6- (4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one derivatives and related compounds as PTPN11(SHP2) inhibitors for the treatment of cance
阅读说明：本技术 用于治疗癌症的作为ptpn11(shp2)抑制剂的6-(4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2,3-二氯苯基)-2-甲基嘧啶-4(3h)-酮衍生物及相关化合物 (6- (4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one derivatives and related compounds as PTPN11(SHP2) inhibitors for the treatment of cance) 是由 P·琼斯 B·扎科 C·L·卡罗尔 P·曼达尔 J·克罗斯 于 2019-08-09 设计创作，主要内容包括：本发明涉及用作PTPN11(SHP2)抑制剂的6-(4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(2,3-二氯苯基)-2-甲基嘧啶-4(3H)-酮衍生物及相关化合物,其用于治疗和预防癌症以及其他PTP-介导的疾病。优选的化合物为,例如,在PTPN11-E76K突变酶抑制测定中的IC50为3nM的6-((3S,4S)-4-氨基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-基)-3-(Ra)-(2,3-二氯-4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-2,5-二甲基嘧啶-4(3H)-酮(实施例18b)。(The present invention relates to 6- (4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one derivatives and related compounds useful as inhibitors of PTPN11(SHP2) for the treatment and prevention of cancer and other PTP-mediated diseases. A preferred compound is, for example, 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (Ra) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2, 5-dimethylpyrimidin-4 (3H) -one with an IC50 of 3nM in the PTPN11-E76K mutant enzyme inhibition assay (example 18 b).)
1. A compound represented by formula I
Or a salt, ester or prodrug thereof, wherein:
subscript a is 0 or 1;
subscript b is 0 or 1;
Y1is a direct bond or CR17R18；
Y2Is selected from C1-4Alkyl, amino, C1-4Alkyl radicalC(O)O-、C1-4Alkylamino and C1-4An aminoalkyl group;
R1is selected from C6-10Aryl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl and 5-10 membered heteroaryl having 1-4 heteroatoms or groups independently selected from N, C (O), O, and S as the ring apex; the R is1Is optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14；
R2、R3、R10And R11Each independently selected from hydrogen and C1-4Alkyl and C3-8A cycloalkyl group;
R4、R5、R8and R9Each independently selected from hydrogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-8Cycloalkyl, halogen and C1-4An alkylamino group;
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, amido, cyano, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with 1 to 5 groups independently selected from: amino, halogen, hydroxyCyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
or R6And R7And together with the carbon atom to which they are attached form a compound having 0 to 3 substituents independently selected from the group consisting of N, C (O), O, and S (O)mA 3 to 7 membered saturated or unsaturated ring having the heteroatom or group as the ring apex;
subscript m is 0,1, or 2;
said is prepared from R6And R7The saturated or unsaturated ring formed is unsubstituted or substituted with 1 to 3 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R2、R3、R4、R5、R7、R8、R9、R10and R11Any two groups of (a) may form a 5 to 6 membered ring having 0 to 2 heteroatoms selected from N, O and S as ring vertices;
R2、R4、R6、R8and R10Any two groups in (a) may form a direct bond or a1 or 2 atom carbon bridge;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl, -NH-NHR19、-NHR19、-OR19、-NHC(O)R19、-NHC(O)NHR19、-NHS(O)2NHR19、-NHS(O)2R19、-C(O)OR19、-C(O)NR19R20、-C(O)NH(CH2)qOH、-C(O)NH(CH2)qR21、-C(O)R21、-NH2、-OH、-S(O)2NR19R20、C3-8Cycloalkyl, aryl, having 1-5 heteroatoms selected from N, O, S and P as ringsA heterocyclic group having an apex, a heteroaryl group having 1 to 5 heteroatoms selected from N, O, S and P as ring apices; wherein subscript q is an integer between 0 and 6; and wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo;
R14、R15and R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: amide, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R17and R18Each independently selected from hydrogen and C1-4Alkyl and CF3；
R19And R20Each independently selected from hydrogen and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group;
each R21Independently selected from: hydrogen, -OH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group.
2. The compound of claim 1, wherein:
subscript a is 0 or 1;
subscript b is 0 or 1;
Y1is a direct bond or CR17R18；
Y2Is selected from C1-4Alkyl, amino, C1-4Alkyl C (O) O-, C1-4Alkylamino and C1-4An aminoalkyl group;
R1is selected from C6-10Aryl, heteroaryl, and heteroaryl,C3-8Cycloalkyl radical, C3-8Cycloalkenyl and 5-10 membered heteroaryl having 1-4 heteroatoms or groups independently selected from N, C (O), O, and S as the ring apex; the R is1Is optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14；
R2、R3、R10And R11Each independently selected from hydrogen and C1-4Alkyl and C3-8A cycloalkyl group;
R4、R5、R8and R9Each independently selected from hydrogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-8Cycloalkyl, halogen and C1-4An alkylamino group;
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, halogen and hydroxyl or selected from amide and C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with 1 to 5 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino radical andC1-4an aminoalkyl group;
or R6And R7And together with the carbon atom to which they are attached form a compound having 0 to 3 substituents independently selected from the group consisting of N, C (O), O, and S (O)mA 3 to 7 membered saturated or unsaturated ring having the heteroatom or group as the ring apex;
subscript m is 0,1, or 2;
said is prepared from R6And R7The saturated ring formed is unsubstituted or substituted with 1 to 3 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R2、R3、R4、R5、R7、R8、R9、R10and R11Any two groups of (a) may form a 5 to 6 membered ring having 0 to 2 heteroatoms selected from N, O and S as ring vertices;
R2、R4、R6、R8and R10Any two groups in (a) may form a direct bond or a1 or 2 atom carbon bridge;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl, -NH-NHR19、-NHR19、-OR19、-NHC(O)R19、-NHC(O)NHR19、-NHS(O)2NHR19、-NHS(O)2R19、-C(O)OR19、-C(O)NR19R20、-C(O)NH(CH2)qOH、-C(O)NH(CH2)qR21、-C(O)R21、-NH2、-OH、-S(O)2NR19R20、C3-8Cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms selected from N, O, S and P as ring vertices, heteroaryl having 1-5 heteroatoms selected from N, O, S and P as ring vertices; wherein subscript q is an integer between 0 and 6; and wherein aryl, heteroaryl, heterocyclylAnd cycloalkyl is substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo;
R14、R15and R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group;
R17and R18Each independently selected from hydrogen and C1-4Alkyl and CF3；
R19And R20Each independently selected from hydrogen and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group;
each R21Independently selected from: hydrogen, -OH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group.
3. The compound of claim 1, wherein subscripts a and b are each 1.
4. The compound of claim 1, wherein Y1Is a straight bond.
5. The compound of claim 1, wherein Y2Is C1-4An alkyl group.
6. The compound of claim 5, wherein Y is2Is methyl.
7. The compound of claim 1, wherein
R13Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6DihydroxyAlkyl radical, C3-8Cycloalkyl, 3 or 6 membered heterocyclyl having 1-3 heteroatoms selected from N, O and S as ring vertices; wherein heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo.
8. The compound of claim 7, wherein R13Selected from hydrogen, halogen, C1-6Alkyl and C1-6A haloalkyl group.
9. The compound of claim 8, wherein R13Is hydrogen, Cl, Br, methyl or CF3。
10. The compound of claim 1, wherein
R1Is selected from C6-10Aryl and a 5 to 9 membered heteroaryl group having 1 to 4 heteroatom groups independently selected from N, C (O), O and S as ring vertices; and optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14。
11. The compound of claim 10, wherein
R1Is phenyl or has 1 to 4 substituents independently selected from N, O and SA 5-to 6-membered heteroaryl group with the heteroatom as the vertex of the ring; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
12. The compound of claim 1, wherein R2，R3，R4，R5，R8，R9，R10And R11Is hydrogen.
13. The compound of claim 1, wherein:
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group; and
R7selected from hydrogen, amido, cyano, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one or two groups selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
14. The compound of claim 13, wherein
R6Is amino or aminomethyl; and
R7selected from hydroxy, C1-4Alkyl and C1-4A hydroxyalkyl group.
15. The compound of claim 1, wherein
R6And R7Together with the carbon atom to which they are attached form a compound having 1-3 substituents independently selected from N, C (O), O and S (O)mIs a 3-7 membered saturated or unsaturated ring as the apex of the ring, and is optionally substituted with one or two groups independently selected from: amino, halogen,Hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
16. The compound of claim 15, wherein
R6And R7And together with the carbon atom to which they are attached form a 4-to 6-membered saturated ring having as the ring vertex 1 to 3 heteroatoms independently selected from N and O, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
17. The compound of claim 1, wherein
R6And R7Together with the carbon atom to which they are both attached form a 3 to 7 membered cycloalkyl ring, optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
18. The compound of claim 1, wherein
R1Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,2, 4-triazinyl; and optionally substituted with 1,2 or 3R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
19. The compound of claim 18, wherein R1Is phenyl or pyridyl, each of which is substituted by 1-3R12And (4) substitution.
20. The compound of claim 1, wherein R1Selected from:
each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
21. The compound of claim 20, wherein R1Selected from:
22. the compound of claim 1, wherein R14Is selected from C6-10Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
23. The compound of claim 22, wherein R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
24. The compound of claim 1, wherein R14Is selected from C6-10Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with 1 or more groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
25. The compound of claim 1, wherein R1Is composed of
Each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group;
R14is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
26. The compound of claim 1, each R12Independently selected from: F. cl, Br, CH3、OCH3、CF3、
27. The compound of claim 1, having a structure selected from the group consisting of:
28. a compound according to claim 1 for use as a medicament.
29. The compound of claim 1 for use in the treatment of diseases driven by one or more PTPN11 mutations.
30. The compound of claim 1 for use in the treatment of cancer.
31. The compound of claim 30, wherein the cancer is selected from the group consisting of leukemia, melanoma, breast cancer, and colon cancer.
32. A compound according to claim 1 for use in the preparation of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of PTPN 11.
33. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
34. A method of inhibiting PTPN11 comprising contacting PTPN11 with a compound of claim 1.
35. A method of treating a PTPN11 mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.
36. The method of claim 35, wherein the disease is cancer.
37. The method of claim 36, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, leukemia, and melanoma.
38. A method of treating a PTPN 11-mediated disease, comprising administering:
a. a therapeutically effective amount of a compound of claim 1;
b. another therapeutic agent.
39. The method of claim 38, wherein the disease is cancer.
40. The method of claim 39, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, leukemia, and melanoma.
Background
Disclosed herein are novel pyrimidinone based compounds and their use as medicaments for the treatment of diseases. Also provided are methods of inhibiting PTPN11(SHP2) activity in a human or animal subject for the treatment of diseases such as cancer, including leukemia and melanoma, and breast, lung and colon cancer.
Tyrosyl phosphorylation regulates human cellular processes from cell differentiation to growth and apoptosis, among others. Tyrosyl phosphorylation is regulated by Protein Tyrosine Kinases (PTKs) and Protein Tyrosine Phosphatases (PTPs). Disruption of the regulatory role determined by PTK and PTP activity is thought to lead to cancer. PTK inhibitors have been developed as potential cancer therapeutics. Recent studies have also revealed a role for PTPs in cell regulation. (AJ Barr et al cell 2009,136,352-363 JN Andersen et al cell biol.2001,21, 7117-.
The non-receptor type protein-tyrosine phosphatase 11(PTPN11, also known as Src homology-2 phosphatase (SHP2)) is a non-receptor type protein tyrosine phosphatase encoded by the PTPN11 gene. The PTP contains two tandem Src homology-2 (SH2) domains that function as a phosphotyrosine binding domain, a catalytic domain, and a C-terminal tail. In the basal state, the protein is usually in an inactive, self-inhibitory configuration with the N-terminal SH2 domain blocking the active site. This self-inhibition is alleviated when stimulated by cytokine and growth factor mediated signal transduction that binds phosphorylated proteins to the SH2 domain, which makes the above active site available for dephosphorylation of PTPN11 substrates (MG Mohl, BG Neel, curr. opin. genetics dev.2007,17, 23-30. KS Grossmann, adv. cancer res.2010,106,53-89. w.q.huang.huang.al.curr. cancer Drug Targets 2014,14,567-588. c.gordon. al.cancer Targets rev.2008,27, 179).
Germline (Germ-line) and somatic mutations of PTPN11 have been reported in a variety of human diseases that result in gain-of-function of catalytic activity, including Noonan syndrome and Leopard syndrome; and various cancers, such as juvenile myelomonocytic leukemia, neuroblastoma, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia/lymphoma, melanoma, acute myelogenous leukemia, and breast, lung, and colon cancers (MG Mohl, BG Neel, curr. opins dev.2007,17, 23-30). Recent studies have shown that a single PTPN11 mutation can induce nononan syndrome, JMML-like myeloproliferative disease, and acute leukemia in mice. These mutations disrupt the self-inhibition between the N-SH2 domain and the catalytic site, allowing substrate to constitutively enter the catalytic site of the enzyme (e.darian et al, Proteins,2011,79,1573-1588.Z-H Yu et al, JBC,2013,288,10472, W Qiu et al BMC struct.biol.2014,14, 10).
PTPN11 is widely expressed in most tissues and plays a regulatory role in a variety of cellular signaling events that are critical to a variety of cellular functions through a variety of signaling pathways, including the Ras-MAPK, JAK-STAT, or PI3K-AKT pathway, including proliferation, differentiation, cell cycle maintenance, EMT transition, mitogenic activation, metabolic control, transcriptional regulation, and cell migration (Tajan, m.et.al.eur.j.medical Genetics,2015,58,509-525. prahalad, a.et.al.cell Reports,2015,12, 1978-.
Furthermore, there is increasing evidence that PTPN11/SHP2 is involved in immune escape during tumorigenesis, and therefore, SHP2 inhibitors can stimulate immune responses in Cancer patients (Cancer res.2015feb 1; 75(3):508-18.T yokoosuka T, J Exp med.2012,209(6),1201.S Amarnath Sci trans med.2011,3,111ra120.T Okazaki, PNAS 2001,98:24,13866-71).
Certain novel compounds and pharmaceutical compositions believed to inhibit PTPN11(SHP2), as well as methods of synthesizing and using the compounds, including methods of treating PTP-mediated diseases in a patient by administering the compounds, have been discovered.
Disclosure of Invention
In certain embodiments of the invention, the compounds are represented by formula I:
or a salt or tautomer thereof, wherein the subscripts a and b, Y1、Y2And R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R13As provided herein.
In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound having formula I and a pharmaceutically acceptable carrier.
In certain embodiments, the present invention provides methods of inhibiting PTPN11(SHP2) activity in a human or animal subject for the treatment of diseases, such as cancer, including leukemia and melanoma, and breast, lung and colon cancer.
Drawings
FIG. 1 shows 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (Ra) Dose-dependent tumor growth inhibition of (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 2b) in KYSE520 xenograft model.
FIG. 2 shows 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (Ra) Dose-dependent tumor growth inhibition of (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 10b) in the KYSE520 xenograft model.
Detailed Description
I. Summary of the invention
Certain compounds of formula I disclosed herein may have useful PTPN11 inhibitory activity and may be useful in the treatment or prevention of diseases or conditions in which PTPN11 plays a positive role. Thus, in a broad sense, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable carrier, and methods of making and using the compounds and compositions. Certain embodiments provide a method of suppressing PTPN 11. Other embodiments provide methods of treating a PTPN 11-mediated disease in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of a compound or composition according to the invention. Also provided is the use of certain compounds disclosed herein in the preparation of a medicament for the treatment of a disease or condition ameliorated by the inhibition of PTPN 11. In particular, the PTPN 11-mediated disease is cancer.
Definition of
As used herein, the following terms have the indicated meanings.
When numerical ranges are disclosed, and the expression "from n" is used1… to n2Is "or" at n1… and n2In which n is1And n2Is a number, then unless otherwise stated the expression is intended to include the number itself as well as ranges there between. The range may be an integer or continuous between (including) the endpoints. For example, a range of "2 to 6 carbons" is intended to include two, three, four, five, and six carbons, as carbons occur in integer units. By way of comparative example, a range of "1 to 3 μ M (micromolar)" is intended to include 1 μ M, 3 μ M, and all significant figures in between (e.g., 1.255 μ M, 2.1 μ M, 2.9999 μ M, etc.).
As used herein, the term "about" is intended to define the numerical value that it modifies, thereby expressing that value as a variable within a margin of error. When a specific error range is not set forth (e.g., the standard deviation of the mean values given in a chart or data sheet), the term "about" should be understood to mean that the range of values recited is covered and, where significant digits are taken into account, the range encompassed by rounding up or down to that number.
The term "acyl" as used herein, alone or in combination, refers to a carbonyl group attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety wherein the atom attached to the carbonyl group is carbon. "acetyl" means-C (O) CH3A group. "alkylcarbonyl" or "alkanoyl" refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.
The term "alkenyl" as used herein, alone or in combination, refers to a straight or branched chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl group will comprise 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system attached at two or more positions, for example, ethenylene [ (-CH ═ CH-), (-C:: C-) ]. Examples of suitable alkenyl groups include ethenyl, propenyl, 2-methylpropenyl, 1, 4-butadienyl, and the like. Unless otherwise indicated, the term "alkenyl" may include "alkenylene" groups.
The term "alkynyl" means having at least 2 carbon atoms and at least one triple bond and having the indicated number of carbon atoms (i.e., C)2-6Representing 2 to 6 carbons) of a straight or branched chain hydrocarbon. Alkynyl groups may contain any number of carbons, e.g. C2、C2-3、C2-4、C2-5、C2-6、C2-7、C2-8、C2-9、C2-10、C3、C3-4、C3-5、C3-6、C4、C4-5、C4-6、C5、C5-6And C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1, 3-pentynyl, 1, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1, 4-hexynyl, 1, 5-hexynyl, 2, 4-hexynyl or 1,3, 5-hexynyl.
The term "alkoxy" as used herein, alone or in combination, refers to an alkyl ether group, wherein the term alkyl is defined below. Examples of suitable alkyl ether groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
The term "alkyl" as used herein, alone or in combination, refers to straight or branched chain alkyl groups containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl group will contain 1 to 10 carbon atoms. In further embodiments, the alkyl group will contain 1 to 8 carbon atoms. Alkyl is optionally substituted as defined herein. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, octyl, nonyl, and the like. The term "alkylene" as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, e.g., methylene (-CH)2-). Unless otherwise indicated, the term "alkyl" may include "alkylene" groups.
The term "alkylamino" as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups can be monoalkylated or dialkylated, which form groups such as, for example, N-methylamino, N-ethylamino, N-dimethylamino, N-ethylmethylamino, and the like.
The term "alkylthio", as used herein, alone or in combination, refers to an alkyl thioether (R-S-) group, wherein the term alkyl is as defined above, and wherein the sulfur may be mono-or di-oxidized. Examples of suitable alkylsulfanyl groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, methylsulfonyl, ethylsulfinyl and the like.
The terms "amido" and "carbamoyl," as used herein, alone or in combination, refer to an amino group, as described below, appended to the parent molecular moiety through a carbonyl group, and vice versa. As used herein, an "amido" group includes both a "C-amido" and an "N-amido" group. The term "C-amido", as used herein, alone or in combination, refers to-C (O) N (RR '), wherein R and R' are as defined herein or as defined by the specified specific list of "R" groups. In some embodiments, an "amido" group includes-C (O) NH2，C1-4Alkylamide and di (C)1-4Alkyl) amide group. As used herein, the term "C1-4Alkylamido "refers to-C (O) NH (C)1-4Alkyl) in which C1-4Alkyl is as defined herein. The term "N-amido", as used herein, alone or in combination, refers to an rc (o) N (R ') -group, wherein R and R' are as defined herein or by the specific recitation of "R" groups as specified. The term "acylamino" as used herein, alone or in combination, includes an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetamido (CH)3C(O)NH-)。
The term "amino", as used herein, alone or in combination, refers to-NRR ', wherein R and R' are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may itself be optionally substituted. Additionally, R and R' may combine to form a heterocycloalkyl, either of which is optionally substituted.
The term "aryl" as used herein, alone or in combination, refers to a carbocyclic aromatic system containing one, two, or three rings, wherein such multiple ring systems are fused together. The term "aryl" includes aromatic groups such as phenyl, naphthyl, anthryl and phenanthryl.
The term "arylalkenyl" or "arylalkenyl", employed alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.
The terms "arylalkoxy" or "arylalkoxy" as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.
The terms "arylalkyl" or "aralkyl," as used herein, alone or in combination, refer to an aryl group attached to the parent molecular moiety through an alkyl group.
The term aryloxy, as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy group.
The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-), which may be attached to the parent molecular moiety from the nitrogen or acid terminus, and which may be optionally substituted as defined herein.
The term "O-carbamoyl" as used herein, alone or in combination, refers to the group-oc (O) NRR ', wherein R and R' are as defined herein.
The term "N-carbamoyl", as used herein, alone or in combination, refers to roc (o) NR ', wherein R and R' are as defined herein.
As used herein, the term "carbonyl" includes formyl [ -c (o) H ] alone, and in combination, is a-c (o) -group.
The term "carboxy" as used herein refers to the-C (O) OH or corresponding "carboxylate" anion, for example in a carboxylate salt. "O-carboxy" refers to an RC (O) O-group, wherein R is as defined herein. A "C-carboxy" group refers to a-C (O) OR group, where R is as defined herein.
The term "cyano," as used herein, alone or in combination, refers to-CN.
The term "cycloalkyl" or "carbocycle", as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl group, any of which ring portions contains 3 to 12 carbon atom ring members and may optionally be a benzo-fused ring system, which is optionally substituted as defined herein. The term "cycloalkenyl" refers to a cycloalkyl group having one or two double bonds. In certain embodiments, the cycloalkyl (or cycloalkenyl) group will contain 5 to 7 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2, 3-dihydro-1H-indenyl, adamantyl and the like. As used herein, "bicyclic" and "tricyclic" are intended to include fused ring systems, such as decahydronaphthalene, octahydronaphthalene, and polycyclic (multicenter) saturated or partially unsaturated types. The latter type of isomers are generally exemplified by bicyclo [1,1,1] pentane, camphor, adamantane, and bicyclo [3,2,1] octane.
The term "ester" as used herein, alone or in combination, refers to a carboxyl group bridging two moieties connected at a carbon atom.
The term "ether" as used herein, alone or in combination, refers to an oxy group that bridges two moieties attached at a carbon atom.
The term "halo" or "halogen", as used herein, alone or in combination, refers to fluoro, chloro, bromo or iodo.
The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
The term "haloalkyl" as used herein, alone or in combination, refers to an alkyl group as defined above wherein one or more hydrogens are replaced with a halogen. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl. For example, monohaloalkyl groups may have iodine, bromine, chlorine or fluorine atoms within the group. The dihalo-and polyhaloalkyl groups may have two or moreThe same halogen atom or a combination of different halogen groups. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF)2-), chloromethylene (-CHCl-), and the like.
The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or combinations thereof, that is fully saturated or contains from 1 to 3 unsaturations, consisting of the recited number of carbon atoms thereof and from 1 to 3 heteroatoms selected from the group consisting of N, O and S, wherein the N and S atoms may optionally be oxidized and the N heteroatom may optionally be quaternized. The heteroatom may be located at any internal position of the heteroalkyl group. Up to two heteroatoms may be consecutive, e.g. -CH2-NH-OCH3。
The term "heteroaryl" as used herein, alone or in combination, refers to a 3 to 15 membered unsaturated heteromonocyclic or fused monocyclic, bicyclic or tricyclic ring system wherein at least one fused ring is aromatic and contains at least one atom selected from N, O and S. In certain embodiments, the heteroaryl group will contain 1-4 heteroatoms as ring members. In further embodiments, the heteroaryl group will contain 1-2 heteroatoms as ring members. In certain embodiments, the heteroaryl group will contain 5 to 7 atoms. The term also includes fused polycyclic groups in which a heterocycle is fused to an aryl ring, in which a heteroaryl ring is fused to another heteroaryl ring, in which a heteroaryl ring is fused to a heterocycloalkyl ring, or in which a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, benzothiophenyl, chromenyl (chromononyl), coumarinyl (coumarinyl), benzopyranyl, tetrahydroquinolyl, tetrazolopyrazinyl, tetrahydroisoquinolinyl, thienopyridyl, furopyridyl, pyrrolopyridyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzindolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.
The terms "heterocycloalkyl" and "heterocycle" used interchangeably herein, alone or in combination, refer to a saturated, partially unsaturated, or fully unsaturated (but not aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group, respectively, that contains at least one heteroatom as a ring member, wherein each of said heteroatoms may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, the heterocycloalkyl group will contain from 1 to 4 heteroatoms as ring members. In a further embodiment, the heterocycloalkyl group will contain 1-2 heteroatoms as ring members. In certain embodiments, the heterocycloalkyl group will contain from 3 to 8 ring members in each ring. In further embodiments, the heterocycloalkyl group will contain from 3 to 7 ring members in each ring. In further embodiments, the heterocycloalkyl group will contain from 5 to 6 ring members in each ring. "heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of the tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; in addition, both terms also include systems in which a heterocyclic ring is fused to an aryl or another heterocyclic group as defined herein. Examples of heterocyclyl groups include aziridinyl, azetidinyl, 1, 3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro [1,3] oxazolo [4,5-b ] pyridyl, benzothiazolyl, indolinyl, dihydropyridyl, 1, 3-dioxanyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, isoindolyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. Unless specifically prohibited, heterocyclyl is optionally substituted.
The term "hydrazino" as used herein, alone or in combination, refers to two amino groups, i.e., -N-linked by a single bond.
The term "hydroxy" as used herein, alone or in combination, refers to-OH.
The term "hydroxyalkyl", as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.
The term "iminohydroxy", used herein, alone or in combination, refers to ═ N (oh) and ═ N-O-.
The term "lower amino" as used herein, alone or in combination, refers to-NRR’Wherein R and R’Independently selected from hydrogen and lower alkyl, any of which is optionally substituted.
The term "mercapto", as used herein, alone or in combination, refers to an RS-group, wherein R is as defined herein.
The term "nitro" as used herein, alone or in combination, refers to-NO2。
The terms "oxygen" or "oxa", as used herein, alone or in combination, refer to-O-.
The term "oxo", as used herein, alone or in combination, refers to ═ O.
The term "perhaloalkoxy" refers to an alkoxy group in which all hydrogen atoms are replaced with halogen atoms.
The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group wherein all of the hydrogen atoms are replaced with halogen atoms.
As used herein, the term "ring," with respect to a chemical structure or portion thereof, refers to a group in which any one of the atoms is a member of a common cyclic structure. Unless otherwise provided, the rings may be saturated or unsaturated, including aromatic, and may have 3 to 9 members. If the ring is heterocyclic, it may contain 1 to 4 heteroatoms or heteroatom-containing groups selected from B, N, O, S, C (O), S (O) m. Unless specifically prohibited, the ring is optionally substituted.
The term "sulphur" as used herein alone or in combinationThe acid salt "and" sulfonic acid "are intended to mean-SO3The H group and its anion (when sulfonic acid is used to form a salt).
The term "sulfanyl", as used herein, alone or in combination, refers to-S-.
The term "sulfinyl", as used herein, alone or in combination, refers to-S (O) -.
The term "sulfonyl", as used herein, alone or in combination, means-S (O)2-。
The term "N-sulfonamido" refers to RS (═ O)2NR '-group, wherein R and R' are as defined herein.
The term "S-sulfonamido" refers to-S (═ O)2NRR 'groups, wherein R and R' are as defined herein.
The term "tautomer" as used herein, alone or in combination, refers to one of two or more isomers that rapidly interconvert. Typically, such interconversion is sufficiently rapid that a single tautomer is not isolated without the other tautomer. The ratio of the amounts of tautomers can depend on the solvent composition, ionic strength and pH, as well as other solution parameters. The ratio of the amount of tautomers can vary in a particular solution and in the microenvironment of the biomolecule binding sites in the solution. Examples of tautomers well known in the art include keto/enol, enamine/imine and lactam/lactim tautomers. Examples of tautomers well known in the art also include the 2-hydroxypyridine/2 (1H) -pyridone and 2-aminopyridine/2 (1H) -iminopyridone tautomers.
The terms "thia" and "thio", as used herein, alone or in combination, refer to an-S-group or an ether in which the oxygen is replaced by sulfur. Included within the definition of thia and thio are the oxidized derivatives of thio, namely sulfinyl and sulfonyl.
The term "thiol" as used herein, alone or in combination, refers to an-SH group.
As used herein, the term "thiocarbonyl" includes thiocarbonyl-c(s) H alone, and in combination, is a-c(s) -group.
The term "N-thiocarbamoyl" refers to the ROC (S) NR '-group, wherein R and R' are as defined herein.
The term "O-thiocarbamoyl" refers to the group-OC (S) NRR ', where R and R' are as defined herein.
The term "thiocyanate" refers to a-CNS group.
Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, any such defined trailing element is an element that is connected to the parent moiety. For example, the complex group alkylamido represents an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl represents an alkoxy group attached to the parent molecule through an alkyl group.
When a group is defined as "null", it means that the group does not exist.
The term "optionally substituted" means that the aforementioned groups may be substituted or unsubstituted. When substituted, the substituents of the "optionally substituted" group may include, but are not limited to, one or more substituents independently selected from the following groups or a particular set of specified groups, used alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxylate, lower carboxamide, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, carboxamide, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3、SH、SCH3、C(O)CH3、CO2CH3、CO2H. Pyridyl, thiophene, furyl, lower carbamate, and lower urea. Where structurally feasible, two substituents may be linked together to form a fused five-, six-or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example to form a methylenedioxy or ethylenedioxy group. Optionally selectingThe substituted radical may be unsubstituted (e.g. -CH)2CH3) Completely substituted (e.g. -CF)2CF3) Monosubstituted (e.g. -CH)2CH2F) Or a group substituted at any level between fully substituted and mono-substituted (e.g., -CH)2CF3). Where substituents are listed without limitation as to substitution, substituted and unsubstituted forms are contemplated. When a substituent is defined as "substituted," the substitution pattern is particularly contemplated. In addition, different groups of optional substituents for a particular moiety may be defined as desired; in these cases, optional substitution by definition will generally immediately follow "optionally substituted".
Unless otherwise defined, the term R or the term R', when present by itself and not numbered, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which is optionally substituted. Such R and R' groups are to be understood as being optionally substituted as defined herein. Each R group, whether or not the R group has a number, includes R, R' and RnThe term "substituent" refers to a group of substituents or terms (e.g., aryl, heterocycle, R, etc.) that are each defined independently of the definition of each other occurrence if any variable, substituent, or term (e.g., aryl, heterocycle, R, etc.) occurs more than one time in a formula or general structure.
The term "bond" refers to a covalent bond between two atoms or two moieties (when the atoms joined by the bond are considered part of a larger substructure). Unless otherwise specified, a bond may be a single, double or triple bond. The dashed line between two atoms in the molecular diagram indicates that there may or may not be other bonds at that position.
Asymmetric centers are present in the compounds disclosed herein. Depending on the configuration of the substituents around the chiral carbon atom, these centers are represented by the symbols "R" or "S". It is to be understood that the present invention encompasses all stereochemically isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as the d-and 1-isomers and mixtures thereof. Individual stereoisomers of the compounds may be synthesized from commercially available starting materials containing chiral centers, or may be prepared by preparing a mixture of enantiomeric products, separating them (e.g., by conversion to a mixture of diastereomers followed by separation or recrystallization), chromatographic techniques, separating the enantiomers directly on a chiral chromatographic column, or by any other suitable method known in the art. Starting compounds having a particular stereochemistry are either commercially available or can be prepared and resolved by techniques known in the art. In addition, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis (cis), trans (trans), cis (syn), trans (anti), E (entgegen) and Z (zusammen) isomers, and suitable mixtures thereof. In addition, the compounds may exist as tautomers. The present invention provides all tautomers. In addition, the compounds disclosed herein may exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms.
Conformers are present in the compounds disclosed herein. In the formula, when R1When aryl or heteroaryl:
the orientation of the aryl or heteroaryl group relative to the pyrimidinone moiety can be different as shown below:
(Saforms) and(Raforms).
These forms are represented by the symbol "Sa"or" RaBy "is meant, depending on the conformation of the aryl or heteroaryl group relative to the pyrimidinone moiety. "S" can be found in examples 1 to 20a"and" Ra"form of embodiment.
As used herein, the term "disease" is generally synonymous with, and is used interchangeably with, the terms "disorder", "syndrome" and "condition" (as in medical conditions) because they each reflect an abnormal state of the human or animal body or part thereof which impairs normal function, usually manifested as significant signs and symptoms, and results in a reduction in the length of life or quality of life of the human or animal.
The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a condition or disorder described in the present disclosure. Such administration includes co-administration of the therapeutic agents in a substantially simultaneous manner, e.g., in a single capsule with a fixed ratio of active ingredients or in multiple separate capsules for each active ingredient. In addition, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the above treatment regimen will provide a beneficial effect of the drug combination in treating the disorders or conditions described herein.
As used herein, "PTPN 11 inhibitor" refers to an IC that exhibits the activity relative to PTPN11 as measured by the PTPN11 assay generally described herein50No greater than about 100 μ M, more typically no greater than about 50 μ M. ' IC50"is the concentration of inhibitor that reduces the activity of an enzyme (e.g., PTPN11) to half of the maximum level. It has been found that certain compounds disclosed herein exhibit inhibitory effects on PTPN 11. In certain embodiments, the IC of the compound relative to PTPN11 is determined as described in the PTPN11 assay described herein50No more than about 50 μ M; in further embodiments, the IC of the compound relative to PTPN1150No more than about 10 μ M; in still other embodiments, the IC of compound to PTPN1150No more than about 1 μ M; in another embodiment, the compounds are relatedIC at PTPN1150Not greater than about 200 nM.
The phrase "therapeutically effective" is intended to define the amount of active ingredient used to treat a disease or disorder or to achieve a clinical endpoint.
The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) that are suitable for contact with the tissues of a patient without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.
As used herein, reference to "treatment" of a patient is intended to include prophylaxis. Treatment may also be preliminary in nature, i.e., it may include prevention of disease. Prevention of disease may involve complete protection against the disease, for example in the case of prevention of infection by a pathogen, or may involve prevention of disease progression. For example, prevention of a disease may not mean complete elimination of any effect associated with the disease at any level, but may mean prevention of symptoms of the disease to a clinically significant or detectable level. Prevention of disease may also mean preventing the disease from progressing to a later stage of the disease.
The term "patient" is generally synonymous with the term "subject" and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs and rabbits, and companion animals such as dogs, cats, rabbits and horses. Preferably, the patient is a human.
The term "prodrug" refers to a compound that has a higher activity in vivo. Certain compounds disclosed herein may also exist as prodrugs. Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the compounds. Alternatively, prodrugs can be converted to compounds by chemical or biochemical methods in an in vitro environment. For example, a prodrug can be slowly converted to a compound when placed in a transdermal patch reservoir (transdermal patch reservoir) with a suitable enzyme or chemical agent. Prodrugs are often useful because, in some cases, they may be easier to administer than the compound or the parent drug. For example, they may be orally administered with bioavailability, whereas the parent drug does not. The prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic or oxidative activation. Without limitation, one example of a prodrug is a compound that is administered as an ester ("prodrug") and then metabolically hydrolyzed to the carboxylic acid (the active entity). Additional examples include peptidyl derivatives of the compounds.
The compounds disclosed herein may exist as therapeutically acceptable salts. The present invention includes the above compounds in the form of salts, including acid addition salts. Suitable salts include those formed with organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, non-pharmaceutically acceptable salts may be used for the preparation and purification of the compounds in question. Basic addition salts may also be formed and are pharmaceutically acceptable.
The term "therapeutically acceptable salt" as used herein means a salt or zwitterionic form of a compound disclosed herein, which is water or oil soluble or dispersible and is therapeutically acceptable as defined herein. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in free base form with the appropriate acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothiocyanate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, picrate, etc, Propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate (p-tosylate) and undecanoate. Likewise, the basic groups in the compounds disclosed herein may be quaternized with: methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl and diamyl sulfates; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids which may be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as oxalic, maleic, succinic and citric acids. Salts may also be formed by coordination of the compound with an alkali or alkaline earth metal ion. Accordingly, the present invention encompasses sodium, potassium, magnesium, and calcium salts, and the like, of the compounds disclosed herein.
Base addition salts can be prepared during the final isolation and purification of the compounds by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate or bicarbonate of a metal cation or ammonia or an organic primary, secondary or tertiary amine. Cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N-dibenzylphenethylamine, 1-phenethylamine (1-phenylenamine) and N, N' -dibenzylethylenediamine. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
Salts of the compounds may be prepared by reacting the appropriate compound in free base form with the appropriate acid.
Compounds of formula (I)
In one aspect, the invention provides compounds represented by formula I:
or a salt, ester or prodrug thereof, wherein:
subscript a is 0 or 1;
subscript b is 0 or 1;
Y1is a direct bond or CR17R18；
Y2Is selected from C1-4Alkyl, amino, C1-4Alkyl C (O) O-, C1-4Alkylamino and C1-4An aminoalkyl group;
R1is selected from C6-10Aryl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl and 5-10 membered heteroaryl having 1-4 heteroatoms or groups independently selected from N, C (O), O, and S as the ring apex; the R is1Is optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14；
R2、R3、R10And R11Each independently selected from hydrogen and C1-4Alkyl and C3-8A cycloalkyl group;
R4、R5、R8and R9Each independently selected from hydrogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-8Cycloalkyl, halogen and C1-4An alkylamino group;
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, amido, cyano, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with 1 to 5 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
or R6And R7And together with the carbon atom to which they are attached form a compound having 0 to 3 substituents independently selected from the group consisting of N, C (O), O, and S (O)mA 3 to 7 membered saturated or unsaturated ring having the heteroatom or group as the ring apex;
subscript m is 0,1, or 2;
said is prepared from R6And R7The saturated or unsaturated ring formed is unsubstituted or substituted with 1 to 3 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R2、R3、R4、R5、R7、R8、R9、R10and R11Any two groups of (a) may form a 5 to 6 membered ring having 0 to 2 heteroatoms selected from N, O and S as ring vertices;
R2、R4、R6、R8and R10Any two groups in (a) may form a direct bond or a1 or 2 atom carbon bridge;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl, -NH-NHR19、-NHR19、-OR19、-NHC(O)R19、-NHC(O)NHR19、-NHS(O)2NHR19、-NHS(O)2R19、-C(O)OR19,-C(O)NR19R20、-C(O)NH(CH2)qOH、-C(O)NH(CH2)qR21、-C(O)R21、-NH2、-OH、-S(O)2NR19R20、C3-8Cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms selected from N, O, S and P as ring vertices, heteroaryl having 1-5 heteroatoms selected from N, O, S and P as ring vertices; wherein subscript q is an integer between 0 and 6; and wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo;
R14、R15and R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: amide, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R17and R18Each independently selected from hydrogen and C1-4Alkyl and CF3；
R19And R20Each independently selected from hydrogen and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group;
each R21Independently selected from: hydrogen, -OH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group.
In some embodiments, the present invention provides compounds represented by formula I:
or a salt, ester or prodrug thereof, wherein:
subscript a is 0 or 1;
subscript b is 0 or 1;
Y1is a direct bond or CR17R18；
Y2Is selected from C1-4Alkyl, amino, C1-4Alkyl C (O) O-, C1-4Alkylamino and C1-4An aminoalkyl group;
R1is selected from C6-10Aryl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl and 5-10 membered heteroaryl having 1-4 heteroatoms or groups independently selected from N, C (O), O, and S as the ring apex; the R is1Is optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14；
R2、R3、R10And R11Each independently selected from hydrogen and C1-4Alkyl and C3-8A cycloalkyl group;
R4、R5、R8and R9Each independently of the otherIs selected from hydrogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-8Cycloalkyl, halogen and C1-4An alkylamino group;
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, halogen and hydroxyl or selected from amide and C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with 1 to 5 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
or R6And R7And together with the carbon atom to which they are attached form a compound having 0 to 3 substituents independently selected from the group consisting of N, C (O), O, and S (O)mA 3 to 7 membered saturated or unsaturated ring having the heteroatom or group as the ring apex;
subscript m is 0,1, or 2;
said is prepared from R6And R7The saturated ring formed is unsubstituted or substituted with 1 to 3 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R2、R3、R4、R5、R7、R8、R9、R10and R11Any two groups of (a) may form a 5 to 6 membered ring having 0 to 2 heteroatoms selected from N, O and S as ring vertices;
R2、R4、R6、R8and R10Any two groups in (a) may form a direct bond or a1 or 2 atom carbon bridge;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl group、C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl, -NH-NHR19、-NHR19、-OR19、-NHC(O)R19、-NHC(O)NHR19、-NHS(O)2NHR19、-NHS(O)2R19、-C(O)OR19、-C(O)NR19R20、-C(O)NH(CH2)qOH,-C(O)NH(CH2)qR21、-C(O)R21、-NH2、-OH、-S(O)2NR19R20、C3-8Cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms selected from N, O, S and P as ring vertices, heteroaryl having 1-5 heteroatoms selected from N, O, S and P as ring vertices; wherein subscript q is an integer between 0 and 6; and wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo;
R14、R15and R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group;
R17and R18Each independently selected from hydrogen and C1-4Alkyl and CF3；
R19And R20Each independently selected from hydrogen and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group; and
each R21Independently selected from: hydrogen, -OH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group.
In some embodiments of formula I, Y1Is a straight bond. In certain embodiments, Y1Is CR17R18. In certain embodiments, R17And R18Each independently selected from hydrogen and C1-4Alkyl and CF3. In certain embodiments, R17And R18Each independently is hydrogen or C1-4An alkyl group. In certain embodiments, Y1is-CH2。
In some embodiments of formula I, Y2Is C1-4An alkyl group. In certain embodiments, Y2Is methyl.
In certain embodiments, the compound is represented by formula Ia:
wherein the subscripts a and b, Y1、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R13As defined and described herein.
In certain embodiments, the compound is represented by formula Ib:
wherein the subscripts a and b, Y2、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R13As defined and described herein.
In certain embodiments, the compound is represented by formula Ic:
wherein the subscripts a and b, R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11And R13As defined and described herein.
In some embodiments of any one of formulas I, Ia, Ib, and Ic, subscripts a and b are each 1.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R13Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl radical, C3-8Cycloalkyl, 3 or 6 membered heterocyclyl having 1-3 heteroatoms selected from N, O and S as ring vertices; wherein heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo. In certain embodiments, R13Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group. In certain embodiments, R13Selected from hydrogen, halogen, C1-6Alkyl and C1-6A haloalkyl group. In certain embodiments, R13Selected from hydrogen, halogen, C1-4Alkyl and C1-4A haloalkyl group. In certain embodiments, R13Is selected from-CH2OH、CF2OH and-CHFOH. In certain embodiments, R13Selected from hydrogen, Cl, Br, methyl and CF3. In certain embodiments, R13Is hydrogen. In certain embodiments, R13Is Cl. In certain embodiments, R13Is Br. In certain embodiments, R13Is methyl. In certain embodiments, R13Is CF3。
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is selected from C6-10Aryl and a 5 to 9 membered heteroaryl group having 1 to 4 heteroatom groups independently selected from N, C (O), O and S as ring vertices; and optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino,C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14。
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is selected from C6-10Aryl and a 5 to 9 membered heteroaryl group having 1 to 4 heteroatom groups independently selected from N, C (O), O and S as ring vertices; and optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14；R14、R15And R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally selected by 1 or more independentlySubstituted from the following groups: amide, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is selected from C6-10Aryl and a 5 to 9 membered heteroaryl group having 1 to 4 heteroatom groups independently selected from N, C (O), O and S as ring vertices; and optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14(ii) a And R14、R15And R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Selected from hydrogen, C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: amide, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Selected from hydrogen, C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or has 1 to 4 substituents independently selected from N, O and SA 5-to 6-membered heteroaryl group with the heteroatom as the vertex of the ring; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is selected from C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is selected from C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or has1 to 4 heteroatoms independently selected from N, O and S as the apex of the ring, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or more groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
Any of formulas I, Ia, Ib and IcIn some embodiments of any, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or more groups independently selected from: c1-4Alkylamide group and C1-4An alkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl having 1 to 4 heteroatoms or groups independently selected from N, C (O), O, and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R2、R3、R10And R11Independently is hydrogen or C1-4An alkyl group. In certain embodiments, R2、R3、R10And R11Each is hydrogen.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R4、R5、R8And R9Independently selected from hydrogen, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-8Cycloalkyl and C1-4An alkylamino group. In certain embodiments, R4、R5、R8And R9Independently is hydrogen or C1-4An alkyl group. In certain embodiments, R4、R5、R8And R9Each is hydrogen.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R1Is phenyl or a 5 to 6 membered heteroaryl having 1 to 4 heteroatoms or groups independently selected from N, C (O), O, and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; r4、R5、R8And R9Independently selected from hydrogen, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-6Cycloalkyl and C1-4An alkylamino group.
In some embodiments of any of formulas I, Ia, Ib, and Ic, R2、R3、R4、R5、R8、R9、R10And R11Each is hydrogen.
In certain embodiments, the compound is represented by formula II:
wherein R is1、R6、R7And R13As defined and described herein.
In some embodiments of any one of formulas I, Ia-Ic and II, R6Selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group; r7Selected from hydrogen, amido, cyano, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one to three substituents selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group. In certain embodiments, R6Selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group; r7Selected from hydrogen, amido, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one or two substituents selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6Selected from amino, C1-4Aminoalkyl and methylamino. In certain embodiments, R6Is amino or C1-4An aminoalkyl group. In certain embodiments, R6Is amino, aminomethyl or methylamino. In certain embodiments, R6Is amino or aminomethyl. In certain embodiments, R6Is an amino group. In certain embodiments, R6Is an aminomethyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R7Selected from hydroxy, C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one or two groups selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group. In certain embodiments, R7Selected from hydroxy, C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl. In certain embodiments, R7Is hydroxy, C1-4Alkyl or C1-4A hydroxyalkyl group. In certain embodiments, R7Is C1-4An alkyl group. In certain embodiments, R7Is methyl. In certain embodiments, R7Is ethyl.
In some embodiments of any one of formulas I, Ia-Ic and II, R6Is C1-4An aminoalkyl group; r7Selected from hydroxy, C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and5 or 6 membered heteroaryl, any of which is optionally substituted with one to three groups selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6Is an aminomethyl group; r7Selected from hydroxy, C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl.
In some embodiments of any one of formulas I, Ia-Ic and II, R6Is amino; r7Selected from hydroxy, C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one to three groups selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6Is amino; r7Selected from hydroxy, C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl.
In some embodiments of any one of formulas I, Ia-Ic and II, R6Is amino; r7Is C1-4A hydroxyalkyl group. In certain embodiments, R6Is amino; r7Is hydroxymethyl. In certain embodiments, R6Is amino; r7Is C1-4An alkyl group. In certain embodiments, R6Is amino; r7Is methyl. In certain embodiments, R6Is amino; r7Is ethyl. In certain embodiments, R6Is an aminomethyl group; r7Is C1-4An alkyl group. In certain embodiments, R6Is an aminomethyl group; r7Is methyl. In certain embodiments, R6Is an aminomethyl group; r7Is ethyl.
In any of the above embodiments, R7The amide group of (A) may be specified as-C(O)NH2。
In some embodiments of any one of formulas I, Ia-Ic and II, R6And R7Together with the carbon atom to which they are attached form a compound having 1-3 substituents independently selected from N, C (O), O and S (O)mIs a 3-7 membered saturated or unsaturated ring as the apex of the ring, and is optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6And R7Together with the carbon atoms to which they are attached form a 4-6 membered saturated or unsaturated ring having 1-3 heteroatoms or groups independently selected from N, C (O) and O as ring vertices, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6And R7Together with the carbon atom to which they are attached form a compound having 1-3 substituents independently selected from N, C (O), O and S (O)mAs a 3-7 membered saturated ring at the apex of the ring, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6And R7Together with the carbon atom to which they are attached form a 4-6 membered saturated ring having 1-3 heteroatoms or groups independently selected from N, C (O) and O as the ring vertex, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6And R7Together with the carbon atom to which they are attached form a 4-6 membered saturated ring having 1-3 heteroatoms or groups independently selected from N and O as the ring apex, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6And R7Together with the carbon atoms to which they are both attached form a 3 to 7 membered cycloalkyl group, optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R6And R7Together with the carbon atoms to which they are both attached form a 4 to 6 membered cycloalkyl group, optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group; r6Selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group; r7Selected from hydrogen, halogen and hydroxyl or selected from amide and C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one or two substituents selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group; r6Is amino or aminomethyl; r7Selected from hydroxy, C1-4Alkyl and C1-4A hydroxyalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical、C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group; r6And R7Together with the carbon atom to which they are attached form a compound having 1-3 substituents independently selected from N, C (O), O and S (O)mIs a 3-7 membered saturated or unsaturated ring as the apex of the ring, and is optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group; r6And R7Together with the carbon atom to which they are attached form a 4-6 membered saturated or unsaturated ring having 1-3 heteroatoms or groups independently selected from N, C (O) and O as ring verticesA ring, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group; r6And R7Together with the carbon atoms to which they are both attached form a 3 to 7 membered cycloalkyl group, optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; r6Selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group; r7Selected from hydrogen, halogen and hydroxyl or selected from amide and C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one or two substituents selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; r6Is amino or aminomethyl; r7Selected from hydroxy, C1-4Alkyl and C1-4A hydroxyalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; r6And R7Together with the carbon atom to which they are attached form a compound having 1-3 substituents independently selected from N, C (O), O and S (O)mIs a 3-7 membered saturated or unsaturated ring as the apex of the ring, and is optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or has 1 to 4A 5-to 6-membered heteroaryl group having as the ring vertex a heteroatom independently selected from N, O and S; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; r6And R7Together with the carbon atoms to which they are attached form a 4-6 membered saturated or unsaturated ring having 1-3 heteroatoms or groups independently selected from N, C (O) and O as ring vertices, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or a 5 to 6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; r6And R7Together with the carbon atoms to which they are both attached form a 3 to 7 membered cycloalkyl group, optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, pyrazinyl, pyridazinyl and 1,2, 4-triazinyl; and optionally substituted by 1,2 or 3R12Substituted, any one of them R12As defined and described herein, in certain embodiments, R1Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,2, 4-triazinyl; and optionally substituted by 1,2 or 3R12SubstitutionWherein each R12As defined and described herein. In certain embodiments, R1Is phenyl or pyridyl; and optionally substituted by 1,2 or 3R12Substituted, wherein each R12As defined and described herein.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,2, 4-triazinyl; and optionally substituted with 1,2 or 3R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,2, 4-triazinyl; and optionally substituted with 1,2 or 3R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or pyridyl, any of which is optionally substituted with 1,2 or 3R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl or pyridyl, any of which is optionally substituted with 1,2 or 3R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is phenyl and is optionally substituted by 1 to 3R12(ii) any one of them is independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14. In certain embodiments, R1Is phenyl and is optionally substituted by 1 to 3R12Substituted, each R12Independently selected from: halogen, hydroxy, amino, methylamino, dimethylamino, cyano, C1-4Alkyl radical, C1-4Haloalkyl and C1-4An alkoxy group. In certain embodiments, R1Is phenyl and is optionally substituted by 1 to 3R12Substituted, each R12Independently selected from: halogen, hydroxy, C1-4Alkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Is pyridyl and optionally substituted by 1-3R12(ii) any one of them is independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14. In certain embodiments, R1Is pyridyl and optionally substituted by 1-3R12Substituted, each R12Independently selected from: halogen, hydroxy, amino, methylamino, dimethylamino, cyano, C1-4Alkyl radical, C1-4Haloalkyl and C1-4An alkoxy group. In certain embodiments, R1Is pyridyl and optionally substituted by 1-3R12Substituted, each R12Independently selected from: halogen, hydroxy, C1-4Alkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from:
and
wherein each R12As defined and described herein.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from:
and
each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14Wherein R is14As defined and described herein.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from:
andand
each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from:
and
each R12Independently selected from: halogen, hydroxy, amino, methylamino, dimethylamino, cyano, C1-4Alkyl radical, C1-4Haloalkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from:
and
each R12Independently selected from: halogen, hydroxy, amino, methylamino, dimethylamino, cyano, C1-4Alkyl radical, C1-4Haloalkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from:
andand
each R12Independently selected from: halogen, hydroxy, amino, methylamino, dimethylamino, cyano, C1-4Alkyl radical, C1-4Haloalkyl and C1-4An alkoxy group.
In some embodiments of any one of formulas I, Ia-Ic and II, each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14. In certain embodiments, each R is12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14. In certain embodiments, each R is12Independently selected from: halogen, hydroxy, amino, methylamino, dimethylamino, cyano, C1-4Alkyl radical, C1-4Haloalkyl and C1-4An alkoxy group. In certain embodiments, each R is12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy and C1-4A haloalkyl group. In certain embodiments, each R is12Independently selected from: F. cl, Br, CH3、OCH3And CF3。
In some embodiments of any one of formulas I, Ia-Ic and II, each R12Independently selected from: F. cl, Br, CH3、OCH3、CF3、And
in some embodiments of any one of formulas I, Ia-Ic and II, R1Selected from:
andand
each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14Wherein R is14As defined and described herein.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Expressed as:
orAnd
each R12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy and C1-4A haloalkyl group. In certain embodiments, each R is12Independently selected from: F. cl, Br, CH3、OCH3And CF3. In certain embodiments, each R is12Is Cl.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Expressed as:
and
each R12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy and C1-4A haloalkyl group. In certain embodiments, each R is12Independently selected from: F. cl, Br, CH3、OCH3And CF3. In certain embodiments, each R is12Independently Cl or Br.
In some embodiments of any one of formulas I, Ia-Ic and II, R14Independently selected from C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group. In certain embodiments, R14Independently selected from C6-10Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group. In certain embodiments, R14Independently selected from C6-10Aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or two groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R14Independently phenyl or a 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or more groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group. In certain embodiments, R14Independently of benzeneA group or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group. In certain embodiments, R14Independently phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R14Is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group. In certain embodiments, R14Is phenyl, optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group. In certain embodiments, R14Is a quilt C1-4Alkyl amido substituted phenyl. In certain embodiments, R14Is phenyl substituted by-C (O) NHMe. In certain embodiments, R14Is phenyl. In certain embodiments, R14Is pyrazolyl, optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group. In certain embodiments, R14Is a quilt C1-4Alkyl-substituted pyrazolyl. In certain embodiments, R14Is pyrazolyl substituted by methyl. In certain embodiments, R14Is N-methyl pyrazolyl. In certain embodiments, R14Is pyrazolyl.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Expressed as:
each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; r14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Expressed as:
each R12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14；R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Expressed as:
each R12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14；R14Selected from phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
In some embodiments of any one of formulas I, Ia-Ic and II, R1Expressed as:
each R12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14；R14Selected from phenyl, quilt C1-4Alkyl amido substituted phenyl, pyrazolyl and substituted by C1-4Alkyl-substituted pyrazolyl. In certain embodiments, each R is12Independently selected from: F. cl, Br, CH3、OCH3And CF3；R14Selected from phenyl, MeNHC (O) -phenyl, pyrazolyl and N-methyl pyrazolyl. In certain embodiments, each R is12Is Cl; r14Selected from phenyl, MeNHC (O) -phenyl, pyrazolyl and N-methyl pyrazolyl.
In certain embodiments, the compound is represented by formula II:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, any of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14；
R6Selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, cyano, amido, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one to three groups selected fromThe substituent (b): amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
In certain embodiments, the compound is represented by formula III:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14；
R6Selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, cyano, amido, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one to three substituents selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
In certain embodiments, the compound is represented by formula IV:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14；
R13Selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group;
each RaIndependently selected from amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
In certain embodiments, the compound is represented by formula V:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridineEach of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14(ii) a And
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group; and
Raselected from amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In certain embodiments, the compound is represented by formula VI:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14(ii) a And
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group; and
each RaIndependently selected from amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In certain embodiments, the compound is represented by formula VII:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14(ii) a And
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group; and
each RaIndependently selected from amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In certain embodiments, the compound is represented by formula VIII:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R1Independently selected from halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14(ii) a And
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group; and
each RaIndependently selected from amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In certain embodiments, the compound is represented by formula IX:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14(ii) a And
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group; and
Raselected from amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
In certain embodiments, the compound is represented by formula X:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14(ii) a And
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group; and
each RaIndependently selected from amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
In certain embodiments, the compound is represented by formula XI:
or a salt, ester or prodrug thereof, wherein:
R1is phenyl or pyridyl, each of which is substituted by 0 to 3R12Substitution;
each R12Independently selected from: halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4HalogenatedAlkyl and OR14(ii) a And
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group;
R14is phenyl or pyrazolyl, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group; and
each RaIndependently selected from amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
In some embodiments of any of formulas II-XI, R1、R6、R7、R12、R13And R14May have the meaning set forth in any one or more of the selected embodiments mentioned above.
In some embodiments of any of formulas II-XI, R13Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl and C3-8A cycloalkyl group. In certain embodiments, R13Selected from hydrogen, halogen, C1-6Alkyl and C1-6A haloalkyl group. In certain embodiments, R13Selected from hydrogen, halogen, C1-4Alkyl and C1-4A haloalkyl group. In certain embodiments, R13Selected from hydrogen, Cl, Br, methyl and CF3. In certain embodiments, R13Is hydrogen. In certain embodiments, R13Is Cl. In certain embodiments, R13Is Br. In certain embodiments, R13Is methyl. In certain embodiments, R13Is CF3。
In some embodiments of any of formulas II-XI, R1Is phenyl or pyridyl, each of which is substituted by 1-3R12Substitution. In certain embodiments, R1Is phenyl or pyridyl, each substituted by 2 or 3R12And (4) substitution. In certain embodiments, R1Is represented by 2 or 3R12A substituted phenyl group. In certain embodiments, R1Is formed by 2R12A substituted phenyl group. In certain embodiments, R1Is formed by 3R12A substituted phenyl group. In certain embodiments, R1Is represented by 2R12A substituted pyridyl group.
In some embodiments of any of formulas II-XI, each R is12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and OR14. In certain embodiments, each R is12Independently selected from: halogen, hydroxy, amino, methylamino, dimethylamino, cyano, C1-4Alkyl radical, C1-4Haloalkyl and C1-4An alkoxy group. In certain embodiments, each R is12Independently selected from: halogen, C1-4Alkyl radical, C1-4Alkoxy and C1-4A haloalkyl group. In certain embodiments, each R is12Independently selected from: F. cl, Br, CH3、OCH3And CF3。
In some embodiments of any of formulas II-XI, each R is12Independently selected from: F. cl, Br, CH3、OCH3、CF3、And
in some embodiments of any of formulas II-XI, R1Is formed by 2R12Substituted phenyl; each R12Independently selected from: F. cl, Br, CH3、OCH3And CF3. In certain embodiments, R1Is formed by 2R12Substituted phenyl; each R12Is Cl.
In formulae II-XIIn some embodiments of one item, R1Is formed by 3R12Substituted phenyl; each R12Independently selected from: F. cl, Br, CH3、OCH3、CF3、 And
in some embodiments of any of formulas II-XI, R1Is formed by 3R12Substituted phenyl; first and second R12Each is Cl; third R12Is Br. In certain embodiments, R1Is formed by 3R12Substituted phenyl; first and second R12Each is Cl; third R12Selected from:
and
in some embodiments of any of formulas II-XI, in certain embodiments, R14Is phenyl, optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group. In certain embodiments, R14Is phenyl, which is substituted by C1-4Alkyl amido. In certain embodiments, R14Is phenyl substituted by-C (O) NHMe. In certain embodiments, R14Is phenyl. In certain embodiments, R14Is pyrazolyl, optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group. In certain embodimentsIn, R14Is a quilt C1-4Alkyl-substituted pyrazolyl. In certain embodiments, R14Is pyrazolyl substituted by methyl. In certain embodiments, R14Is N-methyl pyrazolyl. In certain embodiments, R14Is pyrazolyl.
In some embodiments of formula II or III, R6Is amino or C1-4An aminoalkyl group. In certain embodiments, R6Is amino or aminomethyl. In certain embodiments, R6Is an amino group. In certain embodiments, R6Is an aminomethyl group.
In some embodiments of formula II or III, R7Is hydroxy, C1-4Alkyl or C1-4A hydroxyalkyl group. In certain embodiments, R7Is C1-4An alkyl group. In certain embodiments, R7Is methyl. In certain embodiments, R7Is ethyl.
In some embodiments of formula II or III, R6Is amino; r7Is C1-4An alkyl group. In certain embodiments, R6Is amino; r7Is methyl. In certain embodiments, R6Is amino; r7Is ethyl. In certain embodiments, R6Is an aminomethyl group; r7Is C1-4An alkyl group. In certain embodiments, R6Is an aminomethyl group; r7Is methyl.
In some embodiments of any one of formulas IV-XI, each R isaIndependently selected from amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy and C1-4A haloalkyl group. In certain embodiments, each R isaIndependently is amino or C1-4An alkyl group. In certain embodiments, each R isaIndependently amino or methyl.
In certain embodiments, the compound is represented by a formula selected from:
and
also provided are embodiments in which any of the above embodiments may be combined with any one or more of these embodiments, provided that the combinations are not mutually exclusive.
As used herein, two embodiments are "mutually exclusive" when one embodiment is defined as different from the other embodiment. For example, embodiments in which two groups are combined to form a cycloalkyl group are mutually exclusive of embodiments in which one group is ethyl and the other group is hydrogen. Similarly, one of the radicals is CH2Embodiments of (a) are mutually exclusive from embodiments in which the same group is NH.
Also provided are compounds selected from the examples disclosed herein.
Composition IV
Also provided are pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable carrier.
In certain embodiments, the pharmaceutical composition is formulated for oral administration.
In certain embodiments, the pharmaceutical composition is formulated for parenteral administration.
In certain embodiments, the pharmaceutical composition is formulated for intravenous administration.
In certain embodiments, the pharmaceutical composition is formulated for subcutaneous administration.
In certain embodiments, the oral pharmaceutical composition is selected from a tablet or capsule.
Although it is possible to administer the compounds of the invention as starting chemicals, it is also possible to present them as pharmaceutical preparations. Accordingly, the pharmaceutical formulations provided herein comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, and one or more pharmaceutically acceptable carriers thereof, and optionally one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The correct formulation will depend on the route of administration chosen. Any known techniques, carriers and excipients may be suitably used, as understood in the art. The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, dragee-making, diafiltering, emulsifying, encapsulating, entrapping or compressing processes.
Although the most suitable route of administration depends, for example, on the condition and disorder of the recipient, it includes formulations suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Generally, these methods comprise the step of bringing into association a compound of the present invention, or a pharmaceutically acceptable salt, ester, amide, prodrug or solvate thereof ("active ingredient"), with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired dosage form.
Formulations of compounds suitable for oral administration disclosed herein may be presented as discrete units, such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented in the form of a bolus, granule or paste.
Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be prepared by compression or molding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent or lubricant, surfactant or dispersing agent. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be used in dosages suitable for such administration. The push-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, for example fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores with suitable coatings are provided. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbomer gel (carbopol gel), polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings in order to identify or characterize active compound doses in various combinations.
The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above.
Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound (which may contain anti-oxidants), buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
In addition to the formulations described previously, the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.
For buccal or sublingual administration, the compositions may take the form of tablets, troches, pastilles or gels formulated in conventional manner. Such compositions may comprise active ingredients based on flavouring agents, for example sucrose and gum arabic or tragacanth (tragacanth).
The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycols or other glycerides.
Certain compounds disclosed herein can be administered locally, i.e., by non-systemic administration. This includes applying the compounds disclosed herein topically to the epidermis or outside the oral cavity and instilling the compounds into the ear, eye and nose so that the compounds do not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, for example gels, liniments, lotions, creams, ointments or pastes, and drops suitable for ocular, otic or nasal administration. The active ingredient for topical administration may be present, for example, in an amount of 0.001% to 10% w/w (by weight) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% w/w. In other embodiments, it may comprise less than 5% w/w. In certain embodiments, the active ingredient may be present in an amount of 2% w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/w of the formulation.
For administration by inhalation, the compounds may conveniently be delivered from an insufflator, nebulizer, pressurized pack or other aerosol for convenient delivery. Pressurized packs may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound with a suitable powder base such as lactose or starch. The powder compositions may be presented in unit dosage form, for example in the form of capsules, cartridges, gelatin or blister packs from which the powder may be administered by means of an inhaler or insufflator.
Preferred unit dose formulations are those containing an effective dose of the active ingredient as described herein below or in the appropriate paragraph therein.
It will be understood that the above-described formulations may include, in addition to the ingredients particularly mentioned above, other agents of the type of formulation in question which are conventionally considered in the art, for example those suitable for oral administration may include flavouring agents.
The compounds may be administered orally or by injection at a dose of 0.1 to 500mg/kg per day. The dosage for adults will generally range from 5mg to 2 g/day. Pharmaceutical formulations in tablets or other forms provided in discrete units may conveniently contain an amount of one or more compounds effective at such a dose, or a multiple of such a dose, for example, a unit dose of from 5mg to 500mg, typically from about 10mg to 200 mg.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
V. Process
The present invention also relates to a method of inhibiting at least one PTPN11 function comprising the step of contacting PTPN11 with a compound described herein. Cell phenotype, cell proliferation, activity of PTPN11, changes in biochemical output produced by active PTPN11, expression of PTPN11, or binding of PTPN11 to a natural binding partner (binding partner) can be monitored. The method may be a treatment modality for a disease, a biological assay, a cellular assay, a biochemical assay, and the like.
Also provided herein are methods of treating a PTPN 11-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a salt or tautomer thereof.
In certain embodiments, the disease is cancer.
In certain embodiments, the cancer is selected from breast cancer, colon cancer, leukemia or melanoma.
Also provided herein are methods of treating PTP-mediated diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a salt or tautomer thereof.
In certain embodiments, the disease is selected from the group consisting of Noonan syndrome and Leopard syndrome.
In certain embodiments, the disease is cancer.
In certain embodiments, the cancer is selected from breast cancer, colon cancer, leukemia or melanoma.
Also provided herein are compounds disclosed herein for use as a medicament.
Also provided herein are compounds disclosed herein for use as medicaments for treating PTPN 11-mediated diseases.
Also provided herein are compounds disclosed herein for use as medicaments for treating PTP-mediated diseases.
Also provided is the use of a compound disclosed herein as a medicament.
Also provided is the use of a compound disclosed herein for the manufacture of a medicament for the treatment of a PTPN 11-mediated disease.
Also provided are compounds as disclosed herein for use in the preparation of a medicament for the treatment of a PTPN 11-mediated disease.
Also provided is the use of a compound disclosed herein in the treatment of a disease mediated by PTPN 11.
Also provided is the use of a compound disclosed herein in the treatment of PTP mediated diseases.
Also provided herein are methods of inhibiting PTPN11, comprising contacting PTPN11 with a compound disclosed herein, or a salt or tautomer thereof.
Also provided herein are methods of inhibiting a PTP comprising contacting a PTP with a compound disclosed herein, or a salt or tautomer thereof.
Also provided herein is a method of achieving a cognitive enhancing effect in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a salt or tautomer thereof.
In certain embodiments, the PTPN 11-mediated disease is selected from the group consisting of Noonan syndrome and Leopard syndrome.
In certain embodiments, the PTPN 11-mediated disease is cancer.
In certain embodiments, the PTPN 11-mediated disease is selected from breast cancer, colon cancer, leukemia or melanoma.
Also provided is a method of modulating PTPN 11-mediated function in a subject comprising administering a therapeutically effective amount of a compound disclosed herein.
Administration and combination therapy
The compounds may be administered in a variety of ways, for example orally, topically or by injection. The precise amount of the compound to be administered to a patient will be at the responsibility of the attending physician. The specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise disease to be treated and the severity of the indication or condition being treated. Likewise, the route of administration may vary depending on the condition and its severity.
In certain instances, it may be suitable to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, tautomer, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient receiving one of the compounds herein is hypertension, then administration of an antihypertensive agent in combination with the initial therapeutic agent may be appropriate. Alternatively, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., the adjuvant itself has only minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Alternatively, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (also including a treatment regimen) that also has therapeutic benefit. By way of example only, where administration of one of the compounds described herein is involved in the treatment of diabetes, the therapeutic benefit may also be increased by providing the patient with another therapeutic agent for diabetes. In any event, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may be the sum of only two therapeutic agents, or the patient may experience a synergistic benefit.
Specific non-limiting examples of possible combination therapies include the use of certain compounds of the present invention together with anti-cancer (chemotherapeutic) drugs. Classes of anticancer drugs include, but are not limited to: alkylating agents, antimetabolites, antimitotics, checkpoint inhibitors, plant alkaloids and terpenoids, topoisomerase inhibitors, cytotoxic antibiotics, aromatase inhibitors, angiogenesis inhibitors, anti-steroids and anti-androgens, mTOR inhibitors, tyrosine kinase inhibitors, and the like.
For use in cancer and neoplastic diseases, inhibitors of PTPN11(SHP2) may be used optimally with the following non-limiting examples of one or more anticancer drugs:
(1) alkylating agents, including but not limited to carmustine (carmustine), chlorambucil (LEUKERAN), cisplatin (placin), carboplatin (PARAPLATIN), oxaliplatin (ELOXATIN), streptozotocin (ZANOSAR), sulfolane (myreran), dacarbazine (dacarbazine), ifosfamide (ifosfamide), lomustine (CCNU), melphalan (ALKERAN), procarbazine (MATULAN), Temozolomide (TEMODAR), thiotepa (thiotepa), and cyclophosphamide (endxan);
(2) antimetabolites including, but not limited to, cladribine (Leustatin), mercaptopurine (PURINETHOL), thioguanine, pentostatin (NIPENT), cytosine arabinoside (cytarabine, ARA-C), Gemcitabine (GEMZAR), fluorouracil (5-FU, CARAC), capecitabine (XELODA), folinic acid (FUSILEV), methotrexate (RHEMATREX), raltitrexed (raltitrexed);
(3) antimitotic agents, typically plant alkaloids and terpenoids or derivatives thereof, including but not limited to taxanes such as docetaxel (taxotere) and paclitaxel (ABRAXANE, TAXOL); vinblastine, such as vincristine (ONCOVIN), vinblastine (vinblastine), vindesine (vindesine) and vinorelbine (NAVELBINE);
(4) checkpoint inhibitors, such as anti-PD-1 or PD-L1 antibody pembrolizumab (KEYTRUDA), nivolumab (OPDIVO), MEDI4736 and MPDL 3280A; the anti-CTLA-4 antibody ipilimumab (YERVOY); and target LAG3 (lymphocyte activation gene 3 protein), KIR (killer immunoglobulin-like receptor), 4-1BB (tumor necrosis factor receptor superfamily member 9), TIM3(T cell immunoglobulin and mucin domain comprising-3), and OX40 (tumor necrosis factor receptor superfamily member 4);
(5) topoisomerase inhibitors, including but not limited to Camptothecin (CTP), irinotecan (CAMPTOSAR), topotecan (HYCAMTIN), teniposide (VUMON), and Etoposide (EPOSIN);
(6) cytotoxic antibiotics, including but not limited to actinomycin D (actinomycin, COSMEGEN), Bleomycin (BLENOXANE), doxorubicin (ADRIAMYCIN), daunorubicin (CERUBIDINE), epirubicin (ELLENCE), Fludarabine (FLUDARA), idarubicin (idarubicin), Mircogycin (MITOL), mitoxantrone (NOVANTRONE), prakamycin (plicamycin);
(7) aromatase inhibitors, including but not limited to aminoglutarimide, Anastrozole (ARIMIDEX), letrozole (FEMARA), vorozole (rivZOR), exemestane (AROMASIN);
(8) angiogenesis inhibitors, including but not limited to genistein (genistein), Sunitinib (SUTENT), and bevacizumab (AVASTIN);
(9) anti-steroids and anti-androgens such as aminoglutamine (CYTADREN), bicalutamide (CASODEX), cyproterone (cyproterone), flutamide (EULEXIN), nilutamide (NILANDRON);
(10) tyrosine kinase inhibitors, including but not limited to imatinib (GLEEVEC), erlotinib (TARCEVA), lapatinib (TYKERB), sorafenib (NEXAVAR), and axitinib (INLYTA);
(11) mTOR inhibitors, such as everolimus (everolimus), temsirolimus (toresel) and sirolimus (sirolimus);
(12) monoclonal antibodies, such as trastuzumab (HERCEPTIN) and Rituximab (RITUXAN);
(13) other drugs, such as aminophylline (amsacrine); bacillus Calmette-Guerin vaccine (B-C-G); bunsoln (ETILAMIDE); chloroquine (ARALEN); clodronate, pamidronate and other bisphosphonates; colchicine (colchicine); demethoxyviridin (demethoxyviridin); a salt of dichloroacetic acid; estramustine (estramustine); filgrastim (NEUPOGEN); fludrocortisone (florine f); goserelin (ZOLADEX); an interferon; leucovorin (leucovorin); leuprorelin (LUPRON); levamisole; ranidamine (lonid amine); mesna (mesna); metformin; mitotane (mitotane, o, p' -DDD, Lysodren); nocodazole (nocodazole); octreotide (SANDOSTATIN); perifosine; porfimer (particularly in combination with phototherapy and radiotherapy); suramin (suramin); tamoxifen (tamoxifen); titanocene dichloride; tretinoin (tretinoin); anabolic steroids such as fluorometholone (halostein); estrogens such as estradiol, Diethylstilbestrol (DES) and dienestrol (dienestrol); progestins such as medroxyprogesterone acetate (MPA) and megestrol; and testosterone.
In any case, multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order or even simultaneously. If used simultaneously, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms (as a single pill or as two separate pills, by way of example only). One therapeutic agent may be administered in multiple doses, or both may be administered in multiple doses. The time interval between multiple administrations may be of any duration from a few minutes to four weeks, if not simultaneous.
Thus, in another aspect, certain embodiments provide a method of treating a PTPN 11-mediated disease in a human or animal subject in need of such treatment, the method comprising administering to the subject an amount of a compound disclosed herein effective to alleviate or prevent the disease in the subject in combination with at least one additional agent known in the art for treating the disease. In related aspects, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more other drugs for the treatment of PTPN 11-mediated diseases.
In some embodiments, the methods described herein are for treating a disease condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the condition is a cancer that is resistant to a chemotherapeutic drug and/or ionizing radiation.
In some embodiments, the methods described herein are for treating a disease condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the condition is a cancer that is resistant to a chemotherapeutic drug and/or ionizing radiation.
The compounds, compositions, and methods disclosed herein are useful for treating diseases. In certain embodiments, the disease is one of cell proliferative disorders, including cancer. The cancer may be hormone-dependent or hormone-resistant, for example in the case of breast cancer. In certain embodiments, the cancer is a solid tumor. In other embodiments, the cancer is lymphoma or leukemia. In certain embodiments, the cancer is a drug resistant phenotype of a cancer disclosed herein or known in the art. Tumor invasion, tumor growth, tumor metastasis and angiogenesis can also be treated using the compositions and methods disclosed herein. Precancerous neoplasia may also be treated using the compositions and methods disclosed herein.
Cancers treated by the methods disclosed herein include colon, breast, ovarian, lung, and prostate cancers; oral and pharyngeal cancers (lip, tongue, mouth, larynx, pharynx), esophageal, gastric, small, large, colon, rectal, liver, and biliary tract cancers; pancreatic cancer, bone cancer, connective tissue cancer, skin cancer, cervical cancer, uterine cancer, endometrial cancer, testicular cancer, bladder cancer, kidney cancer, and other urinary tissue cancers, including Renal Cell Carcinoma (RCC); eye, brain, spinal cord and central nervous system cancers and other components of the peripheral nervous system and related structures (e.g., meninges); and endocrine adenocarcinomas such as thyroid gland. The term "cancer" also encompasses cancers that do not necessarily form solid tumors, including Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and hematopoietic malignancies, including leukemias (chronic lymphocytic leukemia (CLL), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML)) and lymphomas, including lymphocytic, myelocytic, and monocytic. Other types of cancers that may be treated using the compounds and methods of the invention include, but are not limited to, adenocarcinoma, angiosarcoma, astrocytoma, acoustic neuroma, anaplastic astrocytoma, basal cell carcinoma, glioblastoma, chondrosarcoma, choriocarcinoma, chordoma, craniopharyngioma, cutaneous melanoma, cystadenocarcinoma, endothelial sarcoma, embryonic carcinoma, ependymoma, Ewing's tumor, epithelial carcinoma, fibrosarcoma, gastric carcinoma, genitourinary tract carcinoma, glioblastoma multiforme, head and neck carcinoma, hemangioblastoma, hepatocellular carcinoma, liver carcinoma, kaposi's sarcoma, large cell carcinoma, leiomyosarcoma, leukemia, liposarcoma, lymphatic system carcinoma, lymphoma, lymphatic sarcoma, lymphatic endothelial cell sarcoma, medullary carcinoma, medulloblastoma, meningiomesothelioma, myeloma, myxosarcoma, neuroblastoma, neurofibrosarcoma, oligodendroglioma, epithelial ovarian cancer, papilloma, papillary adenocarcinoma, paraganglioma, parathyroid tumor, pheochromocytoma, pinealoma, plasmacytoma, retinoblastoma, rhabdomyosarcoma, sebaceous gland carcinoma, seminoma, skin cancer, melanoma, small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, sweat gland carcinoma, synovial carcinoma, thyroid carcinoma, uveal melanoma and Wilm's tumor (Wilm's tumor).
In certain embodiments, the compositions and methods disclosed herein are useful for preventing or reducing tumor invasion and tumor metastasis.
In addition to being useful for human therapy, certain compounds and formulations disclosed herein may also be useful for veterinary therapy of companion, exotic, and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.
VI preparation method
Describing the chirality of a molecule by specifying its configuration using the Cahn-Ingold-Prelog convention, using descriptors R and S for central chirality and R for axial chiralityaAnd SaTo describe the chirality of the molecule. PAC,1996,68,2193, basic terminology of stereochemistry (IUPAC recommendation, 1996), doi:10.1351/PAC199668122193; the IUPAC nomenclature chapter 9,9 months 2004 is preferred. Cahn, c.k.ingold and v.prelog, angelw.chem.lnnat.ed.eng.5, 385-415,511 (1966); prelog and g.helmchen, angelw.chem.lnnat.ed.eng.21, 567-583 (1982).
Synthetic schemes
The following protocol may be used to practice the invention.
General synthetic methods for Compounds
The following schemes may be used as general guidelines for preparing the compounds of the invention.
Abbreviation list:Pd2dba3-tris (dibenzylideneacetone) dipalladium; xanthphos-4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene; HCl ═ hydrogen chloride; TFA ═ trifluoroacetic acid; POCl3-phosphorus oxychloride (V); tf2O-trifluoromethanesulfonic anhydride; DIEA-diisopropylethylamine; DCM ═ dichloromethane; BOP- (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate); DBU-1, 8-diazabicyclo [5.4.0]Undec-7-ene; NBS-N-bromosuccinimide; NCS-N-chlorosuccinimide.
Scheme I
"Pd" catalysts and ligands (e.g., Pd) may be used2dba3And xanthphos) to convert the aryl halide a to the corresponding protected amine B. Amine B can be deprotected to give C, and the corresponding acetamidine D can be formed by treating amine C with acetonitrile and an acid such as HCl. D is reacted with the desired malonate to form aryl-substituted-6-hydroxy-2-methylpyrimidin-4 (3H) -ones E. By using POCl3Or by Tf2Reagent treatment of O and DIEA in DCM can convert E to the corresponding halide or triflate. Subsequent SNAr reactions can provide a protected amine G, which can be converted to an unprotected amine H. F can be directly converted to H in the SNAr reaction. E can be converted directly to H by using reagents such as BOP and DBU. By using a catalyst such as NBS in the presence of t-butyl hydroperoxideNCS or bis (((trifluoromethyl) sulfinyl) oxy) zinc, can further functionalize H as the corresponding bromide, chloride or CF3A derivative (I).
Scheme II
Under SNAr reaction conditions, the fluoronitrobenzene derivative J can be converted to the corresponding ether K using an alcohol or phenol and a base such as sodium hydride. Such as SnCl may be used2.2H2The reducing agent for O reduces the nitro derivative to the amine L. Compound L can then be converted to the desired pyrimidinone derivative M as described in scheme I.
It is to be understood that other synthetic routes may be used in the practice of the present invention.
The invention is further illustrated by the following examples, which can be synthesized and isolated as the free base or as a salt, e.g., TFA or HCl salt.
VII. examples
Abbreviation list
mg-mg; mL-mL; ul ═ microliter; m is molar concentration; mmol-millimole; h is h; min. (min.) is minutes; rt-room temperature; n is a radical of2Nitrogen gas; HCl ═ hydrogen chloride; h2O is water; MS ═ mass spectrum; (ii) electrospray ionization;1H-NMR ═ proton nuclear magnetic resonance; MHz-megahertz; DMSO-d6Is dimethyl sulfoxide-d6(ii) a H ═ hydrogen; rt is room temperature; DEG C is centigrade; br2Bromine; NaOH ═ sodium hydroxide; NaHSO3Sodium hydrogen sulfite; k2CO3Potassium carbonate; NMP ═ N-methyl-2-pyrrolidone; BOP- (benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate); DBU-1, 8-diazabicyclo [5.4.0]Undec-7-ene; DIEA-diisopropylethylamine; MW is microwave; KF ═ potassium fluoride; pd (dppf) Cl21,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride; pd2dba3-tris (dibenzylideneacetone) dipalladium; POCl3Phosphorus oxychloride(V); PE ═ petroleum ether; EA ═ ethyl acetate; CDCl3Deutero-chloroform; MeOH ═ methanol; d2O is deuterium water; HPLC ═ high pressure liquid chromatography; DMSO ═ dimethyl sulfoxide; MeCN (or ACN) ═ acetonitrile; NIS-N-iodosuccinimide; DMF ═ dimethylformamide; k3PO4Tripotassium phosphate; et (Et)2O-diethyl ether; EtOAc-ethyl acetate; EtOH-ethanol; NaOMe-sodium methoxide; NaOEt-sodium ethoxide; NCS-N-chlorosuccinimide; TBDMS ═ TBS ═ tert-butyldimethylsilyl; TFA ═ trifluoroacetic acid; DCM ═ dichloromethane; xanthphos-4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene.
Example 1
6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one TFA salt
Step 1: n- (2, 3-dichlorophenyl) acetamidine
Method A
To a mixture of 2, 3-dichloroaniline (1.6g,10mmol) and MeCN (615mg,15.0mmol) in 1, 2-dichloroethane (10mL) at 0 deg.C was added AlCl3(1.46g,1.10 mmol). The reaction mixture was stirred for 10 minutes and then heated to 100 ℃ in a sealed tube for 18 hours. The reaction was cooled to room temperature, ice water (30mL) was added and the aqueous phase was extracted with DCM (50 mL. times.2). Subsequently, 2M NaOH was added to adjust the pH to 10 and the aqueous phase was extracted with DCM (50mL × 3). The combined organic layers were over MgSO4Dried and concentrated under reduced pressure to give the title compound (950mg, 47%) as a beige oil. MS (ES +) C8H8Cl2N2Calculated values: 202, found: 203[ M + H]+. The product was used in the next step without further purification.
Method B
In a high pressure reaction vessel, MeCN (123mL) was bubbled with HCl gas at 0 ℃ for 15 seconds to give a saturated solution. 2, 3-dichloroaniline (7.30ml, 61.7mmol) was added and a white solid precipitate formed. The vessel was sealed and the mixture was heated at 120 ℃ for 16 h. The reaction mixture was cooled to room temperature and the white precipitate was collected by vacuum filtration. Et for solid2O (20mL × 3) rinse and dry in vacuo to give the title compound (14.5g, 98% yield) as a white solid. MS (ES)+)C8H8Cl2N2Calculated values: 202, found: 203[ M + H]+。
Step 2: 3- (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one
Method A
To a solution of N- (2, 3-dichlorophenyl) acetamide (950mg,4.68mmol) in 2-methoxyethan-1-ol (10mL) was added diethyl malonate (2.99g, 18.7mmol) and NaOMe in MeOH (4M, 4.7mL, 18 mmol). The mixture was heated at 120 ℃ for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50mL) and treated with Et2O (50 mL). The aqueous layer was acidified to pH-2 with HCl (6M, aq) and the solid precipitate was collected by filtration to give the title compound (1g, 77%) as a white solid. MS (ES +) C11H8Cl2N2O2Calculated values: 270, found: 271[ M + H]+。
Method B
To a suspension of N- (2, 3-dichlorophenyl) acetamide (30g,125mmol) in EtOH (125mL) was added diethyl malonate (38.2mL,250mmol) and NaOEt (20% in EtOH) (140mL, 376mmol) and the resulting mixture was stirred in a sealed tube at 120 ℃ for 18 h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. Water (30mL) was addedAdded to the residue, the mixture was cooled to 0 ℃, and the mixture was acidified to pH-2 with HCl (6M, aq). The mixture was allowed to warm to room temperature and stirred for 1 h. The solid was collected by vacuum filtration and taken up in Et2O (20mL × 2) was washed and dried under reduced pressure to give the title compound (26.3g, 77%) as a tan solid (enantiomeric mixture). MS (ES)+)C11H8Cl2N2O2Calculated values: 270, found: 271[ M + H]+。
The compound of step 2 may be 3- (S)a) - (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one and 3- (R)a) A mixture of (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one.
And step 3: 6-chloro-3- (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one
1- (2, 3-dichlorophenyl) -2-methylpyrimidine-4, 6(1H,5H) -dione (250mg,0.92mmol) in POCl3The mixture in (5mL) was heated at 100 ℃ for 4 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and slowly added to ice water. The mixture was extracted with EtOAc (15mL x 3). The organic layer was dried and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc in PE, 20 to 50%) to afford the title compound as an off-white solid (100mg, 37.5%) (enantiomeric mixture). MS (ES +) C11H7Cl3N2Calculated value of O: 288, found: 289[ M + H ]]+。
The compound of step 3 may be 6-chloro-3- (S)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one and 6-chloro-3- (R)a) A mixture of (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one.
And 4, step 4: (1- (1- (2, 3-dichlorophenyl) -2-methyl-6-oxo-1, 6-dihydropyrimidin-4-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester
A mixture of 6-chloro-3- (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (100mg,0.35mmol), (4-methylpiperidin-4-yl) carbamic acid tert-butyl ester (89mg, 0.42mmol) and DIEA (134mg,1.04mmol) in DMF (3mL) was stirred at 100 ℃ for 3H. The reaction mixture was diluted with water and extracted with EtOAc (15 mL. times.3). The organic layer was washed with brine, over MgSO4Dried and concentrated under reduced pressure to afford the title compound. MS (ES +) C22H28Cl2N4O3Calculated values: 466, found: 467[ M + H ]]+. The product was used in the next step without further purification.
The compound of step 4 may be (1- (1- (S))a) - (2, 3-dichlorophenyl) -2-methyl-6-oxo-1, 6-dihydropyrimidin-4-yl) -4-methylpiperidin-4-yl) carbamic acid tert-butyl ester and (1- (1- (R)a) -butyl (2, 3-dichlorophenyl) -2-methyl-6-oxo-1, 6-dihydropyrimidin-4-yl) -4-methylpiperidin-4-yl) carbamate in the form of a mixture.
And 5: 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one TFA salt
To a solution of tert-butyl (1- (1- (2, 3-dichlorophenyl) -2-methyl-6-oxo-1, 6-dihydropyrimidin-4-yl) -4-methylpiperidin-4-yl) carbamate (0.35mmol, crude) in DCM (3mL) was added TFA (1 mL). The resulting solution was stirred at room temperature for 2h and concentrated under reduced pressure. The residue was purified by preparative HPLC (mobile phase: a ═ 0.01% TFA/H)2O, B ═ MeCN; gradient: 60% -95% of B in 18 min; column: venusil CBP C18(L) C18,10um,21.2mm x 250mm, cat. No.: VX902520-L) to provide the title compound as a white solid (110mg, 86%); MS (ES +) C17H20Cl2N4Calculated value of O: 366, found value: 367[ M + H]+；1H NMR(500MHz,DMSO)δ8.03(s,3H),7.80(dd,J＝7.8,1.7Hz,1H),7.61–7.46(m,2H),5.47(s,1H),4.08–3.82(m,2H),3.34–3.29(m,2H),2.00(s,3H),1.71(t,J＝5.5Hz,4H),1.37(s,3H).
Compound of example 1Can be prepared into 6- (4-amino-4-methylpiperidin-1-yl) -3- (S)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one TFA salt and 6- (4-amino-4-methylpiperidin-1-yl) -3- (Ra) A mixture of TFA salts of (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one.
Examples 2a and 2b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 2a):
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 2b):
to 3- (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one (example 1, step 2, 3.50g, 12.9mmol) and (3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5]]To a suspension of decane-4-amine dihydrochloride (3.45g, 14.2mmol) in MeCN (43mL) were added DBU (6.23mL, 41.3mmol) and BOP (6.85g, 15.5mmol) and the resulting mixture was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (containing 2% NH)4OH in 2-15% MeOH in DCM) to provide the title compound as a mixture of diastereomers (4.2g, 77% yield) as an off-white solid. By chiral SFC (mobile phase: CO)2Methanol (0.25% isopropylamine) 60/40; flow rate: 80 g/min; 5 min; column temperature: 25 ℃; back pressure: 100 bar; column: ES Industries chromegachiralccs, 2.0x 25.0cm) separated the diastereomeric mixture to provide the title compound, example 2a (19.7g, 48%) as a white solid and example 2b (11.6g, 28%) as a white solid.
Example 2a 6- ((3S,4S) -4-amino-3-carbaRadical-2-oxa-8-azaspiro [4.5]Decan-8-yl) -3- (S)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one: MS (ES)+)C20H24Cl2N4O2Calculated values: 422, found: 423[ M + H]+；1H NMR(600MHz,CDCl3)δ7.57(dd,J＝8.1,1.5Hz,1H),7.35(t,J＝8.0Hz,1H),7.21(dd,J＝7.9,1.5Hz,1H),5.45(s,1H),4.21–4.16(m,1H),3.86(br s,2H),3.79(d,J＝8.7Hz,1H),3.68(d,J＝8.7Hz,1H),3.40(ddd,J＝13.1,9.1,3.8Hz,1H),3.31(ddd,J＝13.3,9.4,3.2Hz,1H),2.98(d,J＝4.5Hz,1H),2.06(s,3H),1.84(ddd,J＝13.4,9.4,3.9Hz,1H),1.75–1.60(m,3H),1.23(d,J＝6.4Hz,3H)。
Example 2b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one: MS (ES)+)C20H24Cl2N4O2Calculated values: 422, found: 423[ M + H]+；1H NMR(600MHz,CDCl3)δ7.57(dd,J＝8.2,1.5Hz,1H),7.36(t,J＝8.0Hz,1H),7.21(dd,J＝7.9,1.5Hz,1H),5.46(s,1H),4.22–4.14(m,1H),3.95–3.82(m,2H),3.80(d,J＝8.7Hz,1H),3.68(d,J＝8.7Hz,1H),3.45–3.36(m,1H),3.29(ddd,J＝13.3,9.5,3.3Hz,1H),2.99(d,J＝4.6Hz,1H),2.07(s,3H),1.84(ddd,J＝13.4,9.4,3.9Hz,1H),1.77–1.70(m,1H),1.70–1.61(m,2H),1.24(d,J＝6.4Hz,3H)。
The following examples were synthesized using synthetic methods similar to examples 1 and 2, and can generally be prepared by the methods disclosed herein. The examples can be prepared as free base or as TFA salt.
Table 1: examples 3 to 8
The compound of example 3 may be substituted with 6- [4- (aminomethyl) -4-methylpiperidin-1-yl]-3-(Sa) - (2, 3-dichlorophenyl) -2-methyl-3, 4-dihydropyrimidin-4-one and 6- [4- (aminomethyl) -4-methylpiperidin-1-yl]-3-(Ra) A mixture of (2, 3-dichlorophenyl) -2-methyl-3, 4-dihydropyrimidin-4-one.
The compound of example 4 may be prepared as 6- (4-amino-4-ethylpiperidin-1-yl) -3- (S)a) - (2, 3-dichlorophenyl) -2-methyl-3, 4-dihydropyrimidin-4-one and 6- (4-amino-4-ethylpiperidin-1-yl) -3- (R)a) A mixture of (2, 3-dichlorophenyl) -2-methyl-3, 4-dihydropyrimidin-4-one.
The compound of example 5 can be prepared as 6- [ (3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl]-3-(Sa) - (2, 3-difluorophenyl) -2-methyl-3, 4-dihydropyrimidin-4-one and 6- [ (3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl]-3-(Ra) A mixture of (2, 3-difluorophenyl) -2-methyl-3, 4-dihydropyrimidin-4-one.
The compound of example 6 can be synthesized as 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (S)a) - (4-bromo-2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -3- (Ra) A mixture of (4-bromo-2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one.
The compound of example 8 can be synthesized as 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (S)a) - (2-bromo-3-chlorophenyl) -2-methylpyrimidin-4 (3H) -one and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (Ra) A mixture of (2-bromo-3-chlorophenyl) -2-methylpyrimidin-4 (3H) -one.
Example 9
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5-chloro-3- (R)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one
To 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (Ra) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 2 b; 2.5g,5.9mmol) in DCM (30mL) was added NCS (946mg,7.09mmol) and the resulting mixture was stirred at room temperature for 10 min. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (containing 2% NH)4OH in 2-15% MeOH in DCM) to provide the title compound (2.1g, 78% yield) as a white solid. MS (ES)+)C20H23Cl3N4O2Calculated values: 456, found: 457[ M + H]+；1H NMR(600MHz,DMSO-d6)δ7.83(dd,J＝8.1,1.6Hz,1H),7.62(dd,J＝8.0,1.6Hz,1H),7.57(t,J＝8.0Hz,1H),4.09–4.01(m,1H),3.96–3.87(m,2H),3.67(d,J＝8.4Hz,1H),3.53–3.46(m,2H),3.40(ddd,J＝12.9,9.3,3.1Hz,1H),2.91(d,J＝5.1Hz,1H),2.00(s,3H),1.81(ddd,J＝13.2,9.3,3.6Hz,1H),1.71–1.65(m,1H),1.59–1.54(m,1H),1.54–1.48(m,1H),1.08(d,J＝6.4Hz,3H).
Examples 10a and 10b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 10a):
and
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 10b):
method A
Step 1: 3- (2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one
To a suspension of N- (2, 3-dichlorophenyl) acetamide hydrochloride (example 1, step 1) (44g,184mmol) in EtOH (184mL) was added diethyl 2-methylmalonate (62.6mL,367mmol) and EtONa (206mL,551mmol) and the resulting mixture was stirred in a sealed tube at 120 ℃ for 18 h. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. Water (200mL) was added, the mixture was cooled to 0 ℃ and then HCl (6M) was added to adjust the pH to 2. The reaction was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was filtered through glass fiber paper and the resulting solid was treated with Et2O rinse, collect, and dry under reduced pressure to provide the title compound (44.6g,156mmol, 85% yield) as a pale yellow solid. MS (ES)+)C12H10Cl2N2O2Calculated values: 284, found: 285[ M + H ]]+。
The compound of step 1 may be 3- (S)a) - (2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one and 3- (R)a) A mixture of (2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one.
Step 2: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 10a) and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -3- (Ra) - (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 10b)
To 3- (2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one (30g,105mmol) and (3S,4S) -3-methyl-2-oxa-8-azaspiro [ 4.5%]To a suspension of decane-4-amine dihydrochloride (28.1g,116mmol) in acetonitrile (351mL) was added DBU (50.8mL,337mmol) and BOP (51.2g,116mmol) and the resulting mixture was stirred at room temperature for 24 h. Adding (3S,4S) -3-methyl-2-oxoHetero-8-azaspiro [4.5]]Decane-4-amine dihydrochloride (12.8g,52.5mmol) and DBU (15.8mL,105mmol) and the mixture stirred at room temperature for a further 24 h. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between DCM (200mL) and water (200mL), the layers were separated and the aqueous layer was extracted with DCM (200mL × 3). The combined organic layers were washed with Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (containing 2% NH)4OH in 2-15% MeOH in DCM) to provide the title compound as a mixture of diastereomers as an off-white solid. Separation of diastereomer mixtures by chiral SFC (mobile phase: CO)2Methanol (0.25% isopropylamine) 60/40; flow rate: 80 g/min; 5 min; column temperature: 25 ℃; back pressure: 100 bar; column: chiral Technologies Chiral pak AD-H,2.1x 25.0cm) to provide the title compound, example 10a (19.51g, 42%, 98% ee), as a white solid (single diastereomer) and example 10b (19.25g, 42%,>99% ee) as a white solid (single diastereomer).
Example 10a 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one: MS (ES)+)C21H26Cl2N4O2Calculated values: 436, found: 437[ M + H]+；1H NMR(600MHz,DMSO-d6)δ7.83–7.77(m,1H),7.57–7.50(m,2H),4.09–4.02(m,1H),3.66(d,J＝8.4Hz,1H),3.58–3.51(m,2H),3.49(d,J＝8.4Hz,1H),3.21(ddd,J＝12.9,9.3,3.2Hz,1H),3.13(ddd,J＝12.9,9.4,3.0Hz,1H),2.89(d,J＝5.1Hz,1H),1.97(s,3H),1.89(s,3H),1.78(ddd,J＝13.3,9.5,3.6Hz,1H),1.66(ddd,J＝13.1,9.1,3.7Hz,1H),1.57–1.52(m,1H),1.52–1.47(m,1H),1.08(d,J＝6.4Hz,3H)。
Example 10b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one: MS (ES)+)C21H26Cl2N4O2Calculated values: 436, found: 437[ M + H]+；1H NMR(600MHz,DMSO-d6)δ7.83–7.77(t,J＝4.8Hz,1H),7.57–7.50(d,J＝4.8Hz,2H),4.09–4.02(m,1H),3.65(d,J＝8.4Hz,1H),3.58–3.51(m,2H),3.49(d,J＝8.4Hz,1H),3.22(ddd,J＝13,9.5,2.5Hz,1H),3.12(ddd,J＝13.0,9.5,2.5Hz,1H),2.89(d,J＝5.1Hz,1H),1.97(s,3H),1.89(s,3H),1.78(ddd,J＝13.2,9.5,3.7Hz,1H),1.66(ddd,J＝13.2,9.5,3.7Hz,1H),1.58–1.46(m,2H),1.28(bs,2H),1.08(d,J＝6.4Hz,3H)。
Method B
Step 1: 1- (R)a) - (2, 3-dichlorophenyl) -2, 5-dimethyl-6-oxo-1, 6-dihydropyrimidin-4-yl trifluoromethanesulfonate
At-25 ℃ to 3- (S)a) - (2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one and 3- (R)a) (2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one (example 10, method A, step 1) (100g,351mmol) and DIPEA (183mL,1.05mol) in DCM (1.00L) Tf was added dropwise2O (116mL g,701mmol,116 mL). The resulting mixture was stirred at-25 ℃ to-20 ℃ for 1h and at 20 ℃ for 18 h. The two reaction mixtures were combined. To the reaction mixture was added water (1L), and the resulting mixture was treated with CH2Cl2(1 L.times.2) extraction. The combined organic layers were washed with 1M HCl (1L, aq.) over Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc in PE, 20%) to afford a mixture of diastereomers (144g,336mmol, 47.8% yield) as a brown solid. The diastereomer mixture was separated by SFC (column: DAICEL CHIRALPAK AD (250mm 50mm,10 um); mobile phase: [ Neu-IPA: [ Neu-IPA ]](ii) a B%: 15% -15%, 2.9min, 1100min) to provide the title compound (56.4g, 18%, ee ═ 99.5%) as a brown solid. MS (ES)+)C13H9Cl2F3N2O4S calculated value: 416, found: 417[ M + H ]]+。
Step 2: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decane-8-yl)-3-(Ra) - (2, 3-dichlorophenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 10b)
To (3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5] at 0 deg.C]To a solution of decan-4-amine (23.3g,95.6mmol,1.05 eq, 2HCl) in DMF (50.0mL) were added DIPEA (47.1g,364mmol,63.5mL) and 1- (R)a) A solution of (2, 3-dichlorophenyl) -2, 5-dimethyl-6-oxo-1, 6-dihydropyrimidin-4-yl trifluoromethanesulfonate (38.0g,91.1mmol,1.00 eq) in DMF (200 mL). The resulting mixture was stirred at 15 ℃ for 18h, then (3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5] was added]Decan-4-amine (1.11g,4.55mmol,2 HCl). The resulting mixture was stirred at 25 ℃ for 15 h. The reaction mixture was concentrated under reduced pressure. Adding K2CO3(15%, 500mL, aq.) and the aqueous phase extracted with DCM (200 mL. times.3). The combined organic layers were washed with brine (400mL) and Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO)2MeOH in DCM, 5 to 20%) followed by reverse phase column chromatography (0.1% NH)3·H2O, MeCN: H2O (65: 35)). The residue was dissolved in hot MeOH (250mL), activated carbon (2.70g) was added to the resulting solution, and the mixture was stirred at 60 ℃ for 15 minutes. The mixture was filtered and concentrated under reduced pressure to provide the title compound example 10b (26.5g, 66.5%) as an off-white solid.
Example 11
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichlorophenyl) -2-methyl-5- (trifluoromethyl) pyrimidin-4 (3H) -one TFA salt
Reacting 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -5-chloro-3- (R)a) Sonication of a suspension of (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 9) (35mg,0.083mmol), TFA (9.6. mu.L, 0.12mmol) and bis (((trifluoromethyl) sulfinyl) oxy) zinc (55mg,0.16mmol) in DCE (591. mu.L) gaveThe homogeneous suspension was then cooled to ℃ and tert-butyl hydroperoxide (34. mu.L, 0.25mmol) was added dropwise. The resulting mixture was warmed to room temperature and stirred for 2 h. Water (1mL) was added, the layers were separated, and the aqueous layer was extracted with DCM (1 mL. times.3). The combined organic layers were passed over Na2SO4Dried, filtered and concentrated under reduced pressure. The residue was purified by mass triggered preparative HPLC (mobile phase: a ═ 0.1% TFA/H)2O, B ═ 0.1% TFA/MeCN; gradient: b is 20-50%; 20 min; column: XBridge C18,5 μm,19mm x 150mm) to provide the title compound (15mg, 30% yield) as a white solid (single diastereomer): MS (ES)+)C21H23Cl2F3N4O2Calculated values: 490, found: 491[ M + H]+；1H NMR(600MHz,DMSO-d6) δ 7.90(s,3H),7.84(dd, J ═ 7.9,1.8Hz,1H), 7.63-7.56 (m,2H), 4.24-4.17 (m,1H),3.96(d, J ═ 14.0Hz,1H), 3.91-3.83 (m,2H),3.72(d, J ═ 9.0Hz,1H), 3.50-3.44 (m, overlap H)2O,1H), 3.32-3.16 (m, overlap H)2O,2H),2.03(s,3H),1.78(d,J＝13.8Hz,3H),1.61(d,J＝13.2Hz,1H),1.21(d,J＝6.5Hz,3H)。
Examples 12a and 12b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5-bromo-3- (S)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 12a):
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5-bromo-3- (R)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 12b):
step 1: 5-bromo- (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one
To a solution of 3- (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one (example 1, step 2) (540mg,2mmol) in DCM (8mL) was added a solution of NBS (356mg,2mmol) in DCM (2 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was filtered to provide the title compound as a white solid (680mg, 97.1%). MS (ES +) C11H7BrCl2N2O2Calculated values: 350, found: 351[ M + H ]]+。
The compound of step 1 may be substituted with 5-bromo- (S)a) - (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one and 5-bromo- (R)a) A mixture of (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one.
Step 2: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5-bromo-3- (R)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 12a) and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5-bromo-3- (S)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one (example 12b)
5-bromo-3- (2, 3-dichlorophenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one (80mg,0.23mmol), (3S,4S) -3-methyl-2-oxa-8-azaspiro [ 4.5%]A solution of decan-4-amine (67mg,0.27mmol), BOP (121mg,0.27mmol) and DBU (174mg,1.14mmol) in MeCN (2mL) was stirred at room temperature for 2 h. The mixture was concentrated and passed through preparative HPLC (NH)4HCO3) Purification to give a solid. Separation of diastereomer mixtures by chiral SFC (mobile phase: CO)2Methanol (0.2% MEA) ═ 30/70; flow rate: 80 g/min; 5 min; column temperature: 35 ℃; back pressure: 100 bar; column: AD20 × 250mm,10um (daicel) to provide example 12a as a white solid (18mg, 16%) and example 12b as a white solid (15mg, 13%).
Example 12a 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5-bromo-3- (S)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one: MS (ES +)C20H23BrCl2N4O2Calculated values: 500,502, found: 501,503[ M + H ]]+；1H NMR(500MHz,DMSO)δ7.83(dd,J＝8.1,1.5Hz,1H),7.62(dd,J＝8.0,1.5Hz,1H),7.56(t,J＝8.0Hz,1H),4.09–4.02(m,1H),3.93–3.82(m,2H),3.66(d,J＝8.5Hz,1H),3.50–3.36(m,3H),2.91(d,J＝5.1Hz,1H),2.00(s,3H),1.86–1.78(m,1H),1.68–1.59(m,1H),1.61–1.47(m,2H),1.08(d,J＝6.4Hz,3H)。
Example 12b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -5-bromo-3- (R)a) - (2, 3-dichlorophenyl) -2-methylpyrimidin-4 (3H) -one: MS (ES +) C20H23BrCl2N4O2Calculated values: 500,502, found: 501,503[ M + H ]]+；1H NMR(500MHz,DMSO)δ7.83(dd,J＝8.0,1.6Hz,1H),7.62(dd,J＝7.9,1.5Hz,1H),7.56(t,J＝8.0Hz,1H),4.10–4.00(m,1H),3.94–3.82(m,2H),3.66(d,J＝8.4Hz,1H),3.53–3.36(m,3H),2.91(d,J＝5.0Hz,1H),2.00(s,3H),1.81(ddd,J＝13.0,9.3,3.4Hz,1H),1.69(ddd,J＝12.9,9.1,3.6Hz,1H),1.61–1.46(m,2H),1.08(d,J＝6.4Hz,3H)。
Examples 13a and 13b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2-chloro-3-methylphenyl) -2-methylpyrimidin-4 (3H) -one TFA salt (example 13a):
and
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2-chloro-3-methylphenyl) -2-methylpyrimidin-4 (3H) -one TFA salt (example 13b):
step 1: 2-chloro-3-methylphenylcarbamic acid tert-butyl ester
1-bromo-2-chloro-3-methylbenzene (4.0g,19.6mmol), Pd2dba3(1014mg,0.98mmol), Xantphos (566mg,0.98mmol), tert-butyl carbamate (3.41g,29.4mmol) and Cs2CO3A mixture of (9.58g,29.4mmol) in dioxane (120mL) was stirred at 110 ℃ for 2h, then cooled to room temperature. Water (150mL) was added and the mixture was extracted with EtOAc (150 mL. times.2). The organic layer was dried and concentrated. The residue was purified by flash column chromatography (PE, 100%) to provide the title compound (4.2g, 89%). MS (ES +) C12H16ClNO2Calculated values: 241, measured value: 187[ M-55+ H]+。
Step 2: 2-chloro-3-methylaniline
A mixture of tert-butyl 2-chloro-3-methylphenylcarbamate (4.2g,17.4mmol) in 2M HCl (40mL in MeOH) was stirred at room temperature for 1 h. The mixture was concentrated with Et2O (40mL) was washed and dried under vacuum to provide the title compound as a yellow solid (2.3g, 93%). MS (ES +) C7H8Calculated ClN: 141, found: 142[ M + H ]]+。
And step 3: n- (2-chloro-3-methylphenyl) acetamide
2-chloro-3-methylaniline (1.4g,9.93mmol) in HCl (1N CH)3CN solution, 15ml) was heated at 120 ℃ for 4 h. The reaction mixture was cooled to room temperature, filtered and the filter cake was washed with Et2O (15mL) wash. The filter cake was dried under vacuum to provide the title compound (1.2g, 66%). MS (ES +) C9H11ClN2Calculated values: 182,found 183[ M + H]+。
And 4, step 4: 3- (2-chloro-3-methylphenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one
To a solution of N- (2-chloro-3-methylphenyl) acetamide (1.2g,6.6mmol) in 2-methoxyethan-1-ol (12mL) was added diethyl malonate (4.22g,26.36mmol) and CH3ONa/CH3OH (4M,6.6mL,26 mmol). The mixture was heated at 120 ℃ for 16 h. The mixture was cooled to room temperature, poured into water (50mL) and the aqueous phase was treated with Et2O (50mL) wash. The aqueous layer was acidified to pH 2 with 6N HCl and extracted with EtOAc (50 mL. times.3). The organic layer was dried and concentrated. The residue was washed with EtOAc to provide the title compound (300mg, 18%) as a white solid. MS (ES +) C12H11ClN2O2Calculated values: 250, found: 251[ M + H]+。
The compound of step 4 may be in 3- (S)a) (2-chloro-3-methylphenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one and 3- (R)a) (2-chloro-3-methylphenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one in the form of a mixture.
And 5: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2-chloro-3-methylphenyl) -2-methylpyrimidin-4 (3H) -one TFA salts (example 13a) and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2-chloro-3-methylphenyl) -2-methylpyrimidin-4 (3H) -one TFA salt (example 13b)
To a suspension of 3- (2-chloro-3-methylphenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one (150mg,0.6mmol) and (3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine dihydrochloride (173mg,0.72mmol) in MeCN (3ml) were added DBU (183mg,1.2mmol) and BOP (318mg,0.72mmol) and the resulting mixture was stirred at room temperature for 1H. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (A: water (0.05% TFA), B: ACN), B from 18 to 28% in 10min, stopping at 15 min. Column: sunfire prep C1810 μm, OBD19 × 250mm) to provide the title compound TFA salt example 13a, (40mg, 25%) and the title compound TFA salt example 13b (60mg, 38%).
Example 13a 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2-chloro-3-methylphenyl) -2-methylpyrimidin-4 (3H) -one TFA salt: MS (ES +) C23H28ClF3N4O4Calculated values: 402, found: 403[ M + H ]]+；1H NMR(500MHz,DMSO)δ7.92(s,3H),7.49–7.48(m,1H),7.41–7.38(m,1H),7.29–7.28(m,1H),5.43(s,1H),4.21–4.19(m,2H),3.87-3.85(m,1H),3.70-3.68(m,1H),3.41–3.39(m,2H),3.05–3.02(m,2H),2.41(s,3H),1.96(s,3H),1.69-1.68(m,3H),1.55-1.53(m,1H),1.21-1.20(d,J＝7Hz,3H)。
Example 13b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2-chloro-3-methylphenyl) -2-methylpyrimidin-4 (3H) -one TFA salt: MS (ES +) C23H28ClF3N4O4Calculated values: 402, found: 403[ M + H ]]+；1H NMR(500MHz,DMSO)δ8.01(s,3H),7.49–7.47(m,1H),7.41–7.38(m,1H),7.29–7.28(m,1H),5.43(s,1H),4.22–4.19(m,2H),3.88-3.86(m,2H),3.69–3.68(m,1H),3.42–3.40(m,1H),3.06–3.00(m,2H),2.41(s,3H),1.96(s,3H),1.71-1.68(m,3H),1.54-1.51(m,1H),1.22-1.21(d,J＝6Hz,3H)。
Examples 14a and 14b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2-chloro-3- (trifluoromethyl) phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt (example 14a):
and
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2-chloro-3- (trifluoromethyl) phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt (example 14b):
examples 14a and 14b were synthesized by synthetic methods similar to those used for examples 13a and 13b, and can generally be prepared by the methods disclosed herein. The examples can be prepared as free base or as TFA salt.
Example 14a 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2-chloro-3- (trifluoromethyl) phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt: MS (ES +) C21H24ClF3N4O2Calculated values: 456, found: 457[ M + H]+。
Example 14b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2-chloro-3- (trifluoromethyl) phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt: MS (ES +) C21H24ClF3N4O2Calculated values: 456, found: 457[ M + H]+。
Examples 15a and 15b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4-phenoxyphenyl) -2-methylpyrimidin-4 (3H) -one (example 15a):
and
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4-phenoxyphenyl) -2-methylpyrimidin-4 (3H) -one (example 15b):
step 1: 2, 3-dichloro-1-nitro-4-phenoxybenzene
To a solution of phenol (1.1g,12mmol) in anhydrous N, N-dimethylformamide (15mL) at 0 deg.C was added a small portion of NaH (520mg,13mmol, 60%) and the resulting mixture was stirred at 0 deg.C for 10 minutes. 2, 3-dichloro-1-fluoro-4-nitrobenzene (2.1g,10mmol) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was purified by silica gel chromatography (EtOAc in PE, 0 to 15%) to provide the title compound (2.0g, 67%) as a yellow solid. MS (ES +) C12H7Cl2NO3A calculated value 282; measured value: 283.
step 2: 2, 3-dichloro-4-phenoxyaniline
2, 3-dichloro-1-nitro-4-phenoxybenzene (1.8g,6.4mmol) and SnCl2.2H2A solution of O (14.3g,64mmol) in EtOH (20mL) was stirred at 85 ℃ for 5 h. The resulting mixture was taken up in saturated NaHCO3The aqueous solution was adjusted to pH > 9, the solid was filtered and washed with EtOAc (50 mL. times.3). The organic phase was dried, concentrated under reduced pressure and purified by silica gel chromatography (EtOAc in PE, 0 to 40%) to provide the title compound (1.2g, 73%) as a tan solid. MS (ES +) C12H9Cl2Calculated NO 252; measured value: 253.
and step 3: n- (2, 3-dichloro-4-phenoxyphenyl) acetamide
A solution of 2, 3-dichloro-4-phenoxyaniline (1.0g,3.9mmol) in HCl/MeCN (1M,20mL) was heated in a sealed tube at 120 ℃ overnight. The mixture was cooled to room temperature, the solid was filtered and washed with MeCN (5mL) to provide the title compound (0.9g, 70%) as a white solid. MS (ES +) C14H12Cl2N2Calcd 293, found: 294.
and 4, step 4: 3- (2, 3-dichloro-4-phenoxyphenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one
The reaction was carried out as described in example 1, step 2, method B to give the title compound (0.5g, 54%) as a tan solid. MS (ES +) C17H12Cl2N2O3A calculated value 361; measured value 362.
The compound of step 4 may be in 3- (S)a) - (2, 3-dichloro-4-phenoxyphenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one and 3- (R)a) - (2, 3-dichloro-4-phenoxyphenyl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one in the form of a mixture.
And 5: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4-phenoxyphenyl) -2-methylpyrimidin-4 (3H) -one (example 15a) and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4-phenoxyphenyl) -2-methylpyrimidin-4 (3H) -one (example 15b)
The reaction was carried out as described in example 2, step 1. The diastereomeric mixture was separated by chiral SFC chiral-HPLC (cosolvent: MeOH (0.2% methanol-ammonia), column: AD-H, 4.6x 100mm) to provide the title compounds example 15a (25mg, 18%) and 15b (27mg, 19%).
Example 15a 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4-phenoxyphenyl) -2-methylpyrimidin-4 (3H) -one: MS (ES +) C26H28Cl2N4O3Calculated values: 514, found: 515[ M + H]+；1H NMR(400MHz,MeOD)δ7.44(m,2H),7.37(dd,J＝9,2Hz,1H),7.24(t,J＝7.5Hz,1H),7.12(dd,J＝9,1Hz,1H),7.07(dd,J＝9,2Hz,1H),5.51(s,1H),4.25(m,1H),4.07(m,2H),3.88(d,J＝9Hz,1H),3.74(m,1H),3.73(d,J＝9Hz,1H),3.42(m,1H),3.03(d,J＝5Hz,1H),2.13(s,3H),1.83-1.67(m,4H),1.23(d,J＝6Hz,3H)。
Example 15b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4-phenoxyphenyl) -2-methylpyrimidin-4 (3H) -one: MS (ES +) C26H28Cl2N4O3Calculating a value 514; measured value: 515[ M + H]+；1H NMR(500MHz,MeOD)δ7.51–7.41(m,2H),7.36(dd,J＝8.8,2.7Hz,1H),7.24(t,J＝7.4Hz,1H),7.12(dd,J＝8.6,0.8Hz,2H),7.07(dd,J＝8.8,1.8Hz,1H),5.51(d,J＝7.5Hz,1H),4.30–4.21(m,1H),4.07(d,J＝4.8Hz,1H,)4.07(m,1H),3.89(d,J＝8.7Hz,1H),3.74(d,J＝8.7Hz,1H),3.42(t,J＝10.0Hz,1H),3.03(d,J＝5.0Hz,1H),2.14(d,J＝3.9Hz,3H),1.89–1.61(m,4H),1.23(dd,J＝11.7,6.4Hz,3H)。
Examples 16a and 16b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt (example 16a):
and
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt (example 16b):
examples 16a and 16b were synthesized by synthetic methods similar to those used for examples 15a and 15b, and can generally be prepared by the methods disclosed herein. The examples can be prepared as free base or as TFA salt.
Example 16a 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy)Phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt: MS (ES +) C24H28Cl2N6O3Calculated values: 518, found: 519[ M + H ]]+。
Example 16b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2-methylpyrimidin-4 (3H) -one TFA salt: MS (ES +) C24H28Cl2N6O3Calculated values: 518, found: 519[ M + H ]]+。
Example 17
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5-chloro-3- (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one
Step 1: n- (2, 3-dichloropyridin-4-yl) acetamide
To a solution of 2, 3-dichloro-4-iodopyridine (1g mg,3.6mmol) in DMF (5ml) was added acetamide hydrochloride (345mg,3.65mmol), Cs2CO3(2.4g,7.4mmol) and Cu (I) I (70mg,0.36mmol) and the resulting mixture was stirred at 90 ℃ for 12 h. The reaction mixture was diluted with MeCN (20ml), filtered through celite, and the filtrate was concentrated under reduced pressure to give the title compound as a grey solid (0.83g, 100%).
Step 2: 3- (2, 3-dichloropyridin-4-yl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one
To a mixture of N- (2, 3-dichloropyridin-4-yl) acetamide (1) (500mg,2.45mmol) in THF (5ml)To the suspension was added bis (2,4, 6-trichlorophenyl) malonate (1.2g, 2.6mmol) and the resulting mixture was stirred at 90 ℃ for 2 h. Volatiles were removed under reduced pressure. The reaction mixture was diluted with EtOAc (20mL) and washed with water (5 mL). The layers were separated and the organic layer was washed with brine (5mL), MgSO4Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-20% MeOH in DCM) to provide the title compound (280mg, 42% yield) as a light orange solid. MS (ES +) C10H7Cl2N3O2Calculated values: 271, found value: 272[ M + H ]]+。
The compound of step 2 may be 3- (R)a) - (2, 3-dichloropyridin-4-yl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one and 3- (S)a) A mixture of (2, 3-dichloropyridin-4-yl) -6-hydroxy-2-methylpyrimidin-4 (3H) -ones.
And step 3: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one
To 3- (2, 3-dichloropyridin-4-yl) -6-hydroxy-2-methylpyrimidin-4 (3H) -one (100mg, 0.37mol), (3S,4S) -3-methyl-2-oxa-8-azaspiro [4.5]]Decane-4-amine dihydrochloride (89mg, 0.37mmol), BOP (244mg, 0.551mmol) in DMF (2ml) was added DBU (0.11ml, 0.73mmol) and the resulting mixture was stirred at room temperature for 1 h. The residue was purified by mass triggered preparative HPLC (mobile phase: a ═ 0.1% TFA/H)2O, B ═ 0.1% TFA/MeCN; gradient: b is 10-50%; 20 min; column: C18) to provide the title compound (92mg,0.22mmol, 59% yield) as a white solid. MS (ES +) C19H23Cl2N5O2Calculated values: 423, found: 424[ M + H]+。
The compound of step 3 may be substituted with 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (Ra) - (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one and 6- (3H)3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -3- (S)a) A mixture of (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one.
And 4, step 4: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5-chloro-3- (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one
A vial was charged with 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one (40mg,0.047mmol), NCS (15mg,0.11mmol) and DCM (1.0 ml). The mixture was stirred at room temperature for 5 minutes. Volatiles were removed under reduced pressure. The residue was purified by mass triggered preparative HPLC (mobile phase: a ═ 0.1% TFA/H)2O, B ═ 0.1% TFA/MeCN; gradient: b is 10-40%; 20 min; column: C18) to provide the title compound (12mg,0.026mmol, 11% yield) as a white powder. MS (ES +) C19H22Cl3N5O2Calculated values: 457, found: 458[ M + H ]]+；1H NMR(500MHz,DMSO-d6)δ8.64(d,J＝5.0Hz,1H)；7.94(m,2H)；7.82(m.1H)；4.16-4.26(m,2H)；3.86(m,1H)；3.71(d,J＝10Hz,1H)；3.17-3.26(m,3H)；2.81(d,J＝10.68Hz,1H),2.06(s,3H),1.73-1.81(m,3H),1.62(m,1H),1.22(d,J＝5.0Hz,3H)。
The compound of example 17 can be synthesized as 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -5-chloro-3- (S)a) - (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -5-chloro-3- (R)a) A mixture of (2, 3-dichloropyridin-4-yl) -2-methylpyrimidin-4 (3H) -one.
Examples 18a and 18b
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 18a):
and
6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 18b):
step 1: 3- (2, 3-dichloro-4-nitrophenoxy) -1-methyl-1H-pyrazole
Mixing 2, 3-dichloro-1-fluoro-4-nitrobenzene (1.3g,6.2mmol), 1-methyl-1, 2-dihydro-3H-pyrazol-3-one (729mg,7.4mmol) and K2CO3A mixture of (1.7g,12.4mmol) in MeCN (30mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water (50mL) and extracted with EtOAc (100mL × 3). The combined organic phases were dried (Na)2SO4) Filtered and concentrated, and the residue was purified by silica gel chromatography (EtOAc in PE, 10%) to provide the title compound (1.5g, 84%) as a white solid. MS (ES)+)C10H7Cl2N3O3Calculated values: 287; measured value: 288[ M + H]+。
Step 2: 2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) aniline
To a solution of 3- (2, 3-dichloro-4-nitrophenoxy) -1-methyl-1H-pyrazole (1.5g,5.2mmol) in AcOH (10mL) was added Fe (1.4g,26 mmol). The resulting mixture was stirred at 60 ℃ for 2 h. The reaction mixture was poured into ice water (60mL) and extracted with EtOAc (100mL × 3). The combined organic phases were dried (Na)2SO4) Filtered and concentrated. The residue was purified by silica gel chromatography (EtOAc in PE, 50%) to give a extractThe title compound (1.2g, 90%) was provided as a yellow solid. MS (ES +) C10H9Cl2N3Calculated value of O: 257, found: 258[ M + H ]]+。
And step 3: n- (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) acetamide
2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) aniline (1.2g,4.7mmol) in HCl/CH3The mixture in CN (1M,10mL) was stirred in a sealed tube at 120 ℃ for 24 h. The mixture was concentrated and the residue was taken up in Et2O (10mL) wash. The precipitate was filtered to provide the title compound (1.2g, 86%) as a white solid. MS (ES +) C12H12Cl2N4Calculated value of O: 298, found value: 299[ M + H [ ]]+。
And 4, step 4: 3- (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one
To a solution of diethyl 2-methylmalonate (1.4g,8.0mmol) in EtOH (6mL) was added CH3ONa/CH3OH (4M,2 mL). The mixture was stirred at room temperature for 10 minutes. N- (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) acetamide (600mg,2mmol) was added and the mixture was stirred at 120 ℃ for 4H. The mixture was poured into water (30mL) and Et2O (30 mL. times.2). The pH of the aqueous layer was adjusted to 5 with AcOH and extracted with EtOAc (80 mL. times.3). The combined organic phases were dried (Na)2SO4) Filtered and concentrated. The crude product was taken up in Et2O wash (10mL) to provide the title compound (320mg, 42%) as a white solid. MS (ES +) C16H14Cl2N4O3Calculated values: 380, found: 381[ M + H ]]+。
The compound of step 4 may be in 3- (S)a) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one and 3- (R)a) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one in the form of a mixture.
And 5: 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 18a) and 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 18b)
To 3- (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one (100mg,0.26mmol) and (3S,4S) -3-methyl-2-oxa-8-azaspiro [ 4.5%]To a suspension of decane-4-amine dihydrochloride (126mg,0.52mmol) in MeCN (8ml) were added DBU (395mg,2.6mmol) and BOP (230mg,0.52mmol) and the resulting mixture was stirred at room temperature for 48 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (mobile phase: a ═ 0.05% TFA/H)2O, B ═ MeCN; gradient: b is 21-31%; 10 min; column: C18) and a Chiralpak OZ column (20X 250mm) was used with CO2And 0.2% methanolic ammonia (45:55) as eluent, at a flow rate of 80g/min and UV detection (214nm) separated the diastereomer to afford example 18a (7mg, 5%) and example 18b (9mg, 7%) as white solids.
Example 18a 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -3- (S)a) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2, 5-dimethylpyrimidin-4 (3H) -one: MS (ES +) C25H30Cl2N6O3Calculated values: 532 found: 533[ M + H ]]+；1H NMR(500MHz,MeOD)δ7.46(d,J＝2.5Hz,1H),7.14-7.23(m,2H),5.84(d,J＝2.5Hz,1H),4.12-4.15(m,1H),3.71-3.78(m,1H),3.62-3.68(m,6H),3.17-3.20(m,3H),2.95-2.96(m,1H),1.99(s,3H),1.90(s,3H),1.57-1.78(m,4H),1.18(s,1H),1.12(d,J＝6Hz,3H)。
Example 18b 6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -3- (Ra) - (2, 3-dichloro-4- ((1-methyl-1H-pyrazol-3-yl) oxy) phenyl) -2, 5-dimethylpyrimidin-4 (3H) -one: MS (ES +) C25H30Cl2N6O3Calculated values: 532 found: 533[ M + H ]]+；1H NMR(500MHz,MeOD)δ7.58(d,J＝2.5Hz,1H),7.26-7.36(m,2H),5.96(d,J＝3Hz,1H),4.24-4.26(m,1H),3.83-3.89(m,1H),3.74-3.80(m,6H),3.18-3.29(m,3H),3.05-3.06(m,1H),2.69(s,1H),2.11(s,3H),2.02(s,3H),1.66-1.88(m,4H),1.23(d,J＝7Hz,3H)。
Examples 19a and 19b
4- (4- (4- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -2, 5-dimethyl-6-oxopyrimidin-1 (6H) -yl) - (Sa) - (2, 3-dichlorophenoxy) -N-methylbenzamide (example 19a):
and
4- (4- (4- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Decan-8-yl) -2, 5-dimethyl-6-oxopyrimidin-1 (6H) -yl) - (Ra) - (2, 3-dichlorophenoxy) -N-methylbenzamide (example 19b):
examples 19a and 19b were synthesized by synthetic methods similar to those used for examples 15a and 15b, and can generally be prepared by the methods disclosed herein. The examples can be prepared as free base or as TFA salt.
Example 19a 4- (4- (4- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -2, 5-dimethyl-6-oxopyrimidin-1 (6H) -yl) - (Sa) - (2, 3-dichlorophenoxy) -N-methylbenzamide: MS (ES +) C29H33Cl2N5O4Calculated values:585, found: 586[ M + H ]]+。
Example 19b 4- (4- (4- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]]Decan-8-yl) -2, 5-dimethyl-6-oxopyrimidin-1 (6H) -yl) - (Ra) - (2, 3-dichlorophenoxy) -N-methylbenzamide: MS (ES +) C29H33Cl2N5O4Calculated values: 585, found: 586[ M + H ]]+。
Examples 20a and 20b
3- (4- ((1H-pyrazol-3-yl) oxy) - (S)a) -2, 3-dichlorophenyl) -6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 20a):
and
3- (4- ((1H-pyrazol-3-yl) oxy) - (R)a) -2, 3-dichlorophenyl) -6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 20b):
step 1: 3- (2, 3-dichloro-4-nitrophenoxy) -1H-pyrazole-1-carboxylic acid tert-butyl ester
3-oxo-2, 3-dihydro-1H-pyrazole-1-carboxylic acid tert-butyl ester (687mg,3.73mmol), 2, 3-dichloro-1-fluoro-4-nitrobenzene (650mg,3.11mmol) and K2CO3A mixture of (858mg,6.22mmol) in DMSO (10mL) was stirred at room temperature for 4 h. Water (20mL) was added and the mixture was extracted with EtOAc. The combined organic phases are passed over Na2SO4Dried, filtered and purified by column chromatography (EtOAc in PE; 20 to 50%) to provide the title compound (800mg, 67%) as yellowAnd (3) a solid. MS (ES +) C14H13Cl2N3O5Calculated values: 373, found: 318[ M-56+ H]+。
Step 2: 3- (4-amino-2, 3-dichlorophenoxy) -1H-pyrazole-1-carboxylic acid tert-butyl ester
A suspension of 3- (2, 3-dichloro-4-nitrophenoxy) -1H-pyrazole-1-carboxylic acid tert-butyl ester (1.2g,3.2mmol), Pt/C (200mg) in EtOH (100mL) was stirred under a hydrogen atmosphere at room temperature for 16H. The mixture was filtered and the filtrate was concentrated to give the title compound (1.1g, 100%) as a beige solid. MS (ESI +) C14H15Cl2N3O3Calculated values: 343, found: 288[ M-56+ H]+。
And step 3: n- (4- ((1H-pyrazol-3-yl) oxy) -2, 3-dichlorophenyl) acetamide
3- (4-amino-2, 3-dichlorophenoxy) -1H-pyrazole-1-carboxylic acid tert-butyl ester (1.1g,3.2mmol) in HCl/CH3The mixture in CN (1M,20mL) was stirred in a sealed tube at 110 ℃ for 4 hours. The mixture was concentrated to give crude N- (4- ((1H-pyrazol-3-yl) oxy) -2, 3-dichlorophenyl) acetamide. MS (ESI +) C11H10Cl2N4Calculated value of O: 284, found: 285[ M + H ]]+。
And 4, step 4: 3- (4- ((1H-pyrazol-3-yl) oxy) -2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one
To N- (4- ((1H-pyrazol-3-yl) oxy) -2, 3-dichlorophenyl) acetamide (600mg,2.11mmol), diethyl 2-methylmalonate (1).84g,10.6mmol) in EtOH (10mL) CH was added3ONa/CH3OH (4M,2.64 mL). The mixture was stirred at 110 ℃ for 5 h. The mixture was concentrated and dissolved in water (20 mL). The aqueous layer was extracted with EtOAc (20mL) and the pH was adjusted to 5 with 6N HCl. The solid precipitated out and was collected by filtration to give the title compound (300mg, 38.7%) as an off-white solid. MS (ESI +) C15H12Cl2N4O3Calculated values: 366, found value: 367[ M + H]+。
The compound of step 4 may be substituted with 3- (4- ((1H-pyrazol-3-yl) oxy) - (S)a) -2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one and 3- (4- ((1H-pyrazol-3-yl) oxy) - (Ra) -2, 3-dichlorophenyl) -6-hydroxy-2, 5-dimethylpyrimidin-4 (3H) -one in the form of a mixture.
And 5: 3- (4- ((1H-pyrazol-3-yl) oxy) - (S)a) -2, 3-dichlorophenyl) -6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 20a) and 3- (4- ((1H-pyrazol-3-yl) oxy) - (R)a) -2, 3-dichlorophenyl) -6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -2, 5-dimethylpyrimidin-4 (3H) -one (example 20b)
The experiment was performed as described in example 18a and 18b, step 5. A Chiralpak OZ column (20X 250mm) was used with CO2And 0.2% methanolic ammonia (50:50) as eluent, at a flow rate of 80g/min and UV detection (214nm) to provide example 20a (15mg, 11%) and example 20b (13mg, 11%) as white solids.
Example 20a 3- (4- ((1H-pyrazol-3-yl) oxy) - (S)a) -2, 3-dichlorophenyl) -6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -2, 5-dimethylpyrimidin-4 (3H) -one: MS (ES +) C24H28Cl2N6O3Calculated values: 518, found: 519[ M + H ]]+；1H NMR(500MHz,DMSO)δ12.57(d,J＝0.4Hz,1H),7.78(s,1H),7.48(d,J＝8.9Hz,1H),7.18(d,J＝8.9Hz,1H),6.05(s,1H),4.12–3.99(m,1H),3.67(d,J＝8.4Hz,1H),3.60–3.52(m,2H),3.50(d,J＝8.4Hz,1H),3.23–3.07(m,2H),2.93(d,J＝4.9Hz,1H),2.00(s,3H),1.89(s,3H),1.81–1.74(m,1H),1.70–1.63(m,1H),1.59–1.47(m,2H),1.23(s,1H),1.09(d,J＝6.3Hz,3H).
Example 20b 3- (4- ((1H-pyrazol-3-yl) oxy) - (R)a) -2, 3-dichlorophenyl) -6- ((3S,4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl) -2, 5-dimethylpyrimidin-4 (3H) -one: MS (ES +) C24H28Cl2N6O3Calculated values: 518, found: 519[ M + H ]]+；1H NMR(500MHz,DMSO)δ12.57(s,1H),7.81–7.75(m,1H),7.48(d,J＝8.9Hz,1H),7.18(d,J＝9.0Hz,1H),6.05(t,J＝2.1Hz,1H),4.10–4.01(m,1H),3.67(d,J＝8.5Hz,1H),3.61–3.51(m,2H),3.50(d,J＝8.5Hz,1H),3.23–3.18(m,1H),3.15–3.06(m,1H),2.93(d,J＝4.9Hz,1H),2.00(s,3H),1.89(s,3H),1.80–1.75(m,1H),1.70–1.63(m,1H),1.58–1.48(m,2H),1.32–1.19(m,2H),1.09(d,J＝6.4Hz,3H).
Example 21: biological activity assay
The activity of the example compounds disclosed herein as inhibitors of PTPN11 is illustrated in the following assay.
Enzymatic assay for PTPN11
Recombinant full-length wild-type and E76K mutant human PTPN11 proteins were cloned, expressed (e.coli system) and separated by two-step purification with Ni affinity, S75 size exclusion chromatography.
Phosphatase activity of full-length wild-type PTPN11(PTPN11-WT) or PTPN11-E76K mutant enzymes was measured using fluorescent 6, 8-difluoro-4-methyl umbelliferyl phosphate (DiFMUP; molecular probe) as a substrate. The enzyme (250pM) was incubated with compounds with or without increasing concentrations in assay buffer (62.5mM HEPES, 125mM NaCl, 1mM EDTA, 1.25mM TECP, 0.1% BSA) for 30 min at room temperature. The reaction was initiated by adding DiFMUP (50. mu.M) to 384-well black plates at room temperature, and the final reaction volume in assay buffer was 20 uL. After 1 hour, the DiFMUP fluorescence signal was measured using an Envision plate reader (Ex:340/Em: 460). Using ICs50Dose-response curves were analyzed by regression curve fitting (GeneData Screener). Mixing yeastThe lines were normalized to a high control without inhibitor and a low control without substrate. The results are provided in table 2 below.
TABLE 2 inhibition of the biological Activity of the PTPN11-E76K mutant enzyme
ERK phosphorylation (phospho-ERK) target participation assay
KYSE-520 cells (10k cells/well) were plated in 384-well plates in 20uL medium (RPMI-1640, phenol red free, containing 10% FBS) and at 37 deg.C, 5% CO2And culturing for 16 h. DMSO (control) or increasing concentrations of compound were diluted in culture medium, added to 384-well plates (10 uL/well, final DMSO concentration of 1%), and cells were incubated with compound for 2 hours. The level of phospho-ERK was measured using the TR-FRET based phospho-ERK1/2HTRF kit (CisBio, 64ERKPEH) and the fluorescence signal was measured at 665nm and 620nm using a Synergy Neo plate reader, according to the manufacturer's recommendations. Using ICs50Dose-response curves were analyzed by regression curve fitting (GeneData Screener). The curves were normalized to a high control without inhibitor and a low control with 1 μ M selumetinib. Certain compounds of the invention exhibit IC50<1μM。
Colony formation assay
KYSE-520 cells (2000 cells/well) were plated in 6-well plates containing 2mL of medium (RPMI-1640, 10% FBS) in DMSO (control; final concentration 1%) or increasing compound concentration. In moist 5% CO2After 14 days of culture at 37 ℃ in the medium, colonies were fixed and stained with 0.1% crystal violet and 15% ethanol solution. Plates were imaged and colony areas quantified and normalized to DMSO using ImageJ, colony area insert (Guzm an, camiro, PloS one 2014). Some of the compounds of the inventionDisplay IC50<1μM。
Example 22: in vivo studies
The in vivo anti-tumor efficacy of example 2b was evaluated in NSG (NOD scid γ) mice with subcutaneously implanted KYSE520 xenografts. Example 2b was administered once daily by oral gavage at dosage levels of 300mg/kg, 50mg/kg, 15mg/kg and 5mg/kg for 21 days. As shown in fig. 1, example 2b showed dose-dependent tumor growth inhibition in the KYSE520 xenograft model at tolerated dose.
The in vivo anti-tumor efficacy of example 10b was evaluated in NSG mice with subcutaneously implanted KYSE520 xenografts. Example 10b was administered once daily by oral gavage at 200mg/kg, 150mg/kg, 100mg/kg, 30mg/kg, 10mg/kg and 3mg/kg for 21 days. As shown in fig. 2, example 10b showed dose-dependent tumor growth inhibition in the KYSE520 xenograft model at tolerated dose.
All references, patents, or applications cited in this application, whether in the united states or abroad, are hereby incorporated by reference as if fully set forth herein. Where any inconsistency occurs, the material literally disclosed herein controls.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
VIII embodiment
For further explanation, other non-limiting embodiments of the invention are set forth below.
Embodiment 1 is a compound of formula I
Or a salt, ester or prodrug thereof, wherein:
subscript a is 0 or 1;
subscript b is 0 or 1;
Y1is a direct bond or CR17R18；
Y2Is selected from C1-4Alkyl, amino, C1-4Alkyl C (O) O-, C1-4Alkylamino and C1-4An aminoalkyl group;
R1is selected from C6-10Aryl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl and 5-10 membered heteroaryl having 1-4 heteroatoms or groups independently selected from N, C (O), O, and S as the ring apex; the R is1Is optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14；
R2、R3、R10And R11Each independently selected from hydrogen and C1-4Alkyl and C3-8A cycloalkyl group;
R4、R5、R8and R9Each independently selected from hydrogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-8Cycloalkyl, halogen and C1-4An alkylamino group;
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, amido, cyano, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with 1 to 5 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
or R6And R7And together with the carbon atom to which they are attached form a compound having 0 to 3 substituents independently selected from the group consisting of N, C (O), O, and S (O)mA 3 to 7 membered saturated or unsaturated ring having the heteroatom or group as the ring apex;
subscript m is 0,1, or 2;
said is prepared from R6And R7The saturated or unsaturated ring formed is unsubstituted or substituted with 1 to 3 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R2、R3、R4、R5、R7、R8、R9、R10and R11Any two groups of (a) may form a 5 to 6 membered ring having 0 to 2 heteroatoms selected from N, O and S as ring vertices;
R2、R4、R6、R8and R10Any two groups in (a) may form a direct bond or a1 or 2 atom carbon bridge;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl, -NH-NHR19、-NHR19、-OR19、-NHC(O)R19、-NHC(O)NHR19、-NHS(O)2NHR19、-NHS(O)2R19、-C(O)OR19、-C(O)NR19R20、-C(O)NH(CH2)qOH、-C(O)NH(CH2)qR21、-C(O)R21、-NH2、-OH、-S(O)2NR19R20、C3-8Cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms selected from N, O, S and P as ring vertices, heteroaryl having 1-5 heteroatoms selected from N, O, S and P as ring vertices; wherein subscript q is an integer between 0 and 6; and wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo;
R14、R15and R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: amide, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R17and R18Each independently selected from hydrogen and C1-4Alkyl and CF3；
R19And R20Each independently selected from hydrogen and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group;
each R21Independently selected from: hydrogen, -OH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group.
Embodiment 2 is a compound of embodiment 1 wherein:
subscript a is 0 or 1;
subscript b is 0 or 1;
Y1is a direct bond or CR17R18；
Y2Is selected from C1-4Alkyl, amino, C1-4Alkyl C (O) O-, C1-4Alkylamino and C1-4An aminoalkyl group;
R1is selected from C6-10Aryl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl and 5-10 membered heteroaryl having 1-4 heteroatoms or groups independently selected from N, C (O), O, and S as the ring apex; the R is1Is optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14；
R2、R3、R10And R11Each independently selected from hydrogen and C1-4Alkyl and C3-8A cycloalkyl group;
R4、R5、R8and R9Each independently selected from hydrogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, amino, hydroxy, C3-8Cycloalkyl, halogen and C1-4An alkylamino group;
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group;
R7selected from hydrogen, halogen and hydroxyl or selected from amide and C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 memberedHeteroaryl, any of which is optionally substituted with 1 to 5 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
or R6And R7Together with the carbon atom to which they are attached form a ring having 0 to 3 substituents independently selected from N, C (O), O, and S (O)mA 3 to 7 membered saturated or unsaturated ring having the heteroatom or group as the ring apex;
subscript m is 0,1, or 2;
said is prepared from R6And R7The saturated ring formed is unsubstituted or substituted with 1 to 3 groups independently selected from: amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group;
R2、R3、R4、R5、R7、R8、R9、R10and R11Any two groups of (a) may form a 5 to 6 membered ring having 0 to 2 heteroatoms selected from N, O and S as ring vertices;
R2、R4、R6、R8and R10Any two groups in (a) may form a direct bond or a1 or 2 atom carbon bridge;
R13selected from hydrogen, halogen, cyano, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl, -NH-NHR19、-NHR19、-OR19、-NHC(O)R19、-NHC(O)NHR19、-NHS(O)2NHR19、-NHS(O)2R19、-C(O)OR19、-C(O)NR19R20、-C(O)NH(CH2)qOH、-C(O)NH(CH2)qR21、-C(O)R21、-NH2、-OH、-S(O)2NR19R20、C3-8Cycloalkyl, aryl, heterocyclyl having 1-5 heteroatoms selected from N, O, S and P as ring vertices, heteroaryl having 1-5 heteroatoms selected from N, O, S and P as ring vertices; wherein subscript q is an integer between 0 and 6; and wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo;
R14、R15and R16Each independently selected from hydrogen and C1-4Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group;
R17and R18Each independently selected from hydrogen and C1-4Alkyl and CF3；
R19And R20Each independently selected from hydrogen and C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group; and
each R21Independently selected from: hydrogen, -OH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C3-6A cycloalkyl group.
Embodiment 3 is a compound of embodiment 1 or 2 wherein the subscripts a and b are each 1.
Embodiment 4 is a compound of any one of embodiments 1-3 wherein Y1Is a direct bond.
Embodiment 5 is a compound of any one of embodiments 1 to 4, wherein Y2Is C1-4An alkyl group.
Embodiment 6 is a compound of embodiment 5 wherein Y2Is methyl.
Embodiment 7 is a compound of any one of embodiments 1 to 6, wherein
R13Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Hydroxyalkyl radical, C1-6Dihydroxyalkyl radical, C3-8Cycloalkyl, 3 or 6 membered heterocyclyl having 1-3 heteroatoms selected from N, O and S as ring vertices; wherein heterocyclyl and cycloalkyl are substituted with 0 to 3 groups independently selected from: c1-4Alkyl, -OH, -NH2、-OR21Halogen, cyano and oxo.
Embodiment 8 is a compound of embodiment 7 wherein R13Selected from hydrogen, halogen, C1-6Alkyl and C1-6A haloalkyl group.
Embodiment 9 is a compound of embodiment 8 wherein R13Is hydrogen, Cl, Br, methyl or CF3。
Embodiment 10 is a compound of any one of embodiments 1 to 9, wherein
R1Is selected from C6-10Aryl and a 5 to 9 membered heteroaryl group having 1 to 4 heteroatom groups independently selected from N, C (O), O and S as ring vertices; and optionally substituted with 1 to 5R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Hydroxyalkyl radical, C1-4Haloalkyl, C1-4Aminoalkyl radical, C3-8Cycloalkyl radical, C3-8Cycloalkenyl radical, NR15C(O)R14、NR15C(O)OR14、NR14C(O)NR15R16、NR15S(O)R14、NR15S(O)2R14、C(O)NR15R16、S(O)NR15R16、S(O)2NR15R16、C(O)R14、C(O)OR14、OR14、SR14、S(O)R14And S (O)2R14。
Embodiment 11 is a compound of embodiment 10 wherein
R1Is phenyl or has 1 to 4 substituents independently selected fromN, O and a 5-to 6-membered heteroaryl group with the heteroatom of S as the ring vertex; and optionally substituted with 1,2 or 3R independently selected from12And (3) group substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
Embodiment 12 is a compound of any one of embodiments 1 to 11, wherein R2、R3、R4、R5、R8、R9、R10And R11Is hydrogen.
Embodiment 13 is a compound of any one of embodiments 1 to 12 wherein:
R6selected from amino, C1-4Aminoalkyl and C1-4An alkylamino group; and
R7selected from hydrogen, amido, cyano, halogen and hydroxy or selected from C1-4Alkyl radical, C1-4Hydroxyalkyl radical, C3-6Cycloalkyl, phenyl and 5 or 6 membered heteroaryl, any of which is optionally substituted with one or two groups selected from: amino, halogen, hydroxy, cyano, trifluoromethyl, trifluoromethoxy, C1-4Alkyl and C1-4An alkoxy group.
Embodiment 14 is a compound of embodiment 13 wherein
R6Is amino or aminomethyl; and
R7selected from hydroxy, C1-4Alkyl and C1-4A hydroxyalkyl group.
Embodiment 15 is a compound of any one of embodiments 1 to 12, wherein
R6And R7Together with the carbon atoms to which they are attached form a 3-7 membered saturated or unsaturated ring having as the ring apex 1-3 heteroatoms or groups independently selected from N, C (O), O and S (O) m, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
Embodiment 16 is a compound of embodiment 15 wherein
R6And R7Together with the carbon atom to which they are attached form a 4-6 membered saturated ring having 1-3 heteroatoms independently selected from N and O as ring vertices, and optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
Embodiment 17 is a compound of any one of embodiments 1 to 12, wherein
R6And R7Together with the carbon atoms to which they are both attached form a 3 to 7 membered cycloalkyl group, optionally substituted with one or two groups independently selected from: amino, halogen, hydroxy, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino and C1-4An aminoalkyl group.
Embodiment 18 is a compound of any one of embodiments 1 to 17, wherein
R1Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl and 1,2, 4-triazinyl; and optionally substituted with 1,2 or 3R independently selected from12And (3) substitution: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
Embodiment 19 is a compound of embodiment 18 wherein R1Is phenyl or pyridyl, each of which is substituted by 1-3R12And (4) substitution.
Embodiment 20 is a compound of any one of embodiments 1 to 18, wherein R1Selected from: and
each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Aminoalkyl and OR14。
Embodiment 21 is a compound of embodiment 20 wherein R1Selected from:
and
embodiment 22 is a compound of any one of embodiments 1 to 21, wherein R14Is selected from C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
Embodiment 23 is a compound of embodiment 22 wherein R14Is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: halogen, hydroxy, cyano and C1-4An alkyl group.
Embodiment 24 is a compound of embodiment 1 wherein R14Is selected from C6-10Aryl and 5-10 membered heteroaryl, any of which is optionally substituted with 1 or more groups independently selected from: c1-4Alkylamido, amino, halogen, hydroxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C1-4Alkylamino and C1-4An aminoalkyl group.
Embodiment 25 is an embodimentThe compound of scheme 1 wherein R1Is composed of
Each R12Independently selected from: halogen, hydroxy, amino, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl and C1-4An aminoalkyl group; and
R14is phenyl or a 5-6 membered heteroaryl having from 1 to 4 heteroatoms independently selected from N, O and S as ring vertices, each of which is optionally substituted with one or two groups independently selected from: c1-4Alkylamido, halogen, hydroxy, cyano and C1-4An alkyl group.
Embodiment 26 is a compound of embodiment 1, any one of them R12Independently selected from: F. cl, Br, CH3、OCH3、CF3、 And
embodiment 28 is a compound of embodiment 1 or 2 for use as a medicament.
Embodiment 29 is a compound of embodiment 1 or 2 for use in treating a disease driven by one or more PTPN11 mutations.
Embodiment 30 is a compound of embodiment 1 or 2 for use in the treatment of cancer.
Embodiment 31 is the compound of embodiment 30, wherein the cancer is selected from the group consisting of leukemia, melanoma, breast cancer, and colon cancer.
Embodiment 32 is the compound of embodiment 1 or 2 for use in the preparation of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of PTPN 11.
Embodiment 33 is a pharmaceutical composition comprising a compound of embodiment 1 or 2 and a pharmaceutically acceptable carrier.
Embodiment 34 is a method of inhibiting PTPN11 comprising contacting PTPN11 with a compound of embodiment 1 or 2.
Embodiment 35 is a method of treating a PTPN 11-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of embodiment 1 or 2.
Embodiment 36 is the method of embodiment 35, wherein the disease is cancer.
Embodiment 37 is the method of embodiment 36, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, leukemia and melanoma.
Embodiment 38 is a method of treating a PTPN 11-mediated disease, comprising administering:
a. a therapeutically effective amount of a compound of embodiment 1 or 2; and
b. another therapeutic agent.
Embodiment 39 is the method of embodiment 38, wherein the disease is cancer.
Embodiment 40 is the method of embodiment 39, wherein the cancer is selected from the group consisting of breast cancer, colon cancer, leukemia, and melanoma.
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