Bruton's tyrosine kinase inhibitors

Patent metadata

Field	Value
Publication number	US-10577374-B2
Application number	US-201715698171-A
Country	US
Kind code	B2
Filing date	Sep 7, 2017
Priority date	Sep 4, 2009
Publication date	Mar 3, 2020
Grant date	Mar 3, 2020

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 for treating cancer, the method comprising:
administering to a human subject an effective amount of a compound having the formula:

 or a pharmaceutically acceptable salt thereof;
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, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 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, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur,
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—, 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, and a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and 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, and sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and 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, and 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, imidazole, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and 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 an optionally substituted phenylene ring;
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, and sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclic aryl ring, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and 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, and sulfur, and a 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

2. The method of claim 1 , wherein the cancer is leukemia or lymphoma.

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

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

5. 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.

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

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

8. The method of claim 1 , wherein the compound is of formula IV-a:

Assignees

• 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

• A61P43/00

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

• A61P37/06

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title