Diazaindole compounds

Patent metadata

Field	Value
Publication number	US-11299501-B2
Application number	US-201816955108-A
Country	US
Kind code	B2
Filing date	Dec 18, 2018
Priority date	Dec 20, 2017
Publication date	Apr 12, 2022
Grant date	Apr 12, 2022

Abstract

Disclosed are compounds of Formula (I) N-oxides, or salts thereof, wherein G, A, X, Y, Z, R1, 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)

or a salt thereof, wherein:
X is N;
Y is N;
Z is CR 5 ;
G is:

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

 or
(v) 10-membered heterocyclic ring selected from:

A is:
(i) —O-L 1 -R 6 ;
(ii) —NR 7 R 8 ;
(iii) -L 2 -C(O)NR 9 R 10 ;
(iv) —(CR x R x ) 1-3 R 11 , C 1-3 aminoalkyl, —(CR x R x ) 1-3 NR x C(O)R 11 ,
—(CR x R x ) 1-2 NR x C(O)(CH 2 ) 1-2 (piperidinyl),
(CR x R x ) 1-2 NR x C(O)O(CH 2 ) 1-2 (piperidinyl), or
—(CR x R x ) 1-2 NR x C(O)(CH 2 ) 1-2 NR x R x ;

(v) —CR x R 12 R 13 , wherein R 12 and R 13 together with the carbon atom to which they are attached form a cyclic group selected from azabicyclo[4.1.1]octanyl, azepanyl, azetidinyl, C 3-7 cycloalkyl, diazepanyl, diazaspiro[4.5]decanonyl, morpholinyl, octahydrocyclopenta[c]pyrrolyl, piperazinyl, piperidinyl, pyrrolidinyl, and quinuclidinyl, each substituted with zero to 4 R 12a ;
(vi) —CR x ═CR x (piperidinyl); or
(vii) 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 ;
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 —;
L 2 is a bond or —(CR x R x ) 1-3 —;
R 1 is H, Cl, —CN, C 1-4 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 hydroxy-fluoroalkyl, —CR v ═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 1-4 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), —(CH 2 ) 0-2 C(O)NR y R y , —C(O)NR x (C 1-5 hydroxyalkyl), —C(O)NR x (C 2-6 alkoxyalkyl), —C(O)NR x (C 3-6 cycloalkyl), —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 (C 3-6 cycloalkyl), —(CH 2 ) 0-2 S(O) 2 (C 1-3 alkyl), —(CH 2 ) 0-2 (C 3-6 cycloalkyl), —(CH 2 ) 0-2 (phenyl), morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or —C(O)(thiazolyl);
R 2a is C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-6 hydroxyalkyl, C 1-3 aminoalkyl, —(CH 2 ) 0-4 O(C 1-3 alkyl), C 3-6 cycloalkyl, —(CH 2 ) 1-3 C(O)NR x R x , —CH 2 (C 3-6 cycloalkyl), —CH 2 (phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;
each R 2b is independently H, halo, —CN, —NR x R x , C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-3 hydroxyalkyl, C 1-3 fluoroalkoxy, —(CH 2 ) 0-2 O(C 1-3 alkyl), —(CH 2 ) 0-3 C(O)NR x R x , —(CH 2 ) 1-3 (C 3-6 cycloalkyl), —C(O)O(C 1-3 alkyl), —C(O)NR x (C 1-3 alkyl), —CR x ═CR x R x , or —CR x ═CH(C 3-6 cycloalkyl);
R 2c is R 2a or R 2b ;
R 2d is R 2a or R 2b ; provided that one of R 2c and R 2d is R 2a , and the other of R 2c and R 2 is R 2b ;
R 5 is F, Cl, —CN, C 1-3 alkyl, C 1-2 fluoroalkyl, or —OCH 3 ;
R 6 is:
(i) —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);
R 7 is:
(i) R 7a , —CH 2 R 7a , —C(O)R 7a , —C(O)CH(NH 2 )R 7a , —C(O)(CH 2 ) 1-3 NH 2 , —C(O)CH(NH 2 )(C 1-4 alkyl), —C(O)CH(NH 2 )(CH 2 ) 1-2 C(O)OH, —C(O)CH(NH 2 )(CH 2 ) 2-4 NH 2 , or —C(O)CH(NH 2 )(CH 2 ) 1-3 C(O)NH 2 ; or
(ii) C 3-6 cycloalkyl substituted with one substituent selected from NR x (CH 2 ) 2-3 NR y R y , —NR x (methylpiperidinyl), —NR x (CH 2 ) 2-3 (morpholinyl), dimethylamino piperidinyl, and piperazinyl substituted with a substituent selected from C 1-4 alkyl, —C(O)CH 3 , —(CH 2 ) 1-2 OCH 3 , —CH 2 (methylphenyl), —(CH 2 ) 2-3 (pyrrolidinyl), C 3-6 cycloalkyl, pyridinyl, and methylpiperidinyl;

R 7a is azaspiro[3.5]nonanyl, C 3-6 cycloalkyl, diazaspiro[3.5]nonanyl, diazaspiro[5.5]undecanyl, diazepanonyl, diazepanyl, morpholinyl, phenyl, piperazinyl, piperidinyl, pyrrolidinonyl, pyrrolidinyl, or pyrrolyl, each substituted with zero to 1 substituent selected from C 1-3 alkyl, —NH 2 , methylpiperidinyl, methylpyrrolidinyl, —OCH 2 CH 2 (pyrrolidinyl), and —OCH 2 CH 2 NHCH 2 CH 3 ; and zero to 4 substituents selected from —CH 3 ;
R 7b
(i) C 1-4 alkyl, C 1-3 hydroxyalkyl, —(CH 2 ) 2-3 C≡CH, —(CH 2 ) 1-2 O(C 1-2 alkyl), —(CH 2 ) 1-2 S(O) 2 (C 1-2 alkyl), —(CH 2 ) 0-3 NR x R y , —CH 2 C(O)NR x R x , —NR x (C 1-4 hydroxyalkyl), —NR y (C 1-2 cyanoalkyl), —NR x (C 1-2 fluoroalkyl), —NR x (C 2 -4 hydroxyfluoroalkyl), —NR x (CH 2 ) 1-2 C(O)NR x R x , —NR x (CH 2 ) 1-3 NR x R x , —NR x CH 2 CH 2 NR x R x , —NR x C(O)(CH 2 ) 1-2 NR x R x , —O(CH 2 ) 1-3 NR x R x , —C(O)CH 2 NR x R x , —(CH 2 ) 1-2 R 7d , —NHR 7d , —NH(CH 2 ) 1-2 R 7d , or —OR 7d ; or
(ii) azepanyl, azetidinyl, diazepanyl, dioxothiomorpholinyl, morpholinyl, oxaazaspiro[3.3]heptanyl, oxetanyl, piperazinonyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinonyl, pyrrolidinyl, or tetrahydroisoquinolinyl, each substituted with zero to 1 R 8a and zero to 3 R 8b ,

each R 7c is independently F, —CH 3 or —CH 2 CN;
each R 7c is independently F, Cl, —CN, C 1-2 alkyl, —CF 3 , or —CH 2 CN;
R 7d is azaspiro[3.5]nonanyl, bicyclo[1.1.1]pentanyl, C 3-6 cycloalkyl, morpholinyl, oxetanyl, phenyl, piperidinyl, pyrazolyl, pyrrolidinyl, tetrahydro

Assignees

• Bristol Myers Squibb Co

Inventors

• Dyckman Alaric J
• Dodd Dharmpal S
• Mussari Christopher P
• Whiteley Brian K
• Kumar Sreekantha Ratna
• Ramachandra Reddy Anupama Kandhi

Classifications

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61P29/00

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

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title