Combination therapy including KIT inhibitors for use in cancer treatment

Abstract

This disclosure relates to methods and compositions for treating conditions associated with abnormal KIT activity (e.g., cancer). The methods and compositions described herein generally include compounds of formula (I) and M4205 or THE-630.

Claims

1. M4205: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, Compound of formula (I): 【Chemistry 2】 (In the formula: R １ and R １Ａ These are H, halogen, and CH ３ Each is independently selected from, or R １ and R １Ａ They, together with the carbon atoms to which they are bonded, form a cyclopropyl; R ２ is selected from C １～５ alkyl, CD ３ , C ３～６ cycloalkyl, bicyclo[1.1.1]pentane, and a 4- to 6-membered heterocycle containing O, wherein the alkyl, cycloalkyl or heterocycle may be substituted with 1 to 3 R ４ ; Each R ４ Halogen, CH ３ , C ２～３ Alkenyl, OH, CH ２ OH, C ４～６ A cycloalkyl group is independently selected from a 4- to 6-membered heterocycle containing oxygen, and a phenyl group, where the alkyl group, cycloalkyl group, heterocycle, or phenyl group is either OH or NH. ２ , C １～２ Alkyl, CH ２ NH ２ , or they may be substituted with halogens; R ３ C(O)NHR ５ , 【Transformation 3】 And; X １ is either NH or O; X ２ is N or CH; X ３ is N or CH; R ５ H, C １～３ Alkyl, CD ３ , C ３～４ Selected from cycloalkyl and bicyclo[1.1.1]pentane, where the alkyl, cycloalkyl, or bicyclo[1.1.1.]pentane has 1 to 2 R ７ It is also fine if it is replaced with; Each R ７ CN, NH ２ OH, CH ２ Two R groups independently selected from OH, cyclopropyl, pyridinyl, and oxazolyl, or bonded to the same carbon atom. ７ Together with it, it forms a four-membered heterocycle containing N; R ６ C １～５ Alkyl, CHF ２ CF ３ , a four- or five-membered heterocycle containing N or O, and C ３～４ Independently selected from cycloalkyl groups, where the alkyl or heterocycle is one R group. ８ It is also fine if it is replaced with; R ８ OH, NR ９ R ９ , OCH ３ ,CH ３ , and a four-membered heterocycle containing N or O, independently selected, wherein the alkyl or heterocycle is one R １０ It is also fine if it is replaced with; Each R ９ H, CH ３ and CH ２ CF ３ Selected independently of; R １０ CH ３ and CF ３ (Selected from) or a pharmaceutically acceptable salt thereof A method for treating cancer in a subject requiring it, including administering it to that subject.

2. The method according to claim 1, wherein the method comprises administering an effective amount of M4205 or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 or 2, wherein M4205 is administered in an amount of approximately 100 mg to approximately 2000 mg per dose.

4. The method according to any one of claims 1 to 3, wherein M4205 is administered orally.

5. The method according to any one of claims 1 to 4, wherein M4205 and the compound of formula (I) are administered simultaneously.

6. The method according to any one of claims 1 to 4, wherein M4205 and the compound of formula (I) are administered sequentially.

7. The method according to any one of claims 1 to 6, wherein M4205 is administered to the subject daily.

8. The method according to any one of claims 1 to 7, wherein M4205 is administered to the subject once daily.

9. The method according to any one of claims 1 to 7, wherein M4205 is administered to the subject twice a day.

10. The method according to any one of claims 1 to 9, wherein administering M4205 and a compound of formula (I) reduces tumor size compared to administering M4205.

11. The method according to any one of claims 1 to 9, wherein administering M4205 and a compound of formula (I) reduces tumor size compared to administering a compound of formula (I).

12. THE-630 or its pharmaceutically acceptable salts, Compound of formula (I): 【Chemistry 4】 (In the formula: R １ and R １Ａ These are H, halogen, and CH ３ Each is independently selected from, or R １ and R １Ａ They, together with the carbon atoms to which they are bonded, form a cyclopropyl; R ２ C １～５ Alkyl, CD ３ , C ３～６ Selected from cycloalkyl, bicyclo[1.1.1]pentane, and 4- to 6-membered heterocycles containing O, where the alkyl, cycloalkyl, or heterocycle contains 1 to 3 R ４ It is also fine if it is replaced with; Each R ４ Halogen, CH ３ , C ２～３ Alkenyl, OH, CH ２ OH, C ４～６ A cycloalkyl group is independently selected from a 4- to 6-membered heterocycle containing oxygen, and a phenyl group, where the alkyl group, cycloalkyl group, heterocycle, or phenyl group is either OH or NH. ２ , C １～２ Alkyl, CH ２ NH ２ , or they may be substituted with halogens; R ３ C(O)NHR ５ , 【Transformation 5】 And; X １ is either NH or O; X ２ is N or CH; X ３ is N or CH; R ５ H, C １～３ Alkyl, CD ３ , C ３～４ Selected from cycloalkyl and bicyclo[1.1.1]pentane, where the alkyl, cycloalkyl, or bicyclo[1.1.1.]pentane has 1 to 2 R ７ It is also fine if it is replaced with; Each R ７ CN, NH ２ OH, CH ２ Two R groups independently selected from OH, cyclopropyl, pyridinyl, and oxazolyl, or bonded to the same carbon atom. ７ Together with it, it forms a four-membered heterocycle containing N; R ６ is independently selected from C １～５ alkyl, CHF ２ , CF ３ , a 4- or 5-membered heterocyclic ring containing N or O, and C ３～４ cycloalkyl, wherein the alkyl or heterocyclic ring may be substituted with one R ８ ; R ８ is independently selected from OH, NR ９ R ９ OCH ３ CH ３ and a 4-membered heterocyclic ring containing N or O, wherein the alkyl or heterocyclic ring may be substituted with one R １０ ; Each R ９ H, CH ３ and CH ２ CF ３ Selected independently of; R １０ CH ３ and CF ３ (Selected from) or a pharmaceutically acceptable salt thereof A method for treating cancer in a subject requiring it, including administering it to that subject.

13. The method according to claim 12, wherein the method comprises administering an effective amount of THE-630 or a pharmaceutically acceptable salt thereof.

14. The method according to claim 12 or 13, wherein THE-630 is administered in an amount of approximately 0.1 mg to approximately 200 mg per dose.

15. The method according to any one of claims 12 to 14, wherein THE-630 is administered orally.

16. The method according to any one of claims 12 to 15, wherein THE-630 and the compound of formula (I) are administered simultaneously.

17. The method according to any one of claims 12 to 15, wherein THE-630 and the compound of formula (I) are administered sequentially.

18. The method according to any one of claims 12 to 17, wherein THE-630 is administered to the subject daily.

19. The method according to any one of claims 12 to 18, wherein THE-630 is administered to the subject once daily.

20. The method according to any one of claims 12 to 18, wherein THE-630 is administered to the subject twice a day.

21. The method according to any one of claims 12 to 20, wherein administering THE-630 and a compound of formula (I) reduces tumor size compared to administering THE-630.

22. The method according to any one of claims 12 to 20, wherein administering THE-630 and a compound of formula (I) reduces tumor size compared to administering a compound of formula (I).

23. The method according to any one of claims 1 to 22, wherein the method comprises administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

24. The method according to any one of claims 1 to 22, wherein the compound of formula (I) is administered in an amount of about 0.1 mg to about 200 mg per dose.

25. The method according to any one of claims 1 to 22, wherein the compound of formula (I) is administered orally.

26. The method according to any one of claims 1 to 22, wherein the compound of formula (I) is administered to the subject daily.

27. The method according to any one of claims 1 to 22, wherein the compound of formula (I) is administered to the subject once daily.

28. The method according to any one of claims 1 to 22, wherein the compound of formula (I) is administered to the subject twice a day.

29. The method according to any one of claims 1 to 11 and 23 to 28, wherein administering M4205 and a compound of formula (I) reduces tumor size compared to administering a compound of formula (I).

30. The method according to any one of claims 12 to 28, wherein administering THE-630 and a compound of formula (I) reduces tumor size compared to administering a compound of formula (I).

31. The method according to any one of claims 1 to 30, wherein the compound of formula (I) is a compound selected from Table 1 or a pharmaceutically acceptable salt thereof.

32. The method according to any one of claims 1 to 30, wherein the compound of formula (I) is a compound selected from Table 2 or a pharmaceutically acceptable salt thereof.

33. The method according to any one of claims 1 to 32, wherein the subject is resistant to or has acquired resistance to anticancer treatment.

34. The method according to claim 33, wherein anticancer treatment is the administration of an anticancer drug.

35. The method according to claim 34, wherein the anticancer drug is a KIT inhibitor.

36. The method according to claim 34 or 35, wherein the anticancer agent is selected from imatinib, sunitinib, regorafenib, and lipretinib, their pharmaceutically acceptable salts, and combinations thereof.

37. The method according to any one of claims 1 to 32, wherein the subject is resistant to or has acquired resistance to one or more anticancer treatments.

38. The method according to claim 37, wherein each anti-cancer treatment is the administration of an anti-cancer drug.

39. The method according to claim 38, wherein the anticancer drug is a KIT inhibitor.

40. The method according to claim 38 or 39, wherein each of the anticancer agents is independently selected from imatinib, sunitinib, regorafenib, and lipretinib, and combinations thereof.

41. The method according to any one of claims 1 to 40, wherein the subject is undergoing anti-cancer treatment.

42. The method according to claim 41, wherein anticancer treatment is the administration of an anticancer drug.

43. The method according to claim 42, wherein the anticancer drug is a KIT inhibitor.

44. The method according to claim 42 or 43, wherein the anticancer agent is selected from imatinib, sunitinib, regorafenib, and lipretinib, their pharmaceutically acceptable salts, and combinations thereof.

45. The method according to any one of claims 1 to 44, wherein the subject is in a fasting state.

46. The method according to any one of claims 1 to 44, wherein the compound of formula (I) is administered with a meal.

47. The method according to any one of claims 1 to 44, wherein the compound of formula (I) is administered approximately 30 minutes to approximately 1 hour after a meal.

48. The method according to any one of claims 1 to 11 and 23 to 47, wherein M4205 is administered with a meal.

49. The method according to any one of claims 1 to 11 and 23 to 47, wherein M4205 is administered approximately 30 minutes to approximately 1 hour after a meal.

50. The method according to any one of claims 12 to 47, wherein THE-630 is administered with a meal.

51. The method according to any one of claims 12 to 47, wherein THE-630 is administered approximately 30 minutes to approximately 1 hour after a meal.

52. The method according to any one of claims 1 to 51, wherein the compound of formula (I) is a compound of Table 1 or a pharmaceutically acceptable salt thereof.

53. The method according to any one of claims 1 to 51, wherein the compound of formula (I) is a compound of Table 2 or a pharmaceutically acceptable salt thereof.

54. The method according to any one of claims 1 to 53, wherein the cancer is selected from gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminomas, renal cell carcinoma, intracranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

55. The method according to any one of claims 1 to 53, wherein the cancer is a gastrointestinal stromal tumor (GIST).

56. The method according to claim 54 or 55, wherein the GIST is characterized by a tumor having one or more KIT mutations.

57. The method according to claim 56, wherein the tumor has a primary activated KIT mutation.

58. The method according to claim 56 or 57, wherein the GIST is characterized by a tumor having one or more KIT mutations independently selected from exon 9 KIT mutations, exon 11 KIT mutations, exon 13 KIT mutations, exon 14 KIT mutations, and exon 17 KIT mutations, and combinations thereof.

59. The method according to claim 58, wherein each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, K642E, V654A, and N655K, and combinations thereof.

60. The method according to claim 58, wherein the tumor has an exon 9 KIT mutation.

61. The method according to claim 58, wherein the tumor has an exon 11 KIT mutation.

62. The method according to claim 58, wherein the tumor has an exon 13 KIT mutation.

63. The method according to claim 62, wherein the exon 13 KIT mutation is selected from K642E, V654A, and N655K, and combinations thereof.

64. The method according to claim 58, wherein the tumor has an exon 14 KIT mutation.

65. The method according to claim 64, wherein the exon 14 KIT mutation is T670I.

66. The method according to claim 58, wherein the tumor has an exon 17 KIT mutation.

67. The method according to claim 66, wherein the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D.

68. The method according to any one of claims 57 to 67, wherein the tumor is resistant to or has acquired resistance to anticancer treatment.

69. The method according to claim 68, wherein anticancer treatment is the administration of an anticancer drug.

70. The method according to claim 69, wherein the anticancer drug is a KIT inhibitor.

71. The method according to claim 69, wherein the anticancer agent is selected from imatinib, sunitinib, regorafenib, and lipretinib, their pharmaceutically acceptable salts, and combinations thereof.

72. The method according to any one of claims 57 to 67, wherein the tumor is resistant to or has acquired resistance to one or more anticancer treatments.

73. The method according to claim 72, wherein each anti-cancer treatment is the administration of an anti-cancer drug.

74. The method according to claim 73, wherein the anticancer drug is a KIT inhibitor.

75. The method according to claim 73, wherein each anticancer agent is independently selected from imatinib, sunitinib, regorafenib, and lipretinib, their pharmaceutically acceptable salts, and combinations thereof.

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