Aryl hydrocarbon receptor activators

Patent metadata

Field	Value
Publication number	US-12473262-B2
Application number	US-202017630763-A
Country	US
Kind code	B2
Filing date	Jul 30, 2020
Priority date	Jul 30, 2019
Publication date	Nov 18, 2025
Grant date	Nov 18, 2025

Abstract

Small molecule AhR ligands are disclosed. The ligands can induce the differentiation of Tr1 cells to suppress pathogenic immune responses without inducing nonspecific immune suppression. Methods of treatment of autoimmune diseases using the AhR ligands are also disclosed.

First claim

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1 . A compound of the formula:

or a tautomer thereof, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein:
Q 1 is an optionally substituted C6-C10 aryl; optionally substituted C5-C10 heteroaryl; optionally substituted C5-C10 heterocyclyl; optionally substituted C1-C10 alkyl, or optionally substituted C3-C10 cycloalkyl;
Z is C;
R 1 is H or halogen;
R 2 , R 3 , and R 4 are independently H, halogen, CN, optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C1-C6 alkoxy, SO 2 R 5 , CO 2 R 5 , or CONR 5 R 6 , or any one of R 1 and R 2 , R 2 and R 3 , and R 3 and R 4 pairs, together with the carbon atoms to which they are attached, forms an optionally substituted a five- or six-membered cycloalkenyl, heterocyclenyl, aryl or heteroaryl;
R 5 and R 6 are independently H, optionally substituted C1-C10 alkyl, or optionally substituted C3-C10 cycloalkyl, or R 5 and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted 5-membered ring or an optionally substituted 6-membered ring;
R 7 , at each occurrence, is independently H, halogen, CN, optionally substituted C1-C10 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C1-C10 heteroalkyl, optionally substituted C1-C10 heterocyclyl, optionally substituted C6-C10 aryl, optionally substituted C5-C10 heteroaryl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 cycloalkyloxy, OCF 3 , NR 5 R 6 , SCF 3 , or C(O)NR 5 R 6 ; and
m is an integer from 1 to 7.

2 . The compound of claim 1 , wherein Q 1 is an optionally substituted phenyl, an optionally substituted naphthyl, an optionally substituted optionally substituted C3-C6 cycloalkyl or an optionally substituted quinolinyl.

3 . The compound of claim 2 , wherein Q 1 is a phenyl optionally substituted with one, two, or three substituents independently selected from F, Cl, Br, OCH 3 , CN, OCF 3 , SCF 3 , t-Bu, NMe 2 , CONH 2 , piperazyl, piperidyl, OCH 2 CH 2 OH, OCH 2 CH 2 NMe 2 , and 1-naphthyl.

4 . The compound of claim 1 , wherein R 4 is H or halogen.

5 . The compound of claim 1 , wherein all R 7 are H.

6 . A compound of the formula:

or a tautomer thereof, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof,
wherein R 2 and R 3 , independently, F, Cl, Br, O(C1-C5 alkyl), SCF 3 , OCF 3 , CO 2 H, CO 2 (C1-C5 alkyl), or CONR 5 R 6 , wherein R 5 and R 6 are independently H, optionally substituted C1-C10 alkyl, optionally substituted C3-C10 cycloalkyl, or R 5 and R 6 , together with the nitrogen atom to which they are attached, form an optionally substituted morpholinyl; and
Q 1 is an optionally substituted C6-C10 aryl; optionally substituted C5-C10 heteroaryl; optionally substituted C5-C10 heterocyclyl; optionally substituted C1-C10 alkyl, or optionally substituted C3-C10 cycloalkyl; Z is C.

7 . The compound of claim 6 , wherein Q 1 is a phenyl, cyclopropyl, naphthyl, benzodioxanyl, or quinolinyl, each of which is optionally substituted with one, two, or three substituents independently selected from the group consisting of F, Cl, Br, CF 3 , SCF 3 , CN, and OCH 3 .

8 . The compound of claim 1 , or a tautomer thereof, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

9 . A pharmaceutical composition comprising a compound of claim 1 , or a hydrate thereof, or a pharmaceutically acceptable salt thereof.

10 . A pharmaceutical composition comprising a compound of claim 6 , or a hydrate thereof, or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Oregon State

Inventors

• Kolluri Siva Kumar
• Kerkvliet Nancy I
• Bernales Sebastian
• Chakravarty Jit
• Pujala Brahmam
• Khan Pasha
• Kumar Varun
• Danodia Abhinandan
• Ureta Gonzalo

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/16

  Peri-condensed systems · CPC title

• C07D471/06

  Peri-condensed systems · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title