IP Library › Granted Patent US 11,236,085

Granted Patent B2

US 11,236,085 · App. 16/660,219 · Granted Feb 1, 2022

PD-1/PD-L1 inhibitors

Inventors: Zhimin Du (Belmont, CA); Michael Graupe (Pacifica, CA); Paulo A. Machicao Tello (Oakland, CA); Jonathan William Medley (San Mateo, CA); Samuel E. Metobo (Newark, CA); Eric Q. Parkhill (Union City, CA); Barton W. Phillips (San Mateo, CA); Scott P. Simonovich (San Francisco, CA); Peiyuan Wang (San Mateo, CA); Jie Xu (Foster City, CA); Christopher A. Ziebenhaus (San Francisco, CA)

Assignee: Gilead Sciences, Inc.

C07D471/04 C07D217/04 C07D401/12 C07D401/14 C07D413/10 C07D471/08 C07D487/04 C07D495/04 C07D513/04 C07K16/2818 C07K16/2827 C07K16/40

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Quick Facts

Patent No.: US 11,236,085
App. No.: 16/660,219
Granted: Feb 1, 2022
Kind: B2

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Abstract

Compounds and methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.

Claims (140)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is N, CH, or CZ 3 ;

X 2 is N, CH, or CZ 3 ;

Y 1 is O, NH, or CH 2 and the dashed lines are single bonds, or Y 1 is halo or —C 1-6 alkyl and the dashed lines are absent;

ring B is

w is 0, 1, or 2;

each Z 1 is independently halo, —OR a , —NO 2 , cyano, —NR a R b , —N 3 , —S(O) 2 R a , —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —C 3-8 cycloalkyl, or —C 1-6 alkylC3-8 cycloalkyl; and

wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;

x is 0, 1, or 2;

each Z 2 is independently halo, —OR a , —NO 2 , cyano, —NR a R b , —N 3 , —S(O) 2 R a , —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 1-6 haloalkyl, —C 3-8 cycloalkyl, or —C 1-6 alkylC 3-8 cycloalkyl; and

wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;

t is 0, 1, or 2;

each Z 3 is independently halo, —OR a , —N 3 , —NO 2 , cyano, —NR 1 R 2 , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R a , —NR a C(O)R a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —NR a C(O)OR a , —NR a C(O)NR 1 R 2 , —OC(O)NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —O—C 1-6 cyanoalkyl, —O—C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-6 alkylC 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, or R N ; and

NR a C(O)R a , —NR a C(O)OR a , —S(O) 2 R a , —NR a S(O) 2 R b , —S(O) 2 NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , and —C 3-8 cycloalkyl;

R N is independently —C 1-6 alkylNR 1 R 2 , —OC 1-6 alkylNR 1 R 2 , —C 1-6 alkyl-O—C 1-6 alkylNR 1 R 2 , —NR a C 1-6 alkylNR 1 R 2 , —C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)OR 1 ,

SC 1-6 alkylNR 1 R 2 , —C 1-6 alkylOR a , or

wherein:

L 1 is independently a bond, —O—, —NR a —, —S—, —S(O)—, or —S(O) 2 —;

V is independently selected from a bond, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;

L 2 is 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, —NO 2 , —N 3 , —OR a , halo, cyano, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 haloalkyl, —NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 cyanoalkyl, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , —C(O)N(R a )OR b , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , —C 3-8 cycloalkyl, and —C 1-6 alkylC 3-8 cycloalkyl; and

wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;

R E is hydrogen, halo, —OH, —NR 1 C(O)NR 1 R 2 , —C 1-6 alkylOC(O)NR 1 R 2 , —C 1-6 alkylNR 1 C(O)R 2 , —CN, —C 1-9 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 1-8 haloalkyl, C 1-8 alkoxy, or C 3-15 cycloalkyl;

R W is —NR 1 R 2 , —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkyl-O—C 1-6 alkylNR 1 R 2 , —NR a —C 1-6 alkylNR 1 R 2 , —C 1-6 alkylN + R 1 R 2 R 3 , —S—C 1-6 alkylNR 1 R 2 , —C(O)NR 1 R 2 , —S(O) 2 R a , —(CH 2 ) u S(O) 2 NR 1 R 2 , —(CH 2 ) u NR a S(O) 2 NR a R b , —S(O) 2 NR a C 1-6 alkylNR 1 R 2 , —NR a S(O) 2 C 1-6 alkylNR 1 R 2 , —(CH 2 ) u C(O)NR a S(O) 2 NR a R b , —(CH 2 ) + R 1 R 2 O − ; —(CH 2 ) u P + R b R c R d , —(CH 2 ) u P + R c R d O − , —(CH 2 ) u P + O[NR a R b ][NR c R d ], —(CH 2 ) u NR c P(O)(OR c ) 2 , —(CH 2 ) u CH 2 OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(NR a R b )(OR a ), or

wherein:

V 2 is independently a bond, —O—, —NR a —, —S—, —S(O)—, —S(O) 2 —, —C(O)NR a —, —NR a C(O)—, —S(O) 2 NR 1 —, or —NR a S(O) 2 —;

L 3 is independently a bond, —O—, —NR a —, —S—, —S(O)—, —S(O) 2 —, —C(O)NR a —, —NR a C(O)—, —S(O) 2 NR 1 —, or —NR a S(O) 2 —;

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

T is independently hydrogen, —OR a , —(CH 2 ) q NR 1 R 2 , —(CH 2 ) q NR a C(O)R e , or —(CH 2 ) q C(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 E or R W is optionally substituted with 1 to 3 substituents independently selected from the group consisting of —NR a R b , halo, cyano, oxo, —OR a , —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 cyanoalkyl, —C 1-6 alkylNR a R b , —C 1-6 hydroxyalkyl, —C 3-8 cycloalkyl, and —C 1-3 alkylC 3-8 cycloalkyl;

provided that at least one of V 2 , L 3 , ring B′, and T contains a nitrogen atom;

each R 1 is independently selected from hydrogen, —C 1-8 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 1-6 alkylC(O)OR a , —C 2-6 alkenylC(O)OR a , —S(O) 2 R a , —S(O) 2 NR a R b , —C(O)NR a S(O) 2 R a , and —C 1-6 alkylC 3-8 cycloalkyl;

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 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —OC(O)NR a R b , NR a C(O)OR b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkylS(O) 2 NR a R b , —C(O)NR a S(O) 2 R b , —C 1-6 alkylC(O)NR a S(O) 2 R b , —NR a C(O)R b , and —C 1-6 alkylNR a C(O)R b ;

each R 2 is independently selected from hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 2-6 alkyl-OR a , —C 1-6 alkylC(O)OR a , and —C 2-6 alkenylC(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 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —C(O)NR a R b , C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkylS(O) 2 NR a R b , —C(O)NR a S(O) 2 R b , and —NR a C(O)R b ;

or R 1 and R 2 combine to form a heterocyclyl optionally substituted with 1 to 3 groups independently selected from oxo, —C 1-6 alkyl, —C 3-8 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OR a , —C(O)OR a , —C 1-6 cyanoalkyl, —C 1-6 alkylOR a , —C 1-6 haloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C(O)N═S(O)R a NR a R b , —C(O)N═S(O)R a NR a C(O)R b , and —C 1-6 alkylS(O) 2 NR a R b ;

each R 3 is independently hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 3-6 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —C 1-6 alkylheterocyclyl, —C 2-6 alkyl-OR a , —C 1-6 alkylC(O)OR a , or —C 2-6 alkenylC(O)OR a ;

each R a is independently selected from hydrogen, —C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;

each R b is independently selected from hydrogen, —C 1-6 alkyl, —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;

or R a and R b may combine together to form a heterocyclyl optionally substituted with 1 to 4 groups independently selected from —OR f , cyano, halo, —C 1-6 alkylOR f , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R f , —C 1-6 alkylC(O)R f , —C(O)OR f , —C 1-6 alkylC(O)OR f , —NR f R g , —C 1-6 alkylNR f R g , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —S(O) 2 R f , —C 1-6 alkylS(O) 2 R f , —S(O) 2 NR f R g , —C 1-6 alkylS(O) 2 NR f R g , —C(O)NR f S(O) 2 R g , and —NR f C(O)R g ;

each R c is independently selected from hydrogen, —OH, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;

each R d is independently selected from hydrogen, —C 1-6 alkyl, —C 3 -C 8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl;

each R e is independently selected from hydrogen, —C 1-6 alkyl, —O—C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —O—C 3-8 cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, —NR f R g , —C 1-6 alkylNR f R g , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —NHS(O) 2 R f , —C 1-6 alkylS(O) 2 R f , and —C 1-6 alkyl S(O) 2 NR f R g ;

each R f is independently selected from hydrogen, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl; and

each R g is independently selected from hydrogen, —C 1-6 alkyl, —C 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C 1-6 alkylaryl, —C 1-6 alkylheteroaryl, and —C 1-6 alkylheterocyclyl.

2. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

X 1 is N, CH, or CZ 3 ;

X 2 is N, CH, or CZ 3 ;

Y 1 is halo or —C 1-6 alkyl;

ring B is

w is 0, 1, or 2;

wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;

x is 0, 1, or 2;

wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;

t is 0, 1, or 2;

wherein the alkyl, alkenyl, alkynyl, C 3-8 cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from oxo, —NO 2 , —N 3 , —OR a , halo, cyano, —NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 cyanoalkyl, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , —S(O) 2 R a , —NR a S(O) 2 R b , —S(O) 2 NR a R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , and —C 3-8 cycloalkyl;

R N is independently —C 1-6 alkylNR 1 R 2 , —OC 1-6 alkylNR 1 R 2 , —C 1-6 alkyl-O—C 1-6 alkylNR 1 R 2 , —NR a C 1-6 alkylNR 1 R 2 , —C 1-6 alkylC(O)NR 1 R 2 , —O—C 1-6 alkylC(O)NR 1 R 2 ,

O—C 1-6 alkylC(O)OR 1 , —SO 1-6 alkylNR 1 R 2 , —C 1-6 alkylOR a , or

wherein:

L 1 is independently a bond, —O—, —NR a —, —S—, —S(O)—, or —S(O) 2 —;

V is independently selected from a bond, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;

wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;

L 2 is independently a bond, —O—, —NR a —, —S—, —S(O)—, or —S(O) 2 —;

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

wherein the alkyl, alkenyl, or alkynyl group is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl;

R E is hydrogen, halo, —OH, —NR 1 C(O)NR 1 R 2 , —C 1-6 alkylOC(O)NR 1 R 2 , —C 1-6 alkylNR 1 C(O)R 2 , —CN, —C 1-9 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 1-8 haloalkyl, C 1-8 alkoxy, or C 3-8 cycloalkyl;

R W is —NR 3 R 2 , —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkyl-O—C 1-6 alkylNR 1 R 2 , —NR a —C 1-6 alkylNR 1 R 2 , —C 1-6 alkylN + R 1 R 2 R 3 , —S—C 1-6 alkyl NR 1 R 2 , —C(O)NR 1 R 2 , —S(O) 2 R a , —(CH 2 ) u S(O) 2 NR 1 R 2 , —(CH 2 ) u NR a S(O) 2 NR a R b , —S(O) 2 NR a C 1-6 alkylNR 1 R 2 , —NR a S(O) 2 C 1-6 alkylNR 1 R 2 , —(CH 2 ) u C(O)NR a S(O) 2 NR a R b , —(CH 2 ) u N + R 1 R 2 O − , —(CH 2 ) u P + R b R c R d , —(CH 2 ) u P + R c R d O − , —(CH 2 ) u P + O[NR a R b ][NR c R d ], —(CH 2 ) u NR c P(O)(OR c ) 2 , —(CH 2 ) u CH 2 OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(OR c )(OR d ), —(CH 2 ) u OP(O)(NR a R b )(OR a ), or

wherein:

V 2 is independently a bond, —O—, —NR a —, —S—, —S(O)—, —S(O) 2 —, —C(O)NR a —, —NR a C(O)—, —S(O) 2 NR 1 —, or —NR a S(O) 2 —;

L 3 is independently a bond, —O—, —NR a —, —S—, —S(O)—, —S(O) 2 —, —C(O)NR a —, —NR a C(O)—, —S(O) 2 NR 1 —, or —NR a S(O) 2 —;

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

T is independently hydrogen, —OR a , —(CH 2 ) q NR 1 R 2 , —(CH 2 ) q NR a C(O)R e , or —(CH 2 ) q C(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

provided that at least one of V 2 , L 3 , ring B′, and T contains a nitrogen atom;

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 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C(O)OR a , —C 1-6 alkylC(O)OR a , —NR a R b , —OC(O)NR a R b , NR a C(O)OR b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C 1-6 alkylS(O) 2 NR a R b , —C(O)NR a S(O) 2 R b , —C 1-6 alkylC(O)NR a S(O) 2 R b , —NR a C(O)R b , and —C 1-6 alkylNR a C(O)R b ;

or R a and R b may combine together to form a heterocyclyl optionally substituted with 1 to 4 groups independently selected from —OR f , cyano, halo, —C 1-6 alkylOR r , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R f , —C 1-6 alkylC(O)R f , —C(O)OR f , —C 1-6 alkylC(O)OR f , —NR f R g , —C 1-6 alkylNR f R g , —C(O)NR f R g , —C 1-6 alkylC(O)NR f R g , —S(O) 2 R f , —C 1-6 alkylS(O) 2 R f , —S(O) 2 NR f R g , —C 1-6 alkylS(O) 2 NR f R g , —C(O)NR f S(O) 2 R g , and —NR f C(O)R g ;

3. The compound of claim 1 , wherein Z 1 and Z 2 are each independently hydrogen, halo, —NH 2 , —OH, cyano, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 1-6 haloalkyl, or —O—C 1-6 alkyl.

4. The compound of claim 1 , wherein Z 1 and Z 2 are each independently hydrogen, halo, or —C 1-6 alkyl.

5. The compound of claim 1 , represented by Formula (IA):

6. The compound of claim 1 , represented by Formula (IB):

7. The compound of claim 2 , represented by Formula (IIA)

8. The compound of claim 1 , represented by Formula (IA-c):

wherein ring C is

9. The compound of claim 1 , represented by Formula (IB-c):

wherein ring C is

10. The compound of claim 2 , represented by Formula (IIA-c):

wherein ring C is

11. The compound of claim 1 , wherein Z 1 is hydrogen, halo, or —C 1-6 alkyl.

12. The compound of claim 1 , wherein t is 1.

13. The compound of claim 1 , wherein Z 3 is hydrogen, halo, —OH, cyano, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C 1-6 haloalkyl, —O—C 1-6 alkyl or —C 3-8 cycloalkyl.

14. The compound of claim 1 , wherein R E is hydrogen, —OH, —NR 1 C(O)NR 1 R 2 , —C 1-6 alkylOC(O)NR 1 R 2 , or —C 1-6 alkylNR 1 C(O)R 2 .

15. The compound of claim 1 , wherein R E is hydrogen.

16. The compound of claim 1 , wherein each Z 1 is independently halo.

17. The compound of claim 1 , wherein Z 3 is halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —O—C 1-6 cyanoalkyl, —O—C 1-6 haloalkyl, or —O—C 1-6 alkyl.

18. The compound of claim 1 , wherein Z 3 is of the formula:

V is independently selected from a bond, C 1-6 alkyl, C 2-6 alkenyl, and

C 2-6 alkynyl;

wherein each alkyl, alkenyl, or alkynyl is optionally independently substituted with —OR a , halo, cyano, —NR a R b , or —C 3-8 cycloalkyl; and

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, —NO 2 , —N 3 , —OR a , halo, cyano, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —O—C 1-6 haloalkyl, NR a R b , —C(O)R a , —C(O)OR a , —O—C 1-6 alkylCN, —C(O)NR a R b , —NR a C(O)R a , —NR a C(O)OR a , —C(O)N(R a )OR b , —S(O) 2 R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —NR a S(O) 2 NR a R b , —C(O)NR a S(O) 2 NR a R b , —C 3-8 cycloalkyl, and —C 1-6 alkylC 3-8 cycloalkyl.

19. The compound of claim 1 , wherein R W is —C 1-6 alkylNR 1 R 2 , where R 1 and R 2 combine to form a heterocyclyl optionally substituted with 1 to 3 groups independently selected from oxo, —C 1-6 alkyl, —C 3-8 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OR a , —C(O)OR a , —C 1-6 cyanoalkyl, —C 1-6 alkylOR a , —C 1-6 haloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C(O)N═S(O)R a NR a R b , —C(O)N═S(O)R a NR a C(O)R b , and —C 1-6 alkylS(O) 2 NR a R b ; or —C 1-6 alkylNR 1 R 2 , where R 1 is hydrogen and R 2 is —C 1-6 alkylheteroaryl or —C 1-6 alkylheterocyclyl.

20. The compound of claim 1 , wherein R W is —C 1-6 alkylNR 1 R 2 .

21. The compound of claim 1 , wherein R E is hydrogen and R W is —C 1-6 alkylNR b R 2 .

22. The compound of claim 20 , wherein R 1 and R 2 combine to form a heterocyclyl optionally substituted with 1 to 3 groups independently selected from oxo, —C 1-6 alkyl, —C 3-8 cycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OR a , —C(O)OR a , —C 1-6 cyanoalkyl, —C 1-6 alkylOR a , —C 1-6 haloalkyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —C 1-6 alkylC(O)OR a , —NR a R b , —C 1-6 alkylNR a R b , —C(O)NR a R b , —C 1-6 alkylC(O)NR a R b , —S(O) 2 R a , —C 1-6 alkylS(O) 2 R a , —S(O) 2 NR a R b , —C(O)N═S(O)R a NR a R b , —C(O)N═S(O)R a NR a C(O)R b , and —C 1-6 alkylS(O) 2 NR a R b .

23. The compound of claim 1 , wherein R 1 is hydrogen and R 2 is —C 1-6 alkylheteroaryl.

24. The compound of claim 1 , wherein R 1 is hydrogen and R 2 is —C 1-6 alkylheterocyclyl.

25. A compound, or a pharmaceutically acceptable salt thereof, selected from:

and

26. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26 , further comprising at least one additional anticancer agent.

28. The pharmaceutical composition according to claim 27 , wherein the additional anticancer agent is rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, atezolizumab, or ipilimumab.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 12, 2019

From: DU, ZHIMIN; GRAUPE, MICHAEL; MACHICAO TELLO, PAULO A.; MEDLEY, JONATHAN WILLIAM; METOBO, SAMUEL E.; PARKHILL, ERIC Q.; PHILLIPS, BARTON W.; SIMONOVICH, SCOTT P.; WANG, PEIYUAN; XU, JIE; ZIEBENHAUS, CHRISTOPHER A.

To: GILEAD SCIENCES, INC.

Reel/Frame 050984/0013 →

Continuity (2)

Provisional Application 62750209 · Oct 24, 2018

Related Publication 20200157094A1 · May 21, 2020