Bromodomain inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9328117-B2
Application number	US-201214126877-A
Country	US
Kind code	B2
Filing date	Jun 15, 2012
Priority date	Jun 17, 2011
Publication date	May 3, 2016
Grant date	May 3, 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:
ring A is optionally substituted aryl or optionally substituted heteroaryl;
R 6 is optionally substituted alkyl;
R 7 is H or optionally substituted alkyl; or
R 6 and R 7 , together with the atom to which each is attached, forms a carbocyclic or heterocyclic, each of which is optionally substituted;
R 2 is H, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, haloalkyl, or —(CH 2 ) p R x ; or
R 2 and R 6 , together with the atoms to which each is attached, form a heterocyclic or heteroaryl ring, each of which is optionally substituted;
p is 1, 2, 3, 4, 5, or 6;

R 3 is H, OR A , NR A R B , N(R A )S(O) q R A R B , N(R A )C(O)R B , N(R A )C(O)NR A R B , N(R A )C(O)OR A , N(R A )C(S)NR A R B , or OC(O)R A ;
each R A is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O,S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen;
each R B is independently optionally substituted alkyl, optionally substituted alkenyl or optionally substituted alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted heterocyclic; optionally substituted carbocyclic; or hydrogen; or
R A and R B , together with the atoms to which each is attached, can form a heterocycloalkyl or a heteroaryl; each of which is optionally substituted;

R 5 is Me, Et, Pr, —CH 2 CF 3 , —CF 3 , CF 2 CF 3 , CN, F, Cl, Br, or I;
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, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
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 groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; and
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 groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted heteroaryl or heterocycloalkyl group; or
R′ and R″, together with the atoms to which each is attached, can form a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl; each of which is optionally substituted.

2. The compound according to claim 1 , wherein ring A is phenyl, napthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thiophenyl, pyrrolo, isoxazolyl, or isothiazolyl; each of which is optionally substituted.

3. The compound according to claim 1 , wherein R 6 is methyl, ethyl, propyl, butyl, pentyl, or hexyl; each of which is optionally substituted.

4. The compound according to claim 1 , wherein R 2 is H, methyl, ethyl, propyl, butylpentyl, hexyl, phenyl, or napthyl; each of which is optionally substituted.

5. The compound according to claim 1 , wherein R 3 is H, OR A , NR A R B , N(R A )C(O)R B , N(R A )C(O)OR A , or OC(O)R A .

6. The compound according to claim 1 , having the structural formula IV:

or a pharmaceutically acceptable salt thereof, wherein:
R 2 is optionally substituted alkyl;
R 6 is optionally substituted alkyl;
R 8 is selected from hydrogen, —C(O)NR A R B and —C(O)OR A , wherein each of R A and R B is independently selected from hydrogen or alkyl;
each R 10 is an independently selected substituent;
p is 1, 2, 3, 4, 5, or 6; and
m is 0, 1, 2 or 3.

7. The compound according to claim 6 , wherein R 2 is methyl.

8. The compound according to claim 6 , wherein R 5 is methyl.

9. The compound according to claim 6 , wherein R 6 is methyl.

10. The compound according to claim 6 , wherein R 8 is selected from hydrogen, —C(O)—N(CH 3 ) 2 , —C(O)—NH—CH 2 CH 3 , and —C(O)—O—CH 2 CH 3 .

11. The compound according to claim 6 , wherein m is 0 or 1; and when m is 1, R 10 is a para substituent selected from fluoro and chloro.

12. A compound selected from:

or a pharmaceutically acceptable salt thereof.

13. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

14. The composition according to claim 13 , further comprising an additional therapeutic agent.

15. A method of treating diffuse large B-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma, primary central nervous system lymphoma, T-cell lymphoma, or acute myelogenous leukemia in a patient in need thereof, comprising the step of administering to said patient a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

Assignees

• Albrecht Brian K
• Harmange Jean-Christophe
• Cote Alexandre
• Taylor Alexander M
• Constellation Pharmaceuticals Inc

Inventors

• Albrecht Brian K
• Harmange Jean-Christophe
• Cote Alexandre
• Taylor Alexander M

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title