SUBSTITUTED BENZENE COMPOUNDS

• US 20150284370A1
• Filed: 10/15/2013
• Published: 10/08/2015
• Est. Priority Date: 10/15/2012
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Kuntz, Kevin Wayne, Campbell, John Emmerson, Seki, Masashi, Shirotori, Syuji, Zheng, Wanjun, Itano, Wataru
• Granted Patent: US 10,092,572 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

The present invention relates to substituted benzene compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating cancer by administering these compounds and pharmaceutical compositions to subjects in need thereof. The present invention also relates to the use of such compounds for research or other non-therapeutic purposes.

Claims

1. A compound of Formula III:

2. The compound of claim 1, wherein Q_x is a bond or methyl linker, and T_x is tetrahydropyranyl, piperidinyl substituted by 1, 2, or 3 C_1-4 alkyl groups, or cyclohexyl substituted by N(C_1-4 alkyl)₂ wherein one or both of the C_1-4 alkyl is optionally substituted with C_1-6 alkoxy.

3. The compound of claim 1, wherein R⁸⁰⁶ is cyclohexyl substituted by N(C_1-4 alkyl)₂.

4. The compound of claim 1, wherein R⁸⁰⁶ is

5. The compound of any of claims 1-4, wherein R⁸⁰¹ is phenyl or 5- or 6-membered heteroaryl substituted with O—

C_1-6 alkyl-R_x.

6. The compound of claim 1, wherein the compound is of Formula IVa or IVb:

7. The compound of claim 6, wherein R⁸⁰⁷ is —

CH₂CH₂OH, —

CH₂CH₂OCH₃, or —

CH₂CH₂OCH₂CH₂OCH₃.

8. The compound of any of claims 1-7, wherein R⁸⁰² is methyl or isopropyl and R⁸⁰³ is methyl or methoxyl.

9. The compound of any of claims 1-8, wherein R⁸⁰⁴ is methyl.

48. A pharmaceutical composition comprising a compound of any of claims 1-47 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

49. A method of treating an EZH2-mediated disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any of claims 1-47 or a pharmaceutically acceptable salt thereof.

50. The method of claim 49, wherein the EZH2-mediated disorder is cancer.

51. The method of claim 50, wherein the cancer is lymphoma, leukemia or melanoma.

52. The method of claim 50, wherein the cancer is diffuse large B-cell lymphoma (DLBCL), non-Hodgkin'"'"'s lymphoma (NHL), follicular lymphoma, chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, mixed lineage leukemia, or myelodysplastic syndromes (MDS).

53. The method of claim 50, wherein the cancer is malignant rhabdoid tumor or INI1-deficient tumor.

54. A compound of any of claims 1-47 for use in a method of treating an EZH2-mediated disorder.

55. Use of a compound of any of claims 1-47 for the manufacture of a medicament in the treatment of an EZH2-mediated disorder.

56. A pharmaceutical composition for treating an EZH2-mediated disorder comprising a compound of any of claims 1-47 as a main ingredient.

10. A compound of Formula I:

11. The compound of claim 10, wherein R⁷⁰⁶ is cyclohexyl substituted by N(C_1-4 alkyl)₂ wherein one of the C_1-4 alkyl is unsubstituted and the other is substituted with methoxy.

12. The compound of claim 10, wherein R⁷⁰⁶ is

13. The compound of claim 10, wherein the compound is of Formula II:

14. The compound of any of claims 10-13, wherein R⁷⁰² is methyl or isopropyl and R⁷⁰³ is methyl or methoxyl.

15. The compound of any of claims 10-14, wherein R⁷⁰⁴ is methyl.

16. The compound of any of claims 10-15, wherein R⁷⁰¹ is OR⁷⁰⁷ and R⁷⁰⁷ is C_1-3 alkyl optionally substituted with OCH₃ or morpholine.

17. The compound of any of claims 10-15, wherein R⁷⁰¹ is H or F.

18. The compound of any of claims 10-15, wherein R⁷⁰¹ is tetrahydropyranyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, imidazolyl, or pyrazolyl, each of which is optionally substituted with methyl, methoxy, ethyl substituted with morpholine, or —

OCH₂CH₂OCH₃.

19. The compound of any of claims 10-18, wherein R⁷⁰⁸ is morpholine, piperidine, piperazine, pyrrolidine, diazepane, or azetidine, each of which is optionally substituted with OH or C_1-6 alkyl.

20. The compound of any of claims 10-18, wherein R⁷⁰⁸ is morpholine

21. The compound of any of claims 10-18, wherein R⁷⁰⁸ is piperazine substituted with C_1-6 alkyl.

22. The compound of any of claims 10-18, wherein R⁷⁰⁸ is methyl, t-butyl or C(CH₃)₂OH.

23. A compound of Formula VI:

24. The compound of claim 23, wherein R⁵⁰¹ is C(H), and R⁵⁰⁷ is piperidine;

diazepane;

pyrrolidine;

azetidine;

O—

C_1-6 alkyl;

or O-heterocycle, wherein the heterocycle is a 4-7 membered heterocycle containing an oxygen or nitrogen, or both, and wherein the nitrogen can optionally be substituted with C_1-3 alkyl;

wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH, C_1-6 alkyl, or O—

C_1-3 alkyl.

25. The compound of claim 23, wherein R⁵⁰¹ is C(H) and R⁵⁰⁷ is piperidine, diazepane, pyrrolidine, azetidine or O—

C_1-6 alkyl, wherein the piperidine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or C_1-6 alkyl.

26. The compound of claim 23, wherein R⁵⁰¹ is C(H), R⁵⁰⁷ is piperazine optionally further substituted with C_1-6 alkyl, and R⁵⁰⁶ is piperidine substituted by 1, 2, or 3 C_1-4 alkyl groups.

27. The compound of claim 23, wherein R⁵⁰¹ is N, and R⁵⁰⁷ is morpholine, piperidine, piperazine, diazepane, pyrrolidine, azetidine or O—

C_1-6 alkyl, wherein the piperidine, piperazine, diazepane, pyrrolidine or azetidine groups can be optionally further substituted with OH or C_1-6 alkyl.

28. The compound of claim 23, wherein R⁵⁰² is methyl or isopropyl, and R⁵⁰³ is methyl.

29. The compound of any of claims 23-28, wherein R⁵⁰⁴ is methyl.

30. The compound of any of claims 23-29, wherein R⁵⁰⁵ is ethyl.

31. The compound of any of claims 23-30, wherein R⁵⁰⁶ is

32. The compound of any of claims 23-30, wherein R⁵⁰⁶ is

33. The compound of any of claims 23-32, wherein when R⁵⁰¹ is C(H), R⁵⁰⁷ is piperidine or diazepane, which are substituted with OH or C_1-6 alkyl, or when R⁵⁰¹ is N, R⁵⁰⁷ is piperidine, piperazine, or diazepane, which are optionally further substituted with OH or C_1-6 alkyl.

34. The compound of any of claims 23-33, wherein when R⁵⁰¹ is C(H), R⁵⁰⁷ is piperidine substituted with C_1-6 alkyl, or when R⁵⁰¹ is N, R⁵⁰⁷ is piperidine substituted with OH or piperazine substituted with C_1-6 alkyl.

35. The compound of any of the claims 23-34, wherein when R⁵⁰¹ is N, R⁵⁰⁷ is unsubstituted piperazine.

36. The compound of claims 23-35, wherein n₅ is 0 or 1.

37. The compound of claim 23, wherein when R⁵⁰¹ is C(H) or N, R⁵⁰⁷ is O—

C_1-6 alkyl or O-heterocycle, and n₅ is 1.

38. The compound of claim 23, wherein when R⁵⁰¹ is C(H), R⁵⁰⁷ is unsubstituted piperazine and R⁵⁰⁶ is piperidine substituted by 1, 2, or 3 C_1-4 alkyl groups.

39. A compound of Formula VII:

40. The compound of claim 39, wherein R⁶⁰² is methyl or isopropyl and R⁶⁰³ is methyl.

41. The compound of claim 39 or 40, wherein R⁶⁰⁴ is methyl and R⁶⁰⁵ is ethyl.

42. The compound of any of claims 39-41, wherein R⁶⁰⁶ is

43. The compound of any of claims 39-42, wherein R⁶⁰⁶ is

44. The compound of any of claims 39-43, wherein R⁶⁰⁷ is piperidine or diazepane, each of which is substituted with OH or C_1-6 alkyl.

45. The compound of any of claims 39-43, wherein R⁶⁰⁷ is piperidine substituted with OH.

46. The compound of any of claims 39-45, wherein n₆ is 2.

47. A compound selected from those in Tables 1A and 1B, and pharmaceutically acceptable salts thereof.