Biaryl inhibitors of Bruton'S tyrosine kinase

Patent metadata

Field	Value
Publication number	US-10759783-B2
Application number	US-201816108755-A
Country	US
Kind code	B2
Filing date	Aug 22, 2018
Priority date	Dec 11, 2013
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present invention provides compounds and compositions thereof which are useful as inhibitors of Bruton's tyrosine kinase and which exhibit desirable characteristics for the same.

First claim

What is claimed is:

1. A compound of Formula I′:

or a pharmaceutically acceptable salt, wherein:
one of A 1 and A 2 is C—R 6 , and the other of A 1 and A 2 is selected from C—R 6 or N;
A 3 is selected from C—H or N, and is C—H when A 1 or A 2 is N;
Q 1 is selected from C—R 7 and N;
Q 2 is selected from C—R 7 and N;
Q 3 is selected from C—R 7 and N;
wherein at most one of Q 1 , Q 2 , and Q 3 is N;

R 1 is selected from N(R) 2 , phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 8- to 10-membered bicyclic aryl, wherein said phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic aryl are optionally substituted with one or more R 10 ;
R 2 is H or C 1-6 aliphatic;
or R 1 and R 2 , together with their intervening atoms, form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, or 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen and nitrogen, wherein said ring is optionally substituted with one or more R 20 ;

R 3 is selected from H, halogen, —C(O)N(R) 2 , —C(O)OR, —C(O)R, and C 1-6 aliphatic, wherein the C 1-6 aliphatic group is optionally substituted with hydroxyl;
each R 4 is independently selected from halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —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)C(O)OR, —N(R)SO 2 R, —OC(O)N(R) 2 , and C 1-6 aliphatic, wherein said C 1-6 aliphatic is optionally substituted with one or more R 40 ;
or R 3 and R 4 together with their intervening atoms form fused Ring A selected from fused 5- to 7-membered monocyclic carbocycle, fused 5- to 7-membered monocyclic heterocycle having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein said fused Ring A is optionally substituted with one or more R 40 ;

R 5 is selected from H, —C(O)R, —C(O)OR, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, and 8- to 10-membered bicyclic aryl, wherein said C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered saturated or partially unsaturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, 7- to 10-membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, or 8- to 10-membered bicyclic aryl, are optionally substituted with one or more R 50 ;
each of R 6 and R 7 is independently selected from H, halogen, NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)OR, —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)C(O)OR, —N(R)SO 2 R, —OC(O)N(R) 2 , and C 1-6 aliphatic;
each R is independently hydrogen or C 1-6 aliphatic, phenyl, 3- to 8-membered saturated or partially unsaturated carbocyclyl ring, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein said C 1-6 aliphatic, phenyl, 3- to 7-membered saturated or partially unsaturated carbocyclyl ring, 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, are optionally substituted with one or more R 50 ; or
two R groups on the same nitrogen are taken together with their intervening atoms to form a ring selected from 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, or 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein said ring is optionally substituted with one or more R 50 ;

each R 10 is independently selected from halogen, —OR 10a , C 1-6 aliphatic, 3- to 5-membered saturated or partially unsaturated carbocyclyl, and 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein said C 1-6 aliphatic, 3- to 5-membered saturated or partially unsaturated carbocyclyl, 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, are optionally substituted with one or more R 15 ;
each R 15 is independently selected from halogen and —OR 15a ;
R 10a is C 1-6 alkyl optionally substituted with halogen;
R 15a is C 1-6 alkyl;
each R 20 is independently selected from halogen, C 1-6 aliphatic, 3- to 5-membered saturated or partially unsaturated carbocyclyl, and 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein said C 1-6 aliphatic, 3- to 5-membered saturated or partially unsaturated carbocyclyl, 3- to 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, are optionally substituted with one or more R 15 ;
each R 40 is independently selected from halogen, C 1-6 alkyl, 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms selected from carbon, nitrogen and sulfur, —C(O)H, —N(R 40a ) 2 , —N(R 40a )C(O)(R 40b )

Assignees

• Biogen Ma Inc

Inventors

• Hopkins Brian T
• Ma Bin
• Chan Timothy Raymond
• Sun Lihong
• Zhang Lei
• Kumaravel Gnanasambandam
• Lyssikatos Joseph P
• Koch Kevin
• Miao Hua

Classifications

• C07F5/04

  Esters of boric acids · CPC title

• A61P19/04

  for non-specific disorders of the connective tissue · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title