Heteroaryl compounds and therapeutic uses thereof in conditions associated with the alteration of the activity of beta-glucocerebrosidase
The application is directed to compounds of formulae (IA) and (IB) and their salts and solvates, wherein R 1a , R 2a , R 3a , A 1 , A 2 , A 3 , R 1b , R 2b , R 3b , B 1 , and B 2 are as set forth in the specification, as well as to methods for their preparation, pharmaceutical compositions comprising the same, and use thereof for the treatment and/or prevention of, e.g., lysosomal storage diseases, such as Gaucher's disease, and α-synucleinopathies, such as Parkinson's disease.
1 . A compound of formula (IA):
or a pharmaceutically acceptable salt or solvate thereof, wherein
A 1 , A 2 , and A 3 are each independently selected from the group consisting of N, CH and C(R 4a ), provided that at least one of A 1 , A 2 , or A 3 is N and no more than two of A 1 , A 2 , or A 3 are N;
each R 4a is independently selected from the group consisting of halogen, —C 1-4 alkyl, —C 1-4 alkoxy, and —CN;
R 1a is selected from the group consisting of C 5-7 cycloalkyl, phenyl, and —C 1-3 alkyl-phenyl, wherein said C 5-7 cycloalkyl, phenyl and —C 1-3 alkyl-phenyl groups are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —ORb a , —SRb a , —N(Rb a )2, and —C 1-4 alkyl optionally substituted with 1, 2, or 3 halogen atoms; and wherein said C 5-7 cycloalkyl, phenyl, and —C 1-3 alkyl-phenyl is optionally fused to a further (second) ring; and
R 2a is selected from the group consisting of hydrogen and —C 1-4 alkyl; or
R 1a and R 2a together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the group consisting of N, S, or O, and wherein said heterocyclic ring is optionally fused to a phenyl ring;
each Rb a is independently hydrogen or —C 1-4 alkyl, wherein said alkyl group is optionally substituted by 1, 2 or 3 fluorine atoms; and
R 3a is selected from the group consisting of cyclohexyl, phenyl, and pyridinyl, wherein said cyclohexyl, phenyl, and pyridinyl groups are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —ORb a , —SRb a , —N(Rb a ) 2 , and C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —ORb a , and —N(Rb a ) 2 , and wherein said phenyl is optionally fused to a 5- or 6-membered heterocyclic.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein A 1 is N and A 2 and A 3 are each independently selected from the group consisting of CH and C(R 4a ).
3 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein A 2 is N and A 1 and A 3 are each independently selected from the group consisting of CH and C(R 4a ); or A 3 is N and A 1 and A 2 are each independently selected from the group consisting of CH and C(R 4a ); or A 1 and A 2 are both N and A 3 is CH or C(R 4a ); or A 1 and A 3 are both N and A 2 is CH or C(R 4a ); or A 2 and A 3 are both N and A 1 is CH or C(R 4a ).
4 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is unsubstituted phenyl or phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —O(C 1-4 )alkyl, —S(C 1-4 )alkyl, —N(C 1-4 alkyl) 2 , —NH(C 1-4 alkyl), and —C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —O(C 1-4 )alkyl, —N(C 1-4 alkyl) 2 , and —NH(C 1-4 alkyl).
5 . The compound of claim 4 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is phenyl substituted with 1 or 2 substituents each independently selected from the group consisting of F, Cl, Br, I, hydroxy, methyl, methoxy, and —CN.
6 . The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is phenyl substituted with F or hydroxy at the ortho- or meta-position of the phenyl ring.
7 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is unsubstituted phenyl fused to a 5- or 6-membered heterocyclic ring.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is unsubstituted pyridinyl or pyridinyl substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —O(C 1-4 )alkyl, —S(C 1-4 )alkyl, —N(C 1-4 alkyl) 2 , —NH(C 1-4 alkyl), and —C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —O(C 1-4 )alkyl, —N(C 1-4 alkyl) 2 , and —NH(C 1-4 alkyl).
9 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is unsubstituted cyclohexyl or cyclohexyl substituted with 1 or 2 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —O(C 1-4 )alkyl, —S(C 1-4 )alkyl, —N(C 1-4 alkyl) 2 , —NH(C 1-4 alkyl), and —C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —O(C 1-4 )alkyl, —N(C 1-4 alkyl) 2 , and —NH(C 1-4 alkyl).
10 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a is H.
11 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 2a is —C 1-4 alkyl.
12 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is phenyl or —C 1-3 alkyl-phenyl, wherein said phenyl or —C 1-3 alkyl-phenyl is optionally substituted with 1, 2 or 3 groups each independently selected from the group consisting of halogen, hydroxy, —CN, —ORb a , —SRb a , —N(Rb a ) 2 , and —C 1-4 alkyl optionally substituted with 1, 2, or 3 halogen atoms; and wherein said phenyl is optionally fused to a further (second) ring.
13 . The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is unsubstituted phenyl or unsubstituted benzyl.
14 . The compound of claim 12 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is phenyl fused to a 5- or 6-membered heterocyclic ring.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is C 5-7 cycloalkyl, wherein said C 5-7 cycloalkyl is optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —ORb a , —SRb a , —N(Rb a ) 2 , and —C 1-4 alkyl optionally substituted with 1, 2, or 3 halogen atoms; and wherein said C 5-7 cycloalkyl is optionally fused to a further (second) ring.
16 . The compound of claim 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is unsubstituted C 5-7 cycloalkyl fused to a phenyl ring.
17 . A pharmaceutical composition, comprising a compound of claim 16 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
18 . The compound of claim 16 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a is cyclopentyl fused to a phenyl ring.
19 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein Rb a is hydrogen or unsubstituted-C 1-4 alkyl.
20 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a and R 2a together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the group consisting of N, S, or O, and wherein said heterocyclic ring is optionally fused to a phenyl ring.
21 . The compound of claim 20 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1a and R 2a together with the nitrogen atom to which they are attached form a 5- or 6-membered ring optionally fused to a phenyl ring.
22 . The compound of claim 1 , which is selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof.
23 . The compound of claim 1 , which is selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof.
24 . The compound of claim 23 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
25 . A pharmaceutically acceptable salt of the compound of claim 1 , selected from the group consisting of
26 . A pharmaceutical composition, comprising a compound of claim 24 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
27 . A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
28 . A method of treating Gaucher's disease, comprising administering to a patient in need thereof an effective amount of a compound of formula (IA):
or a pharmaceutically acceptable salt or solvate thereof, wherein
A 1 , A 2 , and A 3 are each independently selected from the group consisting of N, CH and C(R 4a ), provided that at least one of A 1 , A 2 , or A 3 is N and no more than two of A 1 , A 2 , or A 3 are N;
each R 4a is independently selected from the group consisting of halogen, —C 1-4 alkyl, —C 1-4 alkoxy, and —CN;
R 1a is selected from the group consisting of C 5-7 cycloalkyl, phenyl, and —C 1-3 alkyl-phenyl, wherein said C 5-7 cycloalkyl, phenyl and —C 1-3 alkyl-phenyl groups are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —ORb a , —SRb a , —N(Rb a ) 2 , and —C 1-4 alkyl optionally substituted with 1, 2, or 3 halogen atoms; and wherein said C 5-7 cycloalkyl, phenyl, and —C 1-3 alkyl-phenyl is optionally fused to a further (second) ring; and
R 2a is selected from the group consisting of hydrogen and —C 1-4 alkyl; or
R 1a and R 2a together with the nitrogen atom to which they are attached form an optionally substituted 5- to 10-membered heterocyclic ring, wherein said heterocyclic ring optionally contains 1, 2, or 3 additional heteroatoms selected from the group consisting of N, S, or O, and wherein said heterocyclic ring is optionally fused to a phenyl ring;
each Rb a is independently hydrogen or —C 1-4 alkyl, wherein said alkyl group is optionally substituted by 1, 2 or 3 fluorine atoms; and
R 3a is selected from the group consisting of cyclohexyl, phenyl, and pyridinyl, wherein said cyclohexyl, phenyl, and pyridinyl groups are optionally substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halogen, hydroxy, —CN, —ORb a , —SRb a , —N(Rb a ) 2 , and C 1-4 alkyl optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, —ORb a , and —N(Rb a ) 2 , and wherein said phenyl is optionally fused to a 5- or 6-membered heterocyclic ring.
29 . The method of claim 28 , further comprising administering to the patient at least one other therapeutic agent.
30 . The method of claim 28 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
31 . A pharmaceutically acceptable salt of the compound of claim 24 , wherein the pharmaceutically acceptable salt is the hydrochloride salt.