Substituted indole compounds

Patent metadata

Field	Value
Publication number	US-11739098-B2
Application number	US-202217699944-A
Country	US
Kind code	B2
Filing date	Mar 21, 2022
Priority date	Nov 14, 2017
Publication date	Aug 29, 2023
Grant date	Aug 29, 2023

Abstract

Disclosed are compounds of Formula (I)or salts thereof, wherein Ring Het, R1, R2, R3, R4, R5, m, n, and p 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 autoimmune diseases.

First claim

What is claimed is:

1. A compound of Formula (I)

or a salt thereof, wherein:
Ring Het is a 10-membered heterocyclic ring selected from:

R 1 is H, Cl, —CN, C 1-4 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 hydroxy-fluoroalkyl, 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), —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 -cyclopropyl), —S(O) 2 (C 1-3 alkyl), C 3-6 cycloalkyl, phenyl, morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or —C(O)(thiazolyl);
R 3 is:
(a) -L 1 -A; or

(b) H, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-3 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-3 hydroxy-fluoroalkyl, —CR x R x CR x (OH)CR x ═CR x R x , —C═N(NR x R x ), —(CR x R x ) 1-4 O(C 1-3 alkyl), —(CR x R x ) 1-4 O(CR x R x ) 1-3 O(C 1-3 alkyl), —CH 2 CH(OH)CH 2 O(C 1-3 alkyl), —(CR x R x ) 1-3 S(C 1-3 alkyl), —(CH 2 ) 1-3 C(O)OC(CH 3 ) 3 , —(CR x R x ) 0-3 NR x R y , —(CR x R x ) 0-3 NR x (C 1-4 hydroxyalkyl), —CH 2 CH(OH)CH 2 NR x R y , —C(O)H, —C(O)(C 1-6 alkyl), —C(O)(C 1-4 hydroxyalkyl), —C(O)(C 1-3 fluoroalkyl), —C(O)(C 1-3 chloroalkyl), —C(O)(C 1-3 cyanoalkyl), —(CR x R x ) 0-3 C(O)OH, —C(O)(CH 2 ) 0-2 O(C 1-4 alkyl), —C(O)(CR x R x ) 0-2 O(CR x R x ) 1-2 O(C 1-3 alkyl), —C(O)(CR x R x ) 0-2 O(CR x R x ) 1-2 NR y R y , —C(O)CR x R x S(O) 2 (C 1-3 alkyl), —C(O)CR x R x NR x S(O) 2 (C 1-3 alkyl), —C(O)CR x R x OC(O)(C 1-3 alkyl), —C(O)(CR x R x ) 0-3 NR y R y , —C(O)(CR x R x ) 0-1 NR x (C 1-3 cyanoalkyl), —C(O)(CR x R x ) 0-2 NR y (C 1-6 hydroxyalkyl), —C(O)(CR x R x ) 0-2 NR x (C 1-3 fluoroalkyl), —C(O)(CR x R x ) 0-1 NR x (C 1-5 hydroxy-fluoroalkyl), —C(O)(CR x R x ) 0-1 NR x (CH 2 ) 1-2 O(C 1-3 hydroxyalkyl), —C(O)(CR x R x ) 0-2 NR x (CH 2 ) 1-2 NR x C(O)(C 1-2 alkyl), —C(O)(CR x R x ) 0-2 NR x ((CR x R x ) 1-2 O(C 1-2 alkyl)), —C(O)(CR x R x ) 0-2 N((CR x R x ) 1-2 O(C 1-2 alkyl)) 2 , —C(O)(CR x R x ) 0-2 NR x (CR x R x ) 1-3 NR x R x , —C(O)CR x (NH 2 )(CR x R x ) 1-4 NR x R x , —C(O)CR x (NH 2 )(CR x R x ) 1-4 NR x C(O)NR x R x , —C(O)(CR x R x ) 0-3 NR x (CH 2 ) 0-1 C(O)(C 1-3 alkyl), —C(O)(CR x R x ) 0-3 N((CH 2 ) 0-1 C(O)(C 1-3 alkyl)) 2 , —C(O)(CR x R x ) 0-1 NR x (CH 2 ) 0-1 C(O)(C 1-3 cyanoalkyl), —C(O)(CR x R x ) 0-2 NR x (CH 2 ) 1-2 C(O)NR y R y , —C(O)(CR x R x ) 1-3 C(O)NR y R y , —C(O)(CR x R x ) 1-3 S(O) 2 NR y R y , —C(O)(CR x R x ) 0-2 NR x (CHR y (CH 2 OH)), —(CR x R x ) 1-2 C(O)NR y R y , —CH(CN)C(O)NR y R y , —(CR x R x ) 1-2 C(O)NR y (C 1-3 fluoroalkyl), —(CR x R x ) 1-2 C(O)NR y (C 1-4 hydroxyalkyl), —(CR x R x ) 1-2 C(O)NR y (C 1-3 cyanoalkyl), —(CR x R x ) 1-2 C(O)NR x (CH 2 ) 1-2 O(C 1-3 alkyl), —(CR x R x ) 1-2 C(O)NR x CH(C 1-4 alkyl)(C 1-3 hydroxyalkyl), —(CR x R x ) 1-2 C(O)NR x CH(C 1-3 hydroxyalkyl)(C 3-6 cycloalkyl), —(CH 2 ) 1-2 C(O)NR x (CH 2 ) 1-2 C(O)NR x R x , —(CH 2 ) 1-2 C(O)NR x (CH 2 ) 1-2 S(C 1-3 alkyl), —(CH 2 ) 1-2 C(O)NR x (CH 2 ) 1-2 S(O) 2 OH, —(CH 2 ) 1-2 C(O)NR x (CH 2 ) 1-2 NR x C(O)(C 1-3 alkyl), —(CH 2 ) 1-2 C(O)NR x (CH 2 ) 1-3 NR x R x , —(CH 2 ) 1-2 C(O)N(CH 2 CH 3 )(CH 2 ) 1-3 NR x R x , —(CR x R x ) 0-3 S(O) 2 (C 1-4 alkyl), —(CH 2 ) 0-2 S(O) 2 (C 1-3 fluoroalkyl), —(CR x R x ) 0-2 S(O) 2 NR y R y , —(CR x R x ) 0-2 NR x S(O) 2 (C 1-3 alkyl), —C(O)C(O)OH, —C(O)C(O)NR y R y , or —C(O)C(O)NR y (CR x R x ) 1-2 NR y R y ;
L 1 is a bond, —(CR x R x ) 1-2 —, —(CR x R x ) 1-2 CR x (OH)—, —(CR x R x ) 1-2 O—, —CR x R x C(O)—, —(CR x R x ) 2 NR x (CR x R x ) 0-1 —, —CR x R x C(O)NR x (CR x R x ) 0-4 —, —C(O)(CR x R x ) 0-3 —, —C(O)(CR x R x ) 0-2 NR x (CR x R x ) 0-2 —, —C(O)(CR x R x ) 0-2 N(C 1-2 hydroxyalkyl)(CR x R x ) 0-2 —, —C(O)(CR x R x ) 0-2 NR x (CR x R x ) 1-2 CR x (OH)—, —C(O)(CR x R x ) 1-2 C(O)NR x —, —(CR x R x ) 0-2 C(O)NR x (CR x R x ) 1-2 CR x (OH)—, —(CR x R x ) 0-2 C(O)N(C 1-2 hydroxyalkyl)(CR x R x ) 1-2 —, —C(O)(CR x R x ) 0-1 O—, —C(O)(CR x R x ) 1-2 NHS(O) 2 —, —C(O)CR x (NH 2 )CR x R x —, —C(O)C(O)(CR x R x ) 0-2 —, —C(O)NR x (CR x R x ) 1-2 —, or —S(O) 2 —;
A is 3-oxa-8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 1,1-dioxidothiomorpholinyl, 1,2-dioxotetrahydro-2H-thiopyranyl, 1,4-diazepanyl, 2-azabicyclo[3.1.0]hexanyl, azabicyclo[3.2.1]octanyl, 2-oxa-6-azaspiro[3.3]heptanyl, azepanyl, C 3-7 cycloalkyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinonyl, piperidinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrazolyl, thiadiazolyl, thiazolyl, or triazolyl, each substituted with zero to 4 substituents independently selected from F, Cl, —OH, —CN, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, —CH 2 NR x R x , C 1-3 alkoxy, —O(CH 2 ) 1-3 NR x R x , —O(CH 2 ) 1-3 NR x (pyridinyl), —C(O)(C 1-3 alkyl), —C(O)O(C 1-3 alkyl), —C(O)NR y R y , —NR x R x , —NR x C(O)(C 1-3 alkyl), —O(pyrimidinyl), C 3-6 cycloalkyl, morpholinyl, phenyl, methyl piperazinyl, pyridinyl, and pyrrolidinyl;
each R x is independently H or —CH 3 ;
each R y is independently H or C 1-6 alkyl;
each R 4 is independently F, —OH, C 1-2 alkyl, or —OCH 3 ; or two R 4 attached to the same carbon atom form ═O; or wherein when m is at least 2, two R 4 , each attached to a different carbon atom adjacent to the nitrogen atom in the piperidinyl ring, can form a —CH 2 CH 2 — bridge;
each R 5 is independently F, Cl, —CN, C 1-2 alkyl, C 1-2 fluoroalkyl, or —OCH 3 ;
m is zero, 1, 2, 3, or 4;
n is zero, 1, or 2; and
p is zero, 1, 2, 3, or 4.

2. The compound according to claim 1 or a salt thereof, wherein:
R 1 is H, Cl, —CN, C 1-4 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 1-4 alkyl, C 1-2 fluoroalkyl, C 1-2 cyanoalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, C 1-4 alkoxy, —NR y R y , —C(O)NR y R y , —C(O)NR x (C 1-4 hydroxyalkyl), —C(O)NR x (C 2-4 alkoxyalkyl), —C(O)NR x (C 3-6 cycloalkyl), —S(O) 2 (C 1-3 alkyl), C 3-6 cycloalkyl, morpholinyl, phenyl, or dimethyl pyrazolyl;
R 3 is:
(a) -L 1 -A; or
(b) H, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-3 cyanoalkyl, C 1-5 hydroxyalkyl, —(CR x R x ) 1-2 O(C 1-2 alkyl), —(CR x R x ) 1-4 O(CR x R x ) 1-3 O(C 1-3 alkyl), —CH 2 CH(OH)CH 2 O(C 1-3 alkyl), —(CR x R x ) 1-3 S(C 1-3 alkyl), —(CH 2 ) 1-3 C(O)OC(CH 3 ) 3 , —(CR x R x ) 0-3 NR x R y , —(CR x R x ) 0-3 NR x (C 1-4 hydroxyalkyl), —CH 2 CH(OH)CH 2 NR x R y , —C(O)(C 1-6 alkyl), —C(O)(C 1-4 hydroxyalkyl), —C(O)(C 1-3 fluoroalkyl), —C(O)(C 1-3 chloroalkyl), —C(O)(C 1-3 cyanoalkyl), —(CR x R x ) 0-3 C(O)OH, —C(O)(CH 2 ) 0-2 O(C 1-4 alkyl), —C(O)(CR x R x ) 0-2 O(CR x R x ) 1-2 O(C 1-3 alkyl), —C(O)(CH 2 ) 0-2 O(CH 2 ) 1-2 NR y R y , —C(O)CR x R x S(O) 2 (C 1-2 alkyl), —C(O)CR x R x NR x S(O) 2 (C 1-2 alkyl), —C(O)CR x R x OC(O)(C 1-3 alkyl), —C(O)(CR x R x ) 0-2 NR

Assignees

• Bristol Myers Squibb Co

Inventors

• Dyckman Alaric J
• Dodd Dharmpal S
• Mussari Christopher P
• Sherwood Trevor C
• Gilmore John L
• Haque Tasir Shamsul
• Whiteley Brian K
• Tortolani David R
• Posy Shoshana L
• Macor John E
• Lombardo Louis J
• Sistla Ramesh Kumar
• Ramachandra Reddy Anupama Kandhi
• Hegde Subramanya
• Pasunoori Laxman
• Kumar Sreekantha Ratna

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title