Pyrazolopyrimidine aryl ether inhibitors of JAK kinases and uses thereof

Patent metadata

Field	Value
Publication number	US-12528812-B2
Application number	US-202117644742-A
Country	US
Kind code	B2
Filing date	Dec 16, 2021
Priority date	Jun 18, 2019
Publication date	Jan 20, 2026
Grant date	Jan 20, 2026

Abstract

Compounds and salts thereof that are useful as JAK kinase inhibitors are described herein. Also provided are pharmaceutical compositions that include such a JAK inhibitor and a pharmaceutically acceptable carrier, adjuvant or vehicle, and methods of treating or lessening the severity of a disease or condition responsive to the inhibition of a Janus kinase activity in a patient.

First claim

The invention claimed is:

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
Ar is: phenyl; 1,2,3,4-tetrahydroisoquinolinyl; pyrazolyl; pyridinyl; or pyridazinyl:
R 1 is: hydrogen; C 1 -C 6 alkyl; halo-C 1 -C 6 alkyl; hydroxy-C 1 -C 6 alkyl; —(CHR a ) h -het 1 ; —(CHR a ) k —NR a -het 1 ; or —(CHR a ) m —C 3-6 cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted once or twice with R d ;
Each R 2 is independently: C 1 -C 6 alkyl; hydroxy-C 1 -C 6 alkyl; halo-C 1 -C 6 alkyl; C 1 -C 6 alkoxy; C 1 -C 6 alkoxy-C 1 -C 6 alkyl; halo-C 1 -C 6 alkoxy; halo-C 1 -C 6 alkoxy-C 1 -C 6 alkyl; C 1 -C 6 alkyl-SO 2 —C 1 -C 6 alkyl; hydroxyl; cyano; cyano-C 1 -C 6 alkyl; halo; acetyl; —(CHR a ) p -het 2 ; —(CHR a ) q —NR b R c ; —(CHR a ) r —C(O)—NR b R c ; —(CHR a ) s —NR a —(CHR a ) s —C(O)—NR b R c ; or —(CHR a ) t —C 3-6 cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted once or twice with R e ;
R 3 , R 4 and R 5 each independently is: hydrogen; or C 1 -C 6 alkyl;
each R a is independently: hydrogen; or C 1-6 alkyl;
each R b is independently: hydrogen; C 1-6 alkyl; or hydroxy-C 1 -C 6 alkyl;
each R c is independently: hydrogen; C 1-6 alkyl; hydroxy-C 1 -C 6 alkyl; cyano-C 1 -C 6 alkyl; C 1 -C 6 alkoxy-C 1 -C 6 alkyl; oxetanyl; 2-morpholinyoethyl; 1-methyl-azetidin-3-yl; 2-(N,N-dimethylamino)-ethyl; hydroxycyclobutyl; or 3-(N,N-dimethylamino)-pyrrolidin-1-yl; —(CHR a ) u C 3-6 cycloalkyl wherein the cycloalkyl moiety may be unsubstituted or substituted once or twice with R e ;
or R b and R c together with the nitrogen atom to which they are attached may form het 3 ;
each R d is independently: C1-C 6 alkyl, hydroxy or halo;
each R e is independently: C 1-6 alkyl; hydroxyl; cyano-C 1 -C 6 alkyl; hydroxy-C 1 -C 6 alkyl; morpholiny; or —(CHR a ) v —NR g R h wherein R g and R h each independently is hydrogen or C 1-6 alkyl;
h is from 0 to 2;
k is from 0 to 2;
m is from 0 to 2;
n is from 0 to 2;
p is from 0 to 2;
q is from 0 to 2;
r is from 0 to 2;
s is from 0 to 2;
t is from 0 to 2;
u is from 0 to 2;
v is from 0 to 2;
het 1 is: oxetanyl; tetrahydrofuranyl; tetrahydropyranyl; or pyrrolodinyl; each of which may be unsubstituted or substituted once or twice with R d ;
het 2 is: azetidinyl; pyrrolidinyl; oxetanyl; piperidinyl; morpholinyl; piperazinyl; azepinyl; quinuclidinyl; or pyrazolyl; each of which may be unsubstituted or substituted once or twice with R e ; and
het 3 is: azetidinyl; pyrrolidinyl; piperidinyl; morpholinyl; piperazinyl; or azepinyl; each of which may be unsubstituted or substituted once or twice with R e .

2 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Ar is: phenyl; or pyrazolyl.

3 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Ar is phenyl.

4 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein Ar is pyrazolyl.

5 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or C 1 -C 6 alkyl.

6 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 is methyl.

7 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 0.

8 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 1.

9 . The compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, wherein n is 2.

10 . The compound of claim 1 , wherein each R 2 is independently selected from:

or a stereoisomer or pharmaceutically acceptable salt thereof.

11 . The compound of claim 1 , wherein each R 2 is independently selected from:

or a stereoisomer or pharmaceutically acceptable salt thereof.

12 . The compound of claim 1 , wherein n is 1, and R 2 is selected from:

or a stereoisomer or pharmaceutically acceptable salt thereof.

13 . The compound of claim 1 , wherein the compound is of formula (II):

or a stereoisomer or pharmaceutically acceptable salt thereof.

14 . The compound of claim 1 , wherein the compound is of formula (III):

or a stereoisomer or pharmaceutically acceptable salt thereof.

15 . A compound selected from:

Assignees

• Genentech Inc

Inventors

• Zak Mark Edward
• Rajapaksa Naomi S
• Cheng Yun-Xing
• Li Wei
• Shore Daniel G M
• Romero F Anthony
• Bryan Marian C

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• C07D239/00

  Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings · CPC title