How to use MYT1 inhibitors

Abstract

This provides novel anti-cancer treatment methods, such as those utilizing small molecules, and in particular, therapies that enable targeted cancer treatment. [Solution] A method for treating cancer in a subject is provided, comprising administering a therapeutically effective amount of a membrane-bound tyrosine and threonine-specific cdc2 inhibitor kinase (Myt1) inhibitor to the subject in need thereof, wherein the cancer has been previously identified as a cancer in which CCNE1 is overexpressed.

Claims

1. A method for treating cancer in a subject, comprising administering a therapeutically effective amount of a membrane-bound tyrosine and threonine-specific cdc2 inhibitory kinase (Myt1) inhibitor to the subject in need thereof, wherein the cancer has been previously identified as a cancer in which CCNE1 is overexpressed.

2. A method for treating cancer in a subject, comprising administering a therapeutically effective amount of a Myt1 inhibitor to the subject in need thereof, wherein the cancer is a cancer in which CCNE1 is overexpressed.

3. A method for inducing cell death in cancer cells overexpressing CCNE1, comprising contacting the cells with an effective amount of a Myt1 inhibitor.

4. The method according to any one of claims 1 to 3, wherein the cancer is uterine cancer, ovarian cancer, breast cancer, gastric cancer, esophageal cancer, lung cancer, or endometrial cancer.

5. A method for treating cancer in a subject, comprising administering a therapeutically effective amount of a Myt1 inhibitor to the subject in need thereof, wherein the cancer has been previously identified as a cancer having an inactivating mutation in the FBXW7 gene.

6. A method for treating cancer in a subject, comprising administering a therapeutically effective amount of a Myt1 inhibitor to the subject in need thereof, wherein the cancer has an inactivating mutation in the FBXW7 gene.

7. A method for inducing cell death in FBXW7 mutant cancer cells, comprising contacting the cells with an effective amount of a Myt1 inhibitor.

8. The method according to any one of claims 5 to 7, wherein the cancer is uterine cancer, colorectal cancer, breast cancer, lung cancer, or esophageal cancer.

9. The method according to claim 3, 4, 7, or 8, wherein the aforementioned cells are included in the subject.

10. The Myt1 inhibitor is a compound of formula (I): 【Chemistry 1】 [During the ceremony, Each of X, Y, and Z is independently N or CR ２ And; R １ and each R ２ is independently hydrogen, optionally substituted C １－６ alkyl, optionally substituted C ２－６ alkenyl, optionally substituted C ２－６ alkynyl, optionally substituted C ３－８ cycloalkyl, optionally substituted C ３－８ cycloalkenyl, optionally substituted C ２－９ heterocyclyl, optionally substituted C ２－９ heterocyclyl C １－６ alkyl, optionally substituted C ６－１０ aryl, optionally substituted C １－９ heteroaryl, optionally substituted C １－９ heteroaryl C １－６ alkyl, halogen, cyano, -N(R ７ ) ２ , -OR ７ , -C(O)N(R ８ ) ２ , -SO ２ N(R ８ ) ２ , -SO ２ R ７Ａ , or -Q-R ７Ｂ ; or R １ is vicinal to one R １ with respect to R ２ and combines to form optionally substituted C ３－６ alkylene; R ３ and R ４ Each of these is independently replaced by C of any choice. １－６ It is an alkyl or halogen; R ５ is H or -N(R ７ ) ２ And; R ６ is -C(O)NH(R ８ ), -C(O)R ７Ａ , or -SO ２ R ７Ａ And; Each R ７ These are independently hydrogen, optionally substituted with C １－６ Alkyl, optionally substituted C ６－１０ Aryl C １－６ Alkyl, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ６－１０ Aaryl, replaced by C of any choice ２－９ Heterocycline, C by optional substitution １－９ Heteroaryl, optionally substituted C １－９ Heteroaryl C １－６ Alkyl, or -SO ２ R ７Ａ is; or two R ７ The group combines with the atoms bonded to it, and is optionally substituted by C. ２－９ It forms heterocyclines; Each R ７Ａ These are independently replaced by C of any choice. １－６ Alkyl, optionally substituted C ３－８ Cycloalkyl or optionally substituted C ６－１０ It is an allele; Each R ７Ｂ These are independently hydroxyl, optionally substituted C １－６ Alkyl, optionally substituted C ６－１０ Aaryl, replaced by C of any choice ２－９ Heterocycline, C by optional substitution １－９ Heteroaryl, -N(R ７ ) ２ , -C(O)N(R ８ ) ２ , -SO ２ N(R) ８ ) ２ , -SO ２ R ７Ａ , or an alkoxy that is optionally substituted; Each R ８ These are independently hydrogen, optionally substituted with C １－６ Alkyl, optionally substituted C ２－６ Alkoxyalkyl groups, optionally substituted C ６－１０ Aryl C １－６ Alkyl, optionally substituted C ６－１０ Aaryl, replaced by C of any choice ３－８ Cycloalkyl or optionally substituted C １－９ It is heteroaryl; or two R ８ However, when combined with the atoms bonded to them, they form C which is optionally substituted. ２－９ It forms heterocyclines; Q is optionally substituted C １－６ alkylene, optionally substituted C ２－６ alkenylene, optionally substituted C ２－６ alkynylene, optionally substituted C ３－８ cycloalkylene, optionally substituted C ３－８ cycloalkenylene, optionally substituted C ６－１０ arylene, optionally substituted C ２－９ heterocyclylene, or optionally substituted C １－９ heteroarylene〕. The method according to any one of claims 1 to 9, wherein the salt is pharmaceutically acceptable or a pharmaceutically acceptable salt thereof.

11. The above compound is an atropisomer of formula (IA): 【Chemistry 2】 The method according to claim 10, or a pharmaceutically acceptable salt thereof, which is concentrated with respect to.

12. X is CR ２ The method according to claim 10 or claim 11, or a pharmaceutically acceptable salt thereof.

13. The aforementioned compound is of formula (II): 【Transformation 3】 The method according to claim 10, or a pharmaceutically acceptable salt thereof.

14. The above compound is an atropisomer of formula (IIA): 【Chemistry 4】 The method according to claim 13, or a pharmaceutically acceptable salt thereof, which is concentrated with respect to.

15. The aforementioned compound is of formula (III): 【Transformation 5】 [During the ceremony, R ２Ａ is hydrogen, optionally substituted C １－６ alkyl, optionally substituted C ２－６ alkenyl, optionally substituted C ２－６ alkynyl, optionally substituted C ３－８ cycloalkyl, optionally substituted C ３－８ cycloalkenyl, optionally substituted C ２－９ heterocyclyl, optionally substituted C ２－９ heterocyclyl C １－６ alkyl, optionally substituted C ６－１０ aryl, optionally substituted C １－９ heteroaryl, optionally substituted C １－９ heteroaryl C １－６ alkyl, halogen, -N(R ７ ), -OR ２ , -C(O)N(R ７ ), -SO ８ N(R ２ ), -SO ２ R ８ , or -Q-R ２ ), or -Q-R ２ R ７Ａ , or -Q-R ７Ｂ is)] The method according to claim 10, or a pharmaceutically acceptable salt thereof.

16. The above compound is an atropisomer of formula (IIIA): 【Transformation 6】 The method according to claim 15, or a pharmaceutically acceptable salt thereof, which is concentrated with respect to.

17. R ２Ａ However, hydrogen and C are optionally substituted. １－６ Alkyl or halogen, The method according to claim 15 or claim 16, or a pharmaceutically acceptable salt thereof.

18. R ３ However, C was replaced by an arbitrary choice. １－６ The method according to any one of claims 10 to 17, or a pharmaceutically acceptable salt thereof, wherein the salt is alkyl.

19. R ３ The method according to any one of claims 10 to 17, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

20. R ４ However, C was replaced by an arbitrary choice. １－６ The method according to any one of claims 10 to 19, or a pharmaceutically acceptable salt thereof, wherein the salt is alkyl.

21. R ４ The method according to any one of claims 10 to 19, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

22. The method according to claim 19 or claim 21, wherein the halogen is chlorine.

23. R ２ The method according to any one of claims 10 to 22, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

24. R ２ However, C was replaced by an arbitrary choice. １－６ The method according to any one of claims 10 to 22, or a pharmaceutically acceptable salt thereof, wherein the salt is alkyl.

25. R ２ However, it is optionally substituted with methyl or optionally substituted with isopropyl. The method according to claim 24, or a pharmaceutically acceptable salt thereof.

26. R ２ The method according to any one of claims 10 to 22, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

27. R １ The method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

28. R １ The method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

29. R １ The method according to claim 28, or a pharmaceutically acceptable salt thereof, wherein is chlorine or bromine.

30. R １ However, C was replaced by an arbitrary choice. １－６ The method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof, wherein the salt is alkyl.

31. R １ The method according to claim 30, or a pharmaceutically acceptable salt thereof, wherein the active ingredient is optionally substituted with methyl, optionally substituted with ethyl, optionally substituted with isopropyl, or optionally substituted with butyl.

32. R １ However, C was replaced by an arbitrary choice. １－９ A heteroaryl, the method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof.

33. R １ However, these are 1,3-thiazolyl, 1,2-thiazolyl, 1,3-oxazolyl, benzo-1,3-thiazolyl, benzo-1,3-oxazolyl, indolyl, benzimidazolyl, pyridyl, imidazolyl, pyrimidyl, pyrazinyl, pyridadinyl, or pyrazolyl. R １ However, C which is replaced by the aforementioned optional selection １－９ The substituents defined for heteroaryls are optionally substituted. The method according to claim 32, or a pharmaceutically acceptable salt thereof.

34. R １ However, C was replaced by an arbitrary choice. ３－８ A cycloalkyl product, according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof.

35. R １ However, these are cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. R １ However, C which is replaced by the aforementioned optional selection ３－８ Substitutions are optionally chosen to be substituents defined for cycloalkyl groups. The method according to claim 34, or a pharmaceutically acceptable salt thereof.

36. R １ However, C was replaced by an arbitrary choice. ２－９ A heterocycline, according to the method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof.

37. R １ However, these are 1,2,3,6-tetrahydropyridinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, oxa-azarspiro[3,3]heptane, or oxa-azarbicyclo[3.2.1]octane. R １ However, C which is replaced by the aforementioned optional selection ２－９ The substituents defined for heterocyclines are optionally substituted. The method according to claim 36, or a pharmaceutically acceptable salt thereof.

38. R １ However, C was replaced by an arbitrary choice. ３－８ A cycloalkyl product, according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof.

39. R １ The method according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the substituted member is optionally substituted with cyclohexenyl or optionally substituted with cyclopentenyl.

40. R １ However, C was replaced by an arbitrary choice. ６－１０ The method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof, wherein the salt is an aryl.

41. R １ The method according to claim 40, or a pharmaceutically acceptable salt thereof, wherein the phenyl is optionally substituted.

42. R １ However, -Q-R ７Ｂ The method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof.

43. Q is replaced by C by arbitrary choice. ２－６ The method according to claim 42, or a pharmaceutically acceptable salt thereof, wherein the salt is alkynylene.

44. Q is replaced by C by arbitrary choice. １－６ The method according to claim 42, or a pharmaceutically acceptable salt thereof, wherein the salt is alkylene.

45. Q is replaced by C by arbitrary choice. ６－１０ The method according to claim 42, or a pharmaceutically acceptable salt thereof, wherein the salt is allirene.

46. R ７Ｂ However, C was replaced by an arbitrary choice. ２－９ A heterocycline, according to the method of any one of claims 42 to 45, or a pharmaceutically acceptable salt thereof.

47. R ７Ｂ However, C was replaced by an arbitrary choice. ６－１０ The method according to any one of claims 42 to 45, or a pharmaceutically acceptable salt thereof, wherein the salt is an aryl.

48. R １ but, Methyl, difluoromethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, hydroxyl, cyano, oxo, -C(O)NH ２ , -C(O)NH(Me), -C(O)N(Me) ２ ,-(CH ２ ) ｎ -C(O)OH and -(CH ２ ) ｎ It is optionally substituted with one, two, or three groups independently selected from the group consisting of -C(O)Ot-Bu, n is 0 or 1, The method according to any one of claims 10 to 47, or a pharmaceutically acceptable salt thereof.

49. R １ However, -N(R ７ ) ２ The method according to any one of claims 10 to 26, or a pharmaceutically acceptable salt thereof.

50. R １ The method according to claim 49, or a pharmaceutically acceptable salt thereof, wherein is diethylamino.

51. R ５ The method according to any one of claims 10 to 50, wherein is hydrogen, or a pharmaceutically acceptable salt thereof.

52. R ５ However, -N(R ７ ) ２ The method according to any one of claims 10 to 50, or a pharmaceutically acceptable salt thereof.

53. R ５ However, -NH ２ The method according to claim 52, or a pharmaceutically acceptable salt thereof.

54. R ６ is -C(O)NH(R ８ The method according to any one of claims 10 to 53, or a pharmaceutically acceptable salt thereof.

55. R ６ However, -C(O)NH ２ The method according to any one of claims 10 to 53, or a pharmaceutically acceptable salt thereof.

56. R ６ The method according to any one of claims 10 to 53, wherein the compound is -C(O)NH(Me), or a pharmaceutically acceptable salt thereof.

57. R ６ However, -SO ２ R ７Ａ The method according to any one of claims 10 to 53, or a pharmaceutically acceptable salt thereof.

58. R ６ However, -SO ２ The method according to claim 57, or a pharmaceutically acceptable salt thereof, wherein Me.

59. The method according to any one of claims 1 to 9, wherein the compound is selected from the group consisting of compounds 1 to 328 and pharmaceutically acceptable salts thereof.

60. The method according to claim 59, wherein the compound is selected from the group consisting of compounds 1 to 288 and pharmaceutically acceptable salts thereof.

61. The method according to any one of claims 1 to 60, wherein the Myt1 inhibitor is administered as a pharmaceutical composition.

62. The method according to claim 61, wherein the pharmaceutical composition is isotope-enriched with deuterium.

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