Modulators of methyl modifying enzymes, compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-2016009718-A1
Application number	US-201414769471-A
Country	US
Kind code	A1
Filing date	Mar 12, 2014
Priority date	Mar 15, 2013
Publication date	Jan 14, 2016
Grant date	—

Abstract

Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.

First claim

1 . A compound having structural formula I:

or a pharmaceutically acceptable salt or tautomer thereof, wherein:
Z is C(R 9 ) or N;
one of Y 1 or Y 2 is N and the other is C;
one of X 1 , X 2 , X 3 , or X 4 is N and each of the others is independently C(R 5 );
each of R 1 , R 2 and R 9 is independently selected from hydrogen, halo, —OH, —CN, C 1 -C 4 alkyl, —O—(C 1 -C 4 alkyl), —N(R 7 ) 2 , —(C 0 -C 4 alkylene)-aryl, —(C 0 -C 4 alkylene)-heteroaryl, —(C 0 -C 4 alkylene)-heterocyclyl, and —(C 0 -C 4 alkylene)-carbocyclyl; or
R 1 and R 9 are taken together with atoms to which they are bound to form an aryl, heteroaryl, heterocyclyl, or carbocyclyl ring; or
R 2 and R 9 are taken together with atoms to which they are bound to form an aryl, heteroaryl, heterocyclyl, or carbocyclyl ring;
each of R 3 , R 4 and R 5 is independently selected from hydrogen, halo, —CN, —(C 0 -C 4 alkylene)-R 8 , —(C 2 -C 6 alkenylene or alkynylene)-R 6 , —(C 1 -C 4 alkylene)-O—R 6 , —(C 1 -C 4 alkylene)-O—(C 1 -C 4 alkylene)-R 8 , —O—(C 0 -C 4 alkylene)-R 6 , —O—(C 2 -C 4 alkylene)-O—R 8 , —O—(C 1 -C 4 alkylene)-R 6 , —(C 0 -C 4 alkylene)-N(R 7 ) 2 , —(C 0 -C 4 alkylene)-C(O)—O—R 6 , —(C 0 -C 4 alkylene)-O—C(O)—R 6 , —(C 0 -C 4 alkylene)-C(O)—N(R 7 ) 2 , —(C 0 -C 4 alkylene)-N(R 7 )—C(O)—R 6 , —O—(C 1 -C 4 alkylene)-C(O)—N(R 7 ) 2 , —O—(C 2 -C 4 alkylene)-N(R 7 )—C(O)—(R 7 ), —(C 0 -C 4 alkylene)-S(O)—R 8 , —(C 0 -C 4 alkylene)-S(O) 2 —R 8 , —(C 0 -C 4 alkylene)-S(O) 2 —N(R 7 ) 2 , —(C 0 -C 4 alkylene)-N(R 7 )—S(O) 2 —R 8 , and —(C 0 -C 4 alkylene)-C(O)—R 8 ;
each R 6 is independently selected from hydrogen or R 8 ;
each R 7 is independently selected from hydrogen, —(C 0 -C 4 alkylene)-R 6 , —(C 0 -C 4 alkylene)-O—R 6 , —S(O) 2 —R 8 , —C(═O)—R 8 , —C(═O)—N(R 6 ) 2 , —(C 1 -C 4 alkylene)-O—C(═O)—R 8 and —(C 0 -C 4 alkylene)-C(═O)—O—R 6 ; or
two R 7 are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl or heteroaryl;
R 8 is selected from C 1 -C 4 alkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl;

wherein unless otherwise designated any alkyl, alkylene, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl or carbocyclyl portion of the compound is optionally substituted.

2 . The compound of claim 1 , wherein Z is CH.

3 . The compound of claim 1 , wherein each of R 1 and R 2 is independently selected from —C 1 -C 3 alkyl, —C 1 -C 3 haloalkyl, O—(C 1 -C 3 alkyl) and —O—(C 1 -C 3 haloalkyl).

4 . The compound of claim 3 , wherein R 1 is methyl.

5 . The compound of claim 4 , wherein R 2 is selected from —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —OCH 3 , and —OCHF 2 .

6 . The compound of claim 5 , wherein Y 1 is N and X 4 is N.

7 . The compound of claim 6 , wherein X 5 is selected from C(H), C(OCH 3 ) and C(CH 3 ).

8 . The compound of claim 5 , wherein Y 1 is N and X 2 is N.

9 . The compound of claim 5 , wherein Y 2 is N and X 3 is N.

10 . The compound of claim 9 , wherein R 3 is methyl or chloro.

11 . The compound of claim 10 , wherein R 4 is selected from -heteroaryl, —CH(CH 3 )-heterocyclyl, —CH(CH 3 )-heteroaryl, —CH(CH 3 )-aryl, —CH(CH 3 )-carbocyclyl, —CH(CH 3 )—N(R 10 )—S(O) 2 —(C 1 -C 4 alkyl), —CH(CH 3 )—N(R 10 )—C(O)—(C 1 -C 4 alkyl), and —CH(CH 3 )N(R 10 ) 2 , wherein R 10 is selected from hydrogen and C 1 -C 4 alkyl, and wherein any aryl, heteroaryl, heterocyclyl or carbocyclyl portion of R 4 is optionally substituted.

12 . The compound of claim 11 , wherein R 4 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 R 4 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 R 5 is hydrogen.

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

or a pharmaceutically acceptable salt or tautomer thereof, wherein:
each of R 1 , R 2 and R 9 is independently selected from hydrogen, C 1 -C 4 alkyl, and —O—(C 1 -C 4 alkyl);
one of Y 1 or Y 2 is N and the other is C;
one of X 2 , X 3 , or X 4 is N and each of the others is independently CH or —O—(C 1 -C 4 alkyl);
R 3 is selected from hydrogen, halo, and C 1 -C 4 alkyl;
R 4 is selected from —C(O)—R 8 , —(C 0 -C 4 alkylene)-R 8 , and —(C 0 -C 4 alkylene)-N(R 7 ) 2 ;
R 7 is selected from hydrogen, C 1 -C 4 alkyl, —S(O) 2 —C 1 -C 4 alkyl, and —C(═O)—C 1 -C 4 alkyl; or
two R 7 are taken together with the nitrogen atom to which they are commonly bound to form an optionally substituted heterocyclyl; and
R 8 is selected from C 1 -C 4 alkyl, aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein each of the aryl, heteroaryl, carbocyclyl and heterocyclyl are optionally substituted.

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.

19 - 24 . (canceled)

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.

Assignees

• Constellation Pharmaceuticals Inc

Inventors

• Albrecht Brian K
• Audia James Edmund
• Cook Andrew
• Côté Alexandre
• Dakin Les A
• Gehling Victor S
• Harmange Jean-Christophe
• Nasveschuk Christopher G
• Vaswani Rishi G

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title