Amide substituted indole compounds useful as tlr inhibitors

Patent metadata

Field	Value
Publication number	US-2020331920-A1
Application number	US-201816954543-A
Country	US
Kind code	A1
Filing date	Dec 18, 2018
Priority date	Dec 19, 2017
Publication date	Oct 22, 2020
Grant date	—

Abstract

N-oxides, or salts thereof, wherein G, L 2 , R 1 , R 5 , R 9 , R 10 , and n are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmunediseases.

First claim

1 . A compound of Formula (I)

N-oxide, or a salt thereof, wherein:
G is:
(i)

(ii)

(iii)

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

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

L 2 is a bond or —(CR x R x ) 1-3 —;
R 1 is H, Cl, —CN, C 1-4 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 hydroxy-fluoroalkyl, —CR v ═CH 2 , C 3-6 cycloalkyl, —CH 2 (C 3-6 cycloalkyl), —C(O)O(C 1-3 alkyl), or tetrahydropyranyl;
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), —(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 ) 1-2 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 ;
each R 5 is independently F, Cl, —CN, C 1-3 alkyl, C 1-2 fluoroalkyl, or —OCH 3 ;
R 9 is C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 hydroxy fluoroalkyl, C 1-3 aminoalkyl, —(CH 2 ) 1-2 O(C 1-3 alkyl), —(CH 2 ) 1-3 NR x R x , —(CH 2 ) 1-2 C(O)NR x R x , —(CH 2 ) 1-3 S(O) 2 OH, —(CR x R) 1-3 NR x S(O) 2 (C 1-2 alkyl), or —(CH 2 ) 0-3 R 9a ;
R 9a is C 3-7 cycloalkyl, furanyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl, thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted with zero to 3 substituents independently selected from F, Cl, —OH, C 1-4 alkyl, C 1-3 hydroxyalkyl, C 1-3 hydroxy fluoroalkyl, C 1-3 aminoalkyl, —NR y R y , oxetanyl, phenyl, piperazinyl, piperidinyl, and pyrrolidinyl;
R 10 is H, C 1-4 alkyl, —(CH 2 ) 1-3 O(C 1-2 alkyl), or C 3-6 cycloalkyl;
or R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl, indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each substituted with zero to 3 R 10a ;
each R 10a is independently selected from C 1-4 alkyl, C 1-4 hydroxyalkyl, —(CH 2 ) 1-3 O(C 1-3 alkyl), —(CH 2 ) 1-3 NR x R x , —(CH 2 ) 1-2 C(O)NR x R x , —(CH 2 ) 1-2 (methyltriazolyl), —CH 2 CH 2 (phenyl), —CH 2 CH 2 (morpholinyl), —C(O)(C 1-2 alkyl), —C(O)NR y R y , —C(O)CH 2 NR y R y , —NR y R y , —NHC(O)(C 1-3 alkyl), —C(O)(furanyl), —O(piperidinyl), —C(O)CH 2 (diethylcarbamoylpiperidinyl), methylpiperazinyl, piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl, isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl, pyrimidinyl, and dihydrobenzo[d]imidazolonyl;
R v is H, C 1-2 alkyl, or C 1-2 fluoroalkyl;
each R x is independently H or —CH 3 ;
each R y is independently H or C 1-6 alkyl;
n is zero, 1, or 2; and
p is zero, 1, 2, 3, or 4.

2 . The compound according to claim 1 , N-oxide, or a salt thereof, wherein:
L 2 is a bond or —(CR x R x ) 1-2 —; R 1 is H, Cl, —CN, C 1-2 alkyl, C 1-2 fluoroalkyl, C 1-2 hydroxyalkyl, or —C(O)O(C 1-2 alkyl); each R 2 is independently F, Cl, —CN, —OH, C 1-3 alkyl, C 1-2 fluoroalkyl, C 1-2 cyanoalkyl, C 1-3 hydroxyalkyl, C 1-2 aminoalkyl, —(CH 2 ) 0-2 O(C 1-3 alkyl), C 3-6 cycloalkyl, —NR x R x , —(CH 2 ) 0-2 C(O)NR x R x , —CH 2 (C 3-6 cycloalkyl), —CH 2 (phenyl), or phenyl; R 2a is C 1-4 alkyl, C 1-2 fluoroalkyl, C 1-4 hydroxyalkyl, —(CH 2 ) 1-3 OCH 3 , C 3-6 cycloalkyl, —CH 2 C(O)NR x R x , —CH 2 (C 3-6 cycloalkyl), —CH 2 (phenyl), tetrahydrofuranyl, or phenyl; each R 2b is independently H, F, Cl, —CN, —NR x R x , C 1-6 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, —(CH 2 ) 0-2 O(C 1-2 alkyl), —(CH 2 ) 0-2 C(O)NR x R x , —(CH 2 ) 1-3 (cyclopropyl), —C(O)O(C 1-2 alkyl), —C(O)NR x (C 1-3 alkyl), —CR x ═CH 2 , or —CH═CH(C 3-6 cycloalkyl); each R 5 is independently F, Cl, —CN, C 1-2 alkyl, or —OCH 3 ; R 9 is C 1-3 alkyl, C 1-5 hydroxyalkyl, C 2-5 hydroxy fluoroalkyl, C 1-2 aminoalkyl, —(CH 2 ) 1-2 O(C 1-2 alkyl), —(CH 2 ) 1-3 N(CH 3 ) 2 , —(CH 2 ) 1-2 C(O)NH 2 , —(CH 2 ) 1-2 S(O) 2 OH, —(CH 2 ) 1-2 CR x R x NHS(O) 2 CH 3 , or —(CH 2 ) 0-3 R 9a ; R 9a is C 5-7 cycloalkyl, furanyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, quinuclidinyl, thiazolyl, or octahydrocyclopenta[c]pyrrolyl, each substituted with zero to 2 substituents independently selected from —OH, C 1-3 alkyl, —NR x R x , oxetanyl, phenyl, piperazinyl, piperidinyl, and pyrrolidinyl; R 10 is H, C 1-3 alkyl, —(CH 2 ) 1-2 O(C 1-2 alkyl), or C 3-6 cycloalkyl; or R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azabicyclo[3.1.1]heptanyl, azaspiro[5.5]undecanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.1.1]heptanyl, diazabicyclo[3.2.0]heptanyl, diazaspiro[3.5]nonanyl, diazaspiro[4.4]nonanyl, diazaspiro[4.5]decanyl, diazepanyl, indolinyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, piperazinonyl, piperazinyl, piperidinyl, and pyrrolidinyl, each substituted with zero to 3 R 10a ; each R 10a is independently selected from C 1-3 alkyl, C 1-3 hydroxyalkyl, —(CH 2 ) 1-2 O(C 1-2 alkyl), —(CH 2 ) 1-2 NR x R x , —CH 2 C(O)NR x R x , —CH 2 (methyltriazolyl), —CH 2 CH 2 (phenyl), —CH 2 CH 2 (morpholinyl), —C(O)(C 1-2 alkyl), —C(O)NH 2 , —C(O)N(C 1-2 alkyl) 2 , —C(O)CH 2 NR x R x , —NR

Assignees

• Bristol Myers Squibb Co

Inventors

• Dyckman Alaric J
• Dodd Dharmpal S
• Mussari Christopher P
• Sherwood Trevor C
• Haque Tasir Shamsul
• Posy Shoshana L
• Kumar Sreekantha Ratna
• Pasunoori Laxman
• Hegde Subramanya
• Anumula Rushith Kumar

Classifications

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• A61P19/02

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

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title