Aryl- or heteroaryl-substituted benzene compounds

• US 9,090,562 B2
• Filed: 05/12/2014
• Issued: 07/28/2015
• 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:
  US14/275,667
• Publication Number:
  US 20140288041A1
• Time in Patent Office: 442 Days
• Field of Search: 514/210.18, 514/218, 514/236.5, 514/318, 514/336, 514/343, 514/351, 544/544, 544/575, 546/194, 546/276
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/443 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 compound of Formula (I) or a pharmaceutically acceptable salt thereof:

2. The compound of claim 1, wherein R₆ is phenyl substituted with one or more -Q₂-T₂.

3. The compound of claim 1, wherein R₆ is 5- or 6-membered heteroaryl containing 1-3 additional heteroatoms selected from N, O, and S and optionally substituted with one or more -Q₂-T₂.

4. The compound of claim 1, wherein R₇ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl or 4 to 12-membered heterocycloalkyl, each optionally substituted with one or more -Q₅-T₅.

5. The compound of claim 1, wherein each of R₁ and R₁₁ is H and each of R₂ and R₄, independently is H or C₁-C₆ alkyl optionally substituted with amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, or C₆-C₁₀ aryl.

6. The compound of claim 1, wherein R₁₂ is methyl, ethyl, ethenyl, or halo;

and R₈ is H, methyl, or ethyl.

7. The compound of claim 1, wherein X₁ is CR₁₁ and X₂ is CR₁₃.

8. The compound of claim 1, wherein X₁ is CR₁₁ and X₂ is N.

9. The compound of claim 1, wherein X₁ is N and X₂ is CR₁₃.

10. The compound of claim 1, wherein X₁ is N and X₂ is N.

11. The compound of claim 1, wherein Z is NR₇R₈.

12. The compound of claim 1, wherein Z is CR₇R₈R₁₄.

13. The compound of claim 1, wherein Z is OR₇.

14. The compound of claim 1, wherein Z is SR₇.

15. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

16. The compound of claim 1, wherein R₆ is C₆-C₁₀ aryl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q₂-T₂, in which Q₂ is a bond or methyl or ethyl linker and T₂ is H, halo, —

OR_a, —

NR_aR_b, —

(NR_aR_bR_c)⁺A⁻

, —

S(O)₂R_a, or —

S(O)₂NR_aR_b.

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

18. The compound of claim 17, wherein R₆ is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q₂-T₂, in which Q₂ is a bond or methyl linker, and T₂ is —

OR_a, —

NR_aR_b, —

(NR_aR_bR_c)⁺A⁻

, or —

S(O)₂R_a.

19. The compound of claim 17, wherein Q₅ is a bond and T₅ is amino, mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino.

20. The compound of claim 17, wherein R₆ is phenyl or 5- or 6-membered heteroaryl, each of which is unsubstituted or substituted with one or more -Q₂-T₂, in which Q₂ is a bond or methyl linker, and T₂ is —

OR_a or —

S(O)₂R_a, in which R_a is H or C₁-C₆ alkyl optionally substituted with one or more -Q₃-T₃.