SUBSTITUTED PYRAZOLO[1,5-a]PYRIMIDINES AS BRUTON'S TYROSINE KINASE MODULATORS

Patent metadata

Field	Value
Publication number	US-2025340560-A1
Application number	US-202519269868-A
Country	US
Kind code	A1
Filing date	Jul 15, 2025
Priority date	Apr 25, 2013
Publication date	Nov 6, 2025
Grant date	—

Abstract

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.

First claim

1 .- 15 . (canceled)

16 . A compound of formula I:

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of 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 bond or double bond, and when S/D is a double bond, R 5 and R 7 are absent;
m is 0;
n is 0, 1, 2, 3 or 4, wherein when n is 2, 3, or 4, each R 2 is different or identical;
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 substitutent R 16 , wherein (R 4 and R 5 ) or (R 4 and R 6 ), or (R 6 and R 7 ), together with the atom(s) to which they are attached, form a ring selected from the group consisting of cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl, each optionally substituted with at least one substitutent 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 13 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, independently forms a ring selected from the group consisting of cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl, each optionally substituted with at least one substitutent R 16 ;
R 16 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted 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 hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein (R′ and R″) and/or (R″ and R′″) together with the atom(s) to which they are attached, independently forms a ring selected from the group consisting of cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl.

17 . The compound of claim 16 , wherein S/D is a single bond.

18 . The compound of claim 16 , wherein S/D is a double bond and R 5 and R 7 are absent.

19 . The compound of claim 16 , wherein A is phenyl.

20 . The compound of claim 16 , wherein 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 substitutent R 16 .

21 . The compound of claim 20 , wherein R 16 is halogen, lower alkyl, or lower alkoxy.

22 . The compound of claim 16 , wherein each R 2 is independently halogen, lower alkyl, or lower alkoxy.

23 . The compound of claim 16 , wherein R 4 and R 5 , together with the atoms to which they are attached, form a ring selected from cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl, each optionally substituted with at least one substitutent R 16 .

24 . The compound of claim 16 , wherein R 4 and R 6 , together with the atoms to which they are attached, form a ring selected from cycloalkyl, saturated or unsaturated heterocyclyl, aryl, and heteroaryl, each optionally substituted with at least one substitutent R 16 .

25 . The compound of claim 24 , wherein R 4 and R 6 , together with the atoms to which they are attached, form a ring of formula:

wherein:
Q is —CH 2 —; J is —CH 2 —; and d and b are each independently 0, 1, 2, 3, or 4.

26 . A compound selected from the group consisting of:

or a stereoisomer or a pharmaceutically acceptable salt thereof.

27 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 16 in unit dosage form and one or more pharmaceutically acceptable carriers.

28 . A combination comprising a therapeutically effective amount of a compound of claim 16 and at least one additional therapeutically active agent.

29 . A method of modulating Bruton's tyrosine kinase activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 16 , or a stereoisomer, or a pharmaceutically acceptable salt thereof.

30 . A method of treating a disease associated with undesirable Btk activity, which comprises administering to a subject in need thereof an effective amount of a compound of claim 16 , or a stereoisomer, or a pharmaceutically acceptable salt thereof,

31 . The method of claim 30 , wherein the disease is an allergic disease, an autoimmune disease, an inflammatory disease, or cancer.

32 . The method of claim 30 , wherein the disease is a B-cell proliferative disorder selected from the group consisting of chronic lymphocytic lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia.

Assignees

• Beigene Switzerland Gmbh

Inventors

• Wang Zhiwei
• Guo Yunhang

Classifications

• A61K31/438

  The ring being spiro-condensed with carbocyclic or heterocyclic ring systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/527

  spiro-condensed · CPC title