Substituted naphthyridinone compounds useful as T cell activators

Patent metadata

Field	Value
Publication number	US-10669272-B2
Application number	US-201916452679-A
Country	US
Kind code	B2
Filing date	Jun 26, 2019
Priority date	Jun 27, 2018
Publication date	Jun 2, 2020
Grant date	Jun 2, 2020

Abstract

Disclosed are compounds of Formula (I):

or a salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , R 5 , and m are defined herein. Also disclosed are methods of using such compounds to inhibit the activity of one or both of diacylglycerol kinase alpha (DGKα) and diacylglycerol kinase zeta (DGKζ), and pharmaceutical compositions comprising such compounds. These compounds are useful in the treatment of viral infections and proliferative disorders, such as cancer.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, F, Cl, Br, —CN, C 1-3 alkyl substituted with zero to 4 R 1a , C 3-4 cycloalkyl substituted with zero to 4 R 1a , C 1-3 alkoxy substituted with zero to 4 R 1a , —NR a R a , —S(O) n R e , or —P(O)R e R e ;
each R 1a is independently F, Cl, —CN, —OH, —OCH 3 , or —NR a R a ;
each R a is independently H or C 1-3 alkyl;
each R e is independently C 3-4 cycloalkyl or C 1-3 alkyl substituted with zero to 4 R 1a ;
R 2 is H, C 1-3 alkyl substituted with zero to 4 R 2a , or C 3-4 cycloalkyl substituted with zero to 4 R 2a ;
each R 2a is independently F, Cl, —CN, —OH, —O(C 1-2 alkyl), C 3-4 cycloalkyl, C 3-4 alkenyl, or C 3-4 alkynyl;
R 3 is H, F, Cl, Br, —CN, C 1-3 alkyl, C 1-2 fluoroalkyl, C 3-4 cycloalkyl, C 3-4 fluorocycloalkyl, or —NO 2 ;
R 4 is —CH 2 R 4a , —CH 2 CH 2 R 4a , —CH 2 CHR 4a R 4d , —CHR 4a R 4b , or —CR 4a R 4b R 4c ;
R 4a and R 4b are independently:
(i) C 1-6 alkyl substituted with zero to 4 substituents independently selected from F, Cl, —CN, —OH, —OCH 3 , —SCH 3 , C 1-3 fluoroalkoxy, —NR a R a , —S(O) 2 R e , or —NR a S(O) 2 R e ;
(ii) C 3-6 cycloalkyl, monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from O, S, and N, phenyl, 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, or 9- or 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, each substituted with zero to 4 substituents independently selected from F, Cl, Br, —CN, —OH, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-4 hydroxyalkyl, —(CH 2 ) 1-2 O(C 1-3 alkyl), C 1-4 alkoxy, —O(C 1-4 hydroxyalkyl), —O(CH) 1-3 O(C 1-3 alkyl), C 1-3 fluoroalkoxy, —O(CH) 1-3 NR c R c , —OCH 2 CH═CH 2 , —OCH 2 C≡CH, —C(O)(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —NR c R c , —NR a S(O) 2 (C 1-3 alkyl), —NR a C(O)(C 1-3 alkyl), —NR a C(O)O(C 1-4 alkyl), —P(O)(C 1-3 alkyl) 2 , —S(O) 2 (C 1-3 alkyl), —O(CH 2 ) 1-2 (C 3-6 cycloalkyl), —O(CH 2 ) 1-2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d ; or
(iii) C 1-4 alkyl substituted with one cyclic group selected from C 3-6 cycloalkyl, monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from O, S, and N, aryl, 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, and 9- or 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, —OH, —CN, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, —OCH 2 CH═CH 2 , —OCH 2 C≡CH, —NR c R c , —NR a S(O) 2 (C 1-3 alkyl), —NR a C(O)(C 1-3 alkyl), —NR a C(O)O(C 1-4 alkyl), and C 3-6 cycloalkyl;

or R 4a and R 4b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from O, S, and N, each substituted with zero to 3 R f ;
each R f is independently F, Cl, Br, —OH, —CN, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, —OCH 2 CH═CH 2 , —OCH 2 C≡CH, —NR c R c , or a cyclic group selected from C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl having 1 to 3 heteroatoms independently selected from O, S, and N, phenyl, 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, and 9- or 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, —OH, —CN, C 1-6 alkyl, C 1-3 fluoroalkyl, C 1-3 alkoxy, C 1-3 fluoroalkoxy, and —NR c R c ;
R 4c is C 1-6 alkyl or C 3-6 cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, —OH, C 1-2 alkoxy, C 1-2 fluoroalkoxy, and —CN;
R 4d is —OCH 3 ;
each R e is independently H or C 1-2 alkyl;
R d is phenyl substituted with zero to 1 substituent selected from F, Cl, —CN, —CH 3 , and —OCH 3 ;
each R 5 is independently —CN, C 1-6 alkyl substituted with zero to 4 R g , C 2-4 alkenyl substituted with zero to 4 R g , C 2-4 alkynyl substituted with zero to 4 R g , C 3-4 cycloalkyl substituted with zero to 4 R g , phenyl substituted with zero to 4 R g , oxadiazolyl substituted with zero to 3 R g , pyridinyl substituted with zero to 4 R g , —(CH 2 ) 1-2 (heterocyclyl having 1 to 3 heteroatoms independently selected from O, S, and N, substituted with zero to 4 R g ), —(CH 2 ) 1-2 NR c C(O)(C 1-4 alkyl), —(CH 2 ) 1-2 NR c C(O)O(C 1-4 alkyl), —(CH 2 ) 1-2 NR c S(O) 2 (C 1-4 alkyl), —C(O)(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —C(O)O(C 3-4 cycloalkyl), —C(O)NR a R a , or —C(O)NR a (C 3-4 cycloalkyl);
each R g is independently F, Cl, —CN, —OH, C 1-3 alkoxy, C 1-3 fluoroalkoxy, —O(CH 2 ) 1-2 O(C 1-2 alkyl), or —NR c R c ;
m is 1, 2, or 3; and
n is zero, 1, or 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, F, Cl, Br, —CN, C 1-3 alkyl substituted with zero to 4 R 1a , cyclopropyl substituted with zero to 3 R 1a , C 1-3 alkoxy substituted with zero to 3 R 1a , —NR a R a , —S(O) n CH 3 , or —P(O)(CH 3 ) 2 ;
each R 1a is independently F, Cl, or —CN;
each R a is independently H or C 1-3 alkyl;
R 2 is H or C 1-2 alkyl substituted with zero to 2 R 2a ;
each R 2a is independently F, Cl, —CN, —OH, —O(C 1-2 alkyl), cyclopropyl, C 3-4 alkenyl, or C 3-4 alkynyl;
R 3 is H, F, Cl, Br, —CN, C 1-2 alkyl, —CF 3 , cyclopropyl, or —NO 2 ;
R 4a and R 4b are independently:
(i) C 1-4 alkyl substituted with zero to 4 substituents independently selected from F, Cl, —CN, —OH, —OCH 3 , —SCH 3 , C 1-3 fluoroalkoxy, and —NR a R a ;
(ii) C 3-6 cycloalkyl, monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from O, S, and N, phenyl, 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, or 9- or 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, each substituted with zero to 4 substituents independently selected from F, Cl, Br, —CN, —OH, C 1-6 alkyl, C 1-3 fluoroalkyl, —CH 2 OH, —(CH 2 ) 1-2 O(C 1-2 alkyl), C 1-4 alkoxy, —O(C 1-4 hydroxyalkyl), —O(CH) 1-2 O(C 1-2 alkyl), C 1-3 fluoroalkoxy, —O(CH) 1-2 NR c R c , —OCH 2 CH═CH 2 , —OCH 2 C≡CH, —C(O)(C 1-4 alkyl), —C(O)OH, —C(O)O(C 1-4 alkyl), —NR c R c , —NR a S(O) 2 (C 1-3 alkyl), —NR a C(O)(C 1-3 alkyl), —NR a C(O)O(C 1-4 alkyl), —P(O)(C 1-2 alkyl) 2 , —S(O) 2 (C 1-3 alkyl), —O(CH 2 ) 1-2 (C 3-4 cycloalkyl), —O(CH 2 ) 1-2 (morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl)azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and R d ; or
(iii) C 1-3 alkyl substituted with one cyclic group selected from C 3-6 cycloalkyl, monocyclic heterocyclyl having 1 to 3 heteroatoms independently selected from O, S, and N, phenyl, 5- or 6-membered monocyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, and 9- or 10-membered bicyclic heteroaryl having 1, 2, or 3 heteroatoms independently selected from O, S, and/or N, said cyclic group

Assignees

• Bristol Myers Squibb Co

Inventors

• Velaparthi Upender
• Chupak Louis S
• Darne Chetan Padmakar
• Ding Min
• Gentles Robert G
• Huang Yazhong
• Kamble Manjunatha Narayana Rao
• Martin Scott W
• Mannoori Raju
• Mcdonald Ivar M
• Olson Richard E
• Rahaman Hasibur
• Jalagam Prasada Rao
• Roy Saumya
• Tonukunuru Gopikishan
• Velaiah Sivasudar
• Warrier Jayakumar Sankara
• Zheng Xiaofan
• Tokarski John S
• Dasgupta Bireshwar
• Reddy Kotha Rathnakar
• Raja Thiruvenkadam

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/12

  Antivirals · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title