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-2023312565-A1
Application number	US-202118042069-A
Country	US
Kind code	A1
Filing date	Aug 18, 2021
Priority date	Aug 19, 2020
Publication date	Oct 5, 2023
Grant date	—

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 (I):

or stereoisomers, tautomer, solvates or salts thereof, wherein:
(i) X is C-A and Y is N; and Q 1 is G and Q 2 is R 3 ;
(ii) X is N and Y is C-A; and Q 1 is G and Q 2 is R 3 ; or
(iii) X is N and Y is C-A; and Q 1 is R 3 and Q 2 is G;
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 stereoisomers, tautomer, solvates or salts thereof, having the structure of Formula (III):

3 . The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, having the structure of Formula (IIIb):

4 . (canceled)

5 . The compound according to claim 1 or stereoisomers, tautomer, solvates or salts thereof, having the structure of Formula (IIa):

6 . (canceled)

7 . The compound according to claim 1 or stereoisomers, tautomer, solvates 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.

8 . The compound according to claim 1 or stereoisomers, tautomer, solvates 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

Assignees

• Bristol Myers Squibb Co

Inventors

• Liu Chunjian
• Regueiro-Ren Alicia

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• 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

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• C07D451/04

  with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title