Heteroaryl substituted pyrrolotriazine amine compounds as PI3K inhibitors

Patent metadata

Field	Value
Publication number	US-10023576-B2
Application number	US-201515521199-A
Country	US
Kind code	B2
Filing date	Oct 21, 2015
Priority date	Oct 22, 2014
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

Disclosed are compounds of Formula (I); or a salt thereof; wherein Qi is (i) Cl, Br, I, —CN, —CH 3 , or —CF 3 ; or (ii) pyrazole, triazole, or pyridinyl, each substituted with R 1 ; Q 2 is pyridinyl, indazolyl, isoquinolinyl, or benzo[d]imidazolyl substituted with R 2 and R 3 ; and R 1 , R 2 , and R 3 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:
Q 1 is:
(i) Cl, I, —CN, —CH 3 , or —CF 3 ; or
(ii) pyrazolyl, triazolyl, or pyridinyl, each substituted with R 1 ;
R 1 is C 1-3 alkyl, C 1-3 fluoroalkyl, C 3-6 cycloalkyl, —NHC(O)(C 1-3 alkyl), or tetrahydropyranyl;
Q 2 is morpholinyl, piperidinyl, pyridinyl, indazolyl, isoquinolinyl, or benzo[d]imidazolyl, each substituted with R 2 and R 3 ;
R 2 is H, F, Cl, Br, C 1-3 alkyl, C 1-3 fluoroalkyl, —C(O)(pyrrolidinyl), —C(O)NR a R a , —CH 2 C(O)NR a R a , —C(O)NR a (C 4-6 cycloalkyl), —C(O)NR a (phenyl), C 1-3 hydroxy-fluoroalkyl, —CH 2 (C 3-6 cycloalkyl), —CH 2 (C 3-6 fluorocycloalkyl), ═O, R x , or —CH 2 R x ;
R x is isoxazolyl, pyrrolidinonyl, tetrahydropyranyl, thiopyran 1,1-dioxide, morpholinyl, morpholinonyl, thiomorpholine 1,1-dioxide, pyridinonyl, phenyl, piperazinyl, piperazinonyl, or piperidinyl, each substituted with zero to 5 substituents independently selected from C 1-3 alkyl, —C(O)NR a R a , —C(O)(C 1-3 alkyl), —C(O)(C 1-3 hydroxyalkyl), —C(O)(C 3-6 cycloalkyl), —C(O)CH 2 O(C 1-3 alkyl), —NHC(O)(C 1-3 alkyl), —S(O) 2 (C 1-3 alkyl), and oxetanyl;
R 3 is H, F, or —CH 3 ;
R 4 is H or F; and
each R a is independently H or C 1-3 alkyl.

2. The compound according to claim 1 or a salt thereof; wherein:
R 1 is —CH 3 , —CH(CH 3 ) 2 , —CH 2 CF 3 , —CH(CH 3 )CF 3 , cyclopropyl, cyclohexyl, —NHC(O)CH 3 , or tetrahydropyranyl; and
R 2 is H, Br, —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 F, —CH 2 C(O)N(CH 3 ) 2 , —CH 2 CH(OH)CH 2 F, —CH 2 (cyclopropyl), —CH 2 (difluorocyclopropyl), —CH 2 (methyl isoxazolyl), —CH 2 (pyrrolidinonyl), ═O, tetrahydropyranyl, dimethyl tetrahydropyranyl, thiopyran 1,1-dioxide, morpholinyl, thiomorpholine 1,1-dioxide, methyl pyridinonyl, phenyl substituted with —C(O)NH 2 , NHC(O)CH 3 , or —S(O) 2 CH 3 ; piperazinyl or piperazinonyl, each substituted with zero to 5 substituents independently selected from —CH 3 , —C(O)CH 3 , —C(O)(cyclopropyl), and oxetanyl; or piperidinyl or piperidinonyl, each substituted with —CH 3 , —C(O)CH 3 , —C(O)CH 2 OH, or —C(O)CH 2 OCH 3 .

3. The compound according to claim 1 or a salt thereof, wherein Q 2 is:

4. The compound according to claim 1 or a salt thereof, wherein:
Q 1 is Cl, I, —CN, or —CF 3 .

5. The compound according to claim 1 or a salt thereof, wherein:
Q 1 is pyrazolyl, triazolyl, or pyridinyl, each substituted with R 1 .

6. The compound according to claim 1 or a salt thereof, wherein Q 2 is:

7. The compound according to claim 1 or a salt thereof, wherein said compound is selected from 1-(4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo [2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)piperazin-1-yl)ethanone, TFA (1); 5-(4-amino-5-(1-cyclohexyl-1H-pyrazol-5-yl)pyrrolo[2,1-J][1,2,4]triazin-7-yl)-1H-benzo[d]imidazol-2(3H)-one (2); 5-(1-cyclohexyl-1H-pyrazol-5-yl)-7-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (3); 1-(4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)piperazin-1-yl)ethanone, TFA (4); 1-(4-(5-(4-amino-5-(1-isopropyl-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)piperazin-1-yl)ethanone, TFA (5); 4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)thiomorpholine 1,1-dioxide (6); 4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)thiomorpholine 1,1-dioxide (7); 4-(5-(4-amino-5-(1-isopropyl-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)thiomorpholine 1,1-dioxide (8); 1-((cis)-4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)-2,6-dimethylpiperazin-1-yl)ethanone (9); 1-((cis)-4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)-2,6-dimethylpiperazin-1-yl)ethanone (10); 1-((cis)-4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)-3,5-dimethylpiperazin-1-yl)ethanone (11); 1-((cis)-4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)-3,5-dimethylpiperazin-1-yl) ethanone (12); 1-((cis)-4-(5-(4-amino-5-(1-isopropyl-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)-3,5-dimethylpiperazin-1-yl)ethanone (13); 1-(4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) pyridin-3-yl)-2,3,5,6-tetramethylpiperazin-1-yl)ethanone (14); 1-(4-(5-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)pyridin-3-yl)-2,3,5,6-tetramethylpiperazin-1-yl)ethanone (15); 7-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (16); 7-(1-(2-fluoroethyl)-1H-indazol-6-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo [2,1-f][1,2,4]triazin-4-amine (17); 5-(6-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-indazol-1-yl)-1-methylpyridin-2(1H)-one (18); 5-(6-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-indazol-1-yl)-1-methylpiperidin-2-one (19); 1-(4-(6-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-indazol-1-yl)piperidin-1-yl)ethanone (20); 1-(4-(6-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-1H-indazol-1-yl) piperidin-1-yl)ethanone (21); 1-(4-(6-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)-2-hydroxyethanone (22); 1-(4-(6-(4-amino-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-1H-benzo[d]imidazol-1-yl) piperidin-1-yl)-2-methoxyethanone (23); 5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (24); 5-(1-isopropyl-1H-1,2,3-triazol-5-yl)-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (25); 5-(1-cyclohexyl-1H-1,2,3-triazol-5-yl)-7-(1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (26); 7-(1-(2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (27); 7-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo [2,1-f][1,2,4]triazin-4-amine (28); 7-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazol-6-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-1,2,3-triazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (29); 7-(1-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazol-6-yl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (30); 5-(1-(tetrahydro-2H-py

Assignees

• Bristol Myers Squibb Co

Inventors

• Bhide Rajeev S
• Ruan Zheming
• Cherney Robert J
• Cornelius Lyndon A M
• Dhar T G Murali
• Gong Hua
• Marcoux David
• Poss Michael A
• Qin Lan-Ying
• Shi Qing
• Tino Joseph A

Classifications

• A61P29/00

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

• C07D487/04 Primary

  Ortho-condensed systems · CPC title