Substituted indole compounds useful as TLR inhibitors

Patent metadata

Field	Value
Publication number	US-11878975-B2
Application number	US-201816955097-A
Country	US
Kind code	B2
Filing date	Dec 18, 2018
Priority date	Dec 19, 2017
Publication date	Jan 23, 2024
Grant date	Jan 23, 2024

Abstract

Disclosed are compounds of Formula (I) N-oxides, or salts thereof, wherein G, A, 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:

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

A is: —CHR 12 R 13 , wherein R 12 and R 13 together with the carbon atom to which they are attached and the hydrogen atom attached to the carbon atom, form a cyclic group selected from azabicyclo[4.1.1]octanyl, azetidinyl, C 3-6 cycloalkyl, diazaspiro[4.5]decanonyl, morpholinyl, octahydrocyclopenta[c]pyrrolyl, or quinuclidinyl, each substituted with zero to 3 R 12a ;
R 1 is —CH 2 CH 3 or —CH(CH 3 ) 2 ;
each R 2 is independently —CH 3 or —OCH 3 ;
R 2a is —CH 3 ;
each R 2b is independently H or —CH 3 ;
each R 12a is independently —OH, —CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CF 3 , —CH 2 CH 2 CH 2 CF 3 , —CH 2 CN, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 C(O)NH(CH 3 ), —CH 2 C(O)N(CH 3 ) 2 , —CH 2 C(O)NH 2 , —CH 2 CH 2 S(O) 2 CH 3 , —CH 2 CH 2 NHS(O) 2 CH 3 , —OCH 3 , —NR x R x , —N(CH 3 )(CH 2 CH 3 ), —N(CH 3 )(CH(CH 3 ) 2 ), —NR x (CH 2 CHF 2 )—NH(CH 2 CF 3 ), —N(CH 3 )(CH 2 CH 2 CF 3 ), —N(CH 3 )(CH 2 CH 2 OCH 3 ), —NH(CH 2 CN), —N(CH 3 )CH 2 N(CH 3 ) 2 , —NH(CH 2 C(CH 3 ) 2 OH), —NH(CH 2 C(O)NH 2 ), —N(CH 3 )(OCH 3 ), —NR x CH 2 CH 2 S(O) 2 CH 3 , —NHC(O)CH 3 , —NHC(O)CH 2 CF 3 , —NHC(O)CHR x NH(CH 3 ), —NR x C(O)CH 2 N(CH 3 ) 2 , —NHC(O)CH 2 N(CH 3 )(CH 2 CH 3 ), —NHC(O)CH 2 N(CH 2 CH 3 ) 2 , —NHC(O)CH 2 NH(CH 2 C(CH 3 ) 2 OH), —NHCH 2 C(O)NR x (CH 3 ), —NHS(O) 2 CH 3 , —C(O)C(CH 3 ) 3 , —C(O)CH(CH 2 CH 3 ) 2 , —C(O)CH 2 OCH 3 , —C(O)CH 2 CH 2 OCH 3 , —C(O)CH 2 NH(CH 3 ), —C(O)CH 2 N(CH 3 ) 2 , —C(O)CH(CH 3 )NH(CH 3 ), —C(O)CH 2 N(CH 3 )(CH 2 CH 3 ), —C(O)CH 2 N(CH 2 CH 3 ) 2 , R 12b , —CH 2 R 12b , —C(O)R 12b , —C(O)CH 2 R 12b , —C(O)CH 2 NHR 12b , —C(O)NR x R 12b , —NR x C(O)CH 2 R 12b , —NR x R 12b , —NR x CH 2 R 12b , —NHC(O)CH 2 NR x R 12b , —NHC(O)CH 2 NR x CH 2 R 12b , —NHCH 2 C(O)NHR 12b , or —OR 12b ;
R 12b is azetidinyl, cyclopropyl, diazabicyclo[2.2.1]heptanyl, dioxolanyl, dioxidotetrahydrothiopyranyl, dioxidothiomorpholinyl, imidazolyl, morpholinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxaazaspiro[3.3]heptanyl, oxetanyl, phenyl, piperazinyl, piperazinonyl, piperidinyl, pyridinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, or triazolyl, each substituted with zero to 4 substituents independently selected from F, —OH, —CH 3 , —CH(CH 3 ) 2 , —CH 2 OH, —OCH 3 , —CH 2 CH 2 OCH 3 , —NR x R x , and —C(O)NH 2 ;
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 azetidinyl, C 3-6 cycloalkyl, or morpholinyl, each substituted with zero to 3 R 12a .

3. The compound according to claim 2 or a salt thereof, wherein A is azetidinyl, cyclopropyl, cyclobutyl, cyclohexyl, or morpholinyl, each substituted with zero to 3 R 12a .

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

5. The compound according to claim 1 , N-oxide, or a salt thereof, wherein A is C 3-6 cycloalkyl, each substituted with zero to 3 R 12a .

6. A compound according to claim 5 or a salt thereof, wherein said compound is:
4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexanamine (1-2);
4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexan-1-amine (3);
4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexan-1-amine (4);
4-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1H-indol-5-yl)cyclohexan-1-amine (5);
N-isopropyl-4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)-N-methylcyclohexanamine (6-7);
N-cyclopropyl-4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)-N-methylcyclohexan-1-amine (8);
N-cyclopropyl-4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)-N-methylcyclohexan-1-amine (9);
N-cyclopropyl-4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)cyclohexan-1-amine (10-11);
N-cyclopropyl-4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)-N-methylcyclohexan-1-amine (12-13);
N-cyclopropyl-4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl)cyclohexan-1-amine (14, 17);
N-cyclopropyl-4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)cyclohexan-1-amine (15-16);
6-(5-(4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-3-isopropyl-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (19-20);
1-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexyl)azetidin-3-ol (20, 22);
6-(5-(4-(3-fluoroazetidin-1-yl)cyclohexyl)-3-isopropyl-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (21, 23);
6-(5-(4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-3-isopropyl-1H-indol-2-yl)-7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridine (24-25);
(1-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl) cyclohexyl)azetidine-3,3-diyl)dimethanol (26-27);
(R)-1-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)cyclohexyl)-N,N-dimethylpyrrolidin-3-amine (28, 30);
(S)-1-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexyl)pyrrolidine-2-carboxamide (29, 31);
(S)-1-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexyl)-N,N-dimethylpyrrolidin-3-amine (32-33);
6-(5-(4-(3,3-difluoropiperidin-1-yl)cyclohexyl)-3-isopropyl-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (34-35);
2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-5-(4-(4-methylpiperazin-1-yl)cyclohexyl)-1H-indole (36-37);
6-(3-isopropyl-5-(4-(4-(2-methoxyethyl)piperazin-1-yl)cyclohexyl)-1H-indol-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (38-39);
(2R,6S)-4-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)cyclohexyl)-2,6-dimethylmorpholine (40);
4-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexyl)-2,6-dimethylmorpholine (41);
4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)-N-(1-methylcyclopropyl)cyclohexan-1-amine (42-43);
N-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexyl)-3-methyloxetan-3-amine (44-45);
N-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyclohexyl)-3-methyloxetan-3-amine (46-47);
N-(4-(2-(7,8-dimethyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-isopropyl-1H-indol-5-yl) cyclohexyl)-3-methyloxetan-3-amine (48);
4-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1H-indol-5-yl)-N-(4-methoxybenzyl)cyclohexan-1-amine (49-50);
4-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1H-indol-5-yl)-N-methylcyclohexan-1-amine (51-52);
4-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1H-indol-5-yl)-N,N-dimethylcyclohexan-1-amine (53);
4-(4-(2-(2,6-dimethylpyridin-4-yl)-3-isopropyl-1H-indol-5-yl)cyclohexyl)morpholine (54-55);
4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)-N-methylcyclohexan-1-amine (56, 58);
N-(4-(3-isopropyl-2-(8-methyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl) cyc

Assignees

• Bristol Myers Squibb Co

Inventors

• Dyckman Alaric J
• Dodd Dharmpal S
• Mussari Christopher P
• Gilmore John L
• Haque Tasir Shamsul
• Sherwood Trevor C
• Whiteley Brian K
• Posy Shoshana L
• Kumar Sreekantha Ratna
• Pasunoori Laxman
• Duraisamy Srinivasan Kunchithapatham
• Hegde Subramanya
• Anumula Rushith Kumar
• Srinivas Pitani Veera Venkata

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/04

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

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title