US 12,351,591 B2
KRas inhibitors
David Anthony Barda, Indianapolis, IN (US); Jolie Anne Bastian, Indianapolis, IN (US); Kelly Wayne Furness, Avon, IN (US); Deqi Guo, Carmel, IN (US); James Robert Henry, Indianapolis, IN (US); Richard Duane Johnston, Greenfield, IN (US); Jason Eric Lamar, Indianapolis, IN (US); Tao Liu, San Diego, CA (US); Michael John Rodriguez, Indianapolis, IN (US); Almudena Rubio, Carmel, IN (US); Chong Si, Zionsville, IN (US); Gaiying Zhao, Carmel, IN (US); Mohammad Sadegh Zia-Ebrahimi, Indianapolis, IN (US); Matthew Patrick Baumgartner, Aldan, PA (US); Isabel Rojo, Madrid (ES); Mario Barberis, Madrid (ES); Santiago Carballares Martin, Madrid (ES); Pablo Garcia Losada, Madrid (ES); Sonia Maria Gutierrez Sanfeliciano, Madrid (ES); Wenceslao Lumeras Amador, Madrid (ES); Victoriano Molero Florez, Madrid (ES); and Maria Lourdes Prieto Vallejo, Madrid (ES)
Assigned to ELI LILLY AND COMPANY, Indianapolis, IN (US)
Filed by ELI LILLY AND COMPANY, Indianapolis, IN (US)
Filed on Mar. 24, 2023, as Appl. No. 18/189,713.
Claims priority of provisional application 63/386,404, filed on Dec. 7, 2022.
Claims priority of provisional application 63/406,906, filed on Sep. 15, 2022.
Claims priority of provisional application 63/323,607, filed on Mar. 25, 2022.
Prior Publication US 2024/0043451 A1, Feb. 8, 2024
Int. Cl. C07D 519/00 (2006.01); C07D 491/048 (2006.01)
CPC C07D 519/00 (2013.01) [C07D 491/048 (2013.01); C07B 2200/05 (2013.01)] 33 Claims
 
1. A compound of the formula:

OG Complex Work Unit Chemistry
wherein:
A is —C(H)— or —N—;
B is —C(R4)— or —N—;
D1 is —CH2—;
X is —S—;
Y is —C(CN)— or —N—;
Z is —C(R3c)— or —N—;
G is —C(R3b)— or —N—;
R1 is methoxy, C1-4 alkyl, C2-4 heteroalkyl, azetidine, N-linked piperazine, piperidine, morpholine, or a group of the formula selected from

OG Complex Work Unit Chemistry
wherein the C1-4 alkyl, C2-4 heteroalkyl, azetidine, piperidine, or N-linked piperazine are optionally substituted with one or more of amino, hydroxyl, methyl, trideuteromethyl, methoxy, oxetane, or C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by one or more halogen, hydroxyl, methyl, hydroxymethyl, methoxy, trifluoromethoxy, difluoromethoxy, —O-trideuteromethyl, cyclopropyl, oxetane, pyrazole, imidazole, amino, —CONR7R7, —O—(CH2)p—OC1-3 alkyl, —O—(CH2)p—OH, or —O—CO—C1-3 alkyl, wherein the piperidine or the N-linked piperazine are optionally bridged by a C1-3 alkyl and wherein the cyclopropyl, imidazole, or pyrazole are each optionally substituted with a hydroxyl or a C1-3 alkyl substituted with one or more hydroxyl;
E1 is —(CR7R7-)n, E2 is —CR7R7—, —NR7— or —O— and E3 is —(CR7R7-)m, wherein m+n is 1, 2, 3 or 4;
p is 1, 2, or 3;
R2 is H, halogen, or methyl;
R3a, R3b, and R3c are each independently H or halogen;
R4 is H, methyl, —CH2—OH, —O—R5-R6, —O—R6, or azetidine optionally substituted with NR7R7, wherein R5 is —CH2—, —CH(CH3)—, or —CH2—CH2—, wherein R6 is H, C1-3 alkyl, C2-3 heteroalkyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, 2-oxo-1,3-dihydrobenzimidazole, imidazole or pyrazole, wherein the C1-3 alkyl, C3-6 cycloalkyl, or C4-6 heterocycloalkyl are optionally substituted with one or more oxo, halogen, hydroxyl, methoxy, difluoromethoxy, NR7R7, C1-4 alkyl, C1-4 alkenyl, —CN, or —CO—CH2OH, wherein the C1-4 alkyl is optionally substituted with one or more halogen, hydroxyl, methoxy, or NR7R7, wherein the C3-6 cycloalkyl or C4-6 heterocycloalkyl are optionally fused with the C1-4 alkyl to form a bicyclic ring, or the C3-6 cycloalkyl or C4-6 heterocycloalkyl are optionally bridged with a C1-3 alkyl; and
each R7 is independently H, or C1-3 alkyl;
or a pharmaceutically acceptable salt thereof.