Modulators of methyl modifying enzymes, compositions and uses thereof

• US 9,745,305 B2
• Filed: 03/12/2014
• Issued: 08/29/2017
• Est. Priority Date: 03/15/2013
• 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, Ct, Alexandre, Dakin, Les A., Gehling, Victor S., Harmange, Jean-Christophe, Nasveschuk, Christopher G., Vaswani, Rishi G.
• Primary Examiner(s): O'Dell, David K
• Application Number:
  US14/769,471
• Publication Number:
  US 20160009718A1
• Time in Patent Office: 1,266 Days
• Field of Search: None
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 Z is CH.

3. The compound of claim 1, wherein each of R¹ and R² is independently selected from —

C₁-C₃ alkyl, —

C₁-C₃ haloalkyl, O—

(C₁-C₃ alkyl) and —

O—

(C₁-C₃ haloalkyl).

4. The compound of claim 3, wherein R¹ is methyl.

5. The compound of claim 4, wherein R² is selected from —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

OCH₃, and —

OCHF₂.

6. The compound of claim 5, wherein Y¹ is N and X⁴ is N.

7. The compound of claim 6, wherein X⁵ is selected from C(H), C(OCH₃) and C(CH₃).

8. The compound of claim 5, wherein Y¹ is N and X² is N.

9. The compound of claim 5, wherein Y² is N and X³ is N.

10. The compound of claim 9, wherein R³ is methyl or chloro.

11. The compound of claim 10, wherein R⁴ is selected from -heteroaryl, —

CH(CH₃)-heterocyclyl, —

CH(CH₃)-heteroaryl, —

CH(CH₃)-aryl, —

CH(CH₃)-carbocyclyl,)—

CH(CH₃)—

N(R¹⁰)—

S(O)₂—

(C₁-C₄ alkyl) —

CH(CH₃)—

N(R¹⁰)—

C(O)—

(C₁-C₄ alkyl), and —

CH(CH₃)N(R¹⁰)₂, wherein R¹⁰ is selected from hydrogen and C₁-C₄ alkyl, and wherein any aryl, heteroaryl, heterocyclyl or carbocyclyl portion of R⁴ is optionally substituted.

12. The compound of claim 11, wherein R⁴ is selected from 1-(1-methylpiperidin-4-yl)ethyl, 5-methyl-isoxazol-4-yl, 3,5-dimethyl-isoxazol-4-yl, 1,5-dimethyl-1H-pyrazol-3-yl, 1-(1-ethylsulfonylpiperidin-4 - yl)ethyl, 1,4-dimethyl-1H-pyrazol-5 -yl, 1-methyl-1H-pyrazol-5-yl, 1-(tetrahydropyran-4-yl)ethyl, 1-(pyridin-3-yl)ethyl, 1-(methylsulfonylamino)ethyl, 1-(1-methyl-2-oxopiperidin-4-yl)ethyl, 1-(methylsulfonyl(N-ethyl)amino)ethyl, 1-(methylsulfonyl(N-methyl)amino)ethyl, 1-phenylethyl, 1-(methylcarbonyl(N-methyl)amino)ethyl, and 1-cyclopropylethyl.

13. The compound of claim 11, wherein R⁴ is selected from 1-(1-(2,2-difluoropropanoyl)piperidin-4-yl)ethyl, 1-(1-(2,2-difluoroethanoyl)piperidin-4-yl)ethyl, 1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl, 1-(1-(2,2,2-trifluoroethanoyl)piperidin-4-yl)ethyl, 1-(1-(2-fluoro-2-methylpropyl)piperidin-4-yl)ethyl, 1-(1-(2,2-difluoropropyl)piperidin-4-yl)ethyl, 1-(1-(3,3,3-trifluoropropanoyl)piperidin-4-yl)ethyl, 1-(1-(3,3,3-trifluoropropyl)piperidin-4-yl)ethyl, 1-(1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)ethyl, 1-(1-(2,2-difluoroethyl)piperidin-4-yl)ethyl, 1-(dimethylamino)ethyl, morpholine-4-carbonyl, 4-methylsulfonylpiperazin-1-ylcarbonyl, 1-(tetrahydro-2H-pyran-4-yl)ethyl, 1-(1-(2-fluoro-2-methylpropanoyl)piperidin-4-yl)ethyl, and 1-(ethyl(methyl)amino)ethyl.

14. The compound of claim 13, wherein each R⁵ is hydrogen.

15. The compound of claim 1, wherein the compound is of the structural formula (II):

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

17. A composition comprising a compound of claim 1;

and a pharmaceutically acceptable carrier.