US 12,077,534 B2
Aza-heterobicyclic inhibitors of MAT2A and methods of use for treating cancer
Zenon D. Konteatis, Chatham, NJ (US); Mingzong Li, Medford, MA (US); Samuel K. Reznik, Cambridge, MA (US); and Zhihua Sui, Suresnes (FR)
Assigned to LES LABORATOIRES SERVIER, Suresnes (FR)
Appl. No. 17/418,442
Filed by Les Laboratoires Servier SAS, Suresnes (FR)
PCT Filed Dec. 27, 2019, PCT No. PCT/US2019/068652
§ 371(c)(1), (2) Date Jun. 25, 2021,
PCT Pub. No. WO2020/139991, PCT Pub. Date Jul. 2, 2020.
Claims priority of provisional application 62/785,519, filed on Dec. 27, 2018.
Prior Publication US 2022/0144820 A1, May 12, 2022
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); C07B 2200/05 (2013.01)] 35 Claims
 
1. A compound according to Formula I:

OG Complex Work Unit Chemistry
wherein:
L is O, S, NR, or a bond;
R is H or C1-C6-alkyl;
R1 is selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C3-C6-carbocyclyl, —(C1-C6-alkyl)(C3-C6-carbocyclyl), and —(C1-C6-alkyl)(C3-C6-cycloalkenyl) wherein
any alkyl in R1 is straight or branched, and
R1 is optionally substituted by 1 to 6 halogen or 1 to 6 deuterium;
or when L is NR, then R and R1 in combination with L represent a 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are, independently, N, O, or S) optionally substituted by one or more of RA,
R2 and R3 are independently selected from the group consisting of (C2-C6)alkynyl, C6-C10-aryl, C3-C6-carbocyclyl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are, independently, N, O, or S), and 3- to 14-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are, independently, N, O, or S),
wherein R2 and R3 are independently and optionally substituted by one or more substituents that are selected from the group consisting of RA, ORA, halogen, —N═N—RA, NRARB, —(C1-C6-alkyl)NRARB, —C(O)ORA, —C(O)NRARB, —OC(O)RA, —Si(C1-C6-alkyl)3 and —CN;
R4 is selected from the group consisting of H, C1-C6-alkyl (optionally substituted by one or more halogen, hydroxy or 3- to 14-membered heterocycloalkoxy (wherein 1-4 heterocycloalkoxy members are, independently, N, O, or S)), —O(C1-C6-alkyl) (optionally substituted by one or more halogen), —OH, halogen, —CN, —(C1-C6-alkyl)NRARB, and —NRARB;
R5 is selected from the group consisting of H, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, halogen, —CN, and —NRCRD;
RA and RB are independently selected from the group consisting of H, —CN, -hydroxy, oxo, C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, —NH2, —S(O)0-2—(C1-C6-alkyl), —S(O)0-2—(C6-C10-aryl), —C(O)(C1-C6-alkyl), —C(O)(C3-C14-carbocyclyl), —C3-C14-carbocyclyl, —(C1-C6-alkyl)(C3-C14-carbocyclyl), C6-C10-aryl, 3- to 14-membered heterocycloalkyl, (wherein 1-4 heterocycloalkyl members are, independently, N, O, or S), —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are, independently, N, O, or S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are, independently, N, O, or S);
wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl moiety of RA and RB is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, halogen, —NR′2 (wherein each R′ is independently selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C6-C10-aryl, 3- to 14-membered heterocycloalkyl (wherein 1-4 ring members are, independently, N, O, or S), —(C1-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are, independently, N, O, or S), 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are, independently, N, O, and S)), —NHC(O)(OC1-C6-alkyl), —NO2, —CN, oxo, —C(O)OH, —C(O)O(C1-C6-alkyl), —C1-C6-alkyl(C1-C6-alkoxy), —C(O)NH2, C1-C6-alkyl, —C(O)C1-C6-alkyl, —OC1-C6-alkyl, —Si(C1-C6-alkyl)3, —S(O)0-2—(C1-C6-alkyl), C6-C10-aryl, —(C1-C6-alkyl)(C6-C10-aryl), 3- to 14-membered heterocycloalkyl, and —(C1-C6-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are, independently, N, O, or S), and —O(C6-C14-aryl),
wherein each alkyl, alkenyl, aryl, and heterocycloalkyl substituent in RA and RB is optionally substituted with one or more substituents selected from the group consisting of hydroxy, —OC1-C6-alkyl, halogen, —NH2, —(C1-C6-alkyl)NH2, —C(O)OH, CN, and oxo;
RC and RD are each, independently, H or C1-C6-alkyl;
or a pharmaceutically acceptable salt thereof.