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

摘要

The invention is substituted 4,5-dihydro- and 4,5,6,7-tetrahydro-pyrazolo[1,5-α]pyrimidine compounds of formula (I),;
and salts thereof, compositions thereof, and methods of use therefor, such as inhibiting protein kinase, including Bruton's tyrosine kinase (Btk), and for treating disorders mediated thereby.

主权项

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 —(CH2)— or —C(O)—; L is a bond, CH2, NR12, O, or S; S/D is a single or double bond, wherein when S/D is a double bond, R5 and R7 are absent; m is 1; n is 0, 1, 2, 3 or 4, wherein when n is 2, 3 or 4, each R2 may be different; p is 1; R1, R4, R5, R6 and R7 are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R16; R2is halogen, alkyl, —S-alkyl, —CN, —NR13R14, —OR13, COR13, —CO2R13,—CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13 SO2 R14; R12 is H or lower alkyl; R13, R14 and R15 are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl, wherein (R13 and R14) and/or (R14 and R15), 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 R16; and R16 is halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, oxo, —CN, —OR′, —NR′R″, —COR′, —CO2R′, —CONR′R″, —C(═NR′)NR″R′″, —NR′COR″, —NR′CONR′R″, —NR′CO2R″, —SO2R′, —SO2aryl, —NR′SO2NR″R′″, or —NR′SO2R″, 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 R16, 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, —ORa, —NRaRb, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaCORb, —NRaCONRaRb, —NRaCO2Rb, —SO2Ra, —SO2aryl, —NRaSO2NRbRc, and —NRaSO2Rb, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl of R16, 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, —ORa, —NRaRb, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaCORb, —NRaCONRaRb, —NRaCO2Rb, —SO2Ra, —SO2aryl, —NRaSO2NRbRc, and —NRaSO2Rb, and wherein each Ra, Rb, and Rc is independently selected from the group consisting of H, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.