1H-pyrrolo[3,2-C]pyridine and 1H-pyrrolo[2,3-C]pyridine derivatives as TLR9 inhibitors for the treatment of fibrosis

Patent metadata

Field	Value
Publication number	US-12590091-B2
Application number	US-202118042069-A
Country	US
Kind code	B2
Filing date	Aug 18, 2021
Priority date	Aug 19, 2020
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

The present invention relates to 1H-pyrrolo[3,2-c]pyridine and 1H-pyrrolo[2,3-c]pyridine derivatives of formula (I) or a salt thereof. The present compounds are inhibitors of TLR9 and useful in treating preventing, or slowing fibrotic diseases, such as e.g. liver fibrosis, renal fibrosis, biliary fibrosis or pancreatic fibrosis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC), or idiopathic pulmonary fibrosis (IPF).

First claim

What is claimed is:

1 . A compound of Formula (IIIb):

or salts thereof, wherein:
G is:
(i) phenyl substituted with 1 to 3 substituents independently selected from —OCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , —S(O) 2 (cyclopropyl), and —S(O)(NH)N(CH 3 ) 2 ;

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

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

A is piperidinyl, phenyl, pyridinyl, pyrimidinyl, 6-azabicyclo[3.2.1]octanyl, 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 —, or —C(O)(CR x R x ) 0-2 —;
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, —(CH 2 ) 1-4 O(C 1-3 alkyl), —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 H, 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 3 is hydrogen, F, C 1-3 alkyl, or C 3-4 cycloalkyl;
R 4 is:
(i) —N(CH 3 ) 2 ;
(ii) morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, pyridinyl, dioxothiomorpholinyl, azaspiro[3.3]heptanyl, azabicyclo[3.2.1]octanyl, diazabicyclo[2.2.2]octanyl, or diazabicyclo[3.2.1]octanyl, each substituted with zero to 4 R 4a ; or

each R 4a is independently —OH, C 1-6 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, —CH 2 (C 3-6 cycloalkyl), —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), or —C(O)O(C 1-4 alkyl);
each R 4b is independently F, Cl, or —CH 3 ;
each R 4c is independently —OH, 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;
each R 5 is independently hydrogen, F, Cl, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 alkoxy, cyclopropyl, or morpholinyl;
each R x is independently H or —CH 3 ;
each R y is independently H or C 1-6 alkyl;
m is zero, 1, or 2;
n is zero, 1, or 2; and
p is zero, 1, 2, 3, or 4.

2 . The compound according to claim 1 or salts thereof, or a salt thereof, wherein:
G is phenyl substituted with 1 to 2 substituents independently selected from —OCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , and —S(O) 2 (cyclopropyl);
A is piperidinyl, phenyl, or pyridinyl, each substituted with -L-R 4 and zero to 2 R 4b ;
L is a bond, —CH 2 —, —C(O)—, —C(O)CH 2 —, or —C(O)CH 2 CH 2 —;
R 1 is hydrogen, —CH 3 , —CHF 2 , or cyclopropyl;
R 3 is hydrogen, F, —CH 3 , or cyclopropyl;
R 4 is:
(i) —N(CH 3 ) 2 ; or
(ii) pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each substituted with zero to 4 R 4a ;

each R 4a is independently —OH, 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;
each R 4b is independently F, Cl, 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;
each R 5 is independently hydrogen, F, Cl, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-2 alkoxy, cyclopropyl, or morpholinyl;
m is zero, 1, or 2; and
n is zero, 1, or 2.

3 . The compound according to claim 1 or salts thereof, wherein:
G is phenyl substituted with 1 to 2 substituents independently selected from —OCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , and —S(O) 2 (cyclopropyl);
A is piperidinyl, phenyl, or pyridinyl, each substituted with -L-R 4 and zero to 2 R 4b ;
L is a bond, —CH 2 —, —C(O)—, —C(O)CH 2 —, or —C(O)CH 2 CH 2 —;
R 1 is hydrogen or —CH 3 ;
R 3 is hydrogen, F, —CH 3 , or cyclopropyl;
R 4 is:
(i) —N(CH 3 ) 2 ; or
(ii) pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each substituted with zero to 4 R 4a ;

each R 4a is independently —OH, —CH 3 , —CHCH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 C(CH 3 ) 3 , —CH 2 CH 2 C(CH 3 ) 3 , —CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 (cyclopropyl), —C(O)CH 3 , —C(O)CH(CH 3 ) 2 , —C(O)CH 2 CH 3 , —C(O)(phenyl), —C(O)CH 2 (phenyl), —C(O)OCH 2 CH 3 , —C(O)O(phenyl), cyclopropyl, cyclobutyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, —(CH 2 ) 1-2 (bromophenyl), or —(CH 2 ) 1-2 (iodophenyl);
each R 4b is F; and
each R 5 is independently hydrogen, —CH 3 , —C(CH 3 ) 2 OH, —OCH 3 , or morpholinyl.

4 . The compound according to claim 1 salts thereof, wherein:
G is phenyl substituted with 1 to 2 substituents independently selected from —OCH 3 , —S(O) 2 CH 3 , —S(O) 2 N(CH 3 ) 2 , and —S(O) 2 (cyclopropyl);
A is piperidinyl, phenyl, or pyridinyl, each substituted with -L-R 4 and zero to 2 R 4b ;
L is a bond, —CH 2 —, —C(O)—, —C(O)CH 2 —, or —C(O)CH 2 CH 2 —;
R 1 is hydrogen or —CH 3 ;
R 3 is hydrogen, F, —CH 3 , or cyclopropyl;
R 4 is:
(i) —N(CH 3 ) 2 ; or
(ii) pyrrolidinyl, piperidinyl, piperazinyl, or pyridinyl, each substituted with zero to 4 R 4a ;

each R 4a is independently —OH, —CH 3 , —CHCH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 C(CH 3 ) 3 , —CH 2 CH 2 C(CH 3 ) 3 , —CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH,

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Chunjian
• Regueiro-Ren Alicia

Classifications

• C07D519/00

  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

• C07D487/08

  Bridged systems · CPC title

• C07D471/08

  Bridged systems · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title