Modulators of stimulator of interferon genes (STING)

Patent metadata

Field	Value
Publication number	US-11377440-B2
Application number	US-201816652221-A
Country	US
Kind code	B2
Filing date	Oct 4, 2018
Priority date	Oct 5, 2017
Publication date	Jul 5, 2022
Grant date	Jul 5, 2022

Abstract

Disclosed are compounds having the formula: (I) wherein q, r, s, A, B, C, RA1, RA2, RB1, RB2, RC1, RC2, R3, R4, R5, R6, R14, R15, R16, R17, Rx, and Ry are as defined herein, or a tautomer thereof, or a salt, particularly a pharmaceutically acceptable salt, thereof.

First claim

What is claimed is:

1. A compound according to Formula (I):

wherein:
q is 0 or 1;
r is 0 or 1;
s is 0 or 1;
wherein q+r+s=1 or 2;

when q is 0, R A1 and R A2 are each independently H, halogen, hydroxy, —O—P(O)(OH) 2 , —O—P(O)(R I )(R II ), —N(R e )(R f ), —CO 2 R f , —N(R f )COR b , —N(R g )SO 2 (C 1 -C 4 alkyl)-N(R e )(R f ), —N(R g )CO(C 1 -C 4 alkyl)-N(R h )(R f ), optionally substituted (C 1 -C 6 alkyl), optionally substituted (C 1 -C 6 alkyl)oxy-, optionally substituted (C 1 -C 6 alkyl)amino-, and optionally substituted (C 1 -C 6 alkyl)(C 1 -C 4 alkyl)amino-,
wherein the (C 1 -C 6 alkyl) of said optionally substituted (C 1 -C 6 alkyl), optionally substituted (C 1 -C 6 alkyl)oxy-, optionally substituted (C 1 -C 6 alkyl)amino- and optionally substituted (C 1 -C 6 alkyl)(C 1 -C 4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, —O—P(O)(OH) 2 , —O—P(O)(R I )(R II ), C 1 -C 4 alkoxy-, —N(R e )(R f ), —CO 2 (R), —CON(R e )(R f ), optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from C 1 -C 4 alkyl, halogen, hydroxy, —O—P(O)(OH) 2 , —O—P(O)(R I )(R II ), amino, (C 1 -C 6 alkyl)amino-, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amino-, —(C 1 -C 6 alkyl)-NH 2 , halo(C 1 -C 6 alkyl), hydroxy-(C 1 -C 4 alkyl)-, —(C 1 -C 4 alkyl)-O—P(O)(OH) 2 , —(C 1 -C 4 alkyl)-O—P(O)(R I )(R II ), halo(C 1 -C 4 alkoxy)-, C 1 -C 4 alkoxy-, hydroxy-(C 2 -C 4 alkoxy)-, —(C 2 -C 4 alkoxy)-O—P(O)(OH) 2 , —(C 2 -C 4 alkoxy)-O—P(O)(R I )(R II ), —C 1 -C 4 alkyl-(C 1 -C 4 alkoxy) and C 1 -C 4 alkoxy-(C 1 -C 4 alkoxy)-;

when r is 0, R B1 and R B2 are each independently H, optionally substituted C 1 -C 6 alkyl, halo(C 1 -C 6 alkyl), optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl,
wherein said optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, —R c , —OH, —O—P(O)(OH) 2 , —O—P(O)(R I )(R II ), —OR c , —NH, —NR c R c , —NR c R d , —OCOR c , —CO 2 H, —CO 2 R c , —SOR c , —SO 2 R c , —CONH 2 , —CONR c R d , —SO 2 NH 2 , —SO 2 NR c R d , —OCONH 2 , —OCONR c R d , —NR d COR c , —NR d SOR c , —NR d CO 2 R c , and —NR d SO 2 R c ;

when s is 0, R C1 is H, halogen, or C 1 -C 4 alkyl and R C2 is optionally substituted C 1 -C 4 alkyl, wherein said optionally substituted C 1 -C 4 alkyl group is optionally substituted by a substituent selected from —OR, —NR c R d , —CO 2 R c , —CONR c R d , —SO 2 NR c R d , and —OCONR c R d ;
when q is 1, R A1 and R A2 are each independently —CH 2 —, —NR e —, or —O—, and A, taken together with R A1 and R A2 , forms a linking group, wherein A is -halo(C 1 -C 12 alkyl)-, optionally substituted —C 1 -C 12 alkyl-, optionally substituted —C 2 -C 12 alkenyl-, optionally substituted —C 2 -C 12 alkynyl-, optionally substituted —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-NR a —C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-(C 3 -C 6 cycloalkyl)-C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-phenyl-C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-(4-6 membered heterocycloalkyl)-C 1 -C 6 alkyl-, or optionally substituted —C 1 -C 6 alkyl-(5-6 membered heteroaryl)-C 1 -C 6 alkyl-,
wherein the alkyl moiety of said optionally substituted —C 1 -C 12 alkyl-, optionally substituted —C 2 -C 12 alkenyl-, optionally substituted —C 2 -C 12 alkynyl-, optionally substituted —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-NR a —C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-(C 3 -C 6 cycloalkyl)-C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-phenyl-C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-(4-6 membered heterocycloalkyl)-C 1 -C 6 alkyl-, or optionally substituted —C 1 -C 6 alkyl-(5-6 membered heteroaryl)-C 1 -C 6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, halo(C 1 -C 4 alkyl), —OH, —O—P(O)(OH) 2 , —O—P(O)(R I )(R II ), —OR c , —NH 2 , —NR c R d , —OCOR c , —CO 2 H, —CO 2 R c , —SOR c , —SO 2 R c , —CONH 2 , —CONR c R d , —SO 2 NH 2 , —SO 2 NR c R d , —OCONH 2 , —OCONR c R d , —NR d COR c , —NR d SOR c , —NR d CO 2 R c , and —NR d SO 2 R c ,
and
the C 3 -C 6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted —C 1 -C 6 alkyl-(C 3 -C 6 cycloalkyl)-C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-phenyl-C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-(4-6 membered heterocycloalkyl)-C 1 -C 6 alkyl-, or optionally substituted —C 1 -C 6 alkyl-(5-6 membered heteroaryl)-C 1 -C 6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, —O—P(O)(OH) 2 , —O—P(O)(R I )(R II ), amino, (C 1 -C 4 alkyl)amino-, (C 1 -C 4 alkyl)(C 1 -C 4 alkyl)amino-, C 1 -C 4 alkyl, halo(C 1 -C 4 alkyl), halo(C 1 -C 4 alkoxy)-, C 1 -C 4 alkoxy-, hydroxy-(C 1 -C 4 alkoxy)-, —(C 1 -C 4 alkoxyl)-O—P(O)(OH) 2 , —(C 1 -C 4 alkoxyl)-O—P(O)(R I )(R II ), and C 1 -C 4 alkoxy-(C 1 -C 4 alkoxy);

when r is 1, R B1 and R B2 are each independently —CR d R f —, and B, taken together with R B1 and R B2 , forms a linking group, wherein B is a bond or B is -halo(C 1 -C 10 alkyl)-, optionally substituted —C 1 -C 10 alkyl-, optionally substituted —C 2 -C 10 alkenyl-, optionally substituted —C 2 -C 10 alkynyl-, optionally substituted —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-NR a —C 1 -C 6 alkyl-, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted —C 1 -C 4 alkyl-(C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl-, optionally substituted —C 1 -C 4 alkyl-phenyl-C 1 -C 4 alkyl-, optionally substituted —C 1 -C 4 alkyl-(4-6 membered heterocycloalkyl)-C 1 -C 4 alkyl-, or optionally substituted —C 1 -C 4 alkyl-(5-6 membered heteroaryl)-C 1 -C 4 alkyl-,
wherein the alkyl moiety of said optionally substituted —C 1 -C 10 alkyl-, optionally substituted —C 2 -C 10 alkenyl-, optionally substituted —C 2 -C 10 alkynyl-, optionally substituted —C 1 -C 6 alkyl-O—C 1 -C 6 alkyl-, optionally substituted —C 1 -C 6 alkyl-NR a —C 1 -C 6 alkyl-, optionally substituted —C 1 -C 4 alkyl-(C 3 -C 6 cycloalkyl)-C 1 -C 4 alkyl-, optionally substituted —C 1 -C 4 alkyl-phenyl-C 1 -C 4 alkyl-, optionally substituted —C 1 -C 4 alkyl-(4-6 membered heterocycloalkyl)-C 1 -C 4 alkyl-, or optionally substituted —C 1 -C 4 alkyl-(5-6 membered heteroaryl-C 1 -C 4 alkyl)- is optionally substituted by 1-4 substituents each independently selected from —C 1 -C 4 alkyl, halogen, halo(C 1 -C 4 alkyl), —OH, —O—P(O)(OH) 2 , —O—P(O)(R I )(R II ), —OR c , —NH 2 , —NR c R d , —OCOR c , —CO 2 H, —CO 2 R c , —SOR c , —SO 2 R c , —CONH 2 , —CONR c R d , —SO 2 NH 2 , —SO 2 NR c R d , —OCONH 2 , —OCONR c R d , —NR d COR c , —NR d SOR c , —NR d CO 2 R c , and —NR d SO 2 R c ,
and
the C 3 -C 6 cyc

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Fosbenner David T
• Graybill Todd L
• Kang Jianxing
• King Bryan W
• Lan Yunfeng
• Leister Lara Kathryn
• Mahajan Mukesh K
• Mehlmann John F
• Morales-Ramos Angel I
• Pesiridis George Scott
• Ramanjulu Joshi M
• Romano Joseph J
• Romeril Stuart Paul
• Schulz Mark J
• Zhou Huiqiang
• Qu Junya

Classifications

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title