INDOLE DERIVATIVES AS MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF

• US 20160185757A1
• Filed: 08/15/2014
• Published: 06/30/2016
• Est. Priority Date: 08/15/2013
• Status: Active Grant

• Current Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Original Assignee: Constellation Pharmaceuticals Incorporated (Morphosys Ag)
• Inventors: Albrecht, Brian K., Audia, James Edmund, Dakin, Les A., Duplessis, Martin, Gehling, Victor S., Harmange, Jean-Christophe, Nasveschuk, Christopher G., Vaswani, Rishi G.
• Granted Patent: US 9,969,716 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 413/14 containing three or more hetero rings

Abstract

Agents of formulas (I)/(II)/(III) 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 having structural formula Ia:

3. The compound of claim 1 having structural formula Ib:

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

OCH₃, chloro, methyl, —

OCHF₂, —

NH(CH₃), —

CH₂CH₃, —

CH₂CH₂CH₃, and —

OCH₂CF₃.

5. The compound of claim 4, wherein R¹ is selected from chloro, —

OCH₃ and —

OCHF₂.

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

(CH₂)₃CF₃, —

CH₂CH(OH)CF₃, —

CH₂CH(OCH₃)CF₃, —

CH₂CF₂H, —

CH₂CF₂CH₃, —

CH₂CF₂CH₂CH₃, —

CH₂CF₂CF₃, —

CH₂CF₂CF₂H, —

CH₂C(O)N(CH₂CH₃)₂, —

CH₂C(O)CH₃, —

CH₂C(CH₃)₂OCH₃, —

CH₂C(CH₃)₂F, —

CH₂C(CH₃)₂CF₃, —

CH(CFH₂)₂, —

C(O)N(CH₃)₂, —

C(O)C(CH₃)₃, —

C(O)C(CH₃)₂CF₃, —

C(O)—

[OCH₂CH₂]6CH₃, —

C(O)—

[OCH₂CH₂]₂CH₃, —

C(CH₃)₂C(O)CH₃, —

C(O)C(CH₃)₂CH₂CH₃, —

C(O)C(CH₃)₂OCH₃, —

C(O)C(O)CH₃, —

C(O)CF₂CH₂OCH₃, —

C(O)CH(CH₃)CH₂CH₃, —

CH(CH₃)CF₂H, —

CH₂C(CH₃)₂CN, —

CH₂CF₂CH₂OCH₃, —

CH₂CF₂CH₂OH, —

S(O)₂C(CH₃)₃, —

CH₂-cyclopropyl, —

S(O)₂-phenyl, —

S(O)₂-cyclopropyl, —

C(O)-phenyl, —

C(O)-cyclopropyl, 4-cyanophenylcarbonyl, benzylcarbonyl, 2-methyl-1H-imidazol-1-ylacetyl, 3-methylisoxazol-5-ylacetyl, 1-fluorocyclobutylcarbonyl, 1-methylcyclopentylcarbonyl, 1-methylcyclopropylcarbonyl, 2,2-difluorocyclopropylcarbonyl, 3,3-difluorocyclopentylcarbonyl, 4-methylcyclohexylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 1,3-dimehtylazetidin-3-ylcarbonyl, 1-methyl-4-fluoropiperidin-4-ylcarbonyl, 1-methylpiperidin-4-ylcarbonyl, 2,2-difluoropyrrolidin-1-ylcarbonyl, 3-methyloxetan-3-ylcarbonyl, 4,4-difluoropiperidine-1-ylcarbonyl, tetrahydrofuran-3-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, 3-fluorobenzyl, 4-cyanobenzyl, 1-methyl-1H-pyrazol-2-ylmethyl, 1-methyl-1H-pyrazol-3-ylmethyl, 1-methyl-1H-pyrazol-4-ylmethyl, 2,6-dimethylpyridin-4-ylmethyl, 2-cyanopyridin-4-ylmethyl, 2-methylpyridin-4-ylmethyl, 2-trifluoromethylpyridin-4-ylmethyl, 3-fluoropyridin-4-ylmethyl, 4-cyanopyridin-3-ylmethyl, 5-cyanopyridin-2-ylmethyl, 5-fluoropyridin-3-ylmethyl, 6-methylpyridin-2-ylmethyl, 6-methylpyrimidin-4-ylmethyl, pyrazin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyridin-3-ylsulfonyl, pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, pyrimidin-5-ylmethyl, cyclopropyl, azetidin-3-ylsulfonyl, morpholin-4-ylethylsulfonyl, morpholin-4-ylcarbonyl, pyrrolidin-1-ylethylsulfonyl, pyridin-2-ylmethyl, piperidin-4-ylsulfonyl, 4-methylpiperazin-1-ylcarbonyl, 4-fluorophenylsulfonyl, 4-fluorophenylmethyl, 4-fluorophenyl, 4-chlorophenyl, 4-(morpholin-1-ylmethyl)phenyl, 3,5-difluorophenylmethyl, 3-(morpholin-4-ylmethyl)phenyl, 2,6-difluorophenylmethyl, 1-trifluoromethylcycloprop-1-ylmethyl, 1-trifluoromethylcycloprop-1-ylcarbonyl, 1-trifluoromethylcyclobut-1-ylmethyl, 1-trifluoromethylcyclobut-1-ylcarbonyl, 1-methylpiperidin-4-ylsulfonyl, 1-methylazetidin-3-ylsulfonyl, 1-fluorocycloprop-1-ylmethyl, and 1-fluorocyclobut-1-ylmethyl.

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

(CH₂)₃CF₃, —

CH₂CH(OH)CF₃, —

CH₂CH(OCH₃)CF₃, —

CH₂CF₂H, —

CH₂CF₂CH₃, —

CH₂CF₂CH₂CH₃, —

CH₂CF₂CF₃, —

CH₂CF₂CF₂H, —

CH₂C(O)N(CH₂CH₃)₂, —

CH₂C(O)CH₃, —

CH₂C(CH₃)₂OCH₃, —

CH₂C(CH₃)₂F, —

CH₂C(CH₃)₂CF₃, —

CH(CFH₂)₂, —

C(O)N(CH₃)₂, —

C(O)C(CH₃)₃, —

C(O)C(CH₃)₂CF₃, —

C(O)—

[OCH₂CH₂]₆CH₃, —

C(O)—

[OCH₂CH₂]₂CH₃, —

CH₂-cyclopropyl, —

S(O)₂-phenyl, —

S(O)₂-cyclopropyl, —

C(O)-phenyl, —

C(O)-cyclopropyl, azetidin-3-ylsulfonyl, morpholin-4-ylethylsulfonyl, morpholin-4-ylcarbonyl, pyrrolidin-1-ylethylsulfonyl, pyridin-2-ylmethyl, piperidin-4-ylsulfonyl, 4-methylpiperazin-1-ylcarbonyl, 4-fluorophenylsulfonyl, 4-fluorophenylmethyl, 4-fluorophenyl, 4-chlorophenyl, 4-(morpholin-1-ylmethyl)phenyl, 3,5-difluorophenylmethyl, 3-(morpholin-4-ylmethyl)phenyl, 2,6-difluorophenylmethyl, 1-trifluoromethylcycloprop-1-ylmethyl, 1-trifluoromethylcycloprop-1-ylcarbonyl, 1-trifluoromethylcyclobut-1-ylmethyl, 1-trifluoromethylcyclobut-1-ylcarbonyl, 1-methylpiperidin-4-ylsulfonyl, 1-methylazetidin-3-ylsulfonyl, 1-fluorocycloprop-1-ylmethyl, and 1-fluorocyclobut-1-ylmethlyl.

8. The compound of claim 5, wherein

R² is selected from —

CH₂-aryl, —

CH₂-cycloalkyl, —

C(O)-cycloalkyl, and —

R⁴—

C(R⁵)(R⁶)—

R⁷, wherein;

R⁴ is —

CH₂—

;

each of R⁵ and R⁶ is independently selected from fluoro and —

CH₃;

R⁷ is selected from hydrogen, fluoro, —

CH₃, —

CF₂H, —

CF₃, and —

CF₂CH₃;

any aryl or cycloalkyl portion of R² is optionally substituted with up to two substituents independently selected from fluoro and —

CF₃; and

n is 0.

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

CH₂CF₂CF₃, —

CH₂CF₂CH₃, —

CH₂CF₂CHF₂, —

CH₂CHF₂, —

CH₂CF₂CH₂CH₃, —

CH₂CF(CH₃)₂, —

C(CH₃)₂C(O)CH₃, —

C(O)C(CH₃)₂CH₂CH₃, —

C(O)C(CH₃)₂OCH₃, —

C(O)CF₂CH₂OCH₃, —

C(O)CH₂CH(CH₃)₂, —

CH(CH₃)CF₂H, —

CH₂C(CH₃)₂OCH₃, —

CH₂CF₂CH₂OCH₃, —

CH₂CH₂CN, —

S(O)₂C(CH₃)₃, 2,6-dimethylpyridin-4-ylmethyl, 1-fluorocyclobutylcarbonyl, 2-cyanopyridin-4-ylmethyl, 2-methylpyridin-4-ylmethyl, 2-trifluoromethylpyridin-4-ylmethyl, 3-fluorobenzyl, 3-fluoropyridin-4-ylmethyl, 4-cyanobenzyl, 4-cyanopyridin-3-ylmethyl, 4-methylcyclohexylcarbonyl, 5-cyanopyridin-2-ylmethyl, 5-fluoropyridin-3-ylmethyl, 6-methylpyridin-2-ylmethyl, 6-methylpyrimidin-4-ylmethyl, benzylcarbonyl, cyclobutylcarbonyl, cyclopropyl, pyrazin-2-ylmethyl, pyrimidin-4-ylmethyl 1-trifluoromethylcyclopropylmethyl, 1-trifluoromethylcyclobutylcarbonyl, 3,5-difluorophenylmethyl, 1-fluorocyclobutylmethyl, and 1-fluorocyclopropylmethyl.

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

CH₂CF₂CF₃, —

CH₂CF₂CH₃, —

CH₂CF₂CHF₂, —

CH₂CHF₂, —

CH₂CF₂CH₂CH₃, —

CH₂CF(CH₃)₂, 1-trifluoromethylcyclopropylmethyl, 1-trifluoromethylcyclobutylcarbonyl, 3,5-difluorophenylmethyl, 1-fluorocyclobutylmethyl, and 1-fluorocyclopropylmethyl.

22. A composition comprising a compound of claim 1;

and a pharmaceutically acceptable carrier.

23. A method of treating cancer in a patient comprising the step of administering to the patient in need thereof a compound according to claim 1.

11. A compound having structural formula II:

12. The compound of claim 11 having structural formula IIa:

13. The compound of claim 11 having structural formula IIb:

14. The compound of claim 13, wherein R¹¹ is selected from chloro, —

OCH₃, —

NH(CH₃), and —

CH₃.

15. The compound of claim 14, wherein R¹² is selected from 5-chloropyrimindin-2-yl, 5-fluoropyrimidin-2-yl, pyridin-3-yl, pyrazin-2-yl, 6-methylpyridin-3-yl, 5-fluoropyridin-2-yl, 5-(morpholin-4-ylmethyl)pyridin-2-yl, pyrimidin-4-yl, 5-bromopyrimidin-2-yl, and 1-acetylazetidin-3-yl.

16. The compound of claim 14, wherein R¹² is selected from 5-chloropyrimindin-2-yl, 5-fluoropyrimidin-2-yl, pyridin-3-yl, pyrazin-2-yl, 6-methylpyridin-3-yl, 5-fluoropyridin-2-yl, 5-(morpholin-4-ylmethyl)pyridin-2-yl, pyrimidin-4-yl, and 5-bromopyrimidin-2-yl.

17. A compound having structural formula III:

18. The compound of claim 17 having structural formula IIIa:

19. The compound of claim 17 having structural formula IIIb:

20. The compound of claim 19, wherein the moiety represented by

21. A compound selected from any one of:

24-30. -30. (canceled)