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

1. An oral dosage form comprising a pharmaceutically acceptable carrier and a compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:

A is a 5- or 6-membered aromatic ring, wherein the 5- or 6-membered aromatic ring comprises 0, 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur;

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

R 1 is H, halogen, CN, alkyl, heteroalkyl, alkenyl, alkynyl, C(NR 13 )NR 14 R 15 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , NR 13 S(O) 2 R 14 , NR 13 S(O) 2 NR 14 R 15 , OR 13 , S(O) 2 R 13 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R 16 substituents;

each R 2 is independently halogen, CN, alkyl, C(NR 13 )NR 14 R 15 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , NR 13 S(O) 2 R 14 , NR 13 S(O) 2 NR 14 R 15 , OR 13 , S-alkyl, or S(O) 2 R 13 ;

R 4 is H, halogen, CN, alkyl, heteroalkyl, alkenyl, alkynyl, C(NR 13 )NR 14 R 15 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , NR 13 S(O) 2 R 14 , NR 13 S(O) 2 NR 14 R 15 , OR 13 , S(O) 2 R 13 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R 16 substituents;

R 5 is H, halogen, CN, alkyl, heteroalkyl, alkenyl, alkynyl, C(NR 13 )NR 14 R 15 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , NR 13 S(O) 2 R 14 , NR 13 S(O) 2 NR 14 R 15 , OR 13 , S(O) 2 R 13 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R 16 substituents;

R 6 is H, halogen, CN, alkyl, heteroalkyl, alkenyl, alkynyl, C(NR 13 )NR 14 R 15 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , NR 13 S(O) 2 R 14 , NR 13 S(O) 2 NR 14 R 15 , OR 13 , S(O) 2 R 13 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R 16 substituents;

R 7 is H, halogen, CN, alkyl, heteroalkyl, alkenyl, alkynyl, C(NR 13 )NR 14 R 15 , C(O)R 13 , C(O)NR 13 R 14 , C(O)OR 13 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 14 R 15 , NR 13 C(O)OR 14 , NR 13 S(O) 2 R 14 , NR 13 S(O) 2 NR 14 R 15 , OR 13 , S(O) 2 R 13 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R 16 substituents;

R 12 is H or lower alkyl;

each R 13 is independently H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R 14 is independently H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R 15 is independently H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

each R 13 and R 14 , together with the atom(s) to which they are attached, independently forms a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally and independently substituted with one or more independently selected R 16 substituents; or

each R 14 and R 15 , together with the atom(s) to which they are attached, independently forms a cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally and independently substituted with one or more independently selected R 16 substituents;

each R 16 is independently halogen, CN, oxo, alkyl, alkenyl, alkynyl, C(NR′)NR″R′″, C(O)R′, C(O)NR′R″, C(O)OR′, NR′R″, NR′C(O)R″, NR′C(O)NR′R″, NR′C(O)OR″, NR'S(O) 2 R″, NR'S(O) 2 NR″R′″, OR′, S(O) 2 R′, S(O) 2 aryl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R′ is independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R″ is independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

each R′″ is independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

each R′ and R″, together with the atom(s) to which they are attached, independently forms a cycloalkyl, heterocyclyl, aryl, or heteroaryl; or

each R″ and R′″, together with the atom(s) to which they are attached, independently forms a cycloalkyl, heterocyclyl, aryl, or heteroaryl;

W is —CH 2 — or —C(O)—;

m is 1;

n is 0, 1, 2, 3, or 4;

p is 1; and

— is a single or double bond;

wherein each alkyl, alkenyl, and alkynyl of each R 16 , R′, R″, and R′″ is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, oxo, C(NR a )NR b R c , C(O)R a , C(O)NR a R b , C(O)OR a , NR a R b , NR a C(O)R b , NR a C(O)NR a R b , NR a C(O)OR b , NR a S(O) 2 R b , NR a S(O) 2 NR b R c , OR a , S(O) 2 R a , S(O) 2 aryl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl of each R 16 , R′, R″, and R′″ is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, CN, oxo, alkyl, alkenyl, alkynyl, C(NR a )NR b R c , C(O)R a , C(O)NR a R b , C(O)OR a , NR a R b , NR a C(O)R b , NR a C(O)NR a R b , NR a C(O)OR b , NR a S(O) 2 R b , NR a S(O) 2 NR b R c , OR a , S(O) 2 R a , S(O) 2 aryl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and

wherein each R a , R b , and R c is independently H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

with the proviso that when ═ is a double bond, R 5 and R 7 are absent.

2. The oral dosage form of claim 1 , wherein the oral dosage form comprises 10 mg to 500 mg of the compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The oral dosage form of claim 1 , wherein the oral dosage form comprises 20 mg to 500 mg of the compound of formula I, or a pharmaceutically acceptable salt or stereoisomer thereof.

4. The oral dosage form of claim 1 , wherein the oral dosage form is a tablet or a capsule.

5. The oral dosage form of claim 1 , wherein A is phenyl.

6. The oral dosage form of claim 1 , wherein L is —O—.

7. The oral dosage form of claim 1 , wherein R 1 is aryl, wherein the aryl is optionally substituted with one or more independently selected R 16 substituents.

8. The oral dosage form of claim 1 , wherein:

each R 2 is independently halogen, lower alkyl, or lower OR 13 ; and

each R 13 is independently alkyl.

9. The oral dosage form of claim 1 , wherein R 4 is

10. The oral dosage form of claim 1 , wherein R 4 is:

11. The oral dosage form of claim 1 , wherein:

R 5 is H;

R 6 is H; and

R 7 is H.

12. The oral dosage form of claim 1 , wherein W is —CH 2 —.

13. The oral dosage form of claim 1 , wherein — is a single bond.

14. The oral dosage form of claim 1 , wherein the compound is of formula II:

or a pharmaceutically acceptable salt or stereoisomer thereof.

15. The oral dosage form of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt or stereoisomer thereof.

16. The oral dosage form of claim 1 , wherein the compound, or stereoisomer thereof, is:

or a pharmaceutically acceptable salt thereof.

17. The oral dosage form of claim 1 , wherein the compound, or stereoisomer thereof, is:

or a pharmaceutically acceptable salt thereof.

18. A method for modulating Bruton's tyrosine kinase activity in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the oral dosage form of claim 1 .

19. The method of claim 18 , wherein the subject has a B-cell proliferative disorder selected from the group consisting of chronic lymphocytic leukemia, chronic lymphocytic lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and non-Hodgkin's lymphoma.