Bicyclic heteroaryl amine compounds

Patent metadata

Field	Value
Publication number	US-10214537-B2
Application number	US-201515521202-A
Country	US
Kind code	B2
Filing date	Oct 21, 2015
Priority date	Oct 22, 2014
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

Disclosed are compounds of Formula (I) or a salt thereof; wherein: X is N or CH; Q 1 is: (i) Cl, Br, I, —CN, —CH 3 , or —CF 3 ; (ii) a 5-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl; (iii) a 6?membered heteroaryl selected from pyridinyl, pyridazinyl, and pyrimidinyl; or (iv) a bicyclic heteroaryl selected from indolyl, pyrrolopyridinyl, pyrazolopyridinyl and benzo[d]oxazolyl; wherein each of said 5-membered, 6-membered, and bicyclic heteroaryl is substituted with zero to 1 R a and zero to 1 R b ; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , and R b are defined herein. Also disclosed are methods of using such compounds as modulators of PI3K, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing inflammatory and autoimmune diseases.

First claim

The invention claimed is:

1. A compound of Formula (I):

or a salt thereof; wherein:
X is N or CH;
Q 1 is:
(i) Cl, I, —CN, —CH 3 , —CD 3 , or —CF 3 ;
(ii) a 5-membered heteroaryl selected from pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl;
(iii) a 6-membered heteroaryl selected from pyridinyl, pyridazinyl, and pyrimidinyl; or
(iv) a bicyclic heteroaryl selected from indolyl, imidazopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl and benzo[d]oxazolyl;
wherein each of said 5-membered, 6-membered, and bicyclic heteroaryls is substituted with zero to 1 R a and zero to 1 R b ;
R a is C 1-6 alkyl, C 1-6 deuteroalkyl, C 1-4 fluoroalkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxyalkyl, C 1-4 hydroxyfluoroalkyl, —CH 2 (C 3-6 cycloalkyl), —CH 2 (oxetanyl), —CH 2 (methyloxetanyl), —NH 2 , —S(O) 2 (C 1-4 alkyl), —S(O) 2 (C 3-6 cycloalkyl), C 3-6 cycloalkyl, C 3-6 fluorocycloalkyl, oxetanyl, tetrahydropyranyl, pyridinyl, pyrimidinyl, pyridazinyl, phenyl, or fluorophenyl substituted with zero to 1 substituent selected from F, —CF 3 , and —OCF 3 ;
R b is Cl, C 1-4 alkyl, C 1-3 haloalkyl, or C 3-5 cycloalkyl;
R 1 is H or F;
R 2 is H or F;
R 3 is H or R x ;
R 4 is H, F, Cl, —CN, —CH 3 , —CHF 2 , —CF 3 , —OCH 3 , —OCD 3 , —(CH 2 ) 1-3 OR c , —CHR c OH, —C(CH 3 ) 2 OH, —C(O)OCH 3 , —C(O)N(R w ) 2 , —C(O)—NR w R 7 , —C(O)R 8 , —C≡C—(C 1-4 alkyl), —S(O) 0-2 (C 1-4 alkyl), or —S(O) 0-2 (C 3-6 cycloalkyl), or triazolyl, wherein the triazolyl is substituted with 0 to 1-CH 3 ;
R c is H, —CH 3 , —CD 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , or cyclopropyl;
R 5 is H, F, Cl, —CH 3 , or —OCH 3 ;
R 6 is H or F;
R 7 is CD 3 , C 1-6 alkyl, C 1-4 haloalkyl, C 1-6 alkyl substituted with 0-1 R 7a , cyclopropyl, cyanoC 1-6 alkyl, or pyridinyl;
R 7a is —CN, —N(R w ) 2 , —OCH 3 , or —S(O) 2 CH 3 ;
R 8 is C 1-6 alkyl, hydroxyC 1-6 alkyl, morpholinyl, or piperazinyl, wherein the piperazinyl is substituted with 0 to 1-CH 3 ;
R w is H or —CH 3 ;
R x is:
(i) C 1-4 hydroxyalkyl, C 1-4 alkoxyalkyl, C 1-4 aminoalkyl, —CR w R w NH(C 1-4 alkyl), —CR w R w N(C 1-4 alkyl) 2 , —CR w R w NR w (CH 2 ) 1-3 O(C 1-3 alkyl), —CR w R w CR w R w N(C 1-3 alkyl) 2 , —CR w R w CR w R w NR w C(O)(C 1-3 alkyl), —CR w R w C(O)(C 1-3 alkyl), —CR w R w NR w C(O)(C 1-4 hydroxyalkyl), —(CR w R w ) 2 R 3a , —CR w (CF 3 )R 3a , —CR w R w NR w R 3a , —CH 2 NHS(O) 2 CH 3 —CH 2 OR 3a , —CH 2 (8-oxa-3-azabicyclo[3.2.1]octanyl), —CH(CH 3 )(dimethylazetidinyl), —CH(CH 3 )(methyl hydroxyazetidinyl), or —CR w R w NR w C(O)R 3a , wherein R 3a is tetrahydropyran, morpholinyl, morpholinonyl, oxazinanonyl, oxazolidinonyl, pyrrolidinyl, pyrrolidinonyl, piperazinyl, pyridinyl, pyrrolidinium, or phenyl, each substituted with zero to 1 substituent selected from F, Cl, C 1-4 alkyl, and —C(O)CH 3 ;
(ii) —C(O)OH or —C(O)R 3b , wherein R 3b is pyrrolidinyl, pyrrolidinonyl, azetidinyl, morpholinyl, dioxidothiomorpholinyl, thiadiazolyl, piperazinyl, piperazinonyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, or piperidinyl, each substituted with zero to 2 substituents independently selected from F, —OH, —CN, C 1-2 alkyl, C 1-3 hydroxyalkyl, —C(O)(C 1-3 alkyl), —C(O)NR w R w , —C(O)O(C 1-3 alkyl), —NR w C(O)(C 1-3 alkyl), —C(O)NH(C 1-3 hydroxyalkyl), and —C(O)tetrahydrofuranyl; —C(O)NR w R w , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —C(O)NR w (C 1-3 fluoroalkyl), —C(O)NR w (C 1-3 hydroxyalkyl), —C(O)NR w (C 1-4 alkoxyalkyl), —C(O)NR w (CR w R w C(O)NR w R w ), —C(O)NR w CR w (C 1-4 alkyl)C(O)NR w R w , —C(O)NR w (C 1-6 hydroxyalkyl), —C(O)NR w R 3c , —C(O)NR w (CR w R w ) 1-2 R 3c , —C(O)NR w CR w R w C(O)R 3c , —C(O)N(C 1-4 alkyl)(C 3-6 cycloalkyl), —C(O)N(C 3-6 cycloalkyl) 2 , —C(O)N(C 3-6 cycloalkyl)R 3c , —C(O)N(C 3-6 cycloalkyl)(CH 2 R 3c ), or —C(O)CR w R w S(O) 2 (C 1-4 alkyl), wherein R 3c is phenyl, oxazolyl, oxopiperidinyl, oxopyrrolidinyl, tetrahydropyranyl, tetrazolyl, thiazolyl, piperidinyl, pyrazolyl, oxetanyl, morpholinyl, pyrrolidinyl, or isoxazolyl, each substituted with zero to 2 substituents independently selected from —CH 3 , —C(O)CH 3 , —C(O)NH 2 , cyclopropyl, and —CH 2 OH;
(iii) —OR 3d wherein R 3d is tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, or pyridinyl, each substituted with zero to 3 substituents independently selected from —CH 3 , ═O, —C(O)CH 3 , and —C(O)CH(CH 3 ) 2 ;
(iv) —NR w C(O)(C 1-3 alkyl), —NR w S(O) 2 (C 1-3 alkyl), or —S(O) 2 NR w R w ;
(v) C 3-6 cycloalkyl substituted with zero to 3 substituents independently selected from F, —OH, C 1-3 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, —C(O)NR w (C 1-4 alkyl), —C(O)NR w (C 1-4 fluoroalkyl), —C(O)NR w (C 3-6 cycloalkyl), and —C(O)NR w R 3d , wherein R 3d is oxetanyl, azetidinyl, morpholinyl, piperidinyl, pyrrolidinyl, cyclobutyl, or tetrahydropyranyl, each substituted with zero to 2 substituents independently selected from F, —CH 3 , and —OCH 3 ; or
(vi) azetidinyl, oxetanyl, tetrahydropyranyl, piperazinyl, pyrrolidinyl, piperidinyl, 1,2-dihydropyridinonyl, morpholinyl, 4,7-diazaspiro[2.5]octanyl, octahydrobenzo[b] [1,4]oxazinyl, or benzo[b][1,4]oxazinyl, each substituted with zero to 8 substituents independently selected from D, —OH, —CN, C 1-4 alkyl, C 1-3 deuteroalkyl, C 1-3 fluoroalkyl, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-3 alkoxy, ═O, —(CH 2 )O(O)CH 3 , —C(O)(C 1-4 alkyl), —C(O)(C 1-4 hydroxyalkyl), —C(O)NR w R w , —C(O)CH 2 CN, —C(O)CH 2 OH, —C(O)(C 3-4 cycloalkyl), —C(O)NH 2 , —S(O) 2 CH 3 , —C(O)OCH 3 , —NHC(O)(C 1-4 alkyl), —NR w S(O)(C 1-3 alkyl), —NR w S(O) 2 (C 1-3 alkyl), —C(O)CR w R w S(O) 2 (C 1-4 alkyl), —C(O)(phenyl), —C(O)(fluorophenyl), —C(O)(chlorophenyl), —C(O)(hydroxypropyl phenyl), —C(O)(difluorocyclopropyl), —C(O)(oxazolyl), —C(O)(pyrazinyl), —C(O)(pyrazolyl), —C(O)(pyridazinyl), —C(O)(pyridinyl), —C(O)(pyrimidinyl), —C(O)(pyrrolidinyl), —C(O)(tetrahydropyranyl), —C(O)(thiazolyl), —C(O)(methyl thiazolyl), —C(O)(imidazolyl), —C(O)(methyl imidazolyl), —C(O)(methyl oxazolyl), —C(O)(methyl phenyl), —C(O)(methyl pyrazolyl), —C(O)(morpholinyl), —C(O)(acetophenonyl), —C(O)CH 2 (oxazolidinonyl), —C(O)CH 2 (pyrrolidinyl), —C(O)CH 2 (dioxidothiazinanyl), —C(O)CH 2 (dioxidothiomorpholinyl), —C(O)CH 2 (dimethyl-oxopyrrolidinyl), —C(O)CH 2 (trimethyl-oxopyrrolidinyl), —C(O)CH 2 NHC(O)CH 3 , —C(O)CH 2 CH 2 NHC(O)CH 3 , —C(O)CH 2 CH 2 S(O) 2 CH 3 , —C(O)CH 2 S(O) 2 CH 3 , —C(O)CH(CH 3 )S(O) 2 CH 3 , —C(O)CH 2 CH 2 NHS(O) 2 CH 3 , —C(O)CH 2 NHS(O) 2 CH 3 , —C(O)CH 2 CH 2 NHS(O) 2 CH 3 , —C(O)CH(CH 3 )NHS(O) 2 CH 3 , —C(O)CH 2 CH 2 (methyl-pyrazolyl), —N(CH 3 ) 2 , —N(CH 3 )(acetyl piperidinyl), —CH 2 C(O)NHCH 2 C(CH 3 ) 2 OH, —N(CH 3 )C(O)CH 3 , —N(CH 3 )C(O)C(CH 3 ) 2 OH, —N(CH 3 )C(O)NH(CH(CH 3 ) 2 ), —N(CH 3 )C(O)(furanyl), —N(CH 3 )C(O)CH 2 (pyrazinyl), —N(CH 3 )C(O)(cyanocyclopropyl), —N(CH 3 )C(O)CH(CH 3 )OH, benzyl, carbamoyl azepanyl, carbamoyl-morpholinyl, chlorophenyl, cyclopropyl, cyclobutyl, dioxothiomorpholinyl, fluorobenzoyl, fluorophenyl, hydroxypiperidinyl, hydroxypyrrolidinyl, hydroxytetrahydropyranyl, methoxytetrahydropyranyl, methyl imidazol[1,2a]pyridinyl, methyloxadiazolyl, methylpiperazinyl, methylpiperazinonyl, methyl pyridinonyl, morpholinyl, oxetanyl, phenyl, piperidinonyl, pyridinyl, and pyrimidinyl;
(vii) phenyl, pyrazolyl, dioxothiazinanyl, pyrrolidinonyl, dimethyloxazolindinonyl, oxazolyl, tetrazolyl, pyridinyl, dioxothiomorpholinyl, quinazolinyl, thiazolyl, octahydropyrrolo[3,4-c]pyrrole, 1H-pyrido[1,2-c] pyrimidine-1,3(2H)-dione, 1,3-oxazinan-2-onyl, 1H,2H,3H,4H,6H-pyrido[1,2-a

Assignees

• Bristol Myers Squibb Co

Inventors

• Bhide Rajeev S
• Batt Douglas G
• Cherney Robert J
• Cornelius Lyndon A M
• Liu Qingjie
• Marcoux David
• Neels James
• Poss Michael A
• Ruan Zheming
• Shi Qing
• Srivastava Anurag S
• Qin Lan-Ying
• Tino Joseph A
• Watterson Scott Hunter

Classifications

• A61P29/00

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

• C07D491/08 Primary

  Bridged systems · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title