MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF

• US 20150259351A1
• Filed: 03/18/2015
• Published: 09/17/2015
• Est. Priority Date: 02/10/2012
• Status: Active Grant

• Current Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Original Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Inventors: Albrecht, Brian K., Audia, James Edmund, Cook, Andrew S., Dakin, Les A., Duplessis, Martin, Gehling, Victor S., Harmange, Jean-Christophe, Nasveschuk, Christopher G., Vaswani, Rishi G.
• Granted Patent: US 9,371,331 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.

Claims

1. A method of treating a subject with a cancer selected from breast cancer, prostate cancer, colon cancer, renal cell carcinoma, glioblastoma multiforme cancer, bladder cancer, melanoma, bronchial cancer, lymphoma, and liver cancer, comprising administering to the subject an effective amount of a compound having structural formula I:

2. The method of claim 1, wherein one R¹ is —

CH₃;

the other R¹ is selected from —

C₁-C₂ alkyl optionally substituted with one or more fluoro and —

O—

(C₁-C₂ alkyl) optionally substituted with one or more fluoro.

3. The method of claim 2 represented by the formula:

4. The method of claim 1, wherein each of X¹ and X² is independently ═

C(R³)—

, wherein two R³ are taken together with the carbon atoms to which they are bound to form an aryl, heteroaryl, or carbocyclyl fused to the ring comprising X¹, X² and X³.

5. The method of claim 4, wherein two R³ are taken together with the carbon atoms to which they are bound to form an optionally substituted aryl or a pyridyl ring fused to the ring comprising X¹, X² and X³.

6. The method of claim 5, wherein the fused ring has the structure:

7. The method of claim 1, wherein:

R^x is —

CH(R⁴)(R⁵);

R⁴ is selected from C₂-C₆ alkyl, —

(C₀-C₂ alkylene)-aryl, —

(C₀-C₂ alkylene)-heterocyclyl, and —

(C₀-C₂ alkylene)-heteroaryl; and

R⁵ is selected from hydrogen and methyl.

8. The method of claim 1, wherein:

R^x is —

CH(R⁴)(R⁵);

R⁴ is selected from —

(C₁-C₃ alkylene)-O-(C₁-C₂ alkyl), 1-substituted-piperidin-4-yl, C₃-C₆ cycloalkyl optionally substituted with one or more fluoro, and tetrahydropyranyl; and

R⁵ is selected from hydrogen and —

CH₃.

9. The method of claim 8, wherein R⁴ is selected from

—

CH₂OCH₃,

—

CH(CH₃)OCH₃,

4,4-difluorocyclohexyl,

cyclopropyl,

tetrayhyrdopyran-4-yl,

1-(t-butoxycarbonyl)-piperidin-4-yl,

1-(isobutoxycarbonyl)-piperidin-4-yl,

1-(isopropoxycarbonyl)-piperidin-4-yl,

1-(2-fluoroethyl)-piperidin-4-yl,

1-(2,2-difluoroethyl)-piperidin-4-yl,

1-(2,2,2-trifluoroethyl)-piperidin-4-yl,

1-(2-hydroxyisobutyl)-piperidin-4-yl,

1-(hydroxyisopropylcarbonyl)-piperidin-4-yl,

1-(ethoxycarbonylmethyl)-piperidin-4-yl,

1-(isopropylcarbonyl)-piperidin-4-yl,

1-methylpiperidin-4-yl,

1-(methylsulfonyl)-piperidin-4-yl,

1-(ethylsulfonyl)-piperidin-4-yl,

1-(isopropylsulfonyl)-piperidin-4-yl,

1-(phenyl)-piperidin-4-yl,

1-(oxetan-3-yl)piperidin-4-yl,

1-(pyridin-2-yl)-piperidin-4-yl, and

1-(pyrimidin-2-yl)-piperidin-4-yl.

10-19. -19. (canceled)

20. A compound selected from

21. A pharmaceutical composition comprising a compound of claim 20, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

22. A method of treating a subject with cancer, comprising administering to the subject an effective amount of a compound according to claim 20, or a pharmaceutically acceptable salt thereof.

23. The method of claim 22, wherein the cancer is characterized by the presence of a mutant EZH2 protein.

24. The method of claim 23, wherein the mutant EZH2 protein comprises a Y641N mutation.

25. The method of claim 22, wherein the cancer is characterized by trimethylation of histone H3 at lysine 27.

26. The method of claim 22, wherein the cancer is selected from breast cancer, prostate cancer, colon cancer, renal cell carcinoma, glioblastoma multiforme cancer, bladder cancer, melanoma, bronchial cancer, lymphoma, and liver cancer.