4-azaindole compounds

Patent metadata

Field	Value
Publication number	US-11820768-B2
Application number	US-202117245595-A
Country	US
Kind code	B2
Filing date	Apr 30, 2021
Priority date	Dec 18, 2017
Publication date	Nov 21, 2023
Grant date	Nov 21, 2023

Abstract

Disclosed are compounds of Formula (I)

N-oxides, or salts thereof, wherein G, A, R 1 , R 5 , 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

A is —O-L 1 -R 6 ;
L 1 is 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 C(O)NR x (CR x R x ) 0-4 —, —CR x R x NR x C(O)(CR x R x ) 0-4 —, or —CR x R x NR x C(O)(CR x R x ) 0-4 —,
R 1 is —CH(CH 3 ) 2 ;
each R 2 is independently —CH 3 , —CH 2 CH 3 , —CH 2 CN, —CH 2 OH, —CH 2 CH 2 OH, —OCH 3 , —CH 2 OCH 3 , or —CH 2 CH 2 S(O) 2 CH 3 ;
each R 5 is independently F or —CH 3 ;
R 6 is:
(i) C 1-3 alkyl, —CR x R x C(O)NR x (CR x R x ) 1-3 OH, —CR x R x C(O)NR x (CR x R x ) 1-2 NR x R x , or —CR x R x C(O)NR x (CR x R x ) 1-2 CHFCR x R x OH; or
(ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl, azetidinyl, C 3-6 cycloalkyl, diazabicyclo[2.2.1]heptanyl, diazaspiro[3.5]nonanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zero to 3 R 6a ;

each R 6a is independently F, Cl, —OH, —CN, C 1-6 alkyl, C 1-4 fluoroalkyl, C 1-6 hydroxyalkyl, —(CH 2 ) 1-2 O(C 1-3 alkyl), —NR x R x , —(CH 2 ) 1-2 NR x R x , —(CR x R x ) 1-2 S(O) 2 (C 1-3 alkyl), —(CR x R x ) 1-2 C(O)NR x R x , —C(O)(CR x R x ) 1-2 NR x R x , oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, isobutylpiperidinyl, piperazinyl, or —O(piperidinyl);
each R x is independently H or —CH 3 ;
n is zero or 1; and
p is zero, 1, or 2.

2. The compound according to claim 1 or a salt thereof, wherein G is

3. The compound according to claim 1 or a salt thereof, wherein:
G is

4. The compound according to claim 1 or a salt thereof, wherein:
R 6 is:
(i) C 1-2 alkyl, —CH 2 C(O)NHCH 2 CR x R x OH, —CH 2 C(O)NHCH 2 CH 2 CR x R x OH, —CH 2 C(O)NHCH 2 CH 2 NR x R x , or —CH 2 C(O)NHCH 2 CHFCR x R x OH; or
(ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl, azetidinyl, C 3-6 cycloalkyl, diazabicyclo[2.2.1]heptanyl, diazaspiro[3.5]nonanyl, morpholinyl, tetrahydropyranyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zero to 3 R 6a ; and

each R 6a is independently F, —OH, C 1-4 alkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, —(CH 2 ) 1-2 OCH 3 , —NR x R x , —N(C 2-3 alkyl) 2 , —(CH 2 ) 1-2 NR x R x , —(CH 2 ) 1-2 S(O) 2 (C 1-2 alkyl), —(CH 2 ) 1-2 C(O)NR x R x , —C(O)CH 2 NR x R x , oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl, piperazinyl, or —O(piperidinyl).

5. The compound according to claim 1 or a salt thereof, wherein:
R 6 is:
(i) —CH 3 , —CH 2 C(O)NHCH 2 C(CH 3 ) 2 OH, —CH 2 C(O)NHCH 2 CH 2 C(CH 3 ) 2 OH, —CH 2 C(O)NHCH 2 CH 2 NH 2 , or —CH 2 C(O)NHCH 2 CHFC(CH 3 ) 2 OH; or
(ii) azabicyclo[3.2.1]octanyl, azaspiro[5.5]undecanyl, azetidinyl, cyclohexyl, diazabicyclo[2.2.1]heptanyl, diazaspiro[3.5]nonanyl, morpholinyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl, or quinuclidinyl, each substituted with zero to 2 R 6a ; and

each R 6a is independently F, —OH, —CH 3 , —CH 2 CH 2 CH 3 , —C(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 CH 2 OH, —CH 2 CH(CH 3 )OH, —CH 2 C(CH 3 ) 2 OH, —CH 2 CH 2 OCH 3 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 2 CH 3 ) 2 , —CH 2 NH 2 , —CH 2 CH 2 NH 2 , —CH 2 CH 2 S(O) 2 CH 3 , —CH 2 C(O)N(CH 3 ) 2 , —C(O)CH 2 N(CH 3 ) 2 , oxetanyl, tetrahydropyranyl, piperidinyl, isobutylpiperidinyl, or —O(piperidinyl).

6. The compound according to claim 1 or a salt thereof, wherein:
A is —OR 6 or —O(CR x R x ) 1-2 —R 6 ;
R 6 is:
(a) —CH 3 ; or
(b) azetidinyl, cyclohexyl, or piperidinyl, each substituted with zero to 2 R 6a ; and

each R 6a is independently —CH 3 , —CH 2 CH 2 CH 3 , —C(CH 3 ) 2 , —CH 2 C(CH 3 ) 2 OH, —N(CH 3 ) 2 , —N(CH 2 CH 2 CH 3 ) 2 , —CH 2 CH 2 S(O) 2 CH 3 , —CH 2 C(O)N(CH 3 ) 2 , or tetrahydropyranyl.

7. A compound, N-oxide, or a salt thereof, wherein said compound is selected from:
6-(3-isopropyl-5-((1-methylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (590);
6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (591);
6-(3-isopropyl-5-((1-isopropylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (592);
6-(3-isopropyl-5-((1-propylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (593);
6-(3-isopropyl-5-((1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methyl-[1,2,4]triazolo[1,5-a]pyridine (594);
6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)azetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (595);
6-(3-isopropyl-5-((1-methylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (596);
1-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-2-methylpropan-2-ol (597);
6-(3-isopropyl-5-((1-isopropylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (598);
1-(3-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)azetidin-1-yl)-2-methylpropan-2-ol (599);
6-(3-isopropyl-5-((1-methylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (600);
6-(3-isopropyl-5-methoxy-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (601);
2-(4-(((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)methyl)piperidin-1-yl)-N,N-dimethylacetamide (602);
6-(3-isopropyl-5-((1-isopropylpiperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (603);
6-(3-isopropyl-5-((1-(2-(methylsulfonyl)ethyl)piperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (604);
4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dipropylcyclohexan-1-amine (605, 611);
6-(3-isopropyl-5-((1-propylpiperidin-4-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (606);
6-(3-isopropyl-5-((1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (607);
6-(3-isopropyl-5-((1-methylazetidin-3-yl)methoxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (608);
2-(4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)piperidin-1-yl)-N,N-dimethylacetamide (609);
4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N,N-dimethylcyclohexan-1-amine (610);
6-(3-isopropyl-5-((1-isopropylazetidin-3-yl)oxy)-1H-pyrrolo[3,2-b]pyridin-2-yl)-8-methoxy-[1,2,4]triazolo[1,5-a]pyridine (612);
1-(4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)piperidin-1-yl)-2-methylpropan-2-ol (613); and
4-((3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl)oxy)-N

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P19/02

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title