(1H-PYRROLO[2,3-B]PYRIDIN-1-YL)PYRIMIDIN-2-YL-AMINO-PHENYL-ACRYLAMIDE INHIBITORS OF EGFR FOR USE IN THE TREATMENT OF BRAIN TUMORS

20240293405

18/573473

June 22, 2022

The invention generally relates to pharmaceuticals and therapeutic methods. More particularly, the invention provides small molecule EGFR inhibitors (e.g., EGFR tyrosine kinase inhibitor compounds) and pharmaceutical compositions thereof, as well as methods of their use in treating various diseases and conditions, such as cancers of the central nervous system (e.g., primary and metastatic brain cancers) and lung cancers.

1. A method of treating glioblastoma multiforme, astrocytoma, congenital tumor of the brain, ependymoma, germinoma, glioma, gliomatosis, gliosarcoma, medulloblastoma, meningioma, meningiosarcoma, oligodendroglioma, pinealoma, retinoblastoma, schwannoma, or spinal cord neurofibroma, comprising administering to a human subject in need thereof a therapeutically effective amount of a compound of Formula I: [chemical expression included] or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein the therapeutically effective amount is at least 100 mg/day, and wherein: Z1, Z2, and Z3 are each independently N or CR8, wherein at least two of Z1, Z2, and Z3 are N; R8 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen; R1 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, or halogen; R2 is H or (C1-C6) alkyl; R3 is (C1-C4) alkoxy, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen; R4 is NR9R10 or a 5- to 7-membered heterocycle comprising 1-3 heteroatoms selected from N, O, and S and optionally substituted with one or more R11; R9 is H or (C1-C4) alkyl; R10 is (C1-C4) alkyl, (C1-C4) alkyl-NH(C1-C4) alkyl, or (C1C4) alkyl-N((C1-C4) alkyl)2; or R9 and R10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R11; each R1 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or halogen; R5 is NR12C(O)R13 or C(O)NR12R13; R12 is H or (C1-C6) alkyl; R13 is (C1-C6) alkyl or (C2-C6) alkenyl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from halogen, OH, CN, and NH2; R6 and R7 together with the nitrogen atom to which they are attached form a substituent of the formula, [chemical expression included] wherein X3 is N; X1, X2, X4, X5 and X6 are each independently CH or CR15; and each R15 is independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, OH, NH2, NH(C1-C6) alkyl, N((C1-C6) alkyl)2, or halogen.

2. The method of claim 1, wherein the subject does not lose more than 10% of its body weight within 1 month after administration.

3. The method of claim 1, wherein the therapeutically effective amount of the compound is administered daily to the subject for at least 1 month; and subject does not lose more than 10% of its body weight within 1 month of daily administration.

4. The method of any one of claims 1-3, wherein the therapeutically effective amount is from 100 mg/day to 1000 mg/day.

5. The method of any one of claims 1-3, wherein the therapeutically effective amount is from 100 mg/day to 800 mg/day.

6. The method of any one of claims 1-3, wherein the therapeutically effective amount is from 100 mg/day to 500 mg/day.

7. The method of any one of claims 1-3, wherein the therapeutically effective amount is from 200 mg/day to 500 mg/day.

8. The method of any one of claim 1-7, further comprising examining the skin of the subject within 1 month after administration, wherein the subject does not exhibit skin lesions within 1 month after administration.

9. The method of any one of claim 1-7, further comprising examining the skin of the subject within 2 months after administration, wherein the subject does not exhibit skin lesions within 2 months after administration.

10. The method of any one of claim 1-9, wherein the method is a method of treating glioblastoma multiforme.

11. The method of claim 10, wherein the glioblastoma multiforme is characterized by elevated levels of EGFR and/or mutated EGFR.

12. The method of claim 10 or claim 11, wherein the compound of Formula I is not a substrate of an efflux transporter.

13. The method of claim 11, wherein the compound of Formula I is characterized by a binding affinity for EGFR and/or mutated EGFR in the subject of no more than 10 nM, such as no more than 9 nM, no more than 8 nM, no more than 7 nM, no more than 6 nM, no more than 5 nM, no more than 4 nM, no more than 3 nM, no more than 2 nM, no more than 1 nM, no more than 0.9 nM, no more than 0.8 nM, no more than 0.7 nM, no more than 0.6 nM, no more than 0.5 nM, no more than 0.4 nM, no more than 0.3 nM, no more than 0.2 nM, no more than 0.15 nM, no more than 0.12 nM, no more than 0.11 nM, or no more than 0.10 nM.

14. The method of any one of claim 1-9, wherein the method is a method of treating an astrocytoma.

15. The method of any one of claims 1-14, wherein Z1 and Z2 are each N and Z3 is CR8.

16. The method of any one of claims 1-15, wherein R1 is H or NH2.

17. The method of any one of claims 1-16, wherein R2 is H.

18. The method of any one of claims 1-17, wherein R3 is (C1-C4) alkoxy.

19. The method of any one of claims 1-18, wherein R4 is NR9R10.

20. The method of any one of claims 1-19, wherein R5 is NR12C(O)R13.

21. The method of any one of claims 1-20, wherein R15 is selected from (C1-C6) alkyl and (C1-C6) haloalkyl.

22. The method of claim 21, wherein R15 is selected from methyl and CF3.

23. The method of any one of claims 1-22, wherein R8 is H or halogen.

24. The method of any one of claims 1-23, wherein R9 is (C1-C4) alkyl.

25. The method of any one of claims 1-24, wherein R10 is (C1-C4) alkyl-NH(C1-C4) alkyl, or (C1-C4) alkyl-N((C1-C4) alkyl)2.

26. The method of any one of claims 1-25, wherein R4 is NR9R10 and R9 and R10 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more R11.

27. The method of any one of claims 1-26, wherein R11 is (C1-C4) alkyl, R12 is H, and R13 is (C2-C6) alkenyl.

28. The method of any one of claims 1-26, wherein Ru is (C1-C4) alkyl, R12 is (C1-C6) alkyl, and R13 is (C2-C6) alkenyl.

29. The method of any one of claims 1-14, wherein the compound of Formula I is a compound of Formula Ia: [chemical expression included] or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein: X1, X2, X4, X5 and X6 are each independently CR15; R91 is (C1-C4) alkyl; R101 is (C1-C4) alkyl-NH(C1-C4) alkyl or (C1-C4) alkyl-N((C1-C4) alkyl)2; or R91 and R101 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocycle optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more Rn.

30. The method of any one of claims 1-14, wherein the compound is selected from the group consisting of: N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide; N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide; N-(4-methoxy-2-(4-methylpiperazin-1-yl)-5-((4-(3-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)phenyl)acrylamide; N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl)acrylamide; and N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(3-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl) pyrimidin-2-yl)amino)phenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

31. The method of any one of claims 1-14, wherein the compound is N-(5-((4-(1H-pyrrolo[2,3-b]pyridin-1-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

32. The method of any one of claims 1-31, wherein the compound is administered once per day.

33. The method of any one of claims 1-31, wherein the compound is administered two times per day.

34. The method of any one of claims 1-31, wherein the compound is administered three times per day.

35. The method of any one of claims 1-34, wherein the compound is administered systemically.

36. The method of claim 35, wherein the compound is administered orally.

37. The method of claim 35, wherein the compound is administered intravenously.

38. A method for treating or reducing a brain tumor, or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 1: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

39. A method for inhibiting or reducing the activity of epidermal growth factor receptor (EGFR) in a subject suffering from a brain tumor, comprising administering to the subject a therapeutically effective amount of a compound having the formula of Compound 1: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

40. A method for treating or reducing a brain disease or condition mediated by epidermal growth factor receptor (EGFR), comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 1: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

41. The method of any one of claims 38-40, wherein the brain tumor comprises a primary tumor.

42. The method of any one of claims 38-40, wherein the brain tumor comprises a metastatic tumor.

43. The method of claim 41, wherein the brain tumor is glioblastoma.

44. The method of any one of claims 38-43, wherein the therapeutically effective amount is in the range from about 0.1 to about 20 mg/kg body weight daily.

45. The method of claim 44, wherein the therapeutically effective amount is in the range from about 0.5 to about 5 mg/kg body weight daily.

46. A pharmaceutical composition for treating a brain tumor, or a related disease or condition, comprising a compound having the formula of Compound 1: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

47. The pharmaceutical composition of claim 46, wherein the brain tumor comprises a primary tumor.

48. The pharmaceutical composition of claim 46, wherein the brain tumor comprises a metastatic tumor.

49. The pharmaceutical composition of claim 47, wherein the brain tumor is glioblastoma.

50. A compound having the structural formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

51. A pharmaceutical composition comprising a compound having the structural formula of Compound 2 [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof, and a pharmaceutically acceptable excipient, carrier, or diluent.

52. The pharmaceutical composition of claim 51, being suitable for oral administration.

53. The pharmaceutical composition of claim 51, being suitable for intravenous administration.

54. The pharmaceutical composition of any one of claims 51-53, suitable for use in treating a disease or condition selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas and myelomas.

55. A unit dosage form comprising a pharmaceutical composition of any one of claims 51-54.

56. A method for treating or reducing a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

57. A method for inhibiting or reducing the activity of epidermal growth factor receptor (EGFR) in a subject suffering from a disease or condition related thereto, comprising administering to the subject a therapeutically amount of a compound having the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

58. A method for treating or reducing a disease or condition mediated by epidermal growth factor receptor (EGFR), comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

59. The method of any one of claims 56-58, wherein the disease or condition is a cancer.

60. The method of any one of claims 56-59, wherein the cancer is selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas and myelomas.

61. The method of claim 60, wherein the cancer comprises a primary tumor.

62. The method of claim 60, wherein the cancer comprises a metastatic tumor.

63. The method of claim 60, wherein the cancer is glioblastoma.

64. The method of claim 60, wherein the cancer is lung cancer.

65. The method of claim 64, wherein the cancer is non-small cell lung cancer (NSCLC).

66. The method of claim 64, wherein the cancer is small cell lung cancer (SCLC).

67. The methods of any one of claims 56-66, wherein the subject carries an EGFR mutation.

68. The method of claim 67, wherein the subject carries T790M EGFR mutation.

69. The method of any one of claims 58-68, wherein the therapeutically effective amount is in the range from about 0.1 to about 20 mg/kg body weight daily.

70. The method of claim 69, wherein the therapeutically effective amount is in the range from about 0.5 to about 5 mg/kg body weight daily.

71. A method for treating or reducing a brain tumor, or a related disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

72. A method for inhibiting or reducing the activity of epidermal growth factor receptor (EGFR) in a subject suffering from a brain tumor, comprising administering to a subject in need thereof a therapeutically amount of a compound having the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

73. A method for treating or reducing a brain disease or condition mediated by epidermal growth factor receptor (EGFR), comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

74. The method of claim 73, wherein the brain tumor comprises a primary tumor.

75. The method of claim 73, wherein the brain tumor comprises a metastatic tumor.

76. The method of any one of claims 71-73, wherein the brain tumor is glioblastoma.

77. Use of a compound or a pharmaceutical composition thereof for treating or reducing a brain tumor, or a related disease or condition, wherein the compound has the formula of Compound 1: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

78. Use of a compound or a pharmaceutical composition thereof for inhibiting or reducing the activity of epidermal growth factor receptor (EGFR) in a subject suffering from a brain tumor, wherein the compound has the formula of Compound 1: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

79. Use of a compound or a pharmaceutical composition thereof for treating or reducing a brain disease or condition mediated by epidermal growth factor receptor (EGFR), comprising administering to the subject in need thereof a therapeutically effective amount of a compound having the formula of Compound 1: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

80. Use of any one of claims 77-79, wherein the brain tumor comprises a primary tumor.

81. Use of any one of claims 77-79, wherein the brain tumor comprises a metastatic tumor.

82. Use of any one of claims 77-79, wherein the brain tumor is glioblastoma.

83. Use of a compound or a pharmaceutical composition thereof for treating or reducing a disease or condition, wherein the compound has the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

84. Use of a compound or a pharmaceutical composition thereof for inhibiting or reducing the activity of epidermal growth factor receptor (EGFR) in a subject suffering from a disease or condition related thereto, wherein the compound has the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

85. Use of a compound or a pharmaceutical composition thereof for treating or reducing a disease or condition mediated by epidermal growth factor receptor (EGFR), wherein the compound has the formula of Compound 2: [chemical expression included] or a pharmaceutically acceptable form or an isotope derivative thereof.

86. Use of any one of claims 83-85, wherein the disease or condition is a cancer.

87. Use of claim 86, wherein the cancer is selected from lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas and myelomas.

88. Use of claim 87, wherein the brain tumor comprises a primary tumor.

89. Use of claim 87, wherein the brain tumor comprises a metastatic tumor.

90. Use of claim 87, wherein the cancer is glioblastoma.

91. Use of claim 87, wherein the cancer is lung cancer.

92. Use of claim 91, wherein the cancer is non-small cell lung cancer (NSCLC).

61; 07

edspap.20240293405