Amide substituted indole compounds useful as TLR inhibitors

Patent metadata

Field	Value
Publication number	US-11420973-B2
Application number	US-201816954543-A
Country	US
Kind code	B2
Filing date	Dec 18, 2018
Priority date	Dec 19, 2017
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

N-oxides, or salts thereof, wherein G, L2, R1, R5, R9, R10, 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 autoimmune diseases.

First claim

What is claimed is:

1. A compound of Formula (I)

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

L 2 is a bond, —CH(CH 3 )—, —C(CH 3 ) 2 —, or —CH 2 CH 2 —;
R 1 is —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CHF 2 , or —CH 2 CF 3 ;
each R 2 is independently —CH 3 , —OCH 3 , or —NH 2 ;
R 2a is —CH 3 ;
each R 2b is independently H, Cl, or —CH 3 ;
R 9 is —CH 3 , —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 C(CH 3 ) 2 CH 2 OH, —CH 2 CHFC(CH 3 ) 2 OH, —CH 2 CH 2 C(CH 3 ) 2 OH, —CH(CH 2 OH) 2 , —CH 2 CH 2 OCH 3 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 C(O)NH 2 , —CH 2 S(O) 2 OH, —CH 2 CH 2 C(CH 3 ) 2 NHS(O) 2 CH 3 , or —(CH 2 ) 0-3 R 9a ;
R 9a is cyclohexyl, cycloheptyl, 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, —NH 2 , —N(CH 3 ) 2 , oxetanyl, phenyl, piperazinyl, piperidinyl, and pyrrolidinyl;
R 10 is H, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 OCH 3 , or cyclopropyl;
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 2 R 10 a;
each R 10a is independently selected from —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OCH 3 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 NH(CH 3 ), —CH 2 C(O)NH(CH 3 ), —CH 2 C(O)N(CH 3 ) 2 , —CH 2 (methyltriazolyl), —CH 2 CH 2 (phenyl), —CH 2 CH 2 (morpholinyl), —C(O)CH 3 , —C(O)NH 2 , —C(O)N(CH 2 CH 3 ) 2 , —C(O)CH 2 NH(CH 3 ), —C(O)CH 2 N(CH 3 ) 2 , —NH 2 , —N(CH 3 ) 2 , —NHC(O)CH 3 , —C(O)(furanyl), —O(piperidinyl), —C(O)CH 2 (diethylcarbamoylpiperidinyl), methylpiperazinyl, piperidinyl, methylpiperidinyl, diethylcarbamoylpiperidinyl, isopropylpiperidinyl, pyridinyl, trifluoromethylpyridinyl, pyrimidinyl, and dihydrobenzo[d]imidazolonyl;
and
p is zero, 1, or 2.

2. The compound according to claim 1 , N-oxide, or a salt thereof, wherein R 9 and R 10 together with the nitrogen atom to which they are attached form a heterocyclic ring selected from diazaspiro[4.5]decanyl, diazepanyl, octahydropyrrolo[3,4-c]pyrrolyl, piperazinyl, piperidinyl, and pyrrolidinyl, each substituted with zero to 2 R 10a .

3. The compound according to claim 1 , N-oxide, or a salt thereof, wherein L 2 is a bond.

4. The compound according to claim 1 , N-oxide, or a salt thereof, wherein L 2 is —CH(CH 3 )—, —C(CH 3 ) 2 —, or —CH 2 CH 2 —.

5. The compound according to claim 1 , N-oxide, or a salt thereof, wherein G is:

6. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.

7. A method of treating an autoimmune disease or a chronic inflammatory disease, comprising administering to a mammalian patient having said autoimmune disease or chronic inflammatory disease a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said autoimmune disease or chronic inflammatory disease is selected from systemic lupus erythematosus (SLE), rheumatoid arthritis, multiple sclerosis (MS), and Sjögren's syndrome.

8. A compound or a salt thereof, wherein said compound is:
2-(3,4-dimethoxyphenyl)-5-{octahydropyrrolo [3,4-c]pyrrole-2-carbonyl}-3-(propan-2-yl)-1H-indole (1);
(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)(4-methyl-1,4-diazepan-1-yl) methanone (2);
2-(3,4-dimethoxyphenyl)-3-isopropyl-N,N-dimethyl-1H-indole-5-carboxamide (3);
2-(3,4-dimethoxyphenyl)-3-isopropyl-N-methyl-1H-indole-5-carboxamide (4);
((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)methanone (5);
2-{-[2-(3,4-dimethoxyphenyl)-3-(propan-2-yl)-1H-indole-5-carbonyl]-octahydropyrrolo [3,4-c]pyrrol-2-yl}-N,N-dimethylacetamide (6);
2(5-(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indole-5-carbonyl) hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N-methylacetamide (7);
1-(2-{5[2-(3,4-dimethoxyphenyl)-3-(propan-2-yl)-1H-indole-5-carbonyl]-octahydropyrrolo[3,4-c]pyrrol-2-yl}-2-oxoethyl)-N,N-diethylpiperidine-3-carboxamide (8);
1-(5-(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indole-5-carbonyl) hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-dimethylamino)ethan-1-one (9);
1-(2-{5-[2-(3,4-dimethoxyphenyl)-3-(propan-2-yl)-1H-indole-5-carbonyl]-octahydro pyrrolo[3,4-c]pyrrol-2-yl}-2-oxoethyl)-N,N-diethylpiperidine-3-carboxamide (10-11);
(2(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)(542-(methylamino)ethyl) hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (12);
(2(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)(5-methylhexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (13);
(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)(5-isopropylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (14);
(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)(5-(1-methylpiperidin-4-yl) hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (15);
1-(5-(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indole-5-carbonyl)hexahydro pyrrolo[3,4-c]pyrrol-2(1H)-yl)-2-(methylamino) ethanone (16);
2-(3,4-dimethoxyphenyl)-N-[2-(dimethylamino)ethyl]-3-ethyl-1H-indole-5-carboxamide (17);
(R)-2-(3,4-dimethoxyphenyl)-3-ethyl-N-(2-fluoro-3-hydroxy-3-methylbutyl)-1H-indole-5-carboxamide (18);
2-(3,4-dimethoxyphenyl)-N-(4-(dimethylamino)cyclohexyl)-3-ethyl-1H-indole-5-carboxamide (19);
N-cycloheptyl-2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indole-5-carboxamide (20);
2-(3,4-dimethoxyphenyl)-3-ethyl-N-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-1H-indole-5-carboxamide (21);
2-(3,4-dimethoxyphenyl)-3-ethyl-N-methyl-N-(pyridin-3-ylmethyl)-1H-indole-5-carboxamide (22);
2-(3,4-dimethoxyphenyl)-3-ethyl-N-methyl-N-((2-(piperidin-4-yl)thiazol-4-yl) methyl)-1H-indole-5-carboxamide (23);
2-(3,4-dimethoxyphenyl)-3-ethyl-N-methyl-N-(2-(pyridin-2-yl)ethyl)-1H-indole-5-carboxamide (24);
(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl) (4-(4-methylpiperazin-1-yl) piperidin-1-yl)methanone (25);
(R)-1-(1-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indole-5-carbonyl)pyrrolidin-3-yl) propan-2-one (26);
(S)-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl)(2-(methoxymethyl)pyrrolidin-1-yl) methanone (27);
(S)-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone (28);
(R)-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl)(3-(dimethylamino) pyrrolidin-1-yl)methanone (29);
(S)-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone (30);
(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl)(4-(dimethylamino)piperidin-1-yl) methanone (31);
(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indol-5-yl)(3,3-dimethylpiperidin-1-yl) methanone (32);
1-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indole-5-carbonyl)-N,N-diethylpiperidine-3-carboxamide (33);
1-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indole-5-carbonyl)piperidine-4-carboxamide (34);
1-(4-(2-(3,4-dimethoxyphenyl)-3-ethyl-1H-indole-5-carbonyl)-1,4-diazepan-1-yl) ethan-1-one (35);
(2-(3,4-dimethoxyphenyl)-3-ethyl-

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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D453/02

  containing not further condensed quinuclidine ring systems · CPC title

• C07D401/12

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

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title