),8.42(s,1H),8.23(d, J ═ 4.1Hz,1H),8.10-8.01 (m,2H),7.52-7.43(m,2H),7.21(d, J ═ 9.1Hz,1H),4.52(s,1H),4.28 (s,1H),2.35(s,3H),1.78-1.50(m,6H),1.34(m,2H) and 1.15(s, 3H).

LCMS RT＝4.1(M+1)530.6。

Formation of 2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanol (562 and 563)

to a solution of 2- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanol 30c (0.41g, 0.77mmol) in THF was added a 1M LiOH solution. The reaction mixture was heated in a microwave at 120 ℃ for 5 min. The reaction mixture was diluted with water, extracted twice with EtOAc and then extracted twice with 10% MeOH/CH2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5-20% MeOH: CH2Cl2) to obtain a white solid as a mixture of trans enantiomers. The two trans enantiomers were separated by preparative chiral HPLC to obtain 562 and 563.

enantiomer 1-563: 1H NMR (300.0MHz, DMSO) δ 12.32(s,1H), 8.86(d, J ═ 2.4Hz,1H),8.28(d, J ═ 2.4Hz,1H),8.20(d,1H),8.15(d, 1H),6.92(d, J ═ 8.2Hz,1H),4.56(s,1H),4.31(dd, J ═ 5.9,8.6Hz,1H), 1.89-1.35(m,8H) and 1.17(s, 3H); LCMS RT ═ 2.5(M +1) 376.4.

general scheme 31:

(a)2, 4-dichloro-5-fluoropyrimidine and acetonitrile/isopropanol are refluxed for 1.5 h; (b) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, Pd (PPh3)4, 2M Na2CO3, acetonitrile, microwave at 120 ℃ for 15 min; (c) TBAF, THF

Formation of (1R,2S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (31b)

The starting racemic diol 31a (1R,2S,3S) -3-aminocyclohexane-1, 2-diol was prepared according to the procedure described in Davies et al org.bio.chem. (2008)6,3751 and 3762. To a solution of racemic diol 31a (0.66g, 5.00mmol) in acetonitrile (5mL) and isopropanol (5mL) was added 2, 4-dichloro-5-fluoro-pyrimidine (0.84g, 5.03mmol) and iPr2NEt (3.25g, 4.38mL, 25.20 mmol). The reaction mixture was sealed and heated to 100 ℃ for 90min, then concentrated to dryness. The crude product was purified by silica gel chromatography (40% -100% EtOAc/Hex) to give the racemate, which was further purified by chiral HPLC separation to give compound 31b (0.26g) as a white solid.

H NMR(300MHz,MeOH-d4)δ7.80(s,1H),4.60(s,6H),4.10(m, 1H),3.80(s,1H), 3.60(m,1H),3.20(s,1H),3.15(s,2H),1.50-1.70(m, 5H),1.20(m,1H)ppm。

LCMS RT＝2.8(M+1)262.0,(M-1)260.1。

Formation of (1R,2S,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (31c)

To a deoxygenated solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.22g, 0.51mmol) and (1R,2S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol 31b (0.08g, 0.24mmol) in acetonitrile (6mL) were added 2M sodium carbonate (0.45mL of a 2M solution, 0.894mmol) and Pd (PPh3)4(34.5mg, 0.030 mmol). The reaction was sealed and heated in a microwave for 15min to 120 ℃. Rxn was diluted with EtOAc and filtered through florisil. The solution was concentrated to a crude product and purified by silica gel chromatography (DCM to 20% MeOH/DCM) to give compound 31c (0.11g) as a pink solid.

LCMS RT＝3.8(M+1)532.2,(M-1)530.2。

Formation of (1R,2S,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (632)

To a solution of (1R,2S,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol 31c (0.11g, 0.21mmol) in THF was added TBAF (0.23g, 0.84 mmol). The reaction was aged at room temperature for 1H, quenched with 1N HCl (1ml), and purified by reverse phase chromatography (5-70% MeCN/H20 and 0.1% TFA). The product was desalted on an SPE bicarbonate cartridge, concentrated to dryness, then triturated with MeOH to provide 18mg compound 632.

H NMR(300MHz,MeOH-d4)δ8.42(s,1H),7.90(s,1H),7.82(s, 1H),7.70(s,1H), 4.15(m,1H),3.95(m,1H),3.70(m,1H),1.75(m,5H), 1.50(m,1H)ppm。

LCMS RT＝3.0(M+1)378.2,(M-1)376.0。

General scheme 32:

(a) Refluxing 2, 4-dichloro-5-fluoropyrimidine, acetonitrile and isopropanol for 1.5 h; (b) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, Pd (PPh3)4, 2M Na2CO3, acetonitrile, microwave at 120 ℃ for 15 min; (c) TBAF, THF

Formation of (1S,2S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (32b)

The starting racemic diol 32a (1S,2S,3S) -3-aminocyclohexane-1, 2-diol was prepared according to the procedure described in Davies et al org.bio.chem. (2008)6,3751 and 3762.

According to the procedure for compound 632, compound 32b (0.03g, 0.11mmol) was produced as a white solid except that the racemate of diol 32a (0.07g, 0.53mmol) was used.

H NMR(300MHz,MeOH-d4)δ7.90(s,1H),4.45(m,1H),3.80(s, 1H),3.62(s,1H), 1.40-1.80(m,6H),0.85(m,1H)ppm。

LCMS RT＝2.7(M+1)262.0。

formation of (1S,2S,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (32c)

according to the procedure for compound 31c, except that compound 32b (0.03g, 0.11mmol) was used, compound 32c (0.06g, 0.11mmol) was produced.

LCMS RT＝3.9(M+1)532.2,(M-1)530.3。

Formation of (1S,2S,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (615)

According to the procedure for compound 624, compound 615(0.015g, 0.035mmol) was produced as a white solid, except that compound 32c (0.06g, 0.11mmol) was used.

H NMR(300MHz,MeOH-d4)δ8.83(s,1H),8.51(s,1H),8.40(s, 1H),8.30(s,1H), 4.00(bs,2H),0.60-0.90(m,4H),0.50(m,2H)ppm。

LCMS RT＝3.7(M+1)378.3,(M-1)376.3。

General scheme 33

Formation of (1R,2R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (33b)

The starting racemic diol 33a (1R,2R,3S) -3-aminocyclohexane-1, 2-diol was prepared according to the procedure described in Davies et al org.lett. (2009)6,1333.

According to Compound procedure 632, except that the racemate of diol 33a (0.13g, 1.01mmol) was used, Compound 33b (0.14g, 0.53mmol) was produced as a white solid.

H NMR(300MHz,MeOH-d4)δ7.90(s,1H),4.05(m,2H),3.70- 3.80(m,0.6H),1.95 (bs,2.5H),1.70(m,1.6H),1.30-1.60(m,5.4H) ppm；C-APT NMR(300MHz,MeOH-d4)δ 148.6,145.2,140.0,139.8, 78.9,75.2,55.4,49.15(m,MeOH-d4),33.9,31.9,22.4ppm。

LCMS RT＝2.4(M+1)262.0,(M-1)260.1。

Formation of (1R,2R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (33c)

According to the procedure for compound 31c, compound 33c (0.008g, 0.015mmol) was produced, except that compound 33b (0.07g, 0.26mmol) was used. DME was used as solvent instead of acetonitrile.

LCMS RT＝4.2(M+1)532.3,(M-1)530.3。

Formation of (1R,2R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexane-1, 2-diol (625)

according to the procedure for compound 624, compound 625(0.005g, 0.012mmol) was produced except that compound 33c (0.008g, 0.015mmol) was used.

H NMR(300MHz,MeOH-d4)δ8.80(s,1H),8.48(s,1H),8.40(s, 1H),8.20(s,1H), 4.5(m,1H),3.55(m,2H),2.12(m,2H),1.95(m,1H), 1.61(m,2H),1.58(m,1H)ppm。

LCMS RT＝2.4(M+1)378.2,(M-1)376.2。

The following compounds 631, 616 and 624 are enantiomers of 632, 615 and 625 and can be prepared by separation from their respective enantiomeric mixtures by chiral preparative HPLC chromatography.

General scheme 35

(a) (1S,2S) -2-aminocyclohexanecarboxylic acid, iPr2NEt, Na2CO3, THF-CH3CN (3:1), microwave at 135 ℃; (b)1N LiOH, THF, microwave 120 ℃; (c)4N HCl-Dioxohexane, EtOH, 70 deg.C

Formation of (1S,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (553)

A mixture of 5-chloro-3- (5-fluoro-4-methanesulfonyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 1a (0.49g, 1.05mmol), (1S,2S) -2-amino-cyclohexanecarboxylic acid (0.30g, 2.10mmol), freshly ground Na2CO3(0.22g, 2.10mmol) and iPr2NEt (0.37mL, 2.10mmol) in THF (10mL) and CH3CN (2mL) was heated in a sealed vessel under microwave irradiation for 30min to 130 ℃. The mixture was cooled to room temperature. A1N LiOH solution (3.1mL, 3.1mmol) was added and the mixture was stirred at 120 ℃ for 10min under microwave irradiation. The mixture was acidified with 1N HCl to pH 2 with vigorous stirring. The newly formed solid was collected by vacuum filtration. The solid was washed with a small amount of water and EtOAc. The solid was dried in vacuo to afford the desired product.

H NMR(300MHz,MeOD)δ8.89(d,J＝2.4Hz,1H),8.44(s,1H), 8.38(d,J＝2.3Hz, 1H),8.29(d,J＝5.6Hz,1H),4.75(m,1H),2.75- 2.66(m,1H),2.25-2.16(m,2H),1.99-1.89 (m,2H),1.71-1.29(m,4H) ppm；LCMS RT＝2.0min,(M+H)390.4。

Other analogs that can be prepared in the same manner as 553 are described below:

Trans-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (541)

LCMS RT＝2.4min,(M+H)390.5。

(1R,2R) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (554)

1H NMR (300MHz, MeOD) δ 8.89(d, J ═ 2.4Hz,1H),8.44(s,1H), 8.38(d, J ═ 2.4Hz,1H),8.29(d, J ═ 5.6Hz,1H),4.77(m,1H), 2.75-2.66 (m,1H),2.24-2.17(m,2H),1.94-1.89(m,2H) and 1.74-1.36(m, 4H) ppm.

LCMS RT＝2.3min,(M+H)390.4。

Cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (559)

1H NMR (300MHz, MeOD) δ 8.75(d, J ═ 2.4Hz,1H),8.38 to 8.35 (m,2H),8.24(d, J ═ 5.1Hz,1H),4.70 to 4.62(m,1H),3.25 to 3.17(m, 1H),2.32(m,1H),2.14 to 1.80(m,4H) and 1.68 to 1.54(m,3H) ppm.

LCMS RT＝2.3min,(M+H)389.8。

(1S,2R) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (579)

1H NMR (300MHz, d6-DMSO) δ 12.52(s,1H),8.68(d, J ═ 2.3Hz,1H), 8.33(d, J ═ 2.5Hz,2H),8.30(d, J ═ 4.4Hz,1H),7.57(s,1H),4.53 (m,1H),3.05(m,1H),2.15-2.07(m,1H),1.96(m,1H),1.81-1.76(m, 3H) and 1.51(m,3H) ppm.

LCMS RT＝2.9min,(M+H)390.4。

(1R,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (578)

1H NMR (300MHz, d6-DMSO) δ 12.51(s,1H),8.68(d, J ═ 2.3Hz,1H), 8.33(d, J ═ 2.3Hz,2H),8.29(d, J ═ 4.3Hz,1H),7.55(s,1H),4.53 (s,1H),3.05(m,1H),2.13(m,1H),1.96(m,1H),1.79(m,3H) and 1.51(m,3H) ppm.

LCMS RT＝2.8min,(M+H)390.4。

cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanecarboxylic acid (558)

1H NMR (300MHz, MeOD) δ 8.78(d, J ═ 2.4Hz,1H),8.38(s,1H), 8.33(d, J ═ 2.2Hz,1H),8.25(d, J ═ 5.2Hz,1H),4.98(dd, J ═ 7.2Hz,1H), 2.27-2.03(m,5H) and 1.86-1.76(m,1H) ppm.

LCMS RT＝2.5min,(M+H)376.2。

(1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanecarboxylic acid (566)

1H NMR (300MHz, d6-DMSO) δ 12.42(s,1H),8.72(d, J ═ 2.2Hz,1H),8.29 (m,2H),8.22(d, J ═ 4.1Hz,1H),7.87(s,1H),4.56-4.49(m, 1H),2.87(dd, J ═ 8.4,25.0Hz,1H),2.87(s,1H),2.42-2.33(m,1H), 2.15-2.04(m,1H),2.00-1.85(m,3H) and 1.81-1.70(m,1H) ppm.

LCMS RT＝2.3min,(M+H)376.4。

(1S,3R) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclopentanecarboxylic acid (565)

1H NMR (300MHz, d6-DMSO) δ 12.48(s,1H),8.71(d, J ═ 2.3Hz,1H), 8.35-8.31(m,2H),8.26(d, J ═ 4.3Hz,2H),8.02(s,1H), 4.57-4.44 (m,1H),2.87(qn, J ═ 8.3Hz,1H),2.39-2.32(m,1H),2.15-2.05 (m,1H),2.00-1.86(m,3H) and 1.82-1.70(m,1H) ppm.

LCMS RT＝2.4min,(M+H)376.4。

(1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (630)

compound 630 is prepared in the same manner from intermediate 18c by removing the Cbz protecting group and reacting with the intermediate, followed by removal of the tosyl protecting group.

LCMS RT＝3.2min,(M+H)390.4,(M-H)388.1。

trans-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylic acid (582)

1H NMR (300.0MHz, d6-DMSO) δ 12.46(s,1H),8.72(d, J ═ 2.4Hz,1H), 8.32-8.28(m,3H),7.10(d, J ═ 7.1Hz,1H),4.27-4.20(m, 1H),2.26(d, J ═ 10.1Hz,1H),1.93(m,1H),1.83(m,1H),1.68-1.59(m, 3H),1.36(m,2H) and 1.24(s,3H) ppm.

LCMS RT＝3.2min,(M+H)404.4。

racemic trans-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylcyclohexanecarboxylic acid (586)

H NMR(300MHz,MeOD)δ8.93(s,1H),8.85(m,2H),8.93- 8.87(m,1H),8.31(dd,J ＝4.5,1.2Hz,2H),8.31(dd,J＝4.5,1.2Hz, 2H),8.30(d,J＝2.3Hz,1H),8.19(d,J＝ 5.0Hz,1H),5.26--5.20(m, 1H),3.37(dd,J＝3.3Hz,1.6,2H),3.33(ddt,J＝6.6,3.3, 1.6Hz,118H), 2.11(dd,J＝8.0,5.8Hz,2H),1.80(tdd,J＝21.2,18.9,11.6Hz,8H), 1.63- 1.54(m,3H),0.86(q,J＝7.4Hz,4H)ppm。

LCMS RT＝2.9min,(M+H)418.4。

Racemic cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylcyclohexanecarboxylic acid (585)

H NMR(300MHz,MeOD)δ8.80-8.76(m,1H),8.37(s,1H), 8.35(d,J＝2.3Hz,1H), 8.27-8.23(m,1H),4.49-4.42(m,1H),2.43- 2.34(m,1H),2.09(d,J＝6.2Hz,1H),1.98- 1.36(m,12H),0.94(dd,J＝ 11.3,3.8Hz,3H)ppm。

LCMS RT＝3.2min,(M+H)418.4。

(3S,4R,5R) -ethyl 3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -4-acetylamino-5- (pentyl-3-oxy) cyclohexene-1-carboxylate (670)

h NMR (300.0MHz, MeOD) d 8.64(d, J ═ 2.3Hz,1H),8.40(s, 1H),8.32(d, J ═ 2.3Hz,1H),8.29(d, J ═ 5.0Hz,1H),6.96(m,1H), 4.84-4.80 (m,1H),4.34(m,1H),4.29-4.19(m,3H),3.54-3.47(m,1H), 3.15-3.07(m,1H),2.68-2.58(m,1H),1.92(s,3H),1.59-1.51(m,4H), 1.26(t, J ═ 7.1Hz,3H),0.95(t, J ═ 7.4, 3H) and 0.89(t, 7.7H), 3H.

LCMS RT＝3.6(M+1)559.4。

(3S,4R,5R) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -4-acetylamino-5- (pentyl-3-oxy) cyclohexene-1-carboxylic acid (671)

h NMR (300.0MHz, MeOD) d 8.66(d, J ═ 2.3Hz,1H),8.39(s, 1H),8.32(d, J ═ 2.3Hz,1H),8.29(d, J ═ 5.0Hz,1H),6.97(m,1H), 4.82-4.79 (m,1H),4.34(m,1H),4.25(dd, J ═ 7.6,10.1Hz,1H),3.54-3.47 (m,2H),3.11-3.04(m,1H),2.65-2.57(m,1H),1.91(s,3H),1.59(m, 4H),0.95(t, J ═ 7.4Hz,3H) and 0.89(t, J ═ 7.4, 3H).

LCMS RT＝3.1(M+1)531.4。

General scheme 36

(1S,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ethyl ester (561)

To a mixed slurry of (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [5,4-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexane-1-carboxylic acid 553(0.090g, 0.231mmol) in ethanol (1.5mL) was added HCl (0.577mL of 4M solution, 2.309mmol) at room temperature. The solution was warmed to 50 ℃. After 6h, the mixture was basified with 1N NaOH, brine was added and the aqueous layer was extracted repeatedly with EtOAc. The organic layer was dried over MgSO4, and filtered through a short silica gel packed column and concentrated in vacuo to afford the desired product.

1H NMR (300MHz, MeOD). delta.8.95 (s,1H),8.19(m,2H),7.99(s, 1H),4.61(m,1H),3.93(m,2H),2.61(m,1H),2.17-2.05(m,2H), 1.89-1.32 (m,7H) and 1.00(m,3H) ppm.

LCMS RT＝2.7min,(M+H)418.4。

The following compounds can be prepared in a manner similar to that described in scheme 36.

(1R,2R) -ethyl 2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylate (560)

1H NMR (300MHz, MeOD). delta.8.95 (s,1H),8.23-8.14(m,2H), 8.00(m,1H),4.61(m,1H),3.96-3.92(m,2H),2.61(m,1H),2.14-2.04 (m,2H),1.89-1.35(m,7H) and 1.04-0.99(m,3H) ppm.

LCMS RT＝3.2min,(M+H)418.5。

(1S,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid methyl ester (575)

1H NMR (300MHz, d6-DMSO) δ 8.76(d, J ═ 2.5Hz,1H),8.26(d, J ═ 2.4Hz,1H),8.19(s,1H),8.13(d, J ═ 4.0Hz,1H),7.53(d, J ═ 8.5Hz, 1H),4.47-4.37(m,1H),3.40(s,3H),2.68-2.59(m,1H),2.05-1.97(m, 2H),1.84-1.75(m,2H),1.63-1.40(m,3H) and 1.31-1.23(m,1H) ppm.

LCMS RT＝3.1min,(M+H)404.4。

(1S,2S) -2-methoxy-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid ethyl ester (574)

1H NMR (300MHz, d6-DMSO) d 8.74(d, J ═ 2.4Hz,1H),8.24(d, J ═ 2.4Hz,1H),8.19(s,1H),8.12(d, J ═ 4.0Hz,1H),7.55(d, J ═ 8.6Hz,1H), 4.42(m,1H),4.02-3.86(m,2H),3.35-3.23(m,2H),3.08(s,3H), 2.69-2.60(m,1H),1.99(m,2H),1.77(m,2H),1.62-1.40(m,3H) and 1.27(m,1H) ppm.

LCMS RT＝3.0min,(M+H)448.4。

(1R,2R) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid isopropyl ester (568)

1H NMR (300MHz, d6-DMSO) δ 8.80(d, J ═ 2.5Hz,1H),8.27(d, J ═ 2.4Hz,1H),8.19(s,1H),8.13(d, J ═ 4.0Hz,1H),7.60(d, J ═ 8.6Hz, 1H),4.72(qn, J ═ 6.2Hz,1H),4.55 to 4.48(m,1H),2.61 to 2.54(m,1H), 1.96(m,2H),1.77(m,2H),1.63 to 1.41(m,3H),1.30 to 1.23(m,1H) and 0.93(d, J ═ 6.2, 6H) ppm.

LCMS RT＝3.08min,(M+H)432.46。

(1S,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid isopropyl ester (569)

1H NMR (300MHz, d6-DMSO) δ 12.57(s,1H),8.80(d, J ═ 2.4Hz,1H), 8.36-8.28(m,4H),4.75(td, J ═ 12.5,6.2Hz,1H),4.52(m,1H), 2.65-2.56(m,1H),2.00(m,2H),1.83-1.76(m,2H),1.57-1.42(m, 3H),1.32-1.24(m,1H) and 0.94(d, J ═ 6.2Hz,6H) ppm.

LCMS RT＝2.7min,(M+H)432.5。

General scheme 37:

Preparation of cis-2-amino-1-methylcyclohexanecarboxylic acid (37c)

(a) NaH, methyl iodide, DMF; (b) NH2OH-HCl, pyridine, EtOH; (c) al (Hg), THF-H2O (4:1)

Formation of ethyl 1-methyl-2-oxocyclohexanecarboxylate (37 a):

The title compound was prepared following the procedures described in Tetrahedron Letters (2005)46, 681-.

Sodium hydride (1.48g, 37.14mmol, 60% in oil) was washed with hexane at 0 ℃ to remove oil and suspended in DMF (57 mL). Then, after more than 5min, ethyl 2-oxocyclohexanecarboxylate (5.40mL, 33.76mmol) was added. The mixture was stirred for 20min and after more than 10min MeI (2.21mL, 35.45mmol) was added. The mixture was warmed to room temperature and after 30min, diluted with EtOAc (150mL) and quenched with saturated NH4 Cl. The layers were separated and the aqueous layer was extracted twice more with EtOAc (2 × 100 mL). The organic layer was washed with brine (2 ×), dried over MgSO4, filtered through silica gel and concentrated to provide the desired product (37 a).

Formation of 3 a-methyl-4, 5,6, 7-tetrahydrobenzo [ c ] isoxazol-3 (3aH) -one (37b)

To a mixture of 1-methyl-2-oxo-cyclohexanecarboxylic acid ethyl ester 37a (2.05g, 11.10mmol) in EtOH (20mL) was added hydroxylamine hydrochloride (0.97g, 13.96mmol) and pyridine (0.99mL, 12.20 mmol). The mixture was heated to 65 ℃ overnight. The solution was concentrated in vacuo and the crude material was partitioned between water and EtOAc. The aqueous layer was extracted twice more with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-35% EtOAc/hexanes) to give the desired product 37 b.

1H NMR (300MHz, CDCl3) δ 2.72-2.65(m,1H),2.29(td, J ═ 13.3, 6.3Hz,1H),2.18-2.09(m,1H),2.07-2.03(m,1H),1.84-1.79(m,1H), 1.76-1.56(m,2H),1.54-1.42(m,1H) and 1.40(s,3H) ppm.

Formation of trans-2-amino-1-methylcyclohexanecarboxylic acid (37c)

To a solution of 3 a-methyl-4, 5,6, 7-tetrahydro-2, 1-benzoxazol-3-one 37b (0.075g, 0.490mmol) in THF-H2O (2.5mL of 4:1 mixture) was added fresh al (hg) amalgam at room temperature. The amalgamated aluminum was rinsed with water and EtOH by immersing a small piece of aluminum foil strip in a 2% HgCl2 solution. After 1h, 65mg of Al (Hg) was added and the mixture was stirred overnight. The gray thick emulsion formed was filtered through celite and rinsed with water and THF. The clear solution was concentrated in vacuo, stripped with methanol and THF to remove residual water and concentrated in vacuo to afford the desired product as a glassy solid as a mixture of cis-trans isomers (-9: 1), the trans isomer being the major isomer. The product was pure enough for the next reaction.

1H NMR (300MHz, MeOD) δ 2.91(dd, J ═ 3.9,11.9Hz,1H),2.25 (dd, J ═ 1.9,13.4Hz,1H),1.89-1.85(m,1H),1.78-1.53(m,3H), 1.47-1.32 (m,2H),1.21(s,3H) and 1.09-0.99(m,1H) ppm.

FIA(M+H)158.1,(M-H)156.2。

Formation of 2-amino-1-ethylcyclohexanecarboxylic acid

This compound was prepared by the procedure described above for the preparation of a mixture of cis-trans isomers (70:30) which could not be separated and used without further purification.

General scheme 38:

Preparation of cis-2-amino-1-alkyl-cyclohexanecarboxylic acid:

(a) LDA, iodoethane, THF; (b) h2, Pd-C, MeOH

An alternative scheme for the preparation of cis-2-amino-1-alkyl-cyclohexanecarboxylic acids is exemplified above. (a) Nemoto, t., Fukuyama, t., Yamamoto, e., Tamura, s., Fukuda, t., Matsumoto, t., Akimoto, y., Hamada, y.org.lett.2007,9(5), 927-; (b) Seebach, D., Estermann, H.tetrahedron Lett.1987,28(27), 3103 and 3106.

(1R,2S) -2- (benzyloxycarbonylamino) -1-ethylcyclohexanecarboxylic acid methyl ester (38b)

To a cold (-78 deg.C) solution of N-isopropyl-2-propylamine (0.77mL, 5.49mmol) in THF (7mL) was added N-butyllithium (3.43mL of a 1.6M solution, 5.49mmol) dropwise. The mixture was stirred at-78 ℃ for 10 min. Then, over 3min, a solution of methyl (1S,2S) -2-benzyloxycarbonylaminocyclohexanecarboxylate 38a (0.40g, 1.37mmol) in THF (2.5mL) was added. After 15min, the mixture was slightly warmed (-40 ℃) for 15min and cooled again for 10min to-78 ℃. Then, iodoethane (0.86g, 0.44mL, 5.49mmol) was added dropwise over 3-5 min. The reaction mixture was kept at-78 ℃ for 2h and allowed to warm to room temperature overnight. The reaction was quenched with 5mL of saturated aqueous NH4Cl solution, extracted with EtOAc (3X), washed sequentially with 1N HCl and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-20% EA/Hex slow gradient elution) afforded 275mg (63% yield) of the desired product (38 b). NMR showed a diastereomeric ratio higher than 10:1 (cis: trans).

1H NMR (300.0MHz, MeOD) δ 7.35-7.28(m,5H),6.62(d, J ═ 9.2 Hz,1H),5.07(dd, J ═ 12.5,16.6Hz,2H),3.67(s,3H),3.59(td, J ═ 10.0, 4.6Hz,1H),2.14(m,1H),1.76-1.29(m,9H) and 0.83(t, J ═ 7.6Hz,3H) ppm.

(1R,2S) -2-amino-1-ethylcyclohexanecarboxylic acid methyl ester (38c)

A solution of methyl (1R,2S) -2-benzyloxycarbonylamino-1-ethylcyclohexanecarboxylate 38b (0.27g, 0.85mmol) in MeOH (7.5mL) was purged with nitrogen and a catalytic amount of (5% palladium on carbon) was added. The solution was placed in H2 and stirred at room temperature. After 1h, the MeOH solution suspension was filtered through celite and concentrated in vacuo to provide the desired product (138mg, 88% yield). The material was diluted in acetonitrile and concentrated to remove residual methanol.

1H NMR (300.0MHz, MeOD) δ 3.69(s,3H),2.71(m,1H), 2.07-2.01 (m,1H),1.82(m,2H),1.71-1.27(m, H),1.64(m,2H),1.56-1.27 (m,5H) and 0.85(t, J ═ 7.5Hz,3H) ppm.

General scheme 39

Preparation of trans-2-amino-1-alkyl-cyclohexanecarboxylic acid:

(a) Benzyl alcohol, toluene, sieving and refluxing; (b) NaH, MeI, DMF; (c) benzylamine, TiCl4, CH2Cl2, then NaCNBH3, MeOH, 0 ℃; (d) h2, Pd-C, MeOH; (e) 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine, Na2CO3, THF/CH3CN, microwave irradiation 135 ℃; (f) HCl, CH3CN, dioxane, 80 deg.C

The general method for the synthesis of trans-2-amino-1-alkyl-cyclohexanecarboxylic acids is shown in the above scheme.

2-Oxocyclohexanecarboxylic acid benzyl ester (39b)

This compound was prepared according to the procedure described in Matsuo, J.et al, tetrahedron: Asymmetry 2007,18, 1906-1910.

1-methyl-2-oxocyclohexanecarboxylic acid benzyl ester (39c)

this compound was prepared according to the procedures described in (a) Hayashi, y., Shoji, m., Kishida, s.tetrahedron lett.2005, 46,681-685 (Winfield, c.j., Al-Mahrizy, z., Gravestock, m., Bugg, t. d.h.j.chem.soc., Perkin trans.1,2000, 3277).

Trans-2- (benzylamino) -1-methylcyclohexanecarboxylic acid benzyl ester (39d) - (racemic trans)

To benzyl 1-methyl-2-oxo-cyclohexanecarboxylate 39c (0.50g, 2.03mmol) and benzylamine (0.61g, 0.63mL, 5.75mmol) in dichloromethane (10.0mL) was added dropwise TiCl4(1.93mL of a 1M solution, 1.93mmol) at room temperature. The mixture was stirred for 2 h. The mixture was cooled to 0 ℃ and after more than 3min a solution of NaBH3CN (0.21g, 3.34mmol) in MeOH was added dropwise. After 15min, the solution was warmed to room temperature and stirred for an additional 45 min. The mixture was then diluted with EtOAc and quenched with 10mL of 1M NaOH. The mixture was partitioned with Et2O and the aqueous layer was extracted several times with Et2O (2 ×) and EtOAc (1 ×). The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-50% EtOAc-gradient elution) and separation of the major components provided the desired product as a single racemic trans isomer (320 mg).

1H NMR (300.0MHz, MeOD) δ 7.34-7.16(m,10H),5.07(dd, J ═ 12.4,31.2Hz,2H),3.78(d, J ═ 13.0Hz,1H),3.57(d, J ═ 13.0Hz,1H), 2.96(m,1H),1.86(m,1H),1.74-1.57(m,3H),1.52-1.25(m,4H) and 1.20(s,3H) ppm.

Trans-2-amino-1-methylcyclohexanecarboxylic acid (39e)

To a solution of racemic trans- (1S,2S) -2- (benzylamino) -1-ethyl-cyclohexanecarboxylic acid benzyl ester 39d (0.32g, 0.91mmol) in MeOH (12.8mL) was added Pd (5% palladium on carbon, 0.07 g). The solution was degassed and placed in 50PSI H2(Parr shaker) overnight. The mixture was filtered through celite and the filtrate was washed with MeOH. The mother liquor was concentrated, then the acetonitrile azeotrope (2x) was concentrated to remove residual MeOH to afford the desired product (162 mg).

1H NMR (300.0MHz, MeOD). delta.3.22 (m,1H),1.93(m,1H),1.77 (m,2H),1.57-1.23(m,5H) and 1.17(s,3H) ppm.

Trans-2- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanecarboxylic acid (39f)

To a vessel containing 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 15a (0.27g, 0.58mmol) and trans-2-amino-1-methyl-cyclohexanecarboxylic acid 39e (0.08g, 0.47mmol) and freshly ground Na2CO3(0.19g, 1.75mmol) was added anhydrous THF (4.5mL) and CH3CN (0.9 mL). The vessel was sealed and heated for 35min to 135 ℃ (microwave irradiation). LC-MS showed complete consumption of the crude material. The reaction mixture was then poured slowly into a vigorously stirred 1N HCl solution (13.5 mL). The pH of the final solution is 1-2. The mixture was extracted with EtOAc (3 ×), dried over Na2SO4 and filtered through celite and concentrated in vacuo. Flash chromatography (SiO2, 0-10% MeOH-dichloromethane, gradient elution) afforded a yellow, viscous foam suspended in acetonitrile. Evaporation of the solvent after sonication provided an amorphous solid as a racemic mixture of the trans stereoisomer (240mg, 74% yield).

1H NMR (300.0MHz, MeOD) δ 9.02(d, J ═ 2.4Hz,1H),8.52(s,1H), 8.33(d, J ═ 2.4Hz,1H),8.09-8.05(m,3H),7.38(d, J ═ 8.1Hz,2H), 5.04(dd, J ═ 3.6,9.5Hz,1H),2.38(s,3H),2.09(m,1H),1.83-1.59 (m,7H),1.29(s,3H) and 1.23(m,1H) ppm.

LCMS RT＝4.00min,(M+H)558.34。

Trans-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanecarboxylic acid (643)

To a slurry of racemic trans-2- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanecarboxylic acid 39f (0.047g, 0.084mmol) in CH3CN (2.35mL) was added HCl in dioxane (1.26mL of a 4M solution, 5.05 mmol). The suspension became clear. The vial was sealed and heated for 2h to 80 ℃ during which time a concentrated slurry was formed. The slurry was allowed to cool to room temperature overnight. Additional CH3CN was added and the mixture was centrifuged. The organic layer was discarded and the solid was triturated 3 more times with CH3CN to provide a white amorphous solid as a racemic mixture of trans-stereoisomers.

1H NMR (300.0MHz, MeOD) δ 8.98(d, J ═ 2.3Hz,1H),8.45(s, 1H),8.38(d, J ═ 2.3Hz,1H),8.30(d, J ═ 5.7Hz,1H),5.26 to 5.22(m, 1H),2.17 to 2.10(m,1H),1.87 to 1.82(m,4H),1.68 to 1.59(m,3H) and 1.36 (s,3H) ppm.

LCMS RT＝3.30min,(M+H)404.36。

General scheme 40

a) Tert-butyl magnesium chloride, I2, Et3N, THF, DME; (b) 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine, DME/H2O, Na2CO3, tetrakis (triphenylphosphine) palladium (0), microwave at 130 ℃; (c) mCPBA, CH2Cl 2; (d) (1S,2S) -2-aminocyclohexanecarboxylic acid, Na2CO3, THF-CH3CN (3:1), microwave at 150 ℃ C

Formation of 4-tert-butyl-2-chloro-5-fluoro-6- (methylthio) pyrimidine (40a)

To a cold (0 ℃ C.) solution of tert-butylmagnesium chloride (7.5mL, 1M solution in THF, 7.5mmol) in THF (15mL) was slowly added 2-chloro-5-fluoro-4- (methylthio) pyrimidine (0.9g, 5.0mmol) in 1, 2-dimethoxyethane (5 mL). The reaction mixture was stirred at 15 ℃ for 1h, then cooled to 0 ℃ and triethylamine (0.7mL, 5.0mmol) was added, followed by a solution of iodine (1.3g, 5.0mmol) in tetrahydrofuran (3 mL). The reaction was quenched by adding water (10mL) and the pH was adjusted to 1 using 6N hydrochloric acid. The liquid phase was extracted twice with ethyl acetate (2 × 15 mL). The combined organic phases were washed with aqueous sodium thiosulfate and then brine, dried over MgSO4, filtered and concentrated in vacuo to yield a brown solid which was used without further purification.

H NMR(300.0MHz,CDCl)δ2.52(s,3H),1.30(s,9H)ppm。

LCMS(M+1)233.0。

Formation of 3- (tert-butyl-5-fluoro-6- (methylthio) pyrimidin-2-yl) -5-chloro-1H-pyrrolo [2,3-b ] pyridine (40b)

To a degassed solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.22g, 0.50mmol), 4-tert-butyl-2-chloro-5-fluoro-6-thiomethoxy-pyrimidine 40a (0.12g, 0.50mmol) in 1, 2-dimethoxyethane (3mL) and aqueous Na2CO3 solution (0.75mL of 2M solution, 1.5mmol) was added tetrakis (triphenylphosphino) palladium (0) (0.03g, 0.03 mmol). The reaction mixture was degassed for a further 15 min. The mixture was heated in a microwave at 150 ℃ for 20 min. Ethyl acetate (15mL) was added. The organic layer was separated and washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (0% -100% EtOAc/hexanes) to give the desired product 40b (47 mg).

H NMR(300MHz,CDCl)δ10.82(br,1H),8.81(d,J＝2.2Hz, 1H),8.27(d,J＝ 2.3Hz,1H),8.20(dd,J＝7.2,2.2Hz,1H),7.18(s,1H), 2.63(s,3H),1.41(s,9H)ppm。

LCMS(M+1)352.3。

Formation of 3- (tert-butyl-5-fluoro-6- (methylsulfinyl) pyrimidin-2-yl) -5-chloro-1H-pyrrolo [2,3-b ] pyridine (40c)

To a solution of 3- (tert-butyl-5-fluoro-6- (methylthio) pyrimidin-2-yl) -5-chloro-1H-pyrrolo [2,3-b ] pyridine 40b (0.05g, 0.11mmol) in CH2Cl2(3.4mL) was added mCPBA (0.02g, 0.11 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was diluted with CH2Cl2(10mL) and saturated NaHCO3 solution (5 mL). The aqueous layer was extracted with CH2Cl2(10 mL). The combined organic phases were washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to obtain the desired product, which was used without further purification.

H NMR(300MHz,CDCl)δ10.93(br,1H),8.79(d,J＝2.2Hz, 1H),8.34(s,1H),8.25 (d,J＝2.2Hz,1H),7.19(s,1H),2.98(s,3H), 1.47(s,9H)ppm。

LCMS(M+1)368.3。

Formation of (1S,2S) -2- (6-tert-butyl-2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (629)

A mixture of 3- (tert-butyl-5-fluoro-6- (methylsulfinyl) pyrimidin-2-yl) -5-chloro-1H-pyrrolo [2,3-b ] pyridine 40c (0.05g, 0.14mmol), (1S,2S) -2-amino-cyclohexanecarboxylic acid (0.04g, 0.27mmol), freshly ground Na2CO3(0.04g, 0.41mmol) and iPr2NEt (0.37mL, 0.27mmol) in THF (1mL) and CH3CN (0.5mL) was heated in a sealed vessel under microwave irradiation for 30min to 140 ℃. The mixture was cooled to room temperature. A solution of 1N HCl (0.5mL, 0.5mmol) was added and the mixture was concentrated to give a yellow solid which was purified by reverse phase HPLC (0% -50% methanol in water) to obtain the desired product 629 as an off-white solid.

1H NMR (300MHz, DMSO) δ 12.26(s,1H),8.79(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.13(d, J ═ 2.7Hz,1H),7.25(d, J ═ 8.3Hz, 1H),4.34(m,1H),2.62(m,1H),2.05(m,2H),1.75(m,2H),1.57(m, 2H),1.39(s,9H) and 1.26-1.17(m,2H) ppm.

LCMS(M+1)446.23。

General scheme 41

(b) 3-amino-1-methylpyrrolidine-2-ketone and DMA, and performing microwave treatment at 140 ℃; (b) i: LiOH, THF, microwave 120 ℃, or ii: NaOMe, MeOH

Formation of 3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylpyrrolidin-2-one (379)

A solution of 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 15a (0.060g, 0.129mmol) in DMA (0.5mL) was treated with 3-amino-1-methylpyrrolidin-2 one (0.030g, 0.258mmol) and the reaction heated at 140 ℃ for 20 min. The reaction mixture was cooled to room temperature, then treated with 0.5mL of 25% NaOMe in MeOH and heated at 50 ℃ for 15 min. The mixture was then partitioned between saturated aqueous Na2CO3 and EtOAc. The aqueous layer was extracted twice more with EtOAc and the combined organic phases were concentrated in vacuo. The crude material was purified by preparative HPLC. The isolated product was filtered through basic resin to remove residual TFA and provide the desired product.

1H NMR (300MHz, MeOD) δ 8.72(d, J ═ 2.3Hz,1H),8.21(d, J ═ 2.4Hz,1H),8.11 to 8.07(m,2H),4.94(t, J ═ 9.3Hz,1H),3.64 to 3.51(m, 2H),2.97(s,3H),2.68 to 2.54(m,1H) and 2.37 to 2.23(m,1H) ppm.

LCMS RT＝2.3min,(M+H)361.3。

The following compounds can also be prepared in a manner analogous to that described in scheme 41.

3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) pyrrolidin-2-one (380)

1H NMR (300MHz, MeOD) δ 8.79(d, J ═ 2.4Hz,1H),8.20(d, J ═ 2.4Hz,1H),8.13(s,1H),8.07(d, J ═ 3.9Hz,1H),4.91(dd, J ═ 8.7,10.6 Hz,1H),3.61-3.46(m,2H),2.68-2.58(m,2H) and 2.48-2.31(m,1H) ppm.

LCMS RT＝2.3min,(M+H)347.3。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylpiperidin-2-one (397)

1H NMR (300.0MHz, DMSO) δ 8.65(d, J ═ 2.5Hz,1H),8.27(d, J ═ 2.4Hz,1H),8.20-8.19(m,2H),7.63(d, J ═ 7.8Hz,1H),4.78-4.74 (m,1H),3.41(t, J ═ 5.4Hz,2H),3.17(MeOH),2.89(s,3H),2.50 (DMSO),2.18-2.15(m,1H) and 1.99(d, J ═ 7.4Hz,2H) ppm.

LCMS RT＝2.2min,(M+H)375.4。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-2-one (416)

LCMS RT＝1.6min,(M+H)361.3。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cycloheximide-2-one (417)

1H NMR (300MHz, DMSO) δ 12.33(s,1H),8.74(d, J ═ 2.3Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.21(t, J ═ 3.7Hz,2H),8.02-7.98(m, 1H),7.21(d, J ═ 5.8Hz,1H),4.86(dd, J ═ 6.3,10.5Hz,1H),3.51-3.41 (m,1H),3.25-3.16(m,1H),2.13-1.85(m,4H),1.66-1.52(m,1H) and 1.40-1.20(m,1H) ppm.

LCMS RT＝1.7min,(M+H)375.4。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylpiperidin-2-one (460)

LCMS RT＝2.0min,(M+H)389.1。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanimin-2-one (461)

LCMS RT＝2.0min,(M+H)389.1。

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-ethylcycloheximide-2-one (462)

1H NMR (300MHz, d6-DMSO) δ 12.35(s,1H),8.68(d, J ═ 1.7Hz,1H), 8.27(d, J ═ 2.0Hz,1H),8.21(m,2H),7.28(d, J ═ 6.0Hz,1H),4.98 (dd, J ═ 6.9,10.7Hz,1H),3.88-3.79(m,1H),3.84(dd, J ═ 11.4,15.5 Hz,1H),3.49-3.17(m,5H),2.08(d, J ═ 13.1Hz,1H),1.95-1.88(m, 3H),1.65-1.58(m,1H),1.42(m,1H) and 1.04(t, J ═ 0, 3H).

LCMS RT＝3.3min,(M+H)403.4。

(R) -5- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) methyl) pyrrolidin-2-one (503)

LCMS RT＝2.2min,(M+H)361.2。

(S) -3- (5-fluoro-2- (5- (trifluoromethyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cycloheximide-2-one (502)

LCMS RT＝2.3min,(M+H)409。

(S) -6- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -4- (4-methoxybenzyl) -1, 4-oxocycloheximide-5-one (505)

LCMS RT＝3.1min,(M+H)497.7。

According to Blizzard, Timothy A.; chen, Helen y.; wu, Jane Yang; kim, Seongkon; ha, sokhee; mortko, Christopher j.; variankaval, Narayan; the procedure specified in Chiu, Anna.7-Oxo-2,6-Diazabicyclo [3.2.0] heptanes-6-sulfonic acid derivatives as b-lactic acids inhibitors and the preparation, pharmaceutical compositions and uses in the treatment of bacterial infections. PCT. int. appl. (2008), p.101, WO2008039420 prepares the starting amines of this compound.

(S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cyclohexyliden-2-one (500)

LCMS RT＝1.6min,(M+H)357.6。

(S) -3- (2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cyclohexyliden-2-one (501)

LCMS RT＝1.6min,(M+H)341.4。

3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -7, 7-dimethylcycloheximide-2-one (504)

LCMS RT＝3.2min,(M+H)403.6。

The amines of this compound can be prepared according to the procedures described in J.A.Robl, E.Sieber-McMaster, R.Sulsky Synthetic routes for the generation of 7,7-dialkyl-2-azepinones. tetrahedron Letters (1996),37(50),8985 + 8988.

General scheme 42

(a) 3-amino-1-methylpyrrolidine-2-ketone and DMA, and performing microwave treatment at 140 ℃; (b) LiOH, THF, microwave, 120 ℃; (c) EDCI, HOAt, iPr2NEt, DCM-DMF (2:1)

6- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1, 4-oxocycloheximide-5-one (513)

A mixture of 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 15a (0.17g, 0.36mmol) and (6S) -6-amino-1, 4-oxocycloheximide-5-one (0.06g, 0.43mmol) in DMF (2mL) and iPr2NEt (0.10mL, 0.57mmol) was heated to 90 ℃. After 1h, the temperature was raised to 100 ℃. After 24h, the mixture was heated (microwaved) for 15min to 140 ℃. The mixture was partitioned between water and EtOAc and the aqueous layer was re-extracted twice with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo.

The resulting crude material (0.16g) was treated with LiOH (1N solution, 1mL) in THF (3mL) overnight. LC-MS showed hydrolysis with demethylated benzenesulfonamide. The mixture was concentrated in vacuo and purified by preparative HPLC to afford the semi-purified product (23 mg). This material was subjected to cyclization conditions without further purification.

To a flask containing the crude material (0.020g, 0.051mmol), EDCI (0.010g, 0.056mmol), HOAt (0.002g, 0.015mmol) and DCM (1mL) were added iPr2NEt (0.018mL, 0.100mmol) and DMF (0.5 mL). After 1h, EDCI (0.7eq) was added. After 3.5h, the reaction was complete and the mixture was concentrated in vacuo. Purification by preparative HPLC followed by removal of the TFA salt by basic resin filtration afforded the desired product: LCMS RT 1.9min, (M + H) 377.5.

The starting amines of this compound were prepared according to the procedures specified in J.A.Robl, E.Sieber-McMaster, R.Sulsky Synthetic routes for the generation of 7, 7-dialkyl-2-azones tetrahedron Letters (1996), 37(50), 8985-8988.

General scheme 43

the following is a general procedure for converting cyclohexanecarboxylic acid 553 or 35a to a class 43a carboxamide:

(a) Amine, HATU, DMF; (b) BOC2O, NH4CO3H, pyridine, DMF; (c) i: amine, HATU, DMF; and then ii: 1N LiOH

Formation of (1S,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-ethylcyclohexanecarboxamide (521)

To a mixture of (1S,2S) -2- [ [2- (5-chloro-1H-pyrrolo [5,4-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexane-1-carboxylic acid 553(0.049g, 0.126mmol) and HATU (0.056g, 0.147mmol) in DMF (1.0mL) was added ethylamine (0.189mL of a 2M solution, 0.377mmol) at room temperature. The mixture was stirred at room temperature until all starting material was converted as judged by HPLC. After 45min, the mixture was partitioned between aqueous K2CO3 and EtOAc, the organic layer was separated and dried over Na2SO4 and concentrated in vacuo. Preparative HPLC provided the desired product as a TFA salt, which was eluted through a basic PSA cartridge with MeOH, then concentrated in vacuo to convert the TFA salt to the parent compound (14mg, 30% yield).

1H NMR (300MHz, MeOD) δ 8.93(d, J ═ 2.4Hz,1H),8.22(d, J ═ 2.3Hz,1H),8.18(s,1H),7.99(d, J ═ 4.0Hz,1H),4.53(ddd, J ═ 7.1, 11.1Hz,1H),3.15-3.02(m,2H),2.43-2.34(m,1H),2.30-2.26(m, 1H),1.97-1.82(m,3H),1.77-1.65(m,2H),1.47-1.35(m,2H) and 0.97 (t, J ═ 7.3Hz,3H) ppm.

LCMS RT＝2.0min,(M+H)417.5。

(1S,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N-diethylcyclohexanecarboxamide

LCMS RT＝2.26min,(M+H)445.58。

Formation of cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxamide (544) and cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N-dimethylcyclohexanecarboxamide (543)

To a mixture of cis-2- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanecarboxylic acid 554(0.30g, 0.77mmol) in DMF (5mL) at room temperature was added pyridine (0.61g, 0.62mL, 7.70mmol), followed by di-tert-butyl dicarbonate (0.50g, 2.31mmol) and NH4CO3H (0.33g, 4.22 mmol). The mixture was stirred at room temperature overnight. LC-MS showed the presence of the desired primary amide ethyl N, N-dimethylamide product. A 1mL aliquot of the reaction solution was acidified with HOAc and diluted with DMSO. Preparative HPLC chromatography provided small amounts of both products.

Primary amide 544, racemic mixture- (8.6 mg): LCMS RT ═ 1.94min, (M + H) 389.42.

Dimethylamide 543, racemic mixture- (3.7 mg): LCMS RT 2.52min, (M + H) 417.44.

Formation of (1R,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N, N-diethylcyclohexanecarboxamide (518)

To a mixture of (1R,2S) -2- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexane-1-carboxylic acid (0.050g, 0.092mmol) and HATU (0.045g, 0.120mmol) in DMF (1mL) at room temperature was added N, N-diethylamine (0.138mL of a 2M solution, 0.280 mmol). When the reaction appeared to be complete as judged by HPLC, LiOH (0.4mL of a 1M solution, 0.4mmol) in water was added. After 6h, LiOH (0.4mL of a 1M solution, 0.4mmol) was again added and the mixture was stirred overnight. The mixture was quenched with saturated aqueous NH4Cl solution. Aqueous K2CO3 was added and the mixture was extracted with EtOAc (3 ×). The combined organic phases were washed with saturated aqueous NH4Cl solution, filtered and concentrated in vacuo. Preparative HPLC provided the desired product as a TFA salt, which was converted to the HCl salt by treatment with HCl in MeOH, followed by evaporation of the solvent (12.9mg, 28% yield).

1H NMR (300MHz, MeOD) δ 8.67(d, J ═ 2.3Hz,1H),8.53(s,1H), 8.41(d, J ═ 2.3Hz,1H),8.35(d, J ═ 5.5Hz,1H),4.75-4.73(m,1H), 3.74-3.58(m,1H),3.42(m,2H),3.29-3.22(m,2H),2.57(m,1H), 2.09-2.03 (m,1H),1.96-1.76(m,4H),1.06(t, J ═ 7.1Hz,3H) and 0.94(t, J ═ 7.1Hz,3H) ppm.

LCMS RT＝3.3min,(M+H)445.6。

(1R,2S) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-ethylcyclohexanecarboxamide (519)

LCMS RT＝2.95min,(M+H)417.5。

Cis-2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N-methylcyclohexanecarboxami (539) -racemic mixture

LCMS RT＝2.13min,(M+H)403.44。

General scheme 44

(a) Pd (PPh3)4, sodium carbonate, DME/water, refluxing; (b) meta-chloroperoxybenzoic acid and dichloromethane at room temperature; (c)20a, tetrahydrofuran, 50 ℃; (d) trifluoroacetic acid, dichloromethane, room temperature; (e) morpholine-4-carbonyl chloride, dimethylformamide, room temperature; (f) sodium methoxide, methanol, room temperature

Formation of 5-fluoro-3- [ 5-fluoro-4- (methylthio) pyrimidin-2-yl ] -1-tosyl-1H-pyrrolo [2,3-b ] pyridine (44b)

2-chloro-5-fluoro-4-methylsulfonyl-pyrimidine (34.1g, 191.0mmol), 5-fluoro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine 44a (53.0g, 127.3mmol) and Na2CO3(40.5g, 381.9mmol) were dissolved in a mixture of DME (795mL) and water (159 mL). The mixture was purged with nitrogen for 20min and treated with Pd (PPh3)4(7.4g, 6.6 mmol). After flushing with nitrogen for 20min, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (600 mL). The resulting suspension was stirred at room temperature for 30min and the precipitate was collected by filtration, washed with water and acetonitrile and dried at 50 ℃ to obtain 48.2g of 5-fluoro-3- [ 5-fluoro-4- (methylthio) pyrimidin-2-yl ] -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine as a white solid.

H NMR(300MHz,DMSO-d6)δ8.70–8.58(m,2H),8.54–8.41 (m,2H),8.09(d,J＝ 8.4Hz,2H),7.45(d,J＝8.2Hz,2H),2.76(s,3H), 2.36(s,3H)。

Formation of 5-fluoro-3- [ 5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl ] -1-tosyl-1H-pyrrolo [2,3-b ] pyridine (44c)

5-fluoro-3- [ 5-fluoro-4- (methylthio) pyrimidin-2-yl ] -1-tosyl-1H-pyrrolo [2,3-b ] pyridine 44b (48.2g, 111.5mmol) was dissolved in dichloromethane (2.3L) and treated with m-CPBA (27.5g, 122.6mmol) in portions while keeping the temperature below 20 ℃. After complete addition, the reaction was stirred at room temperature for 2h, then treated with another portion of m-CPBA (1.9g) and stirred for an additional 1 h. The reaction mixture was washed with 12% aqueous K2CO3 solution (2 × 1.0l) and the organic layer was dried over Na2SO4 and concentrated in vacuo to provide 50g of 5-fluoro-3- [ 5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl ] -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine as a yellow solid.

H NMR(300MHz,DMSO-d6)δ9.11(d,J＝1.5Hz,1H),8.69(s, 1H),8.65(dd,J＝ 9.0,2.9Hz,1H),8.52(dd,J＝2.8,1.2Hz,1H),8.11(d, J＝8.4Hz,2H),7.46(d,J＝8.3Hz, 2H),3.05(s,3H),2.36(s,3H)。

Formation of tert-butyl N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate (44d)

5-fluoro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine 44c (5.9g, 10.5mmol) and tert-butyl N- [ (1R,3S) -3-aminocyclohexyl ] carbamate (3g, 12.60mmol) were dissolved in THF (100 mL). The reaction mixture was heated for 6h to 50 ℃ and then cooled to room temperature. Celite was added and the solvent was removed under reduced pressure. The residue loaded with celite was purified by silica gel chromatography (20-80% EtOAc/hexanes gradient) to provide 3.7g of tert-butyl N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate.

H NMR(300MHz,CDCl)δ8.51(s,1H),8.46-8.41(m,1H), 8.29(d,J＝1.6Hz,1H), 8.11(s,1H),8.08(s,1H),8.06(d,J＝3.2Hz, 1H),7.27(d,J＝8.4Hz,2H),4.91(d,J＝ 8.0Hz,1H),4.41(s,1H),4.29 -4.01(m,1H),3.64(s,1H),2.47(d,J＝11.5Hz,1H),2.36(s, 3H),2.24 (d,J＝13.1Hz,1H),2.08(d,J＝10.9Hz,1H),1.91(d,J＝13.8Hz,1H), 1.43(s, 9H),1.30-1.03(m,4H)。

Formation of (1S,3R) -N1- [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] cyclohexane-1, 3-diamine (44e)

tert-butyl N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] carbamate 44d (3.7g, 6.2mmol) was dissolved in dichloromethane (105mL) and treated with trifluoroacetic acid (31 mL). After 5min, the volatiles were evaporated under reduced pressure and the resulting residue was treated with 1N NaOH (75 mL). The resulting precipitate was collected by filtration, washed with water (3 × 30mL) and dried in vacuo to afford 2.7g of (1S,3R) -N1- [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] cyclohexane-1, 3-diamine as a white solid.

H NMR(300MHz,MeOD)d 8.56(dd,J＝8.0,3.9Hz,2H),8.35- 8.26(m,1H),8.12 (dd,J＝10.3,6.1Hz,3H),7.43(d,J＝8.4Hz,2H), 4.36-4.21(m,1H),3.28-3.13(m,1H), 2.48(d,J＝12.3Hz,1H),2.46 (s,3H),2.25-1.97(m,J＝17.3,10.6,4.1Hz,4H),1.76-1.28 (m,3H)。

Formation of N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] morpholine-4-carboxamide (44f)

(1S,3R) -N1- [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] cyclohexane-1, 3-diamine 44e (2.3g, 4.6mmol) was dissolved in DMF (50mL) and treated with morpholine-4-carbonyl chloride (2.1g, 13.8mmol) and DIPEA (4.2g, 5.6mL, 32.3 mmol). After 1h, the resulting solution was diluted with water (400mL) and stirred for an additional 2 h. The resulting precipitate was collected by filtration, washed with water (3 × 50mL) and dried to provide the crude product. This material was purified by flash chromatography on a 40g column using EtOAc/DCM 20-100% to provide 2.0g of N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] morpholine-4-carboxamide as a white solid.

H NMR(300MHz,DMSO-d6)δ8.53-8.43(m,J＝11.9,2.7Hz, 3H),8.22(d,J＝ 3.9Hz,1H),8.07(d,J＝8.4Hz,2H),7.44(d,J＝8.3 Hz,2H),6.32(d,J＝7.5Hz,1H),4.05 (s,J＝19.4Hz,1H),3.62(s,1H), 3.58-3.45(m,4H),3.27-3.18(m,4H),2.36(s,3H),2.12 (d,J＝11.7 Hz,1H),1.99(d,J＝9.5Hz,1H),1.83(d,J＝10.3Hz,2H),1.53-1.11 (m,J＝ 32.3,22.8,10.9Hz,4H)。

Formation of N- [ (1R,3S) -3- [ [ 5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] morpholine-4-carboxamide (706)

N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] morpholine-4-carboxamide 44f (2.0g, 3.2mmol) was suspended in methanol (50mL) and treated with 25% sodium methoxide in methanol (19.9mL, 92.3 mmol). After stirring for 1h, the solvent was evaporated under reduced pressure and the residue was partitioned between water (100mL) and ethyl acetate (100 mL). The organic layer was collected, dried over Na2SO4 and concentrated to provide the crude product as a yellow solid. This material was purified by silica gel chromatography on a 40g column using DCM/MeOH 1-6%. The purified fractions were treated with 2N HCl in ether and concentrated to afford 1.5g of N- [ (1R,3S) -3- [ [ 5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] cyclohexyl ] -morpholine-4-carboxamide as a white solid.

formation of (1S,3R) -N1- (2-fluoro-5- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) cyclohexane-1, 3-diamine (44e)

To a solution of tert-butyl (1R,3S) -3- (2-fluoro-5- (5-fluoro-1-tosyl-1H-pyrrole- [2,3-b ] pyridin-3-yl) phenylamino) cyclohexylcarbamate 44d (0.65g, 1.09mmol) in dichloromethane (22mL) was added hydrogen chloride (2.71mL of a 4M solution in 1, 4-dioxane, 10.86 mmol). The reaction was added to 50 ℃ and stirred for 6 h. The mixture was cooled to room temperature and concentrated in vacuo to yield a yellow solid. The crude residue was purified by silica gel chromatography (25-50% ethyl acetate/hexane gradient). The desired fractions were combined and concentrated in vacuo to yield 350mg 44e as a yellow powder.

Synthesis of 1-cyano-N- ((1R,3S) -3- (2-fluoro-5- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenylamino) cyclohexyl) cyclopropanecarboxamide (871)

To a solution of 1-cyano-1-cyclopropane-carboxylic acid (0.058g, 0.527mmol) in THF at room temperature was added HATU (0.200g, 0.527mmol) followed by N, N-diisopropylethylamine (0.334mL, 1.91 mmol). The solution was stirred for 10 min. Then (1S,3R) -N1- (2-fluoro-5- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) phenyl) cyclohexane-1, 3-diamine 44e (0.200g, 0.584mmol) was added and the solution stirred at room temperature for 4H. The mixture was concentrated in vacuo and purified by silica gel chromatography (30-60% ethyl acetate/hexanes) to give 80mg 871 as an off-white solid.

H NMR(300MHz,DMSO)δ12.80(s,1H),8.95(s,1H),8.78(s, 1H),8.43(d,J＝ 5.2Hz,1H),8.37(d,J＝1.6Hz,1H),8.07(d,J＝7.9 Hz,1H),4.22(s,2H),3.80(s,1H), 2.17–1.94(m,2H),1.90–1.71(m, 2H),1.71–1.06(m,8H)。

General scheme 45

(a) 4-chlorobutyryl chloride, Et3N, CH2Cl 2; (b) KOtBu, THF; (c) h2, Pd-C, MeOH; (d)45c, Na2CO3, THF-CH3CN, 135 ℃; (e)4M HCl, dioxane-CH 3CN

(1S,3R) -3- (4-chlorobutyrylamino) cyclohexylcarbamic acid benzyl ester (45a)

To a stirred slurry of benzyl N- [ (1S,3R) -3-aminocyclohexyl ] carbamate 18e (0.97g, 3.41mmol) in CH2Cl2(34mL) was added Et3N (1.00mL, 7.15mmol) followed by 4-chlorobutyryl chloride (0.40mL, 3.58 mmol). After stirring at room temperature, the mixture was diluted with CH2Cl2, washed with 1N HCl (2 ×), 1N NaOH (2 ×) and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 1.07g of the desired product.

1H NMR (300MHz, MeOD) δ 7.33-7.26(m,5H),5.04(s,2H), 3.73-3.65(m,1H),3.56(t, J ═ 6.5Hz,2H),3.44(dq, J ═ 3.9,15.6Hz, 1H),2.33-2.28(m,2H),2.11-1.97(m,3H),1.90-1.75(m,3H), 1.45-1.28 (m,1H) and 1.18-1.02(m,3H) ppm.

(1S,3R) -3- (2-oxopyrrolidin-1-yl) cyclohexyl carbamic acid benzyl ester (45b)

To benzyl (1S,3R) -3- (4-chlorobutyrylamino) cyclohexylcarbamate 45a (0.21g, 0.58mmol) in THF (8.2mL) was added potassium tert-butoxide (0.08g, 0.69mmol) at room temperature. After stirring at room temperature for 25h, the mixture was quenched with saturated aqueous NH4Cl solution and extracted with Et2O (3 ×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-100% EtOAc-hexanes, gradient) provided a single fraction (168mg) consisting of the desired product and a small amount of starting material. This material was immediately subjected to a deprotection condition.

1H NMR (300MHz, MeOD) δ 7.33-7.27(m,5H),5.04(s,2H), 3.95-3.88(m,1H),3.58-3.38(m,3H),2.38-2.28(m,2H),2.11-1.76 (m,6H),1.63(d, J ═ 2.7Hz,1H),1.46-1.34(m,3H) and 1.21-1.06(m, 2H) ppm.

Formation of 1- ((1R,3S) -3-aminocyclohexyl) pyrrolidin-2-one (45c)

A degassed solution of benzyl (1S,3R) -3- (2-oxopyrrolidin-1-yl) cyclohexylcarbamate 45b (0.165g, 0.522mmol) and palladium on carbon (10% wet, Degussa, 0.050g, 0.024mmol) in MeOH (15mL) was placed under H2 atmosphere (balloon). After 105min, TLC (10% MeOH-DCM) showed complete consumption of the starting material. H2 was removed and the solution was filtered and concentrated in vacuo. The crude product was azeotroped with CH3CN (2 ×) to remove any residual MeOH and provide the desired product (96 mg): FIA (M + H +) 183.27.

Formation of 1- ((1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl) pyrrolidin-2-one (45d)

A mixture of 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridine 1a (0.14g, 0.29mmol), 1- ((1R,3S) -3-aminocyclohexyl) pyrrolidin-2-one 45c (0.10g, 0.53mmol) and freshly ground Na2CO3(0.09g, 0.88mmol) in THF (2.25mL) and CH3CN (0.45mL) was heated for 30min to 135 ℃. The mixture was poured slowly into 15mL 1M HCl and extracted with EtOAc (5 ×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-20% MeOH-CH2Cl2 gradient) provided the final product as a viscous residue. Trituration with CH3CN afforded an off-white powder (105mg) which was impure but was directly subjected to the final deprotection step.

LC/MS R＝3.90min,(M+H)589.49。

Formation of 1- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) cyclohexyl) pyrrolidin-2-one (956)

A mixture of partially purified 1- ((1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl) pyrrolidin-2-one 45d (0.105g, 0.180mmol) in CH3CN (5mL) was treated with HCl in dioxane (2mL, 4M, 8.00mmol) at 70 ℃. After 2h, the mixture was cooled to room temperature. Then CH3CN was added and the precipitated solid was triturated with more CH3CN (3 ×). Preparative HPLC provided the desired product as HCl salt (35 mg).

1H NMR (300MHz, MeOD) δ 8.72(d, J ═ 2.2Hz,1H),8.49(s,1H), 8.39(d, J ═ 2.1Hz,1H),8.29(d, J ═ 5.5Hz,1H),4.54-4.47(m,1H), 4.13(t, J ═ 11.8Hz,1H),3.57-3.45(m,2H),2.42-2.36(m,2H),2.25 (m,1H),2.15-2.00(m,4H),1.90-1.59(m,4H) and 1.53-1.43(m,1H) ppm; LC/MS RT 3.15min, (M + H) 429.53.

General scheme 46

(a) 30% ammonium hydroxide and water at 50 ℃; (b) acetyl chloride, diisopropylethylamine and dichloromethane at room temperature; (c) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, Pd (PPh3)4, 2M sodium carbonate, acetonitrile, 130 ℃, microwave

Formation of (1S,3S) -1- (aminomethyl) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (46b)

2-chloro-5-fluoro-N- [ (3S,5S) -1-oxaspiro [2.5] octan-5-yl ] pyrimidin-4-amine 46a (0.19g, 0.73mmol) was dissolved in water (75mL) and treated with 30% ammonium hydroxide (10mL, 86.0 mmol). The suspension was heated for 5h to 50 ℃ and then stirred at room temperature overnight. The volatiles were evaporated under reduced pressure and the residue (1S,3S) -1- (aminomethyl) -3- (2-chloro-5-fluoro-pyrimidin-4-ylamino) cyclohexanol was subjected to the next step without further purification.

Formation of N- { [ (1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl ] methyl } acetamide (46c)

(1S,3S) -1- (aminomethyl) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol 46b (0.19g, 0.69mmol) was dissolved in dichloromethane (15mL) and treated with DIPEA (1.20mL, 6.91mmol) and acetyl chloride (0.10mL, 1.38 mmol). After 5min, the reaction mixture was diluted in 1N HCl (30mL) and the aqueous layer was brought to alkaline pH by addition of 1N NaOH. The resulting suspension was extracted with dichloromethane (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography (20-100% EtOAc/hexanes gradient) to afford 195mg of N- { [ (1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclo-hexyl ] methyl } acetamide as a white foamy solid. LCMS RT ═ 2.82 (M +1) 317.33.

Formation of N- { [ (1S,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl ] methyl } acetamide (857)

N- { [ (1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl ] -methyl } -acetamide 46c (0.2g, 0.6mmol) was dissolved in acetonitrile (6mL) and treated with 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.5g, 1.2mmol) followed by Pd (PPh3)4(0.07g, 0.06 mmol). 2M aqueous sodium carbonate solution (3.0mL, 6.1mmol) was added and the vial was sealed and heated in a microwave for 30min to 130 ℃. The organic layer was collected and concentrated in vacuo to afford the crude product, which was dissolved in DMSO and purified by HPLC using 5-70% MeOH/H2O and 6mM HCl over 15min to afford 75mg after concentration of/\/- { [ (1S,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl ] methyl } acetamide hydrochloride as an off-white crystalline solid.

H NMR(300MHz,DMSO-d6)δ13.02(s,1H),9.22(s,1H),9.03 (d,J＝2.4Hz,1H), 8.71(d,J＝2.1Hz,1H),8.46(d,J＝5.5Hz,1H), 8.41(d,J＝2.1Hz,1H),7.81(t,J＝5.8Hz, 1H),4.64(d,J＝8.0Hz,1H), 3.16-2.99(m,2H),2.09-1.73(m,3H),1.85(s,3H),1.73-1.42 (m,3H), 1.28(dd,J＝27.5,10.6Hz,2H).；LCMS RT＝3.47(M+1)433.37。

general scheme 47

(a) N-methyl-N- (2-oxoethyl) carbamic acid tert-butyl ester, diisopropylethylamine, THF/EtOH, 70 ℃; (b) HCl/dioxane, THF/MeOH; (c) di (4-nitrophenyl) carbonate, diisopropylethylamine, DMF

Formation of tert-butyl 2- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl-amino) ethyl (methyl) carbamate (47b)

To a flask charged with (1S,3R) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) cyclohexane-1, 3-diamine 47a (0.14g, 0.39mmol) in THF/EtOH were added tert-butyl N-methyl-N- (2-oxoethyl) carbamate (0.10g, 0.58mmol) and diisopropylethylamine (0.13mL, 0.77 mmol). The solution was heated at 70 ℃ for 30 min. Sodium triacetoxyborohydride (0.08g, 0.39mmol) was added. The solution was stirred at room temperature for 12 h. The solution was filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by HPLC using 5-70% MeOH/H2O and 6mM HCl to afford the desired product.

formation of (1S,3R) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N3- (2- (methylamino) ethyl) cyclohexane-1, 3-diamine (47c)

To a flask charged with tert-butyl 2- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexylamino) ethyl (methyl) carbamate 47b (0.02g, 0.04mmol) in a dichloromethane/MeOH mixture was added HCl in dioxane (3.86mL of a 4M solution, 15.44 mmol). The solution was stirred at room temperature for 12 h. The solvent was evaporated under reduced pressure and used without further purification.

Formation of 1- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl) -3-methylimidazolidin-2-one (958)

Diisopropylethylamine (0.025mL, 0.144mmol) and bis (4-nitrophenyl) carbonate (0.016g, 0.053mmol) were added to a flask containing (1S,3R) -N1- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) -N3- (2- (methylamino) ethyl) cyclohexane-1, 3-diamine 47c (0.020g, 0.048mmol) in DMF. The reaction mixture was stirred at room temperature for 3 h. The resulting residue was purified by HPLC using 5-70% MeOH/H2O and 6mM HCl to afford the desired product.

General scheme 48

(a) 2-methoxyethylamine, HATU, DIEA, CH3CN, DMF

Formation of (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -N- (2-methoxyethyl) cyclohexanecarboxamide (789)

(1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanecarboxylic acid (HCl salt) (0.05g, 0.12mmol), HATU (0.09g, 0.24mmol), diisopropylethylamine (0.06g, 0.47mmol) and 2-methoxyethylamine (0.04g, 0.47mmol) were stirred together in 1ml each of DMF and CH3CN at room temperature overnight. All volatiles were removed with nitrogen and hot steam. The residue was dissolved in methanol and purified by phase preparative HPLC with 10-90% MeOH/water (HCl modifier) to yield the desired product as an HCl salt.

General scheme 49

(a) Methyl (triphenyl) phosphonium bromide, (bis (trimethylsilyl) amino) lithium, THF; (b) 3-chloroperoxybenzoic acid, MeOH, H2O; (c) sodium methylsulfonate, THF; (d) 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine, Na2CO3, tetrakis (triphenylphosphine) palladium (0), CH3 CN; (e) 3-chloroperoxybenzoic acid, CH2Cl 2; (f) NaOMe, MeOH

Formation of (S) -2-chloro-5-fluoro-N- (3-methylenecyclohexyl) pyrimidin-4-amine (49a)

To a suspension of methyl (triphenyl) phosphonium bromide (0.86g, 2.40mmol) in THF (100mL) in a flame-dried flask was added (bis (trimethylsilyl) amino) lithium (2.40mL of a 1M solution, 2.40mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. A solution of (S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanone 29b (0.48g, 2.00mmol) in 20mL of THF was added. The reaction was stirred at room temperature for 2 h. The mixture was quenched by pouring into brine and the liquid phase was extracted with EtOAc. The layers were separated and the organic was dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 270mg of the desired product: LCMS RT:3.83min, (M +1): 242.2.

Formation of 2-chloro-5-fluoro-N- ((3R,5S) -1-oxaspiro [2.5] octan-5-yl) pyrimidin-4-amine (49b, 49c)

3-Chloroperoxybenzoic acid (0.40g, 1.79mmol) was added to a solution of (S) -2-chloro-5-fluoro-N- (3-methylenecyclohexyl) pyrimidin-4-amine 49a (0.27g, 1.12mmol) in water (0.6mL) and MeOH (1.5mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The organic phase was dried (MgSO4), filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to yield two diastereomers 49b and 49 c. The separated upper (less polar) spot 49b continues: LCMS RT ═ 3.21(M +1) 258.2.

Formation of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1- (methyl-thiomethyl) cyclohexanol (49d)

2-chloro-5-fluoro-N- ((3R,5S) -1-oxaspiro [2.5] octan-5-yl) pyrimidin-4-amine 49b (0.10g, 0.38mmol) was dissolved in THF (2 mL). Sodium methylsulfonate (0.08g, 1.15mmol) was added to the reaction and the mixture was stirred at room temperature for 3 h. An additional 36mg of sodium methylsulfonate in THF (2mL) was added and the reaction mixture was stirred at room temperature overnight. After LCMS showed starting material still present, the reaction was warmed to 50 ℃ and stirred for 1 h. The reaction was quenched with water and diluted with EtOAc. The layers were separated and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (gradient 0-100% Etoac/hexanes). The product (contaminated with small amounts of starting material) was carried on to the next step without further purification. LCMS RT ═ 3.56(M +1) 306.2.

Formation of (1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- (methylthiomethyl) cyclohexanol (49e)

To a solution of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1- (methylthiomethyl) cyclohexanol 49d (0.09g, 0.28mmol) in CH3CN (4mL) was added 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.14g, 0.33mmol), followed by aqueous Na2CO3 (0.42mL of a 2M solution, 0.83 mmol). The reaction was degassed with nitrogen for 15min and tetrakis (triphenylphosphine) palladium (0) (0.02g, 0.01mmol) was added. The reaction was heated by microwave for 20min to 140 ℃. The mixture was cooled to room temperature and diluted with water/EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (gradient 0-100% EtOAc/hexanes).

1H NMR(300MHz,DMSO)δ8.76(d,J＝1.8Hz,1H),8.47(d,J＝ 8.1Hz,1H),8.30(t,J ＝26.7Hz,1H),8.05(d,J＝8.1Hz,2H),7.95– 7.45(m,2H),7.43(s,1H),4.81(s,1H),4.32– 3.84(m,1H),2.70(d,J＝ 19.5Hz,2H),2.36(s,2H),2.14(s,1H),2.13(s,1H),2.14–1.94 (m,2H), 2.14–1.59(m,6H),1.48–0.83(m,3H)。

Formation of (1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- (methylsulfonylmethyl) cyclohexanol (49f)

To a cold (0 ℃ C.) solution of (1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- (methylthiomethyl) cyclohexanol 49e (0.044g, 0.077mmol) in CH2Cl2(2mL) was added 3-chloroperoxybenzoic acid (0.034g, 0.155 mmol). After stirring at 0 ℃ for 1h, the mixture was diluted with water and CH2Cl 2. The layers were separated and the organics were washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (gradient 0-100% EtOAc/hexanes). LCMS RT ═ 4.20(M +1) 608.3.

Formation of (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- (methylsulfonylmethyl) cyclohexanol (886)

To a solution of (1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1- (methylsulfonylmethyl) cyclohexanol 49f (0.045g, 0.074mmol) in MeOH (2mL) was added NaOMe (2mL of 25% w/v, 9.255 mmol). The reaction mixture was stirred at room temperature for 5min, after which time the mixture was quenched by addition of saturated aqueous NH4Cl solution and then diluted with EtOAc. The layers were separated and the organics were washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-10% MeOH in CH2Cl2 gradient).

General scheme 50

(a) AlMe3, [ Rh2(cod)2Cl2], (S) -BINAP, THF, 0 ℃; (b) TBSCl, imidazole, DMAP, DMF; (c) 3-chloroperoxybenzoic acid, CH2Cl 2; (d) sodium azide, NH4Cl, MeOH, H2O; (e) h2, Pd-C (10%), EtOAc; (f) 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, iPr2NEt, microwave, 70 ℃; (g) TBAF, THF

Formation of (R) -1-methylcyclohexen-2-ol (50a)

A mixture of (S) -BINAP (6.2g, 10.0mmol) and Rh2(cod)2Cl2(2.1g, 4.2mmol) in dry THF (350mL) was stirred at room temperature under nitrogen in a 100mL flame-dried round bottom flask for 30 min. The red homogeneous reaction mixture was then cooled to 0 ℃ and cyclohex-2-en-1-one (16.0g, 166.4mmol) was added, followed by pure trimethylaluminum (12.4g, 16.5mL, 166.4mmol) dropwise. The mixture was allowed to warm to room temperature for 30min and then stirred for 1 h. The reaction was monitored by NMR and the reacted aliquot showed complete conversion to tertiary alcohol.

When the reaction was complete, the reaction temperature was reduced to 0 ℃ and carefully quenched with saturated aqueous NH4Cl solution (500 mL). The layers were separated and the aqueous phase was further washed with ether (5X100mL) and the combined organics were dried (MgSO4), filtered through a pad of celite and concentrated in vacuo to a tan crude oil. Vacuum distillation (38 ℃ at 0.5-1mm Hg) afforded 13.9g (72%) of a light amber oil.

Formation of (R) -t-butyldimethyl (1-methylcyclohexenyl-2-oxy) silane (50b)

To a solution of (R) -1-methylcyclohexen-2-ol 50a (1.00g, 8.91mmol) in 20 dry DMF was added 4H-imidazole (1.82g, 26.74mmol), t-butyldimethylchlorosilane (2.02g, 13.33mmol) and a catalytic amount of 4-dimethylaminopyridine (0.11g, 0.89mmol) at room temperature. It was then diluted with ether and washed successively with water, citric acid and water. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 1.98g of a colorless crude oil was used directly in the next step without further purification.

formation of t-butyldimethyl ((1R,2R,6R) -2-methyl-7-oxabicyclo [4.1.0] heptanyl-2-oxy) silane (50c)

to a stirred solution of (R) -tert-butyldimethyl (1-methylcyclohexenyl-2-oxy) silane 50b (1.98g, 8.87mmol) and sodium bicarbonate in 30mL of anhydrous dichloromethane was added 3-chloroperbenzoic acid (2.47g, 11.00mmol) in one portion at room temperature under nitrogen. The resulting mixture was stirred for 20 h. Then, 25% sodium sulfite solution was added and the resulting biphasic mixture was stirred for 15 min. Layers were separated and the aqueous layer was extracted with dichloromethane (2X20 mL). The combined organic phases were washed with saturated aqueous NaHCO3, dried (Na2SO4) and filtered in vacuo. The crude residue was purified by silica gel chromatography (0-10% EtOAc-hexanes gradient) to provide 647mg of compound 50 c.

Formation of (1R,2R,3S) -3-azido-1- (tert-butyldimethylsilyloxy) -1-methylcyclohexan-2-ol (50d)

To a stirred solution of tert-butyl-dimethyl- [ [ (1R,5R,6R) -5-methyl-7-oxabicyclo [4.1.0] heptan-5-yl ] oxy ] silane 50c (0.05g, 2.15mmol) in methanol (5mL) and H2O (0.6mL) was added NH4Cl (0.23g, 0.15mL, 4.30mmol) followed by sodium azide (0.42g, 1.26mL, 6.45mmol) in portions. The resulting reaction mixture was warmed to 60 ℃ and stirred for 12h, at which time TLC analysis showed a trace of starting material. The reaction mixture was cooled to ambient temperature, quenched with H2O (2mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (3 × 15mL), washed with brine (10mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (2.5-10% diethyl ether gradient in hexane) to obtain 254mg of (1R,2S,6R) -2-azido-6- [ tert-butyl (dimethyl) silyl ] oxy-cyclohexanol 50d as a clear oil.

Formation of (1R,2R,3S) -3-amino-1- (tert-butyldimethylsilyloxy) -1-methylcyclohexan-2-ol (50e)

a solution of azide 50d (0.25g, 0.89mmol) in 20mL of ethyl acetate was hydrogenated with Degussa palladium (20 mol%) under 1 atmosphere of hydrogen overnight. The reaction mixture was filtered through celite and the celite was eluted with 2X10mL EtOAc. The filtrate was concentrated in vacuo to give 230mg of oil which was used directly in the next step without further purification.

Formation of (1R,2R,6S) -2- (tert-butyldimethylsilyloxy) -6- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -2-methylcyclohexanol (50f)

to a stirred solution of (1R,2R,6S) -6-amino-2- [ tert-butyl (dimethyl) silyl ] oxy-2-methyl-cyclohexanol 50e (0.16g, 0.62mmol) in THF (8mL) was added 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine 1a (0.29g, 0.63mmol) followed by N-ethyl-N-isopropyl-propan-2-amine (0.13mL, 0.74 mmol). The resulting reaction mixture was capped and warmed to-70 ℃ and stirred for 14 h. The reaction mixture was cooled to ambient temperature, water (2mL) was added, and concentrated under reduced pressure to remove THF. The crude product was diluted with ethyl acetate (25mL) and the insoluble material (sulfone 1a) was removed by filtration. The organic layer was separated, washed with brine (2 × 5mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column packing on silica gel using 10-30% ethyl acetate in hexane as eluent to obtain 350mg of (1R,2R,6S) -2- [ tert-butyl (dimethyl) silyl ] oxy-6- [ [ 2-methyl [ 5-chloro-1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyridin-4-yl ] amino ] cyclohexanol (50 f).

Formation of (1R,2R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) -1-methylcyclohexane-1, 2-diol (860)

To a stirred solution of (1R,2R,6S) -2- [ tert-butyl (dimethyl) silyl ] oxy-6- [ [ 2-methyl [ 5-chloro-1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyridin-4-yl ] amino ] cyclohexanol 50f (0.11g, 0.16mmol) in THF (2mL) at room temperature was added tetrabutylammonium fluoride (1.5 equiv) and the reaction mixture was stirred for 1.5h at which time HPLC analysis showed no starting material but a slightly desilylated product of demethylbenzenesulfonylation was observed. An additional equivalent of TBAF was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was suspended in ethyl acetate (10mL) and washed with H2O (2 × 4mL), saturated aqueous NH4Cl (2mL) and brine (2 mL). The organic phase was dried (Na2SO4) and concentrated in vacuo to provide 139mg of crude residue. The crude residue was purified by reverse phase HPLC (5-95% MeOH/water w/HCl buffer over 15min) to obtain 15mg of the desired product 860. LCMS M +1 ═ 392.34

General scheme 51

(a) NaH, BnBr, THF, 60 ℃; (b) 3-chloroperoxybenzoic acid, CH2Cl2, 0 ℃; (c) h2SO4, MeOH; (d) TBSCl, imidazole, DMAP, DMF; (e) h2, Pd-C (10%), EtOAc; (f) triphenylphosphine, diisopropyl azedicarboxylate, diphenyl phosphorazidate, THF; (g) h2, Pd-C (10%), EtOAc; (h)2, 4-dichloro-5-fluoropyrimidine, K2CO3, CH3 CN/IPA; (i) TsOH, MeOH; (j) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, aqueous Na2CO3, CH3CN, microwave, 120 ℃; (k) LiOH, H2O/THF, microwave, 120 ℃ C

Formation of ((cyclohexenyl-2-oxy) methyl) benzene (51a)

A solution of cyclohex-2-enyl-1-ol (10.0g, 101.9mmol) in anhydrous THF (100mL) was added to a stirred suspension (60% dispersed in oil) containing sodium hydride (8.0g, 199.7mmol) and benzyl bromide in anhydrous THF (250mL) maintained at 50 ℃. The resulting solution was stirred at 55-60 ℃ for 18 h. After cooling to room temperature, the reaction was quenched by addition of water and the mixture was diluted with ether (500 mL). The organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuo to an oil filtered through a plug of gelcaps to afford 16.1g of the desired product 51a, which was used directly in the next step without further purification.

Formation of racemic cis-and trans-1-benzyloxy) -7-oxabicyclo [4.1.0] heptane (51b and 51c)

A solution of dibenzyl ether 51a (16.10g, 0.89mol) in 500mL of CH2Cl2 was treated in portions with 77% m-CPBA (21.08g, 0.09mol) at 0 deg.C. The reaction mixture was stirred at 0 ℃ for 2h and then at room temperature for 12 h. When the reaction was complete, the reaction was quenched with sodium thiosulfate (100mL) and the organic phase was further washed with 100mL of sodium thiosulfate, then with aqueous NaHCO3, 5% NaOH (200mL), and finally with water. The organic phase was dried (Na2SO4) and concentrated in vacuo to give an oil which was purified by silica gel chromatography (5% -20% Et 2O/hexane) to give 11.44g of trans epoxide 51b and to isolate 3.95g of cis epoxide 51c (66:34 ratio).

formation of racemic 1-benzyloxy-3-methoxycyclohexan-2-ol (51d)

A solution of cis-1-benzyloxy) -7-oxabicyclo [4.1.0] heptane 51c (2.0g, 9.8mmol) in 0.2N sulfuric acid (9.8mmol) in 30mL of absolute ethanol was stirred at room temperature for 30 min. The reaction was diluted with water and extracted with ether. The organic phase was dried (Na2SO4) and concentrated in vacuo to give 2.31g of an oil which was used directly in the next step without further purification.

Rac [ 1-benzyloxy-3-methoxy-2-cyclohexyloxy ] tert-butyl-dimethylsilane (51e)

To a solution of 1-benzyloxy-3-methoxy-cyclohexan-2-ol 51d (2.31g, 9.78mmol), tert-butyl-chlorodimethyl-silane (2.21g, 2.73mL, 14.66mmol) in dry DMF at room temperature was added 4H-imidazole (1.997g, 29.33mmol) and a catalytic amount of 4-dimethylaminopyridine (0.12g, 0.98 mmol). The resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with ether, washed with water, saturated aqueous citric acid and then water. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The colorless crude oil was used directly in the next step without further purification.

Formation of racemic [ 1-hydroxy-3-methyl-2-cyclohexanyloxy ] tert-butyl-dimethylsilane (51f)

A solution of rac [ 1-benzyloxy-3-methyl-2-cyclohexyloxy ] tert-butyl-dimethylsilane 51e (3.4g, 9.7mmol) was dissolved in ethyl acetate (50mL) and hydrogenated with Pd-C10% under 45PSI hydrogen for 1 h. The reaction mixture was filtered through a nylon/glass fiber filter to provide 2.72g of the desired product 51f after concentration in vacuo. This material was used directly in the next step without further purification.

Formation of racemic [ 1-azido-3-methyl-2-cyclohexyloxy ] tert-butyl-dimethylsilane (51g)

To a solution of racemic [ 1-hydroxy-3-methyl-2-cyclohexyloxy ] tert-butyl-dimethylsilane 51f (2.5g, 9.6mmol) in 60mL of anhydrous THF at room temperature were added triphenylphosphine (5.0g, 19.2mmol), DIAD (3.9g, 19.2mmol) and diphenylphosphorylazide (5.3g, 19.2mmol) and the reaction mixture was stirred at room temperature for 60 h. The solvent was concentrated in vacuo and the product was purified by silica gel chromatography (10% Et 2O-hexanes/ether gradient) to afford 2.57g of the desired product, 51 g.

Formation of racemic [ 1-amino-3-methyl-2-cyclohexanyloxy ] tert-butyl-dimethylsilane (51h)

a solution of 51g (2.57g, 6.3mmol) of racemic [ 1-azido-3-methyl-2-cyclohexyloxy ] tert-butyl-dimethylsilane hydrogenated in 20mL of ethyl acetate was hydrogenated with Pd-C10% (5 mol%, Degussa) in a Parr hydrogenation apparatus under 45PSI for 1 h. The reaction mixture was filtered on a nylon and glass fiber filter and concentrated in vacuo to afford 2.32g of the desired product as a white solid for 51 h.

formation of racemic N- ((1-2- (tert-butyldimethylsilyloxy) -3-methoxycyclohexyl) -2-chloro-5-fluoropyrimidin-4-amine (51i)

Racemic [ 1-amino-3-methyl-2-cyclohexyloxy ] tert-butyl-dimethylsilane (2.32g, 6.26mmol) was placed in a flask. MeCN and IPA (1.5:1v/v) were added to the flask to a total volume of 125 mL. Potassium carbonate (4.32g, 31.30mmol) was added to the solution and the mixture was stirred at room temperature for 30min (to remove any water that may be present). To the mixture was added 2, 4-dichloro-5-fluoro-pyrimidine (3.14g, 18.78mmol) and the mixture was stirred at room temperature for 60 h. The reaction mixture was filtered through celite and concentrated in vacuo. The crude residue was purified by silica gel chromatography (20-100% ether/hexane gradient) to obtain 2.27g of pure racemic compound 51 i.

Formation of (1R,2S,6R) -2- (2-chloro-5-fluoropyrimidin-4-ylamino) -6-methyl-cyclohexanol (51j)

To a solution of compound rac N- ((1-2- (tert-butyldimethylsilyloxy) -3-methoxycyclohexyl) -2-chloro-5-fluoropyrimidin-4-amine 51i (1.96g, 5.03mmol) in 30mL of MeOH was added p-toluenesulfonic acid (1.73g, 10.06 mmol). the reaction mixture was stirred at room temperature for 3h and then concentrated to dryness the residue was dissolved in EtOAc (125mL) and washed with saturated aqueous potassium carbonate solution 1M (2X50mL) then brine the organic phase was dried (Na2SO4), filtered and concentrated in vacuo to yield 635mg of chiral alcohol 51j as a white solid after SFC enantiomeric separation (50% EtOH-50% CO2, 10mL/min, 100 bar).

(1R,2S,6R) -2- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -6-methoxycyclohexanol (51k)

5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.10g, 0.23mmol) was placed in a microwave tube. Acetonitrile (0.61mL) was added to the microwave tube and the oxidation of the solution was removed with nitrogen. To the reaction were added (1R,2S,6R) -2- (2-chloro-5-fluoropyrimidin-4-ylamino) -6-methyl-cyclohexanol 51j (0.04g, 0.14mmol) and palladium catalyst (24mg), followed by aqueous sodium carbonate (0.21mL of a 2M solution, 0.41 mmol). The reaction was sealed and heated in a microwave reactor for 15min to 120 ℃. The reaction was diluted in ethyl acetate (40mL), filtered through florisil and concentrated in vacuo to yield the crude product as a green solid. The crude product was purified by silica gel chromatography (20-75% EtOAc/hexanes gradient). The resulting product was used directly in the next step.

LCMS(M+1)＝546.35。

formation of (1R,2S,6R) -2- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -6-methoxycyclohexanol (831)

Azaindole 51k (0.050g, 0.092mmol) was placed in a microwave vial. To this was added 3mL of THF and 0.9mL of 0.8M LiOH. The vial was sealed and heated in a microwave for 15min to 120 ℃. When the reaction was complete, it was neutralized with 9 equivalents of 1N HCl (0.704mL), then saturated aqueous NaHCO3 was added and the organic phase was separated and loaded onto silica gel for purification and eluted with a w/2% MeOH to 12% gradient over 10min (4g column) to afford 34.5mg (91%) of the desired product 831.

General scheme 52

(a) LDA, methyl iodide, THF, -78 deg.C; (b) SOCl2, DMF, CH2Cl2, reflux, then NH4 OH; (c) TMSOTf, iodine, Et3N, pentane, CH2Cl2(d) Boc2O, DMAP, CH2Cl 2; (e)1, 8-diazabicyclo [5.4.0] undec-7-ene, toluene, reflux (f) Cs2CO3, MeOH; (g) h2, Pd-C (5%), MeOH, 2 days; (h) performing chiral separation on HCl, MeOH, 2, 4-dichloro-5-fluoropyrimidine, iPr2NEt, DMF and SFC; (i) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, Pd (Ph3P)4, Na2CO3, THF/H2O, reflux; (j) NaH, MeOH; (k) LiOH, H2O/MeOH; (l) Benzotriazol-1-yl- [ bis (dimethylamino) methylene ] oxonium hexafluorophosphate, iPr2NEt, THF, NH4Cl

Formation of 1-methyl-3-cyclohexene-1-carboxylic acid (52a)

N-isopropyl-2-propylamine (50.1g, 69.5mL, 495.5mmol) was dissolved in 50mL of THF. To the solution was added n-butyllithium (174.4mL of a 2.5M solution in hexane, 436.0mmol) at-78 ℃. The resulting solution was stirred at-78 ℃ for 30 minutes. Cyclohex-3-ene-1-carboxylic acid (25.0g, 198.2mmol) was then added to the reaction and the reaction was allowed to warm to 60 ℃ for 2 h. The reaction was allowed to cool to room temperature and methyl iodide (29.5g, 13.0mL, 208.1mmol) was added and the reaction was allowed to stir overnight before quenching with 1N HCl until pH < 4. The crude product was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo to a yellow oil (27g) and used without further purification.

MS/RT:141.09(M+H)/1.65

Formation of 1-methylcyclohex-3-ene-1-carboxamide (52b)

to a solution of 1-methylen-3-cyclohexa-1-carboxylic acid 52a (54.0g, 385.2mmol) in CH2Cl2(200mL) was added thionyl chloride (56.2mL, 770.4mmol) and 1mL of DMF. The reaction was allowed to warm to reflux for 3h, then cooled and concentrated in vacuo. The residue was dissolved in 200mL of CH2Cl 2. Ammonium hydroxide (148.2mL of 13M solution, 1.9mol) was added slowly to the reaction. The reaction was stirred overnight. The reaction was extracted into CH2Cl2 and water. The organic phase was concentrated in vacuo and purified by flash silica gel chromatography (EtOAc) to yield 25g of 1-methyl-3-cyclohexene-1-carboxamide.

MS/RT:139.96(M+H)/2.66

formation of 4-iodo-1-methyl-6-azabicyclo [3.2.1] octan-7-one (52c)

A solution of 1-methylcyclohex-3-ene-1-carboxamide 52b (5.0g, 35.9mmol) dissolved in 100mL of pentane and CH2Cl2 was cooled to 0 deg.C and treated with triethylamine (11.0mL, 79.0mmol) and trimethylsilyl trifluoromethanesulfonate (14.3mL, 79.0mmol) in that order. The resulting mixture was stirred at room temperature for 1 h. The lower layer was removed by pipette. The upper pentane was concentrated in vacuo and the resulting residue was dissolved in THF (100 mL). Iodine (20.1g, 79.02mmol) was added to the stirring reaction and the reaction was stirred at room temperature overnight. After quenching with Na2SO3 and NaHCO3, the reaction was partitioned between CH2Cl2 and water. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to a dark yellow oil (9.5g) which was used without further purification.

MS/RT:266.06(M+H)/2.39

Formation of 4-iodo-1-methyl-7-oxo-6-azabicyclo [3.2.1] octane-6-carboxylic acid tert-butyl ester (52d)

To a solution of 4-iodo-1-methyl-6-azabicyclo [3.2.1] octan-7-one 52c (9.5g, 35.8mmol) in CH2Cl2(100mL) were added DMAP (0.2g, 1.8mmol), triethylamine (15.0mL, 107.5mmol) and tert-butoxycarbonyl tert-butylcarbonate (7.8g, 35.8 mmol). The reaction was stirred at room temperature overnight. The product was extracted into CH2Cl2 and water. The organic layer was concentrated in vacuo and the residue was purified by silica gel chromatography (4:1 hexane: EtOAc), yielding 7.6 g.

MS/RT:366.06(M+H)/3.95

Formation of 4-iodo-1-methyl-7-oxo-6-azabicyclo [3.2.1] oct-3-ene-6-carboxylic acid tert-butyl ester (52e)

To a solution of tert-butyl 4-iodo-1-methyl-7-oxo-6-azabicyclo [3.2.1] octane-6-carboxylate 52d (7.6g, 20.8mmol) in 100mL of toluene was added 1, 8-diazabicyclo [5.4.0] deca-7-ene (6.2mL, 41.6 mmol). The reaction was allowed to warm to reflux and stirred overnight. The reaction was concentrated in vacuo and the resulting residue was purified by silica gel chromatography (4:1 hexanes: EtOAc) to yield 4.9g of the desired product 52 e.

MS/RT:238.14(M+H)/3.33

Formation of methyl 5- (tert-butoxycarbonylamino) -1-methyl-3-cyclohexenecarboxylate (52f)

to tert-butyl 1-methyl-7-oxo-6-azabicyclo [3.2.1] oct-3-ene-6-carboxylate 52e (4.93g, 20.78mmol) in MeOH (100mL) was added cesium carbonate (13.54g, 41.56 mmol). The reaction was stirred overnight and then concentrated in vacuo. The cesium salt was precipitated with Et2O and filtered. The ether filtrate was evaporated to give 5.5g of a yellow oil which was used without further purification.

MS/RT:270.17(M+H)/3.64

formation of methyl 5- (tert-Butoxycarbonylamino) -1-methylcyclohexanecarboxylate (52g)

Methyl 5- (tert-butoxycarbonylamino) -1-methyl-3-cyclohexenecarboxylate 52f (5.59g, 20.75mmol) was dissolved in 100mL of MeOH. To the stirred solution was added 5% palladium on carbon (1.11g, 10.38mmol) and the reaction was stirred under a hydrogen balloon for 2 days. The reaction was filtered through celite, and the filtrate was concentrated in vacuo and used without further purification.

MS/RT:272.24(M+H)/3.62

Isolation of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methyl-cyclohexanecarboxylic acid methyl ester (52h)

A stirred solution of 52g (5.63g, 20.75mmol) of methyl 5- (tert-butoxycarbonylamino) -1-methylcyclohexanecarboxylate in MeOH (20mL) was treated with HCl gas for 10 min. The resulting solution was stirred at room temperature for 1h, then concentrated to dryness and redissolved in THF (50 mL). To the reaction mixture was added iPr2NEt (10.84mL, 62.25mmol) followed by 2, 4-dichloro-5-fluoro-pyrimidine (5.20g, 31.12 mmol). The reaction was stirred at reflux overnight, concentrated in vacuo and the resulting residue was purified by silica gel chromatography (1:1 hexanes: EtOAc) to yield 2.2g of the racemic product as a yellow oil. 300mg of racemic methyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylate were subjected to SFC chiral separation to give 100mg of the desired product as a yellow oil for 52 h.

MS/RT:302.16(M+H)/3.68

Formation of methyl (1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylate (52i)

In a 25mL round bottom flask, (1R,3S) -methyl 3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylate 52h (0.061g, 0.202mmol), 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.096g, 0.222mmol), sodium carbonate (0.064g, 0.607mmol) were combined into 5mL THF and 1mL water. The reaction mixture was degassed by a stream of nitrogen. Tetrakis (triphenylphosphine) palladium (0) (0.021g, 0.202mmol) was added to the reaction and the reaction stirred at reflux overnight. The reaction was concentrated in vacuo and purified by silica gel chromatography (4:1 hexanes: EtOAc) to yield 85mg of the desired product, 52 i.

MS/RT:572.33(M+H)/6.27

formation of methyl (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylate (52j)

To a stirred solution of (1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylic acid methyl ester 52i (0.085g, 0.149mmol) in 10mL of MeOH at room temperature was added NaH (0.004g, 0.178 mmol). The resulting suspension was stirred for 2h and quenched with solid NH4 Cl. The mixture was concentrated in vacuo and purified by silica gel chromatography (3:1 hexanes: EtOAc) to yield 55mg of the desired product 52 j.

MS/RT:418.32(M+H)/3.30

(1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylic acid (826)

To a solution of (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexanecarboxylic acid methyl ester 52j (0.035g, 0.083mmol) in MeOH (5mL) and water (1mL) was added LiOH (0.004g, 0.168 mmol). The reaction was stirred at room temperature for 2 days, then concentrated to dryness. The residue was washed with ethanol. The combined ethanol washes were concentrated in vacuo to yield 30mg of the desired product as an off-white solid.

1H NMR (300MHz, DMSO) δ 12.34(s, H),8.74(d, J ═ 2.3Hz, H),8.33(d, J ═ 2.3Hz, H),8.28(d, J ═ 1.6Hz, H),8.17-8.12(m, H),4.34(s, H),4.29(s, H),3.89(s, H),3.55(d, J ═ 6.3Hz, H),3.32(s, H),2.50(s, H),2.29(s, H),1.95-1.90(m, H),1.82(d, J ═ 6.6Hz, H),1.76(s,3H), 1.67(s, H),1.55(s, H),1.44-1.42(m, H),1.31(s, H), 1.84 (s, H),1.07(s, H),1.07 (H), 1.6.6H, H),1.6 (s, H),1.07 (H); MS/RT 404.24(M + H)/3.39.

formation of (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanecarboxamide (924)

(1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanecarboxylic acid 826(0.050g, 0.108mmol), benzotriazol-1-yl- [ bis (dimethylamino) methylene ] oxonium hexafluorophosphate (0.081g, 0.216mmol) and N-ethyl-N-isopropyl-propan-2-amine (0.075mL, 0.432mmol) were combined in 5mL THF. Ammonia hydrochloride (0.002g, 0.032mmol) was then added to the reaction and the reaction stirred at room temperature overnight. After concentration under reduced pressure, the mixture was purified by reverse phase HPLC chromatography to yield 3.3mg of the desired product.

H NMR(300MHz,MeOD)δ8.85(d,J＝2.4Hz,H),8.22(d,J＝ 2.3Hz,H),8.16(s,H), 7.99(d,J＝4.1Hz,H),7.86(s,H),3.48(d,J＝ 7.0Hz,H),2.80(s,H),2.15(s,H),2.0(s, H),1.86(qn,J＝3.3Hz,H), 1.80(s,3H),1.74(m,2H),1.44(s,6H)；LC/MS:403.34(M+H),RT ＝1.77。

Formation of 2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S,3R) -3-isocyanato-3-methylcyclohexyl) pyrimidin-4-amine (52m)

To (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-methyl-cyclohexanecarboxylic acid 826(0.100g, 0.216mmol) and (azido (phenoxy) phosphono) phenol (0.093mL, 0.432mmol) in 10mL of toluene was added 1mL of N-ethyl-N-isopropyl-propan-2-amine. The reaction was allowed to warm to reflux overnight. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (EtOAc) to yield 40mg of the desired product as a white foam.

MS/RT:401.23(M+H)/3.89

formation of N- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-methylcyclohexyl) pyrrolidine-1-carboxamide (926)

A solution of 2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S,3R) -3-isocyanato-3-methylcyclohexyl) pyrimidin-4-amine 52m (0.035g, 0.087mmol) in 3mL of NMP and 0.5mL of pyrrolidine is warmed up to 200 ℃ in a microwave. The reaction was then concentrated in vacuo and purified by reverse phase HPLC chromatography to yield 8.7mg of the desired product as a tan solid.

1H NMR (300.0MHz, MeOD) δ 8.76(d, J ═ 2.4Hz, H),8.44-8.38 (m,2H),8.27(d, J ═ 5.6Hz, H),4.87(d, J ═ 5.1Hz, H),4.64-4.56(m, 4H),3.38-3.19(m,2H),2.65(s,2H),2.46(m, H),2.42(s,3H), 2.16(s, H),2.07(t, J ═ 12.0Hz, H),2.00(s, H),1.88(q, J ═ 6.6Hz, H),1.88 (s, H),1.70(s, H) and 1.61(d, J ═ 12.8Hz, H) ppm; 472.38 for MS/RT.

General scheme 53

(a)H、Pd-C、MeOH；(b)NaCO、THF–CHCN，135℃；(c)NaOMe、 MeOH、DCM；(d)NaOH、 MeOH、THF

Formation of methyl (+/-) -2, 3-trans-3-nitrobicyclo [2.2.1] hept-5-ene-2-carboxylate (53a)

this compound was prepared as a mixture of trans isomers (endo: exo 84:16) according to the procedure described in Chang, Linda L, Truong, Quang, Doss, George A, MacCoss, Malcolm, Lyons, Kathryn, McCauley, Ermengilda, Mumford, Richard, Forrest, Gail, Vincent, Stella, Schmidt, John A, Hagmann, Willig K, bioorg.Med.Chem.Lett.2007,17(3), 597-reservoir 601.

Formation of methyl (+/-) -2, 3-trans-3-aminobicyclo [2.2.1] heptane-2-carboxylate (53b)

a mixture of methyl (+/-) -2, 3-trans-3-nitrobicyclo [2.2.1] hept-5-ene-2-carboxylate 53a (0.32g, 1.62mmol) and Pd-C (10%) in MeOH was purged and placed under H2 atmosphere (50PSI) and shaken overnight. The mixture was filtered through celite, concentrated in vacuo and azeotroped twice with CH3CN to remove traces of MeOH.

1H NMR of the crude mixture showed the presence of endo and exo products (84: 16. endo: exo) and the next reaction was carried out directly without further purification.

Formation of methyl (+/-) -2, 3-trans-3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylate (53c)

A mixture of 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine 1a (0.46g, 1.00mmol), (+/-) -trans-3-aminobicyclo [2.2.1] heptane-2-carboxylic acid methyl ester 53b (0.27g, 1.60mmol) (84: 16. endo: exo) and freshly ground Na2CO3(0.32g, 2.99mmol) in THF (3.7mL) and CH3CN (1.2mL) was heated in a microwave for 20min to 120 ℃. The reaction mixture was filtered and the solid was washed with Et2O and THF. The organic layer was concentrated in vacuo to afford the crude product, which was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to afford the desired product (352mg) as an inseparable mixture of trans endo and trans exo isomers (endo: exo 85:15) as shown by NMR.

LC/MS R＝6.13min,(M+H)570.34。

(+/-) -methyl 2, 3-trans-endo-3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylate (53d) & (+/-) -methyl 2, 3-trans-exo-3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylate (53d)

To a solution of trans-endo-and trans-exo-3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylic acid methyl ester 53c (0.18g, 0.31mmol) in MeOH (3mL) and CH2Cl2(1mL) was added NaOMe (3mL of 25% w/v, 13.88 mmol). After 90s, the reaction was quenched by addition of NH4Cl solution (5 mL). The mixture was partitioned between aqueous NH4Cl (half saturated) and EtOAc. The aqueous layer was re-extracted and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-15% MeOH-DCM, gradient) yielded the desired product as a mixture. (white solid): 112 mg. 1H NMR showed the desired product to be present as a mixture of endo and exo isomers (endo: exo 84:16), which was taken on to the hydrolysis step.

(+/-) -methyl 2, 3-trans-exo-3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylate (53 d): minor isomer (exo form): LC/MS (method: M117) Rt ═ 3.17min, (M + H) 416.27.

(+/-) -2, 3-trans-endo-3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylate (53d) the major isomer (endo): LC/MS (method: M117) Rt ═ 3.49min, (M + H) 416.27.

(946) (+/-) -2, 3-trans-endo-3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylic acid & (947) (+/-) -2, 3-trans-exo-3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylic acid

To a stirred solution of the starting methyl ester 53d (0.076g, 0.183mmol) (84: 16. endo: exo) in THF (0.60mL) and MeOH (0.10mL) was added NaOH (0.10mL of 2M, 0.201 mmol). The progress of the reaction was monitored by TLC. After 30min, NaOH (0.18mL of a 2M solution, 0.37mmol) and MeOH (0.18mL) were added. The mixture was stirred at room temperature for a further 16 h. The mixture was neutralized with HCl (1M) and concentrated in vacuo. Purification by preparative HPLC provided 52mg of the major isomer (946) and 11mg of the minor isomer (947) as the hydrochloride salt.

(946) Major (endo) isomer: 1H NMR (300MHz, MeOD) δ 8.82(d, J ═ 2.2Hz,1H),8.48(s,1H),8.39(d, J ═ 2.2Hz,1H),8.31(d, J ═ 5.6Hz, 1H),5.11(m,1H),2.85(br s,1H),2.68(br s,1H),2.62(d, J ═ 4.8Hz, 1H),1.92(d, J ═ 10.1Hz,1H) and 1.77-1.51(m,5H) ppm; LC/MS Rt 3.51, (M + H) 402.32.

(947) Minor (exo) isomer: 1H NMR (300MHz, MeOD) δ 8.87(d, J ═ 2.1Hz,1H),8.48(s,1H),8.39(d, J ═ 1.9Hz,1H),8.30(d, J ═ 5.7Hz, 1H),4.73(d, J ═ 3.3Hz,1H),3.12(m,1H),2.76(br s,1H),2.56(d, J ═ 4.2Hz,1H),1.86(d, J ═ 9.5Hz,2H),1.79-1.49 (composite m,2H) and 1.51 (embedded d, J ═ 10.4Hz,2H) ppm; LC/MS Rt 3.42, (M + H) 402.32.

(1184) (2S,3S) -3- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Compound 1184 was prepared in a similar form as compound 946 and 947 described above.

(1070) (2S,3S) -3- ((2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) bicyclo [2.2.2] octane-2-carboxylic acid

Compound 1070 was prepared in a similar form to compounds 946 and 947 as described above.

General scheme 54

(a) Cyanogen chloride, DMF, 0 ℃; (b) pd (OH) 2/carbon, H2, 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, iPr2NEt/THF, 45 ℃; (c) Na/MeOH; (d) (n-Bu)2SnO, TMSN3, toluene, 110 DEG C

Formation of benzyl (1S,3R) -3-cyanocyclohexylcarbamate (54a)

A suspension of benzyl N- [ (1S,3R) -3-carboxamidocyclohexyl ] carbamate 18d (0.69g, 2.50mmol) in DMF (10mL) at 0 deg.C was treated with 2,4, 6-trichloro-1, 3, 5-triazine (0.61g, 3.29mmol) and allowed to stir while slowly warming to room temperature. After 20min, the color of the solution turned to gold. After 1h, a precipitate formed. After stirring for another 3h, quench with ice water (100mL) and extract with CH2Cl2(2X125mL) then wash with 1N HCl (100 mL). The organic layer was concentrated in vacuo to obtain 730mg of residue, which was purified using a pad of silica gel (45mL) using 30% EtOAc/hexanes as the eluent to obtain 621mg of white solid after drying in vacuo.

H NMR(300MHz,CDCl3)δ7.45-7.30(m,5H),5.09(s,2H), 4.67(s,1H),3.49(s, 1H),2.66-2.32(m,2H),2.16-1.79(m,3H),1.52- 1.03(m,4H)。

Preparation of (1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarbonitrile (54b)

Benzyl N- [ (1S,3R) -3-cyanocyclohexyl ] carbamate (0.26g, 1.02mmol) was dissolved in THF (15mL) and washed with 0.13g of 20% palladium on carbon (50% wet weight). Degassing with hydrogen as suspension for 2min, and placing in static hydrogen. After 135min, TLC showed no starting material remaining. The suspension was filtered through celite, washed with THF and degassed with nitrogen, then iPr2NEt (0.21mL, 1.23mmol) and 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine 1a (0.48g, 1.02mmol) were added. The mixture was allowed to stir at 45 ℃ overnight, then concentrated to dryness, adsorbed on silica gel and purified by silica gel chromatography using a gradient of 0-60% EtOAc/hexanes to give 293mg of a white solid.

H NMR(300MHz,CDCl3)δ8.74(d,J＝2.4Hz,1H),8.49(s,1H), 8.39(d,J＝2.4Hz, 1H),8.15–8.05(m,3H),7.37–7.23(m,2H),5.01 (d,J＝6.2Hz,1H),4.13(s,1H),2.75(d,J ＝23.0Hz,1H),2.58(s,1H), 2.38(s,3H),2.20(d,J＝9.1Hz,2H),2.03(d,J＝7.8Hz,1H), 1.78– 1.43(m,4H),1.26(s,1H)。

Preparation of (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarbonitrile (54c)

(1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarbonitrile 54b (0.29g, 0.55mmol) was suspended in MeOH (15mL), metallic sodium was added and the mixture was heated at 45 ℃. Sodium dissolved before the compound. The mixture was allowed to stir until TLC and LCMS showed completion. Concentrated to reduced volume and then quenched with a 1:1 aqueous saturated NH4Cl: water mixture (1ml) and then concentrated to dryness. The residue was diluted with EtOAc and washed with water and brine. The organic layer was concentrated in vacuo to give 0.3g of a yellow solid which was adsorbed on silica gel and purified using a 40g isco column using 20% MeOH: DCM as eluent on the following gradient to give 146mg of a white solid: 0-25%/6 min, keeping for 4 min; 25-50%/4 min, and maintaining for 9 min. LCMS (10-90% MeOH: water and formic acid). LCMS RT 4.01ES +371, ES-369.

Preparation of (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarboxamide (847)

A sample of (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanecarbonitrile was treated with 4N HCl/dioxane and heated at 78 ℃ overnight. Concentrated to dryness, then quenched with saturated aqueous sodium bicarbonate and CH2Cl2 added to produce a slurry. Filtered and extracted with CH2Cl 2. The organic phase was dried over Na2SO4 and concentrated in vacuo to give 189mg of an orange residue that was purified by silica gel chromatography (0-10% MeOH: CH2Cl2 gradient) to afford 9.9mg of a solid: LCMS (10-90% MeOH: water and formic acid) RT 3.79min ES + 389.

Preparation of N- ((1S,3R) -3- (1H-tetrazol-5-yl) cyclohexyl) -2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (855)

A suspension of dibutyl (oxo) tin (0.016g, 0.064mmol) and (1R,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexane-carbonitrile (54c) (0.043g, 0.107mmol) in toluene (3mL) was treated with azido (trimethyl) silane (0.200mL, 1.507 mmol). The mixture was heated in a sealed tube at 120 ℃ overnight. The mixture was adsorbed onto silica gel and purified by silica gel chromatography (20% MeOH: DCM containing 0.5% AcOH modifier, 25-50% gradient). The combined fractions were concentrated to dryness to give a residue, which was triturated with ether and then dried under vacuum at 45 ℃ to give 44mg of a yellow solid.

H NMR(300MHz,DMSO)δ12.33(s,1H),8.74(d,J＝2.4Hz, 1H),8.41–8.04(m,3H), 7.62(d,J＝7.4Hz,1H),4.30(s,1H),3.54– 3.06(m,3H),2.67–2.31(m,1H),2.23–1.33(m, 6H)。

General scheme 55

(a) hydroxylamine-HCl, EtOH; (b) 5-ethyl-2-methyl-pyridine borane, HCl, MeOH; (c) n- (oxomethylene) carbamoyl chloride, THF; (d) NaOMe, MeOH

Formation of (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) cyclohexanone oxime (55a)

To a solution of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanone (0.41g, 0.81mmol) in EtOH (8.2mL) was added hydroxylamine hydrochloride (0.11g, 1.61 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then warmed to 70 ℃ for 15 min. The reaction mixture was concentrated in vacuo, suspended in EtOAc-DCM, washed with half-saturated brine (2 ×) and filtered through a SiO2 packed column. The resulting residue was azeotroped with CH3CN (2 ×) to provide an off-white powder which was used without further purification.

1H NMR (300MHz, MeOD) δ 8.78(d, J ═ 2.4Hz,1H),8.51(d, J ═ 10.8Hz,1H),8.32(d, J ═ 2.3Hz,1H),8.10-8.04(m,3H),7.38(d, J ═ 8.2Hz,2H),4.29-4.15(m,1H),3.79-3.74(m,0.6H),2.41(m,1H), 2.38(s,3H),2.30-2.16(m,2H),2.06-1.84(m,4H) and 1.66-1.59(m, 2H) ppm; LC/MS (method: M120) Rt 3.90min, (M + H) 529.44.

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S,3R) -3- (hydroxyamino) cyclohexyl) pyrimidin-4-amine (55c) &2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S,3S) -3- (hydroxyamino) cyclohexyl) pyrimidin-4-amine (55 b):

After addition of (5-ethyl-2-methyl-pyridine borane (0.12mL, 0.76mmol) to a stirred solution of (S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanone oxime (0.20g, 0.38mmol) and HCl (0.19mL, 6M, 1.134mmol) in MeOH (10mL) at room temperature for 30min, the reaction was quenched with NaHCO3, the mixture was extracted successively with Et2O, EtOAc, CH2Cl2, and EtOAc, each organic fraction was washed with brine and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo flash chromatography (SiO2, 20-100% EtOAc-hexanes) afforded the cis-4 (74mg) and trans-3 (64mg) isomers.

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S,3S) -3- (hydroxyamino) cyclohexyl) pyrimidin-4-amine (stereoisomer-3)

1H NMR (300MHz, MeOD) δ 8.83(d, J ═ 2.4Hz,1H),8.50(s,1H), 8.33(d, J ═ 2.4Hz,1H),8.07-8.04(m,1H),7.37(d, J ═ 8.4Hz,1H), 4.24-4.17(m,1H),3.07-3.00(m,1H),2.34(m,1H),2.14-2.08(m, 1H),1.93(t, J ═ 3.5Hz,2H),1.66-1.53(m,1H) and 1.44-1.12(m,3H) ppm; LC/MS RT 3.64min, (M + H) 531.47.

2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S,3R) -3- (hydroxyamino) cyclohexyl) pyrimidin-4-amine (stereoisomer-4)

1H NMR (300MHz, MeOD) δ 8.84(d, J ═ 2.4Hz,1H),8.53(s,1H), 8.32(d, J ═ 2.4Hz,1H),8.07-8.04(m,1H),7.37(d, J ═ 8.2Hz,1H), 4.58-4.54(m,1H),3.26-3.23(m,1H),2.38(s,3H),1.98-1.83(m,4H) and 1.69-1.60(m,4H) ppm; LC/MS RT 3.67min, (M + H) 531.47.

2- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl-amino) cyclohexyl) -1,2, 4-oxadiazolidine-3, 5-dione (796)

To a solution of 2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-N- ((1S,3R) -3- (hydroxyamino) cyclohexyl) pyrimidin-4-amine 55b (0.072g, 0.136mmol) in THF (2mL) at 0 ℃ was added N- (oxymethylene) carbamoyl chloride (0.014mL, 0.176 mmol). A white solid formed immediately. The slurry was shaken and sonicated to make a uniform suspension/slurry. CH2Cl2(1mL) was then added to help solvate the slurry. After 135min, the mixture was treated with NaOMe (2mL, 25% w/v). After 2min, quench with saturated NH4Cl and acidify with 1M HCl. The mixture was extracted with EtOAc (3 ×) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Preparative HPLC provided the desired product (25 mg).

1H NMR (300MHz, MeOD). delta.8.73 (s,1H),8.52(s,1H),8.38(s, 1H),8.31(br s,1H),4.34(m,1H),2.60-2.56(m,1H),2.27(m,1H), 2.08(m,3H) and 1.89-1.78(m,3H) ppm; LC/MS RT 3.12min, (M + H) 446.45.

2- ((1S,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexyl) -1,2, 4-oxadiazolidine-3, 5-dione (798)

1H NMR (300MHz, MeOD). delta.8.67 (s,1H),8.56(s,1H),8.38(s, 1H),8.31(br s,1H),4.47(m,1H),4.21(m,1H),2.41(m,1H),2.22(m, 1H),2.10-1.90(m,3H),1.72(m,2H) and 1.50(m,1H) ppm; LC/MS RT 3.37min, (M + H) 446.34.

General scheme 56

(a) Paraformaldehyde, methoxyphosphonyl oxymethane, a 4A sieve and toluene at 90 ℃; (b) NaOMe, MeOH

Formation of dimethyl (S) - (3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) methylphosphonate (56a)

To a solution of 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [5,4-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -3-piperidinyl ] pyrimidin-4-amine 1c (2.00g, 3.99mmol) in dry toluene were added molecular sieves and methoxyphosphonyloxymethane (0.97g, 0.81mL, 8.78 mmol). While stirring under nitrogen, paraformaldehyde (0.90g, 9.98mmol) was added portionwise. The mixture was heated at 90 ℃ for 90 min. The reaction was allowed to cool to room temperature, diluted with saturated aqueous NaHCO3, and extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a gradient of 0-10% MeOH/CH2Cl2 to afford 2.0g of the desired product. LCMS RT ═ 4.47(M + H) 623.3.

formation of dimethyl (S) - (3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidin-1-yl) methylphosphonate (690)

To 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -N- [ (3S) -1- (dimethoxyphosphonomethyl) -3-piperidinyl ] -5-fluoro-pyrimidin-4-amine 56a (1.00g, 1.61mmol) in MeOH (40mL) was added sodium methoxide (20mL of 25% w/v, 92.55mmol) and the reaction mixture was stirred at room temperature for 30 min. All volatiles were removed under reduced pressure and the resulting residue was diluted with saturated aqueous NH4Cl solution and extracted twice with CH2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a gradient of 0-10% MeOH: CH2Cl2 to provide 270mg of a white solid.

1H NMR (300.0MHz, DMSO) δ 12.33(s,1H),8.70(d, J ═ 2.4Hz,1H), 8.28(d, J ═ 2.4Hz,1H),8.20(d, J ═ 2.6Hz,1H),8.17(d, J ═ 4.0Hz,1H), 7.35(d, J ═ 7.8Hz,1H),4.27-4.17(m,1H),3.67(s,3H),3.64 (s,3H),3.21-3.16(m,1H),2.96-2.90(m,3H),2.33-2.20(m,2H), 1.99-1.94(m,1H),1.80-1.60(m,2H) and 1.47-1.35(m, 1H); LCMS RT ═ 3.84(M +1) 469.47.

General scheme 57

(a) Pyrazole-1-formamidine hydrochloride, iPr2NEt, a sieve and toluene at 90 ℃; (b) NaOMe, MeOH

Formation of ((S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) piperidine-1-carboxamidine (57a)

To a solution of pyrazole-1-carboxamidine hydrochloride (0.12g, 0.80mmol) and 2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-N- [ (3S) -3-piperidinyl ] pyrimidin-4-amine 1c (0.40g, 0.80mmol) in DMF (0.9mL) was added iPr2NEt (0.14mL, 0.80 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was diluted in water, filtered, washed with water and then ether. The filtrate was concentrated in vacuo. The resulting residue (product eluted with 20% MeOH) was purified by silica gel chromatography using a gradient of 5-20% MeOH/CH2Cl2 to afford 190mg of the desired product.

H NMR(300MHz,DMSO)δ8.73(d,J＝2.2Hz,1H),8.50-8.45 (m,2H),8.33(d,J＝ 3.7Hz,1H),8.07(d,J＝8.2Hz,2H),7.90(d,J＝ 7.0Hz,1H),7.53-7.42(m,J＝9.0Hz,6H), 3.87(d,J＝13.6Hz,1H), 3.17(d,J＝5.2Hz,1H),3.03(q,J＝10.9Hz,2H),2.36(s,3H), 2.11(d,J ＝9.9Hz,1H),1.90(d,J＝12.6Hz,1H),1.68(dd,J＝24.5,13.9Hz,2H)； LCMS RT ＝3.07(M+1)543.34。

Formation of (S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) piperidine-1-carboxamidine (881)

To a solution of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] piperidine-1-carboxamidine 57b (0.18g, 0.32mmol) in MeOH (5mL) was added sodium methoxide (3mL of 25% w/v, 13.88mmol) and the reaction stirred at room temperature. After 5min, the mixture was concentrated in vacuo to a pale yellow solid. The crude residue was purified by preparative HPLC (MeOH/1% aqueous HCl) to obtain the desired product.

H NMR(300MHz,DMSO)δ12.79(s,1H),8.77(s,1H),8.60(d,J ＝2.3Hz,1H),8.43 (d,J＝4.8Hz,1H),8.37(d,J＝2.3Hz,1H),7.52(s, 3H),4.29(s,1H),4.08(d,J＝12.6Hz, 1H),3.90(d,J＝13.7Hz,1H), 3.16-2.95(m,2H),2.17(d,J＝9.7Hz,1H),1.92(d,J＝ 8.5Hz,1H), 1.81-1.57(m,2H)；LCMS RT＝2.03(M+1)389.27。

General scheme 58

(a) 3-bromo-1-propene, zinc dust, DMF; (b) 5-chloro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, Pd (Ph3P)4, Na2CO3, acetonitrile, water, 120 ℃ microwave; (c) OsO4, pyridine, 4-methylmorpholine-N-oxide, tert-butanol, water, THF, 120 ℃; (d) NaOMe, MeOH

Formation of (3S) -1-allyl-3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanol (58a)

To a solution of (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone 29b (0.60g, 2.46mmol) and 3-bromo-1-propene (0.43mL, 4.92mmol) in DMF was added zinc dust (0.32g, 4.92 mmol). The reaction was stirred at room temperature for 3 days. The mixture was diluted in saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hexanes afforded 553mg of the desired product 58a as an oil. LC/MS-two peaks correspond to two diastereomeric products: 286.4(M + H), RT 3.41 and 3.78.

Formation of (1R,3S) -1-allyl-3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanol and (1R,3S) -1-allyl-3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) cyclohexanol (58b and 58c)

5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.57g, 1.32mmol) and (3S) -1-allyl-3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanol 58a (0.32g, 1.10mmol) in acetonitrile (12mL) and Na2CO3(1.65mL of 2M aqueous solution, 3.31mmol) were placed in a microwave tube. The mixture was deoxygenated with nitrogen for 15 min. Tetrakis (triphenylphosphine) palladium (0) (0.03g, 0.02mmol) was added to the mixture. The reaction was sealed and heated to 120 ℃ for 20 min. The mixture was diluted with brine and extracted twice with CH2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a gradient of 10-60% EtOAc/hexanes to give two diastereomers:

Diastereomer 1 (strongly polar spot-58 c): LCMS RT 4.45min, (M + H556.48

Diastereomer 2 (weakly polar spot-58 b): LCMS RT 4.48min (M + H) 556.48

Formation of 3- ((1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) propane-1, 2-diol (58d)

to a solution of (3S) -1-allyl-3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanol 58c (0.30g, 0.54mmol) in 2-methyl-2-propanol (9.23mL), THF (3.69mL), and water (1.85mL) was added pyridine (0.09mL, 1.08mmol), osmium tetroxide (0.27mL of 2.5% w/v, 0.03mmol), and 4-methylmorpholine N-oxide (0.07mL, 0.65 mmol). The reaction mixture was heated for 20h to 80 ℃. After cooling to room temperature, the mixture was diluted in saturated aqueous sodium bisulfite and extracted twice with 20% isopropanol/CH 2Cl 2. The combined organic phases were washed with more saturated aqueous sodium bisulfite, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 5-10% MeOH/CH2Cl2 to afford 175mg of the desired product 58d as a racemic mixture.

1H NMR (d6-DMSO) δ 8.77(t, J ═ 2.6Hz,1H),8.48(d, J ═ 2.4Hz,1H),8.42 (d, J ═ 6.0Hz,1H),8.25-8.23(m,1H),8.07(d, J ═ 7.4Hz, 2H),7.74(dd, J ═ 7.6,13.5Hz,1H),7.44(d, J ═ 8.3Hz,2H),4.97(d, J ═ 12.8Hz,1H),4.76-4.72(m,1H),4.54-4.51(m,1H),4.31(m,1H),3.83 (m,1H),2.36(s,3H),1.99-1.91(m, 1H), 1.63-4.77 (m,1H), 1.46-1H (m, 46 ppm; LCMS RT ═ 4.31(M + H) 590.5.

Formation of 3- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) propane-1, 2-diol (718)

To a solution of 3- ((1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) propane-1, 2-diol 58d (0.11g, 0.18mmol) in MeOH (5mL) was added sodium methoxide (2mL of a 25% w/v solution, 9.26mmol) and the reaction mixture was stirred at room temperature. After 20min, the reaction mixture was diluted with saturated aqueous NH4Cl solution and extracted twice with 20% IPA/CH2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification was by silica gel chromatography using a gradient of 5-20% MeOH: CH2Cl2 to obtain 56mg of a white solid.

1H NMR (300MHz, d6-DMSO) δ 12.29(s,1H),8.71(t, J ═ 2.3Hz,1H),8.27(d, J ═ 2.4Hz,1H),8.19(dd, J ═ 2.8,4.5Hz,1H),8.15(t, J ═ 3.7Hz,1H),7.52(t, J ═ 7.7Hz,1H),4.97(d, J ═ 16.0Hz,1H),4.77(dd, J ═ 3.8,10.5Hz,1H),4.54(t, J ═ 5.6Hz,1H),4.32(m,1H),3.86(m,1H), 2.00-1.97(m,2H),1.82-1.63(m,4H) and 1.59(m, 4H); LCMS RT ═ 3.71(M +1) 436.48.

General scheme 59

(a) Benzyloxy phosphonyl oxygen toluene, triethylamine, 95 degree centigrade, microwave; (b) NaOMe, MeOH

Formation of dibenzyl (1S,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl phosphonate and dibenzyl (1R,3S) -3- (2- (5-chloro-1-methanesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl phosphonate (59a and 59b)

To a solution of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanone 28a (0.40g, 0.78mmol) in benzyloxyphosphonoxytoluene (2.58mL, 11.67mmol) was added triethylamine (0.22mL, 1.56 mmol). The reaction mixture was heated for 15h to 95 ℃. The mixture was diluted with saturated aqueous NaHCO3, extracted with EtOAc, and washed with saturated aqueous NaHCO 3. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to a white solid. The crude product was purified by silica gel chromatography using a gradient of 0-10% MeOH in CH2Cl2 to give 518mg of a mixture of diastereomers, which contained some benzyloxyphosphonotoluene. The mixture was used directly in the next step without further purification. LCMS RT ═ 4.6(M + H) 776.32.

Formation of dimethyl (1S,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl phosphonate and dimethyl (1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl phosphonate (741, 742)

To (1R,3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-dibenzyloxyphosphonyl-cyclohexanol and (1S,3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-dibenzyloxy ] in MeOH was added sodium methoxide, and the reaction was stirred at room temperature. After 15min, the reaction mixture was diluted with saturated aqueous NH4Cl solution and extracted twice with 20% IPA/CH2Cl 2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography using 0-5% MeOH CH2Cl2 to elute impurities, using 5% -10% to elute the bottom two light spots.

diastereomer 1[741] 1H NMR (300MHz, DMSO) δ 12.32(s,1H), 8.70(d, J ═ 2.4Hz,1H),8.27(d, J ═ 2.4Hz,1H),8.26(d, J ═ 2.8Hz,1H), 8.18(d, J ═ 3.9Hz,1H),7.34(d, J ═ 7.1Hz,1H),5.77(d, J ═ 2.9Hz,1H),4.60(s,1H),3.73(dd, J ═ 10.1,6.3Hz,6H),2.30-2.15(m, 1H),2.04-1.86(m,1H),1.85-1.50(m, 6H); LCMS RT ═ 3.82(M +1) 470.5.

Diastereomer 2[742] 1H NMR (300MHz, DMSO) δ 12.30(s, 1H),8.75(d, J ═ 2.4Hz,1H),8.27(d, J ═ 2.4Hz,1H),8.18(d, J ═ 2.8Hz,1H), 8.14(d, J ═ 4.0Hz,1H),7.44(d, J ═ 7.7Hz,1H),5.38(s,1H), 4.55-4.36(m,1H),3.71(d, J ═ 3.1Hz,3H),3.68(d, J ═ 3.2Hz,3H), 2.16-2.01(m,2H),2.00-1.72(m,3H),1.71-1.41(m,2H), 1.39-1H (m, 1H); LCMS RT ═ 3.70(M +1) 470.5.

General scheme 60

Formation of ethyl 2- ((1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxy-cyclohexyl) acetate (60a)

Zinc dust (1.61g, 24.62mmol) was heated with a hot air gun under N2. THF (8.0mL) was added, followed by a solution of chloro (trimethyl) silane (0.63mL, 4.93mmol) in THF (8.0mL) and stirred at room temperature for 15min, then heated to reflux. After cooling to room temperature, a solution of ethyl 2-bromoacetate (2.73mL, 24.62mmol) in THF (6.0mL) was slowly added to the zinc mixture. Then, a solution of (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone 29b (2.00g, 8.21mmol) in THF (6.0mL) was added. The mixture was refluxed for 2h and then concentrated in vacuo. EtOAc and saturated aqueous NaHCO3 were added and the product was extracted with EtOAc (3 ×), dried (Na2SO4) and concentrated in vacuo. The 2 products were isolated by silica gel chromatography (hexane: EtOAc). The first peak was 60a (2.05g, 6.18mmol, 75%). LCMS +:332.20, 3.57min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of ethyl 2- ((1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetate (60c)

To a solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.31g, 0.72mmol) in acetonitrile (6.0mL) was added ethyl 2- ((1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxy-cyclohexyl) acetate 60a (0.20g, 0.60mmol) and degassed under N2. Na2CO3(0.90mL of 2M, 1.81mmol) was added followed by Pd (PPh3)4(0.10g, 0.09 mmol). The reaction was sealed and microwave heated at 120 ℃ for 30 min. The material was concentrated under reduced pressure, then diluted in EtOAc and saturated aqueous NaHCO3, then extracted with EtOAc (3 ×), dried (Na2SO4) and concentrated in vacuo. This material was diluted in DCM and silica gel chromatography (hexanes: EtOAc) afforded 217mg of product 60 c. LC MS +:602.49, 4.62min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of 2- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetic acid (60d)

To a solution of ethyl 2- ((1R,3S) -3- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetate, 60c (0.14g, 0.22mmol) in THF (5.0mL) was added LiOH (1.12mL of a 1M aqueous solution, 1.12 mmol). The reaction was heated with microwave at 130 ℃ for 30min, neutralized with HCl (0.56mL of 2M, 1.12mmol) and concentrated under reduced pressure, diluted in toluene and concentrated (2X) to give 60d which was used without further purification. LC MS +:420.30, 3.05min (10-90% MeOH, 3/5 gradient/run, formic acid).

formation of 2- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-ylamino) -1-hydroxycyclohexyl) -N-methylacetamide (751)

To a solution of 2- ((1R,3S) -3- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetic acid 60d (0.032g, 0.076mmol) in MeCN (1.6mL) and DMF (1.6mL) was added HATU (0.058g, 0.152mmol), methylamine (0.154mL of a 2M solution, 0.305mmol) and iPr2NEt (0.053mL, 0.305 mmol). The reaction was heated to 60 ℃ overnight and then concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (water/HCl: MeOH). The pure fractions were combined and concentrated in vacuo to yield 29mg of 751 as the HCl salt.

General scheme 61

Ethyl 2- ((1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) propanoate (61b) (step a):

zinc dust (1.21g, 18.47mmol, 3 equiv.) was heated with a hot air gun under N2. THF (6.0mL) was added, followed by a solution of chloro (trimethyl) silane (0.47mL, 3.69mmol) in THF (6.0mL) and stirred at room temperature for 15min, then heated to reflux and cooled. To the zinc mixture was slowly added a solution of ethyl 2-bromopropionate (3.34g, 18.47mmol) and (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone (61a) (1.50g, 6.16mmol) in THF (6.0 mL). The mixture was refluxed for 2h, then concentrated in vacuo. EtOAc and saturated aqueous NaHCO3 were added and the product was extracted with EtOAc (3 ×), dried (Na2SO4) and concentrated in vacuo. The 2 products were isolated by silica gel chromatography (hexane: EtOAc). The first product was eluted at 20-35% ethyl acetate and the second product was eluted at 35-40%. The fraction of the second product was concentrated in vacuo to yield 760mg of 61 b. LCMS +: 346.23, 3.35min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of ethyl 2- ((1S,3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) propionate (61c)

to a solution of 5-fluoro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.21g, 0.38mmol) in acetonitrile (3.6mL) was added ethyl 2- ((1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxy-cyclohexyl) propionate (61b) (0.12g, 0.35mmol) and degassed under N2. Na2CO3(0.52mL of a 2M aqueous solution, 1.041mmol) was added followed by Pd (PPh3)4(0.06g, 0.052 mmol). The reaction was sealed and heated in a microwave at 120 ℃ for 30 min. The material was concentrated under reduced pressure and then diluted in EtOAc and saturated aqueous NaHCO3, then extracted with EtOAc (3 ×). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. This material was diluted in CH2Cl2 and subjected to silica gel chromatography (hexanes: EtOAc) to yield 200mg of product 61 c. LCMS +: 600.35, 4.22min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of 2- ((1S,3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) propionic acid (61d)

To ethyl 2- ((1S,3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) propionate (61c) (0.20g, 0.33mmol) in THF (3mL) was added LiOH (3mL of a 1M aqueous solution, 3.0 mmol). The reaction was stirred at room temperature for more than 2 days, then neutralized with HCl (1.5mL of 2M, 3.0mmol) and concentrated to dryness, diluted in toluene and concentrated again (2 ×) to give 61d which was used without further purification. LCMS +:418.32, 2.62min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of (4R,5S,7S) -7- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -4-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (967)

To a solution of 2- [ (1S,3S) -3- [ [ 5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] -1-hydroxy-cyclohexyl ] propanoic acid (61d) (0.095g, 0.228mmol) in toluene (5mL) and triethylamine (0.048mL, 0.341mmol) was added (azido (phenoxy) phosphono) phenol (0.059mL, 0.273 mmol). The reaction was heated to 120 ℃ overnight in a sealed tube. The reaction was concentrated in vacuo and purified by reverse phase HPLC (water/HCl: MeOH) to isolate the diastereomer. To remove traces of remaining starting material, the first peak product was diluted in MeOH (1mL) and passed through a PL-HCO3MP SPE cartridge to obtain the free base. This material was then salted (HCl in water) and concentrated in vacuo to yield 16mg of 967 as the HCl salt.

General scheme 62

Formation of ethyl (S) -2- (3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexylidene) acetate (62a)

To a solution of (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone (29b) (2.00g, 8.21mmol) in toluene (40mL) was added ethyl 2-triphenylphosphoranylacetate (4.29g, 12.31 mmol). The reaction was refluxed overnight, then concentrated in vacuo and purified by silica gel chromatography (hexane: EtOAc). The desired product was eluted with 15% ethyl acetate. The clean fractions were combined and concentrated to yield 2.57g of 62 a. LCMS +:314.18, 3.75min (10-90% MeOH, 3/5 gradient/run, formic acid).

Ethyl 2- ((3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1- (nitromethyl) cyclohexyl) acetate (62b)

To a solution of (S) -ethyl 2- (3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexylene) acetate 62a (2.58g, 8.22mmol) in nitromethane (44.53mL, 822.3mmol) was added 1,1,3, 3-tetramethylguanidine (1.55mL, 12.33 mmol). The reaction was refluxed overnight, then concentrated in vacuo and purified by silica gel chromatography (hexanes: EtOAc) followed by a second chromatography (CH2Cl2: 20% MeOH in CH2Cl 2). Fractions containing pure product were combined and concentrated to yield 1.8g of 62 b. LCMS +:375.32, 3.64min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of (7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5] decan-3-one (62c)

To a solution of ethyl 2- ((3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1- (nitromethyl) cyclohexyl) acetate 62b (1.60g, 4.27mmol) in MeOH (20mL) was added raney nickel (0.03g, 0.43 mmol). The reaction was shaken overnight on a Parr apparatus at 40psi H2. The reaction was filtered, concentrated in vacuo and purified by silica gel chromatography (CH2Cl2: 20% MeOH in CH2Cl2) to yield 155mg of 62 c. LCMS +:299.13, 2.87min (10-90% MeOH, 3/5 gradient/run, formic acid).

formation of (7S) -7- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5] decan-3-one (62d)

To a solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.083g, 0.195mmol) in acetonitrile (1.6mL) was added (7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5] decan-3-one (62c) (0.053g, 0.177mmol) and degassed under N2. Aqueous Na2CO3 solution (0.266mL of a 2M solution, 0.5320mmol) was added followed by Pd (PPh3)4(0.031g, 0.027 mmol). The reaction was sealed and heated in a microwave at 120 ℃ for 30min, then concentrated in vacuo. The material was diluted in CH2Cl2 and silica gel chromatography was performed using a hexane: EtOAc gradient, followed by 20% MeOH in CH2Cl 2. The pure fractions were combined and concentrated to yield 91mg of 62 d. LCMS +:569.26, 4.20min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of (7S) -7- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5] decan-3-one (969)

To a solution of (7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -2-azaspiro [4.5] decan-3-one 62d (0.091g, 0.159mmol) in MeOH (2mL) was added NaOMe (2mL of 25% w/v, 9.255 mmol). The reaction was stirred for 0.5h, then concentrated in vacuo. The material was purified by reverse phase HPLC (water/HCl: MeOH) to yield a mixture of diastereomers. Fractions containing pure product were combined and concentrated to yield 50mg of the HCl salt of 969.

General scheme 63

Formation of ethyl 2- ((1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetate (63a)

Zinc dust (1.61g, 24.62mmol) was heated with a hot air gun under N2. THF (8.0mL) was added, followed by a solution of chloro (trimethyl) silane (0.63mL, 4.93mmol) in THF (8.0mL) and stirred at room temperature for 15min, then heated to reflux and cooled. To the zinc mixture was slowly added a solution of ethyl 2-bromoacetate (2.73mL, 24.62mmol) in THF (6.0mL), followed by a solution of (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone 29b (2.00g, 8.21mmol) in THF (6.0 mL). The mixture was refluxed for 2h, then concentrated in vacuo. EtOAc and saturated aqueous NaHCO3 were added and the product was extracted with EtOAc (3 ×), dried (Na2SO4) and concentrated in vacuo. The 2 products were isolated by silica gel chromatography (hexane: EtOAc). Fractions containing the second (minor) peak product were combined and concentrated to yield 470mg of 63 a. LCMS +:332.13, 3.2min (10-90% MeOH, 3/5 gradient/run, formic acid).

formation of (5S,7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-oxa-3-azaspiro [4.5] decan-2-one (63b)

To a solution of ethyl 2- ((1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetate 63a (0.40g, 1.20mmol) in anhydrous MeOH (6mL) was added hydrazine (0.75mL, 23.4 mmol). The reaction was stirred at room temperature overnight and then concentrated under a stream of N2. The reaction was diluted with HCl (20mL of a 1M solution, 20mmol) until acidic and cooled to 0-5 ℃. Then, NaNO2(1.44mL of 1M solution, 1.44mmol) was added slowly. 1:1 benzene CHCl3(20mL) was added and the mixture was stirred. The organic layer was separated and slowly added to refluxing benzene. Reflux for 0.5h, then concentrate. Silica gel chromatography (CH2Cl2: 20% MeOH in CH2Cl2) yielded 92mg of pure product 63 b. LCMS +:301.15, 2.76min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of (5S,7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (63c)

A solution of (5S,9S) -9- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] -1-oxa-3-azaspiro [4.5] decan-2-one 63b (0.049g, 0.163mmol) in DMF (8.2mL) was cooled to 0 ℃. NaH (0.010mg, 0.244mmol) was added followed by MeI (0.011mL, 0.179 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and concentrated in vacuo. Saturated aqueous NaHCO3 was added and the product was extracted with EtOAc (3 ×), washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification using silica gel chromatography (CH2Cl2: 20% MeOH in CH2Cl2) gave 63 b. LCMS +:315.19, 2.83min (10-90% MeOH, 3/5 gradient/run, formic acid).

Formation of (5S,7S) -7- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (63d)

To a solution of 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (0.031g, 0.0724mmol) in acetonitrile (0.570mL) was added (5S,7S) -7- (2-chloro-5-fluoropyrimidin-4-ylamino) -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one 63c (0.019g, 0.060mmol) and degassed under N2. Na2CO3(0.091mL, 2M, 0.1810mmol) was added followed by Pd (PPh3)4(0.010g, 0.009 mmol). The reaction was sealed and heated in a microwave at 120 ℃ for 30 min. The mixture was then concentrated in vacuo. This material was diluted in CH2Cl2 and silica gel chromatography (hexanes: EtOAc followed by 20% MeOH in CH2Cl2) yielded product 63 d. LCMS +:585.25, 4.17min (10-90% MeOH, 3/5 gradient/run, formic acid).

(5S,7S) -7- (2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one (971)

To a solution of (5S,7S) -7- (2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-ylamino) -3-methyl-1-oxa-3-azaspiro [4.5] decan-2-one 63d (0.035g, 0.060mmol) in MeOH (2mL) was added NaOMe (2mL, 25% w/v, 9.255 mmol). The mixture was stirred for 30min, then concentrated in vacuo and purified by reverse phase HPLC (water/HCl: MeOH). The pure fractions were combined and concentrated in vacuo to afford product 971 as the HCl salt.

General scheme 64

Formation of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanone (64a)

5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (2.13g, 4.93mmol) and (3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone in DME (22.2mL) and aqueous Na2CO3 solution (5.13mL of 2M solution, 10.26mmol) were placed in a microwave tube. The mixture was deoxygenated with nitrogen for 20 min. Tetrakis (triphenylphosphine) palladium (0.47g, 0.41mmol) was added to the reaction mixture. The reaction was sealed and heated to 120 ℃ for 30 min. The reaction was diluted with ethyl acetate (40mL) and filtered through celite. The filtrate was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 10-80% EtOAc/hexanes gave (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanone 64 a.

formation of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-trimethylsiloxy-cyclohexanecarbonitrile (64b)

To a solution of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] cyclohexanone 64a (0.58g, 1.13mmol) in CH2Cl2(20mL) was added zinc iodide (0.36g, 1.13mmol) and trimethylsilylcarbonitrile (0.30mL, 2.26mmol) at room temperature. The reaction was refluxed overnight. The mixture was purified by silica gel chromatography to obtain 600mg of (3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-trimethyl-siloxy-cyclohexanecarbonitrile 64 b.

Formation of (1S,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-hydroxy-cyclohexanecarboxylic acid (64c)

(3S) -3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -1-trimethylsiloxy-cyclohexanecarbonitrile 64b (0.57g, 0.93mmol) is heated in HCl (20mL of a 12M solution, 240.0mmol) in a sealed tube at 80 ℃ overnight. The solvent was evaporated and the crude product was purified by preparative HPLC to provide 200mg of (1S,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-hydroxy-cyclohexanecarboxylic acid 64 c.

H NMR(300MHz,MeOD)δ8.70(d,J＝2.2Hz,1H),8.47(s,1H), 8.37(d,J＝2.2Hz, 1H),8.28(d,J＝5.5Hz,1H),5.37-4.57(m,49H), 3.38-3.26(m,26H),2.42(dd,J＝13.3, 4.2Hz,2H),2.15(d,J＝10.4Hz, 1H),2.07-1.87(m,3H),1.77(dd,J＝18.1,8.6Hz,3H)； LCMS:406.35 (M+1)。

Formation of (1S,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -N-ethyl-1-hydroxy-cyclohexanecarboxamide (779)

(1S,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -1-hydroxy-cyclohexanecarboxylic acid 64c (0.040g, 0.090mmol) was dissolved in DMF (3mL), followed by the addition of iPr2NEt (0.047mL, 0.271mmol) and ethylamine (0.135mL of a 2M solution, 0.271mmol), followed by HATU (0.080g, 0.210 mmol). The reaction was stirred at room temperature for an additional 2 h. The solution was evaporated and the product purified by preparative HPLC to give 10mg of (1S,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -N-ethyl-1-hydroxy-cyclohexanecarboxamide 779.

H NMR(300MHz,MeOD)d 8.72(d,J＝2.2Hz,2H),8.48(s,2H), 8.34(dd,J＝23.7, 3.9Hz,3H),4.99(d,J＝5.4Hz,3H),4.88(s,1H), 4.85-4.67(m,32H),3.44-2.95(m,4H), 2.29(dd,J＝13.5,4.1Hz,3H), 2.11(d,J＝9.5Hz,2H),2.04-1.80(m,7H),1.76(s,3H), 1.13(t,J＝7.2 Hz,4H)；LCMS:433.42(M+1)。

General scheme 65

Formation of 3-amino-2-hydroxy-cyclohexanecarboxylic acid (65a)

2-hydroxy-3-nitro-benzoic acid (5.0g, 27.3mmol) and HCl (125mL, 0.5M, 62.5mmol) and platinum oxide (1.0g, 4.4mmol) were combined in a hydrogenation flask. The mixture was placed on a Parr shaker (50psi H2) for 24H. The catalyst was filtered and washed with hot H2O. The filtrate was evaporated to afford 3-amino-2-hydroxy-cyclohexanecarboxylic acid as a mixture of stereoisomers, which was used directly in the next step without further purification.

Formation of 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-cyclohexanecarboxylic acid (65b)

5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridine 65a (0.30g, 0.64mmol), 3-amino-2-hydroxy-cyclohexanecarboxylic acid (0.19g, 0.97mmol), iPr2NEt (0.45mL, 2.58mmol) in DMF (23.2mL) was heated in a microwave at 130 ℃ for 10 min. The solvent of the reaction mixture was removed under reduced pressure and the residue was purified by preparative HPLC to give 240mg of 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-cyclohexanecarboxylic acid 65b as a mixture of stereoisomers.

formation of 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -N-ethyl-2-hydroxy-cyclohexanecarboxamide (65c)

3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-cyclohexanecarboxylic acid 65b (0.100g, 0.179mmol) was dissolved in DMF (2mL) and iPr2NEt (0.124mL, 0.714mmol) and ethylamine hydrochloride (0.029g, 0.357mmol) was added at room temperature. HATU (0.081g, 0.214mmol) was then added to the solution at room temperature. After 30min, EtOAc was added and the mixture was washed with 1N HCl, saturated aqueous NH4Cl solution, and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used directly in the next step without further purification.

Formation of 3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -N-ethyl-2-hydroxy-cyclohexanecarboxamide (815)

3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -N-ethyl-2-hydroxy-cyclohexanecarboxamide 65c was treated with NaOMe in MeOH. The product was purified by preparative HPLC to provide 3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -N-ethyl-2-hydroxy-cyclohexanecarboxamide as a mixture of stereoisomers. LCMS:433.35(M + 1).

General scheme 66

Formation of methyl 1-methyl-2-cyclohexene-1-carboxylate (66a)

freshly distilled N-isopropylpropan-2-amine (4.20mL, 29.96mmol) in THF (150mL) was added dropwise nBuLi (12.65mL of a 2.2M solution, 27.82mmol) at cold (0 ℃ C.) under argon. After 15min, the solution was cooled to-78 ℃ and anhydrous HMPA (4.84mL, 27.82mmol) was added. The mixture was stirred at-78 ℃ for 30min, then cyclohexene-1-carboxylic acid methyl ester (3.00g, 21.40mmol) was added. After stirring for a further 10min, iodomethane (2.00mL, 32.10mmol) was added. Then the solution was warmed to-5 ℃ over 2 h. A saturated aqueous solution of NH4Cl was poured into the orange mixture. After dilution with hexane and washing with brine, the organic layer was dried over Na2SO4 and carefully evaporated to yield 3.3g of methyl 1-methyl-2-cyclohexene-1-carboxylate 66a used without further purification.

H NMR(300MHz,CDCl3)δ5.77(dt,J＝10.1,3.5Hz,1H),5.66 (s,1H),3.71-3.58 (m,3H),2.16(ddd,J＝12.9,7.0,3.4Hz,1H),2.03- 1.88(m,2H),1.72-1.53(m,2H),1.49- 1.37(m,1H),1.32-1.14(m, 3H)。

Formation of racemic cis-5-methyl-7-oxabicyclo [4.1.0] heptane-5-carboxylic acid methyl ester (66b)

Methyl 1-methyl-2-cyclohexene-1-carboxylate 66a (3.30g, 21.40mmol) was treated with 3-chloroperoxybenzoic acid (7.39g, 42.80mmol) in CH2Cl2(75mL) at room temperature for 2 h. The solution was clear, but a white precipitate was observed after 1 h. The resulting white solid was filtered and washed with hexane, and the filtrate was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, then brine. The organic phase was then dried over Na2SO4, concentrated in vacuo and the crude residue was purified by silica gel chromatography (hexane/ethyl acetate 100/0 to 10/1 gradient) to afford two products. The weakly polar light spot was a colorless oil, determined by 1H NMR to be cis-5-methyl-7-oxabicyclo [4.1.0] heptane-5-carboxylic acid methyl ester (1.2g), and the second fraction was a white solid which was trans-5-methyl-7-oxabicyclo [4.1.0] heptane-5-carboxylic acid methyl ester (2.2 g).

Racemic cis isomer (66b) 1H NMR (300MHz, CDCl3) δ 3.67(d, J ═ 4.3Hz,3H), 3.23-3.12 (m,1H),3.08(d, J ═ 3.8Hz,1H), 2.02-1.78 (m,2H),1.68(dtd, J ═ 9.7,6.8,3.2Hz,1H), 1.49-1.27 (m,2H), 1.25-1.15 (m,3H),1.06(ddd, J ═ 9.1,7.4,3.2Hz, 1H).

Formation of racemic methyl 3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylate (66c)

Racemic cis-5-methyl-7-oxabicyclo [4.1.0] heptane-5-carboxylic acid methyl ester 66b (2.2g, 12.93mmol) was added under nitrogen to a flask containing MeOH (90mL) and H2O (10 mL). NH4Cl (1.38g, 0.90mL, 25.86mmol) and NaN3(2.52g, 38.79mmol) were then added to the reaction mixture. The mixture was heated to reflux for 16 h. The solvent was evaporated under reduced pressure and the oil was added to H2O and extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO 4. The crude product was purified by silica gel chromatography to obtain 900mg of racemic 3-azido-2-hydroxy-1-methyl-cyclohexanecarboxylic acid methyl ester.

H NMR(300MHz,CDCl3)δ3.74(d,J＝3.1Hz,3H),3.64–3.43 (m,2H),3.25–3.05 (m,1H),2.25–2.09(m,1H),2.00(ddd,J＝9.7,4.8, 2.9Hz,1H),1.73–1.50(m,1H),1.40(d, J＝6.3Hz,3H),1.32–1.03(m, 3H)。

Racemic methyl 3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate (66d)

A solution of racemic 3-azido-2-hydroxy-1-methyl-cyclohexane-carboxylic acid methyl ester 66c (0.90g, 4.22mmol) in a mixture of MeOH (50mL) and AcOH (10mL) was stirred under hydrogen (balloon) in the presence of palladium (0.50g, 0.47mmol) at room temperature overnight. The mixture was filtered through a celite bed and washed with MeOH. The combined filtrates were evaporated to give methyl 3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylate as an oil. Et2O was added and the resulting acetate salt was stirred for 0.5h and then filtered to give 1.0g of racemic 3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylic acid methyl ester acetate as a white solid.

Formation of racemic 3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid methyl ester (66e)

To 2, 4-dichloro-5-fluoro-pyrimidine (0.43g, 2.58mmol) and racemic 3-amino-2-hydroxy-1-methyl-cyclohexanecarboxylic acid methyl ester acetate 66d (0.58g, 2.35mmol) in THF (10mL) and MeOH (8mL) was added iPr2NEt (1.23mL, 7.04mmol) at room temperature. After stirring the reaction at room temperature overnight, the solvent was evaporated under reduced pressure and the crude residue was purified by silica gel chromatography (hexane/EtOAc 100/0 to 0/100, Rf ═ 0.7 at hexane/EtOAc 2/1) to afford 650mg of rac-3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid methyl ester 66e as a white solid. LCMS:318.16(M + 1).

formation of racemic methyl 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylate (66f)

To a solution of rac-3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid methyl ester 66e (0.65g, 2.05mmol) and 5-chloro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine (1.32g, 3.05mmol) in THF (20mL) was added an aqueous Na2CO3 solution (3.52mL of a 2M solution, 7.04 mmol). The solution was degassed with N2 for 20 min. Tetrakis (triphenylphosphine) palladium (0) (0.14g, 0.12mmol) was added and the mixture was refluxed overnight. LCMS showed good conversion, but some starting material remained. More degassed 2N Na2CO3 was added followed by another portion of tetrakis (triphenylphosphine) palladium (0) (0.14g, 0.12 mmol). The reaction was refluxed for an additional 4 h. The mixture was cooled to rt and extracted with EtOAc. The organic phase was washed with brine and dried over Na2SO 4. After evaporation of the solvent, the crude mixture was purified by silica gel chromatography (hexane/EtOAc 100/0 to 0/100) to afford 1.0g of racemic methyl 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylate 66 f. LCMS: 588.26(M + 1).

Formation of (1S,2S,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid (928)

Racemic methyl 3- [ [2- [ 5-chloro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylate 66f (0.100g, 0.170mmol) was dissolved in MeOH (1mL) and THF (1mL) and treated with aqueous LiOH (0.24mL of a 1M solution, 0.24mmol) and heated to reflux overnight. The reaction was allowed to cool to room temperature and the resulting material was directly purified by preparative HPLC to obtain 20mg of racemic 3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid. The enantiomers of the racemic material were separated by chiral SFC purification to obtain 6mg of (1R,2R,3R) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid and 6mg of (1S,2S,3S) -3- [ [2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoro-pyrimidin-4-yl ] amino ] -2-hydroxy-1-methyl-cyclohexanecarboxylic acid. LCMS:420.36(M + 1).

General scheme 67

(a) Pd/C (wet, Degussa), hydrogen, EtOH; (b) refluxing 2, 4-dichloro-5-fluoropyrimidine, iPr2NEt and THF; (c) LiOH, THF/water, 50 ℃; (d) DPPA, Et3N, THF, 85 ℃; (e) 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, XPhos, Pd2(dba)3, K3PO4, 2-methyl THF, water, 125 ℃ (f)

Formation of ethyl (1R,3S) -3-aminocyclohexanecarboxylate (67b)

To a solution of (1R,3S) -3- (benzyloxycarbonylamino) cyclohexane-carboxylic acid ethyl ester 18b (14.0g, 45.9mmol) in ethanol (3mL) was added Pd/C (wet, Degussa (2.4g, 2.3mmol) the mixture was evacuated and then stirred at room temperature under nitrogen overnight the reaction mixture was filtered through a pad of celite and the resulting filtrate was concentrated in vacuo to afford an oil which was used without further purification.

formation of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-carboxylic acid ethyl ester (67c)

To a solution of ethyl (1R,3S) -3-aminocyclohexanecarboxylate 67b (5.1g, 24.1mmol) and 2, 4-dichloro-5-fluoropyrimidine (6.0g, 36.0mmol) in THF (60mL) was added diisopropylethylamine (9.6mL, 55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to provide 6.7g of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-carboxylic acid ethyl ester as a white solid: LCMS RT ═ 3.1 (M + H) 302.2.

Formation of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexanecarboxylic acid (67d)

To a solution of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-carboxylic acid ethyl ester 67c (20.0g, 66.3mmol) in THF (150mL) was added a solution of LiOH hydroxide (8.3g, 198.8mmol) in 100mL water. The reaction mixture was stirred at 50 ℃ overnight. To the reaction mixture was added HCl (16.6mL of 12M solution, 198.8mmol) and EtOAc. The organic phase was washed with brine and dried over MgSO4, and the solvent was removed under reduced pressure to obtain 17.5g of the product used without further purification: 1H NMR (300MHz, CDCl3) δ 7.91(d, J ═ 2.7Hz,2H),5.24(d, J ═ 7.3Hz,2H), 4.19-4.03 (m,3H), 3.84-3.68 (m,3H),2.59(ddd, J ═ 11.5,8.2,3.6Hz,2H),2.38(d, J ═ 12.4Hz, 2H),2.08(d, J ═ 9.6Hz,6H), 1.99-1.76 (m,5H), 1.63-1.34 (m,6H), 1.32-1.15 (m, 4H).

Formation of N- ((1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexyl) -pyrrolidine-1-carboxamide (67e)

A solution of (1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexane-carboxylic acid 67d (8.2g, 30.0mmol), (azido (phenoxy) phosphono) phenol (9.7mL, 45.0mmol), and triethylamine (5.8mL, 42.0mmol) in THF (200mL) was degassed under nitrogen for 15 min. The reaction mixture was heated at 85 ℃ for 30min until LC/MS showed complete consumption of carboxylic acid 67 d. Pyrrolidine (7.5mL, 90.0mmol) was added to the reaction mixture and the reaction was heated at 85 ℃ for an additional 15 min. The mixture was diluted in brine and extracted with EtOAc. The organic phase was separated and dried over MgSO 4. The product was isolated by filtration after partial removal of the solvent in vacuo (6.25 g): 1H NMR (300MHz, CDCl3) δ 7.87(d, J ═ 2.8Hz,2H),5.04(d, J ═ 8.1Hz,2H), 4.09(ddd, J ═ 26.9,13.4,5.6Hz,4H), 3.91-3.71 (m,2H),3.32 (t, J ═ 6.5Hz,7H),2.45(d, J ═ 11.5Hz,2H),2.08(dd, J ═ 22.1,12.0Hz, 4H), 1.96-1.82 (m,9H),1.54(dd, J ═ 18.6,8.5Hz,2H), 1.22-1.01 (m, 6H).

Formation of N- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cyclohexyl) pyrrolidine-1-carboxamide (67f)

A solution of N- ((1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexyl) -pyrrolidine-1-carboxamide 67e (6.8g, 20.0mmol), 5-fluoro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine 44a (12.5g, 30.0mmol) and K3PO4(17.0g, 80.0mmol) in 2-methyl THF (180mL) and water (20mL) was degassed under nitrogen for 30 min. Dicyclohexyl- [2- (2,4, 6-triisopropylphenyl) phenyl ] phosphine (XPhos) (1.1g, 2.4mmol) and Pd2(dba)3(0.5g, 0.5mmol) were added to the mixture. The reaction mixture was heated at 125 ℃ for 2.5h in a high pressure gas cylinder. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (8% MeOH/CH2Cl2) to afford 11.5g of the desired product: 1H NMR (300MHz, CDCl3) δ 8.54(s,1H),8.49(dd, J ═ 9.0,2.8Hz,1H), 8.32(d, J ═ 2.1Hz,1H),8.13(d, J ═ 8.3Hz,2H),8.07(d, J ═ 3.2Hz,1H), 7.30(d, J ═ 8.5Hz,2H),4.98(d, J ═ 6.3Hz,1H), 4.37-4.16 (m,1H), 4.08(d, J ═ 7.3Hz,1H), 3.99-3.80 (m,1H),3.33(t, J ═ 6.5Hz, 4H),2.52(d, J ═ 11.6, 1H),2.39(s, 3.81H), 2.31H (d, 1H), 1H), 1H (d, 1H), 1H.

Formation of N- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -pyrimidin-4-ylamino) cyclohexyl) pyrrolidine-1-carboxamide (895)

To a solution of N- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cyclohexyl) pyrrolidine-1-carboxamide 67f (11.5g, 19.3mmol) in THF (150mL) was added sodium methoxide (4.173g, 19.31 mmol). After stirring the reaction mixture for 2min, the mixture was poured into a saturated aqueous solution of NaHCO 3. The organic phase was washed with brine, dried over MgSO4 and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (10% MeOH/CH2Cl2) to obtain 6.5g of the desired product. The product was converted to the HCl salt by dissolving in MeOH (100mL) at room temperature and adding 2.4mL of 12M HCl solution. The solution was stirred for 1h, the HCl salt precipitated and filtered to provide 7.05g of HCl salt: 1H NMR (300MHz, DMSO) δ 9.36(s,2H),9.05(d, J ═ 3.0Hz, 2H),8.49(d, J ═ 5.6Hz,2H),8.41(dd, J ═ 2.6,1.4Hz,2H),8.31(d, J ═ 9.5Hz,2H),5.92(s,3H),4.24(s,3H),3.64(s,2H),3.18(t, J ═ 6.6Hz, 7H),2.07(dt, J ═ 22.7,11.5Hz,4H),1.87(t, J ═ 12.6Hz,4H),1.77 (dd, J ═ 8.0,5.3Hz,7H), 1.65-1.13 (m, 8H).

general scheme 68

(a) TsCl, NaH, DMF, 45 ℃; (b) methyl iodide, K2CO3, DMF; (c) bromine, CHCl3, 0 ℃ to room temperature; (d) bis (pinacolato) diborane, palladium (II) dichlorobis (tricyclohexylphosphine), KOAc, 2-methyl THF, 125 ℃; (e) (R) -N- ((1R,3S) -3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) -3-fluoropyrrolidine-1-carboxamide, XPhos, Pd2(dba)3, K3PO4, 2-methyl THF, water, 125 ℃ C

Formation of 5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-ol (68a)

to a solution of 5-fluoro-1H-pyrrolo [2,3-b ] pyridin-4-ol (1.2g, 7.9mmol) in 80mL of DMF at 0 deg.C was added tosyl chloride (1.8g, 9.5mmol) followed by NaH (0.8g, 19.7mmol, 60% w/w). After 3h the reaction was slowly warmed to 45 ℃ and stirred for an additional 3 h. The mixture was then concentrated in vacuo. The crude oil was diluted in 100mL EtOAc and washed with water (2 × 50mL) and brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10% EtOAc/hexanes) to give 1.5g of the desired product.

formation of 5-fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b ] pyridine (68b)

To a solution of 5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-4-ol 68a (0.70g, 2.29mmol) in DMF (25mL) was added iodomethane (0.14mL, 2.29mmol) and K2CO3(0.32g, 2.29 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction was diluted with deionized water and EtOAc. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 720mg of the desired product, which was used in the next step without further purification.

Formation of 5-fluoro-4-methyl-3-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridine (68c)

To a cold (0 ℃) solution of 5-fluoro-4-methyl-1-tosyl-1H-pyrrolo [2,3-b ] pyridine 68b (0.79g, 2.45mmol) in chloroform (50mL) was added bromine (0.13mL, 2.45 mmol). The reaction mixture was stirred at 0 ℃ for 3h, then slowly warmed to ambient temperature. The mixture was diluted with deionized water and quenched with aqueous sodium carbonate. The liquid phase was extracted with dichloromethane and dried with sodium sulfate. The resulting solid was purified by silica gel chromatography (15-30% EtOAc/hexanes) to yield 170mg of the desired product.

Formation of 5-fluoro-4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-methanesulfonyl-1H-pyrrolo [2,3-b ] pyridine (68d)

To a solution of 5-fluoro-4-methyl-3-bromo-1-tosyl-1H-pyrrolo [2,3-b ] pyridine 68c (0.17g, 0.43mmol) in 2-Me-THF (9mL) in a microwave vial was added bis (pinacol) diborane (0.16g, 0.64mmol), followed by potassium acetate (0.23g, 1.06mmol) and palladium (II) dichlorobis (tricyclohexylphosphine) (0.02g, 0.02 mmol). The reaction flask was sealed and irradiated with microwaves at 125 ℃ for 90 min. The mixture was filtered and purified by silica gel chromatography (10-30% EtOAc/hexanes) to obtain 100mg of the desired product.

Formation of (R) -3-fluoro-N- ((1R,3S) -3- ((5-fluoro-2- (5-fluoro-4-methyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl) pyrrolidine-1-carboxamide (1104):

To a solution of 5-fluoro-4-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine 68d (0.100g, 0.220mmol) in 2-Me-THF (2mL) was added (R) -N- ((1R,3S) -3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexyl) -3-fluoropyrrolidine-1-carboxamide (0.060g, 0.170 mmol). Potassium phosphate (0.130g, 0.600mmol) and deionized water (0.5mL) were then added and the solution degassed under a stream of nitrogen for 10 min. 2-dicyclohexylphosphine-2 ', 4 ', 6 ' -triisopropyldiphenyl (XPhos) (0.006g, 0.012mmol) and tris (dibenzylideneacetone) -dipalladium (0) (0.023mg, 0.026mmol) were then added and the solution degassed under a stream of nitrogen for a further 5 min. The vial was sealed and heated for 3h to 80 ℃. The solution was cooled to ambient temperature and filtered and concentrated in vacuo. The crude oil was dissolved in anhydrous THF (5mL) and 2N LiOH solution (2mL) was added. The reaction mixture was heated for 2h to 80 ℃. The solution was cooled to ambient temperature and concentrated in vacuo. Purification by preparative HPLC afforded 6mg of the desired product.

General scheme 69

(a) NaCN, LiClO4, CH3 CN; (b) 5-fluoro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine, Na2CO3, Pd (PPh3)4, dimethoxyethane, 120 ℃; (c) sodium methoxide, MeOH

Formation of 2- ((1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxy-cyclohexyl) -acetonitrile (69a)

A suspension of 49c (0.50g, 1.94mmol) 2-chloro-5-fluoro-N- [ (3S) -1-oxaspiro [2.5] octan-7-yl ] pyrimidin-4-amine, NaCN (0.11g, 2.33mmol) and lithium perchlorate (0.25g, 2.33mmol) in CH3CN was heated at 100 ℃ for 3h in a pressure tube. The mixture was diluted in EtOAc and the organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc/hexanes) to afford the desired product: 1H NMR (300.0MHz, CDCl3) δ 7.78(d, J ═ 2.7Hz, 1H),4.85(d, J ═ 6.6Hz,1H),4.28(qn, J ═ 4.0Hz,1H),2.45(s,2H), 2.16(d, J ═ 13.0Hz,1H),2.05(d, J ═ 11.7Hz,1H),1.80-1.71(m,3H), 1.46-1.28(m,2H) and 1.17-1.06(m,1H) ppm; LCMS RT ═ 2.15(M + H) 285.34.

Formation of 2- ((1S,3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetonitrile (69b)

A solution of 5-fluoro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine 44a (0.23g, 0.55mmol), 2- ((1S,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) -1-hydroxycyclohexyl) -acetonitrile 69a (0.14g, 0.50mmol), and Na2CO3(0.75mL of a 2M solution, 1.50mmol) in dimethoxyethane (15mL) with nitrogen was degassed for 30 min. Palladium, triphenylphosphine (0.03g, 0.03mmol) were added to the reaction mixture and degassing of the solution was continued for 15 min. The reaction mixture was heated at 120 ℃ in a pressure tube for 45 min. The reaction mixture was filtered through celite and the filtrate was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (40% EtOAc/hexanes) to obtain 150mg of the desired product: LCMS RT ═ 3.55(M + H) 539.42.

2- ((1S,3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetonitrile (979)

To a solution of 2- ((1S,3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) -1-hydroxycyclohexyl) acetonitrile 69b (0.14g, 0.26mmol) in methanol (10mL) was added sodium methoxide (0.06g, 0.26 mmol). After stirring at room temperature for 2min, the reaction mixture was diluted in EtOAc and brine. The separated organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (10% MeOH/CH2Cl2) to yield 46mg of the desired product: 1H NMR (300.0MHz, MeOD) δ 8.65(dd, J ═ 2.8,9.6Hz,1H),8.19(s,1H), 8.14(dd, J ═ 2.0,2.5Hz,1H),7.98(d, J ═ 4.1Hz,1H),4.66(dd, J ═ 8.0, 15.8Hz,1H),2.64(s,2H),2.20(d, J ═ 12.6Hz,2H),2.01(dd, J ═ 3.4, 9.8Hz,2H),1.84-1.75(m,1H),1.63-1.47(m,2H),1.33(dd, J ═ 3.6, 12.4Hz,1H) ppm; LCMS RT ═ 2.31(M + H) 385.45.

General scheme 70

(a) Tert-butyl N- (N-tert-butoxycarbonyl-C-pyrazol-1-yl-carbo-imino) carbamate, CH2Cl 2; (b) 5-fluoro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine, Na2CO3, Pd (PPh3)4, dimethoxyethane, 120 ℃; (c) sodium methoxide, THF, MeOH

Formation of tert-butyl (tert-butoxycarbonylamino) ((1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexylamino) methylenecarbamate (70b)

To a solution of (1S,3R) -N1- (2-chloro-5-fluoro-pyrimidin-4-yl) cyclohexane-1, 3-diamine 70a (0.122g, 0.500mmol) in CH2Cl2(10mL) was added tert-butyl N- (N-tert-butoxycarbonyl-C-pyrazozol-1-yl-carbo-imino) carbamate (0.155g, 0.500 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo and used without further purification: 1H NMR (300MHz, CDCl3) δ 11.51(s,3H),8.29(d, J ═ 8.3Hz, 3H),7.88(d, J ═ 2.8Hz,3H),5.01(d, J ═ 7.4Hz,3H),4.28 to 4.18(m, 4H),2.48(d, J ═ 11.7Hz,3H),2.12(d, J ═ 9.4Hz,3H),1.87(dd, J ═ 10.3,3.5Hz,3H),1.52(s,24H),1.50(s,25H),1.24 to 1.10(m, 8H); LCMS RT ═ 3.97(M + H) 487.12.

Formation of N- [ N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] carboxamidine ] -carbamic acid tert-butyl ester (70c)

A solution of (Z) - (tert-butoxycarbonylamino) ((1R,3S) -3- (2-chloro-5-fluoropyrimidin-4-ylamino) cyclohexylamino) methylene carbamic acid tert-butyl ester 70b (0.200g, 0.411mmol), 5-fluoro-1- (p-toluenesulfonyl) -3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrrolo [2,3-b ] pyridine 44a (0.205g, 0.493mmol), and Na2CO3(0.616mL of a 2M solution, 1.232mmol) in dimethoxyethane (15mL) was degassed for 30 min. Palladium triphenylphosphine (0.023g, 0.021mmol) was added to the mixture and the reaction mixture was heated in pressure tube at 120 ℃ for 45 min. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. An attempt was made to purify the resulting residue by silica gel chromatography (10% MeOH/CH2Cl2) to yield a mixture containing predominantly the desired product, which was used without further purification: LCMS RT ═ 2.30(M + H) 641.02.

formation of 1- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cyclohexyl) guanidine (1143)

to a solution of tert-butyl N- [ N- [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] formamidine ] carbamate 70c (0.100g, 0.156mmol) in THF (20mL) was added sodium methoxide (0.033g, 0.156mmol) at room temperature. After 1min, the reaction mixture was diluted in EtOAc and saturated aqueous NaHCO 3. The organic phase was dried over MgSO4, filtered and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography to obtain 95mg of the desired product. To a 10mL solution of the product in MeOH was added hydrochloride/IPA (0.031mL of a 5M solution, 0.156 mmol). The reaction mixture was stirred at room temperature for 1h, after which the solvent was removed under reduced pressure to obtain the product as the hydrochloride salt: 1H NMR (300MHz, MeOD) δ 8.63(s,1H),8.40(dd, J ═ 9.1,2.7Hz, 1H),8.36(s,1H),8.32(d, J ═ 5.5Hz,1H),4.46(d, J ═ 11.7Hz,1H), 3.78-3.53 (m,1H),2.41(d, J ═ 11.7Hz,1H),2.28(d, J ═ 12.0Hz,1H), 2.18-1.98 (m,2H),1.69(dd, J ═ 23.6,11.8Hz,2H), 1.56-1.28 (m, 2H); LCMS RT ═ 1.45(M + H) 387.06.

General scheme 71

(a) DBU, 2-chloro-oxazole-4-carboxylic acid methyl ester, DMF, 75 ℃; (b) LiOH, THF

Formation of methyl 2- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cyclohexylamino) oxazole-4-carboxylate (71a)

To a solution of (1S,3R) -N1- [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] cyclohexane-1, 3-diamine 44e (0.089g, 0.178mmol) in DMF (1.5mL) was added methyl 2-chlorooxazole-4-carboxylate (0.031g, 0.195mmol) followed by DBU (0.029mL, 0.195 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was warmed to 75 ℃ and allowed to stir for 3 h. An additional 16mg of benzoxazole ester was added and the reaction was heated at 75 ℃ overnight. The mixture was diluted in water and EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2) to afford 28mg of the desired product: LCMS RT ═ 3.73(M +1) 624.12.

Formation of 2- ((1R,3S) -3- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) cyclohexylamino) oxazole-4-carboxylic acid (1144)

to a solution of methyl 2- [ [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] -amino ] oxazole-4-carboxylate 71a (0.028g, 0.045mmol) in THF (1mL) was added LiOH (1mL of a 1M solution, 1.000mmol) and the reaction mixture was warmed to 130 ℃ by microwave irradiation. After heating and stirring for 20min, the mixture was cooled to room temperature. All volatiles were removed under a stream of nitrogen and hot gas. The crude residue was suspended in MeOH and several drops of trifluoroacetic acid (solution formed) were added to the protonated molecules. The mixture was filtered and purified by reverse phase HPLC (5-95% CH3CN/H2O) to obtain 5mg of the desired product as a TFA salt: 1H NMR (300MHz, MeOD) δ 8.83(s,1H), 8.67-8.09 (m,4H),2.67(s,3H),2.18(m,5H),1.34(d, J ═ 29.6Hz, 3H); LCMS RT ═ 1.78(M +1) 456.07.

General scheme 72

(a) NaHCO3, Br2, H2O; (b) NaOH; (c) TMSCl, MeOH; (d) sodium methoxide, MeOH, 150 ℃; (e) sodium borohydride, MeOH; (f)2- (tert-butoxycarbonylamino) -2-oxo-acetic acid ethyl ester, DEAD, PPh3, 85 ℃; (g) NaOH, MeOH; (h) trifluoroacetic acid, CH2Cl2, 1N HCl/ether; (i) 5-fluoro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, iPr2NEt, THF; (j) lithium hydroxide, THF; (k) DPPA, Et3N, pyrrolidine

Formation of 6-bromohexahydro-2H-3, 5-methylenecyclopenta [ b ] furan-2-one (72a)

To a solution of bicyclo [2.2.1] hept-5-ene-3-carboxylic acid (25.0mL, 204.3mmol) in aqueous NaHCO3(51.5g, 612.9mmol) was added dropwise bromine (32.7g, 204.3mmol) at 0 deg.C. The solution was stirred for 1h and extracted with ether, and the organic phase was washed successively with a 1N Na2S2SO3 solution and brine, then dried (Na2SO4), filtered and concentrated in vacuo to obtain 30g of crude product used without further purification.

Formation of 6-oxonorbornane-2-carboxylic acid (72b)

6-Bromohexahydro-2H-3, 5-methylenecyclopenta [ b ] furan-2-one 72a (28.0g, 129.0mmol) was treated with NaOH (258.0mL of a 2M solution, 516.0mmol) in H2O (350mL) at room temperature for 2H. The reaction mixture was acidified with concentrated HCl and extracted with Et 2O. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% MeOH in CH2Cl2 gradient) to provide 16g of 6-oxonorbornane-2-carboxylic acid.

Formation of endo-6-oxonorbornane-2-carboxylic acid methyl ester (72c)

A solution of 6-oxonorbornane-2-carboxylic acid 72b (16.0g, 103.8mmol) in methanol (350.0mL) was treated with TMSCl (42.04g, 49.11mL, 387.0 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (10% EtOAc/hexanes) to provide 12g of endo-6-oxonorbornane-2-carboxylic acid methyl ester.

Formation of exo-6-oxonorbornane-2-carboxylic acid methyl ester (72d)

Internal 6-oxonorbornane-2-carboxylic acid methyl ester 72c (3.5g, 20.8mmol) was heated in sodium methoxide (2.1mL of a 2M solution in methanol, 4.2mmol) in a sealed tube at 150 ℃ for 17 h. The solvent was evaporated and the crude product was purified by silica gel chromatography (0-16% EtOAc/hexanes gradient) to obtain 3.3g of the starting endo-6-oxonorbornane-2-carboxylic acid methyl ester (PMA staining) as a first fraction and 4.0g of the desired exo-product as a second spot. The recovered starting material was again treated under the same conditions to regenerate 1.0g of the desired appearance product.

Formation of methyl 6-hydroxynorbornane-2-carboxylate (72e)

To a solution of exo 6-oxonorbornane-2-carboxylic acid methyl ester 72d (4.7g, 27.9mmol) in MeOH (50mL) at 0 deg.C was added 5 parts sodium borohydride (1.6g, 41.9 mmol). TLC after 2h showed complete conversion. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. MeOH was evaporated under reduced pressure, and the liquid phase was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes, Rf 0.5, 50% EtOAc/hexanes) to give 3.96g of the desired product: 1H NMR (300MHz, CDCl3) δ 4.23-4.06(m,1H),3.56(s,3H),3.37 (s,1H),3.03(dd, J ═ 8.9,5.5Hz,1H),2.41(d, J ═ 3.9Hz,1H),2.13(s, 1H),1.93-1.69(m,2H),1.63-1.42(m,1H),1.34(ddt, J ═ 10.3,3.2,1.6 Hz,1H),1.20(dd, J ═ 10.4,0.7Hz,1H),0.77(dt, J ═ 12.6,3.4Hz, 1H).

Formation of methyl 6- (N- (tert-butoxycarbonyl) -2-ethoxy-2-oxoacetamido) bicyclo [2.2.1] heptane-2-carboxylate (72f)

To a cold (0 ℃ C.) solution of methyl 6-hydroxynorbornane-2-carboxylate 72e (3.2g, 18.8mmol) in THF (150mL) was added ethyl 2- (tert-butoxycarbonylamino) -2-oxo-acetate (4.9g, 22.6mmol) and triphenylphosphine (5.9g, 22.6mmol), followed by dropwise addition of diisopropyl azodicarboxylate (4.5g, 22.6 mmol). The reaction was then heated to 85 ℃ and held at this temperature for 2 days. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 6g of methyl 6- (N- (tert-butoxycarbonyl) -2-ethoxy-2-oxoacetylamino) bicyclo [2.2.1] heptane-2-carboxylate: LCMS 392.34(M + Na +); 1H NMR (300MHz, CDCl3) δ 4.26(q, J ═ 7.2Hz,2H),4.08(dt, J ═ 14.3,7.2Hz,1H),3.62(d, J ═ 2.1Hz,3H),2.72(s,1H), 2.42-2.26 (m,2H), 2.08-1.80 (m,2H), 1.80-1.51 (m,3H),1.45(s,9H), 1.38-1.25 (m, 3H).

Formation of 6- (tert-Butoxycarbonylamino) norbornane-2-carboxylic acid (72g)

To a solution of methyl 6- [ tert-butoxycarbonyl- (2-ethoxy-2-oxo-acetyl) amino ] norbornane-2-carboxylate 72f (0.80g, 2.17mmol) in methanol (20mL) at room temperature was added NaOH (4.33mL of a 2N solution, 8.66 mmol). The reaction mixture was stirred overnight. The mixture was diluted in 0.5N HCl in ice and extracted with EtOAc. The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to obtain 600mg of the desired product which was used without further purification.

Formation of 6-aminobicyclo [2.2.1] heptane-2-carboxylic acid (72h)

a72 g solution of 6- (tert-butoxycarbonylamino) norbornane-2-carboxylic acid in dichloromethane (5mL) was treated with trifluoroacetic acid (5mL) at room temperature for 1 h. The solvent was evaporated under reduced pressure and the resulting product was dissolved in 2mL TFA and added to stirred 1N HCl in Et2O solution. After stirring the mixture for 0.5h, the resulting precipitate was filtered and washed with anhydrous Et2O to give 6-aminobicyclo [2.2.1] heptane-2-carboxylic acid.

Formation of 6- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-ylamino) bicyclo [2.2.1] heptane-2-carboxylic acid (72j)

To a solution of 5-fluoro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine (0.187g, 0.417mmol) and 6-aminobicyclo- [2.2.1] heptane-2-carboxylic acid 72h (0.080g, 0.417mmol) in THF (3mL) was added diisopropylethylamine (0.291mL, 1.670 mmol). The reaction mixture was heated at 80 ℃ overnight. Aqueous LiOH (3mL of a 2M solution, 6.000mmol) was added and the mixture was heated for an additional 7 h. The mixture was diluted with MeOH, neutralized with trifluoroacetic acid, filtered and the resulting filtrate was purified by preparative HPLC chromatography to obtain 50mg of the desired product.

Formation of N- [6- [ [ 5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] norbornan-2-yl ] pyrrolidine-1-carboxamide (1045)

To a solution of 72j (0.030g, 0.078mmol) of 6- [ [ 5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl ] amino ] norbornane-2-carboxylic acid in THF (0.375mL) was added triethylamine (0.032mL, 0.234mmol) and (azido (phenoxy) phosphono) phenol (0.018mL, 0.085 mmol). The reaction mixture was heated for 2.5h to 95 ℃, cooled to 5 ℃, and treated with pyrrolidine (0.010mL, 0.117 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was directly injected into a preparative HPLC system for purification to provide the product as an racemic mixture. The single enantiomers were isolated by chiral purification using SFC to give 5.7mg of the desired product as well as 1.4mg of the enantiomer.

general scheme 73

(a) iPr2NEt, THF, reflux; (b)1N LiOH, THF/H2O, 130 ℃, microwave

Formation of (1R,2R,3S) -3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cycloheptane-1, 2-diol (73b)

The amino diol 73a was synthesized by the following literature method (JOC 2009,74, 6735). Aminodiol (0.040mg), diisopropylethylamine (0.054mL, 0.310mmol) and 5-fluoro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine (0.139g, 0.310mmol) in THF were refluxed overnight. The solution was concentrated in vacuo and purified by silica gel chromatography (0-100% EtOAc/CH2Cl2) to afford 43mg of the desired product as a white solid: 1H NMR (300MHz, CDCl3) δ 8.40(q, J ═ 2.8Hz,2H), 8.22(d, J ═ 1.8Hz,1H), 8.08-7.94 (M,3H),7.20(d, J ═ 10.1Hz,3H), 5.26(d, J ═ 4.9Hz,1H), 4.21-3.99 (M,1H),3.84(s,1H), 3.75-3.57 (M,1H), 3.43(t, J ═ 8.7Hz,1H),2.73(s,1H),2.30(s,3H), 2.11-1.85 (M,2H), 1.84-1.36 (M,8H),1.18(s,2H),0.79(dd, 15.8H), 6.8H (+) and Z (+ H).

formation of (1R,2R,3S) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cycloheptane-1, 2-diol (984)

LiOH (0.5mL of a 1N solution, 0.5mmoL) was added to (1R,2R,3S) -3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cycloheptan-1, 2-diol 73a in THF (3 mL). The reaction mixture was heated in a microwave at 130 ℃ for 40 min. To the mixture was added HCl (0.5mL of a 1.25N solution in MeOH) and MeOH. The solution was purified by preparative HPLC (MeCN/H2O 10-70%) to yield the desired product as a TFA salt. Neutralization and reacidification with hydrogen chloride (1N in MeOH) afforded the desired product (28mg) as a white solid (HCl salt): 1H NMR (300MHz, MeOD) δ 8.52(s,1H),8.48(d, J ═ 2.8Hz,1H),8.34(s,1H),8.28(d, J ═ 5.6Hz, 1H), 4.62-4.35 (m,1H),3.65(m,2H), 2.11-1.43 (m, 8H); 19F NMR (282MHz, MeOD) δ -137.38-137.51 (m,1H), -156.06(d, J ═ 5.6Hz, 1H); LCMS (+ H): M/Z-376.28.

General scheme 74

(a) CuI, 2- (2-methylpropionyl) cyclohexanone and DMF; (b) h2, Pd/C, MeOH; (c) 5-fluoro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridine; (d)1N LiOH, THF/H2O, microwave at 130 deg.C

Formation of benzyl ((1S,3R) -3- (pyrazin-2-ylamino) cyclohexyl) carbamate (74a)

A suspension of CuI (0.006g, 0.030mmol), benzyl N- [ (1S,3R) -3-aminocyclohexyl ] carbamate 18e (0.075g, 0.302mmol) and cesium carbonate (0.197g, 0.604mmol) in DMF was evacuated and filled with nitrogen several times. 2-iodopyrazine (0.036mL, 0.362mmol) and 2- (2-methylpropionyl) cyclohexanone (0.020mLg, 0.121mmol) were then added and the reaction was stirred at room temperature overnight. The reaction was diluted in ethyl acetate and saturated aqueous sodium carbonate solution. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to afford 40mg of the desired product as a yellow solid.

Formation of (1R,3S) -N1- (pyrazin-2-yl) cyclohexane-1, 3-diamine (74b)

to benzyl N- [ (1S,3R) -3- (pyrazin-2-ylamino) cyclohexyl ] carbamate 74a (0.040g, 0.123mmol) in methanol (10mL) was added 10% Pd/C (0.043g, 0.040mmol) and the resulting suspension was stirred under hydrogen for 3h until LCMS showed reaction completion. The solution was filtered through a celite bed and concentrated in vacuo to yield a yellow solid which was used without further purification.

Formation of (1S,3R) -N1- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) -N3- (pyrazin-2-yl) cyclohexane-1, 3-diamine (74c)

A solution of (1R,3S) -N1-pyrazine-2-cyclohexane-1, 3-diamine 74b diisopropylethylamine (0.30mmol) and 5-chloro-3- (5-fluoro-4-methylsulfinyl-pyrimidin-2-yl) -1- (p-toluenesulfonyl) -pyrrolo [2,3-b ] pyridine (0.06g, 0.13mmol) in THF (3mL) was refluxed overnight. The mixture was then concentrated in vacuo and the resulting residue was purified by silica gel chromatography (0-20% MeOH/CH2Cl2 gradient) to yield 39mg of the desired product: 1H NMR (300MHz, CDCl3) δ 8.91-8.72 (m,1H),8.50(d, J ═ 11.8Hz,1H), 8.38(t, J ═ 7.5Hz,1H),8.06(dd, J ═ 14.8,5.9Hz,3H),7.88(d, J ═ 1.4Hz,1H),7.82(s,1H),7.62(t, J ═ 6.8Hz,1H),7.33(dd, J ═ 16.6, 7.1Hz,3H),5.91(s,1H),4.27(s,1H),3.98(t, J ═ 11.3Hz,1H),2.59(d, J ═ 12.0Hz,1H),2.39(s,3H), 2.34.34H, 2.91 (m,1H), 1H, 14.09 (d, 1H), 1H, 14, 13.48H, 1H, and 1H.

LCMS(+H):M/Z＝593.25

Formation of (1S,3R) -N1- (5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) -N3- (pyrazin-2-yl) cyclohexane-1, 3-diamine (985)

LiOH (0.3mL of a 1N solution, 0.3mmoL) was added to a solution of (1S,3R) -N1- (5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) -N3- (pyrazin-2-yl) cyclohexane-1, 3-diamine 74c (35mg) in THF (3mL) and the reaction was heated in a microwave at 130 ℃ for 40 min. HCl solution (0.5mL of 1.25N in MeOH) was added and the resulting solution was purified by Gilson HPLC (MeCN/H2O 10-70%, 8 min) to give the pure TFA salt product. Neutralization and re-acidification with hydrogen chloride (1.25N in MeOH) afforded 23mg of the HCl salt of the desired product as a pale yellow solid: 1H NMR (300MHz, MeOD) δ 8.76(d, J ═ 2.4Hz,1H),8.63(s,1H),8.41(d, J ═ 2.3Hz,1H),8.36(d, J ═ 5.7Hz,1H),8.16(s,1H),7.96(s,1H),7.76 (s,1H),4.51(m, J ═ 11.8Hz,1H), 4.16-3.92 (m,1H), 2.35-2.14 (m,2H), 2.09(m, J ═ 13.8Hz,1H),1.63(d, J ═ 11.8Hz, 4H); 19F NMR (282 MHz, MeOD) delta-155.25 (s, 1H); LCMS (+ H): M/Z-439.24.

General scheme 75

a) NaBH4, MeOH; (b) 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, 2-Me-THF, water, K3PO4, Pd (PPh3)4, XPhos, tris (dibenzylideneacetone) dipalladium, refluxing; (c) bis (2, 5-dioxopyrrolidin-1-yl) carbonate, iPr2NEt, CH3 CN; (d) (3R) -3-fluoropyrrolidine, iPr2NEt, CH3 CN; (e)2N LiOH, THF

Formation of (1R,3S) -3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) cyclohexanol (75a)

(3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanone 18e (1.05g, 4.31mmol) was mixed in MeOH (20mL) and dichloromethane (10mL) and cooled to-78 deg.C using an external dry ice/acetone bath and monitored with an internal thermometer. After 30min, one portion of NaBH4(0.16g, 4.31mmol) was added and stirring was continued. (slightly warmed up) and then cooled back to-78 ℃. The consumption of starting material by the reaction was monitored by HPLC as the reaction was allowed to warm to room temperature overnight. The reaction was diluted with brine and EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography to obtain 1.0g of a colorless foamy solid: LCMS method m201:10-90 CH3CN/H2O, formic acid modifier, 5min, (C18); RT 2.08min, MH + 246.21.

formation of (1R,3S) -3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexanol (75b)

K3PO4(2.59g, 12.21mmol) in water (6mL) and 2-Me-THF (20mL) was purged with a stream of nitrogen for 30 min. (1R,3S) -3- [ (2-chloro-5-fluoro-pyrimidin-4-yl) amino ] cyclohexanol 75a (1.00g, 4.07mmol) and 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine 44a (2.03g, 4.88mmol) were added, followed by purging with a stream of nitrogen for a further 15 min. The reaction was then heated to 70 ℃ and charged with tris (dibenzylideneacetone) dipalladium (0.07g, 0.08mmol) and X-Phos (0.14g, 0.28mmol) under nitrogen. (note the color changed from purple to dark green). The reaction was heated to reflux for 1h and 20 min. The reaction was allowed to cool slowly to room temperature overnight. The mixture was treated with 100mL of brine and 100mL of ethyl acetate and the two layers were separated. The liquid phase was extracted with EtOAc (50 mL). The combined organic layers were passed through a fluorouracil plug, dried over Na2SO4, clarified and the solvent removed by rotary evaporation to give the crude product, which was then purified by silica gel chromatography (25-50% EtOAc/hexanes) to give the desired product.

2, 5-dioxopyrrolidin-1-yl ((1S,3R) -3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl) carbonate (75c)

To a solution of (1R,3S) -3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -pyrimidin-4-yl) amino) cyclohexanol 75b (0.50g, 1.00mmol) and N, N-diisopropylethylamine (1.40mL, 10.01mmol) was added bis (2, 5-dioxopyrrolidin-1-yl) carbonate (1.28g, 5.01mmol) in CH3CN (4mL) and stirred at room temperature overnight. The reaction mixture was used for the next reaction. LCMS method m201:10-90 CH3CN/H2O, formic acid modifier, 5min, (C18); RT 3.73min, MH + 641.43 (strong).

Formation of (R) - (1S,3R) -3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl 3-fluoropyrrolidine-1-carboxylate (75d)

To (2, 5-dioxopyrrolidin-1-yl) [ (1R,3S) -3- [ [ 5-fluoro-2- [ 5-fluoro-1- (p-toluenesulfonyl) pyrrolo [2,3-b ] pyridin-3-yl ] pyrimidin-4-yl ] amino ] cyclohexyl ] carbonate 75c (0.125g, 0.195mmol) which has been in acetonitrile was added (3R) -3-fluoropyrrolidine (0.445g, 4.991mmol) and the reaction mixture was stirred at room temperature for 20 h. The reaction was monitored by HPLC until no more starting material remained. The reaction mixture was concentrated in vacuo and the next reaction was carried out without further purification.

Formation of (S) - (1S,3R) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -pyrimidin-4-yl) amino) cyclohexyl 3-fluoropyrrolidine-1-carboxylic acid ester (1151)

To a solution of crude (R) - (1S,3R) -3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) cyclohexyl 3-fluoropyrrolidine-1-carboxylate 75d (0.119g, 0.019mmol) in THF (2mL) was added 5mL of 2N LiOH (10 mmol). The reaction mixture was heated at 50 ℃ for 2 h. The mixture was diluted in saturated aqueous ammonium chloride (2mL), extracted with EtOAc (2 × 10mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified 3 times by semi-preparative HPLC using 10-70% CH3 CN/H2O; the homogeneous fractions were combined and the solvent was removed under a stream of nitrogen, then the residual solvent was removed on a rotary evaporator to yield 74mg of the desired product: LCMS RT 2.15min (M + H) 461.51.

general scheme 76

(a) Rh/Al2O3, H2O, 100 ℃, 105 atmospheric pressures H2, 19H; (b)2, 4-dichloro-5-fluoropyrimidine, IPA and MeCN at room temperature; (c) CDI, iPr2 NEt; (S) -3-fluoropyrrolidine, THF, RT, 2 days; (d) 5-fluoro-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, MeTHF, K3PO4, X-Phos, Pd2dba3, H2O, microwave, 120 ℃, 20 min; (e) 25% NaOMe, RT, 30min in MeOH; (f) SFC separation

Formation of 5-methylcyclohexane-1, 3-diamine (76a)

3-methyl-5-nitroaniline (10.0g, 65.7mmol) was added to water (146ml) and treated with 6N HCl (22.5ml, 135.0mmol) and 5% rhodium on alumina catalyst (1.9g, 0.9 mmol). The mixture was charged with 105 atmospheres of hydrogen and heated to 19h to 100 ℃. The reaction was cooled and filtered through celite, concentrated to dryness to give 5-methylcyclohexane-1, 3-diamine dihydrochloride (12.9g, 64.5mmol) as a racemic mixture. The salt (6.5g, 32.5mmol) was dissolved in isopropyl alcohol (100ml) and acetonitrile (100ml) and treated with potassium carbonate (25.2g, 182.0 mmol). The mixture was stirred at room temperature overnight, filtered through celite and concentrated in vacuo to give 2.2g of 5-methylcyclohexane-1, 3-diamine as a brown oil: LCMS RT ═ 0.41(M +1) 128.9.

Formation of N1- (2-chloro-5-fluoropyrimidin-4-yl) -5-methylcyclohexane-1, 3-diamine (76b)

To a solution of 5-methylcyclohexane-1, 3-diamine 76a (2.2g, 17.2mmol) in isopropyl alcohol (40ml) and acetonitrile (40ml) was added 2, 4-dichloro-5-fluoropyrimidine (1.4g, 8.6 mmol). The mixture was stirred at room temperature overnight, concentrated to dryness, and purified on silica gel, eluting with 1-20% methanol/dichloromethane to give 0.6g of racemic N1- (2-chloro-5-fluoropyrimidin-4-yl) -5-methylcyclohexane-1, 3-diamine: 1H NMR (300MHz, MeOD) δ 7.85(d, J ═ 3.5Hz,1H), 4.07(ddd, J ═ 11.9,7.9,4.1Hz,1H),3.54(qd, J ═ 11.3,4.2Hz,1H),2.82 (tt, J ═ 11.4,3.7Hz,1H),2.16(dd, J ═ 15.0,13.0Hz,1H),1.89(t, J ═ 13.4Hz,2H),1.50(dd, J ═ 76.0,21.9Hz,2H),1.10(dt, J ═ 17.9,9.0Hz, 1H),0.99(dd, J ═ 8.5,5.0, 3H),0.81(dd, 8, 23.8, 1H); LCMS RT ═ 1.24(M +1) 259.1.

Formation of (3S) -N- (3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) -5-methylcyclohexyl) -3-fluoropyrrolidine-1-carboxamide (76c)

to a solution of N1- (2-chloro-5-fluoropyrimidin-4-yl) -5-methylcyclohexane-1, 3-diamine 76b (0.14g, 0.54mmol) in THF (2.5mL) was added carbonyldiimidazole (0.10g, 0.60mmol) and iPr2NEt (0.28mL, 1.62 mmol). The reaction was aged at room temperature for 2h and treated with (S) -3-fluoropyrrolidine hydrochloride (0.07g, 0.54 mmol). The reaction was stirred at room temperature for 2 days, then concentrated to dryness to obtain 202mg of (3S) -N- (3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) -5-methylcyclohexyl) -3-fluoropyrrolidine-1-carboxamide used without purification: LCMS RT ═ 2.46(M +1)374.2, (M-1) 372.

Formation of (3S) -3-fluoro-N- (3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide (76d)

To a solution of (3S) -N- (3- ((2-chloro-5-fluoropyrimidin-4-yl) amino) -5-methyl-cyclohexyl) -3-fluoropyrrolidine-1-carboxamide XXc (0.101g, 0.270mmol) in 2-methyltetrahydrofuran (4ml) were added potassium phosphate (0.090g, 0.950mmol), x-phos (0.027g, 0.057mmol) and Pd2dba3(0.015g, 0.016mmol) in water (1.2 ml). The reaction was heated in a microwave at 120 ℃ for 20min and the organic phase was filtered through a florisil pad and the filtrate was concentrated in vacuo. The crude product was purified on silica gel, eluting with EtOAc to give 127mg of rac (3S) -3-fluoro-N- (3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide: LCMS RT ═ 3.58(M +1) 628.3, (M-1) 626.

Formation of (S) -3-fluoro-N- ((1R,3S,5R) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide (76e)

To a solution of (3S) -3-fluoro-N- (3- ((5-fluoro-2- (5-fluoro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide 76d (0.090g, 0.143mmol) in MeOH (2.5ml) was added 25% sodium methoxide in methanol (2 ml). The reaction was stirred at room temperature for 30min and quenched with saturated aqueous NH4Cl solution. The methanol was removed in vacuo and the residue was extracted with EtOAc and water. The organics were dried over sodium sulfate and evaporated to dryness. The resulting crude racemate was purified by SFC separation on a chiral column. The second peak product was concentrated in vacuo to yield 32mg of enantiomerically pure (S) -3-fluoro-N- ((1R,3S,5R) -3- ((5-fluoro-2- (5-fluoro-1H-pyrrolo [2,3-b ] pyridin-3-yl) pyrimidin-4-yl) amino) -5-methylcyclohexyl) pyrrolidine-1-carboxamide as a white solid: LCMS RT ═ 1.89(M +1)474.2, (M-1) 472.4; SFC RT 3.2min, 15% MeOH @ 5mL/min on ODH (4.6 × 100), 100bar,35C,220 nm; 1H NMR (300MHz, DMSO) δ 12.26(s,1H),8.41(dd, J ═ 9.9,2.8Hz,1H), 8.32-8.18 (m,2H),8.14(d, J ═ 4.0Hz,1H),7.53(d, J ═ 7.6Hz,1H),6.02(d, J ═ 7.9Hz,1H),5.28(d, J ═ 53.6Hz,1H), 4.35-4.00 (m,1H), 3.81-3.09 (m,12H), 2.24-1.77 (m, J ═ 41.2,26.1,10.6Hz,4H), 1.74-1.51 (m,1H), 1.51-1.22 (m,1H), 1.14-0.70H).

General scheme 77

(a) (R) -nopinone, O-methylhydroxylamine hydrochloride, pyridine, EtOH; (b) nBuLi, THF, -78 ℃, ethyl formate; (c) NaBH4, MeOH; (d) TBDPSCl, imidazole, DMF; (e) BH3-THF, 75 ℃; (f) 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-tosyl-1H-pyrrolo [2,3-b ] pyridine, iPr2NEt, 75 ℃; (g) HCl, dioxane

Formation of (1R,5S) -6, 6-dimethylbicyclo [3.1.1] heptan-2-one O-methyloxime (77a)

To a solution of (1S,5R) -6, 6-dimethylnorbornane-2-one (3.09g, 22.35mmol) in ethanol (70mL) was added O-methylhydroxylamine hydrochloride (2.05g, 24.59mmol) and pyridine (1.29mL, 15.92 mmol). The reaction mixture was heated for 4h to 80 ℃. The solvent was removed under reduced pressure. The residue was diluted with 1N HCl and extracted twice with ether. The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried (MgSO4), filtered, and concentrated in vacuo to give 3.36g of a colorless oil (mixture of oxime isomers) which was used without further purification.

formation of (1R,3S,5R) -2- (methoxyimino) -6, 6-dimethylbicyclo [3.1.1] heptane-3-carbaldehyde (77b)

To a cold (-78 ℃ C.) solution of (1R,5S) -6, 6-dimethylbicyclo [3.1.1] heptan-2-one O-methyloxime 77a (1.27g, 7.59mmol) in THF (33mL) was added dropwise an n-butyllithium solution (3.34mL of a 2.5M solution in hexane, 8.35 mmol). After the mixture was stirred at-78 ℃ for 20min, ethyl formate (0.61mL, 7.59mmol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 3h and quenched by pouring into saturated aqueous NaHCO3 solution. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-20% EtOAc/hexanes gradient) to give 810mg of a yellow oil: LCMS RT ═ 3.54(M + H) 196.28.

Formation of (1R,3S,5R) -3- (hydroxymethyl) -6, 6-dimethylbicyclo [3.1.1] heptan-2-one O-methyloxime (77c)

To a solution of (1R,3S,5R) -2- (methoxyimino) -6, 6-dimethylbicyclo [3.1.1] heptane-3-carbaldehyde 77b (0.70g, 3.58mmol) in methanol (15mL) was added sodium borohydride (0.16g, 4.30 mmol). After stirring at room temperature for 30min, the reaction was diluted in saturated aqueous NaHCO3 and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-50% EtOAc/hexanes gradient) to give 330mg of the desired alcohol as a mixture of oxime isomers.

Formation of (1R,3S,5R) -3- (((tert-butyldiphenylsilyl) oxy) methyl) -6, 6-dimethyl-bicyclo [3.1.1] heptan-2-one O-methyloxime (77d)

To a solution of (1R,3S,5R) -3- (hydroxymethyl) -6, 6-dimethylbicyclo [3.1.1] heptan-2-one O-methyloxime 77c (0.32g, 1.60mmol) in DMF (6mL) was added tert-butyldiphenylchlorosilane (0.55g, 2.00mmol) and imidazole (0.22g, 3.20 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was diluted in saturated aqueous NH4Cl and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-15% EtOAc/hexanes gradient) to give 200mg of one oxime isomer and 197mg of the second oxime isomer.

Formation of (1R,3S,5R) -3- (((tert-butyldiphenylsilyl) oxy) methyl) -6, 6-dimethyl-bicyclo [3.1.1] hept-2-amine (77e)

To a solution of (1R,3S,5R) -3- (((tert-butyldiphenylsilyl) oxy) methyl) -6, 6-dimethyl-bicyclo [3.1.1] heptan-2-one O-methyloxime 77d (0.20g, 0.46mmol) in THF (3mL) was added borane-THF (1.38mL of a 1M solution, 1.38 mmol). The reaction was heated for 18h to 75 ℃. The mixture was diluted in 1N NaOH (50mL) and extracted twice with EtOAc. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo to give 178mg of a colourless oil used without further purification: LCMS RT ═ 2.53(M + H) 408.54.

Formation of N- ((1R,2S,3S,5R) -3- (((tert-butyldiphenylsilyl) oxy) methyl) -6, 6-dimethylbicyclo [3.1.1] heptan-2-yl) -2- (5-chloro-1-tosyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine (77f)

To a solution of (1R,3S,5R) -3- (((tert-butyldiphenylsilyl) oxy) methyl) -6, 6-dimethyl-bicyclo [3.1.1] heptan-2-amine 77e (0.20g, 0.46mmol) and 5-chloro-3- (5-fluoro-4- (methylsulfinyl) pyrimidin-2-yl) -1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridine (0.14g, 0.30mmol) in DMF (1.5mL) was added diisopropylethylamine (0.11mL, 0.61 mmol). The reaction was heated for 18h to 75 ℃. The mixture was diluted in saturated aqueous NH4Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (0-5% MeOH in CH2Cl2 gradient) to yield 78mg of the desired product.

Formation of ((1R,2S,3S,5R) -2- ((2- (5-chloro-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-yl) amino) -6, 6-dimethylbicyclo [3.1.1] heptan-3-yl) methanol (1229)

To a solution of N- ((1R,2S,3S,5R) -3- (((tert-butyldiphenylsilyl) oxy) methyl) -6, 6-dimethylbicyclo [3.1.1] heptan-2-yl) -2- (5-chloro-1-toluenesulfonyl-1H-pyrrolo [2,3-b ] pyridin-3-yl) -5-fluoropyrimidin-4-amine 77f (0.037g, 0.046mmol) in acetonitrile (1.1mL) was added HCl (0.221mL of a 4M solution in dioxane, 0.883 mmol). The mixture was heated for 18h to 70 ℃ during which time a precipitate formed. The reaction was concentrated in vacuo and triturated 3 times with CH3CN to obtain 4mg of the desired product as a white solid: 1H NMR (300.0MHz, MeOD) δ 8.72-8.64(m,1H),8.39(s,1H),8.32(d, J ═ 2.3Hz,1H), 8.21(d, J ═ 5.2Hz,1H),4.71(d, J ═ 6.3Hz,1H),3.67-3.57(m, 2H),2.33-2.26(m,1H),2.10(m,1H),1.78-1.70(m,1H),1.28-1.25 (m,7H) and 1.19(s,3H) ppm; LCMS RT ═ 3.13(M + H) 416.42.

Anti-influenza virus detection

Antiviral assays were performed using two cell-based methods:

A modified version of a 384 well microtiter plate was developed for the standard cytopathic effect (CPE) assay, similar to the microtiter plate of Noah et al. (Antiviral Res.73:50-60, 2006). Briefly, MDCK cells were incubated with test compound and influenza a virus (a/PR/8/34) at multiplicity of infection (approximately MOI 0.005) at 37 ℃ for 72h, and cell viability was measured using ATP assay (CellTiter Glo, Promega Inc.). Control wells containing cells and virus showed cell death, while wells containing cells, virus and active antiviral compound showed cell survival (cytoprotection). Different concentrations of test compounds were evaluated in quadruplicate, e.g., ranging from about 20 μ M to 1 nM. Dose response curves were generated using standard 4-parameter curve fitting methods and the concentration of test compound that caused 50% cell protection or cell viability equivalent to 50% uninfected wells was designated as IC 50.

the development of a second cell-based antiviral assay relies on the proliferation of virus-specific RNA molecules in infected cells, with RNA levels being measured directly by branched-chain DNA (bDNA) hybridization (Wagaman et al, J.Virol Meth,105:105-114, 2002). In this assay, cells are initially infected in wells of a 96-well microtiter plate, the virus is allowed to replicate in the infected cells and spread to additional cells, the cells are then lysed and viral RNA content is measured. This assay was stopped early in the CPE assay, usually after 18-36h, while all target cells were still viable. The viral RNA was quantified by hybridizing the well lysates of the wells with specific oligonucleotide probes immobilized on the detection wells, followed by amplification of the signal sequence by hybridization with additional probes linked to reporter enzymes according to the instructions of the kit manufacturer (Quantigene 1.0, Panomics, Inc.). Negative strand viral RNA was assayed using probes designed for the type A hemagglutination consensus gene. Control wells containing cells and virus were used to define 100% virus replication levels and dose response curves of antiviral test compounds were analyzed using a 4-parameter curve fitting method. The concentration of test compound that produced a viral RNA level equal to 50% of the control wells was designated EC 50.

Virus and cell culture methods: Madin-Darby canine kidney cells (CCL-34 American Type Culture Collection) were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 2mM L-glutamine, 1,000U/ml penicillin, 1,000. mu.g/ml streptomycin, 10mM HEPES and 10% fetal calf medium. For CPE detection, the day before detection, cells were suspended by trypsin treatment and 50 μ Ι cells were dispensed into wells of 384-well plates, 10,000 cells per well. On the day of detection, adherent cells were washed with DMEM without fetal bovine serum, with 3 changes containing 1. mu.g/ml TPCK-treated trypsin. Detection was started by adding 30TCID50 virus and test compound to trypsin containing 1. mu.g/ml TPCK treated trypsin in a final volume of 50. mu.l. The plates were incubated at 37 ℃ in 5% CO2 humidified air for 72 h. Alternatively, cells were grown in DMEM + fetal calf serum as above, but on the day of the assay the cells were trypsinized, washed 2 times and suspended in serum-free EX cell MDCK cell culture medium (SAFC Biosciences, Lenexa, KS) and seeded into wells at 20,000 cells per well. After 5h incubation, the wells were used for detection without washing.

Influenza strain A/PR/8/34 (adapted for tissue culture) was obtained from ATCC (VR-1469). Low passage virus seedlings were prepared in MDCK cells using standard methods (WHO Manual on Animal infection Diagnosis and surveyability, 2002) and were measured by serial dilution of MDCK cells as tested in 384 well CPE detection format above and TCID50 measurements were performed using the Karber method to calculate results.

The average values of IC50 (all average values) for certain specific compounds are summarized in tables 1-5:

IC50 (all mean) <5 μ M;

B5 MuM is less than or equal to IC50 (the total average value) is less than or equal to 20 MuM;

C IC50 (all averages) >10 μ M;

D IC50 (all averages) >20 μ M;

E IC50 (all averages) >3.3 μ M.

Average values of EC50 (all average values) for certain compounds are also summarized in tables 1-5:

EC50 (all mean) <5 μ M;

b5 mu M is less than or equal to EC50 (all average values) is less than or equal to 10 mu M;

C EC50 (all averages) >3.3 μ M;

D EC50 (all averages) >10 μ M.

As seen in tables 1-5, many of the compounds of the present invention showed a positive effect on the survival of A/PR/8/34 infected cells and an inhibitory effect on A/PR/8/34 virus replication. Exemplary IC50 and EC50 values are as follows: compound 428 had an IC50 of 0.03 μ M; compound 895 had an IC50 of 0.0008 μ M and an EC50 of 0.001 μ M; compound 833 has an IC50 of 5.6. mu.M and an EC50 of 3.5. mu.M.

table 1: IC50, EC50, NMR and LCMS data for the compound of figure 3:

Table 2: IC50, EC50, NMR and LCMS data for the compounds of FIGS. 4 and 5

Table 3: IC50, EC50, NMR and LCMS data for the compound of FIG. 6

Table 4: IC50, EC50, NMR and LCMS data for the compound of FIG. 7

Table 5: IC50, EC50, NMR and LCMS data for the compound of FIG. 8

In vitro assay

For efficacy studies, Balb/c mice (4-5 weeks old) were challenged by intranasal instillation (25. mu.l/nostril) of 5X103TCID50 under general anesthesia (ketamine/xylazine) in a total volume of 50. mu.l. Uninfected controls were challenged with tissue culture medium (DMEM, total volume 50. mu.l). For the prophylactic study (fig. 1), 2h prior to infection an initial dose of either compound 514(100mg/kg) or vehicle (0.5% methylcellulose 0.5% Tween 80) alone (10mL/kg) was administered by oral gavage and continued for 5 days, 2 times daily. For the treatment study (fig. 2), compound 588(200mg/kg) alone or vehicle (0.5% methylcellulose/0.5% Tween 80) was administered orally gavage 24h post-infection and continued for 10 days, 2 times daily. Animals were monitored for 21 days of survival and Kaplan Meier curves were plotted. As shown in figures 1 and 2, compound 514 and compound 588 provided complete survival of vehicle-treated controls, statistically significant (P < 0.0001).

TABLE 6 influenza treatment mouse model (30 mg/kg BID dose administered at 48h post-infection for 10 days)

compound (I)	Percentage of survival	Percent weight loss (day 8)
			895	100	12.8
936	100	20.9
			933	100	28.0
706	75	27.0
			967	75	30.9
866	62.5	29.5
			968	37.5	32.7

All references provided herein are incorporated by reference in their entirety. All abbreviations, symbols and conventions as used herein are consistent with those used in the contemporary scientific literature. See, for example, Janet S.Dodd et al, The ACS Style Guide, A Manual for Authors and Editors, 2 nd edition, Washington, D.C. American Chemical Society, 1997.

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, but rather by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

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