Bromodomain inhibitors and uses thereof

Patent metadata

Field	Value
Publication number	US-9249161-B2
Application number	US-201113990906-A
Country	US
Kind code	B2
Filing date	Dec 2, 2011
Priority date	Dec 2, 2010
Publication date	Feb 2, 2016
Grant date	Feb 2, 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:
Hy is a 5-membered fused heteroaryl ring having 2-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 6-membered fused heteroaryl ring having 2-3 nitrogen atoms;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L 1 is a covalent bond or an optionally substituted bivalent C 1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by —NR′—, —N(R′)C(O)—, —C(O)N(R′)-, —N(R′)SO 2 —, —SO 2 N(R′)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —;
p is 0-3;
R x is halogen, optionally substituted C 1-6 aliphatic, —OR, —SR, —CN, —N(R′) 2 , —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R′) 2 , —C(O)SR, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)N(R′) 2 , —C(S)OR, —S(O)R, —SO 2 R, —SO 2 N(R′) 2 , —N(R′)C(O)R, —N(R′)C(O)N(R′) 2 , —N(R′)C(S)N(R′) 2 , —N(R′)SO 2 R, —N(R′)SO 2 N(R′) 2 , —N(R′)N(R′) 2 , —N(R′)C(═N(R′))N(R′) 2 , —C═NN(R′) 2 , —C═NOR, —C(═N(R′))N(R′) 2 , —OC(O)R, —OC(O)N(R′) 2 ;
R 1 and R 2 are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated or partially unsaturated spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 7-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
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 an optionally substituted group selected from a 4-7 membered monocyclic saturated or partially unsaturated ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 7-12 membered bicyclic saturated, partially unsaturated, or aromatic fused ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
W is

R 3 and X are taken together with their intervening atoms to form an optionally substituted triazolyl ring;
each of m and n is independently 0-4, as valency permits; and
each of R 4 and R 5 is independently —R, halogen, —OR, —SR, —N(R′) 2 , —CN, —NO 2 , —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R′) 2 , —C(O)SR, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)N(R′) 2 , —C(S)OR, —S(O)R, —SO 2 R, —SO 2 N(R′) 2 , —N(R′)C(O)R, —N(R′)C(O)N(R′) 2 , —N(R′)C(S)N(R′) 2 , —N(R′)SO 2 R, —N(R′)SO 2 N(R′) 2 , —N(R′)N(R′) 2 , —N(R′)C(═N(R′))N(R′) 2 , —C═NN(R′) 2 , —C═NOR, —C(═N(R′))N(R′) 2 , —OC(O)R, or —OC(O)N(R′) 2 .

2. The compound according to claim 1 , wherein Hy is pyrimidino, pyrazino, isothiazolo, or pyridazino.

3. The compound according to claim 1 , wherein Ring B is phenyl.

4. The compound according to claim 1 , wherein L 1 is a covalent bond.

5. A compound selected from

or a pharmaceutically acceptable salt thereof.

6. A composition comprising a compound of claim 1 and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

7. The compound of claim 1 , wherein the compound is of formula I-a-ii:

or a pharmaceutically acceptable salt thereof.

8. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is pyrido, pyrimidino, pyrazino, pyridazino, triazino, furano, pyrrolo, thiazolo, isothiazolo, oxazolo, isoxazolo, pyrazolo, or imidazole;
Ring B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, phenyl, an 8-10 membered bicyclic saturated, partially unsaturated, or aryl ring, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
L 1 is a covalent bond or an optionally substituted bivalent C 1-6 hydrocarbon chain wherein one or two methylene units is optionally replaced by —NR′—, —N(R′)C(O)—, —C(O)N(R′)—, —N(R′)SO 2 —, —SO 2 N(R′)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO 2 —;
R 1 is halogen, optionally substituted C 1-6 aliphatic, —OR, —SR, —CN, —N(R′) 2 , —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R′) 2 , —C(O)SR, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(S)N(R′) 2 , —C(S)OR, —S(O)R, —SO 2 R, —SO 2 N(R′) 2 , —N(R′)C(O)R, —N(R′)C(O)N(R′) 2 , —N(R′)C(S)N(R′) 2 , —N(R′)SO 2 R, —N(R′)SO 2 N(R′) 2 , —N(R′)N(R′) 2 , —N(R′)C(═N(R′))N(R′) 2 , —C═NN(R′) 2 , —C═NOR, —C(═N(R′))N(R′) 2 , —OC(O)R, —OC(O)N(R′) 2 , or —(CH 2 ) p R x ;
p is 0-3;
R x is halogen, optionally substituted C 1-6 aliphatic, —OR, —SR, —CN, —N(R′) 2 , —C(O)R, —C(S)R, —CO 2 R, —C(O)N(R′) 2 , —C(O)SR, —C(O)C(

Assignees

• Albrecht Brian K
• Audia James Edmund
• Côté Alexandre
• Gehling Victor S
• Harmange Jean-Christophe
• Hewitt Michael Charles
• Nasveschuk Christopher G
• Taylor Alexander M
• Vaswani Rishi G
• Constellation Pharmaceuticals Inc

Inventors

• Albrecht Brian K
• Audia James Edmund
• Côté Alexandre
• Gehling Victor S
• Harmange Jean-Christophe
• Hewitt Michael Charles
• Nasveschuk Christopher G
• Taylor Alexander M
• Vaswani Rishi G

Classifications

• C07D513/14

  Ortho-condensed systems · CPC title

• C07D498/10

  Spiro-condensed systems · CPC title

• C07D495/14

  Ortho-condensed systems · CPC title

• C07D495/20

  Spiro-condensed systems · CPC title

• C07D513/20 Primary

  Spiro-condensed systems · CPC title