MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF

• US 20160009718A1
• Filed: 03/12/2014
• Published: 01/14/2016
• 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.
• Granted Patent: US 9,745,305 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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-(methyl sulfonyl(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 any one of compounds 100-145.

17. A composition comprising a compound of claim 1;

and a pharmaceutically acceptable carrier.

18. A method of treating cancer in a patient comprising administering to the patient an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or tautomer thereof.

25. The method of claim 18, wherein the cancer is characterized by trimethylation of histone H3 at lysine 27.

26. The method of claim 18, 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.

19-24. -24. (canceled)