Modulators of methyl modifying enzymes, compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-9745305-B2
Application number	US-201414769471-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 15, 2013
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

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

First claim

We 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-(methylsulfonyl(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

or a pharmaceutically acceptable salt thereof.

17. A composition comprising a compound of claim 1 ; and a pharmaceutically acceptable carrier.

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