Bicyclic CX3CR1 receptor agonists
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.
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 with the carbon to which R 2 and R 3 attach, forms a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furan-3-yl, pyran-3-yl, and pyran-4-yl, any 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.
20. The method as recited in claim 11 , wherein R 5 and R 6 are each independently C 1 -C 3 alkyl.
21. The method as recited in claim 11 , or a stereoisomer thereof, of a wherein 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.
22. The method as recited in claim 11 , wherein X is chosen from C, O, or NH.
23. The method as recited in claim 11 , wherein
X is chosen from C, O, and NR 11 ; and
R 11 is C 1 -C 3 alkyl.
24. The method as recited in claim 1 , wherein:
n is a number between 1 and 4, forming a 6-10-membered cycloalkyl;
A is 3-methylthiophene;
R 1 is chosen from hydrogen and methyl;
R 2 and R 3 are independently 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 chosen from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furan-3-yl, pyran-3-yl, and pyran-4-yl, any 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, methyl, and C 1 -C 3 alkyloxy, optionally substituted with methoxy;
p is 1 or 2; and
X is chosen from C, O, and NR 11 ; and
R 11 is C 1 -C 3 alkyl.
25. 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 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 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 R 5 and R 6 are not both methyl.
26. The method as recited in claim 25 , wherein A is thiophene.
27. The method as recited in claim 25 , wherein A is 3-methylthiophene.
28. The method as recited in claim 25 , wherein R 1 is chosen from hydrogen and methyl.
29. The method as recited in claim 25 , wherein R 5 and R 6 are each independently C 1 -C 3 alkyl.
30. The method as recited in claim 25 , 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.
31. The method as recited in claim 25 , wherein X is chosen from C, O, or NH.
32. The method as recited in claim 25 , 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 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.
33. The method of claim 1 , wherein the compound is chosen from any one of
or a stereoisomer thereof, or a salt thereof.
34. The method as recited in claim 1 , wherein the neurodegenerative disorder is Alzheimer's Disease.