Substituted bicyclic heteroaryl compounds useful as inhibitors of tlr9

Patent metadata

Field	Value
Publication number	US-2025163054-A1
Application number	US-202318839055-A
Country	US
Kind code	A1
Filing date	Feb 17, 2023
Priority date	Feb 18, 2022
Publication date	May 22, 2025
Grant date	—

Abstract

Disclosed are compounds of Formulas (I) or a salt thereof, wherein Q, G, R 1 , R 5,a , and R 5b are defined herein. Also disclosed are methods of using such compounds as inhibitors of TLR9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing fibrotic diseases.

First claim

What is claimed is:

1 . A compound of Formula (I):

or a salt thereof, wherein:
G is:
(i) phenyl substituted with 1 to 3 substituents independently selected from F, Cl, Br, C 1-2 alkoxy, C 1-2 fluoroalkoxy, C 3-4 cycloalkyl, —C(O)NR y R y , —S(O) 2 CH 3 , —S(O) 2 (phenyl), —S(O) 2 NR x R x , and —S(O)(NH)NR x R x ;

(v) a 9-membered heterocyclic ring selected from:

or
(vi) 10-membered heterocyclic ring selected from:

Q is piperidinyl, phenyl, tetrahydropyridinyl, pyridinyl, or azabicyclo[3.2.1]octanyl, each substituted with -L-R 4 and zero to 2 R 4b ;
L is a bond, —(CR x R x ) 1-2 —, —CR x R x NR x —, —C(O)CR x R x ) 0-2 —, or —C(O)NR x —;
R 1 is hydrogen, C 1-3 alkyl, C 1-2 fluoroalkyl, or C 3-4 cycloalkyl;
each R 2 is independently halo, —CN, —OH, —NO 2 , C 1-4 alkyl, C 1-2 fluoroalkyl, C 1-2 cyanoalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, —O(CH 2 ) 1-2 OH, —(CH 2 ) 0-4 O (C 1-4 alkyl), C 1-3 fluoroalkoxy, —O(CH 2 ) 1-2 OC(O)C 1-3 alkyl), —O(CH 2 ) 1-2 NR x R x , —C(O)O(C 1-3 alkyl), —(CH 2 ) 0-2 C(O)NR y R y , —C(O)NR x (C 1-5 hydroxyalkyl), —C(O)NR x (C 2-6 alkoxyalkyl), —C(O)NR x (C 3-6 cycloalkyl), —NR y R y , —NR y (C 1-3 fluoroalkyl), —NR y (C 1-4 hydroxyalkyl), —NR x CH 2 (phenyl), —NR x S(O) 2 (C 3-6 cycloalkyl), —NR x C(O)C 1-3 alkyl), —NR x CH 2 (C 3-6 cycloalkyl), —S(O) 2 (C 1-3 alkyl), —S(O) 2 N(C 1-3 alkyl) 2 , —S(O)(NH)N(C 1-3 alkyl) 2 , —(CH 2 ) 0-2 (C 3-6 cycloalkyl), —(CH 2 ) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or —C(O)thiazolyl);
R 2a is C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-3 aminoalkyl, —(CH 2 ) 0-4 O (C 1-3 alkyl), C 3-6 cycloalkyl, —(CH 2 ) 1-3 C(O)NR x R x , —CH 2 (C 3-6 cycloalkyl), —CH 2 (phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;
each R 2b is independently hydrogen, halo, —CN, —NR x R x , C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkoxy, —(CH 2 ) 0-2 O(C 1-3 alkyl), —(CH 2 ) 0-3 C(O)NR x R x , —(CH 2 ) 1-3 (C 3-6 cycloalkyl), —C(O)O(C 1-3 alkyl), —C(O)NR x (C 1-3 alkyl), —CR x ═CR x R x , or —CR x ═CH(C 3-6 cycloalkyl);
R 2c is R 2a or R 2b ;
R 2d is R 2a or R 2b ; provided that one of R 2c and R 2d is R 2a , and the other of R 2c and R 2d is R 2b ;
R 4 is:
(i) —N(CH 3 ) 2 ;
(ii) azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, pyridinyl, azaspiro[3.3]heptanyl, octahydrocyclopenta[c]pyrrolyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, diazaspiro[3.4]octanyl, diazaspiro[3.5]nonanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each substituted with zero to 2 R 4a ; or

each R 4a is independently C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, —(CH 2 ) 1-3 OCH 3 C 3-6 cycloalkyl, —(CH 2 ) 1-3 (C 3-6 cycloalkyl), —(CH 2 ) 1-3 (oxetanyl), —(CH 2 ) 1-3 (phenyl), —(CH 2 ) 1-3 (methoxypiperidinyl), —(CH 2 ) 1-3 (morpholinyl), —C(O)C 1-4 alkyl), —C(O)(C 3-6 cycloalkyl), —C(O)(phenyl), —C(O)CH 2 (C 3-6 cycloalkyl), —C(O)CH 2 (phenyl), —C(O)O(C 1-4 alkyl), —NR y R y , —NR x (C 3-6 cycloalkyl), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, phenyl, —C(O)(methylphenyl), or piperidinyl substituted with zero to 2 substituents selected from —OH or —CH 3 ;
R 4b is F, Cl, —CN, or —CH 3 ;
each R 4c is independently C 1-6 alkyl, C 1-3 fluoroalkyl, —CH 2 (C 3-6 cycloalkyl), —C(O)(C 1-4 alkyl), —C(O)(phenyl), —C(O)CH 2 (phenyl), —C(O)OCH 2 CH 3 , or C 3-6 cycloalkyl;
R 5a is hydrogen, F, Cl, C 1-2 alkyl, C 1-2 fluoroalkyl, or cyclopropyl;
R 5b is hydrogen, F, Cl, C 1-2 alkyl, C 1-2 fluoroalkyl, or cyclopropyl;
each R x is independently hydrogen or —CH 3 ;
each R y is independently hydrogen or C 1-6 alkyl;
m is zero, 1, or 2;
n is zero, 1, or 2;
p is zero, 1, 2, 3, or 4; and
q is 1 or 2.

2 . The compound according to claim 1 or a salt thereof, wherein:
G is:
(i) phenyl substituted with 1 to 3 substituents independently selected from F, Cl, Br, —CN, C 1-2 alkoxy, C 1-2 fluoroalkoxy, C 3-4 cycloalkyl, —C(O)NR y R y , —S(O) 2 CH 3 , —S(O) 2 (phenyl), —S(O) 2 (cyclopropyl), —S(O) 2 NR x R x , —S(O)(NH)NR x R x , and —NHS(O) 2 CH 3 ;

Q is piperidinyl, phenyl, tetrahydropyridinyl, or pyridinyl, each substituted with -L-R 4 and zero to 1 R 4b ;
L is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 NH—, or —C(O)NH—;
R 1 is hydrogen, C 1-3 alkyl, —CHF 2 , —CF 3 , or C 3-4 cycloalkyl;
each R 2 is independently Cl, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CN, —OCH 3 , or —CH 2 OCH 3 ;
R 4 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, pyridinyl, azaspiro[3.3]heptanyl, diazaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, diazaspiro[3.4]octanyl, diazaspiro[3.5]nonanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each substituted with zero to 1 R 4a ;
R 4a is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —C(O)CH(CH 3 ) 2 , cyclopropyl, cyclobutyl, —CH 2 (cyclopropyl), —CH 2 (cyclobutyl), —CH 2 (oxetanyl), —CH 2 (phenyl), —CH 2 (methoxypiperidinyl), —(CH 2 ) 1-3 (morpholinyl), —N(CH 3 ) 2 , —N(CH 3 )(CH 2 CH 3 ), —N(CH 3 )(cyclopropyl), azetidinyl, oxetanyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, phenyl, —C(O)(methylphenyl), or piperidinyl substituted with zero to 2 substituents selected from —OH or —CH 3 ;
R 4b is F, —CN, or —CH 3 ;
R 5a is hydrogen, —CH 3 , —CF 3 , or cyclopropyl; and
R 5b is hydrogen, F, —CH 3 , or —CF 3 .

3 . The compound according to claim 1 or a salt thereof, wherein:
G is:
(i) phenyl substituted —S(O) 2 CH 3 or phenyl substituted with two —OCH 3 ;

R 1 is —CH 3 or cyclopropyl;
each R 2 is independently —CH 3 or —OCH 3 ;
Q is piperidinyl, phenyl, or tetrahydropyridinyl, each substituted with -L-R 4 and zero to 1 Rb;
L is a bond, —CH 2 —, —CH 2 CH 2 —, —CH 2 NH—, or —C(O)NH—;
R 4 is azetidinyl, piperidinyl, piperazinyl, diazaspiro[3.3]heptanyl, diazaspiro[3.4]octanyl, diazaspiro[3.5]nonanyl, or hexahydropyrrolo[3,4-c]pyrrolyl, each substituted with zero or 1 R 4a ;
R 4a is —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 (cyclopropyl), —CH 2 (oxetanyl), —CH 2 (phenyl), —CH 2 (methoxypiperidinyl), —CH 2 CH 2 (morpholinyl), —CH 2 CH 2 CH 2 (morpholinyl), —N(CH 3 ) 2 ,

Assignees

• Bristol Myers Squibb Co

Inventors

• Yoon David S
• Liu Chunjian
• Regueiro-Ren Alicia
• Posy Shoshana L

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/438

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

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title