[1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds

Patent metadata

Field	Value
Publication number	US-RE49893-E
Application number	US-202217584155-A
Country	US
Kind code	E1
Filing date	Jan 25, 2022
Priority date	Jun 29, 2016
Publication date	Apr 2, 2024
Grant date	Apr 2, 2024

Abstract

Disclosed are compounds of Formula (I)

or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , 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

The invention claimed is:

1. A compound of Formula (I)

or a salt thereof, wherein:
R 1 is H, Cl, —CN, C 1-4 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxy-fluoroalkyl, —CR z ═CH 2 , 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 1-3 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 , —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), C 3-6 cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or —C(O)(thiazolyl);
R 3 is -L 1 -A;
L 1 is bond;
A is 2-oxa-6-azaspiro[3,3]heptanyl, 4-oxaspiro[2.5]octanyl, 7-azaspiro[3.5]nonanyl, 8-azabicyclo[3.2.1]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 9-azabicyclo[3.3.1]nonanyl, adamantanyl, azepanyl, azetidinyl, C 3-6 cycloalkyl, diazepanyl, dihydroinonyl, dihydropyrimidinonyl, dioxanyl, dioxidothiadiazinanyl, dioxidothiazolidinyl, dioxidothiomorpholinyl, dioxoisothiazolidinyl, dioxidothiazinanyl, dioxotetrahydrothiophenyl, dioxotetrahydrothiopyranyl, dioxothiomorpholinyl, furanyl, imidazolyl, imidazolidinonyl, indolyl, isoquinolinyl, isoxazolyl, morpholinyl, morpholinonyl, naphthalenyl, octahydrocyclopenta[b]pyranyl, octahydropyrrolo[3,4-b]pyridinyl, oxazolidinonyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperidinyl, piperidinonyl, piperazinyl, piperazinonyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridazinonyl, pyridinonyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolyl, quinolinyl, quinolizinonyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrazolyl, thiadiazolyl, thiazolyl, triazolonyl, or triazolyl, each substituted with -L 2 -R a and zero to 4 R b ;
L 2 is a bond or —CR x R x —;
R a is:
(a) H, F, Cl, —CN, —OH, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-5 hydroxyalkyl, —(CH 2 ) 0-4 O(C 1-3 alkyl), —(CR x R x ) 1-3 S(C 1-3 alkyl), —NHC(O)OC(CH 3 ) 3 , —(CR x R x ) 1-3 NHC(O)O(C 1-4 alkyl), —(CR x R x ) 1-3 NR y R y , —(CR x R x ) 1-3 C(O)NR y R y , —O(C 1-3 fluoroalkyl), —S(O) 2 NR x R x , —O(CR x R x ) 1-3 NR x R x , —NHS(O) 2 (C 1-3 alkyl), —NR x R x , —NR x (C 1-4 alkyl), —NR x C(O)(C 1-4 alkyl), —(CR x R x ) 0-3 C(O)OH, —C(O)(C 1-5 alkyl), —C(O)(C 1-3 fluoroalkyl), —C(O)O(C 1-4 alkyl), —C(O)NH(C 1-3 cyanoalkyl), —C(O)NR y R y , —C(O)NR x CH 2 C(O)NR x R x , or —C(O)NR x CH 2 CH 2 NHC(O)(C 1-3 alkyl);
(b) C 3-6 cycloalkyl or —C(O)NH(C 3-6 cycloalkyl), wherein each cycloalkyl is substituted with zero to 2 substituents independently selected from —OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkyl, and —C(O)O(C 1-3 alkyl); or
(c) A 1 , —CH 2 A 1 , —C(O)A 1 , —NR x A 1 , or —C(O)NR x A 1 , wherein A 1 is furanyl, imidazolyl, indolyl, isoxazolyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazolyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thiophenyl, or triazolyl, each substituted with zero to three substituents independently selected from —OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, —C(O)(C 1-2 alkyl), —C(O)O(C 1-3 alkyl), —NR x R x , phenyl, trifluoromethyl-phenyl, —CH 2 (bromophenyl), and —CH 2 CH 2 (pyrrolidinyl);

each R b is independently F, —OH, —CH 3 , —CF 3 , or —OCH 3 ;
each R x is independently H or —CH 3 ;
each R y is independently H or C 1-6 alkyl;
R z is H, C 1-2 alkyl, or C 1-2 fluoroalkyl;
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 salt thereof, wherein:
R 1 is H, Cl, —CN, C 1-4 alkyl, or C 1-2 fluoroalkyl;
each R 2 is independently F, Cl, —CN, —OH, C 1-3 alkyl, C 1-2 fluoroalkyl, C 1-2 cyanoalkyl, C 1-3 hydroxyalkyl, C 1-3 aminoalkyl, —O(CH 2 ) 1-2 OH, —O(C 1-4 alkyl), C 1-2 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 , —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), C 3-6 cycloalkyl, morpholinyl, dioxothiomorpholinyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or —C(O)(thiazolyl);
A is azetidinyl, C 3-6 cycloalkyl, dioxotetrahydrothiopyranyl, dioxidothiadiazinanyl, dioxidothiomorpholinyl, furanyl, imidazolyl, isoquinolinyl, morpholinyl, oxazolyl, 2-oxa-6-azaspiro[3.3]heptanyl, octahydropyrrolo[3,4-b]pyridinyl, oxetanyl, phenyl, piperazinonyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolyl, quinolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, or triazolyl, each substituted with -L 2 -R a and zero to 4 R b ;
R a is:
(a) H, F, —CN, —OH, C 1-3 alkyl, C 1-2 fluoroalkyl, C 1-3 hydroxyalkyl, —(CH 2 ) 0-2 O(C 1-3 alkyl), —NHC(O)OC(CH 3 ) 3 , —(CR x R x ) 1-3 NHC(O)O(C 1-4 alkyl), —(CR x R x ) 1-3 NH 2 , —(CR x R x ) 1-3 NR x (C 1-4 alkyl), —O(C 1-2 fluoroalkyl), —S(O) 2 NR x R x , —NHS(O) 2 (C 1-3 alkyl), —NR x R x , —NR x (C 1-4 alkyl), —(CR x R x ) 1-2 C(O)OH, —C(O)OH, —C(O)(C 1-3 alkyl), —C(O)O(C 1-4 alkyl), —C(O)NR x (C 1-2 alkyl), —C(O)N(C 1-3 alkyl) 2 , —C(O)NR x CH 2 C(O)NR x R x , or —C(O)NR x CH 2 CH 2 NHC(O)(C 1-3 alkyl);
(b) C 3-6 cycloalkyl or —C(O)NH(C 3-6 cycloalkyl), wherein each cycloalkyl is substituted with zero to 2 substituents independently selected from —OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkyl, and —C(O)O(C 1-3 alkyl); or
(c) A 1 , —CH 2 A 1 , —C(O)A 1 , or —C(O)NHA 1 , wherein A 1 is furanyl, imidazolyl, indolyl, isoxazolyl, octahydropyrrolo[3,4-c]pyrrolyl, oxazolyl, oxetanyl, phenyl, piperazinyl, piperidinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl, thiadiazolyl, thiazolyl, thiophenyl, or triazolyl, each substituted with zero to three substituents independently selected from —OH, C 1-3 alkyl, C 1-3 hydroxyalkyl, —C(O)(C 1-2 alkyl), —C(O)O(C 1-3 alkyl), —NR x R x , phenyl, trifluoromethylphenyl, —CH 2 (bromophenyl), and —CH 2 CH 2 (pyrrolidinyl);

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;
R 5 is F, Cl, —CN, —CH 3 , —CF 3 , or —OCH 3 ;
each R b is independently —OH, —CH 3 , or —CF 3 ;
each R x is independently H or —CH 3 ;
each R y is independently H or C 1-5 alkyl;
m is zero, 1, or 2;
n is zero or 1; and
p is zero, 1, or 2.

3. The compound according to claim 1 or salt thereof, wherein:
R 1 is —CH 2 CH 3 , —CH(CH 3 ) 2 , or —CH 2 CHF 2 ;
each R 2 is independently F, Cl, —CN, —CH 3 , —CD 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CF 3 , —CH 2 CN, —CH 2 OH, —CH 2 CH 2 OH, —CH(CH 3 )OH, —C(CH 3 ) 2 OH, —OCH

Assignees

• Bristol Myers Squibb Co

Inventors

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

Classifications

• A61K31/4196 Primary

  1,2,4-Triazoles · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4427

  containing further heterocyclic ring systems · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D249/00

  Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms · CPC title