	US 11,697,657 B2
	Small molecule inhibitors of KRAS G12C mutant
Indu Bharathan, Somerville, MA (US); Symon Gathiaka, Waltham, MA (US); Yongxin Han, Needham, MA (US); Xiaoshen Ma, Boston, MA (US); Ryan D. Otte, Natick, MA (US); David L. Sloman, Newton, MA (US); Thomas H. Graham, Somerville, MA (US); Timothy Henderson, Natick, MA (US); Elisabeth Hennessy, Weston, MA (US); and Anandan Palani, Needham, MA (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
Filed on Oct. 27, 2020, as Appl. No. 17/81,477.
Claims priority of provisional application 63/030,014, filed on May 26, 2020.
Claims priority of provisional application 62/926,879, filed on Oct. 28, 2019.
Prior Publication US 2021/0122764 A1, Apr. 29, 2021
Int. Cl. A61K 31/519 (2006.01); A61P 35/00 (2006.01); C07D 498/22 (2006.01); C07D 471/22 (2006.01); C07D 519/00 (2006.01)

CPC C07D 498/22 (2013.01) [A61K 31/519 (2013.01); A61P 35/00 (2018.01); C07D 471/22 (2013.01); C07D 519/00 (2013.01); C07B 2200/05 (2013.01)]

22 Claims

1. A compound selected from the group consisting of:

2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-18,21-difluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-ethenopyrido[4,3-f]pyrimidol[1,6,h][1,8,10]benzoxadiazacyclotridecin-4-one;

(5aS_a,17aR_a)-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-dihydro-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido [1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one;

(5aS_a,17aR_a)-20-Chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-14,17-difluoro-6-(propan-2-yl)-11,12-di[(²H)hydro](11,12-²H₂)-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one;

(5aR_a,18aR_a)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18,21-tetrafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one;

(5aR_a,18aR_a)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,17,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one;

(5aR_a,18aR_a)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,15,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one;

(5aR_a,18aR_a)-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,16,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,8,10]benzoxadiazacyclotridecin-4-one;

(5 aS_a,17aR_a)-20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-16,17-difluoro-6-(propan-2-yl)-11,12-di[(²H)hydro](11,12-²H₂)-4H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,4,7,9]benzodioxadiazacyclododecin-4-one;

2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,17,18,21-pentafluoro-6-(propan-2-yl)-10,11,12,13-tetrahydro-4H-1,19-(ethanediylidene)dipyrimido[4,5-f1′,6′-h][1,8,10]benzoxadiazacyclotridecin-4-one;

21-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-12,12,18-trifluoro-6-(propan-2-yl)-12,13-dihydro-4H,11H−1,19-(ethanediylidene)pyrido[4,3-f]pyrimido[1,6-h][1,5,8,10]benzodioxadiazacyclotridecin-4-one;

20-chloro-2-[(2S,5R)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-1-yl]-17-fluoro-6-(propan-2-yl)-11,12-dihydro-4H,10H-1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[1,6-g][1,7,9]benzoxadiazacyclododecin-4-one; or

a pharmaceutically acceptable salt thereof.