US 12,454,531 B2
Substituted piperazine derivatives useful as T cell activators
Upender Velaparthi, Princeton Junction, NJ (US); Chetan Padmakar Darne, Ewing, NJ (US); Richard E. Olson, Cambridge, MA (US); and Jayakumar Sankara Warrier, Bangalore (IN)
Assigned to Bristol-Myers Squibb Company, Princeton, NJ (US)
Appl. No. 17/785,749
Filed by BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US)
PCT Filed Dec. 22, 2020, PCT No. PCT/US2020/066504
§ 371(c)(1), (2) Date Jun. 15, 2022,
PCT Pub. No. WO2021/133749, PCT Pub. Date Jul. 1, 2021.
Claims priority of application No. 201911053559 (IN), filed on Dec. 23, 2019.
Prior Publication US 2023/0118629 A1, Apr. 20, 2023
Int. Cl. C07D 471/04 (2006.01); A61P 35/00 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/04 (2013.01) [A61P 35/00 (2018.01); C07D 519/00 (2013.01)] 13 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a salt thereof, wherein:
X is N;
Y is CR3 or N;
R4 is —CR4aR4c-L-R4b;
L is L1 or —(CH2)1-2L1-;
R is Cl or —CN;
R2 is —CH3;
R3 is H;
L1 is —C(O)—, —C(O)O—, —C(O)NRd—, —C(O)NHO—, —C(O)NHS(O)2—, —CH2C(O)—, —CH2NRd—, —CH2NHC(O)—, —CH2NHC(O)O—, —CH2NHS(O)2—, —CH2C(O)O—, —CH2C(O)NRd—, —CH2CH2NHC(O)O—, —CH2CH2NHS(O)2—, or —P(O)(CH3)—;
R4a is:
(i) —CH3; or
(ii) phenyl or pyridinyl, each substituted with zero to 2 substituents independently selected from F, —CH3, —CF3, and —OCH3;
R4b is:
(i) H, —CN, C1-4 alkyl, —CH2CN, —CH2CHF2, —CH2CF3, —CH2CH2OH, —CH2CH2CN, —CH2CH2CF3, —CH2CH2OCH3, —CH2CH2S(O)2CH3, —CH2C(CH3)2OH, —CH2(cyclopropyl), —CH2(hydroxycyclopropyl),

OG Complex Work Unit Chemistry
 or
(ii) azetidinyl, cyclopropyl, cyclopentyl, morpholinyl, pyrazolyl, isoxazolyl, piperidinyl, piperazinyl, pyrazolyl, pyrrolidinyl, dioxidothiomorpholinyl, or azaspiro[2.5]octanyl, each substituted with zero to 2 Rb;
each Rb is independently F, —OH, —CH3, —CH2OH, —C(CH3)2OH, —CH2OCH3, —OCH3, or —S(O)2CH3;
R4c is H;
Rd is H or —CH3;
each R5 is independently H, —CH3, or —CH2CH3;
each R6 is hydrogen; and
m is zero, 1, or 2.
 
12. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a salt thereof, wherein:
X is CR6 or N;
Y is CR3 or N;
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)nRf, or —P(O)RfRf;
each R1a is independently F, Cl, —CN, —OH, —OCH3, or —NRaRa;
each Ra is independently H or C1-3 alkyl;
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;
R3 is H, F, Cl, Br, —CN, C1-3 alkyl, C1-2 fluoroalkyl, C3-4 cycloalkyl, C3-4 fluorocycloalkyl, —NO2, or pyridinyl substituted with zero to 2 R3a;
each R3a is halo, —CN, C1-3 alkyl, or C1-3 alkoxy;
R4 is —CR4aR4c-L-R4b;
L is L1 or —(CH2)1-3L1-;
L1 is —C(O)—, —C(O)O—, —C(O)NRd—, —C(O)NRdO—, —NRd—, —NRdC(O)—, —NRdC(O)O—, —NRdC(O)NRd—, —C(O)NRdO—, —S(O)2—, —S(O)2NRd—, —NRdS(O)2—, or —P(O)Re—;
R4a is:
(i) H or C1-6 alkyl substituted with zero to 4 substituents independently selected from F, Cl, —CN, —OH, —OCH3, —SCH3, C1-3 fluoroalkoxy, —NRaRa, —S(O)2Rf, or —NRaS(O)2Rf; or
(ii) C3-6 cycloalkyl, C5-14 heterocyclyl, C6-10 aryl, or C5-14 heteroaryl, each substituted with zero to 4 Rb;
each Rb is independently 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), —C(O)NH2, —C(O)NH(C1-4 alkyl), —C(O)N(C1-4 alkyl)2, —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), C3-6 cycloalkyl, cyanocyclopropyl, methylazetidinyl, acetylazetidinyl, triazolyl, tetrahydropyranyl, morpholinyl, thiophenyl, methylpiperidinyl, or —CRcRc(phenyl);
R4b is:
(i) —CH2CH2OCH2CH2OCH2CH2NH2;
(ii) —CH2CH2OCH2CH2OCH2CH2NHC(O)OC(CH3)3; or

OG Complex Work Unit Chemistry
R4c is H or C1-6 alkyl;
each Rc is independently H or C1-2 alkyl;
each Rd is independently H or C1-6 alkyl;
Re is C1-6 alkyl;
each Rf is independently C3-4 cycloalkyl or C1-3 alkyl substituted with zero to 4 R1a;
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.