Substituted pyrazolo[1,5-a]pyrimidines as Bruton's tyrosine kinase modulators
The invention is fused heterocyclic compounds of formula (I), and salts thereof, compositions thereof, and methods of use therefor. In particular, disclosed herein are certain fused heterocyclic compounds that can be useful for inhibiting protein kinase, including Bruton's tyrosine kinase (Btk), and for treating disorders mediated thereby.
1. A method for modulating Bruton's tyrosine kinase activity in a patient suffering from a B-cell proliferative disorder, comprising administering to the patient a therapeutically effective amount of a compound of formula I:
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein:
A is a 5- or 6-membered aromatic ring comprising 0, 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen;
W is —(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(s) to which they are attached, may independently form a ring selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;
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 method of claim 1 , wherein the B-cell proliferative disorder is selected from a chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.
3. The method of claim 1 , wherein S/D is a single bond.
4. The method of claim 1 , wherein A is a phenyl.
5. The method of claim 1 , wherein L is O.
6. The method of claim 1 , wherein R 1 is aryl, optionally substituted with at least one substituent R 16 .
7. The method of claim 1 , wherein each R 2 is independently halogen, lower alkyl, or lower alkoxy.
8. The method of claim 1 , wherein R 4 is
9. The method of claim 1 , wherein R 4 is
10. The method of claim 1 , wherein R 5 , R 6 and R 7 are each independently H.
11. The method of claim 1 , wherein W is —(CH 2 )—.
12. The method of claim 1 , wherein the compound is of formula II:
13. The method of claim 1 , wherein the compound is
14. The method of claim 1 , wherein the compound is
15. The method of claim 1 , wherein the compound is