Claims for Patent: 9,447,106

Summary for Patent: 9,447,106

Title:	Substituted pyrazolo[1,5-a]pyrimidines as bruton's tyrosine kinase modulators
Abstract:	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.
Inventor(s):	Zhiwei Wang, Yunhang Guo
Assignee:	Beigene Switzerland GmbH
Application Number:	US14/723,417
Patent Claims:	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 SO 2 R 14; 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. 2. The compound of claim 1, wherein: (i) S/D is a double bond and R5 and R7 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 R5 and R7 are absent; R1 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 R16; A is phenyl; and each R2 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 R5 and R7 are absent; or (ii) S/D is a single bond; A is phenyl; and each R2 is independently halogen, lower alkyl, or lower alkoxy. 5. The compound of claim 4, wherein: S/D is a double bond and R5 and R7 are absent; R1 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 R16; and R16 is halogen, lower alkyl, or lower alkoxy. 6. The compound of claim 4, wherein: S/D is a double bond and R5 and R7 are absent; A is phenyl; and each R2 is independently halogen, lower alkyl, or lower alkoxy. 7. The compound of claim 4, wherein: S/D is a double bond and R5 and R7 are absent; A is phenyl; each R2 is independently halogen, lower alkyl, or lower alkoxy; and R1 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 R16. 8. The compound of claim 4, wherein: S/D is a single bond; A is phenyl; each R2 is independently halogen, lower alkyl, or lower alkoxy; R1 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 R16; and R16 is halogen, lower alkyl, or lower alkoxy. 9. The compound of claim 4, wherein: S/D is a single bond; A is phenyl; each R2 is independently halogen, lower alkyl, or lower alkoxy; and R1 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 R16. 10. The compound of claim 1, represented by: 11. The compound of claim 10, wherein R4 is C1-C8 alkyl-NR′R″, saturated C3-C8 heterocyclyl containing at least one nitrogen atom, or phenyl, each optionally substituted with at least one substituent R16. 12. The compound of claim 10, wherein R4 is (i) —CH2NR′R″ or Ph-NR′R″, or (ii) azetidinyl, pyrrolidinyl, piperidinyl or azacycloheptenyl, each optionally N-substituted with at least one substituent R16. 13. The compound of claim 10, wherein R4 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.