	US 12,410,135 B2
	PD-1/PD-L1 inhibitors
Evangelos Aktoudianakis, Redwood City, CA (US); Todd Appleby, San Francisco, CA (US); Aesop Cho, Mountain View, CA (US); Zhimin Du, Belmont, CA (US); Michael Graupe, Pacifica, CA (US); Juan A. Guerrero, Concord, CA (US); Salman Y. Jabri, San Francisco, 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); Prasenjit Kumar Mukherjee, South San Francisco, CA (US); Devan Naduthambi, San Bruno, CA (US); Gregory Notte, Redwood City, CA (US); Eric Q. Parkhill, Union City, CA (US); Barton W. Phillips, San Mateo, CA (US); Scott Preston Simonovich, San Francisco, CA (US); Neil H. Squires, San Francisco, CA (US); Chandrasekar Venkataramani, San Carlos, 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 Nov. 13, 2020, as Appl. No. 17/098,171.
Application 17/098,171 is a continuation of application No. 16/840,217, filed on Apr. 3, 2020, abandoned.
Application 16/840,217 is a continuation of application No. 16/551,550, filed on Aug. 26, 2019, abandoned.
Application 16/551,550 is a continuation of application No. 15/957,739, filed on Apr. 19, 2018, abandoned.
Claims priority of provisional application 62/507,678, filed on May 17, 2017.
Claims priority of provisional application 62/488,017, filed on Apr. 20, 2017.
Prior Publication US 2021/0323922 A1, Oct. 21, 2021
Int. Cl. C07D 213/69 (2006.01); A61K 31/44 (2006.01); A61K 31/444 (2006.01); A61K 31/4545 (2006.01); A61K 31/497 (2006.01); A61K 31/5377 (2006.01); A61K 45/06 (2006.01); C07D 213/30 (2006.01); C07D 213/61 (2006.01); C07D 213/64 (2006.01); C07D 213/85 (2006.01); C07D 295/088 (2006.01); C07D 401/04 (2006.01); C07D 401/14 (2006.01); C07D 405/14 (2006.01); C07D 487/08 (2006.01); C07D 487/10 (2006.01); C07D 491/107 (2006.01); C07D 498/04 (2006.01); C07D 519/00 (2006.01)

CPC C07D 213/69 (2013.01) [A61K 31/44 (2013.01); A61K 31/444 (2013.01); A61K 31/4545 (2013.01); A61K 31/497 (2013.01); A61K 31/5377 (2013.01); A61K 45/06 (2013.01); C07D 213/30 (2013.01); C07D 213/61 (2013.01); C07D 213/64 (2013.01); C07D 213/85 (2013.01); C07D 295/088 (2013.01); C07D 401/04 (2013.01); C07D 401/14 (2013.01); C07D 405/14 (2013.01); C07D 487/08 (2013.01); C07D 487/10 (2013.01); C07D 491/107 (2013.01); C07D 498/04 (2013.01); C07D 519/00 (2013.01)]

18 Claims

1. A compound of formula (VIII):

wherein:

each of X⁴and X⁵are independently N, CH, or CZ³;

each Z¹is independently halo, —OR^a, —NO₂, —CN, —NR^aR^b, —N₃, —SO₂R^a, —C_1-6alkyl, —C_1-6haloalkyl, —C_2-6alkenyl, —C_2-6alkynyl, —O—C_1-6alkyl, —O—C_1-6haloalkyl, —C_3-8cycloalkyl, or —C_1-6alkyl-C_3-8cycloalkyl; and

wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO₂, —N₃, —OR^a, halo, and cyano;

each w is independently 0, 1, or 2;

each Z³is independently halo, —OR^a, —N₃, —NO₂, —CN, —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^aSO₂NR^aR^b, —C(O)NR^aSO₂NR^aR^b, —C_1-6alkyl, —C_2-6alkenyl, —C_2-6alkynyl, —O—C_1-6alkyl, —C_3-8cycloalkyl, —C_1-6alkylC_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, or RN, 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, —SO₂R^a, —NR^aSO₂R^b, —SO₂NR^aR^b, —NR^aSO₂NR^aR^b, —C(O)NR^aSO₂NR^aR^b, and —C_3-8cycloalkyl;

R^Nis independently —C_1-6alkylNR¹R², —O—C_1-6alkylNR¹R², —C_1-6alkylOC_1-6alkylNR¹R², —NR^aC_1-6alkylNR¹R², —C_1-6alkylC(O)NR¹R², —O—C_1-6alkylC(O)NR¹R², —O—C_1-6alkylC(O)OR¹, —SC_1-6alkylNR¹R², —C_1-6alkylOR^a, or

wherein: L¹is independently a bond, O, NR^a, S, SO, or SO₂;

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, SO, or SO₂;

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, —O—C_1-6alkylCN, —C(O)NR^aR^b, —NR^aC(O)R^a, —NR^aC(O)OR^a, —C(O)N(R^a)OR^b, —SO₂R^a, —SO₂NR^aR^b, —NR^aSO₂R^b, —NR^aSO₂NR^aR^b, —C(O)NR^aSO₂NR^aR^b, C_3-8cycloalkyl, 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;

R^Eand R^Ware each independently —NR¹R², —C_1-6alkylNR¹R², —O—C_1-6alkylNR¹R², —C_1-6alkylOC_1-6alkylNR¹R², —NR^a—C_1-6alkylNR¹R², —C_1-6alkylN⁺R¹R²R³, —S—C_1-6alkylNR¹R², —C(O)NR¹R², —SO₂R^a, —(CH₂)_uSO₂NR¹R², —(CH₂)_uNR^a—SO₂NR^aR^b, —SO₂NR^a—C_1-6alkylNR¹R², —NR^aSO₂—C_1-6alkylNR¹R², —(CH₂)_uC(O)NR^aSO₂NR^aR^b, —(CH₂)_uN⁺R¹R²O⁻, —(CH₂)_uP⁺R^bR^cR^d, (CH₂)_uP⁺R^cR^dO⁻, —(CH₂)_uP⁺O[NR^aR^b][NR^cR^d], —(CH₂)_uNR^cP(O)(OR^c)₂, —(CH₂)_uCH₂OP(O)(OR^c)(OR^d), —(CH₂)_uOP(O)(OR^c)(OR^d), —(CH₂)_uOP(O)NR^aR^b)(OR^a), or

wherein:

V²is independently a bond, O, NR^a, S, SO, SO₂, C(O)NR^a, NR^aC(O), SO₂NR¹, or NR^aSO₂;

L³is independently a bond, O, NR^a, S, SO, SO₂, C(O)NR^a, NR^aC(O), SO₂NR¹, or NR^aSO₂;

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

T is independently H, OR^a, (CH₂)_qNR¹R², (CH₂)_qNR^aC(O)R^e, or (CH₂)_qC(O)R^e;

p is independently 0, 1, 2, 3, 4, or 5;

q is independently 0, 1, 2, 3, 4, or 5;

u is 0, 1, 2, 3, or 4;

z is 0, 1, 2, or 3; and

wherein the alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl of R^Eor R^Wis optionally substituted with 1 to 3 substituents independently selected from the group consisting of NR^aR^b, halo, cyano, oxo, OR^a, —C_1-6alkyl, —C_1-6haloalkyl, —C_1-6cyanoalkyl, —C_1-6alkylNR^aR^b, —C_1-6alkylOH, —C_3-8cycloalkyl, and —C_1-3alkylC_3-8cycloalkyl;

provided that at least one of V², L³, ring B, and T contains a nitrogen atom;

each R¹is independently selected from H, —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, —SO₂R^a, —SO₂NR^aR^b, —C(O)NR^aSO₂R^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, —CN, 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 H, —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, —CN, 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, —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, and —NR^aC(O)R^b;

or R¹and R²combine 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 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, —SO₂R^a, —C_1-6alkylSO₂R^a, —SO₂NR^aR^b, and C_1-6alkylSO₂NR^aR^b;

each R³is independently H, —C_1-6alkyl, —C_2-6alkenyl, —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, or —C_2-6alkenylC(O)OR^a;

each R^ais independently selected from H, —C_1-6alkyl, —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 H, —C_1-6alkyl, —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 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 —OR^f, —CN, 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, —SO₂R^f, —C_1-6alkylSO₂R^f, —SO₂NR^fR^g, —C_1-6alkylSO₂NR^fR^g, —C(O)NR^fSO₂R^g, and —NR^fC(O)R^g;

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

R^dis independently selected from H, —C_1-6alkyl, —C₃-C₈cycloalkyl, aryl, heteroaryl, heterocyclyl, —C_1-3alkylC_3-8cycloalkyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, and —C_1-6alkylheterocyclyl;

each R^eis independently selected from H, —C_1-6alkyl, —O—C_1-6alkyl, —C_3-8cycloalkyl, aryl, heteroaryl, heterocyclyl, —O—C_3-8cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —C_1-3alkylC_3-8cycloalkyl, —C_1-6alkylaryl, —C_1-6alkylheteroaryl, —NR^fR^g, —C_1-6alkylNR^fR^g, —C(O)NR^fR^g, —C_1-6alkylC(O)NR^fR^g, —NHSO₂R^f, —C_1-6alkylSO₂R^f, and —C_1-6alkylSO₂NR^fR^g;

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

or a pharmaceutically acceptable salt thereof.