MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF

• US 20140315949A1
• Filed: 11/19/2012
• Published: 10/23/2014
• Est. Priority Date: 11/18/2011
• Status: Active Grant

• Current Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Original Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Inventors: Albrecht, Brian K., Audia, James Edmund, Gagnon, Alexandre, Harmange, Jean-Christophe, Nasveschuk, Christopher G.
• Granted Patent: US 9,051,269 B2
• Time in Patent Office: Days
• US Class Current: 514/314
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/81 Amides; Imides
• 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

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 R¹ is independently selected from hydrogen and —

CH₃.

4. The compound of claim 3, wherein each R¹ is —

CH₃.

5. The compound of claim 1, wherein one R¹ is —

CH₃; and

the other R¹ is selected from —

OCH₃ and —

NHCH₃.

6. The compound of claim 1, wherein each of X¹, X², X³ and X⁴ is ═

C(R³)—

; and

X⁵ is ═

C—

.

7. The compound of claim 1, wherein each R³ is independently selected from hydrogen, halo, C₁-C₄ alkyl and —

O-phenyl.

8. The compound of claim 7, wherein each R³ is independently selected from hydrogen, chloro, —

CH₃ and —

O-phenyl.

9. The compound of claim 1, wherein —

R⁵—

H is selected from —

CH₃, —

CH(CH₃)₂, —

(CH₂)₂CH₃, —

CH₂CH₃, —

OCH₂CH₃, —

OCH(CH₃)₂, —

OCH₃, —

OCH₂CH(CH₃)₂, —

OH, —

CH₂OH, —

(CH₂)₂OH, —

(CH₂)₂—

O—

CH₃, —

NH—

C(═

O)—

CH₃, —

(CH₂)₂—

NH—

CH₃, —

(CH₂)₂—

NH—

C(═

O)—

CH₃, —

CH₂—

C(═

O)NH₂, —

NH—

S(═

O)₂—

CH₃, and —

NH—

C(═

O)—

NH—

CH₃.

10. The compound of claim 9, wherein —

R⁵—

H is selected from —

CH₃, —

CH(CH₃)₂, —

(CH₂)₂CH₃, —

CH₂CH₃, —

OCH₂CH₃, —

OCH(CH₃)₂, —

OCH₃, and —

OCH₂CH(CH₃)₂.

11. The compound of claim 1, wherein —

R⁴—

H is selected from hydrogen and —

CH₃.

12. The compound of claim 1, wherein:

—

R⁴—

H is selected from hydrogen and methyl; and

R⁶ is hydrogen.

13. The compound of claim 1 having structural formula I-i:

14. The compound of claim 1 having structural formula I-i:

15. The compound of claim 1, wherein one methylene unit in R⁵ is taken together with X⁴, when X⁴ is ═

C(R³)—

, and the intervening atoms to form an optionally substituted heterocyclyl selected from;

17. The compound of claim 1, wherein:

when Z is ═

C(R²)—

, X⁴ is ═

N—

or ═

C(R³)—

, and X¹ and X⁴ are not simultaneously ═

N—

, then the portion of the compound represented by —

C(R⁴—

H)(R⁵—

H)(R⁶) is other than C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, any of which is optionally substituted with one or more of halo, hydroxyl, COOH, C(O)O—

C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino or di-C₁-C₆ alkylamino; and

when Z is ═

C(R²)—

, each of X¹ and X⁴ is ═

C(R³)—

, and the portion of the compound represented by —

C(R⁴—

H)(R⁵—

H)(R⁶) is C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, any of which is optionally substituted with one or more of halo, hydroxyl, COOH, C(O)O—

C₁-C₆ alkyl, cyano, C₁-C₆ alkoxyl, amino, mono-C₁-C₆ alkylamino or di-C₁-C₆ alkylamino, then each of the R³ portions of X¹ and X⁴ are independently selected from hydrogen, halo, —

OH, —

CN, C₁-C₄ alkyl, C₂-C₄ alkenyl or alkynyl, —

O—

(C₁-C₄ alkyl), N(R⁷)₂, —

(C₁-C₄ alkylene)-aryl, —

(C₁-C₄ alkylene)-heteroaryl, —

(C₀-C₄ alkylene)-heterocyclyl, —

(C₀-C₄ alkylene)-carbocyclyl, —

O—

(C₀-C₄ alkylene)-aryl, —

O—

(C₀-C₄ alkylene)-heteroaryl, —

O—

(C₀-C₄ alkylene)-heterocyclyl, —

O—

(C₀-C₄ alkylene)-carbocyclyl, —

C(O)OR⁹, —

C(O)N(R⁹)₂, —

S(O)R⁸, —

S(O)₂R⁸ and —

S(O)₂N(R⁹)₂.

18. A method of treating a subject suffering from a disease and/or disorder associated with cellular proliferation, comprising the step of administering to the subject a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein the disease is cancer.

20. The method of claim 19, 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.

16. A pharmaceutically acceptable composition comprising:

a) a compound having Structural Formula I;