Therapeutic compounds and uses thereof

Patent metadata

Field	Value
Publication number	US-10183009-B2
Application number	US-201715592013-A
Country	US
Kind code	B2
Filing date	May 10, 2017
Priority date	Nov 10, 2014
Publication date	Jan 22, 2019
Grant date	Jan 22, 2019

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.

First claim

We claim:

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-methylpro

Assignees

• Genentech Inc
• Constellation Pharmaceuticals Inc

Inventors

• Albrecht Brian K
• Bellon Steven F
• Burdick Daniel J
• Cote Alexandre
• Crawford Terry
• Dakin Les A
• Hsiao-Wei Tsui Vickie
• Hewitt Michael Charles
• Leblanc Yves
• Magnuson Steven R
• Nasveschuk Christopher G
• Romero F Anthony
• Tang Yong
• Taylor Alexander M
• Wang Shumei

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P5/38

  of the suprarenal hormones · CPC title