Bruton'S tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9249146-B2
Application number	US-201414316710-A
Country	US
Kind code	B2
Filing date	Jun 26, 2014
Priority date	Sep 4, 2009
Publication date	Feb 2, 2016
Grant date	Feb 2, 2016

Abstract

The present invention provides compounds useful as inhibitors of Btk, compositions thereof, and methods of using the same.

First claim

What is claimed is:

1. A method of decreasing the enzymatic activity of Bruton's tyrosine kinase comprising contacting Bruton's tyrosine kinase with an effective amount of a compound formula I:

wherein:
X 1 is —O—, —CR 5 R 6 — or —NR 7 —;
X 2 is ═CR 8 — or ═N—;
p is 0-5;
y is 0, 1, or 2;
z is 0, 1, or 2, wherein z is 0 or 1 when y is 2, and z is 1 or 2 when y is 0;
each R 1 is independently halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R 1 groups on adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R 1 groups on non-adjacent carbon atoms are taken together with their intervening atoms to form an optionally substituted bridge of a bridged bicyclic group, wherein the bridge is a C 1-3 hydrocarbon chain wherein one methylene unit is optionally replaced by —NR—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—S—, or —S—, or:
two R 1 groups on the same carbon atom are taken together with their intervening atoms to form an optionally substituted spiro fused ring selected from a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 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 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:
two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of R 2 , R 3 , R 5 , R 6 , and R 8 is independently R, halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, or —OC(O)N(R) 2 ; or:
R 3 and R 4 are optionally taken together with their intervening atoms to form an optionally substituted ring selected from pyrrole, pyrazole, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of R 4 and R 7 is independently R, —CN, —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —C(O)N(R) 2 , —S(O)R, —S(O) 2 R, or —S(O) 2 N(R) 2 ;
Ring A 1 is:

 and is optionally substituted,
wherein T is an optionally substituted, bivalent C 1-5 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of T are optionally and independently replaced by —C(R) 2 —, —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—, —SO 2 —, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N 2 )—;

Ring A 2 is an optionally substituted ring selected from phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
L is a covalent bond or an optionally substituted, bivalent C 1-7 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one, two, or three methylene units of L are independently replaced by —Cy-, —CR 2 —, —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—, —SO 2 —, —C(═S)—, —C(═NR)—, —N═N—, or —C(═N 2 )—, wherein at least one methylene unit of L is replaced by —N(R)—; and
each Cy is independently an optionally substituted bivalent ring selected from phenylene, a 3-7 membered saturated or partially unsaturated carbocyclylene, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein L is —NH—C(O)—NH—, —NH—C(O)—, —NH—, or —NHSO 2 —.

3. The method of claim 2 , wherein L is —NH—C(O)—NH— or —NH—.

4. The method of claim 1 , wherein L is:

wherein s and t are independently 0, 1, or 2, and the sum of s and t is 0-4.

5. The method of claim 1 , wherein the compound is of formula I-a-i, or I-a-ii:

6. The method of claim 1 , wherein the compound is of formula I-b-i, or I-b-ii:

Assignees

• Biogen Idec Inc
• Sunesis Pharmaceuticals Inc
• Biogen Ma Inc

Inventors

• Bui Minna
• Conlon Patrick
• Cuervo Julio H
• Erlanson Daniel A
• Fan Junfa
• Guan Bing
• Hopkins Brian T
• Jenkins Tracy J
• Kumaravel Gnanasambandam
• Lugovskoy Alexey A
• Marcotte Doug
• Powell Noel
• Scott Daniel
• Silvian Laura
• Taveras Art
• Wang Deping
• Zhong Min

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title