IP Library › Granted Patent US 10,183,009
Granted Patent B2
US 10,183,009 · App. 15/592,013 · Granted Jan 22, 2019

Therapeutic compounds and uses thereof

Inventors: Brian K. Albrecht (Cambridge, MA); Steven F. Bellon (Cambridge, MA); Daniel J. Burdick (South San Francisco, CA); Alexandre Cote (Cambridge, MA); Terry Crawford (South San Francisco, CA); Les A. Dakin (Cambridge, MA); Vickie Hsiao-Wei Tsui (South San Francisco, CA); Michael Charles Hewitt (Cambridge, MA); Yves LeBlanc (Cambridge, MA); Steven R. Magnuson (South San Francisco, CA); Christopher G. Nasveschuk (Cambridge, MA); F. Anthony Romero (South San Francisco, CA); Yong Tang (Cambridge, MA); Alexander M. Taylor (Cambridge, MA); Shumei Wang (South San Francisco, CA)
Assignees: GENENTECH, INC.; CONSTELLATION PHARMACEUTICALS, INC.
A61K31/40C07D471/04
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Quick Facts
Patent No.
US 10,183,009
App. No.
15/592,013
Granted
Jan 22, 2019
Kind
B2
Abstract

The present invention relates to compounds of formula (I): and to salts thereof, wherein R 1 , R 2 , and Q have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of bromodomains. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various bromodomain-mediated disorders.

Claims (169)

1. A compound of formula (I):

or a salt thereof, wherein:

R 1 is methyl substituted with one or more groups R m , ethyl substituted with one or more groups R n , C 3-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, or heterocyclyl, wherein any C 3-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, or heterocyclyl of R 1 is optionally substituted with one or more groups R a ;

R 2 is H, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-8 cycloalkyl, wherein each C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, or C 3-8 cycloalkyl of R 2 is optionally substituted with one or more groups R b ;

Q is carbocyclyl or heterocyclyl, which carbocyclyl or heterocyclyl is optionally substituted with one or more groups R c ;

each R a is independently selected from the group consisting of oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO 2 , —N(R v ) 2 , —CN, —C(O)—N(R v ) 2 , —S(O)—N(R v ) 2 , —S(O) 2 —N(R v ) 2 , —O—R v , —S—R v , —O—C(O)—R v , —O—C(O)—O—R v , —C(O)—R v , —C(O)—O—R v , —S(O)—R v , —S(O) 2 —R v , —O—C(O)—N(R v ) 2 , —N(R v )—C(O)—OR v , —N(R v )—C(O)—N(R v ) 2 , —N(R v )—C(O)—R v , —N(R v )—S(O)—R v , —N(R v )—S(O) 2 —R v , —N(R v )—S(O)—N(R v ) 2 , and —N(R v )—S(O) 2 —N(R v ) 2 ;

each R b is independently selected from the group consisting of oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO 2 , —N(R w ) 2 , —CN, —C(O)—N(R w ) 2 , —S(O)—N(R w ) 2 , —S(O) 2 —N(R w ) 2 , —O—R w , —S—R w , —O—C(O)—R w , —O—C(O)—O—R w , —C(O)—R w , —C(O)—O—R w , —S(O)—R w , —S(O) 2 —R w , —O—C(O)—N(R w ) 2 , —N(R w )—C(O)—OR w , —N(R w )—C(O)—N(R w ) 2 , —N(R w )—C(O)—R w , —N(R w )—S(O)—R w , —N(R w )—S(O) 2 —R w , —N(R w )—S(O)—N(R w ) 2 , and —N(R w )—S(O) 2 —N(R w ) 2 , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, or heterocyclyl of R b is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R w ) 2 , —CN, —C(O)—N(R w ) 2 , —S(O)—N(R w ) 2 , —S(O) 2 —N(R w ) 2 , —O—R w , —S—R w , —O—C(O)—R w , —C(O)—R w , —C(O)—O—R w , —S(O)—R w , —S(O) 2 —R w , —C(O)—N(R w ) 2 , —N(R w )—C(O)—R w , —N(R w )—S(O)—R w , —N(R w )—S(O) 2 —R w and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;

each R c is independently selected from the group consisting of oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO 2 , —N(R u ) 2 , —CN, —C(O)—N(R u ) 2 , —S(O)—N(R u ) 2 , —S(O) 2 —N(R u ) 2 , —O—R u , —S—R u , —O—C(O)—R u , —O—C(O)—O—R u , —C(O)—R u , —C(O)—O—R u , —S(O)—R u , —S(O) 2 —R u , —O—C(O)—N(R u ) 2 , —N(R u )—C(O)—OR u , —N(R u )—C(O)—N(R u ) 2 , —N(R u )—S(O)—R u , —N(R u )—S(O) 2 —R u , —N(R u )—S(O)—N(R u ) 2 , and —N(R u )—S(O) 2 —N(R u ) 2 , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, or heterocyclyl of R is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R u ) 2 , —CN, —C(O)—N(R u ) 2 , —S(O)—N(R u ) 2 , —S(O) 2 —N(R u ) 2 , —O—R u , —S—R u , —O—C(O)—R u , —C(O)—R u , —C(O)—O—R u , —S(O)—R u , —S(O) 2 —R u , —N(R u )—C(O)—R u , —N(R u )—S(O)—R u , —N(R u )—S(O) 2 —R u and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;

each R m is independently selected from the group consisting of oxo, carbocyclyl, heterocyclyl, —F, —NO 2 , —CN, —C(O)—N(R v ) 2 , —S(O)—N(R v ) 2 , —S(O) 2 —N(R v ) 2 , —C(O)—R v , —C(O)—O—R v , —S(O)—R v , and —S(O) 2 —R v , wherein carbocyclyl is optionally substituted with one or more —O—R v ;

each R n is independently selected from the group consisting of oxo, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO 2 , —N(R v ) 2 , —CN, —C(O)—N(R v ) 2 , —S(O)—N(R v ) 2 , —S(O) 2 —N(R v ) 2 , —O—R v , —S—R v , —O—C(O)—R v , —O—C(O)—O—R v , —C(O)—R v , —C(O)—O—R v , —S(O)—R v , —S(O) 2 —R v , —O—C(O)—N(R v ) 2 , —N(R v )—C(O)—OR v , —N(R v )—C(O)—N(R v ) 2 , —N(R v )—C(O)—R v , —N(R v )—S(O)—R v , —N(R v )—S(O) 2 —R v , —N(R v )—S(O)—N(R v ) 2 , and —N(R v )—S(O) 2 —N(R v ) 2 ;

each R u is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, or heterocyclyl of R u is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —N(R ua ) 2 , hydroxyl, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R u are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, C 1-3 alkyl and heteroaryl wherein C 1-3 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, hydroxyl, —N(R ua ) 2 , halo, and heteroaryl that is optionally substituted with one or more —N(R ua ) 2 ;

each R v is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, or heterocyclyl of R v is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —N(R va ) 2 , hydroxyl, carbocyclyl, heterocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R v are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;

each R w is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, or heterocyclyl of R w is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —N(R wa ) 2 , hydroxyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R w are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo;

each R ua is independently selected from the group consisting of hydrogen and C 1-6 alkyl;

each R va is independently selected from the group consisting of hydrogen and C 1-6 alkyl; and

each R wa is independently selected from the group consisting of hydrogen and C 1-6 alkyl.

2. The compound of claim 1 wherein R 1 is methyl that is substituted with one or more groups R m .

3. The compound of claim 1 wherein R 1 is ethyl that is substituted with one or more groups R n .

4. The compound of claim 1 wherein R 1 is butyl, 2-cyclopropylethyl, cyclopentylmethyl, 2-penten-1-yl, cyclohexylmethyl, cyclobutylmethyl, 2-cyclohexylethyl, pentyl, 2-methylpropyl, 2-buten-1-yl, butyl, 2-furylmethyl, 3-methylbut-1-yl, 2-propenyl, 3-methyl-2-buten-1-yl, 3-buten-1-yl, 2-methoxyethyl, 3-methoxypropyl, or 4-methoxybenzyl.

5. The compound of claim 1 wherein R 2 is methyl.

6. The compound of claim 1 wherein Q is C 3 -C 8 cycloalkyl that is optionally substituted with one or more groups R c .

7. The compound of claim 1 wherein Q is aryl that is optionally substituted with one or more groups R c .

8. The compound of claim 1 wherein Q is phenyl that is optionally substituted with one or more groups R c .

9. The compound of claim 1 wherein Q is C 3 -C 8 heterocycloalkyl that is optionally substituted with one or more groups R c .

10. The compound of claim 1 wherein Q is heteroaryl that is optionally substituted with one or more groups R c .

11. The compound of claim 1 wherein Q is:

wherein:

ring A is optionally substituted with one or more groups R g , or ring A is optionally fused with a carbocyclyl or a heterocyclyl to form a polycyclyl that is optionally substituted with one or more groups R g ;

R e is hydrogen, —F, —Cl, —Br, —I, —CN, —O—R x , C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R x ) 2 , —CN, —C(O)—N(R x ) 2 , —S(O)—N(R x ) 2 , —S(O) 2 —N(R x ) 2 , —O—R x , —S—R x , —O—C(O)—R x , —C(O)—R x , —C(O)—O—R x , —S(O)—R x , —S(O) 2 —R x , —N(R x )—C(O)—R x , —N(R x )—S(O)—R x , and —N(R x )—S(O) 2 —R x ;

R f is hydrogen, —F, —Cl, —Br, —I, —CN, —O—R y , C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, —F, —Cl, —Br, —I, —NO 2 , —N(R y ) 2 , —CN, —C(O)—N(R y ) 2 , —S(O)—N(R y ) 2 , —S(O) 2 —N(R y ) 2 , —O—R y , —S—R y , —O—C(O)—R y , —C(O)—R y , —C(O)—O—R y , —S(O)—R y , —S(O) 2 —R y , —N(R y )—C(O)—R y , —N(R y )—S(O)—R y and —N(R y )—S(O) 2 —R y ;

each R g is independently selected from the group consisting of oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —Br, —I, —NO 2 , —N(R z ) 2 , —CN, —C(O)—N(R z ) 2 , —S(O)—N(R z ) 2 , —S(O) 2 —N(R z ) 2 , —O—R z , —S—R z , —O—C(O)—R z , —O—C(O)—O—R z , —C(O)—R z , —C(O)—O—R z , —S(O)—R z , —S(O) 2 —R z , —O—C(O)—N(R z ) 2 , —N(R z )—C(O)—OR z , —N(R z )—C(O)—N(R z ) 2 , —N(R z )—C(O)—R z , —N(R z )—S(O)—R z , —N(R z )—S(O) 2 —R z , —N(R z )—S(O)—N(R z ) 2 , and —N(R z )—S(O) 2 —N(R z ) 2 , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, or heterocyclyl of R g is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R z ) 2 , —CN, —C(O)—N(R z ) 2 , —S(O)—N(R z ) 2 , —S(O) 2 —N(R z ) 2 , —O—R z , —S—R z , —O—C(O)—R z , —C(O)—R z , —C(O)—O—R z , —S(O)—R z , —S(O) 2 —R z , —N(R z )—C(O)—R z , —N(R z )—S(O)—R z , —N(R z )—S(O) 2 —R z and C 1-6 alkyl and heteroaryl wherein C 1-3 alkyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, hydroxyl, —N(R ua ) 2 , halo, and heteroaryl that is optionally substituted with one or more —N(R ua ) 2 ;

each R x is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxyl, and C 1 -C 6 alkyl;

each R y is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxyl, and C 1 -C 6 alkyl; and

each R z is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, and heterocyclyl, wherein each C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, amino, hydroxyl, heterocyclyl, carbocyclyl, and C 1 -C 6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo; or two R z are taken together with the nitrogen to which they are attached to form a heterocyclyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo and C 1-3 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo.

12. The compound of claim 1 , wherein each R c is independently selected from the group consisting of oxo, C 1-6 alkyl, heterocyclyl, —F, —Cl, —CN, —C(O)—N(R u ) 2 , —O—R u , and —N(R u )—S(O) 2 —R u , wherein any C 1-6 alkyl or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of —O—R u and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo.

13. The compound of claim 1 wherein Q is selected from the group consisting of:

14. The compound of claim 1 that is selected from the group consisting of:

3-(6-allyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

3-(6-butyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

N,N-dimethyl-3-[6-(3-methylbut-2-enyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]benzamide;

3-[6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

3-[6-(cyclopentylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

3-[6-[(4-methoxyphenyl)methyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

N,N-dimethyl-3-[7-oxo-6-[(E)-pent-2-enyl]-1H-pyrrolo[2,3-c]pyridin-4-yl]benzamide;

3-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

3-[6-(cyclohexylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

3-(6-isopentyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

3-[6-(cyclobutylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

3-[6-(2-cyclohexylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

N,N-dimethyl-3-(7-oxo-6-pentyl-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;

3-[6-(2-methoxyethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

3-[6-(3-methoxypropyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

3-(6-isobutyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

3-[6-(cyclopropylmethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N,N-dimethylbenzamide;

6-but-3-enyl-4-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-5-fluoro-N,N-dimethylbenzamide;

4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluorobenzamide;

6-but-2-enyl-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-fluorobenzamide;

6-but-2-enyl-4-(4-tert-butylphenyl)-1H-pyrrolo[2,3-c]pyridin-7-one;

4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylbenzamide;

3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-methylbenzamide;

3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-cyclopropylbenzamide;

6-but-2-enyl-4-[3-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-cyclopropylbenzamide;

6-but-2-enyl-4-[4-(hydroxymethyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)benzamide;

6-but-2-enyl-4-(4-isopropylphenyl)-1H-pyrrolo[2,3-c]pyridin-7-one;

3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

6-but-2-enyl-4-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

N-[4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]methanesulfonamide;

3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N-isopropylbenzamide;

4-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

6-but-2-enyl-4-[4-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-(6-but-2-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy-benzonitrile;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluorobenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-fluorobenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-fluoro-N,N-dimethylbenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-fluoro-N,N-dimethylbenzamide;

4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chloro-N,N-dimethylbenzamide;

4-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chlorobenzamide;

6-(2-furylmethyl)-4-phenyl-1H-pyrrolo[2,3-c]pyridin-7-one;

3-(6-butyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy-benzonitrile;

3-[6-(2-cyclopropylethyl)-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-benzonitrile;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclopropyl-4-methoxybenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N,N-dimethylbenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-tetrahydrofuran-3-ylbenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-ethyl-4-methoxybenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-methylbenzamide;

6-[(E)-but-2-enyl]-4-[2-methoxy-5-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(2,2-difluoroethyl)-4-methoxybenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-isobutyl-4-methoxybenzamide;

4-[5-(azetidine-1-carbonyl)-2-methoxy-phenyl]-6-[(E)-but-2-enyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-[2-(dimethylamino)ethyl]-4-methoxybenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(2-hydroxyethyl)-4-methoxybenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-propylbenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-cyclobutyl-4-methoxybenzamide;

3-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-N-(cyclopropylmethyl)-4-methoxybenzamide;

4-[5-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-methoxy-phenyl]-6-[(E)-but-2-enyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

4-[5-(6-acetyl-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2-methoxy-phenyl]-6-butyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-butyl-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-butyl-4-(4-(2-hydroxypropan-2-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-7(6H)-one;

6-(2-cyclopropylethyl)-4-[4-(1-hydroxy-1-methyl-ethyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-(6-(2-cyclopropylethyl)-2-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

3-(6-butyl-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethylbenzamide;

3-(6-butyl-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-4-methoxy-N,N-dimethylbenzamide;

3-[6-(2-cyclopropylethyl)-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N,N-dimethylbenzamide;

7-[6-[(E)-but-2-enyl]-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2-one;

6-but-3-enyl-4-[3,4-difluoro-5-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[3-fluoro-5-(3-methylmorpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

3-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-5-(morpholine-4-carbonyl)benzonitrile

6-[(E)-but-2-enyl]-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[3-chloro-4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[3-fluoro-5-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[4-fluoro-3-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[3-(difluoromethoxy)-5-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[6-(morpholine-4-carbonyl)-1H-benzimidazol-4-yl]-1H-pyrrolo[2,3-c]pyridin-7-one;

7-(6-but-3-enyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl)-N,N-dimethyl-3H-benzimidazole-5-carboxamide;

6-but-3-enyl-4-[7-(morpholine-4-carbonyl)-3H-benzimidazol-5-yl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[3-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[3-ethyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[1-methyl-7-(morpholine-4-carbonyl)benzimidazol-5-yl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[1-methyl-6-(morpholine-4-carbonyl)benzimidazol-4-yl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[4-chloro-3-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-2-methyl-4-[4-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-2-methyl-4-[4-(pyrrolidine-1-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one

6-[(E)-but-2-enyl]-4-[3-chloro-4-(pyrrolidine-1-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[2,3-difluoro-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[3-methoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[3-fluoro-5-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-but-3-enyl-4-[4-fluoro-3-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[5-chloro-6-(morpholine-4-carbonyl)-3-pyridyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[3-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-2-methyl-4-[3-methyl-4-(morpholine-4-carbonyl)phenyl]-1H-pyrrolo[2,3-c]pyridin-7-one;

6-allyl-4-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-allyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[3-methoxy-5-(morpholine-4-carbonyl)-2-pyridyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[4-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-2-methyl-4-[2-(morpholine-4-carbonyl)pyrimidin-5-yl]-1H-pyrrolo[2,3-c]pyridin-7-one;

5-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-(morpholine-4-carbonyl)benzonitrile;

6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2-methoxy-phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one

6-[(E)-but-2-enyl]-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-(pyrazin-2-ylmethyl)benzamide

6-but-2-enyl-4-[3-methoxy-5-(4-methylpiperazine-1-carbonyl)-2-pyridyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[6-chloro-5-(morpholine-4-carbonyl)-2-pyridyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

1-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chloro-benzoyl]piperidine-4-carboxylic acid;

1-[4-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-2-chloro-benzoyl]piperidine-4-carboxamide;

6-[(E)-but-2-enyl]-4-[3-isopropoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[3-(cyclopropylmethoxy)-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

4-[4-[3-(3-aminopyrazol-1-yl)azetidine-1-carbonyl]-3-chloro-phenyl]-6-[(E)-but-2-enyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

4-[4-[3-(3-aminopyrazol-1-yl)azetidine-1-carbonyl]phenyl]-6-[(E)-but-2-enyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-[(E)-but-2-enyl]-4-[4-(1-hydroxy-1-methyl-ethyl)-2,5-dimethoxy-phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

3-[6-[(E)-but-2-enyl]-2-methyl-7-oxo-1H-pyrrolo[2,3-c]pyridin-4-yl]-4-methoxy-N-(pyrimidin-5-ylmethyl)benzamide;

6-butyl-4-[2,5-dimethoxy-4-(morpholine-4-carbonyl)phenyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

6-butyl-4-[3-methoxy-5-(4-methylpiperazine-1-carbonyl)-2-pyridyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one; and

6-butyl-4-[3-methoxy-5-(morpholine-4-carbonyl)-2-pyridyl]-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-one;

or a salt thereof.

15. A composition comprising a compound of formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

16. A method for treating a bromodomain-mediated disorder in an animal comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof as described in claim 1 , to the animal, wherein the bromodomain-mediated disorder is cancer.

17. A method of increasing efficacy of a cancer treatment comprising a cytotoxic agent in an animal comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 .

18. A method of delaying or preventing development of cancer resistance to a cytotoxic agent in an animal, comprising administering to the animal a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 .

19. A method of extending the duration of response to a cancer therapy in an animal, comprising administering to an animal undergoing the cancer therapy a compound of formula (I) or a pharmaceutically acceptable salt thereof, as described in claim 1 , wherein the duration of response to the cancer therapy when the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered is extended over the duration of response to the cancer therapy in the absence of the administration of the compound of formula (I) or the pharmaceutically acceptable salt thereof.

20. A method of treating cancer in an individual comprising administering to the individual (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof as described in claim 1 , and (b) a cytotoxic agent.

21. The compound of claim 1 , wherein each R c is independently selected from the group consisting of oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, heterocyclyl, —F, —Cl, —N(R u ) 2 , —CN, —C(O)—N(R u ) 2 , —O—R u , and —N(R u )—S(O) 2 —R u , wherein any C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, carbocyclyl, or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R u ) 2 , —CN, —C(O)—N(R u ) 2 , —S(O)—N(R u ) 2 , —S(O) 2 —N(R u ) 2 , —O—R u , —S—R u , —O—C(O)—R u , —C(O)—R u , —C(O)—O—R u , —S(O)—R u , —S(O) 2 —R u , —N(R u )—C(O)—R u , —N(R u )—S(O)—R u , —N(R u )—S(O) 2 —R u , and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo.

22. The compound of claim 1 , wherein each R is independently selected from the group consisting of oxo, C 1-6 alkyl, heterocyclyl, —F, —Cl, —CN, —C(O)—N(R u ) 2 , —O—R u , and —N(R u )—S(O) 2 —R u , wherein any C 1-6 alkyl or heterocyclyl is optionally substituted with one or more groups independently selected from the group consisting of oxo, halo, —NO 2 , —N(R u ) 2 , —CN, —C(O)—N(R u ) 2 , —S(O)—N(R u ) 2 , —S(O) 2 —N(R u ) 2 , —O—R u , —S—R u , —O—C(O)—R u , —C(O)—R u , —C(O)—O—R u , —S(O)—R u , —S(O) 2 —R u , —N(R u )—C(O)—R u , —N(R u )—S(O)—R u , —N(R u )—S(O) 2 —R u and C 1-6 alkyl that is optionally substituted with one or more groups independently selected from the group consisting of oxo and halo.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 31, 2018
From: ALBRECHT, BRIAN K.; BELLON, STEVEN F.; COTE, ALEXANDRE; DAKIN, LES A.; HEWITT, MICHAEL CHARLES; LEBLANC, YVES; NASVESCHUK, CHRISTOPHER C.; TANG, YONG; TAYLOR, ALEXANDER M.
To: CONSTELLATION PHARMACEUTICALS, INC.
Reel/Frame 045951/0932 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2017
From: BURDICK, DANIEL J.; CRAWFORD, TERRY; TSUI, VICKIE HSIAO-WEI; MAGNUSON, STEVEN R.; ROMERO, F. ANTHONY; WANG, SHUMEI
To: GENENTECH, INC.
Reel/Frame 042819/0324 →
Continuity (3)
Continuation PCTUS2015060003 · Nov 10, 2015
Provisional Application 62077703 · Nov 10, 2014
Related Publication 20170340605A1 · Nov 30, 2017
Cited By (4)
US 12,391,686 US 12,528,825 US 12,590,079 US 12,686,687