Substituted pyrazolo[1,5-a]pyrimidines as bruton's tyrosine kinase modulators

1. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms selected from N, S or O;

each W is independently —(CH 2 )— or —C(O)—;

L is a bond, CH 2 , NR 12 , O, or S;

S/D is a single or double bond, wherein when S/D is a double bond, R 5 and R 7 are absent;

m is 1;

n is 0, 1, 2, 3 or 4, wherein when n is 2, 3 or 4, each R 2 may be different;

p is 1;

R 1 , R 4 , R 5 , R 6 and R 7 are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR 13 R 14 , —OR 13 , —COR 13 , —CO 2 R 13 , —CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ;

R 2 is halogen, alkyl, —S-alkyl, —CN, —NR 13 R 14 , —OR 13 , COR 13 , —CO 2 R 13 ,—CONR 13 R 14 , —C(═NR 13 )NR 14 R 15 , —NR 13 COR 14 , —NR 13 CONR 14 R 15 , —NR 13 CO 2 R 14 , —SO 2 R 13 , —NR 13 SO 2 NR 14 R 15 , or —NR 13 SO 2 R 14 ;

R 12 is H or lower alkyl;

R 13 , R 14 and R 15 are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl, wherein (R 13 and R 14 ) and/or (R 14 and R 15 ), together with the atom(s) to which they are attached, may independently form a ring selected from cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl, each optionally substituted with at least one substituent R 16 ; and

R 16 is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO 2 R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO 2 R″, —SO 2 R′, —SO 2 aryl, —NR′SO 2 NR″R′″, or —NR′SO 2 R″, wherein R′, R″, and R′″ are independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein (R′ and R″) and/or (R″ and R″′), together with the atom to which they are attached, may independently form a ring selected from cycloalkyl, aryl, heteroaryl, and heterocyclyl,

wherein each alkyl, alkenyl and alkynyl of R 16 , R′, R″, and R′″ is optionally substituted with at least one substituent selected from the group consisting of halogen, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, —CN, —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a COR b , —NR a CONR a R b , —NR a CO 2 R b , —SO 2 R a , —SO 2 aryl, —NR a SO 2 NR b R c , and —NR a SO 2 R b ,

wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl of R 16 , R′, R″, and R′″ is optionally substituted with at least one substituent selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, —CN, —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —C(═NR a )NR b R c , —NR a COR b , —NR a CONR a R b , —NR a CO 2 R b , —SO 2 R a , —SO 2 aryl, —NR a SO 2 NR b R c , and —NR a SO 2 R b , and

wherein each R a , R b , and R c is independently selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

2. The compound of claim 1 , wherein:

(i) S/D is a double bond and R 5 and R 7 are absent; and

A is phenyl; or

(ii) S/D is a single bond; and

A is phenyl.

3. The compound of claim 1 , wherein:

(i) S/D is a double bond and R 5 and R 7 are absent;

R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ;

A is phenyl; and

each R 2 is independently halogen, lower alkyl, or lower alkoxy; or

(ii) S/D is a single bond.

4. The compound of claim 1 , wherein:

(i) S/D is a double bond and R 5 and R 7 are absent; or

(ii) S/D is a single bond;

A is phenyl; and

each R 2 is independently halogen, lower alkyl, or lower alkoxy.

5. The compound of claim 4 , wherein:

S/D is a double bond and R 5 and R 7 are absent;

R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ; and

R 16 is halogen, lower alkyl, or lower alkoxy.

6. The compound of claim 4 , wherein:

S/D is a double bond and R 5 and R 7 are absent;

A is phenyl; and

each R 2 is independently halogen, lower alkyl, or lower alkoxy.

7. The compound of claim 4 , wherein:

S/D is a double bond and R 5 and R 7 are absent;

A is phenyl;

each R 2 is independently halogen, lower alkyl, or lower alkoxy; and

R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 .

8. The compound of claim 4 , wherein:

S/D is a single bond;

A is phenyl;

each R 2 is independently halogen, lower alkyl, or lower alkoxy;

R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 ; and

R 16 is halogen, lower alkyl, or lower alkoxy.

9. The compound of claim 4 , wherein:

S/D is a single bond;

A is phenyl;

each R 2 is independently halogen, lower alkyl, or lower alkoxy; and

R 1 is H, halogen, alkoxy, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R 16 .

10. The compound of claim 1 , represented by:

11. The compound of claim 10 , wherein R 4 is C 1 -C 8 alkyl-NR′R″, saturated C 3 -C 8 heterocyclyl containing at least one nitrogen atom, or phenyl, each optionally substituted with at least one substituent R 16 .

12. The compound of claim 10 , wherein R 4 is (i) —CH 2 NR′R″ or Ph-NR′R″, or (ii) azetidinyl, pyrrolidinyl, piperidinyl or azacycloheptenyl, each optionally N-substituted with at least one substituent R 16 .

13. The compound of claim 10 , wherein R 4 is selected from:

14. The compound of claim 10 , wherein the compound is:

15. The compound of claim 10 , wherein the compound is:

16. The compound of claim 1 , selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , selected from the group consisting of:

or a stereoisomer or pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in unit dosage form and one or more pharmaceutically acceptable carriers.

19. A combination comprising a therapeutically effective amount of a compound of claim 1 and an additional therapeutically active agent.

20. A method of modulating Bruton's tyrosine kinase activity in a person, comprising administering to said person a therapeutically effective amount of a compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof.

21. A compound:

or a pharmaceutically acceptable salt thereof.

22. A compound:

or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 22 in unit dosage form and one or more pharmaceutically acceptable carriers.