Bicyclic CX3CR1 receptor agonists

Patent metadata

Field	Value
Publication number	US-12258337-B2
Application number	US-202318470029-A
Country	US
Kind code	B2
Filing date	Sep 19, 2023
Priority date	Jul 23, 2019
Publication date	Mar 25, 2025
Grant date	Mar 25, 2025

Abstract

Disclosed herein are novel cycloalka[b]heteroaryl compounds having CX3CR1/fractalkine receptor (CX3CR1) agonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds and their use in the treatment or prophylaxis of diseases associated with CX3CR1 receptor activity in animals, in particular humans.

First claim

What is claimed is:

1. A process of making a compound of structural formula (I)

comprising reacting a compound of structural formula (IX)

with a hydride in a solvent, wherein
n is an integer between 1 and 4, forming a 6-10-membered cycloalkyl;
A is chosen from phenyl and heteroaryl, optionally substituted with one or more C 1 -C 3 alkyl substituents;
R 1 is hydrogen;
R 2 and R 3 are independently chosen from hydrogen, phenyl, and C 1 -C 6 alkyl; or R 2 and R 3 are joined together via a group Y, such that R 2 -Y-R 3 , together with the carbon to which R 2 and R 3 attach, forms C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, halogen, and C 1 -C 6 alkyl; or the C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl is fused with a phenyl ring which is optionally substituted with one or more substituents chosen from hydroxyl, halogen, and C 1 -C 6 alkyl;
Y is chosen from C and O;
R 4 is chosen from

R 5 and R 6 are each independently C 1 -C 6 alkyl;
R 7 , R 8 , R 9 , and R 10 are independently chosen from hydrogen and hydroxyl, or is independently chosen from C 1 -C 6 alkyl and C 1 -C 6 alkyloxy, either of which is optionally substituted with methoxy;
p is 1 or 2; and
X is chosen from C, O, or NR 11 where R 11 is hydrogen or C 1 -C 3 alkyl;
with the proviso that if A is thiophene, n is 2 or 3, R 1 is hydrogen, and R 4 is

then either R 5 and R 6 are not both methyl, and/or R 2 and R 3 are not both methyl, and further provided that if A is thiophene, n is 2 or 3, R 1 is hydrogen, and R 4 is

then R 2 and R 3 are not hydrogen.

2. The process of claim 1 , wherein the solvent is THF.

3. The process of claim 1 , wherein the hydride is LiAlH 4 .

4. The process of claim 1 , wherein the reaction is carried out at room temperature.

5. A process of making a compound of structural formula (I)

comprising reacting a compound of structural formula (II)

with a compound of structural formula (III)

wherein
n is an integer between 1 and 4, forming a 6-10-membered cycloalkyl;
A is chosen from phenyl and heteroaryl, optionally substituted with one or more C 1 -C 3 alkyl substituents;
R 1 is hydrogen;
R 2 and R 3 are independently chosen from hydrogen, phenyl, and C 1 -C 6 alkyl; or R 2 and R 3 are joined together via a group Y, such that R 2 -Y-R 3 , together with the carbon to which R 2 and R 3 attach, forms C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, halogen, and C 1 -C 6 alkyl; or the C 3 -C 7 cycloalkyl or C 3 -C 7 heterocycloalkyl is fused with a phenyl ring which is optionally substituted with one or more substituents chosen from hydroxyl, halogen, and C 1 -C 6 alkyl;
Y is chosen from C and O;
R 4 is chosen from

R 5 and R 6 are each independently C 1 -C 6 alkyl;
R 7 , R 8 , R 9 , and R 10 are independently chosen from hydrogen and hydroxyl, or is independently chosen from C 1 -C 6 alkyl and C 1 -C 6 alkyloxy, either of which is optionally substituted with methoxy;
p is 1 or 2; and
X is chosen from C, O, or NR 11 where R 11 is hydrogen or C 1 -C 3 alkyl;
with the proviso that if A is thiophene, n is 2 or 3, R 1 is hydrogen, and R 4 is

then either R 5 and R 6 are not both methyl, and/or R 2 and R 3 are not both methyl, and further provided that if A is thiophene, n is 2 or 3, R 1 is hydrogen, and R 4 is

then R 2 and R 3 are not hydrogen.

6. The process of claim 5 , wherein the reaction is carried out in a reaction-inert solvent.

7. The process of claim 6 , wherein the reaction-inert solvent is chosen from CH 2 Cl 2 , THF, and toluene.

8. The process of claim 5 , wherein the reaction is carried out in the presence of a suitable coupling reagent.

9. The process of claim 8 , wherein the suitable coupling reagent is chosen from CDI, HATU, PyBOP, and SOCl 2 .

10. The process of claim 5 , wherein the reaction is carried out in the presence of a suitable base.

11. The process of claim 10 , wherein the suitable base is chosen from TEA and DBU.

12. The process of claim 5 , wherein the reaction is carried out at a temperature between room temperature and the reflux temperature of the reaction mixture.

13. The process of claim 12 , further comprising converting the compound of formula (I) into an addition salt thereof.

Assignees

• Univ Texas
• Golgi Neurosciences S R L

Inventors

• Pevarello Paolo
• Ray William J
• Hamby Mary
• Lightfoot Yaima Luzardo
• Jones Philip
• Thomas Russell
• Liberati Chiara
• Torino Domenica
• Cusano Valentina
• Piscitelli Francesco
• Yousif Ali Munaim
• Bovolenta Silvia

Classifications

• C07D409/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D333/78 Primary

  condensed with rings other than six-membered or with ring systems containing such rings · CPC title

• C07C233/78

  with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom · CPC title

• C07D333/80

  Seven-membered rings · CPC title

• C07D409/14 Primary

  containing three or more hetero rings · CPC title