US 12,338,233 B2
PD-1/Pd-L1 inhibitors
Evangelos Aktoudianakis, Redwood City, CA (US); Aesop Cho, Mountain View, CA (US); Zhimin Du, Belmont, CA (US); Michael Graupe, Pacifica, CA (US); Lateshkumar Thakorlal Lad, Belmont, CA (US); Paulo A. Machicao Tello, Oakland, CA (US); Jonathan William Medley, San Bruno, CA (US); Samuel E. Metobo, Newark, CA (US); Prasenjit Kumar Mukherjee, South San Francisco, CA (US); Devan Naduthambi, San Bruno, CA (US); Eric Q. Parkhill, Union City, CA (US); Barton W. Phillips, San Mateo, CA (US); Scott Preston Simonovich, Oakland, CA (US); Neil H. Squires, San Francisco, CA (US); Peiyuan Wang, San Mateo, CA (US); William J. Watkins, Saratoga, CA (US); Jie Xu, Foster City, CA (US); Kin Shing Yang, Foster City, CA (US); and Christopher Allen Ziebenhaus, San Francisco, CA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on Dec. 1, 2022, as Appl. No. 18/060,934.
Application 18/060,934 is a division of application No. 16/891,880, filed on Jun. 3, 2020, granted, now 11,555,029.
Application 16/891,880 is a continuation of application No. 16/274,106, filed on Feb. 12, 2019, granted, now 10,710,986, issued on Jul. 14, 2020.
Claims priority of provisional application 62/747,029, filed on Oct. 17, 2018.
Claims priority of provisional application 62/763,116, filed on Apr. 19, 2018.
Claims priority of provisional application 62/640,534, filed on Mar. 8, 2018.
Claims priority of provisional application 62/630,187, filed on Feb. 13, 2018.
Prior Publication US 2023/0212155 A1, Jul. 6, 2023
Int. Cl. C07D 403/14 (2006.01); A61K 31/496 (2006.01); A61K 31/497 (2006.01); A61P 31/20 (2006.01); A61P 35/00 (2006.01); A61P 35/02 (2006.01); C07D 241/18 (2006.01); C07D 241/20 (2006.01); C07D 405/14 (2006.01); C07D 487/08 (2006.01); C07D 487/10 (2006.01); C07D 491/107 (2006.01); C07D 519/00 (2006.01); C07K 16/28 (2006.01)
CPC C07D 403/14 (2013.01) [A61K 31/496 (2013.01); A61K 31/497 (2013.01); A61P 31/20 (2018.01); A61P 35/00 (2018.01); A61P 35/02 (2018.01); C07D 241/18 (2013.01); C07D 241/20 (2013.01); C07D 405/14 (2013.01); C07D 487/08 (2013.01); C07D 487/10 (2013.01); C07D 491/107 (2013.01); C07D 519/00 (2013.01); C07K 16/2818 (2013.01); C07K 16/2827 (2013.01)] 4 Claims
 
1. A method for inhibiting PD-1, PD-L1 and/or the PD-1/PD-L1 interaction comprising administering a compound of Formula (IIId):

OG Complex Work Unit Chemistry
wherein:
each Z1 is independently halo;
each Z3 is independently halo or —O—C1-6 alkyl;
each R1 is independently selected from the group consisting of H, —C1-8 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, —C1-6 alkylheterocyclyl, —C1-6 alkylC(O)ORa, —C2-6 alkenylC(O)ORa, —S(O)2Ra, —S(O)2ORa, —S(O)2NRaRb, —C(O)NRaS(O)2Ra, and —C1-6 alkylC3-8cycloalkyl;
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —ORa, —CN, —NO2, halo, —C1-6alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)2Ra, —C(O)ORa, —C1-6 alkylC(O)2ORa, —NRaRb, —OC(O)NRaRb, —NRaC(O)ORb, —NRaC(O)Rb, —C1-6 alkylNRaRb, —C(O)NRaRb, —C1-6 alkylC(O)NRaRb, —S(O)2Ra, —S(O)2ORa, —C1-6 alkylS(O)2Ra, —S(O)2NRaRb, —C1-6 alkylS(O)2NRaRb, —C(O)NRaS(O)2Rb, —NRaC(O)NRb, —C1-6 alkylC(O)NRaS(O)2Rb, —NRaC(O)Rb, and —C1-6alkylNRaC(O)Rb;
each R2 is independently selected from the group consisting of H, —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, —C3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl,
—C1-6 alkylheterocyclyl, —C2-6 alkyl-ORa, —C1-6 alkylC(O)ORa, and —C2-6 alkenylC(O)ORa;
wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —ORa, —CN, halo, —C1-6alkyl, —C1-6 alkylORa, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, —C1-6 alkylC(O)Ra, —C(O)ORa, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6 alkylNRaRb, —C(O)NRaRb, C1-6 alkylC(O)NRaRb, —S(O)2Rb, —C1-6 alkylS(O)2Ra, —S(O)2NRaRb, —C1-6 alkylS(O)2NRaRb, —C(O)NRaS(O)2Rb, and —NRaC(O)Rb;
or R1 and R2 combine to form a heterocyclyl group optionally containing 1, 2, or 3 additional heteroatoms independently selected from oxygen, sulfur, and nitrogen, and optionally substituted with 1 to 3 groups independently selected from the group consisting of oxo, —C1-6 alkyl, —C3-8 cycloalkyl, —C2-6 alkenyl, —C2-6 alkynyl, aryl, heteroaryl, heterocyclyl, —ORa, —CN, halo, —C(O)ORa, —C1-6 cyanoalkyl, —C1-6 alkylORa, —C1-6 haloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Ra, C1-6 alkylC(O)Rb, —C1-6 alkylC(O)ORa, —NRaRb, —C1-6 alkylNRaRb, —C(O)NRaRb, —NRaC(O)OR′, —NRaC(O)NRaRb, —NRaS(O)2NRaRb, —NRaS(O)2Rb, —C1-6 alkylC(O)NRaRb, —S(O)2Ra, —C1-6 alkylS(O)2Ra, —S(O)2NRaRb, and —C1-6 alkylS(O)2NRaRb;
each Ra is independently selected from the group consisting of H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6alkylheterocyclyl;
each Rb is independently selected from the group consisting of H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-2cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
or Ra and Rb may combine together to form a ring consisting of 3-8 ring atoms that are C, N, O, or S; wherein the ring is optionally substituted with 1 to 4 groups independently selected from the group consisting of —ORf, —CN, halo, —C1-6 alkylORf, —C1-6 cyanoalkyl, —C1-6 haloalkyl, —C3-8 cycloalkyl, —C1-3 alkylC3-8cycloalkyl, —C(O)Rf, —C1-6 alkylC(O)Rf, —C(O)ORf, —C1-6 alkylC(O)ORf, —NRfRg, —C1-6 alkylNRfRg, —C(O)NRfRg, —C1-6 alkylC(O)NRfRg, —S(O)2Rf, —C1-6 alkylS(O)2Rf, —S(O)2NRfRg, —C1-6 alkylS(O)2NRfRg, —C(O)NRfS(O)2Rg, and —NRfC(O)Rg;
each Rf is independently selected from the group consisting of H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl; and
each Rg is independently selected from the group consisting of H, —C1-6 alkyl, —C3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C1-3 alkylC3-8 cycloalkyl, —C1-6 alkylaryl, —C1-6 alkylheteroaryl, and —C1-6 alkylheterocyclyl;
or a pharmaceutically acceptable salt thereof, to a human.