PD-1/PD-L1 inhibitors

Patent metadata

Field	Value
Publication number	US-10899735-B2
Application number	US-201916388517-A
Country	US
Kind code	B2
Filing date	Apr 18, 2019
Priority date	Apr 19, 2018
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

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.

First claim

The invention claimed is:

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

X is CH, CZ 3 , or N;
each Z 1 is independently halo, —OR a , —SR a , —NO 2 , —CN, —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;
wherein each alkyl, alkenyl, alkynyl, and cycloalkyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of oxo, —NO 2 , —N 3 , —OR a , halo, and cyano;

each Z 3 is independently halo, oxo, —OR a , N 3 , NO 2 , —CN, —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 3-8 cycloalkyl, —C 1-6 alkylC 3-8 cycloalkyl, aryl, heteroaryl, heterocyclyl and R N ;
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 the group consisting of 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 alkylCN, —CONR a R b , NR a COR 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;

each R N is independently —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOC 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 , —S—C 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 the group consisting of a bond, C 1-6 alkyl,
C 2-6 alkenyl, and C 2-6 alkynyl;
L 2 is independently a bond, O, NR a , S, S(O), or S(O) 2 ;
wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —OR a , halo, cyano, NR a R b and —C 3-8 cycloalkyl;

ring A is cycloalkyl, aryl, heteroaryl, or heterocyclyl;
wherein the cycloalkyl, aryl, heteroaryl, or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of 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, —CONR a R b , —NR a COR a , —NR a C(O)OR 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;
wherein the alkyl, alkenyl or alkynyl group is optionally independently substituted with —OR a , halo, cyano, NR a R b and —C 3-8 cycloalkyl;

R E and R W are each independently —NR 1 R 2 , —C 1-6 alkylNR 1 R 2 , —O—C 1-6 alkylNR 1 R 2 , —C 1-6 alkylOC 1-6 alkylNR 1 R 2 , —C 1-6 alkylNR a 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 , —NR 1 C(O)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 , —(CH 2 ) u NR a N(R a )NR a R b , —(CH 2 ) u C(O)NR 1 R 2 , —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 cycloalkyl, aryl, heteroaryl or heterocyclyl;
T is independently H, —OR a , (CH 2 ) q NR 1 R 2 , (CH 2 ) q S(O) 2 R e , (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 2-6 alkenyl, —C 1-6 haloalkyl, —C 1-6 cyanoalkyl, —C 1-6 alkylNR a R b , —C 1-6 alkylOH, —C 3-8 cycloalkyl, —C 1-3 alkylC 3-8 cycloalkyl and —C 1-6 alkylheterocyclylCN;
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 the group consisting of H, —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 , —CONR a S(O) 2 R a , and C 1-6 alkylC 3-8 cycloalkyl;
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 —OR a , —CN, halo, C 1-6 alkyl, —C 1-6 alkylOR a , —C 1-6 cyanoalkyl, —C 1-6 haloalkyl, C 3-8 cycloalkyl, heteroaryl, heterocyclyl, —C 1-3 alkylC 3-8 cycloalkyl, —C(O)R a , —C 1-6 alkylC(O)R a , —O—C 1-6 alkylC(O)NR a R b , —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 , —NR a C(O)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 , —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 the group consisting of H, —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, cycloalkyl, aryl, heteroaryl or heterocyclyl group is optionally substituted with 1 to 4 groups independently selected from the group consisting of —OR a , —CN, 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 , —CONR a R b , C 1-6 alkylCONR 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 , —CONR a S(O) 2 R b and —NR a C(O)R b ;

or R 1 and R 2 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 halo, oxo, —C 1-6 alkyl, —C 3-8 cycloalkyl, heteroaryl, heterocyclyl, —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

Assignees

• Gilead Sciences Inc

Inventors

• Aktoudianakis Evangelos
• Cho Aesop
• Du Zhimin
• Graupe Michael
• Lad Lateshkumar Thakorlal
• Machicao Tello Paulo A
• Medley Jonathan William
• Metobo Samuel E
• Mukherjee Prasenjit Kumar
• Naduthambi Devan
• Parkhill Eric Q
• Phillips Barton W
• Simonovich Scott Preston
• Squires Neil H
• Wang Peiyuan
• Watkins William J
• Xu Jie
• Yang Kin Shing
• Ziebenhaus Christopher Allen

Classifications

• C07K16/40

  against enzymes · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• C07D491/10

  Spiro-condensed systems · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title