Substituted benzene compounds

• US 10,092,572 B2
• Filed: 10/15/2013
• Issued: 10/09/2018
• 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, Itano, Wataru, Zheng, Wanjun
• Primary Examiner(s): Jarrell, Noble E
• Application Number:
  US14/435,704
• Publication Number:
  US 20150284370A1
• Time in Patent Office: 1,820 Days
• Field of Search: None
• 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 (i) R⁸⁰⁶ is cyclohexyl substituted by N(C_1-4 alkyl)₂;

or (ii) R⁸⁰⁶ is

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

5. The compound of claim 4, wherein R⁸⁰⁷ is —

CH₂CH₂OH, —

CH₂CH₂OCH₃, or —

CH₂CH₂OCH₂CH₂OCH₃.

6. A compound of Formula II:

7. The compound of claim 6, wherein (i) R⁷⁰² is methyl or isopropyl and R⁷⁰³ is methyl or methoxyl;

or (ii) R⁷⁰⁴ is methyl;

or (iii) R⁷⁰¹ is OR⁷⁰⁷ and R⁷⁰⁷ is C_1-3 alkyl optionally substituted with OCH₃ or morpholino;

or (iv) R⁷⁰¹ is H or F;

or (v) 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;

or (vi) R⁷⁰⁸ is morpholine, piperidine, piperazine, pyrrolidine, diazepane, or azetidine, each of which is optionally substituted with OH or C_1-6 alkyl;

or (vii) R⁷⁰⁸ is morpholine;

or (viii) R⁷⁰⁸ is piperazine substituted with C_1-6 alkyl;

or (ix) R⁷⁰⁸ is methyl, t-butyl or C(CH₃)₂OH.

8. A compound of Formula VI or VII:

9. The compound of claim 8, wherein the compound is of Formula (VI), wherein (i) 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;

or (ii) 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;

or (iii) 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;

or (iv) 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.

10. The compound of claim 8, wherein the compound is of Formula (VI), wherein (i) R⁵⁰² is methyl or isopropyl, and R⁵⁰³ is methyl;

or (ii) R⁵⁰² is methyl or isopropyl, and R⁵⁰³ is methyl;

or (iii) R⁵⁰⁴ is methyl;

or (iv) R⁵⁰⁵ is ethyl;

or (v) R⁵⁰⁶ is

11. The compound of claim 8, wherein the compound is of Formula (VI), wherein (i) 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;

or (ii) 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;

or (iii) when R⁵⁰¹ is N, R⁵⁰⁷ is unsubstituted piperazine;

or (iv) when R⁵⁰¹ is C(H) or N, R⁵⁰⁷ is O—

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

or (v) when R⁵⁰¹ is C(H), R⁵⁰⁷ is unsubstituted piperazine and R⁵⁰⁶ is piperidine substituted by 1, 2, or 3 C_1-4 alkyl groups;

or (vi) n₅ is 0 or 1.

12. The compound of claim 8, being of Formula VII:

13. The compound of claim 12, wherein (i) R⁶⁰² is methyl or isopropyl and R⁶⁰³ is methyl;

or (ii) R⁶⁰⁴ is methyl and R⁶⁰⁵ is ethyl;

or (iii) R⁶⁰⁷ is piperidine or diazepane, each of which is substituted with OH or C_1-6 alkyl;

or (iv) R⁶⁰⁷ is piperidine substituted with OH;

or (v) R⁶⁰⁶ is

14. A pharmaceutical composition comprising a compound of claim 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. A method of treating a cancer selected from lymphoma, leukemia, melanoma, myelodysplastic syndromes, malignant rhabdoid tumor, or INI1-deficient tumor, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 8 or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, 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, or mixed lineage leukemia.

17. The method of claim 15, wherein the cancer is INI1-deficient tumor.

18. The method of claim 15, wherein the cancer is lymphoma.

19. The method of claim 15, wherein the cancer is leukemia.

20. The method of claim 15, wherein the cancer is melanoma.

21. The method of claim 15, wherein the cancer is myelodysplastic syndromes.

22. The method of claim 15, wherein the cancer is malignant rhabdoid tumor.

23. The method of claim 16, wherein the cancer is diffuse large B-cell lymphoma (DLBCL).

24. The method of claim 16, wherein the cancer is non-Hodgkin'"'"'s lymphoma (NHL).

25. The method of claim 16, wherein the cancer is follicular lymphoma.

26. The method of claim 16, wherein the cancer is chronic myelogenous leukemia (CML).

27. The method of claim 16, wherein the cancer is acute myeloid leukemia.

28. The method of claim 16, wherein the cancer is acute lymphocytic leukemia.

29. The method of claim 16, wherein the cancer is mixed lineage leukemia.

30. The method of claim 17, wherein the cancer is follicular lymphoma.

31. The method of claim 17, wherein the cancer is malignant rhabdoid tumor.