Toll-like receptor antagonist compounds and methods of use

Patent metadata

Field	Value
Publication number	US-12378255-B2
Application number	US-202318484588-A
Country	US
Kind code	B2
Filing date	Oct 11, 2023
Priority date	Nov 11, 2016
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

The invention relates to compounds of formula (I):

or a salt or solvate thereof, wherein the variables are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are antagonists of toll-like receptors such as TLR7, TLR8 and/or TLR9 that are useful for inhibiting immune response and treating diseases associated with undesirable immune response.

First claim

The invention claimed is:

1. A method of inhibiting the production of a cytokine in a subject in need thereof, comprising:
administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein:
A 1 is C or N;
A 2 is CR 2 , N, or NR 2a ;
A 3 is CR 30 , N, or NR 3a ;
A 4 is N or CR 4 ;
A 5 is N or CR 5 ;
provided that two, three, or four of A 1 , A 2 , A 3 , A 4 , and A 5 are N; wherein the dashed lines indicate partial or delocalized bonds in an aromatic ring;
i and j are independently 0, 1, or 2;
R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;
each R 2 , R 3 , R 30 , R 4 , and R 5 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;
each R 2a and R 3a is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;
each R 6 , where present, is independently C 1 -C 6 alkyl optionally substituted by R 10A ;
n is 0, 1, 2, 3, or 4;
U is a bond or methylene optionally substituted by R 10 ;
V is a bond or C 1 -C 2 alkylene optionally substituted by R 10 ;
W is a bond or C 1 -C 4 alkylene optionally substituted by one or both of R W1 and R W2 ;
X is —CR X1 R X2 —;
Y is —CR Y1 R Y2 —;
R 7 is hydrogen, C 1 -C 6 alkyl, or taken together with R 8 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R X1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 ;
R 8 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 , C 6 -C 14 aryl, 5-10-membered heteroaryl, or taken together with R 7 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R X1 , R X2 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R 10 , where present, to form a C 1 -C 6 alkylene, or taken together with R 9 and the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;
R 9 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 , or taken together with R 8 and the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;
R W1 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 , or R Y1 to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R W2 , R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;
R W2 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R W1 , R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;
R X1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R Y1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;
R X2 is hydrogen or C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R X1 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R 8 to form a C 1 -C 6 alkylene optionally substituted by R 10 ;
R Y1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;
R Y2 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R 8 to form a C 1 -C 6 alkylene optionally substituted by R 10 ;
each R 10 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -C 14 aryl, halogen, —CN, —OR 11 , —SR 11 , —NR 12 R 13 , —NO 2 , —C═NH(OR 11 ), —C(O) R 11 , —OC(O) R 11 , —C(O)OR 11 , —C(O) NR 12 R 13 , —NR 11 C(O) R 12 , —NR 11 C(O) OR 12 , —NR 11 C(O) NR 12 R 13 , —S(O) R 11 , —S(O) 2 R 11 , —NR 11 S(O) R 12 , —NR 11 S(O) 2 R 12 , —S(O) NR 12 R 13 , —S(O) 2 NR 12 R 13 , or —P(O) (OR 12 ) (OR 13 ); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered

Assignees

• Dynavax Tech Corp

Inventors

• Candia Iii Albert Frederick
• Beresis Richard Thomas
• Coffman Robert L

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D235/18

  with aryl radicals directly attached in position 2 · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/00

  Antineoplastic agents · CPC title