Mutant-selective EGFR inhibitors

Abstract

The disclosure relates to compounds that act as allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising the compounds; and methods of treating or preventing kinase-mediated disorders, including cancer and other proliferation diseases.

Description

This disclosure relates to compounds as allosteric inhibitors of epidermal growth factor receptor (EGFR); pharmaceutical compositions comprising said compounds; and methods for treating or preventing kinase-mediated conditions, including cancer and other proliferative diseases. Abstract

Claims

CLAIMS1. A compound of Formula I:or a pharmaceutically acceptable salt thereof; wherein:= indicates a single bond or a double bond;A and A’ are each, independently, CH, CR10, CH2, O, or N;W and Z are each, independently, N or CR9;X and Y are each, independently, N, CH, or CR3; provided that at least one of W, X, Y, or Z is CH;R1is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; each R2is independently selected from the group consisting of Ci-C3alkyl, Ci-C3haloalkyl, Ci-C3alkoxy, Ci-C3haloalkoxy, Ci-C3alkylamine, halogen, OH, NO2, NH2, NH(Ci- C6alkyl), N(CI-C6alkyl)2, (CH2)I.4OH, S(O)0.2H, S(O)0.2NH2, CN, and 3-10 membered cycloalkyl; alternatively, two R2, together with the atom to which they are attached, form 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;R3is, independently at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, C6-Ci0aryl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5;R4is, independently at each occurrence, selected from the group consisting of H, Ci- C6alkyl, (CH2)O.3-(C3-C7 cycloalkyl), (CH2)o-3-(C4-C7cycloalkenyl), (CH2)O-3-(C6-CIO aryl), (CH2)O.3-(5-6 membered heteroaryl), and (CH2)0.3-(4-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R6;R5is independently, at each occurrence, selected from the group consisting of Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(Ci-C6alkyl), O(CH2)I-3-OH, NH2, NH(CI-C6alkyl), N(Ci- C6alkyl)2, OH, CN, (CH2)0-3-(C6-CI0aryl), (CH2)0-3-(5-6 membered heteroaryl), and (CH2)0-3- (4-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R7;R6is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)I.4OH, S(0)o-2H, S(O)0.2NH2, or CN;R7is independently, at each occurrence, selected from the group consisting of substituents independently selected from Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, halogen, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, SO2NH2, SO2NH(Ci-C6alkyl), SO2N(Ci-C6alkyl)2, (CH2)I.2-OH, C(O)(CH2)i.2-OH, C(O)(Ci-C6alkyl), and C(O)O(Ci-C6alkyl);R8is, independently at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)I- OH, S(O)0.2H, S(0)O-2NH2, and CN;R9is independently, at each occurrence, selected from the group consisting of H, halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy;R10is, independently at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)I- OH, S(O)0.2H, S(0)o-2NH2, and CN; and n is 0, 1 , 2, or 3.

2. The compound of claim 1 , wherein A is CH2.

3. The compound of claim 1 , wherein A is CH.

4. The compound of claim 1 , wherein = indicates a single bond.

5. The compound of claim 1 , wherein = indicates a double bond.

6. The compound of any one of claims 1-5, wherein R1is 5-10 membered heteroaryl optionally substituted with one, two, or three R8.

7. The compound of any one of claims 1-6, wherein R1is thiazolyl or pyridinyl, both of which are optionally substituted with one, two, or three R8.

8. The compound of any one of claims 1-7, R1is selected from the group consisting of:both of which are optionally substituted with one, two, or three R8.

9. The compound of any one of claims 1-8, wherein the compound of Formula I is a compound of Formula la:or a pharmaceutically acceptable salt thereof.

10. The compound of any one of claims 1-8, wherein the compound of Formula I is a compound of Formula lb:or a pharmaceutically acceptable salt thereof.11 . The compound of any one of claims 1-8, wherein the compound of Formula I is a compound of Formula Id:(Id) or a pharmaceutically acceptable salt thereof.

12. The compound of any one of claims 1-11 , wherein when X is CR3, then Y is CH.

13. The compound of any one of claims 1-11 , wherein when Y is CR3, then X is CH.

14. The compound of any one of claims 1-3 and 5-13, wherein A’ is N.

15. The compound of any one of claims 1-3 and 5-13, wherein A’ is CH.

16. The compound of any one of claims 1-4 and 6-13, wherein A’ is CH2.

17. The compound of any one of claims 1-4 and 6-13, wherein A’ is O.

18. The compound of any one of claims 1-8 and 12-17, wherein Z is CH or C-halo.

19. The compound of any one of claims 1-18, wherein R2is halogen or C1-C3 alkyl.

20. The compound of any one of claims 1-19, wherein R3is 6-10 membered aryl substituted with one or two R5.21 . The compound of any one of claims 1-20, wherein R5is 4-7 membered heterocyclyl optionally substituted one, two, or three times with R7.

22. The compound of any one of claims 1-21 , wherein R3is23. The compound of any one of claims 1-22, wherein R7is Ci-C6alkyl.

24. The compound of any one of claims 1-23, wherein n is 0 or 1.

25. The compound of claim 1 , wherein= indicates a single bond or a double bond;A and A’ are each, independently, CH, CH2, O, or N;W and Z are each, independently, CH or CR9;X and Y are each, independently, CH or CR3;R1is 5-10 membered heteroaryl optionally substituted with one, two, or three R8;R2is halogen or C1-C3 alkyl; alternatively, two R2, together with the atom to which they are attached, form 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;R3is 6-10 membered aryl substituted with one or two R5;R5is 4-7 membered heterocyclyl optionally substituted one, two, or three times withR7;R7is Ci-C6alkyl;R8is, independently at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)I-4OH , S(O)0.2H, S(O)Q-2NH2, and CN;R9is independently, at each occurrence, selected from the group consisting of halo, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkoxy; and n is 0 or 1.

26. The compound of any one of claims 1-25, wherein the compound of Formula I is selected from the group consisting ofor a pharmaceutically acceptable salt27. A compound of Formula II:or a pharmaceutically acceptable salt thereof;A and A’ are each, independently, CH, CR10, or N;R1is selected from the group consisting of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, and 3-10 membered cycloalkyl, all of which are optionally substituted with one, two, or three R8; each R2is independently selected from the group consisting of Ci-C3alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, Ci-C3alkylamine, halogen, OH, NO2, NH2, NH(Ci- C6alkyl), N(CI-C6alkyl)2, (CH2)I.4OH, S(O)0-2H, S(O)0.2NH2, CN, and 3-10 membered cycloalkyl; alternatively, two R2, together with the atom to which they are attached, form 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;R3is, independently at each occurrence, selected from the group consisting of halogen, OR4, NR4R4, SO2R4, SO2NHR4, NHSO2R4, C(O)OR4, C(O)NHR4, C(O)R4, Ci-C6alkyl, C2-Ce alkenyl, C2-Ce alkynyl, 3-7 membered cycloalkyl, C4-C7 cycloalkenyl, Ce-C-io aryl, 5-6 membered heteroaryl, and 4-7 membered heterocyclyl, wherein alkyl, alkenyl, or alkynyl are each optionally substituted one, two, or three times with R4, and wherein aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R5;R4is, independently at each occurrence, selected from the group consisting of H, Ci- C6alkyl, (CH2)O.3-(C3-C7 cycloalkyl), (CH2)0.3-(C4-C7 cycloalkenyl), (CH2)O-3-(C6-CIO aryl), (CH2)O-3-(5-6 membered heteroaryl), and (CH2)o-3-(4-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times withR5is independently, at each occurrence, selected from the group consisting of Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, C1-C3 alkylamine, 3-10 membered cycloalkyl, halogen, COOH, C(O)O(Ci-C6alkyl), O(CH2)I-3-OH, NH2, NH(CI-C6alkyl), N(Ci- C6alkyl)2, OH, CN, (CH2)O-3-(C6-CIO aryl), (CH2)0-3-(5-6 membered heteroaryl), and (CH2)0-3- (4-7 membered heterocyclyl), wherein the aryl, heteroaryl, or heterocyclyl are each optionally substituted one, two, or three times with R7;R6is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NO2, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)i.4OH, S(O)0-2H, S(O)0.2NH2, or CN;R7is, independently at each occurrence, selected from the group consisting of substituents independently selected from Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy, Ci-C6haloalkoxy, halogen, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, SO2NH2, SO2NH(CI-C6alkyl), SO2N(Ci-C6alkyl)2, (CH2)i.2-OH, C(O)(CH2)i.2-OH, C(O)(Ci-C6alkyl), and C(O)O(Ci-C6alkyl);R8is, independently at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)I-4OH , S(O)0.2H, S(O)0-2NH2, and CN;R10is, independently at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, 3-6 membered cycloalkyl, halogen, OH, NO2, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)I-4OH , S(O)0.2H, S(O)0-2NH2, and CN; and n is 0, 1 , 2, or 3.

28. The compound of claim 27, wherein R1is 5-10 membered heteroaryl optionally substituted with one, two, or three R8.

29. The compound of claim 27 or 28, wherein R1is thiazolyl or pyridinyl, both of which are optionally substituted with one, two, or three R8.

30. The compound of any one of claims 27-29, wherein R1is selected from the group consisting of:both of which are optionally substituted with one, two, or three R8.31 . The compound of any one of claims 27-30, wherein the compound of Formula II is a compound of Formula Ila:or a pharmaceutically acceptable salt thereof.

32. The compound of any one of claims 27-31 , wherein A’ is N.

33. The compound of any one of claims 27-31 , wherein A’ is CH.

34. The compound of any one of claims 27-33, wherein R2is halogen.

35. The compound of any one of claims 27-34, wherein R3is 6-10 membered aryl substituted with one or two R5.

36. The compound of any one of claims 27-35, wherein R5is 4-7 membered heterocyclyl optionally substituted one, two, or three times with R7.

37. The compound of any one of claims 27-36, wherein R3is38. The compound of any one of claims 27-37, wherein R7is Ci-C6alkyl.

39. The compound of any one of claims 27-38, wherein n is 0 or 1 .

40. The compound of claim 27, whereinA and A’ are each, independently, CH or N;R1is 5-10 membered heteroaryl optionally substituted with one, two, or three R8;R2is halogen; alternatively, two R2, together with the atom to which they are attached, form 3-10 membered cycloalkyl or 3-10 membered heterocycloalkyl;R3is 6-10 membered aryl substituted with one or two R5;R5is 4-7 membered heterocyclyl optionally substituted one, two, or three times with R7;R7is Ci-C6alkyl;R8is independently, at each occurrence, selected from the group consisting of C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 alkylamine, halogen, OH, NH2, NH(CI-C6alkyl), N(CI-C6alkyl)2, (CH2)I-4OH , S(O)0.2H, S(O)0.2NH2, and ON; and n is 0 or 1.41 . The compound of any one of claims 27-40, wherein the compound of Formula II is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

42. A pharmaceutical composition comprising a compound of any one of claims 1-41 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

43. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42.

44. The method according to claim 43, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, breast cancer, endometrial cancer, thyroid cancer, glioma, squamous cell carcinoma, and prostate cancer.

45. The method according to claim 43, wherein the cancer is non-small cell lung cancer (NSCLC).

46. The method according to any one of claims 43-45, wherein the method further comprises administering a second active agent.

47. A method of inhibiting a kinase in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42.

48. The method according to claim 47, wherein the kinase is EGFR.

49. A method of treating a kinase-mediated disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-41 or the pharmaceutical composition according to claim 42.

50. The method according to claim 49, wherein the kinase-mediated disorder is an EGFR-mediated disorder.