	US 12,269,812 B2
	PD-1/PD-L1 inhibitors
Evangelos Aktoudianakis, Redwood City, CA (US); Aesop Cho, Mountain View, CA (US); Michael Graupe, Pacifica, CA (US); Lateshkumar Thakorlal Lad, Belmont, CA (US); Paulo A. Machicao Tello, Oakland, CA (US); Jonathan William Medley, San Mateo, CA (US); Samuel E. Metobo, Newark, CA (US); Devan Naduthambi, San Bruno, CA (US); Barton W. Phillips, San Mateo, CA (US); Scott Preston Simonovich, 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, San Mateo, 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 Jul. 8, 2020, as Appl. No. 16/923,750.
Application 16/923,750 is a continuation of application No. 16/510,647, filed on Jul. 12, 2019, granted, now 10,774,071.
Claims priority of provisional application 62/808,763, filed on Feb. 21, 2019.
Claims priority of provisional application 62/747,033, filed on Oct. 17, 2018.
Claims priority of provisional application 62/697,932, filed on Jul. 13, 2018.
Prior Publication US 2021/0024494 A1, Jan. 28, 2021
Int. Cl. C07D 401/14 (2006.01); A61K 31/444 (2006.01); A61K 31/497 (2006.01); A61K 31/704 (2006.01); A61K 31/7068 (2006.01); A61K 39/395 (2006.01); C07D 471/08 (2006.01)

CPC C07D 401/14 (2013.01) [A61K 31/444 (2013.01); A61K 31/497 (2013.01); A61K 31/704 (2013.01); A61K 31/7068 (2013.01); A61K 39/3955 (2013.01); C07D 471/08 (2013.01)]

11 Claims

1. A compound of formula (IIA):

or a pharmaceutically acceptable salt thereof, wherein:

each of X¹, X², X³and X⁴are independently N, CH, or CZ³;

Z¹is halo, —OR^a, cyano, or —C_1-6alkyl;

each Z³is independently halo, —OR^a, —N₃, —NO₂, cyano, —NR¹R², —SO₂R^a, —SO₂NR^aR^b, —NR^aSO₂R^a, —NR^aC(O)R^a, —C(O)R^a, —C(O)OR^a, —C(O)NR^aR^b, —NR^aC(O)OR^a, —NR^aC(O)NR¹R², —OC(O)NR^aR^b, —NR^aS(O)₂NR^aR^b, —C(O)NR^aS(O)₂NR^aR^b, —C_1-6alkyl, —C_2-6alkenyl, —C_2-6alkynyl, —O—C_1-6alkyl, —C_1-6cyanoalkyl, —C_1-6haloalkyl, —O—C_1-6cyanoalkyl, —O—C_1-6haloalkyl, —C_3-8cycloalkyl, —C_1-6alkyl C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, and R^N; and

wherein the alkyl, alkenyl, alkynyl, C_3-8cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from oxo, —NO₂, —N₃, —OR^a, halo, cyano, —NR^aR^b, —C(O)R^a, —C(O)OR^a, —O—C_1-6cyanoalkyl, —C(O)NR^aR^b, —NR^aC(O)R^a, —NR^aC(O)OR^a, —S(O)₂R^a, —NR^aS(O)₂R^b, —S(O)₂NR^aR^b, —NR^aS(O)₂NR^aR^b, —C(O)NR^aS(O)₂NR^aR^b, and —C_3-8cycloalkyl;

R^Nis independently —C_1-6alkylNR¹R², —OC_1-6alkylNR¹R², —C_1-6alkylOC_1-6alkylNR¹R², —NR^a—C_1-6alkylNR¹R², —C_1-6alkylC(O)NR¹R², —O—C_1-6alkylC(O)NR¹R², —O—C_1-6alkylC(O)OR¹, —S—C_1-6alkylNR¹R², —C_1-6alkylOR^a, or

wherein: L¹is independently a bond, —O—, —NR^a—, —S—, —S(O)—, or —S(O)₂—;

V is independently selected from a bond, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl;

wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with —OR^a, halo, cyano, —NR^aR^b, or —C_3-8cycloalkyl;

L²is independently a bond, —O—, —NR^a—, —S—, —S(O)—, or —S(O)₂—;

ring A is independently cycloalkyl, aryl, heteroaryl, or heterocyclyl;

wherein each cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO₂, —N₃, —OR^a, halo, cyano, —C_1-6alkyl, —C_1-6haloalkyl, —C_2-6alkenyl, —C_2-6alkynyl, —O—C_1-6haloalkyl, NR^aR^b, —C(O)R^a, —C(O)OR^a, —OC_1-6alkylCN, —C(O)NR^aR^b, —NR^aC(O)R^a, —NR^aC(O)OR^a, —C(O)N(R^a)OR^b, —S(O)₂R^a, —S(O)₂NR^aR^b, —NR^aS(O)₂R^b, —NR^aS(O)₂NR^aR^b, —C(O)NR^aS(O)₂NR^aR^b, —C_3-8cycloalkyl, heteroaryl, and —C_1-6alkylC_3-8cycloalkyl; and

wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —OR^a, halo, cyano, —NR^aR^b, or —C_3-8cycloalkyl;

each t is independently 0, 1, or 2;

each R¹is independently selected from hydrogen, —C_1-8alkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C_3-6cycloalkyl, aryl, heteroaryl, heterocyclyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, —C_1-6alkylheterocyclyl, —C_1-6alkylC(O)OR^a, —C_2-6alkenylC(O)OR^a, —S(O)₂R^a, —S(O)₂NR^aR^b, —C(O)NR^aS(O)₂R^a, and —C_1-6alkylC_3-8cycloalkyl;

wherein each alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —OR^a, cyano, halo, C_1-6alkyl, —C_1-6alkylOR^a, —C_1-6cyanoalkyl, —C_1-6haloalkyl, C_3-8cycloalkyl, —C_1-3alkylC_3-8cycloalkyl, —C(O)R^a, —C_1-6alkylC(O)R^a, —C(O)OR^a, —C_1-6alkylC(O)OR^a, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)OR^b, —C_1-6alkylNR^aR^b, —C(O)NR^aR^b, —C_1-6alkylC(O)NR^aR^b, —SO₂R^a, —C_1-6alkylSO₂R^a, —SO₂NR^aR^b, —C_1-6alkylSO₂NR^aR^b, —C(O)NR^aSO₂R^b, —C_1-6alkylC(O)NR^aSO₂R^b, —NR^aC(O)R^b, and —C_1-6alkylNR^aC(O)R^b;

each R²is independently selected from hydrogen, —C_1-6alkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C_3-6cycloalkyl, aryl, heteroaryl, heterocyclyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, —C_1-6alkylheterocyclyl, —C_2-6alkyl-OR^a, —C_1-6alkylC(O)OR^a, and —C_2-6alkenylC(O)OR^a;

wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with 1 to 4 groups independently selected from —OR^a, cyano, halo, C_1-6alkyl, —C_1-6alkylOR^a, —C_1-6cyanoalkyl, —C_1-6haloalkyl, —C_3-8cycloalkyl, —C_1-3alkylC_3-8cycloalkyl, —C(O)R^a, —C_1-6alkylC(O)R^a, —C(O)OR^a, —C_1-6alkylC(O)OR^a, —NR^aR^b, —C₁⁻₆alkylNR^aR^b, —C(O)NR^aR^b, C_1-6alkylC(O)NR^aR^b, —S(O)₂R^a, —C_1-6alkyl S(O)₂R^a, —S(O)₂NR^aR^b, —C_1-6alkyl S(O)₂NR^aR^b, —C(O)NR^aS(O)₂R^b, and —NR^aC(O)R^b;

or R¹and R²combine to form a heterocyclyl optionally substituted with 1 to 3 groups independently selected from oxo, —C_1-6alkyl, —C_3-8cycloalkyl, —C_2-6alkenyl, —C_2-6alkynyl, —OR^a, —C(O)OR^a, —C_1-6cyanoalkyl, —C_1-6alkylOR^a, —C_1-6haloalkyl, —C_1-3alkylC_3-8cycloalkyl, —C(O)R^a, —C_1-6alkylC(O)R^a, —C_1-6alkylC(O)OR^a, —NR^aR^b, —C_1-6alkylNR^aR^b, —C(O)NR^aR^b, —C_1-6alkylC(O)NR^aR^b, —S(O)₂R^a, —C_1-6alkyl S(O)₂R^a, —S(O)₂NR^aR^b, —C(O)N═S(O)R^aNR^aR^b, —C(O)N═S(O)R^aNR^aC(O)R^b, and —C_1-6alkyl S(O)₂NR^aR^b;

each R^ais independently selected from hydrogen, —C_1-6alkyl, —C_1-6cyanoalkyl, —C_1-6haloalkyl, —C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, —C_1-3alkylC_3-8cycloalkyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, and —C_1-6alkylheterocyclyl;

each R^bis independently selected from hydrogen, —C_1-6alkyl, —C_1-6cyanoalkyl, —C_1-6haloalkyl, —C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, —C_1-3alkylC_3-8cycloalkyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, and —C_1-6alkylheterocyclyl;

or R^aand R^bmay combine together to form a heterocyclyl optionally substituted with 1 to 4 groups independently selected from —OR^f, cyano, halo, —C_1-6alkylOR^f, —C_1-6cyanoalkyl, —C_1-6haloalkyl, —C_3-8cycloalkyl, —C_1-3alkylC_3-8cycloalkyl, —C(O)R^f, —C_1-6alkylC(O)R^f, —C(O)OR^f, —C_1-6alkylC(O)OR^f, —NR^fR^g, —C_1-6alkylNR^fR^g, —C(O)NR^fR^g, —C_1-6alkylC(O)NR^fR^g, —S(O)₂R^f, —C_1-6alkyl S(O)₂R^f, —S(O)₂NR^fR^g, —C_1-6alkyl S(O)₂NR^fR^g, —C(O)NR^fS(O)₂R^g, and —NR^fC(O)R^g,

each R^fis independently selected from hydrogen, —C_1-6alkyl, —C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, —C_1-3alkylC_3-8cycloalkyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, and —C_1-6alkylheterocyclyl, and

each R^gis independently selected from hydrogen, —C_1-6alkyl, —C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, —C_1-3alkylC_3-8cycloalkyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, and —C_1-6alkylheterocyclyl.