apoptosis-inducing agent

文档序号：1785625 发布日期：2019-12-06 浏览：23次中文

阅读说明：本技术 凋亡诱导剂 (apoptosis-inducing agent ) 是由刘洪彬容悦张华杰陈志方谭锐何成喜李志福周祖文谭浩瀚冉凯王宪龙于 2018-04-17 设计创作，主要内容包括：本发明涉及一类Bcl-2抑制剂、及其药物组合物和使用方法。(The invention relates to a Bcl-2 inhibitor, a pharmaceutical composition and a using method thereof.)

1. A compound of formula (I):

Or a pharmaceutically acceptable salt thereof, wherein:

L1, L2, L3 and L4 are independently selected from- (crd) u-, - (crd) uo (crd) t-, - (crd) unra (crcd) t-, - (crd) us (crd) t-, - (crd) uC (o) (crd) t-, - (crd) uC (c) (NRE) (crd) t-, - (crd) uC(s) (crd) ucc (crd) t-, - (crd) uC (o) (crd) t-, - (crd) uo (crd) t-, - (crd) uC (o) (nra crd) t-, - (crd) unnrac (c) (crd) t-, - (crd) nrc (nrc) nrc (crd) t-, - (crd) nrc (crd) t-, -, - (CRD) uC (S) NRA (CRD) t-, - (CRD) uNRAC (S) NRB (CRCRD) t-, - (CRCRD) uS (O) r (CRD) t-, - (CRD) uS (O) rNRA (CRD) t-, - (CRD) uNRAS (O) r (CRD) t-and- (CRD) uNRAS (O) rNRB (CRD) t-;

Q1 and Q2 are independently selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, substituent independently selected from RX;

q3 is selected from the group consisting of aryl, C3-10 cycloalkyl, heteroaryl, and heterocyclyl, wherein aryl, cycloalkyl, heteroaryl, and heterocyclyl are each unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RX;

when Q3 is C3-10 cycloalkyl, Y1, Y2 and Y3 are independently selected from (CR6aR6b) o, wherein cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from RX;

When Q3 is heteroaryl, Y1, Y2 and Y3 are independently selected from the group consisting of a bond, C, N, O and S, wherein heteroaryl is unsubstituted or substituted with at least 1 or 2 substituents independently selected from RX;

When Q3 is heterocyclyl, Y1, Y2 and Y3 are independently selected from (CR6aR6b) O, N, O and S, wherein heterocyclyl is unsubstituted or substituted with at least one substituent independently selected from RX;

X1 and X2 are independently selected from C and N;

X3 is selected from CR4d and O;

Y4 is selected from C and N;

z is selected from C and N;

Each R1 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA1RB1, -ORA1, -C (O) RA1, -C (═ NRE1) RA1, -C (═ N-ORB1) RA1, -C O) ORA1, -oc RB1, -C (O) RA 86a 1RB1, -NRA1C (O) RB1, -C (═ NRE1) NRA1RB1, -NRA1 (NRA) 1 (NRA 1) RB1 (NRE 1) NRA1, -NRA1 (nro 1) 1a 1 (nro 1) 363672 a 1a 363672 (nro 1) 1a 1 (nro 1) NRA 1a 1b 1, -s (O) rRA1, -s (O) (═ NRE1) RB1, -N ═ s (O) RA1RB1, -s (O)2ORA1, -os (O)2RA1, -NRA1S (O) rRB1, -NRA1S (O) (═ NRE1) RB1, -s (O) NRA1RB1, -s (O) (═ NRE1) NRA1RB1, -NRA1S (O)2NRA1RB1, -NRA1S (O) (-NRE 1) NRA1RB1, -p (O) RA1RB1 and-p (O) (ORA1) (ORB1) wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from the group consisting of 1,2,3 or 4;

Each R2 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA2RB2, -ORA2, -C (O) RA2, -C (═ NRE2) RA2, -C (═ N-ORB2) RA2, -C O) ORA2, -oc O) RA2, -C (O) NRA2RB2, -NRA2C (O) RB2, -C (═ NRE2) NRA2RB2, -NRA2 (RB 2) RB2 (NRE 2) RB2, -NRA2 (nro) 2a 2, NRA2 (nro 2) 2a 2)2 (nro 2a 2) 2a 2 (nro 2) nro 2a 2b 2a 2b, -s (O) rRA2, -s (O) (═ NRE2) RB2, -N ═ s (O) RA2RB2, -s (O)2ORA2, -os (O)2RA2, -NRA2S (O) rRB2, -NRA2S (O) (═ NRE2) RB2, -s (O) NRA2RB2, -s (O) (═ NRE2) NRA2RB2, -NRA2S (O)2NRA2RB2, -NRA2S (O) (-NRE 2) NRA2RB2, -p (O) RA2RB2 and-p (O) (ORA2) (ORB2), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from the group;

each R3 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA3RB3, -ORA3, -C (O) RA3, -C (═ NRE3) RA3, -C (═ N-ORB3) RA3, -C O) ORA3, -oc O) RA3, -C (O) NRA3RB3, -NRA3C (O) RB3, -C (═ NRE3) NRA3RB3, -NRA3RB3 (RB 3) RB3 (NRE 3) NRA3, NRA3 (nro) 3a 3)3, NRA3 (nro 3a 3) 3a 3 (nro 3) 3a 3 (nro 3) NRA 3a 3 (nro 3) nro 3a 3b 3, -s (O) rRA3, -s (O) (═ NRE3) RB3, -N ═ s (O) RA3RB3, -s (O)2ORA3, -os (O)2RA3, -NRA3S (O) rRB3, -NRA3S (O) (═ NRE3) RB3, -s (O) NRA3RB3, -s (O) (═ NRE3) NRA3RB3, -NRA3S (O)2NRA3RB3, -NRA3S (O) (-NRE 3) NRA3RB3, -p (O) RA3RB3 and-p (O) (ORA3) (ORB3) wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from the group consisting of 1,2,3 or 4;

R4a, R4b, R4C and R4d are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA4RB4, -ORA4, -C (O) RA4, -C (═ NRE4) RA4, -C (═ N-ORB4) RA4, -C (O) ORA4, -oc (O) RA4, -C (O) NRA4RB4, -NRA 44 (O) 36rb, -C (═ NRE4) NRA4RB4, -NRA4 (nro) 4a 4 (NRA 4) 4a 4) 4 (nro) 4a 4) 4 (NRA 4) 4a 4 (nro) 4a 4 (NRA 4) 4a 4 (NRA 4) b), -NRA4C (═ NRE4) NRA4RB4, -s (O) rRA4, -s (O) (═ NRE4) RB4, -N ═ s (O) RA4RB4, -s (O)2ORA4, -os (O)2RA4, -NRA4S (O) rRB4, -NRA4S (O) (═ NRE4) RB4, -s (O) rrna 4RB4, -s (O) (═ NRE4) NRA4RB4, -NRA4S (O)2NRA4RB4, -NRA4S (O) (═ NRE4) NRA4RB4, -p (O) RA4RB4, and-p (O) (ORA4) (ORB4), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently substituted by at least one, such as RX 3, RX 4, RX 3, or RX 4;

Or "R4 a and R4 b" or "R4 c and R4 d" together with the carbon atom or atoms to which they are attached form a 3-7 membered ring containing 0, 1, 2or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1, 2or 3 RX groups;

Each R5a is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently unsubstituted or substituted with at least one, such as 1,2,3 or 4, substituent independently selected from RX;

R5-5 b is selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA5RB5, -ORA5, -C (O) RA5, -C (═ NRE5) RA5, -C (═ N-ORB5) RA5, -C (O) ORA5, -oc RB5, -C (O) NRA5RB5, -NRA5C (O) RB5, -C (═ NRE5) NRA5RB, -NRA5 (RB) 5, -NRA5 (NRE 5) 5 (NRA 5), NRA5 (nro) 5, NRA5 (NRA 5) 5, NRA5 (NRE 5) 5a 5 (NRA 5) 5a 5b 5 (NRA 5) b 5b, -s (O) rRA5, -s (O) (═ NRE5) RB5, -N ═ s (O) RA5RB5, -s (O)2ORA5, -os (O)2RA5, -NRA5S (O) rRB5, -NRA5S (O) (═ NRE5) RB5, -s (O) NRA5RB5, -s (O) (═ NRE5) NRA5RB5, -NRA5S (O)2NRA5RB5, -NRA5S (O) (-NRE 5) NRA5RB5, -p (O) RA5RB5 and-p (O) (ORA5) (ORB5) wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from the group;

each R6 and R6 is independently selected from hydrogen, halogen, C-10 alkyl, C-10 alkenyl, C-10 alkynyl, C-10 cycloalkyl-C-4 alkyl, heterocyclyl-C-4 alkyl, aryl-C-4 alkyl, heteroaryl-C-4 alkyl, CN, NO, -NRA6RB, -ORA, -C (O) RA, -C (═ NRE) RA, -C (═ N-ORB) RA, -C (O) ORA, -oc (O) RA, -C (O) NRA6RB, -NRA6 (O) RB, -C (═ NRE) NRA6, -RB, -oc (O) NRA6, -RB 6 (O) ORB, -NRA6 (O) NRA6RB, -NRA6 (S) NRA6, C (R) NRA6RB, -NRA6C (═ NRE6) NRA6RB6, -s (O) rRA6, -s (O) (═ NRE6) RB6, -N ═ s (O) RA6RB6, -s (O)2ORA6, -os (O)2RA6, -NRA6S (O) rRB6, -NRA6S (O) (═ NRE6) RB6, -s (O) rrna 6RB6, -s (O) (═ NRE6) NRA6RB6, -NRA6S (O)2NRA6RB6, -NRA6S (O) (═ NRE6) NRA6RB6, -p (O) RA6RB6, and-p (O) (ORA6) (ORB6), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently substituted by at least one, such as RX 3, RX 4, or RX 4;

Or R6a and R6b together with the carbon atom or atoms to which they are attached form a 3-7 membered ring containing 0, 1, 2or 3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted by 1, 2or 3 RX groups;

Each RA, RA1, RA2, RA3, RA4, RA5, RA6, RB1, RB2, RB3, RB4, RB5, and RB6 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively, is unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RX;

Or each of "RA and RB", "RA 1 and RB 1", "RA 2 and RB 2", "RA 3 and RB 3", "RA 4 and RB 4", "RA 5 and RB 5" and "RA 6 and RB 6" together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1, 2or 3 RX groups;

each RC and RD is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively, is unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RX;

or RC and RD taken together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted with 1, 2or 3 RX groups;

Each RE, RE1, RE2, RE3, RE4, RE5 and RE6 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, ORa1, SRa1, -s (o) rRa1, -C (o) Ra1, C (o) ORa1, -C) NRa1Rb1 and-s (o) Ra1Rb1, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is individually unsubstituted or substituted with at least one, such as 1,2,3 or 4, RY is independently selected from the group of substituents;

Each RX is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, - (CRc1Rd1) tNRa1Rb1, - (CRc1Rd1) tnrb 1, - (CRc1Rd1) tC) Ra1, - (CRc1Rd1) tC (═ NRe1) Ra1, - (CRc1Rd1) tC (═ N-ORb1) Ra1, - (C1 Rd1) tC (nrrb) 1), (nrrb 36r 1), (nrc 36rb 36r 1) and (nrc 36rb 1)1 (36rb 1) 36rb 1 (36rb 1) 36c 36rb 1 (36rb 1) 1a 36rb 1) 36rb 1a 36rb 1 (36rb 1) 36rb 1b 1 (36rb 1) 1b 36rb 1b 36rb 1, - (CRc1Rd1) tNRa1C (O) ORb1, - (CRc1Rd1) tNRa 1Rd1 (O) NRa1Rb1, - (CRc1Rd1) tNRa 11 (S) NRa1Rb1, - (CRc1Rd1) tNRa 1Rd1 (NRe 1) tNRa1Rb1, - (CRc1Rd1) ts (O) (═ NRe1) Rb1, - (CRc1Rd1) tN (S) (O) Ra1Rb1, - (c 1Rd1) ts (O) ORb1, - (CRc1Rd1) tNRa 1)1, or (nro 1) 36rb 1)1, wherein each of (nro, tNRa) 1, tNRa 1)1, tNRa 1)1, nor (nro 1)1, nor (nro 1) 36rb 1 (1) 1, nor 1 (1) 1 (NRa 1) 36rb 1)1 (nro 1)1, nor 1)1 (NRa 1 (1) 1 (NRa 1) 36rb 1)1 (1) 36rb 1(1, nor 1)1 (1) 36rb 1 (NRa 1)1 (1) 36, such as 1,2,3 or 4, independently selected from RY;

Each Ra1 and each Rb1 is independently selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively, is unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RY;

Or Ra1 and Rb1 together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1, 2or 3 RY groups;

Each Rc1 and each Rd1 is independently selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RY;

Or Rc1 and Rd1 together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted with 1, 2or 3 RY groups;

Each Re1 is independently selected from hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, CN, NO2, -ORa2, -SRa2, -S (O) rRa2, -C (O) Ra2, -C (O) ORa2, -S (O) rNRa2Rb2, and-C (O) NRa2Rb 2;

Each RY is independently selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, halogen, CN, NO2, - (CRc2Rd2) tNRa2Rb2, - (CRc2Rd2) tnorb 2, - (CRc2Rd2) tC Ra2, - (CRc2Rd2) tC (═ NRe2) Ra1, - (CRc2Rd2) tC (═ N-ORb2) Ra2, - (CRc2Rd2) tC (nro 2), (NRa) - (nrrb 2), (C36rb 2), (C2 Rd2) nrrb 2, - (CRc 36rb 2)2 (nrrb) 2) 36rb 2 (nrc 36rb) 2 a- (nroc 2) 36rb 2 a- (nroc 36rb 2) 2b 2 (nrc 36rb) 2b 36rb, - (CRc2Rd2) tNRa2C (O) ORb2, - (CRc2Rd2) tNRa 22 (O) NRa2Rb2, - (CRc2Rd2) tNRa 22 (S) NRa2Rb2, - (CRc2Rd2) tNRa2r 2 (NRe 2) tNRa2Rb2, - (CRc2Rd2) ts (O) (═ NRe2) Rb2, - (CRc2Rd2) tN (S) (O) Ra2Rb2, - (c 2Rd2) ts (O) ORb2, - (CRc2Rd2) tNRa2r 2) tNRa2, - (CRc2Rd2) tNRa2, nor (r 2) nor (r 2) nor (r, such as 1,2,3 or 4, substituted with substituents independently selected from OH, CN, amino, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

Each Ra2 and each Rb2 is independently selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl, and heteroaryl is unsubstituted or at least one, such as 1,2,3 or 4, substituted with substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

Or Ra2 and Rb2 together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

Each Rc2 and each Rd2 is independently selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl, and heteroaryl is unsubstituted or at least one, such as 1,2,3 or 4, substituted with substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

Or Rc2 and Rd2 taken together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

Each Re2 is independently selected from hydrogen, CN, NO2, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 cycloalkyl, C3-10 cycloalkoxy, -C (O) C1-4 alkyl, -C (O) C3-10 cycloalkyl, -C (O) OC1-4 alkyl, -C (O) OC3-10 cycloalkyl, -C (O) N (C1-4 alkyl) 2, -C (O) N (C3-10 cycloalkyl) 2, -S (O)2C1-4 alkyl, -S (O)2C3-10 cycloalkyl, -S (O)2N (C1-4 alkyl) 2, and-S (O)2N (C3-10 cycloalkyl) 2;

m is selected from 0, 1,2 and 3;

n is selected from 0, 1,2 and 3;

o is selected from 0, 1 and 2;

p is selected from 0, 1,2,3 and 4;

q is selected from 0 and 1;

Each r is independently selected from 0, 1 and 2;

Each t is independently selected from 0, 1,2,3 and 4,

Each u is independently selected from 0, 1,2,3, and 4.

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

Q1 is aryl, wherein aryl is unsubstituted or substituted with at least one substituent independently selected from RX;

Q2 is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RX;

L1 is- (CRCRCD) u-; l2 is selected from the group consisting of- (CRCRD) u-, - (CRCRD) uO (CRCRD) t-, - (CRD) uS (CRD) t-, - (CRD) uS (O) r (CRCRD) t-;

X1 is N; x2 is N; x3 is-CR 4cR4 d; z is C;

R1 is NO 2or SO2CF 3; r2 is hydrogen; r3 is hydrogen; m is 1; n is 1; p is 1;

R4a and R4b are independently selected from hydrogen and C1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from RX.

3. The compound of claim 2or a pharmaceutically acceptable salt thereof, wherein

Q1 is phenyl, wherein the phenyl is unsubstituted or substituted with at least one, independently selected from C1-4 alkyl, C3-6 cycloalkyl, halogen, CN, CF3 and OCF 3;

q2 is selected from the group consisting of each of which is unsubstituted or substituted with at least one substituent independently selected from RX;

l1 is- (CH2) u-; l2 is selected from the group consisting of a bond, -O-, -S-, and-S (O) r-;

x1 is N; x2 is N; x3 is selected from-CH 2-and-C (CH3) 2;

R1 is NO 2;

R4a and R4b are independently selected from hydrogen and C1-10 alkyl.

4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein Q1 is Q2 selected from

L1 is-CH 2-; l2 is selected from a bond or-O-;

x1 is N; x2 is N; x3 is selected from-CH 2-;

r4a and R4b are independently selected from hydrogen and methyl.

5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Q3 is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least 1 or 2 substituents independently selected from RX.

6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein Q3 is

7. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein Q3 is heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with at least 1 or 2 substituents independently selected from RX.

8. the compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Q3 is selected from the group consisting of unsubstituted or substituted with at least 1 or 2 substituents independently selected from RX.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein Q3 is

10. a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from- (crd) u-, - (crd) uo (crd) t-, - (crd) uc (o) (crd) t-, - (crd) uoc (o) (crd) t-, - (crd) uc (o) (crd) t-, - (crd) ucc (o) (crd) t-, - (crd) unrac (o) (crd) t-, - (crd) uc (o) nra crd) t-, - (crd) unrac (o) (o crd) t-, - (crd) us (o) (crd) r (crd) t-and (crd 5RD5) unras (o) r (crd) t-.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein u is selected from 0, 1 and 2, and t is selected from 0 and 1.

12. a compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from the group consisting of a bond, -CH2-, - (CH2)2-, -CH2O-, - (CH2)2O-, - (CH2)2oc (O) -, -c (O) O-, -CH2C (O) -, -CH2C (O) O-, -CH2OC (O) -, -c (O) NCH3-, -CH2NHC (O) O-, - (CH2)2NHC (O) -, - (CH2)2NHC (O) O-, - (CH2)2SO2-, and-CH 2NHSO 2-.

13. the compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein q is selected from 0 and 1.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein each R5a is independently selected from C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from RX.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R5a is selected from phenyl, pyridinyl, which are unsubstituted or substituted with at least one substituent independently selected from RX.

16. the compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein L4 is selected from- (CRCRD) u-and u is selected from 0, 1, and 2.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R5b is selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 heterocyclyl, CN, -ORA5, -NRA5RB5, -NRA5C (O) ORB5, -N ═ s (O) RA5RB5, -C (O) RA5, -C (O) ORA5, -C (O) NRA5RB5 and-s (O) rRA 5.

18. A compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R5b is selected from hydrogen, fluoro, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CN, OH, -OCH3, -N (CH3)2, -N ═ s (o) (CH3)2, -nhc (o) OCH3, -C (o) CH3, -C (o) C2H5, -C (o) -, -C3H7, -C (o) OCH3, -C (o) OC (CH3)3, -C (o) N (CH3)2, -SOCH3, and-s (o)2CH 3.

19. a compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein R5b is selected from-NRA 5RB5, -N ═ s (o) RA5RB5, wherein RA5 and RB5 together with the atoms to which they are attached form a 4-6 membered heterocyclic ring containing 0 or 1 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1, 2or 3 RX groups.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R5b is selected from

21. a compound selected from

And pharmaceutically acceptable salts thereof.

22. A pharmaceutical composition comprising a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

23. A method of treating, ameliorating, or preventing a condition responsive to inhibition of Bcl-2, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

24. use of a compound of any one of claims 1-21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a cell proliferation disorder.

Technical Field

The present invention relates to a class of compounds or pharmaceutically acceptable salts that inhibit anti-apoptotic Bcl-2 family proteins, and as medicaments for the treatment of hyperproliferative diseases, such as cancer and inflammation, and immune and autoimmune diseases.

background

Hyperproliferative diseases such as cancer and inflammation have attracted the academic community to provide effective treatments for them. And efforts have been made in this regard to identify and target specific mechanisms that play a role in proliferative diseases.

Protein-Protein Interactions (PPIs) regulate a variety of biological processes, such as cell proliferation, growth, differentiation, signal transduction, and apoptosis. Abnormal regulation of PPIs leads to a variety of diseases. Therefore, PPIs are an important new molecular target for the treatment of human diseases.

The B-cell lymphoma-2 (B-cell lymphoma-2) family protein is important for regulating and controlling apoptosis, and the apoptosis is very critical to normal tissue development and cell homeostasis maintenance. Activation of two different pathways will induce apoptosis. The external pathway, mediated by cell surface death receptors, and the internal pathway involving Bcl-2 family proteins. Bcl-2 family proteins include anti-apoptotic proteins such as Bcl-2, Bcl-XL, and Mcl-1, and pro-apoptotic proteins such as Bid, Bim, Bad, Bak, and Bax, among others.

Anti-apoptotic Bcl-2 family members are found to be upregulated in tumor cells and are associated with disease staging and prognosis. Therefore, Bcl-2 protein has been studied as a potential drug therapy target, including Bcl-2 and Bcl-XL. Bcl-2 protein expression can be used as an independent index of poor prognosis of tumors such as Chronic Lymphocytic Leukemia (CLL), prostate cancer and Small Cell Lung Cancer (SCLC). In other tumors, such as colon cancer, Bcl-XL expression correlates with disease severity and stage, and in hepatocellular carcinoma, Bcl-XL expression can be used as an independent indicator of poor overall survival and disease-free survival.

Therefore, compounds having CDK inhibitory activity are of great interest for the prevention and treatment of cancer. Based on the above, the invention provides a novel Bcl-2 inhibitor. Although Bcl-2 inhibitors have been reported in the literature, e.g., WO 2011149492, many have short half-lives or are toxic. Thus, there is an increasing need for new Bcl-2 inhibitors that have advantages in at least one of therapeutic efficacy, stability, selectivity, safety, pharmacodynamic profile, and pharmacokinetic profile. The invention relates to a novel Bcl-2 inhibitor.

Disclosure of Invention

The invention relates to a novel compound, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and application thereof as a medicament.

In one aspect, the invention provides a compound of formula (I):

Or a pharmaceutically acceptable salt thereof, wherein:

L1, L2, L3 and L4 are independently selected from- (crd) u-, - (crd) uo (crd) t-, - (crd) uNRA (crd 5) t-, - (crd) us (crd) t-, - (crd) uC (o) (crd) t-, - (crd) uC (NRE) (crd) t-, - (crd) uC (crd) s (crd) t-, - (crd) uC (o) (crd) t-, - (crd) uoc (o) (crd) t-, - (crd) uC (nrc) (crd) t-, - (crd) nruc (o) (c) nrc (crd) t-, - (crd) nrc (nrc) (crd) t-, - (crd) nrc (c (crd) t-, - (crd) nrc (crd) t-) (crd) nrc (crd) t-, - (crd) nrc (cr, - (CRD) uC (S) NRA (CRD) t-, - (CRD) uNRAC (S) NRB (CRCRD) t-, - (CRCRD) uS (O) r (CRD) t-, - (CRD) uS (O) rNRA (CRD) t-, - (CRC5RD5) uNRAS (O) r (CRCRCRD) t-and- (CRD) uNRAS (CRD) t-;

q1 and Q2 are independently selected from aryl and heteroaryl, wherein aryl and heteroaryl are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, substituent independently selected from RX;

Q3 is selected from the group consisting of aryl, C3-10 cycloalkyl, heteroaryl, and heterocyclyl, wherein aryl, cycloalkyl, heteroaryl, and heterocyclyl are each unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RX;

when Q3 is heteroaryl, Y1, Y2 and Y3 are independently selected from the group consisting of a bond, C, N, O and S, wherein heteroaryl is unsubstituted or substituted with at least 1 or 2 substituents independently selected from RX;

X1 and X2 are independently selected from C and N;

x3 is selected from CR4d and O;

Y4 is selected from C and N;

Z is selected from C and N;

Each R3 is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA3RB3, -ORA3, -C (O) RA3, -C (═ NRE3) RA3, -C (═ N-ORB3) RA3, -C O) ORA3, -oc O) RA3, -C (O) NRA3RB3, -NRA3C (O) RB3, -C (═ NRE3) NRA3RB3, -NRA3RB3 (RB 3) RB3 (NRE 3) NRA3, NRA3 (nro) 3a 3)3, NRA3 (nro 3a 3) 3a 3 (nro 3) 3a 3 (nro 3) NRA 3a 3 (nro 3) nro 3a 3b 3, -s (O) rRA3, -s (O) (═ NRE3) RB3, -N ═ s (O) RA3RB3, -s (O)2ORA3, -os (O)2RA3, -NRA3S (O) rRB3, -NRA3S (O) (═ NRE3) RB3, -s (O) NRA3RB3, -s (O) (═ NRE3) NRA3RB3, -NRA3S (O)2NRA3RB3, -NRA3S (O) (-NRE 3) NRA3RB3, -p (O) RA3RB3 and-p (O) (ORA3) (ORB3) wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each unsubstituted or substituted with at least one, such as 1,2,3 or 4, independently selected from the group consisting of 1,2,3 or 4;

r4a, R4b, R4C and R4d are independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl-C1-4 alkyl, CN, NO2, -NRA4RB4, -ORA4, -C (O) RA4, -C (═ NRE4) RA4, -C (═ N-ORB4) RA4, -C (O) ORA4, -oc (O) RA4, -C (O) NRA4RB4, -NRA 44 (O) 36rb, -C (═ NRE4) NRA4RB4, -NRA4 (nro) 4a 4 (NRA 4) 4a 4) 4 (nro) 4a 4) 4 (NRA 4) 4a 4 (nro) 4a 4 (NRA 4) 4a 4 (NRA 4) b), -NRA4C (═ NRE4) NRA4RB4, -s (O) rRA4, -s (O) (═ NRE4) RB4, -N ═ s (O) RA4RB4, -s (O)2ORA4, -os (O)2RA4, -NRA4S (O) rRB4, -NRA4S (O) (═ NRE4) RB4, -s (O) rrna 4RB4, -s (O) (═ NRE4) NRA4RB4, -NRA4S (O)2NRA4RB4, -NRA4S (O) (═ NRE4) NRA4RB4, -p (O) RA4RB4, and-p (O) (ORA4) (ORB4), wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently substituted by at least one, such as RX 3, RX 4, RX 3, or RX 4;

or each of "RA and RB", "RA 1 and RB 1", "RA 2 and RB 2", "RA 3 and RB 3", "RA 4 and RB 4", "RA 5 and RB 5" and "RA 6 and RB 6" together with the single or multiple atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1, 2or 3 RX groups;

Or RC and RD taken together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted with 1, 2or 3 RX groups;

or Rc1 and Rd1 together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted with 1, 2or 3 RY groups;

each Re1 is independently selected from hydrogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, CN, NO2, -ORa2, -SRa2, -S (O) rRa2, -C (O) Ra2, -C (O) ORa2, -S (O) rNRa2Rb2, and-C (O) NRa2Rb 2;

each Ra2 and each Rb2 is independently selected from the group consisting of hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl, and heteroaryl is unsubstituted or at least one, such as 1,2,3 or 4, substituted with substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

each Rc2 and each Rd2 is independently selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, C1-10 alkylamino, C3-10 cycloalkylamino, di (C1-10 alkyl) amino, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cycloalkoxy, alkylthio, cycloalkylthio, alkylamino, cycloalkylamino, heterocyclyl, aryl, and heteroaryl is unsubstituted or at least one, such as 1,2,3 or 4, substituted with substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

m is selected from 0, 1,2 and 3;

n is selected from 0, 1,2 and 3;

o is selected from 0, 1 and 2;

p is selected from 0, 1,2,3 and 4;

q is selected from 0 and 1;

Each r is independently selected from 0, 1 and 2;

Each t is independently selected from 0, 1,2,3 and 4,

Each u is independently selected from 0, 1,2,3, and 4.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the present invention provides a method for modulating Bcl-2, the method comprising administering to a system or subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, thereby modulating Bcl-2.

In another aspect, the present invention also provides a method of treating, ameliorating or preventing a condition responsive to inhibition of Bcl-2 comprising administering to a system or subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, optionally in combination with a second therapeutic agent, for treating the condition.

Alternatively, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition mediated by Bcl-2. In particular embodiments, the compounds can be used alone or in combination with a second therapeutic agent to treat a Bcl-2 mediated disorder.

Alternatively, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of a Bcl-2 mediated disorder.

In particular, wherein the disorder includes, but is not limited to, an autoimmune disease, a transplant disease, an infectious disease, or an abnormal cell proliferation.

In addition, the present invention provides a method of treating a cell proliferative disorder comprising administering to a system or subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or pharmaceutical composition thereof, optionally in combination with a second therapeutic agent, to treat the disorder.

Alternatively, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cell proliferative disorder. In particular embodiments, the compounds may be used alone or in combination with chemotherapeutic agents to treat abnormal cell proliferation disorders.

In particular, wherein the abnormal cell proliferation disorder includes, but is not limited to, lymphoma, osteosarcoma, melanoma, or a tumor of the breast, kidney, prostate, colorectal, thyroid, ovarian, pancreatic, neuronal, lung, uterine or gastrointestinal tract.

In the above methods of using the compounds of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered to a system comprising cells or tissues, or to an individual including a mammalian individual, such as a human or animal individual.

Term(s) for

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this patent belongs. All patents, patent applications, published publications, etc. referred to herein are incorporated by reference in their entirety unless otherwise indicated. As used in this patent, the same terms are defined differently than the definitions in this section.

it is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any claims. In this application, the use of the singular includes the plural unless otherwise indicated. It is noted that, in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is also noted that "or" represents "and/or" unless stated otherwise. Furthermore, "comprising," "including," and like terms are not intended to be limiting.

Standard definitions of chemical terms are referred to in the reference books, including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY, 4 th edition. Volumes "A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, the conventional techniques of mass spectrometry, nuclear magnetic resonance, high performance liquid chromatography, infrared and ultraviolet spectroscopy, and pharmacology used in this patent are prior art. Unless specifically defined, the nomenclature, protocols, and techniques involved in analytical chemistry, synthetic organic chemistry, pharmaceutical and pharmaceutical chemistry are those known in the art. Standard techniques are available for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and administration, and treatment of patients. The reaction and purification techniques may be carried out with reference to the manufacturer's instructions, or with reference to known, commonly used techniques, or with reference to the methods described in this patent. The techniques and procedures described above can be performed using methods that are conventional and well known in the literature cited in this specification. In the specification, groups and substituents may be selected by one skilled in the art to form stable structures and compounds.

When a substituent is referred to by a formula, the substituents in the formula are written from left to right as they are from right to left. As a non-limiting example, CH2O is the same as OCH 2.

"substituted" means that the hydrogen atom is replaced with a substituent. It is noted that substituents on a particular atom are constrained by their valency. In the definitions section, "Ci-j" refers to a range including a start point and an end point, where i and j are both integers representing the number of carbon atoms. For example, C1-4, C1-10, C3-10, and the like.

"alkyl", alone or in combination with other terms, refers to branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. "alkyl" means C1-10 alkyl, unless otherwise noted. For example, "C1-6" in "C1-6 alkyl" refers to a straight or branched arrangement of groups having 1,2,3,4, 5, or 6 carbon atoms. For example, "C1-8 alkyl" includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, heptyl, and octyl.

"cycloalkyl" whether used alone or in combination with other terms, refers to a monocyclic or bridged hydrocarbon ring system. Monocyclic cycloalkyl groups contain 3 to 10 carbon atoms, no heteroatoms, no double bonds. Examples of monocyclic systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Monocyclic cycloalkyl groups may contain one or two alkylene bridges, each comprising 1, 2or 3 carbon atoms, which are bonded to two non-adjacent carbon atoms in the ring system. Representative examples of bridged cycloalkyl systems include, but are not limited to, bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, bicyclo [4.2.1] nonane, tricyclo [3.3.1.03,7] nonane, and tricyclo [3.3.1.13,7] decane (adamantane). Monocyclic and bridged cycloalkyl groups may be attached to the parent molecular moiety through any substitutable atom in the ring system.

"alkenyl", alone or in combination with other terms, refers to a nonaromatic, straight chain, branched or cyclic hydrocarbon radical containing from 2 to 10 carbon atoms and having at least one carbon-carbon double bond. In some embodiments, 1 carbon-carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present. Thus, "C2-6 alkenyl" refers to alkenyl groups containing 2-6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain a double bond, and substituted alkenyl groups, if indicated, may be substituted.

"alkynyl", whether used alone or in combination with other terms, refers to a straight, branched or cyclic hydrocarbon radical containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to 3 carbon-carbon triple bonds may be present. Thus, "C2-6 alkynyl" refers to alkynyl groups containing 2-6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, 3-methylbutynyl, and the like. The straight, branched or cyclic portion of the alkynyl group may contain a triple bond, and a substituted alkynyl group, if indicated, may be substituted.

"halogen" means fluorine, chlorine, bromine, iodine.

"alkoxy", used alone or in combination with other terms, refers to an alkyl group attached to an oxygen atom by a single bond. The alkoxy group is attached to the molecule through an oxygen atom. Alkoxy groups may be represented as-O-alkyl. "C1-10 alkoxy" refers to an alkoxy group containing 1-10 carbon atoms and may be straight or branched. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, and the like.

"Cycloalkoxy", used alone or in combination with other terms, means a cycloalkyl group attached by a single bond to an oxygen atom. The cycloalkoxy group is attached to the molecule through an oxygen atom. Cycloalkoxy can be represented as-O-cycloalkyl. "C3-10 cycloalkoxy" means a cycloalkoxy group containing 3 to 10 carbon atoms. Cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.

"alkylthio", used alone or in combination with other terms, refers to an alkyl group attached by a single bond to a sulfur atom. Alkylthio groups are attached to the molecule through a sulfur atom. Alkylthio groups may be represented by-S-alkyl. "C1-10 alkylthio" refers to an alkylthio group containing 1-10 carbon atoms and having either a straight chain or a branched structure. Alkylthio includes, but is not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hexylthio, and the like.

"Cycloalkylsulfanyl", used alone or in combination with other terms, means a cycloalkyl group attached by a single bond to a sulfur atom. The cycloalkylthio group is bonded to the molecule through a sulfur atom. The cycloalkylthio group may be represented as-S-cycloalkyl. "C3-10 cycloalkylthio" means a cycloalkylthio group containing 3 to 10 carbon atoms. Cycloalkylthio groups include, but are not limited to, cyclopropylthio, cyclobutylthio, and cyclohexylthio, and the like.

"alkylamino", used alone or in combination with other terms, refers to an alkyl group attached to a nitrogen atom by a single bond. The alkylamino group is attached to the molecule through a nitrogen atom. Alkylamino can be represented as-NH (alkyl). "C1-10 alkylamino" refers to alkylamino groups containing 1-10 carbon atoms and can be straight or branched. Alkylamino includes, but is not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, hexylamino and the like.

"Cycloalkylamino", used alone or in combination with other terms, refers to a cycloalkyl group attached to a nitrogen atom by a single bond. The cycloalkylamino group is attached to the molecule through a nitrogen atom. The cycloalkylamino group may be represented as-NH (cycloalkyl). "C3-10 cycloalkylamino" refers to cycloalkylamino groups having 3 to 10 carbon atoms. Cycloalkylamino groups include, but are not limited to, cyclopropylamino, cyclobutylamino, cyclohexylamino and the like.

"Di (alkyl) amino", used alone or in combination with other terms, refers to two alkyl groups attached to a nitrogen atom by a single bond. The di (alkyl) amino group is attached to the molecule through a nitrogen atom. The di (alkyl) amino group may be represented by-N (alkyl) 2. "Di (C1-10 alkyl) amino" refers to a di (C1-10 alkyl) amino group in which the two alkyl moieties each contain 1-10 carbon atoms and which may be straight chain or branched.

"aryl", used alone or in combination with other terms, includes: 5-and 6-membered aromatic carbocyclic rings, such as phenyl; bicyclic rings having at least one aromatic carbon ring, such as naphthyl, indane and 1,2,3, 4-tetrahydroquinoline, and tricyclic rings having at least one aromatic carbon ring, such as fluorene. Aryl substituents are considered to be linked through an aromatic ring if they are bicyclic or tricyclic and at least one of the rings is non-aromatic.

for example, aryl includes 5-and 6-membered aromatic carbocyclic rings fused to a 5-to 7-membered heterocyclic ring containing one or more heteroatoms selected from N, O and S, provided that the site of attachment is an aromatic carbocyclic ring. Divalent radicals, which are formed from substituted benzene derivatives and have free valence electrons present at the ring atoms, are designated as substituted phenylene radicals. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals whose name ends with "-yl", which are obtained by removing one more hydrogen atom from a carbon atom containing a free valence electron, are named after the name of the monovalent radical plus "-idene (-idene)", for example, naphthyl, which has two attachment sites, is called naphthylidene. The definition of aryl, however, does not include, nor overlap with, heteroaryl, and is defined individually as follows. Thus, if one or more aromatic carbocyclic rings are fused to an aromatic heterocyclic ring, the ring system formed should be considered heteroaryl as defined herein rather than aryl.

"heteroaryl", used alone or in combination with other terms, means

A 5-to 8-membered aromatic monocyclic ring, which contains 1 to 4, and in certain embodiments 1 to 3, heteroatoms selected from N, O and S, with the remaining ring atoms being carbon atoms;

an 8-to 12-membered bicyclic ring containing a number of 1 to 4, and in certain embodiments 1 to 3, heteroatoms selected from N, O and S, the remaining ring atoms being carbon atoms, and wherein at least one heteroatom is present in the aromatic ring; and

11-to 14-membered tricyclic rings. The ring contains from 1 to 4, and in certain embodiments from 1 to 3 heteroatoms selected from N, O and S, the remaining ring atoms being carbon atoms, and at least one of the heteroatoms being present in the aromatic ring.

When the total number of S and O atoms in the heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 1.

Examples of heteroaryl groups include, but are not limited to (the numbering of the attachment site is preferred, as in position 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2, 3-pyrazinyl, 3, 4-pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 1-pyrazolyl, 2, 3-pyrazolyl, 2, 4-imidazolinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolinyl, pyridazinyl (pyridizinyl), triazolyl, quinolinyl, pyrazolyl, and 5,6,7, 8-tetrahydroisoquinolinyl.

further, heteroaryl groups include, but are not limited to, pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridazinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl. As defined below for heterocyclic groups, "heteroaryl" includes N-oxide derivatives of nitrogen-containing heteroaryl groups.

The nomenclature of a monovalent heteroaryl group ends with the "radical", the divalent group derived by removing a hydrogen atom from a carbon atom containing a free valence electron, is that name given to the monovalent group plus a "ene" (for example: the pyridyl group having two attachment sites is called a pyridylidene. The definition of heteroaryl does not include, nor overlap with, aryl as defined above.

If the substituents of the heteroaryl group are bicyclic or tricyclic and at least one of the rings is non-aromatic or free of heteroatoms, it is generally considered to be linked via an aromatic ring or a heteroatom-containing ring, respectively.

"heterocycle" (and derivatives thereof such as "heterocyclic" or "heterocyclyl") refers broadly to a single cyclic aliphatic hydrocarbon, typically having from 3 to 12 ring atoms, containing at least 2 carbon atoms, and further containing one or more, preferably 1-3 heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, as well as combinations comprising at least one of the foregoing heteroatoms. Alternatively, the heterocyclic ring as defined above may be a polycyclic ring system (e.g. bicyclic) wherein two or more rings are joined by a fused, bridged or spiro ring form, wherein at least one ring contains one or more heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus. "heterocyclic ring" also refers to 5-to 7-membered heterocyclic rings fused to 5-and 6-membered aromatic carbocyclic rings containing one or more heteroatoms selected from oxygen, sulfur, nitrogen, and phosphorus, provided that the site of attachment is on the heterocyclic ring. Heterocycles may be saturated or contain one to more double bonds (i.e., partially unsaturated). The heterocyclic ring may be substituted by oxo (oxo) or an imine, which may be unsubstituted or substituted. Either the carbon atom or the heteroatom of the heterocycle may be the attachment site, provided that a stable structure is formed. When a substituent is present on the heterocycle, the substituent may be attached to any heteroatom or carbon atom on the heterocycle, provided that a stable chemical structure is formed. The heterocyclic and heteroaryl definitions described herein do not overlap.

Suitable heterocycles include, for example (attachment site is preferably 1) 1-pyrrolidinyl, 2, 4-imidazolidinyl, 2, 3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2, 5-piperazinyl, 1, 4-piperazinyl and 2, 3-pyridazinyl. Morpholinyl is also contemplated, and 2-morpholinyl and 3-morpholinyl (oxygen position numbering is preferably 1) are also included. Substituted heterocycles also include ring systems substituted with one or more oxo groups, such as piperidinyl-N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl. Bicyclic heterocyclic compounds include, for example:

And

As used herein, "aryl-alkyl" refers to an aryl-substituted alkyl group. Exemplary aralkyl groups include benzyl, phenethyl, naphthylmethyl, and the like. In some embodiments, aralkyl groups contain 7 to 20 or 7 to 11 carbon atoms. When "aryl C1-4 alkyl" is used, wherein "C1-4" refers to the number of carbon atoms in the alkyl moiety rather than in the aryl moiety.

As used herein, "heterocyclyl-alkyl" refers to a heterocyclyl-substituted alkyl group. When "heterocyclyl-C1-4 alkyl" is used, wherein "C1-4" refers to the number of carbon atoms in the alkyl moiety rather than in the heterocyclyl moiety.

As used herein, "cycloalkyl-alkyl" refers to a cycloalkyl-substituted alkyl group. When "C3-10 cycloalkyl-C1-4 alkyl" is used, wherein "C3-10" refers to the number of carbon atoms in the cycloalkyl moiety rather than the alkyl moiety. Wherein "C1-4" refers to the number of carbon atoms in the alkyl moiety rather than the cycloalkyl moiety.

As used herein, "heteroaryl-alkyl" refers to heteroaryl-substituted alkyl. When "heteroaryl-C1-4 alkyl" is used, wherein "C1-4" refers to the number of carbon atoms in the alkyl moiety rather than in the heteroaryl moiety.

to avoid ambiguity, for example: when alkyl, cycloalkyl, heterocyclylalkyl, aryl and/or heteroaryl substituents are mentioned, it is meant that each of these groups is substituted individually or that these groups are mixed. That is: if R1 is aryl-C1-4 alkyl, the aryl moiety may be unsubstituted or substituted by at least one, such as 1,2,3 or 4, substituent groups independently selected from RX, and the alkyl moiety may also be unsubstituted or substituted by at least one, such as 1,2,3 or 4, substituent groups independently selected from RX.

"pharmaceutically acceptable salt" refers to salts with pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. The salt of an inorganic base may be selected, for example, from: aluminum, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganese, manganous, potassium, sodium and zinc salts. Further, the salt of a pharmaceutically acceptable inorganic base may be selected from ammonium, calcium, magnesium, potassium and sodium salts. One or more crystal structures may be present in the solid salt, as well as in the form of hydrates. The pharmaceutically acceptable salts of organic non-toxic bases may be selected, for example, from: primary, secondary and tertiary amine salts, the substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine and tripropylamine, tromethamine.

When the compounds disclosed herein are bases, it is desirable to prepare salts thereof with at least one pharmaceutically acceptable non-toxic acid selected from inorganic and organic acids. For example, selected from the group consisting of acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In some embodiments, these acids may be selected, for example: citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric and tartaric acids.

By "administering" or "administration" of a compound or a pharmaceutically acceptable salt thereof is meant providing a compound of the invention or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

An "effective amount" is an amount of a compound or a pharmaceutically acceptable salt thereof that is capable of eliciting a biological or medical response in a tissue, system, animal or human that is observable by a researcher, veterinarian, clinician or other clinician.

The "composition" includes: the invention may take the form of a kit, article of manufacture, or any combination thereof. The pharmaceutical composition comprises: products comprising the active ingredient and an inert ingredient as a carrier, as well as products produced by any two or more of the ingredients, directly or indirectly, by combination, complexation or aggregation, or by dissociation of one or more of the ingredients, or by other types of reactions or interactions of one or more of the ingredients.

By "pharmaceutically acceptable" is meant compatible with the other ingredients of the formulation and not unacceptably toxic to the subject.

"subject" refers to a subject having a disease, disorder, or the like, and includes mammals and non-mammals. Mammals include, but are not limited to, any member of the mammalian family: humans, non-human primates such as chimpanzees, and other apes and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs, and cats; the experimental animals include rodents such as rats, mice, guinea pigs, and the like. Non-mammalian animals include, but are not limited to, birds, fish, and the like. In one embodiment of the invention, the mammal is a human.

"treating" includes alleviating, alleviating or ameliorating a disease or condition, preventing other conditions, ameliorating or preventing a metabolic factor underlying a condition, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, promoting remission of a disease or condition, or arresting the signs of a disease or condition, and extends to include prevention. "treating" also includes achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit refers to eradication or amelioration of the condition being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disease, and amelioration of the disease in the patient is observed, although the patient may still be suffering from the underlying disease. Prophylactic benefit refers to the use of a composition by a patient to prevent the risk of a disease, or the use of a patient presenting with one or more physiological conditions of a disease, although the disease has not yet been diagnosed.

"protecting group" (Pg) refers to a class of substituents used to block or protect a particular functional group by reacting with other functional groups on a compound. For example, "amino protecting group" refers to a substituent attached to an amino group that blocks or protects the amino functionality on a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-Butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and-9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a class of hydroxy substituents that are effective in blocking or protecting the hydroxy function. Suitable protecting groups include, but are not limited to, acetyl and silyl groups. "carboxy protecting group" refers to a class of carboxy substituents that function effectively to block or protect a carboxy group. Common carboxyl protecting groups include-CH 2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfinyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For general description and instructions for use of protecting groups, see references: greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

"NH protecting group" includes, but is not limited to, trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzoyl, o-bromobenzyloxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, t-pentyloxycarbonyl, t-butyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl, 8-quinolinyloxycarbonyl, benzyl, benzhydryl, trityl, 2-nitrophenylthio, methanesulfonyl, p-toluenesulfonyl, N, n-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-l-naphthylmethylene, 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3-dimethyl-5-oxocyclohexylidene, diphenylphosphoryl, dibenzylphosphoryl, 5-methyl-2-oxo-2H-l, 3-dioxol-4-yl-methyl, trimethylsilyl, triethylsilyl and triphenylsilyl.

"C (O) OH" protecting groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 1-dimethylpropyl, n-butyl, t-butyl, phenyl, naphthyl, benzyl, benzhydryl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl, acetylmethyl, phenacyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 2,2, 2-trichloroethyl, 2- (trimethylsilyl) ethyl, acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl, succinimidylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, Benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

"OH or SH" protecting groups include, but are not limited to, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, 1-dimethylpropoxycarbonyl, isopropyloxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2, 2-trichloroethoxycarbonyl, 2,2, 2-tribromoethoxycarbonyl, 2- (trimethylsilane) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 4-ethoxy-1-naphthyloxycarbonyl, N-phenyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2,2, 2-trichloroethyl, 2-trimethylsilylethyl, 1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), p-methoxybenzyl, 3, 4-dimethoxybenzyl, diphenylmethyl, triphenylmethyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2, 2-trichloro-ethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 1-, 1-ethoxyethyl group, methanesulfonyl group, p-toluenesulfonyl group, trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, diethylisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, diphenylmethylsilyl group and tert-butylmethoxyphenylsilyl group.

Geometric isomers may exist in the compounds of the present invention. Compounds of the present invention may have carbon-carbon double bonds or carbon-nitrogen double bonds in either the E or Z configuration, where "E" represents the preferred substituent on the opposite side of the carbon-carbon double bond or carbon-nitrogen double bond and "Z" represents the preferred substituent on the same side of the carbon-carbon double bond or carbon-nitrogen double bond, as defined by Cahn-Ingold-Prelog preference. The compounds of the invention may also exist as mixtures of "E" and "Z" isomers. The substituents around the cycloalkyl or heterocyclyl group may be in either the cis or trans configuration. In addition, the present invention includes different isomers and mixtures thereof formed by different arrangements of substituents around the adamantane ring system. Two substituents around a single ring in an adamantane ring system are designated in either the Z or E relative configuration. See, for example, C.D.Jones, M.Kaselj, R.N.Salvatore, W.J.le Noble J.org.chem.1998,63, 2758-.

Compounds of the invention may contain asymmetrically substituted carbon atoms of R or S configuration, "R" and "S" are defined in IUPAC 1974Recommendations for Section E, functional Stereochemistry, Pure appl. chem. (1976)45, 13-10. Compounds containing asymmetrically substituted carbon atoms are racemates if the amounts of R and S configuration are the same. If one of the configurations is present in greater amounts than the other, the configuration of the chiral carbon atom is represented by the more abundant configuration, preferably with an enantiomeric excess of about 85-90%, more preferably about 95-99%, and even more preferably about 99% or more. Thus, the present invention encompasses racemic mixtures, relative and absolute stereoisomers, and mixtures of relative and absolute stereoisomers.

Isotopically enriched or labelled compounds

The compounds of the invention may exist in isotopically-labelled or enriched forms containing one or more atoms of different mass and mass numbers from the atom mass and mass number most prevalent in nature. The isotope may be a radioactive or non-radioactive isotope. Isotopes of atoms such as hydrogen, carbon, nitrogen, phosphorus, sulfur, fluorine, chlorine, and iodine include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 32P, 35S, 18F, 36Cl, and 125I. Other isotopes and/or other atoms containing these atoms are also within the scope of the present invention.

in another embodiment, the isotopically labeled compounds contain deuterium (2H), tritium (3H), or 14C isotopes. Isotopically-labeled compounds of the present invention can be obtained by employing procedures well known to those skilled in the art. These isotopically labeled compounds can be obtained by substituting a non-labeling reagent with an isotopically labeled reagent by referring to the examples and reaction schemes of the present invention. In certain examples, the compounds may be treated with isotopic labeling agents to replace atoms with isotopic atoms, e.g., replacement of hydrogen with deuterium may be exchanged by the action of a deuterated acid such as D2SO 4/D2O. In addition, relevant synthetic steps and intermediates can be found, for example, in Lizondo, J et al, Drugs Fut,21(11),1116 (1996); brickner, S J et al, J Med Chem,39(3),673 (1996); mallesham, B et al, Org Lett,5(7),963 (2003); PCT publication nos. WO1997010223, WO2005099353, WO1995007271, WO 2006008754; U.S. patent nos. 7538189, 7534814, 7531685, 7528131, 7521421, 7514068, 7511013; and U.S. patent application publication nos. 20090137457, 20090131485, 20090131363, 20090118238, 20090111840, 20090105338, 20090105307, 20090105147, 20090093422, 20090088416, and 20090082471, for specific methods see references.

isotopically-labelled compounds of the present invention are useful as standard compounds in binding assays for determining the effectiveness of a Bcl-2 inhibitor. Isotopically-containing compounds are useful in pharmaceutical research, evaluating the mechanism of action and metabolic pathways of non-isotopically-labelled parent compounds, and studying the in vivo metabolism of compounds (Blake et al, J. pharm. Sci.64,3,367-391 (1975)). Such metabolic studies are important for designing safe and effective therapeutic agents, and can be judged to be toxic or carcinogenic to the active compound administered to the patient in vivo or to the metabolite of the parent compound (Foster et al, Advances in Drug Research Vol.14, pp.2-36, Academic press, London, 1985; Kato et al, J.Labelled Comp.Radiopharmaceut.,36(10):927-932 (1995); Kushner et al, Can.J.Physiol.Pharmacol,77,79-88 (1999)).

In addition, drugs containing non-reflex active isotopes, such as deuterated drugs, known as "heavy drugs," are useful for treating diseases and disorders associated with Bcl-2 activity. The proportion of a certain isotope in a compound that exceeds its natural abundance is called enrichment. The amount of enrichment is, for example, from about 0.5, 1,2,3,4, 5,6,7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96 to about 100 mol%. In mammals, replacement of up to about 15% of the common atoms with heavy isotopes is effective and can last for days to weeks, including rodents and dogs, with fewer adverse effects (Czajka D M and Finkel A J, Ann.N.Y.Acad.Sci.196084: 770; Thomson J F, Ann.New York Acad.Sci 196084: 736; Czakja D M et al, am.J.Physiol.1961201: 357). Replacement of up to 15-23% of the body fluids in humans with deuterium does not cause toxicity (Blagojevic N et al in "Dosimetry & Treatment Planning for Neutron Capture Therapy", Zamenhof R, Solares G and Harling O eds.1994.advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23:251 (1997)).

Stable isotopic labels of drugs can alter the physicochemical properties of the drug, such as pKa and liquid solubility. If isotopic substitution affects the region associated with ligand-receptor interaction, then these effects and changes may affect the pharmacodynamic response of the drug molecule. Certain physical properties of stable isotope-labeled molecules differ from those of unlabeled molecules, while chemical and biological properties are the same, but with one important difference: any chemical bond containing a heavy isotope and another atom is stronger than a light isotope due to the increased mass of the heavy isotope. Accordingly, the presence of isotopes at the metabolic or enzymatic conversion sites slows the reaction and may alter its pharmacokinetic or pharmacodynamic properties compared to non-isotopically labeled compounds.

In embodiment (1), the present invention provides a compound represented by formula (I):

Or a pharmaceutically acceptable salt thereof, wherein:

L1, L2, L3 and L4 are independently selected from- (crd) u-, - (crd) uo (crd) t-, - (crd) uNRA (crd 5) t-, - (crd) us (crd) t-, - (crd) uC (o) (crd) t-, - (crd) uC (NRE) (crd) t-, - (crd) uC (crd) s (crd) t-, - (crd) uC (o) (crd) t-, - (crd) uoc (o) (crd) t-, - (crd) uC (nrc) (crd) t-, - (crd) nruc (o) (c) nrc (crd) t-, - (crd) nrc (nrc) (crd) t-, - (crd) nrc (c (crd) t-, - (crd) nrc (crd) t-) (crd) nrc (crd) t-, - (crd) nrc (cr, - (CRD) uC (S) NRA (CRD) t-, - (CRD) uNRAC (S) NRB (CRCRD) t-, - (CRD) uS (O) r (CRD) t-, - (CRD) uS (O) rNRA5(CRC5RD5) t-, - (CRC5RD5) uNRAS (O) r (CRCRD) t-and- (CRD) uNRAS (O) rNRB (CRD) t-;

When Q3 is C3-10 cycloalkyl, Y1, Y2 and Y3 are independently selected from (CR6aR6b) o, wherein cycloalkyl is unsubstituted or substituted with at least one substituent independently selected from RX;

X1 and X2 are independently selected from C and N;

X3 is selected from CR4d and O;

y4 is selected from C and N;

z is selected from C and N;

each RA, RA1, RA2, RA3, RA4, RA5, RA6, RB1, RB2, RB3, RB4, RB5, and RB6 is independently selected from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively, is unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RX;

Each RC and RD is independently selected from hydrogen, halogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, heterocyclyl-C1-4 alkyl, aryl-C1-4 alkyl, heteroaryl, and heteroaryl-C1-4 alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, respectively, is unsubstituted or substituted with at least one, such as 1,2,3, or 4, substituent independently selected from RX;

or Ra2 and Rb2 together with the atom or atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

or Rc2 and Rd2 taken together with the carbon atom or atoms to which they are attached form a 3-12 membered ring containing 0, 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen, which ring may be optionally substituted with 1 or 2 substituents independently selected from halogen, CN, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, hydroxy, C1-10 alkoxy, C3-10 cycloalkoxy, C1-10 alkylthio, C3-10 cycloalkylthio, amino, C1-10 alkylamino, C3-10 cycloalkylamino and di (C1-10 alkyl) amino;

m is selected from 0, 1,2 and 3;

n is selected from 0, 1,2 and 3;

o is selected from 0, 1 and 2;

p is selected from 0, 1,2,3 and 4;

q is selected from 0 and 1;

each r is independently selected from 0, 1 and 2;

Each t is independently selected from 0, 1,2,3 and 4,

Each u is independently selected from 0, 1,2,3, and 4.

In another embodiment (2), the present invention provides a compound of embodiment (1), or a pharmaceutically acceptable salt thereof, wherein Q1 is aryl, wherein aryl is unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (3), the present invention provides a compound of embodiment (2), or a pharmaceutically acceptable salt thereof, wherein Q1 is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (4), the present invention provides a compound of embodiment (3), or a pharmaceutically acceptable salt thereof, wherein Q1 is phenyl, wherein phenyl is unsubstituted or substituted with at least one substituent independently selected from C1-4 alkyl, C3-6 cycloalkyl, halogen, CN, CF3, and OCF3, wherein alkyl and cycloalkyl are each unsubstituted or substituted with at least one substituent independently selected from RY.

In another embodiment (5), the present invention provides a compound of embodiment (4), or a pharmaceutically acceptable salt thereof, wherein Q1 is phenyl, wherein the phenyl is substituted with halo.

In another embodiment (6), the present invention provides a compound of embodiment (5) or a pharmaceutically acceptable salt thereof, wherein Q1 is

In another embodiment (7), the present invention provides a compound of embodiment (1), or a pharmaceutically acceptable salt thereof, wherein Q1 is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (8), the present invention provides a compound of any one of embodiments (1) - (7), or a pharmaceutically acceptable salt thereof, wherein Q2 is aryl, wherein aryl is unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (9), the present invention provides a compound of any one of embodiments (1) - (7), or a pharmaceutically acceptable salt thereof, wherein Q2 is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (10), the present invention provides a compound of embodiment (9), or a pharmaceutically acceptable salt thereof, wherein Q2 is selected from and it is unsubstituted or substituted with at least one substituent independently selected from RX.

in another embodiment (11), the present invention provides a compound of any one of embodiments (1) to (10), or a pharmaceutically acceptable salt thereof, wherein L1 is- (CRCRD) u-.

In another embodiment (12), the present invention provides a compound of embodiment (11), or a pharmaceutically acceptable salt thereof, wherein L1 is-CH 2-.

In another embodiment (13), the present invention provides a compound of any one of embodiments (1) to (12), or a pharmaceutically acceptable salt thereof, wherein L2 is selected from the group consisting of- (CRCRD) u-, - (crd) uo (crcrcrd) t-, - (crd) us (crd) t-, - (crd) us (o) r (crd) t-.

In another embodiment (14), the present invention provides a compound of embodiment (13), or a pharmaceutically acceptable salt thereof, wherein L2 is selected from the group consisting of-O-, -S-, and-S (O) r-.

In another embodiment (15), the present invention provides a compound of embodiment (14), or a pharmaceutically acceptable salt thereof, wherein L2 is-O-.

in another embodiment (16), the present invention provides a compound of embodiment (14), or a pharmaceutically acceptable salt thereof, wherein L2 is-S-.

In another embodiment (17), the present invention provides a compound of embodiment (13), or a pharmaceutically acceptable salt thereof, wherein L2 is- (CRCRD) u-and u is 0.

In another embodiment (18), the present invention provides a compound of any one of embodiments (1) - (17), or a pharmaceutically acceptable salt thereof, wherein X1 is C.

In another embodiment (19), the present invention provides a compound of any one of embodiments (1) - (17), or a pharmaceutically acceptable salt thereof, wherein X1 is N.

In another embodiment (20), the present invention provides a compound of any one of embodiments (1) - (19), or a pharmaceutically acceptable salt thereof, wherein X2 is C.

In another embodiment (21), the present invention provides a compound of any one of embodiments (1) - (19), or a pharmaceutically acceptable salt thereof, wherein X2 is N.

In another embodiment (22), the present invention provides a compound of any one of embodiments (1) - (21), or a pharmaceutically acceptable salt thereof, wherein X3 is CR4aR4 b.

In another embodiment (23), the present invention provides a compound of embodiment (22), or a pharmaceutically acceptable salt thereof, wherein X3 is selected from CH2 and C (CH3) 2.

In another embodiment (24), the present invention provides a compound of any one of embodiments (1) - (21), or a pharmaceutically acceptable salt thereof, wherein X3 is O.

In another embodiment (25), the invention provides a compound of embodiment (1), or a pharmaceutically acceptable salt thereof, wherein

Q1 is aryl, wherein aryl is unsubstituted or substituted with at least one substituent independently selected from RX;

Q2 is heteroaryl, wherein heteroaryl is unsubstituted or substituted with at least one substituent independently selected from RX;

L1 is- (CRCRCD) u-; l2 is selected from the group consisting of- (CRCRD) u-, - (CRCRD) uO (CRCRD) t-, - (CRD) uS (CRD) t-, - (CRD) uS (O) r (CRCRD) t-;

x1 is N; x2 is N; x3 is-CR 4cR4 d; z is C;

R1 is NO 2or SO2CF 3; r2 is hydrogen; r3 is hydrogen; m is 1; n is 1; p is 1;

R4a and R4b are independently selected from hydrogen and C1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from RX.

in another embodiment (26), the invention provides a compound of embodiment (25), or a pharmaceutically acceptable salt thereof, wherein

q1 is phenyl, wherein the phenyl is unsubstituted or substituted with at least one, independently selected from C1-4 alkyl, C3-6 cycloalkyl, halogen, CN, CF3 and OCF 3;

q2 is selected from and each of which is independently unsubstituted or substituted with at least one substituent independently selected from RX;

L1 is- (CH2) u-; l2 is selected from the group consisting of a bond, -O-, -S-, and-S (O) r-;

x1 is N; x2 is N; x3 is selected from-CH 2-and-C (CH3) 2;

R1 is NO 2;

r4a and R4b are independently selected from hydrogen and C1-10 alkyl.

In another embodiment (27), the invention provides a compound of embodiment (26), or a pharmaceutically acceptable salt thereof, wherein

q1 is Q2 is selected from the group consisting of

L1 is-CH 2-; l2 is a bond or-O-;

x1 is N; x2 is N; x3 is-CH 2-;

R4a and R4b are independently selected from hydrogen and methyl.

In another embodiment (28), the present invention provides a compound of any one of embodiments (1) - (27), or a pharmaceutically acceptable salt thereof, wherein Q3 is heterocyclyl.

in another embodiment (29), the present invention provides a compound of embodiment (28), or a pharmaceutically acceptable salt thereof, wherein Y1 is NRE 9.

in another embodiment (30), the present invention provides a compound of embodiment (29), or a pharmaceutically acceptable salt thereof, wherein Y1 is NH.

In another embodiment (31), the present invention provides a compound of embodiment (28), or a pharmaceutically acceptable salt thereof, wherein Y1 is O.

In another embodiment (32), the present invention provides a compound of embodiment (28), or a pharmaceutically acceptable salt thereof, wherein Y1 is S.

in another embodiment (33), the present invention provides a compound of any one of embodiments (28) - (32), or a pharmaceutically acceptable salt thereof, wherein Y2 is CR6aR6 b.

in another embodiment (34), the present invention provides a compound of embodiment (33), or a pharmaceutically acceptable salt thereof, wherein Y2 is CH 2.

in another embodiment (35), the present invention provides a compound of any one of embodiments (28) - (32), or a pharmaceutically acceptable salt thereof, wherein Y2 is NH.

in another embodiment (36), the present invention provides a compound of any one of embodiments (28) - (32), or a pharmaceutically acceptable salt thereof, wherein Y2 is O.

In another embodiment (37), the present invention provides a compound of any one of embodiments (28) - (32), or a pharmaceutically acceptable salt thereof, wherein Y2 is S.

in another embodiment (38), the present invention provides a compound of any one of embodiments (28) - (37), or a pharmaceutically acceptable salt thereof, wherein Y3 is selected from (CR6aR6b) o, and o is selected from 0 and 1.

In another embodiment (39), the present invention provides a compound of embodiment (38), or a pharmaceutically acceptable salt thereof, wherein Y3 is CR6aR6 b.

in another embodiment (40), the present invention provides a compound of embodiment (39), or a pharmaceutically acceptable salt thereof, wherein R6a and R6b are independently selected from hydrogen and C1-10 alkyl.

In another embodiment (41), the present invention provides a compound of any one of embodiments (28) to (40), or a pharmaceutically acceptable salt thereof, wherein Y4 is C.

In another embodiment (42), the present invention provides a compound of any one of embodiments (28) - (40), or a pharmaceutically acceptable salt thereof, wherein Y4 is N.

In another embodiment (43), the present invention provides a compound of any one of embodiments (1) - (27), or a pharmaceutically acceptable salt thereof, wherein Q3 is aryl.

In another embodiment (44), the present invention provides a compound of any one of embodiments (1) - (27), or a pharmaceutically acceptable salt thereof, wherein Q3 is heteroaryl.

In another embodiment (45), the present invention provides a compound of embodiment (44), or a pharmaceutically acceptable salt thereof, wherein Q3 is

in another embodiment (46), the present invention provides a compound of any one of embodiments (28) - (42), or a pharmaceutically acceptable salt thereof, wherein Q3 is selected from the group consisting of

In another embodiment (47), the invention provides a compound of any one of embodiments (1) - (27), or a pharmaceutically acceptable salt thereof, wherein Q3 is C3-10 cycloalkyl.

in another embodiment (48), the invention provides a compound of any one of embodiments (1) - (47), or a pharmaceutically acceptable salt thereof, wherein Z is C.

In another embodiment (49), the present invention provides a compound of any one of embodiments (1) - (47), or a pharmaceutically acceptable salt thereof, wherein Z is N.

in another embodiment (50), the present invention provides a compound of any one of embodiments (1) - (49), or a pharmaceutically acceptable salt thereof, wherein R1 is selected from NO2 and SO2CF3, and m is 1.

In another embodiment (51), the present invention provides a compound of any one of embodiments (1) - (50), or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, CN, alkoxy, CN, -NRA2RB2, and-ORA 2.

In another embodiment (52), the present invention provides a compound of embodiment (51), or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

In another embodiment (53), the present invention provides a compound of any one of embodiments (1) - (52), or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, CN, -NRA3RB3, and-ORA 3.

in another embodiment (54), the present invention provides a compound of embodiment (53), or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen.

In another embodiment (55), the present invention provides a compound of any one of embodiments (1) - (54), or a pharmaceutically acceptable salt thereof, wherein R4a and R4b are independently selected from hydrogen and C1-10 alkyl, wherein alkyl is unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (56), the present invention provides a compound of embodiment (55), or a pharmaceutically acceptable salt thereof, wherein R4a and R4b are independently selected from hydrogen and methyl.

In another embodiment (57), the invention provides a compound of any one of embodiments (1) - (56), or a pharmaceutically acceptable salt thereof, wherein L3 is selected from the group consisting of- (crd) u-, - (crd) uo (crd) t-, - (crd) uc (o), (crd) t-, - (crd) uoc (o), (crd) t-, - (crd) uc (o), (crd) t-, - (crd) urnrac (o), (crd) t-, - (crd) uc (o) nra (crd) t-, - (crd) urnac (o) o (crd) t-, - (crd) us (o) crd) t-, - (crd) crd r (crd) t-and- (5 RD5) nrus (o) t-, - (crd) t-.

In another embodiment (58), the invention provides a compound of embodiment (57), or a pharmaceutically acceptable salt thereof, wherein u is selected from 0, 1 and 2, and t is selected from 0 and 1.

In another embodiment (59), the invention provides a compound of embodiment (58), or a pharmaceutically acceptable salt thereof, wherein L3 is selected from the group consisting of a bond, -CH2-, - (CH2)2-, -CH2O-, - (CH2)2O-, - (CH2)2oc (O) -, -c (O) O-, -CH2C (O) -, -CH2C (O) O-, -CH2OC (O) -, -c (O) NCH3-, -CH2NHC (O) O-, - (CH2)2NHC (O) -, - (CH2)2NHC (O) O-, - (CH2)2SO2-, and-CH 2NHSO 2-.

In another embodiment (60), the present invention provides a compound of any one of embodiments (1) - (59), or a pharmaceutically acceptable salt thereof, wherein q is selected from 0 and 1.

In another embodiment (61), the invention provides a compound of embodiment (60), or a pharmaceutically acceptable salt thereof, wherein q is 0.

in another embodiment (62), the present invention provides a compound of embodiment (60), or a pharmaceutically acceptable salt thereof, wherein q is 1.

In another embodiment (63), the present invention provides a compound of any one of embodiments (1) - (62), or a pharmaceutically acceptable salt thereof, wherein each R5a is independently selected from C1-10 alkyl, C3-10 cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein alkyl, cycloalkyl, and heterocyclyl are each unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (64), the present invention provides a compound of embodiment (63), or a pharmaceutically acceptable salt thereof, wherein R5a is selected from the group consisting of phenyl, pyridyl, pyridinyl, substituted pyridinyl,

And which is unsubstituted or substituted with at least one substituent independently selected from RX.

In another embodiment (65), the present invention provides a compound of embodiment (64), or a pharmaceutically acceptable salt thereof, wherein R5a is selected from the group consisting of phenyl, pyridyl, pyridinyl, substituted pyridinyl,

And wherein phenyl and pyridyl are unsubstituted or substituted with at least one substituent independently selected from the group consisting of halogen, CN, ORA5, and-s (o) rRA 5.

in another embodiment (66), the invention provides a compound of any one of embodiments (1) - (65), or a pharmaceutically acceptable salt thereof, wherein L4 is selected from- (CRCRD) u-and u is selected from 0, 1 and 2.

in another embodiment (67), the present invention provides a compound of any one of embodiments (1) - (66), or a pharmaceutically acceptable salt thereof, wherein R5b is selected from hydrogen, halogen, C1-10 alkyl, C3-10 cycloalkyl, C3-10 heterocyclyl, CN, -ORA5, -NRA5RB5, -NRA5C (O) ORB5, -N ═ s (O) RA5RB5, -C (O) RA5, -C (O) ORA5, -C (O) NRA5RB5, and-s (O) rRA 5.

in another embodiment (68), the present invention provides a compound of embodiment (67), or a pharmaceutically acceptable salt thereof, wherein R5b is selected from hydrogen, fluoro, methyl, ethyl, isopropyl, cyclopropyl, oxetanyl, CN, OH, -OCH3, -N (CH3)2, -N ═ s (o) (CH3)2, -nhc (o) OCH3, -C (o) -C-CH3, -C (o) C2H5, -C (o) -, -C3H7, -C (o) OCH3, -C (o) OC (CH3)3, -C (o) N (CH3)2, -SOCH3, and-s (o)2CH 3.

In another embodiment (69), the present invention provides a compound of embodiment (67), or a pharmaceutically acceptable salt thereof, wherein R5b is selected from-NRA 5RB5, -N ═ s (o) RA5RB5, wherein RA5 and RB5 together with the atoms to which they are attached form a 4-12 membered heterocyclic ring containing 0, 1 or 2 additional heteroatoms independently selected from oxygen, sulfur, nitrogen and phosphorus, which ring may be optionally substituted with 1, 2or 3 RX groups.

In another embodiment (70), the present invention provides a compound of embodiment (69), or a pharmaceutically acceptable salt thereof, wherein R5b is selected from the group consisting of

In another embodiment (71), the compounds provided herein are selected from

Or a pharmaceutically acceptable salt thereof.

In another embodiment (71), the invention provides a pharmaceutical composition comprising a compound of any one of embodiments (1) to (70), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

in another embodiment (72), the invention provides a method of treating, ameliorating, or preventing a disorder that inhibits Bcl-2, comprising administering to a subject in need thereof an effective amount of the compound of any one of embodiments (1) - (70), or a pharmaceutically acceptable salt thereof, or at least one pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

in another embodiment (73), the invention provides the use of a compound of any one of embodiments (1) - (70), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a cell proliferation disorder.

in another aspect, the invention provides a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and instructions including one or more of the following: instructions for what disease state the composition is to be applied to, information stored on the composition, dosage information, and how to use the composition. In one particular variant, the kit comprises the compound in a multiple dose form.

In another aspect, the present invention provides an article of manufacture comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof; and a packaging material. In one variation, the packaging material includes a container containing the compound. In one particular variation, the container includes a label that identifies one or more of the following: instructions for what disease the compound applies to, stored information, dosage information, and/or how to use the compound. In another variation, the article of manufacture comprises the compound in a multiple dose form.

In another aspect, the invention provides a method of treatment comprising administering to a subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a method of inhibiting Bcl-2 kinase comprising contacting a compound disclosed herein, or a pharmaceutically acceptable salt thereof, with Bcl-2.

In another aspect, the invention provides a method of inhibiting Bcl-2 comprising causing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in a subject to inhibit Bcl-2 activity in the subject.

In another aspect, the invention provides a method of inhibiting Bcl-2 comprising administering to a subject a first compound that converts in vivo to a second compound, wherein the second compound inhibits Bcl-2 activity in vivo, and the second compound is a compound or variant of any of the above embodiments.

In another aspect, the invention provides a method of treating a disease state in which Bcl-2 activity contributes to the pathology and/or symptomology of the disease state, comprising causing a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, to be present in an individual.

In another aspect, the invention provides a method of treating a disease state for which Bcl-2 activity contributes to the pathology and/or symptomology of the disease state, the method comprising administering to a subject a first compound that converts in vivo to a second compound, wherein the second compound inhibits Bcl-2 activity in vivo. It is noted that the compound of the present invention may be the first or second compound.

in variations of each of the above methods, the disease state is selected from: cancerous proliferative diseases (e.g., brain, lung, squamous cell, bladder, stomach, pancreas, breast, head, neck, kidney, ovary, prostate, colorectal, epidermal, esophageal, testicular, gynecological, or thyroid cancer); non-cancerous proliferative diseases (e.g., benign skin hyperplasia (e.g., psoriasis), restenosis, and Benign Prostatic Hypertrophy (BPH)); pancreatitis; kidney disease; pain; preventing implantation of blastocysts; treating diseases associated with angiogenesis or vasculogenesis (e.g., tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, colon cancer, and epidermoid cancer); asthma; neutrophil chemotaxis (e.g., reperfusion injury from myocardial infarction and stroke and inflammatory arthritis); septic shock; t cell mediated diseases in which immunosuppression is of value (e.g. prevention of organ transplant rejection, graft versus host disease, lupus erythematosus, multiple sclerosis and rheumatoid arthritis); atherosclerosis; inhibiting keratinocytes responsive to the growth factor mixture; chronic Obstructive Pulmonary Disease (COPD) and other diseases.

in another aspect, the present invention provides a method of treating a disease state for which a Bcl-2 gene mutation contributes to the pathology and/or symptomology of the disease state, such as melanoma, lung cancer, colon cancer and other types of tumors.

In another aspect, the present invention relates to the use of compounds and variants of any one of the above embodiments as medicaments. In another aspect, the present invention relates to the use of compounds and variants of any one of the above embodiments for the preparation of a medicament for inhibiting Bcl-2.

in another aspect, the present invention relates to the use of compounds and variants of any one of the above embodiments for the manufacture of a medicament for the treatment of disease states for which Bcl-2 activity contributes to its pathology and/or symptomology.

Administration and pharmaceutical compositions

Generally, the compounds of the present invention will be administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any of the usual and acceptable means known in the art. The therapeutically effective amount may vary widely depending on the severity of the disease, age and relative health of the subject, the potency of the compound used and other factors known in the art. For example, for the treatment of neoplastic diseases and immune system diseases, the required dosage will vary depending upon the mode of administration, the particular condition being treated and the desired effect.

In general, satisfactory results are achieved at daily dosages of from 0.001 to 100mg/kg body weight, in particular from about 0.03 to 2.5mg/kg body weight. Daily doses for larger mammals, such as humans, may be administered in a convenient form, for example in divided doses up to four times a day or in sustained release form, from about 0.5mg to about 2000mg, or more specifically, from 0.5mg to 1000 mg. Suitable unit dosage forms for oral administration contain from about 1 to 50mg of the active ingredient.

The compounds of the present invention may be administered in the form of pharmaceutical compositions, by any conventional route; e.g., enterally, e.g., orally, e.g., in the form of tablets or capsules, parenterally, e.g., in the form of injectable solutions or suspensions; or topically, e.g., in the form of a lotion, gel, ointment, or cream, or in the form of a nasal or suppository.

pharmaceutical compositions containing a compound of the invention in free base or pharmaceutically acceptable salt form in association with at least one pharmaceutically acceptable carrier or diluent may be manufactured in conventional manner by means of mixing, granulating, coating, dissolving or lyophilizing processes. For example, pharmaceutical compositions comprising a compound of the invention in combination with at least one pharmaceutically acceptable carrier or diluent may be formulated in conventional manner by admixture with a pharmaceutically acceptable carrier or diluent. Unit dosage forms for oral administration contain, for example, from about 0.1mg to about 500mg of active substance.

In one embodiment, the pharmaceutical composition is a solution, including a suspension or dispersion, such as an isotonic aqueous solution, of the active ingredient. In the case of lyophilized compositions comprising the active ingredient alone or in admixture with a carrier such as mannitol, dispersions or suspensions may be prepared prior to use. The pharmaceutical compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid, microbicides such as sorbic acid or benzoic acid. The solution or suspension may also contain a thickening agent including, but not limited to, sodium carboxymethylcellulose, dextran, polyvinylpyrrolidone, gelatin, or a solubilizing agent such as tween 80 (polyoxyethylene (20) sorbitan monooleate).

Suspensions in oils may contain, as oily component, vegetable oils, synthetic or semi-synthetic oils, commonly used for injection purposes. Examples include liquid fatty acid esters containing as the acid component a long chain fatty acid having from 8 to 22 carbon atoms, or in some embodiments, from 12 to 22 carbon atoms. Suitable liquid fatty acid esters include, but are not limited to, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic acid, behenic acid or corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassidic acid and linoleic acid, if desired, with antioxidants such as vitamin E, 3-carotene or 3, 5-di-tert-butylhydroxytoluene. The alcohol component of these fatty acid esters may have six carbon atoms and may be monovalent or polyvalent, such as mono-, di-or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol or pentanol or isomers thereof, ethylene glycol and glycerol.

Other suitable fatty acid esters include, but are not limited to, ethyl oleate, isopropyl myristate, isopropyl palmitate, M2375 (polyoxyethylene glycerol), M1944 CS (unsaturated pegylated glycerides prepared by alcoholysis of almond oil and containing glycerides and polyethylene glycol esters), LABRASOLTM (saturated pegylated glycerides prepared by alcoholysis of TCM and containing glycerides and polyethylene glycol esters; both available from GaKefosse, France), and/or 812 (saturated fatty acid triglycerides of chain length C8 to C12, Huls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil or peanut oil.

pharmaceutical compositions for oral administration may be obtained, for example, by mixing the active ingredient with one or more solid carriers, if desired granulating a resulting mixture, and processing the mixture or granules by adding further excipients, in the form of tablets or tablet cores.

Suitable carriers include, but are not limited to, fillers, for example sugars, such as lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, for example starches, such as corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrants, such as the above-mentioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients include flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol, or derivatives thereof.

the tablet cores may be provided with a suitable, optionally enteric, coating by using, inter alia, a concentrated sugar solution, which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or a coating solution in a suitable organic solvent or solvent mixture, or, for enteric coatings, a solution of a suitable cellulose preparation, such as an acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate solution. Dyes or pigments may be added to the tablets or tablet coatings, for example for identification purposes or to indicate different doses of the active ingredient.

pharmaceutical compositions for oral administration may also include hard capsules, including gelatin or soft, sealed capsules containing gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active ingredients in the form of granules, for example in admixture with fillers such as corn starch, binders and/or glidants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient may be dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oils or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, to which stabilizers and detergents, for example of the fatty acid ester type of polyoxyethylene sorbitol, are added.

pharmaceutical compositions suitable for rectal administration, for example suppositories, comprise a combination of the active ingredient and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.

pharmaceutical compositions suitable for parenteral administration may comprise the active ingredient in water-soluble form, for example as a water-soluble salt or as an aqueous injection suspension comprising a viscosity-increasing substance, for example sodium carboxymethylcellulose, an aqueous solution of sorbitol and/or dextran, if desired, and a stabilizer. The active ingredient, optionally together with excipients, may also be in a lyophilized form and may be prepared as a solution by addition of a suitable solvent prior to parenteral administration. The solutions used, for example for parenteral administration, can also be used as infusion solutions. Injectable preparations are generally prepared under sterile conditions, and filled, for example, in ampoules or vials, and in sealed containers.

The invention also provides a pharmaceutical combination, e.g. a kit, comprising a) a compound disclosed herein, in free form or in pharmaceutically acceptable salt form, and b) at least one auxiliary agent. The kit may contain instructions for its use.

combination therapy

The compounds or pharmaceutically acceptable salts described in this disclosure may be used alone or in combination with other therapeutic agents.

For example, the therapeutic benefit of a compound of the invention may be enhanced by the use of an adjuvant drug (e.g., the therapeutic benefit of the adjuvant drug alone may be minimal, but the therapeutic benefit of the subject may be enhanced when used in combination with another drug), or, for example, the therapeutic benefit of the subject may be enhanced by the use of a compound of the invention in combination with another therapeutic agent that is also therapeutically effective. For example, in the treatment of gout, the compound of the invention may be used in combination with another drug for gout therapy to enhance clinical benefit. Alternatively, for example, if the adverse effect of using the compounds of the present invention is nausea, then an anti-nausea agent may be used in combination. Alternatively, therapies that can be combined include, but are not limited to, physical therapy, psychotherapy, radiation therapy, compression therapy of the diseased area, rest, dietary improvement, and the like. Regardless of the disease, disorder, or condition being treated, both therapies should have additive or synergistic effects to benefit the treatment of an individual.

where the compounds described herein are used in combination with other therapeutic agents, the route of administration of the pharmaceutical compositions of the compounds described herein may be the same as the other drugs, or the route of administration may be different due to differences in physical and chemical properties. For example, oral administration of a compound described herein may produce and maintain good blood levels, while intravenous administration of another therapeutic agent may be required. Thus, the compounds described herein and another therapeutic agent may be administered simultaneously, sequentially or separately.

The compounds of formula (I) are expected to be effective in combination with one or more of the following: alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors, promoters of other apoptosis (e.g., Bcl-xL, Bcl-w, and Bfl-1) inhibitors, death receptor pathway activators, Bcr-Abl kinase inhibitors, antibodies to BiTE (bispecific T-cell engagers), antibody drug conjugates, biological response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 ErbB inhibitors, DVDs, leukemia virus oncogene homolog (2) receptor inhibitors, growth factor inhibitors, Heat Shock Protein (HSP) -90 inhibitors, histone acetylases (HDAC) inhibitors, hormonal therapies, immunological agents, inhibitors of apoptosis protein Inhibitors (IAPs), intercalating antibiotics, inhibitors of apoptosis proteins, and the like, Kinase inhibitors, kinesin inhibitors, Jak2 inhibitors, rapamycin inhibitors directed to mammals, microRNAs, mitogen-activated extracellular signal-regulated kinase inhibitors, multivalent binding proteins, nonsteroidal anti-inflammatory drugs (NSAIDs), poly ADP (adenosine diphosphate) -ribose polymerase (PARP) inhibitors, platinum-based chemotherapeutic drugs, polo-like kinase (Plk) inhibitors, phosphoinositide 3 kinase (PI3K) inhibitors, proteasome inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine kinase inhibitors, retinoid/deltoid plant alkaloids, small interfering RNAs (siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and the like.

examples

there are various methods for synthesizing the compound of formula (I) or a pharmaceutically acceptable salt thereof, and representative methods are listed in this example. However, it is to be noted that the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be obtained by synthesis in other synthetic schemes.

In certain compounds of formula (I), the attachment of atoms to other atoms may result in the presence of particular stereoisomers (e.g. chiral centres). The synthesis of a compound of formula (I) or a pharmaceutically acceptable salt thereof may result in a mixture of different isomers (enantiomers, diastereomers). Unless a particular configuration is specified, all recited compounds include different stereoisomers that may exist.

The compounds of formula (I) may also be prepared as pharmaceutically acceptable acid addition salts, for example, by reacting the free base form of the compounds of the invention with a pharmaceutically acceptable inorganic or organic acid. Or a compound of formula (I) in free acid form with a pharmaceutically acceptable inorganic or organic base, to form a pharmaceutically acceptable base addition salt. Inorganic and organic acids and bases suitable for preparing pharmaceutically acceptable salts of the compounds of formula (I) are described in the definitions section herein. In addition, salt forms of the compounds of formula (I) can also be prepared by using salts of the starting materials or intermediates.

The free acid or base of the compound of formula (I) may be prepared from the corresponding base addition salt or acid addition salt thereof. The acid addition salt forms of the compounds of formula (I) may be converted to the corresponding free base, for example by treatment with a suitable base such as ammonium hydroxide solution, sodium hydroxide and the like. The base addition salt forms of the compounds of formula (I) may be converted to the corresponding free acids, for example by treatment with a suitable acid such as hydrochloric acid and the like.

an N-oxide of a compound of formula (I) or a pharmaceutically acceptable salt thereof may be prepared by methods known in the art. For example, the N-oxide can be obtained by reacting a non-oxidized form of the compound of formula (I) with an oxidizing agent (e.g., trifluoroperacetic acid, peroxymaleic acid (permaleic acid), perbenzoic acid, peracetic acid, m-chloroperoxybenzoic acid, etc.) in an inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at a temperature of approximately 0 to 80 ℃. Alternatively, the N-oxides of the compounds of formula (I) may also be prepared from the N-oxides of the starting materials.

The non-oxidized compound of formula (I) can be prepared by reacting N-oxide thereof with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide and the like) in a corresponding inert organic solvent (such as acetonitrile, ethanol, dioxane aqueous solution and the like) at 0-80 ℃.

Protected derivatives of compounds of formula (I) may be prepared by methods well known to those skilled in the art. For a detailed technical description of the addition and removal of protecting groups see: greene, Protecting Groups in Organic Synthesis,3rd edition, John Wiley & Sons, Inc.1999.

the labels and common sense, charts and examples used in these reactions are consistent with the current scientific literature, e.g., the journal of the American chemical Association or the journal of biochemistry. Unless otherwise indicated, standard single or three letter abbreviations generally refer to L-amino acid residues. All starting materials used were purchased from commercial suppliers and used without further purification unless otherwise indicated. For example, the following abbreviations are used in the examples and throughout the specification: g (g), mg (mg), L (L), mL (mL), μ L (μ L), psi (pounds per square inch), M (moles), mM (millimole), i.v. (intravenous), Hz (Hertz), MHz (megahertz), mol (mole), mmol (millimole), RT (ambient temperature), min (min), h (hour), mp (melting point), TLC (thin layer chromatography), Rr (retention time), RP (reversed phase), MeOH (methanol), i-PrOH (isopropanol), TEA (triethylamine), TFA (trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), DMSO (dimethyl sulfoxide), EtOAc (ethyl acetate), DME (1, 2-dimethoxyethane), DCM (dichloromethane), DCE (dichloroethane), DMF (N, N-dimethylformamide), DMPU (N, N-dimethylpropyleneurea), CDI (1, 1-carbonyldiimidazole), IBCF (isobutyl chloroformate), HOAc (acetic acid), HOSu (N-hydroxysuccinimide), HOBT (1-hydroxybenzotriazole), Et2O (diethyl ether), EDCI (1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride), BOC (t-butyloxycarbonyl), FMOC (9-fluorenylmethoxycarbonyl), DCC (dicyclohexylcarbodiimide), CBZ (benzyloxycarbonyl), Ac (acetyl), atm (atmospheric pressure), TMSE (2- (trimethylsilyl) ethyl), TMS (trimethylsilyl), TIPS (triisopropylsilyl), TBS (t-butyldimethylsilyl), DMAP (dimethylaminopyridine), Me (methyl), OMe (methoxy), Et (ethyl), tBu (t-butyl), high performance liquid chromatography, bis (2-oxo-3-oxazolidinyl) hypophosphoryl chloride), TBAF (tetrabutylammonium fluoride), mCPBA (m-chloroperoxybenzoic acid).

Ether or Et2O both refer to diethyl ether; brine is then a saturated aqueous NaCl solution. Unless otherwise indicated, all temperatures refer to degrees Celsius (degrees Celsius) and all reactions are carried out in an inert atmosphere at room temperature.

1H NMR spectra were recorded using a Varian Mercury Plus 400 NMR spectrometer. Chemical shifts are expressed in ppm. The coupling constants are all in hertz (Hz). Apparent diversity is described in the split mode and is assigned as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).

Low resolution Mass Spectrometry (MS) and compound purity data were from a Shimadzu LC/MS single quadrupole system equipped with an electrospray ion detector (ESI), ultraviolet detectors (220 and 254nm) and an Evaporative Light Scattering Detector (ELSD). Thin layer chromatography was performed using 0.25mm Asahi-poise silica gel plate (60F-254), 5% ethanol phosphomolybdate solution, ninhydrin or p-methoxybenzaldehyde solution and observing under an ultraviolet lamp. Silica gel (200-300 mesh, Qingdao ocean chemical Co., Ltd.) was used for flash column chromatography.

synthetic schemes

The synthetic schemes for all compounds of the present invention are illustrated by the following schemes and examples. The starting materials used are commercially available or may be prepared according to established procedures or by methods exemplified herein.

The intermediates listed in the following schemes are known in the literature or are prepared by one skilled in the art according to similar methods.

As an illustration, scheme 1 discloses a method of synthesis of the presently disclosed compounds of formula I. As shown in the scheme, the compound shown in the formula I can be resolved into an intermediate III and an intermediate II of a synthetic method reported in the literature, and the compound shown in the formula I is obtained by the condensation reaction of a carboxylic acid intermediate II and a sulfonamide intermediate III.

As an illustration of the preparation of the intermediate of formula III, one synthetic approach to intermediate IIIa is shown in scheme 2. Starting from a commercially available or literature-reported benzo-heterocycle IIIa-A, the sulfonyl chlorides IIIa-B are obtained by reaction with chlorosulfonic acid, the IIIa-B are nitrated under HNO3/H2SO4 to obtain IIIa-C, and then reacted with NH3 to obtain sulfonamides IIIa-D. Finally, IIIa-D and IIIa-E are subjected to substitution reaction to obtain an intermediate IIIa.

As an alternative illustration of the preparation of the intermediate of formula III, one synthetic approach to intermediate IIIb is shown in scheme 3. Commercially available IIIb-A is brominated to give IIIb-B, which is then reacted with IIIb-C to give IIIb-D. IIIb-D is subjected to intramolecular ring closure by coupling reaction under metal catalysis, such as Buchwald reaction or other coupling reactions known in the literature to obtain IIIb-G. Similarly, intermediates IIIb-G can also be prepared by three steps of hydroxymesylation of IIIb-D, SN2 reaction and intramolecular cyclization. And connecting IIIb-G and IIIa-E to obtain a target intermediate IIIb.

As another illustration of the preparation of the intermediate of formula III, scheme 4 provides a synthesis of intermediate IIIc. The commercially available IIIc-A is used as a starting material and selectively reacted with the commercially available IIIc-B on the hydroxyl group at the C-3 position of the nitrobenzene of IIIc-A under basic conditions to produce IIIc-C. IIIc-C is reacted with an acid, such as HBr/AcOH, and cyclized intramolecular ethereally under basic conditions to give IIIc-D. The hydroxy group of IIIc-D is mesylated to a leaving group to give IIIc-E. Sulfonylation of IIIc-E with chlorosulfonic acid under PCl5 gave IIIc-F, which was then reacted with NH3 to give IIIc-G. IIIc-G are linked to IIIa-E to give compounds of formula IIIc.

In some cases, the above synthetic schemes may be ordered as appropriate in order to facilitate the reaction or to avoid the production of unnecessary reaction products. In order that the invention may be more fully understood, the following examples are set forth. These examples are only examples and should not be construed as limiting the invention.

preparation of intermediates

intermediate A

(S) -2- (iodomethyl) -7-nitroindoline-5-sulfonamide (intermediate A)

(S) -indoline-2-methanol (A-1)

(S) -indoline-2-methanol (A-1) was prepared according to patent WO 2009/109364.

(S) -9,9 a-dihydro-1H, 3H-oxazol [3,4-a ] indol-3-one (A-2)

(S) -indoline-2-methanol (A-1) (1.63g,10.9mmol) and CDI (1.78g,10.9mmol) in tetrahydrofuran (25mL) was stirred for 2.5 h at 60 ℃. After the reaction, the reaction system was concentrated, extracted with ethyl acetate, washed with saturated brine, dried over Na2SO4, and concentrated. And (3) separating and purifying the residue by silica gel column chromatography, wherein a developing agent is petroleum ether/ethyl acetate (8: 1-6: 1), and a target compound (S) -9,9 a-dihydro-1H, 3H-oxazolo [3,4-a ] indol-3-one (A-2) is obtained, and MS-ESI (M/z) is 176[ M +1] +.

(S) -3-oxo-9, 9 a-dihydro-1H, 3H-oxazol [3,4-a ] indole-7-sulfonyl chloride (A-3)

Chlorosulfonic acid (1mL) was added to (S) -9,9 a-dihydro-1H, 3H-oxazol [3,4-a ] indol-3-one (A-2) (0.10g,0.6mmol) at 0 deg.C, and the reaction mixture was stirred at 0 deg.C for 1 hour, followed by addition of ice water (20mL) at 0 deg.C to quench the reaction. After the reaction, ethyl acetate (2X 50mL) was added to the reaction system for extraction, the mixture was washed with saturated brine (50mL), and then dried by adding Na2SO4, and the mixture was concentrated to give a crude product of (S) -3-oxo-9, 9 a-dihydro-1H, 3H-oxazol [3,4-a ] indole-7-sulfonyl chloride (A-3), which was used as it was in the next reaction without further purification.

(S) -5-Nitro-3-oxo-9, 9 a-dihydro-1H, 3H-Azole [3,4-a ] indole-7-sulfonyl chloride (A-4)

(S) -3-oxo-9, 9 a-dihydro-1H, 3H-oxazol [3,4-a ] indole-7-sulfonyl chloride (A-3) (0.05g,0.18mmol) was added to concentrated sulfuric acid (1mL) at 0 deg.C, KNO3(0.038g,0.36mmol) was added, and stirring was carried out at 0 deg.C for 1 hour. The reaction was terminated and quenched by the addition of ice water (20mL) at 0 ℃. The system was extracted with ethyl acetate, washed with saturated brine (15mL), dried over Na2SO4, filtered, and concentrated to give (S) -5-nitro-3-oxo-9, 9 a-dihydro-1H, 3H-oxazol [3,4-a ] indole-7-sulfonyl chloride (a-4) which was used as such in the next reaction without further purification.

(S) - (7-nitro-5-sulfamoylindolin-2-yl) carbamate (A-5)

(S) -5-Nitro-3-oxo-9, 9 a-dihydro-1H, 3H-oxazol [3,4-a ] indole-7-sulfonyl chloride (A-4) (51mg,0.16mmol) and NH3 methanol solution (3mL) were stirred at room temperature for 1 hour. After the reaction is finished, the system is concentrated to obtain a crude product of (S) - (7-nitro-5-sulfamoylindolin-2-yl) carbamate (A-5), and the crude product is used for the next reaction without further purification. MS-ESI (M/z) 315[ M-1] -.

(S) -2- (hydroxymethyl) -7-nitroindoline-5-sulfonamide (A-6)

(S) - (7-Nitro-5-sulfamoylindolin-2-yl) carbamate (A-5) (21mg,0.068mmol) and NaOH (2N,0.2mL) were reacted in methanol (1mL) with stirring at 50 ℃ for 3.5 hours. After the reaction, the mixture was extracted with dichloromethane, the pH of the aqueous phase was adjusted to 4 to 5 by adding 1N hydrochloric acid, the mixture was extracted with ethyl acetate (4 × 80mL), washed with saturated brine (100mL), and dried over Na2SO 4. Concentrating to obtain a crude product of (S) -2- (hydroxymethyl) -7-nitroindoline-5-sulfonamide (A-6), and using the crude product as the next reaction without further purification. MS-ESI (M/z) 272[ M-1] -.

(S) -2- (iodomethane) -7-nitroindoline-5-sulfonamide (intermediate A)

(S) -2- (hydroxymethyl) -7-nitroindoline-5-sulfonamide (A-6) (0.2g,0.73mmol), PPh3(0.48g,1.83mmol) and imidazole (0.12g,1.83mmol) were dissolved in acetonitrile (10mL) and I2(0.37g,1.46mmol) was added at 0 ℃ and the reaction stirred for 10 min. The reaction was then slowly warmed to room temperature and stirred overnight. After the reaction was complete, the reaction was quenched by addition of saturated Na2S2O3 solution (50mL), extracted with ethyl acetate (2X 30mL), washed with saturated brine (30mL), dried over Na2SO4 and concentrated. And separating and purifying the residue by silica gel column chromatography, wherein a developing agent is petroleum ether/ethyl acetate (4: 1-2: 1), and (S) -2- (iodomethyl) -7-nitroindoline-5-sulfonamide (intermediate A) is obtained, and MS-ESI (M/z) is 384[ M +1] +.

intermediate B

(R) -2- (iodomethyl) -7-nitroindoline-5-sulfonamide (intermediate B)

The synthesis of compound (R) -2- (iodomethyl) -7-nitroindoline-5-sulfonamide (intermediate B) refers to the synthesis method of (S) -2- (iodomethyl) -7-nitroindoline-5-sulfonamide (intermediate A), wherein (S) -indoline-2-methanol (A-1) is replaced by (R) -indoline-2-methanol for reaction to obtain MS-ESI (M/z):384[ M +1] +.

Intermediate C

(R) - (5-Nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methanesulfonic acid methyl ester (intermediate C)

3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1)

NBS (11g,61.8mmol) was added portionwise to a mixture of 4-chloro-3-nitrobenzenesulfonamide (10g,42.5mmol) and concentrated sulfuric acid (30mL) with stirring at 50 deg.C, and the reaction was warmed to 60 deg.C and stirred for 2 hours. After the reaction, ice (200g) was added to the system, and the mixture was stirred for 10 minutes and filtered, and the filter cake was washed with 30mL of water, dried and dehydrated to give a crude product of 3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1), which was used for the next reaction without further purification. MS-ESI (M/z) 313[ M-1] -.

methyl O- (tert-butyldimethylsilyl) -L-serine (C-2)

Synthesis reference Synthesis of methyl O- (tert-butyldimethylsilyl) -L-serine (C-2) 2009,6,951.

(R) -2-amino-3- ((tert-butyldimethylsilyl) oxy) -1-propanol (C-3)

the Synthesis of (R) -2-amino-3- ((tert-butyldimethylsilyl) oxy) -1-propanol (C-3) is described in Synthesis 2009,6,951.

(R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (C-4)

3-bromo-4-chloro-5-nitrobenzenesulfonamide (C-1) (2.9g,9.26mmol) and (R) -2-amino-3- ((tert-butyldimethylsilyl) oxy) -1-propanol (C-3) (1.73g,8.44mmol), DIPEA (5.5g,42.6mmol) were dissolved in 25mL acetonitrile and stirred at 80 ℃ overnight. After the reaction is finished, concentrating, and separating and purifying the residue by silica gel column chromatography to obtain the target compound (R) -3-bromo-4- ((1- ((tert-butyl dimethyl silicon) oxy) -3-hydroxypropane-2-yl) amino) -5-nitrobenzenesulfonamide (C-4). MS-ESI (M/z) 484[ M +1] +.

(R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5)

(R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (C-4) (10mg,0.021mmol), Me4phen (2.5mg,0.010mmol), CuI (4.0mg,0.021mmol) and Cs2CO3(10mg,0.032mmol) were dissolved in 1.5mL of toluene and stirred at 105 ℃ for 5 hours under the protection of N2. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. And separating and purifying the residue by silica gel column chromatography to obtain the target compound (R) -3- (((tert-butyl dimethyl silicon base) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5), MS-ESI (M/z):404[ M +1] +.

(S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-6)

(R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5) (1.7mg,0.042mmol) and 2N HCl (0.3mL) were stirred in MeOH (1mL) at room temperature for 0.5H. After the reaction is finished, saturated NaHCO3(10mL) solution is used for quenching, ethyl acetate is used for extraction, an organic phase is washed by saturated saline solution (20mL), dried by Na2SO4 and concentrated to obtain a crude product of (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-6), and the crude product is directly used for the next reaction without purification. MS-ESI (M/z) 290[ M +1] +.

(R) - (5-Nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methanesulfonic acid methyl ester (intermediate C)

(S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-6) (10.0mg,0.0346mmol) was dissolved in DCM/CH3CN (2mL/0.5mL), MsCl (4.8mg,0.415mmol) was added at 0 deg.C, a solution of TEA (3.5mg,0.0346mmol) in dichloromethane was added and stirred at 0 deg.C for 5 min. After the reaction, the mixture is quenched by saturated NaHCO3 solution, extracted by DCM, the organic phase is washed by saturated saline solution (20mL), dried by Na2SO4 and concentrated to obtain crude (R) - (5-nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methyl methanesulfonate (intermediate C), and the crude product is directly used for the next reaction without purification. MS-ESI (M/z) 368[ M +1] +.

intermediate D

(S) - (5-Nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methanesulfonic acid methyl ester (intermediate D)

synthesis of Compound (S) - (5-Nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methanesulfonic acid methyl ester (intermediate D) synthesized with reference to the synthetic procedure for (R) - (5-nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methanesulfonic acid methyl ester (intermediate C), substituting O- (tert-butyldimethylsilyl) -D-serine methyl ester for O- (tert-butyldimethylsilyl) -L-serine methyl ester (C-2), MS-ESI (M/z):368[ M +1] +.

Intermediate E

E)(R) -3- (2-iodoethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (intermediate E)

D-homoserine methyl ester hydrochloride (E-1)

D-homoserine (4.76g,40.0mmol) was dissolved in MeOH (100mL) and added SOCl2(3.5mL,40.0mmol) in an ice bath and stirred at 50 ℃ for 1h. After the reaction is finished, the crude product of D-homoserine methyl ester hydrochloride (E-1) is obtained by concentration and is directly used for the next reaction without purification. MS-ESI (M/z) 170[ M +1] +.

(R) -3-bromo-4- ((4- ((tert-butyldimethylsilyl) oxy) -1-hydroxybutan-2-yl) amino) -5-nitrobenzenesulfonamide (E-2)

Synthesis of compound (R) -3-bromo-4- ((4- ((tert-butyldimethylsilyl) oxy) -1-hydroxybutan-2-yl) amino) -5-nitrobenzenesulfonamide (E-2) referring to the synthesis of (R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (C-4), L-serine methyl ester hydrochloride was replaced with D-homoserine methyl ester hydrochloride (E-1). MS-ESI (M/z):418[ M +1] +.

(R) -3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (E-3)

Synthesis of the compound (R) -3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (E-3) is synthesized by referring to the synthetic procedure for (R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5) by replacing (R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (C-4) with (R) -3-bromo -4- ((4- ((tert-butyldimethylsilyl) oxy) -1-hydroxybutan-2-yl) amino) -5-nitrobenzenesulfonamide (E-2). MS-ESI (M/z):418[ M +1] +.

(R) -3- (2-hydroxyethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (E-4)

Synthesis of Compound (R) -3- (2-hydroxyethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (E-4) referring to the Synthesis method of (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-6) for (R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5) to (R) -3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) 5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (E-3). MS-ESI (M/z) 304[ M +1] +.

E)(R) -3- (2-iodoethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (intermediate E)

the compound (R) -3- (2-iodoethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (intermediate E), is synthesized by referring to the synthetic method of (S) -2- (iodomethyl) -7-nitroindoline-5-sulfonamide (intermediate A), the (S) -2- (hydroxymethyl) -7-nitroindoline-5-sulfonamide (A-6) is replaced by (R) -3- (2-hydroxyethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (E-4) for reaction. MS-ESI (M/z) 414[ M +1] +.

Intermediate F

F)(S) -3- (2-iodoethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (intermediate F)

The compound (S) -3- (2-iodoethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] -oxazine-7-sulfonamide (intermediate F) is synthesized by referring to the synthetic method of (S) -2- (iodomethane) -7-nitroindoline-5-sulfonamide (intermediate E), and is prepared by replacing D-homoserine with L-homoserine and reacting. MS-ESI (M/z) 414[ M +1] +.

Intermediate G

(R) - (5-Nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-3-yl) methanesulfonic acid methyl ester (intermediate G)

(S) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (G-1)

The compound (S) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (G-1) was synthesized with D-serine hydrochloride replaced with L-serine hydrochloride with reference to the synthesis method of (R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (C-4). MS-ESI (M/z) 484[ M +1] +.

(R) -2- ((2-bromo-6-nitro-4-sulfamoylphenyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propyl methanesulfonate (G-2)

The compound (R) -2- ((2-bromo-6-nitro-4-sulfamoylphenyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propyl methanesulfonate (G-2) was synthesized with reference to (R) - (5-nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methanesulfonic acid methyl ester (intermediate C), replacing (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-sulfonamide (C-6) with (S) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropane (iii) Synthesis of (2-yl) amino) -5-nitrobenzenesulfonamide (G-1) MS-ESI (M/z):562[ M +1] +.

(R) -S- (2- ((2-bromo-6-nitro-4-sulfamoylphenyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propyl) acetyl thioester (G-3)

(R) -2- ((2-bromo-6-nitro-4-sulfamoylphenyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propyl methanesulfonate (G-2) (0.5G,0.89mmol) was dissolved in DMF (10mL) and AcSK (0.3G,2.6mmol) was added and stirred at room temperature for 1 hour. The reaction was quenched with water, extracted with ethyl acetate (2X 25mL), and the organic phase was washed with saturated brine (20mL), dried over Na2SO4, and concentrated. Separating and purifying the residue by silica gel column chromatography, developing with ethyl acetate/petroleum ether (1:4) to obtain target compound (R) -S- (2- ((2-bromo-6-nitro-4-sulfamoylphenyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propyl) acetyl thioester (G-3), MS-ESI (M/z):542[ M +1] +.

(R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-mercaptopropan-2-yl) amino) -5-nitrobenzenesulfonamide (G-4)

(R) -S- (2- ((2-bromo-6-nitro-4-sulfamoylphenyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propyl) acetyl thioester (G-3) (0.3G,0.55mmol) was dissolved in methanol (15mL) and K2CO3(0.26G,1.88mmol) was added. The reaction was stirred at room temperature for 10 minutes. After the reaction is finished, water quenching is carried out, concentrated hydrochloric acid is added to adjust the pH value to be 6-7, DCM (3 multiplied by 25mL) is added for extraction, saturated saline solution is used for washing, Na2SO4 is dried, and the concentration is carried out to obtain the target compound (R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-mercaptopropane-2-yl) amino) -5-nitrobenzenesulfonamide (G-4), MS-ESI (M/z):500[ M +1] +.

(R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-7-sulfonamide (G-5)

The compound (R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-7-sulfonamide (G-5) is a synthetic procedure referring to (R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5) by replacing (R) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (C-4) with (R) -3-bromo-4- ((1, 4] oxazine-7-sulfonamide (C-4) MS-ESI (M/z):420[ M +1] +, synthesized, ((tert-butyldimethylsilyl) oxy) -3-mercaptopropan-2-yl) amino) -5-nitrobenzenesulfonamide (G-4).

(R) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-7-sulfonamide (G-6)

The compound (R) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazine-7-sulfonamide (G-6) is a synthetic procedure referenced to (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-6) by replacing (R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5) with (R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, MS-ESI (M/z):306[ M +1] +, synthesized from 4-dihydro-2H-benzo [ b ] [1,4] thiazine-7-sulfonamide (G-5).

(R) - (5-Nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-3-yl) methanesulfonic acid methyl ester (intermediate G)

Compound (R) - (5-nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-3-yl) methyl methanesulfonate (intermediate G) the synthesis of (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methyl methanesulfonate (intermediate C) was referenced by replacing (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-6) with (R) -3- (hydroxymethyl) -5-nitro-3, MS-ESI (M/z):384[ M +1] +, synthesized from 4-dihydro-2H-benzo [ b ] [1,4] thiazine-7-sulfonamide (G-6).

Intermediate H

(R) -2- (5-Nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-3-yl) ethylmethanesulfonate (intermediate H)

the compound (R) -2- (5-nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-3-yl) ethyl methanesulfonate (intermediate H) is a synthetic procedure referenced to (R) - (5-nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] thiazin-3-yl) methyl methanesulfonate (intermediate G) replacing (S) -3-bromo-4- ((1- ((tert-butyldimethylsilyl) oxy) -3-hydroxypropan-2-yl) amino) -5-nitrobenzenesulfonamide (G-1) with (R) -3-bromo-4- ((4- ((tert-butyldimethylsilyl) oxy) ) MS-ESI (M/z):398[ M +1] +, synthesized for (E-2) -1-hydroxybutan-2-yl) amino) -5-nitrobenzenesulfonamide (E-2).

Intermediate I

(S) - (8-Nitro-6-sulfamoyl-1, 2,3, 4-tetrahydroquinoxalin-2-yl) methylmethanesulfonate (intermediate I)

(S) -4- ((1-azido-3- ((tert-butyldimethylsilyl) oxy) propan-2-yl) amino) -3-bromo-5-nitrobenzenesulfonamide (I-1)

(R) -2- ((2-bromo-6-nitro-4-sulfamoylphenyl) amino) -3- ((tert-butyldimethylsilyl) oxy) propyl methanesulfonate (G-2) (30mg,0.0534mmol) was dissolved in DMF (1.5mL) and NaN3(17mg,0.267mmol) was added and stirred at 30 ℃ overnight. After the reaction was completed, water was added to quench, and the mixture was extracted with ethyl acetate (2X 25mL), and the organic phase was washed with saturated brine (20mL), dried over Na2SO4, and concentrated. And (3) separating and purifying the residue by silica gel column chromatography, developing with ethyl acetate/petroleum ether (1: 5-1: 3) to obtain a target compound (S) -4- ((1-azido-3- ((tert-butyl dimethyl silicon base) oxy) propane-2-yl) amino) -3-bromo-5-nitrobenzenesulfonamide (I-1), MS-ESI (M/z):509[ M +1] +.

(S) -4- ((1-amino-3- ((tert-butyldimethylsilyl) oxy) propan-2-yl) amino) -3-bromo-5-nitrobenzenesulfonamide (I-2)

(S) -4- ((1-azido-3- ((tert-butyldimethylsilyl) oxy) propan-2-yl) amino) -3-bromo-5-nitrobenzenesulfonamide (I-1) (0.235g,0.463mmol) dissolved in H2O/THF (0.125mL/5mL) was added PPh3 under nitrogen

(0.346g,1.388mmol) and the reaction was carried out overnight at 35 ℃ under nitrogen. Adding water to quench after the reaction is finished, extracting with DCM, washing an organic phase with saturated saline solution (20mL), drying with Na2SO4, concentrating, separating and purifying residues through silica gel column chromatography, and obtaining a target product (S) -4- ((1-amino-3- ((tert-butyldimethylsilyl) oxy) propane-2-yl) amino) -3-bromo-5-nitrobenzenesulfonamide (I-2) through a developing solvent petroleum ether/dichloromethane (50: 1-20: 1), MS-ESI (M/z):483[ M +1] +.

(S) -2- (((tert-butyldimethylsilyl) oxy) methyl) -8-nitro-1, 2,3, 4-tetrahydroquinoxaline-6-sulfonamide (I-3)

(S) -4- ((1-amino-3- ((tert-butyldimethylsilyl) oxy) propan-2-yl) amino) -3-bromo-5-nitrobenzenesulfonamide (I-2) (20mg,0.0415mmol), Me4phen (10mg,0.0415mmol), CuI (12mg,0.0622mmol), Cs2CO3(20mg,0.0622mmol) was added to dioxane (1.5mL) and stirred under nitrogen at 100 ℃ for 5 hours. After the reaction is finished, cooling to room temperature, concentrating, separating and purifying residues through silica gel column chromatography, developing solvent ethyl acetate/petroleum ether (1: 3-1: 1) to obtain target compound (S) -2- (((tert-butyldimethylsilyl) oxy) methyl) -8-nitro-1, 2,3, 4-tetrahydroquinoxaline-6-sulfonamide (I-3), MS-ESI (M/z):403[ M +1] +.

(S) -2- (hydroxymethyl) -8-nitro-1, 2,3, 4-tetrahydroquinoxaline-6-sulfonamide (I-4)

the compound (S) -2- (hydroxymethyl) -8-nitro-1, 2,3, 4-tetrahydroquinoxaline-6-sulfonamide (I-4) is a synthetic procedure with reference to (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-6), replacing (R) -3- (((tert-butyldimethylsilyl) oxy) methyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazine-7-sulfonamide (C-5) with (S) -2- (((tert-butyldimethylsilyl) oxy) methyl) -8-nitro-1, 2,3, 4-tetrahydroquinoxaline-6-sulfonamide (I-3). MS-ESI (M/z) 289[ M +1] +.

(S) - (8-Nitro-6-sulfamoyl-1, 2,3, 4-tetrahydroquinoxalin-2-yl) methylmethanesulfonate (intermediate I)

the compound (S) - (8-nitro-6-sulfamoyl-1, 2,3, 4-tetrahydroquinoxalin-2-yl) methylmethanesulfonate (intermediate I) is a synthetic procedure referred to (R) - (5-nitro-7-sulfamoyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-3-yl) methylmethanesulfonate (intermediate C) by replacing (S) -3- (hydroxymethyl) -5-nitro-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-7-sulfonamide (C-6) with (S) -2- (hydroxymethyl) -8-nitro-1, 2,3, 4-tetrahydroquinoxaline-6-sulfonamide (I-4) to obtain MS-ESI (M/z):367[ M +1] +.

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