Modulators of methyl modifying enzymes, compositions and uses thereof

• US 9,085,583 B2
• Filed: 02/11/2013
• Issued: 07/21/2015
• 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.
• Primary Examiner(s): REESE, HEIDI L
• Application Number:
  US14/377,214
• Publication Number:
  US 20150011546A1
• Time in Patent Office: 890 Days
• Field of Search: None
• 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 compound having structural formula I:

2. The compound 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 compound of claim 2 represented by the formula:

4. The compound 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 compound 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 compound of claim 5, wherein the fused ring has the structure:

7. The compound 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 compound of claim 1, wherein:

R^x is —

CH(R⁴)(R⁵);

R⁴ is selected from —

(C₁-C₃ alkylene)-O—

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

R⁵ is selected from hydrogen and —

CH₃.

9. The compound 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.

11. A method of treating a subject with cancer, comprising administering to the subject an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. The method of claim 11, wherein the cancer is characterized by the presence of a mutant EZH2 protein.

13. The method of claim 12, wherein the mutant EZH2 protein comprises a Y641N mutation.

14. The method of claim 11, wherein the cancer is characterized by trimethylation of histone H3 at lysine 27.

10. A composition comprising:

a. a compound having structural formula I;