Bromodomain inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9422292-B2
Application number	US-201214114983-A
Country	US
Kind code	B2
Filing date	May 4, 2012
Priority date	May 4, 2011
Publication date	Aug 23, 2016
Grant date	Aug 23, 2016

Abstract

The present invention relates to compounds useful as inhibitors of bromodomain-containing proteins. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders.

First claim

We claim:

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is alkyl, alkenyl, alkynyl, aralkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or halo, each of which is optionally substituted; or CN, OR A , NR A R B , N(R C )S(O) q R A R B , N(R A )C(O)R B , N(R C )C(O)NR A R B , N(R A )C(O)OR A , N(R C )C(S)NR A R B , S(O) q R A , C(O)R A , C(O)OR A , OC(O)R A , or C(O)NR A R B ;
each R A is independently optionally substituted alkyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen;
each R B is independently optionally substituted alkyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen;
each R C is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen;

each of A 1 , A 2 , A 3 , and A 4 is independently CR, N, NR, O, or S;
B is phenyl optionally substituted with 1 to 5 independently selected R 4 groups;
R 2 and R 3 are each independently H, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R, —CO 2 R, C(O)N(R′)(R″), —C(O)SR, or —(CH 2 ) p R x ; or
R 2 and R 3 together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R 6 is H, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl —OR, —SR, —N(R′)(R″), —C(O)R, —CO 2 R, —C(O)N(R′)(R″), or —(CH 2 ) p R x ;
R 7 is H, halogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, —OR, —SR, —N(R′)(R″), —C(O)R, —CO 2 R, —C(O)N(R′)(R″), or —(CH 2 ) p R x ;
or R 6 and R 7 together with the atoms to which each is attached, forms an optionally substituted 3-7 membered saturated or unsaturated spiro-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or any one of R 2 and R 3 , together with any one of R 6 and R 7 , together with the atoms to which each is attached, may form an optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
each R x is independently halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, —OR, —SR, —CN, —N(R′)(R″), —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO 2 R, —SO 2 N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″), —N(R′)C(S)N(R′)(R″), —N(R′)SO 2 R, —N(R′)SO 2 N(R′)(R″), —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″), —OC(O)R, —OC(O)N(R′)(R″);
each R is independently hydrogen, C 1-6 aliphatic, a 5-6 membered aryl ring, a 3-7 membered saturated, partially unsaturated, or completely unsaturated carbocyclic ring, a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated carbocyclic ring, a 3-7 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 3-7 membered saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; each of which is optionally substituted;
each R′ is independently —R, —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R) 2 , —C(S)N(R) 2 , —S(O)R, —SO 2 R, —SO 2 N(R) 2 , or two R on the same nitrogen are taken together with their intervening atoms to form a 3-7 membered monocyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of which is optionally substituted;
each R″ is independently —R, —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R) 2 , —C(S)N(R) 2 , —S(O)R, —SO 2 R, —SO 2 N(R) 2 , or two R on the same nitrogen are taken together with their intervening atoms to form a 3-7 membered monocyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of which is optionally substituted; or
R′ and R″, together with the atoms to which each is attached, can form a 3-7 membered monocyclic saturated, partially unsaturated, or completely unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-12 membered bicyclic saturated, partially unsaturated, or completely unsaturated fused heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered monocyclic heteroaryl ring; or a 7-12 membered bicyclic heteroaryl; each of which is optionally substituted;
each R 4 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, halogen, —OR, —SR, —N(R′)(R″), —CN, —NO 2 , —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO 2 R, —SO 2 N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″), —N(R′)C(S)N(R′)(R″), —N(R′)SO 2 R, —N(R′)SO 2 N(R′)(R″), —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R 1 )(R″);
each R 5 is independently —R, halogen, —OR, —SR, —N(R′)(R″), —CN, —NO 2 , —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R′)(R″), —C(O)SR, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)N(R′)(R″), —C(S)OR, —S(O)R, —SO 2 R, —SO 2 N(R′)(R″), —N(R′)C(O)R, —N(R′)C(O)N(R′)(R″), —N(R′)C(S)N(R′)(R″), —N(R′)SO 2 R, —N(R′)SO 2 N(R′)(R″), —N(R′)N(R′)(R″), —N(R′)C(═N(R′))N(R′)(R″), —C═NN(R′)(R″), —C═NOR, —C(═N(R′))N(R′)(R″), —OC(O)R, or —OC(O)N(R 1 )(R″);
r is 0 or 1;
n is 0-5;
each q is independently 0, 1, or 2; and
each p is independently an integer selected from 1-6.

Assignees

• Albrecht Brian K
• Gehling Victor S
• Hewitt Michael Charles
• Taylor Alexander M
• Harmange Jean-Christophe
• Constellation Pharmaceuticals Inc

Inventors

• Albrecht Brian K
• Gehling Victor S
• Hewitt Michael Charles
• Taylor Alexander M
• Harmange Jean-Christophe

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title