Biaryl inhibitors of Bruton'S tyrosine kinase

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 ), —N(R 40a )C(O) 2 (R 40a ), —OR 40a , —SR 40a , and —C(O) 2 R 40a , wherein said C 1-6 alkyl group is optionally substituted with halogen or —OR 40a ;

each R 40a is independently selected from H and C 1-6 alkyl; or two R 40a 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, and 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur;

each R 40b is independently selected from C 2-6 alkenyl and 5- or 6-membered heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein said 5- or 6-membered heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, is optionally substituted with one or more R 45 ;

R 45 is C 1-6 alkyl;

each R 50 is independently selected from C 1-6 aliphatic, —OR 50a , —N(R 50a ) 2 , —C(O)N(R 50a ) 2 , —C(O) 2 R 50a , oxo, 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and 3- to 10-membered heterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein said C 1-6 alkyl, 3- to 6-membered saturated or partially unsaturated monocyclic carbocyclyl, 3- to 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, and 3- to 10-membered heterocyclyalkyl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, are optionally substituted with one or more R 55 ;

R 50a is selected from H and C 1-6 alkyl;

each R 55 is independently selected from 5- to 6-membered heterocyclyl having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur, C 1-6 alkyl, —OR 55a , —C(O)N(R 55a ) 2 , halogen, —N(R 55a ) 2 , —C(O) 2 R 55a , —S(O) 2 R 55b , and —S(O) 2 (NR 55a ) 2 ;

R 55a is selected from H and C 1-6 alkyl, wherein said C 1-6 alkyl is optionally substituted with halogen; and

R 55b is C 1-6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, phenyl, and 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein R 1 is optionally substituted with one or more R 10 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, R 4 is halogen or C 1-6 aliphatic optionally substituted with one or more R 40 , wherein R 40 is halogen.

5. The compound of claim 1 , wherein R 3 and R 4 , together with their intervening atoms, form fused Ring A selected from fused 5- to 7-membered monocyclic carbocycle, and fused 5- to 7-membered heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, and sulfur.

6. The compound of claim 1 , wherein R 5 is selected from hydrogen, —C(O)R, and 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur is optionally substituted with one or more R 50 .

7. The compound of claim 6 , wherein R 5 is selected from pyrazolyl, imidazolyl, isoxazolyl, triazolyl, tetrazolyl, thiadiazolyl, and pyridyl, wherein R 5 is optionally substituted with one or more R 50 .

8. The compound of claim 7 , wherein R 5 is

9. The compound of claim 1 , wherein each R 6 is independently selected from hydrogen, halogen, and C 1-6 aliphatic.

10. The compound of claim 1 , wherein the compound is of formula VI-a or VI-c:

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.