Aryl and heteroaryl substituted indole compounds

Patent metadata

Field	Value
Publication number	US-11420958-B2
Application number	US-201816955314-A
Country	US
Kind code	B2
Filing date	Dec 19, 2018
Priority date	Dec 20, 2017
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

Disclosed are compounds of Formula (I) or salts thereof, wherein A, G, R1, R5, 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:

or
(ii) a 9-membered heterocyclic ring selected from:

A is an aromatic group selected from [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl, quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl, tetrahydrothiazolo[5,4-c]pyridinyl, tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl, thiooxadiazolyl, and triazolyl, each substituted with zero to 2 R 14a and zero to 3 R 14b ;
R 1 is —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CHF 2 , or —CH 2 CF 3 ;
each R 2 is independently —CH 3 or —NH 2 ;
each R 14a is independently selected from:
(i) H, F, Cl, —OH, —CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 CH 2 C(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —CH 2 OH, —OCH 3 , —CH 2 CH 2 OCH 3 , —CHR x NR x (CH 3 ), —CH 2 N(CH 3 )(CH(CH 3 ) 2 ), —CH 2 NH(CH 2 C(CH 3 ) 3 ), —CH 2 NH(CH 2 CN), —CH 2 N(CH 3 )(CH 2 CH 2 OCH 3 ), —CH 2 N(CH 2 CH 2 OCH 3 ) 2 , —CH 2 NR x (CH 2 C≡CH), —CH 2 NHCH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NR x (CH 3 ), —CH 2 CR x (CH 3 )NH 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH(NH 2 )(CH 2 ) 3-4 NH 2 , —CH 2 NHCH 2 CH 2 O(C 1-3 alkyl), —CH 2 NHCH 2 CH 2 OCH 2 CH 2 OH, —CH 2 NHCH 2 CH 2 S(O) 2 OH, —CH 2 C(O)NR x CH 3 ), —NR x R x , —NH(CH(CH 3 ) 2 ), —NHCH 2 CH 2 NH(CH 3 ), —NHCH 2 CH 2 CH 2 N(CH 3 ) 2 , —NHC(O)CH 3 , —NHC(O)CF 3 , —NHC(O)OC(CH 3 ) 3 , —NHC(O)CH 2 N(CH 3 ) 2 , —NHC(O)CH 2 CH 2 N(CH 3 ) 2 , —NHCH 2 C(O)CH 2 NH(CH 3 ), —C(O)CH 3 , —C(O)CH 2 CH(CH 3 )OH, —C(O)CH 2 NR x (CH 3 ), —C(O)NR x R x , —C(O)NH(CH 2 CN), —C(O)NHCH 2 CH 2 CH 2 NR x R x , —C(O)NHCH 2 CH(CH 3 )CH 2 NH 2 , —C(O)NHCH 2 C(O)NH 2 , —C(O)N(CH 3 )CH 2 CH 2 CH 2 N(CH 3 ) 2 , —C(O)N(CH 2 CH 3 )CH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 CH 2 N(CH 3 ) 2 , —C(O)NHCH 2 CH 2 NHC(O)CH 3 , —S(O) 2 NH 2 , and —C(O)CH 2 S(O) 2 CH 3 ;
(ii) 8-azabicyclo[3.2.1]octanyl, azaspiro[3.5]nonanyl, azetidinyl, benzo[c][1,2,5]oxadiazolyl, cyclopentyl, cyclohexyl, diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinonyl, quinolinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydropyridinyl, or thiazolidinyl, each substituted with zero to 2 substituents independently selected from —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH(CH 3 )OH, —NH 2 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NH(CH 3 ), —C(O)CH 3 , —C(O)CH 2 NH(CH 3 ), —C(O)CH 2 N(CH 3 ) 2 , —C(O)O(C(CH 3 ) 3 ), —CH 2 C(O)NR x (CH 3 ), cyclobutyl, cyclopentyl, —CH 2 (phenyl), —CH 2 (pyrrolyl), —CH 2 (morpholinyl), —CH 2 (methylpiperazinyl), —CH 2 (thiophenyl), methylpiperidinyl, isobutylpiperidinyl, and pyridinyl; or
(iii) -L 3 -R 14c ;

each R 14b is —CH 3 ;
L 3 is —(CH 2 ) 1-3 —, —CH(CH 3 )—, —CH(NH 2 )—, —CH 2 NH—, —C(O)—, —C(O)NH(CH 2 ) 0-4 —, —C(O)N(CH 3 )CH 2 CH 2 —, —NH—, —NHC(O)—, —NHCH 2 —, —NHCH 2 C(O)—, —O—, or —OCH 2 CH 2 —;
R 14c is adamantanyl, azetidinyl, cyclopropyl, cyclohexyl, diazepanyl, imidazolyl, indolyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, or tetrazolyl, each substituted with zero to 1 substituent selected from —OH, —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —C(CH 3 ) 2 OH, —NH 2 , —N(CH 3 ) 2 , —NH(C(CH 3 ) 2 , —NHC(O)CH 3 , —C(O)CH 3 , —C(O)NH 2 , —C(O)N(CH 2 CH 3 ) 2 , —C(O)(tetrahydrofuranyl), —C(O)OCH 2 CH 3 , —CH 2 C(O)NH(CH(CH 3 ) 2 ), morpholinyl, methylpiperidinyl, pyrazinyl, pyridinyl, and pyrrolidinyl;
each R x is independently H or —CH 3 ;
n is zero; and
p is zero, 1, 2, or 3.

2. The compound according to claim 1 , N-oxide, or a salt thereof, wherein:
A is an aromatic group selected from [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, imidazolyl, indazolyl, isoquinolinyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyrazolo[3,4-b]pyridinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinonyl, quinolinyl, quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl, tetrahydrothiazolo[5,4-c]pyridinyl, tetrahydrothieno[2,3-c]pyridinyl, thiadiazolyl, thiazolyl, thiooxadiazolyl, and triazolyl, each substituted with zero to 1 R 14a and zero to 2 R 14b .

3. The compound according to claim 1 , N-oxide, or a salt thereof, wherein:
R 1 is —CH(CH 3 ) 2 ;
each R 14a is independently selected from:
(i) H, F, Cl, —OH, —CH 3 , —CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —CH 2 CH 2 CH 2 C(CH 3 ) 2 , —CF 3 , —CH 2 CF 3 , —CH 2 OH, —OCH 3 , —CH 2 CH 2 OCH 3 , —CHR x NR x (CH 3 ), —CH 2 N(CH 3 )(CH(CH 3 ) 2 ), —CH 2 NH(CH 2 C(CH 3 ) 3 ), —CH 2 NH(CH 2 CN), —CH 2 N(CH 3 )(CH 2 CH 2 OCH 3 ), —CH 2 N(CH 2 CH 2 OCH 3 ) 2 , —CH 2 NR x (CH 2 C≡CH), —CH 2 NHCH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NR x (CH 3 ), —CH 2 CR x (CH 3 )NH 2 , —CH 2 CH 2 CH 2 N(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 2 NH 2 , —CH(NH 2 )(CH 2 ) 3 -4NH 2 , —CH 2 NHCH 2 CH 2 O(C 1-3 alkyl), —CH 2 NHCH 2 CH 2 OCH 2 CH 2 OH, —CH 2 NHCH 2 CH 2 S(O) 2 OH, —CH 2 C(O)NR x (CH 3 ), —NR x R x , —NH(CH(CH 3 ) 2 ), —NHCH 2 CH 2 NH(CH 3 ), —NHCH 2 CH 2 CH 2 N(CH 3 ) 2 , —NHC(O)CH 3 , —NHC(O)CF 3 , —NHC(O)O C(CH 3 ) 3 , —NHC(O)CH 2 N(CH 3 ) 2 , —NHC(O)CH 2 CH 2 N(CH 3 ) 2 , —NHCH 2 C(O)CH 2 NH(CH 3 ), —C(O)CH 3 , —C(O)CH 2 CH(CH 3 )OH, —C(O)CH 2 NR x (CH 3 ), —C(O)NR x R x , —C(O)NH(CH 2 CN), —C(O)NHCH 2 CH 2 CH 2 NR x R x , —C(O)NHCH 2 CH(CH 3 )CH 2 NH 2 , —C(O)NHCH 2 C(O)NH 2 , —C(O)N(CH 3 )CH 2 CH 2 CH 2 N(CH 3 ) 2 , —C(O)N(CH 2 CH 3 )CH 2 CH 2 N(CH 3 ) 2 , —OCH 2 CH 2 CH 2 N(CH 3 ) 2 , —C(O)NHCH 2 CH 2 NHC(O)CH 3 , —S(O) 2 NH 2 , and —C(O)CH 2 S(O) 2 CH 3 .

4. The compound according to claim 1 , N-oxide, or a salt thereof, wherein A is phenyl.

5. The compound according to claim 4 , N-oxide, or a salt thereof, wherein A is oxazolyl or oxadiazolyl.

6. The compound according to claim 1 , N-oxide, or a salt thereof, wherein A is pyridinyl, pyrazinyl, or pyridazinyl.

7. The compound according to claim 1 , N-oxide, or a salt thereof, wherein A is [1,2,4]triazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[3,4-b]pyridinyl, quinolinonyl, quinolinyl, quinoxalinyl, tetrahydro-[1,2,4]triazolo[1,5-a]pyrazinyl, tetrahydroimidazo[1,2-a]pyrazinyl, tetrahydroisoquinolinyl, tetrahydrothiazolo[5,4-c] pyridinyl, or tetrahydrothieno[2,3-c]pyridinyl.

8. A compound, N-oxide, or a salt thereof, wherein said compound is:
2-(3,4-dimethoxyphenyl)-5-[3-(piperazine-1-carbonyl)phenyl]-3-(propan-2-yl)-1H-indole (1);
2-(3,4-dimethoxyphenyl)-5-[5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl]-3-(propan-2-yl)-1H-indole (2);
1-(4-{5-[2-(3,4-dimethoxyphenyl)-3-(propan-2-yl)-1H-indol-5-yl]-1,3,4-oxadiazol-2-yl}piperidin-1-yl)-2-(dimethylamino)ethan-1-one (3);
2-(3,4-dimethoxyphenyl)-3-(propan-2-yl)-5-{5-[1-(propan-2-yl)piperidin-4-yl]-1,3,4-oxadiazol-2-yl}-1H-indole (4);
(3-(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)phenyl)(4-methyl-1,4-diazepan-1-yl)methanone (5);
N-((1R,4R)-4-aminocyclohexyl)-3-(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)benzamide (6);
3-(2-(3,4-dimethoxyphenyl)-3-isopropyl-1H-indol-5-yl)-N-((1r,4r)-4-(2-hydroxypropan-2-yl)c

Assignees

• Bristol Myers Squibb Co

Inventors

• Dyckman Alaric J
• Mussari Christopher P
• Haque Tasir Shamsul
• Whiteley Brian K
• Posy Shoshana L
• Kumar Sreekantha Ratna
• Pasunoori Laxman
• Hegde Subramanya
• Ramachandra Reddy Anupama Kandhi
• Anumula Rushith Kumar

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D401/04

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

• C07D401/12

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

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title