Bicyclic CX3CR1 receptor agonists

Patent metadata

Field	Value
Publication number	US-11958839-B2
Application number	US-202117481653-A
Country	US
Kind code	B2
Filing date	Sep 22, 2021
Priority date	Jul 23, 2019
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

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 method of treatment of a neurodegenerative disorder chosen from Alzheimer's disease, Lewy body dementia, fronto-temporal dementia, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, HIV-induced neuroinflammation, essential tremors, and Charcot-Marie-Tooth neuropathy comprising the administration of a therapeutically effective amount of a compound of the following formula (I)

or a stereoisomer thereof, or a salt thereof, to a subject in need thereof,
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 chosen from hydrogen and C 1 -C 3 alkyl;
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, wherein 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 method as recited in claim 1 , wherein A is thiophene.

3. The method as recited in claim 1 , wherein R 1 is chosen from hydrogen and methyl.

4. The method as recited in claim 3 , wherein R 2 and R 3 are independently chosen from hydrogen, methyl, ethyl, and phenyl; or R 2 and R 3 are joined together via a group Y, wherein R 2 —Y—R 3 , together with the carbon to which R 2 and R 3 attach, forms C 3 -C 6 cycloalkyl or heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, fluorine, and methyl; 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.

5. The method as recited in claim 4 , wherein R 2 and R 3 are independently chosen from hydrogen, methyl, ethyl, and phenyl.

6. The method as recited in claim 4 , wherein R 2 and R 3 are joined together via a group Y, wherein R 2 —Y—R 3 , together with the carbon to which R 2 and R 3 attach, forms C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, fluorine, and methyl; or the C 3 -C 6 cycloalkyl or C 3 -C 6 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.

7. The method as recited in claim 4 , wherein R 5 and R 6 are each independently C 1 -C 3 alkyl.

8. The method as recited in claim 4 , wherein R 7 , R 8 , R 9 , and R 10 are independently hydrogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, optionally substituted with methoxy.

9. The method as recited in claim 4 , wherein X is chosen from C, O, or NH.

10. The method as recited in claim 1 , wherein:
n is a number between 1 and 4, forming a 6-10-membered cycloalkyl;
A is thiophene;
R 1 is chosen from hydrogen and methyl;
R 2 and R 3 are independently chosen from hydrogen, methyl, ethyl, and phenyl; or R 2 and R 3 are joined together via a group Y, wherein R 2 —Y—R 3 , together with the carbon to which R 2 and R 3 attach, forms C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, fluorine, and methyl; or the C 3 -C 6 cycloalkyl or C 3 -C 6 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 independently C 1 -C 3 alkyl;
R 7 , R 8 , R 9 , and R 10 are independently chosen from hydrogen, hydroxyl, C 1 -C 3 alkyl, and C 1 -C 3 alkoxy, optionally substituted with methoxy;
p is 1 or 2; and
X is chosen from C, O, or NR 11 ; and
R 11 is C 1 -C 3 alkyl.

11. The method as recited in claim 1 , wherein A is 3-methylthiophene.

12. The method as recited in claim 11 , wherein R 1 is chosen from hydrogen and methyl.

13. The method as recited in claim 11 , wherein R 2 and R 3 are independently chosen from hydrogen, methyl, ethyl, and phenyl; or R 2 and R 3 are joined together via a group Y, wherein R 2 —Y—R 3 , together with the carbon to which R 2 and R 3 attach, forms a C 3 -C 6 cycloalkyl or C 3 -C 6 heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, fluorine, and methyl; or the C 3 -C 6 cycloalkyl or C 3 -C 6 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.

14. The method as recited in claim 11 , wherein R 2 and R 3 are independently chosen from hydrogen, methyl, ethyl, and phenyl.

15. The method as recited in claim 11 , wherein R 2 and R 3 are joined together via a group Y, wherein R 2 —Y—R 3 , together with the carbon to which R 2 and R 3 attach, forms C 3 -C 6 cycloalkyl or heterocycloalkyl, either of which is optionally substituted with one or more substituents chosen from hydroxyl, fluorine, and methyl; or the C 3 -C 6 cycloalkyl or C 3 -C 6 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.

16. The method as recited in claim 11 , wherein either:
R 2 is hydrogen and R 3 is methyl or phenyl; or
R 2 and R 3 are both methyl or both ethyl.

17. The method as recited in claim 16 , wherein R 2 is hydrogen and R 3 is methyl or phenyl.

18. The method as recited in claim 16 , wherein R 2 and R 3 are both methyl or ethyl.

19. The method as recited in claim 11 , wherein
Y is chosen from C and O; and
R 2 and R 3 are joined together via the group Y, wherein the group R 2 —Y—R 3 , together wit

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

• C07D409/14 Primary

  containing three or more hetero 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

• C07D333/78 Primary

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

• C07D409/12 Primary

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

• C07D333/80

  Seven-membered rings · CPC title