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US 12,492,172 B2Granted
Substituted quinazolinyl compounds useful as T cell activators
AssigneeBristol-Myers Squibb Company
InventorsUpender Velaparthi, Richard E. Olson, Jayakumar Sankara Warrier, Hasibur Rahaman
Life of this patent
Estimating the term…
Abstract
Disclosed are compounds of Formula (I): (I) or a salt thereof, wherein: R1, R2, R4, R5, R6, 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.
Claims12
A compound of Formula (I):
- or a salt thereof, wherein:
- R1 is F, Cl, Br, —CN, C1-3 alkyl substituted with zero to 4 R1a, C3-4 cycloalkyl substituted with zero to 4 R1a, C1-3 alkoxy substituted with zero to 4 R1a, —C(O)NRaRa, —NRaRa, —S(O)nRe, or —P(O)ReRe;
- each R1a is independently F, Cl, —CN, —OH, —OCH3, or —NRaRa;
- each Ra is independently H or C1-3 alkyl;
- each Re is independently C3-4 cycloalkyl or C1-3 alkyl substituted with zero to 4 R1a;
- R2 is H, C1-3 alkyl substituted with zero to 4 R2a, C2-3 alkenyl substituted with zero to 4 R2a, or C3-4 cycloalkyl substituted with zero to 4 R2a;
- each R2a is independently F, Cl, —CN, —OH, —O(C1-2 alkyl), C3-4 cycloalkyl, C3-4 alkenyl, or C3-4 alkynyl;
- R4 is —CH2R4a, —CH2CH2R4a, —CH2CHR4aR4d, —CHR4aR4b, or —CR4aR4bR4c;
- R4a and R4b are independently:
- (i) C1-6 alkyl substituted with zero to 4 substituents independently selected from F, Cl, —CN, —OH, —OCH3, —SCH3, C1-3 fluoroalkoxy, —NRaRa, —S(O)2Re, or —NRaS(O)2Re;
- (ii) C3-6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, —CN, —OH, C1-6 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, —(CH2)1-2O(C1-3 alkyl), C1-4 alkoxy, —O(C1-4 hydroxyalkyl), —O(CH)1-3O(C1-3 alkyl), C1-3 fluoroalkoxy, —O(CH)1-3NRcRc, —OCH2CH═CH2, —OCH2C≡CH, —C(O)(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —NRcRc, —NRaS(O)2(C1-3 alkyl), —NRaC(O)(C1-3 alkyl), —NRaC(O)O(C1-4 alkyl), —P(O)(C1-3 alkyl)2, —S(O)2(C1-3 alkyl), —O(CH2)1-2(C3-6 cycloalkyl), —O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl) azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Rd;
- or
- (iii) C1-4 alkyl substituted with one cyclic group selected from C3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, —OH, —CN, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, —OCH2CH═CH2, —OCH2C≡CH, —NRcRc, —NRaS(O)2(C1-3 alkyl), —NRaC(O)(C1-3 alkyl), —NRaC(O)O(C1-4 alkyl), and C3-6 cycloalkyl;
- or R4a and R4b together with the carbon atom to which they are attached form a C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;
- each Rf is independently F, Cl, Br, —OH, —CN, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, —OCH2CH═CH2, —OCH2C≡CH, —NRcRc, or a cyclic group selected from C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, —OH, —CN, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, and —NRcRc;
- R4c is C1-6 alkyl or C3-6 cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, —OH, C1-2 alkoxy, C1-2 fluoroalkoxy, and —CN;
- R4d is —OCH3;
- each Rc is independently H or C1-2 alkyl;
- Rd is phenyl substituted with zero to 1 substituent selected from F, Cl, —CN, —CH3, and —OCH3;
- each R5 is independently F, Cl, —CN, —OH, C1-6 alkyl substituted with zero to 4 Rg, C1-3 alkoxy substituted with zero to 4 Rg, C2-4 alkenyl substituted with zero to 4 Rg, C2-4 alkynyl substituted with zero to 4 Rg, C3-4 cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, —(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), —(CH2)1-2NRcC(O)(C1-4 alkyl), (CH2)1-2NRcC(O)O(C1-4 alkyl), —(CH2)1-2NRcS(O)2(C1-4 alkyl), —C(O)(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —C(O)O(C3-4 cycloalkyl), —C(O)NRaRa, or —C(O)NRa(C3-4 cycloalkyl), or two R5 attached to the same carbon atom form ═O;
- each Rg is independently F, Cl, —CN, —OH, C1-3 alkoxy, C1-3 fluoroalkoxy, —O(CH2)1-2O(C1-2 alkyl), C3-5 cycloalkyl, or —NRcRc;
- each R6 is H, F, Cl, —CN, —CH3, —CH2F, —CHF2, —CF3, or —OCH3;
- m is zero, 1, 2, or 3;
- and
- n is zero, 1, or 2.
22 more elements
A compound of Formula (I):
- or a salt thereof, wherein:
- R1 is H, F, Cl, Br, —CN, C1-3 alkyl substituted with zero to 4 R1a, C3-4 cycloalkyl substituted with zero to 4 R1a, C1-3 alkoxy substituted with zero to 4 R1a, —C(O)NRaRa, —NRaRa, —S(O)nRe, or —P(O)ReRe;
- each R1a is independently F, Cl, —CN, —OH, —OCH3, or —NRaRa;
- each Ra is independently H or C1-3 alkyl;
- each Re is independently C3-4 cycloalkyl or C1-3 alkyl substituted with zero to 4 R1a;
- R2 is H, C1-3 alkyl substituted with zero to 4 R2a, C2-3 alkenyl substituted with zero to 4 R2a, or C3-4 cycloalkyl substituted with zero to 4 R2a;
- each R2a is independently F, Cl, —CN, —OH, —O(C1-2 alkyl), C3-4 cycloalkyl, C3-4 alkenyl, or C3-4 alkynyl;
- R4 is —CH2R4a, —CH2CH2R4a, —CH2CHR4aR4d, —CHR4aR4b, or —CR4aR4bR4c;
- R4a and R4b are independently:
- (i) C1-6 alkyl substituted with zero to 4 substituents independently selected from F, Cl, —CN, —OH, —OCH3, —SCH3, C1-3 fluoroalkoxy, —NRaRa, —S(O)2Re, or —NRaS(O)2Re;
- (ii) C3-6 cycloalkyl, heterocyclyl, phenyl, or heteroaryl, each substituted with zero to 4 substituents independently selected from F, Cl, Br, —CN, —OH, C1-6 alkyl, C1-3 fluoroalkyl, C1-4 hydroxyalkyl, —(CH2)1-2O(C1-3 alkyl), C1-4 alkoxy, —O(C1-4 hydroxyalkyl), O(CH)1-3O(C1-3 alkyl), C1-3 fluoroalkoxy, —O(CH)1-3NRcRc, —OCH2CH═CH2, OCH2C≡CH, —C(O)(C1-4 alkyl), —C(O)OH, —C(O)O(C1-4 alkyl), —NRcRc, —NRaS(O)2(C1-3 alkyl), —NRaC(O)(C1-3 alkyl), —NRaC(O)O(C1-4 alkyl), —P(O)(C1-3 alkyl)2, —S(O)2(C1-3 alkyl), —O(CH2)1-2(C3-6 cycloalkyl), —O(CH2)1-2(morpholinyl), cyclopropyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, (tert-butoxycarbonyl) azetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, and Ra;
- or
- (iii) C1-4 alkyl substituted with one cyclic group selected from C3-6 cycloalkyl, heterocyclyl, aryl, and heteroaryl, said cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, —OH, —CN, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, —OCH2CH═CH2, —OCH2C≡CH, —NRcRc, —NRaS(O)2(C1-3 alkyl), —NRaC(O)(C1-3 alkyl), —NRaC(O)O(C1-4 alkyl), and C3-6 cycloalkyl;
- or R4a and R4b together with the carbon atom to which they are attached form a C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, each substituted with zero to 3 Rf;
- each Rf is independently F, Cl, Br, —OH, —CN, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, —OCH2CH═CH2, —OCH2C≡CH, —NRcRc, or a cyclic group selected from C3-6 cycloalkyl, 3- to 6-membered heterocyclyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl, each cyclic group substituted with zero to 3 substituents independently selected from F, Cl, Br, —OH, —CN, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 alkoxy, C1-3 fluoroalkoxy, and —NRcRc;
- R4c is C1-6 alkyl or C3-6 cycloalkyl, each substituted with zero to 4 substituents independently selected from F, Cl, —OH, C1-2 alkoxy, C1-2 fluoroalkoxy, and —CN;
- R4d is —OCH3;
- each Rc is independently H or C1-2 alkyl;
- Rd is phenyl substituted with zero to 1 substituent selected from F, Cl, —CN, —CH3, and —OCH3;
- each R5 is independently F, Cl, —CN, —OH, C1-6 alkyl substituted with zero to 4 Rg, C1-3 alkoxy substituted with zero to 4 Rg, C2-4 alkenyl substituted with zero to 4 Rg, C2-4 alkynyl substituted with zero to 4 Rg, C3-4 cycloalkyl substituted with zero to 4 Rg, phenyl substituted with zero to 4 Rg, oxadiazolyl substituted with zero to 3 Rg, pyridinyl substituted with zero to 4 Rg, —(CH2)1-2(heterocyclyl substituted with zero to 4 Rg), —(CH2)1-2NRcC(O)(C1-4 alkyl), (CH2)1-2NRcC(O)O(C1-4 alkyl), —(CH2)1-2NRcS(O)2(C1-4 alkyl), —C(O)(C1-4 alkyl), —C(O) OH, —C(O)O(C1-4 alkyl), —C(O)O(C3-4 cycloalkyl), —C(O)NRaRa, or —C(O)NRa(C3-4 cycloalkyl), or two R5 attached to the same carbon atom form ═O;
- each Rg is independently F, Cl, —CN, —OH, C1-3 alkoxy, C1-3 fluoroalkoxy, —O(CH2)1-2O(C1-2 alkyl), C3-5 cycloalkyl, or —NRcRc;
- each R6 is H, F, Cl, —CN, —CH3, —CH2F, —CHF2, —CF3, or —OCH3;
- m is 1, 2, or 3;
- and
- n is zero, 1, or 2.
22 more elements
Dependencies are inferred from the claim text.