Aryl- or heteroaryl-substituted benzene compounds

• US 8,765,732 B2
• Filed: 12/20/2012
• Issued: 07/01/2014
• Est. Priority Date: 04/13/2011
• Status: Active Grant

• Current Assignee: Epizyme, Inc. (Ipsen Sa)
• Original Assignee: Epizyme, Inc. (Ipsen Sa)
• Inventors: Kuntz, Kevin Wayne, Chesworth, Richard, Duncan, Kenneth William, Keilhack, Heike, Warholic, Natalie, Klaus, Christine, Knutson, Sarah Kathleen, Wigle, Timothy James Nelson, Seki, Masashi, Shirotori, Syuji, Kawano, Satoshi
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US13/722,807
• Publication Number:
  US 20130123234A1
• Time in Patent Office: 558 Days
• Field of Search: 514/210.18, 514/218, 514/236.5, 514/318, 514/336, 514/343, 514/351, 540/544, 540/575, 546/194, 546/276
• US Class Current: 514/210.18
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• 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 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/553 having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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: 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
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 491/08 : Bridged systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07D 498/08 : Bridged systems

Abstract

The present invention relates to aryl- or heteroaryl-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 method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (Ig) or a pharmaceutically acceptable salt thereof:

2. The method of claim 1, wherein R₆ is C₆-C₁₀ aryl or 5- or 6-membered heteroaryl, each of which is optionally, independently substituted with one or more -Q₂-T₂, wherein Q₂ is a bond or C₁-C₃ alkyl linker, and T₂ is H, halo, cyano, —

OR_a, —

NR_aR_b, —

(NR_aR_bR_c)⁺A⁻

, —

C(O)NR_aR_b, —

NR_bC(O)R_a, —

S(O)₂R_a, or R_S2, in which each of R_a and R_b, independently is H or R_S3, each of R_S2 and R_S3, independently, is C₁-C₆ alkyl, or R_a and R_b, together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatom, and each of R_S2, R_S3, and the 4 to 7-membered heterocycloalkyl ring formed by R_a and R_b, is optionally, independently substituted with one or more -Q₃-T₃, wherein Q₃ is a bond or C₁-C₃ alkyl linker and T₃ is selected from the group consisting of halo, C₁-C₆ alkyl, 4 to 7-membered heterocycloalkyl, OR_d, —

S(O)₂R_d, and —

NR_dR_e, each of R_d and R_e independently being H or C₁-C₆ alkyl, or -Q₃-T₃ is oxo;

or any two neighboring -Q₂-T₂, together with the atoms to which they are attached form a 5- or 6-membered ring optionally containing 1-4 heteroatoms selected from N, O and S.

3. The method of claim 1, wherein the compound is of Formula (II) or a pharmaceutically acceptable salt thereof:

4. The method of claim 1, wherein the compound is of Formula (IIa) or a pharmaceutically acceptable salt thereof:

5. The method of claim 4, wherein R_a and R_b, together with the N atom to which they are attached, form a 4 to 7-membered heterocycloalkyl ring having 0 or 1 additional heteroatoms to the N atom and the ring is optionally substituted with one or more -Q₃-T₃, wherein the heterocycloalkyl is azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, or morpholinyl.

6. The method of claim 5, wherein R₇ is piperidinyl, tetrahydropyran, tetrahydro-2H-thiopyranyl, cyclopentyl, cyclohexyl, pyrrolidinyl, or cycloheptyl, each optionally substituted with one or more -Q₅-T₅.

7. The method of claim 6, R₈ is H or C₁-C₆ alkyl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, COOH, C(O)O—

C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino, and di-C₁-C₆ alkylamino.

8. The method of claim 4, wherein R₇ is C₃-C₈ cycloalkyl or 4 to 7-membered heterocycloalkyl, each optionally substituted with one or more -Q₅-T₅.

9. The method of claim 1, wherein the compound is selected from

10. The method of claim 1, wherein the compound is

11. The method of claim 1, wherein the compound is a pharmaceutically acceptable salt of

12. The method of claim 1, wherein the cancer is lymphoma selected from non-Hodgkin lymphoma, follicular lymphoma and diffuse large B-cell lymphoma.

13. The method of claim 1, wherein the cancer is leukemia selected from chronic myelogenous leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, and mixed lineage leukemia.

14. The method of claim 1, wherein the cancer is breast cancer.

15. The method of claim 1, wherein the subject has a cancer expressing a Y641 mutant of EZH2.

16. The method of claim 15, further comprising performing an assay to detect a Y641 mutant of EZH2 in a sample comprising cancer cells from the subject having a cancer before administering to the subject expressing the Y641 mutant of EZH2a therapeutically effective amount of the compound of Formula (Ig) or a pharmaceutically acceptable salt thereof.

17. The method of claim 1, wherein the compound is administered orally to the subject in need thereof.

18. A method of treating lymphoma comprising administering to a subject in need thereof a therapeutically effective amount of

19. The method of claim 18, wherein said lymphoma is selected from non-Hodgkin lymphoma, follicular lymphoma and diffuse large B-cell lymphoma.