SELECTIVE INHIBITORS OF CLINICALLY IMPORTANT MUTANTS OF THE EGFR TYROSINE KINASE

• US 20200131176A1
• Filed: 07/05/2018
• Published: 04/30/2020
• Est. Priority Date: 07/05/2017
• Status: Active Application

• Current Assignee: CS Pharmatech Limited
• Original Assignee: CS Pharmatech Limited
• Inventors: SONG, Yuntao, BRIDGES, Alexander James, CHEN, Xiaoqi
• Application Number:
  US16/628,831
• Publication Number:
  US 20200131176A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 495/04 Ortho-condensed systems

Abstract

The present invention provides compounds of Formula (I) or a subgeneric structure or species thereof, or a pharmaceutically acceptable salt, ester, solvate, and/or prodrug thereof, and methods and compositions for treating or ameliorating abnormal cell proliferative disorders, such as cancer, wherein A, R², R³, R¹⁰, E¹, E², E³, Y, and Z are as defined herein.

Claims

1. A compound of formula (A) or (B):

2. The compound of claim 1, wherein the compound has the structure of formula (A):

3. The compound of claim 1 or 2, wherein R³ is —

N(CH₃)CH₂CH₂NR¹⁰R¹⁰.

4. The compound of any one of claims 1-3, wherein R¹⁰ is each independently H, —

CD₃, C_1-6 alkyl, C_3-6 cycloalkyl, or C_2-6 hydroxyalkyl.

5. The compound of any one of claims 1-3, wherein R¹⁰ is each independently H, —

CD₃, methyl, ethyl, or isopropyl.

6. The compound of any one of claims 1-5, wherein Y is

7. The compound of claim 6, wherein R^5a, R^6e, and R^6z are each H.

8. The compound of any one of claims 1-7, wherein R^4a is H, —

C_1-6 alkyl, or —

NR⁸R⁹.

9. The compound of claim 8, wherein R⁸ and R⁹ are independently H, —

CD₃, or C_1-6 alkyl.

10. The compound of any one of claims 1-9, wherein R^4b and R^4c are each independently H, cyano, F, Cl, Br, —

C_1-6 alkyl, CF₃, CHF₂, CONH₂ or C(═

O)NR⁸R⁹.

11. The compound of any one of claims 1-10, wherein R^4b and R^4c are each independently H, cyano, F, Cl, Br, CH₃, CF₃, CHF₂, CONH₂ or C(═

O)NR⁸R⁹.

12. The compound of claim 1, wherein the compound has the structure of formula (C):

13. The compound of claim 12, wherein:

R¹ is hydrogen;

R² is methoxy, —

OCD₃, ethoxy, or isopropoxy;

R^4a is NR⁸R⁹;

R^4b is H, or CH₃;

R^4c is H, F, Cl, Br, or CH₃;

R⁸ and R⁹ are each independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂; and

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

14. The compound of claim 1, wherein the compound has the structure of formula (C-I):

15. The compound of claim 14, wherein:

R¹ is hydrogen;

R² is methoxy, —

OCD₃, ethoxy, or isopropoxy;

R^4a is NR⁸R⁹;

R^4b is H, or CH₃;

R^4c is H, F, Cl, Br, —

CF₃, —

CH₃, —

CH₂CH₃ or —

CH(CH₃)₂;

R⁸ and R⁹ are each independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂; and

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

16. The compound of any one of claims 1-15, wherein the compound is:

17. The compound of any one of claims 1-15, wherein the compound is:

55. A pharmaceutical composition comprising a compound of any one of claims 1-54 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, and a pharmaceutically acceptable carrier.

56. A method for treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-54 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

57. The method of claim 56, wherein the cancer is selected from lung cancer, colorectal cancer, pancreatic cancer, head and neck cancers, breast cancer, ovarian cancer, uterine cancer, liver cancer, and stomach cancer.

58. The method of claim 56 or 57, wherein the cancer is non-small cell lung cancer (NSCLC).

59. The method of claim 58, wherein the cancer results from a mutation in the exon 20 domain of EGFR.

60. The method claim 59, wherein the mutation in the exon 20 domain of EGFR is selected from NPG, ASV, or T790M.

61. The method of claim 60, wherein the mutation in the exon 20 domain of EGFR is T790M concurrent with an exon 19 insertion mutation or an exon 21 point mutation.

62. The method of any one of claims 56-61, wherein the patient is resistant to a kinase inhibitor other that a compound of any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

63. The method of claim 62, wherein the kinase inhibitor is an EGFR inhibitor.

64. A method for inhibiting EGFR, or a mutation thereof, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1-54, or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof.

65. The method of claim 64, wherein the mutation is in the exon 20 domain of EGFR.

18. A compound of formula (D):

22. The compound of any one of claims 18-21, wherein the compound is not:

23. The compound of any one of claims 18-21, wherein the compound is:

31. The compound of claim 18, wherein the compound has the structure of formula (H)

32. The compound of claim 31, wherein

X⁷ is CH or N;

X² is independently CH or CCH₃;

R² is methoxy, —

OCD₃, ethoxy, or isopropoxy;

R^4b is H, F, Cl, or CH₃;

R^4N is H, —

CD₃, CH₃, Et, or CH(CH₃)₂; and

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

33. The compound of claim 31 or 32, wherein the compound is:

34. The compound of claim 18, wherein the compound has the structure of formula (H-I):

35. The compound of claim 31, 32 or 34, wherein the compound is:

19. A compound of formula (D-I):

24. The compound of claim 19, wherein

X² is CH or CR⁴;

R⁴ is methyl, ethyl, or isopropyl;

R^4c is cyano, —

CF₃, Cl, or F;

R^4N is —

CD₃, methyl, ethyl, or isopropyl; and

R^4b is H, halo, methyl, ethyl, or isopropyl.

25. The compound of claim 19 or 24, wherein the compound is:

26. The compound of claim 19, wherein

X² is N;

R^4c is cyano, —

CF₃, Cl, or F;

R^4N is —

CD₃, methy-CF₃, Cl, or isopropyl; and

R^4b is H, halo, methyl, ethyl, or isopropyl.

27. The compound of claim 26, wherein the compound is

20. A compound of formula (E):

36. The compound of claim 20, wherein the compound has the structure of formula (J):

37. The compound of claim 36, wherein:

X⁶ is C—

CN;

X² is C—

H or C—

CH₃;

X³ is C—

H or C—

CH₃;

R^4N is H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂;

R² is methoxy, —

OCD₃, ethoxy, or isopropoxy;

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

38. The compound of claim 36 or 37, wherein the compound is:

39. The compound of claim 36 or 37, wherein the compound is:

21. A compound of formula (F) or (G):

28. A compound of formula (E-I):

29. The compound of claim 28, wherein

R³ is N(R¹⁰)C_2-6 alkyl-NR¹⁰R¹⁰ or —

N(R¹⁰)(C_3-10 cycloalkylalkyl)-NR¹⁰R¹⁰;

each R⁴ is independently H, cyano, halo, —

C_1-6 alkyl, or —

C_1-6 haloalkyl; and

R^4N is H, —

CD₃, or —

C_1-6 alkyl; and

each R¹⁰ is independently H, —

CD₃, or —

C_1-6 alkyl.

30. The compound of claim 28 or 29, wherein the compound is

40. A compound of formula (K):

41. The compound of claim 40, wherein the compound has the structure of formula (L):

42. The compound of claim 41, wherein:

X² is CR⁴a or N;

X⁶ is CR⁴b or N;

X⁸ is CH or N;

R² is methoxy, —

OCD₃, ethoxy, or isopropoxy;

R^4a is H, F, Cl, CH₃, CF₃, or CHF₂;

R^4b is H, cyano, nitro, halo, —

C_1-6 alkyl, or —

C_1-6 haloalkyl;

R^4N is H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂; and

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

43. The compound of claim 41, wherein:

X² is CR^4a or N;

X⁶ is CR⁴b;

X⁸ is CH;

R² is methoxy, —

OCD₃, ethoxy, or isopropoxy;

R^4a is H, F, CH₃, CF₃, or CHF₂;

R^4b is H, CH₃, F, Cl, CF₃, or CHF₂;

R^4N is H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂;

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

44. The compound of any one of claims 41-43, wherein the compound is:

45. A compound of formula (M):

46. The compound of claim 45, wherein:

Z is CH;

R¹ is hydrogen, methyl, fluoro, chloro, bromo, —

CF₃, or cyano;

R² is methoxy, —

OCD₃, ethoxy, or isopropoxy;

R³ is —

N(CH₃)CH₂CH₂NR¹⁰R¹⁰;

R^4a is —

NR⁸R⁹;

R^4b is H, CH₃, F, Cl, CF₃, or CHF₂;

R⁸ and R⁹ are independently H, —

CD₃, C_1-6 alkyl, C_3-8 cycloalkyl, C_3-8 cycloalkyl-(C_1-3 alkyl)-, C₁-C₆ acyl, phenyl, monocyclic heteroaryl, or monocyclic heterocyclyl; and

R⁸ and R⁹ may be further independently substituted with up to three substituents chosen from hydroxyl, C_1-6 alkoxy, oxo, thiono, cyano or halo; and

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

47. The compound of claim 45 or 46, wherein the compound is

48. A compound having the formula (N):

49. The compound of claim 48, wherein the compound has the structure of formula (O):

50. The compound of claim 48 or 49, wherein the compound is:

51. A compound of formula (P):

52. The compound of claim 51, wherein:

Z is CH or N;

R¹ is hydrogen, methyl, fluoro, chloro, bromo, —

CF₃, or cyano;

R³ is N(R¹⁰)C_2-6 alkyl-NR¹⁰R¹⁰;

each R⁴ is independently H, cyano, halo, —

C_1-6 alkyl, —

C_1-6 haloalkyl;

R^4a is independently H, cyano, nitro, halo, —

C_1-6 alkyl, —

C_1-6 haloalkyl, —

C_1-6 alkoxy, —

C_1-6 haloalkoxy, —

C(═

O)NR⁸R⁹, or —

NR⁸R⁹;

R⁸ and R⁹ are independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂; and

each R¹⁰ is independently H, —

CD₃, —

CH₃, —

CH₂CH₃, or —

CH(CH₃)₂.

53. The compound of claim 51 or 52, wherein the compound is:

54. A compound having the structure: