Heterocyclic inhibitors of ATR kinase
阅读说明：本技术 Atr激酶的杂环抑制剂 (Heterocyclic inhibitors of ATR kinase ) 是由 M·E·迪弗朗西斯科 P·琼斯 C·L·卡罗尔 J·B·克劳斯 Z·康 M·G·约翰逊 于 2018-08-17 设计创作，主要内容包括：本发明涉及杂环化合物和方法,这些化合物可用作ATR激酶的抑制剂,用于治疗或预防癌症。(The present invention relates to heterocyclic compounds and methods that are useful as inhibitors of ATR kinase, for the treatment or prevention of cancer.)
1. A compound having the structural formula (I):
or a salt thereof, wherein:
R1is a 4-to 10-membered heterocycloalkyl group, and is optionally substituted with one or more R4Substituted by groups;
R2is a 5-to 10-membered heteroaryl group, and is optionally substituted with one or more R5Substituted by groups;
R3selected from H, C1-6Alkyl and C1-6A haloalkyl group;
each R4Independently selected from halogen, cyano, hydroxy, alkyl, C3-7Cycloalkyl, haloalkyl, hydroxyalkyl, (C)3-7Cycloalkyl) alkyl, (5-to 10-membered heterocycloalkyl) alkyl, (alkoxy) alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, (C)3-7Cycloalkyl) alkoxy, (5-to 10-membered heterocycloalkyl) alkoxy, (alkoxy) alkoxy, C3-7Cycloalkyl radical, C3-7Halogenocycloalkyl, C3-7Hydroxycycloalkyl, (alkoxy) C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl, (halo) 5-to 10-membered heterocycloalkyl, (hydroxy) 5-to 10-membered heterocycloalkyl, (alkoxy) 5-to 10-membered heterocycloalkyl, NR7R8、C(O)R6、C(O)OR6、C(O)NR7R8、NR7C(O)NR7R8、NR7C(O)OR6、NR7C(O)R6、S(O)R6、S(O)2R6、S(NR7)R8、S(O)(NR7)R8、SO2NR7R8Oxo and ═ NR10；
Each R5Independently selected from amino, fluoro, chloro, cyano, C1-3Alkyl radical, C1-3Aminoalkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl;
each R6、R7And R8Independently selected from H, C1-3Alkyl radical, C3-7Cycloalkyl radical, C1-3Hydroxyalkyl group, (C)1-3Alkoxy) C1-3Alkyl, (C)3-7Cycloalkyl) C1-3Alkyl and 5-to 10-membered heterocycloalkyl, and optionally substituted with one or more R9Substitution;
R7and R8Optionally forming, together with the nitrogen to which they are both attached, a 5-to 10-membered heterocycloalkyl ring containing one or two heteroatoms;
each R6、R7Or R8Can be reacted with R4Forming a ring;
each R9Independently selected from halo, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl and C1-3An alkoxy group; and is
Each R10Independently selected from H, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Haloalkyl, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl.
2. A compound or salt thereof according to claim 1, wherein R3Is methyl.
3.A compound or salt thereof according to claim 2, wherein R1Is a single ring C3-6Heterocycloalkyl, and optionally substituted with one, two or three R4And (4) substituting the group.
4. A compound or salt thereof according to claim 3, wherein each R is4Independently selected from halogen, cyano, hydroxy, alkyl, C3-7Cycloalkyl, haloalkyl, hydroxyalkyl, alkoxy, C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl, C (O) R7、C(O)OR7、C(O)NR8R9、S(O)R7、S(O)2R7、S(NR8)R9、S(O)(NR8)R9、SO2NR8R9Oxo and ═ NR10。
5. The compound or salt thereof of claim 4, wherein each R4Independently selected from alkyl, C3-7Cycloalkyl, alkoxy, C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl, C (O) R7、C(O)OR7、C(O)NR8R9、S(O)2R7Oxo and ═ NR10。
6. A compound or salt thereof according to claim 5, wherein R1Comprising a group selected from: -C (O) NR4-、-NR4-、-O-、-C(O)-、-S(O)-、-S(O)2-、-S(O)2NR4-、-S(NR10) and-S (O) (NR)10)-。
7. The compound or salt thereof according to claim 6, wherein:
R1is selected from
R4aSelected from H, alkyl and C3-7A cycloalkyl group;
R4bselected from S (O)2R6、C(O)R6、C(O)OR6And C (O) NR7R8(ii) a And is
n is selected from 1 and 2 inclusive.
8. A compound or salt thereof according to claim 7, wherein R2Selected from indolyl, indazolyl, benzo [ d ]]Imidazolyl, pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl, pyrrolopyrazinyl, pyrazolopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridazinyl, pyrazolopyridazinyl and imidazopyridazinyl, any of which is optionally substituted with one or more R5And (4) substituting the group.
9. The compound or salt thereof of claim 8, wherein each R4Independently selected from alkyl, C3-7Cycloalkyl, C (O) R7、C(O)OR7、C(O)NR8R9、S(O)2R7Oxo and ═ NR10。
10. The compound of claim 1, having structural formula (II):
or a salt thereof, wherein:
y is selected from N and CR5c；
Z is selected from N and CR5d；
R1Is a 4-to 10-membered heterocycloalkyl group, and is optionally substituted with one or more R4Substituted by groups;
R3selected from H, C1-6Alkyl and C1-6A haloalkyl group;
each R4Independently selected from halogen, cyano, hydroxy, alkyl, C3-7Cycloalkyl, haloalkyl, hydroxyalkyl, (C)3-7Cycloalkyl) alkyl, (5-to 10-membered heterocycloalkyl) alkyl, (alkoxy) alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, (C)3-7Cycloalkyl) alkoxy, (5-to 10-membered heterocycloalkyl) alkoxy, (alkoxy) alkoxy, C3-7Cycloalkyl radical, C3-7Halogenocycloalkyl, C3-7Hydroxycycloalkyl, (alkoxy) C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl, (halo) 5-to 10-membered heterocycloalkyl, (hydroxy) 5-to 10-membered heterocycloalkyl, (alkoxy) 5-to 10-membered heterocycloalkyl, NR7R8、C(O)R6、C(O)OR6、C(O)NR7R8、NR7C(O)NR7R8、NR7C(O)OR6、NR7C(O)R6、S(O)R6、S(O)2R6、S(NR7)R8、S(O)(NR7)R8、SO2NR7R8Oxo and ═ NR10；
Each R5aAnd R5bIndependently selected from H, amino, fluorine, chlorine,Cyano radicals, C1-3Alkyl radical, C1-3Aminoalkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl,
or R5aAnd R5bTaken together with the intervening atoms to form a heteroaryl ring, optionally substituted with one or more R5Substituted by groups;
each R5cAnd R5dIndependently selected from fluorine, chlorine, cyano, C1-3Alkyl radical, C1-3Aminoalkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl;
each R5Independently selected from amino, fluoro, chloro, cyano, C1-3Alkyl radical, C1-3Aminoalkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl;
each R6、R7And R8Independently selected from H, C1-3Alkyl radical, C3-7Cycloalkyl radical, C1-3Hydroxyalkyl group, (C)1-3Alkoxy) C1-3Alkyl, (C)3-7Cycloalkyl) C1-3Alkyl and 5-to 10-membered heterocycloalkyl, and optionally substituted with one or more R9Substitution;
R7and R8Optionally forming, together with the nitrogen to which they are both attached, a 5-to 10-membered heterocycloalkyl ring containing one or two heteroatoms;
each R6、R7Or R8Can be reacted with R4Forming a ring;
each R9Independently selected from halo, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl and C1-3An alkoxy group; and is
Each R10Independently selected from H, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Haloalkyl, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl.
11. A compound or salt thereof according to claim 10, wherein
R1Is selected from
R4aSelected from H, alkyl and C3-7A cycloalkyl group;
R4bselected from S (O)2R6、C(O)R6、C(O)OR6And C (O) NR7R8(ii) a And is
n is selected from 1 and 2 inclusive.
12. A compound or salt thereof according to claim 11, wherein:
R5ais NH2(ii) a And is
R5bIs H.
13. The compound of claim 1, having structural formula III
Or a salt thereof, wherein:
y is selected from N and CR5c；
Z is selected from N and CR5d；
R1Is selected from
R4aSelected from H, alkyl and C3-7A cycloalkyl group;
R4bselected from S (O)2R6、C(O)R6、C(O)OR6And C (O) NR7R8(ii) a And is
Each R5cAnd R5dIndependently selected from H, fluorine, chlorine, cyano, C1-3Alkyl radical, C1-3Aminoalkyl and C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl;
R5zselected from H, fluorine, chlorine, cyano, C1-3Alkyl radical, C1-3Aminoalkyl radical, C1-3Hydroxyalkyl and C1-3A haloalkyl group;
each R6、R7And R8Independently selected from H, C1-3Alkyl radical, C3-7Cycloalkyl radical, C1-3Hydroxyalkyl group, (C)1-3Alkoxy) C1-3Alkyl, (C)3-7Cycloalkyl) C1-3Alkyl and 5-to 10-membered heterocycloalkyl, and optionally substituted with one or more R9Substitution;
R7and R8Optionally forming, together with the nitrogen to which they are both attached, a 5-to 10-membered heterocycloalkyl ring containing one or two heteroatoms;
each R9Independently selected from halo, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl and C1-3An alkoxy group;
R10selected from H, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Haloalkyl, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl; and is
n is selected from 1 and 2 inclusive.
14. A compound or salt thereof according to claim 13, wherein
Y is selected from C (R)5a) And N;
z is N; and is
R5cSelected from H and chlorine.
15. The compound of claim 1, or a salt thereof, having structural formula V:
or a salt thereof, wherein:
y is selected from N and CR5c；
Z is selected from N and CR5d；
R1Is a 4-to 10-membered heterocycloalkyl group, and is optionally substituted with one or more R4Substituted by groups;
R3selected from H, C1-6Alkyl and C1-6A haloalkyl group;
each R4Independently selected from halogen, cyano, hydroxy, alkyl, C3-7Cycloalkyl, haloalkyl, hydroxyalkyl, (C)3-7Cycloalkyl) alkyl, (5-to 10-membered heterocycloalkyl) alkyl, (alkoxy) alkyl, alkoxy, haloalkoxy, hydroxyalkoxy, (C)3-7Cycloalkyl) alkoxy, (5-to 10-membered heterocycloalkyl) alkoxy, (alkoxy) alkoxy, C3-7Cycloalkyl radical, C3-7Halogenocycloalkyl, C3-7Hydroxycycloalkyl, (alkoxy) C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl, (halo) 5-to 10-membered heterocycloalkyl, (hydroxy) 5-to 10-membered heterocycloalkyl, (alkoxy) 5-to 10-membered heterocycloalkyl, NR7R8、C(O)R6、C(O)OR6、C(O)NR7R8、NR7C(O)NR7R8、NR7C(O)OR6、NR7C(O)R6、S(O)R6、S(O)2R6、S(NR7)R8、S(O)(NR7)R8、SO2NR7R8Oxo and ═ NR10；
Each R5cAnd R5dIndependently selected from fluorine, chlorine, cyano, C1-3Alkyl radical, C1-3Aminoalkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl;
or R5cAnd R5dTaken together with the intervening atoms to form an aryl or heteroaryl ring optionally substituted with one or more R5Substituted by groups;
each R5Independently selected from fluorine, chlorine, cyano, C1-3Alkyl radical, C1-3Aminoalkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C1-3Haloalkoxy, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl;
each R6、R7And R8Independently selected from H, C1-3Alkyl radical, C3-7Cycloalkyl radical, C1-3Hydroxyalkyl group, (C)1-3Alkoxy) C1-3Alkyl, (C)3-7Cycloalkyl) C1-3Alkyl and 5-to 10-membered heterocycloalkyl, and optionally substituted with one or more R9Substitution;
R7and R8Optionally forming, together with the nitrogen to which they are both attached, a 5-to 10-membered heterocycloalkyl ring containing one or two heteroatoms;
each R6、R7Or R8Can be reacted with R4Forming a ring;
each R9Independently selected from halo, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl, C3-7Cycloalkyl, 5-to 10-membered heterocycloalkyl and C1-3An alkoxy group; and is
Each R10Independently selected from H, C1-3Alkyl radical, C1-3Alkoxy radical, C1-3Haloalkyl, C3-7Cycloalkyl and 5-to 10-membered heterocycloalkyl.
16. A compound or salt thereof according to claim 13, wherein
R1Is selected from
R4aSelected from H, alkyl and C3-7A cycloalkyl group;
R4bselected from S (O)2R6、C(O)R6、C(O)OR6And C (O) NR7R8(ii) a And is
n is selected from 1 and 2 inclusive.
17. The compound of claim 14, wherein
Y is CR5c；
Z is N; and is
R5cSelected from H, fluorine, chlorine, cyano, C1-3Alkyl radical, C1-3Haloalkyl and C1-3A hydroxyalkyl group.
18. A compound or salt thereof according to claim 1, having a structure selected from:
19. a compound or salt thereof according to claim 1, having a structure selected from:
20. a compound according to claim 1 for use as a medicament.
21. A compound according to claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of ATR kinase.
22. The compound of claim 21, wherein the disease is cancer.
23. The compound of claim 22, wherein the cancer is a chemotherapy-resistant cancer.
24. The compound of claim 22, wherein the cancer is a radiation therapy resistant cancer.
25. The compound of claim 22, wherein the cancer is ALT-positive cancer.
26. The compound of claim 22, wherein the cancer is sarcoma.
27. The compound of claim 22, wherein the cancer is selected from osteosarcoma and glioblastoma.
28. The compound of claim 22, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.
29. The compound of claim 22, wherein the cancer is selected from non-small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.
30. The compound of claim 22, wherein the cancer has a defect in base excision repair protein.
31. A pharmaceutical composition comprising the compound of claim 1 together with a pharmaceutically acceptable carrier.
32. A method of sensitizing a cell to a DNA damaging agent comprising administering to a patient a compound of claim 1.
33. A method of preventing cellular repair DNA damage comprising administering to a patient a compound of claim 1.
34. A method of inhibiting ATR kinase comprising contacting ATR kinase with a compound of claim 1.
35. A method of treating an ATR kinase-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 a chemotherapy-resistant cancer.
38. The method of claim 36, wherein the cancer is a radiation therapy resistant cancer.
39. The method of claim 36, wherein the cancer is ALT-positive cancer.
40. The method of claim 36, wherein the cancer is a sarcoma.
41. The method of claim 36, wherein the cancer is selected from osteosarcoma and glioblastoma.
42. The method of claim 36, wherein the cancer is selected from lung cancer, head and neck cancer, pancreatic cancer, gastric cancer, and brain cancer.
43. The method of claim 36, wherein the cancer is selected from non-small cell lung cancer, pancreatic cancer, biliary tract cancer, head and neck cancer, bladder cancer, colorectal cancer, glioblastoma, esophageal cancer, breast cancer, hepatocellular carcinoma, and ovarian cancer.
44. The method of claim 36, wherein the cancer has a defect in base excision repair protein.
45. The method of claim 36, wherein the cancer has a defect in the ATM signaling cascade.
46. The method of claim 45, wherein the defect is altered expression or activity of one or more of: TM, p53, CHK2, MRE11, RAD50, NBS 1, 53BP1, MDC1, H2AX, MCPH1/BRIT1, CTIP or SMC 1.
47. The method of claim 35, further comprising administering another therapeutic agent to the patient, wherein the other therapeutic agent inhibits or mediates base excision repair protein.
48. A method of treating an ATR kinase-mediated disease comprising administering:
a. a therapeutically effective amount of a compound of claim 1; and
b. another therapeutic agent.
49. The method of claim 48, wherein the other therapeutic agent is an immune checkpoint inhibitor comprising anti-PD-1, anti-PDL-1, anti-LAG 3, and anti-TIM 3 agents.
50. The method of claim 48, wherein the other therapeutic agent is a DNA repair inhibitor, such as a PARP inhibitor, an ATM inhibitor, a CHK1 inhibitor, or a CHK2 inhibitor.
51. The method of claim 50, wherein the PARP inhibitor is selected from Olaparib or Nilaparib.
52. The method of claim 50, wherein the CHK1 inhibitor is selected from MK-8776, LY2603618, V158411, PF-477736, UCN-01, and AZD 7762.
53. The method of claim 48, wherein the other therapeutic agent is a DNA damaging agent.
54. The method of claim 53, wherein the DNA damaging agent is selected from the group consisting of ionizing radiation, radio-carcinoids, platinating agents, Topo I inhibitors, Topo II inhibitors, antimetabolites, alkylating agents, alkyl sulfonates, and antibiotics.
55. The method of claim 54, wherein the platinating agent is selected from cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, triplatin tetranitrate, picoplatin, satraplatin, ProLindac, and alloplatin.
56. The method of claim 54, wherein the Topo I inhibitor is selected from camptothecin, topotecan, irinotecan/SN 38, rubitecan, and belotecan.
57. The method of claim 54, wherein the TopoII inhibitor is selected from etoposide, daunorubicin, doxorubicin, aclarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin, and teniposide.
58. The method of claim 54, wherein the antimetabolite is selected from the group consisting of aminopterin, methotrexate, pemetrexed, raltitrexed, pentostatin, cladribine, clofarabine, fludarabine, thioguanine, mercaptopurine, fluorouracil, capecitabine, tegafur, carmofur, floxuridine, cytarabine, gemcitabine, azacitidine, and hydroxyurea.
59. The method of claim 54, wherein the alkylating agent is selected from the group consisting of dichloromethyldiethylamine, cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, melphalan, prednimustine, bendamustine, uramustine, estramustine, carmustine, lomustine, semustine, fotemustine, nimustine, ranimustine, streptozotocin, busulfan, mannosuman, troosulfan, carboquone, thiotepa, triimidyl quinone, trittamine, procarbazine, dacarbazine, temozolomide, hexamethylmelamine, dibromomannitol, actinomycin, bleomycin, mitomycin, and plicamycin.
60. The method of claim 36, wherein the method further comprises administering a non-chemical method of cancer treatment.
61. The method of claim 60, wherein the method further comprises administering radiation therapy.
62. The method of claim 60, wherein the method further comprises administering surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or any combination thereof.
63. A method of increasing the sensitivity of a cancer cell to a cancer therapy selected from chemotherapy or radiation therapy by administering to a patient a compound of claim 1.
64. The method of claim 63, wherein the cancer cell is a pancreatic cancer cell.
65. A method for achieving an effect in a patient comprising administering to the patient a therapeutically effective amount of a compound of claim 1, wherein the effect is increased sensitivity to a chemotherapeutic agent.
example 6: a compound or salt thereof as in embodiment 1, wherein R2Selected from monocyclic heteroaryl and bicyclic heteroaryl, any of which is optionally substituted with one or more R5And (4) substituting the group.
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