1,2,4-oxadiazole derivatives as histone deacetylase 6 inhibitors
The invention relates to compounds of Formula (I) as described herein, useful as histone deacetylase 6 (HDAC6) inhibitors. The invention also relates to pharmaceutical compositions comprising these compounds and to their use in therapy.
1 . A compound of Formula (I) or a salt thereof:
wherein
m is 0, 1, or 2;
each R 1 is independently selected from halo, methyl, and trifluoromethyl;
A is selected from the cyclic groups listed below:
wherein A is optionally substituted with one or two R 2 and in addition A is optionally substituted with one R 3 ;
each R 2 is independently selected from halo, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and —(C 1-6 alkylene)-OR 4 ;
R 3 is selected from -L 1 -R 5 , -L 2 -OR 6 , -L 3 -NR 7 R 8 , -L 4 -CONR 9 R 10 , -L 5 -NR 11 COR 12 , —Y-L 6 -OR 6 , and —Y-L 7 -NR 7 R 8 ;
L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from a bond and C 1-6 alkylene;
L 6 and L 7 are each independently selected from C 2-6 alkylene;
each Y is independently selected from —O—, —NR 13 —, —CONR 14 —, and —NR 15 CO—;
each R 4 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and C 3-7 cycloalkyl-C 1-6 alkyl;
each R 5 is independently selected from carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein the carbocyclyl, the aryl, the heterocyclyl, and the heteroaryl are each optionally substituted with one or more R 16 ;
R 6 and R 12 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and -L 1 -R 5 ;
R 7 and R 8 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, —(C 1-6 alkylene)-OR 4 , and -L 1 -R 5 ;
R 9 and R 10 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, —(C 1-6 alkylene)-OR 4 , and -L 1 -R 5 , or R 9 and R 10 taken together with the N atom to which they are attached form a saturated 4- to 12-membered heterocyclic ring optionally containing one additional heteroatom selected from N, O, and S, wherein said heterocyclic ring is optionally substituted with one or more R 16 ;
R 11 , R 13 , R 14 , and R 15 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-6 alkyl, and —(C 1-6 alkylene)-OR 4 ;
each R 16 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, —OH, —NR 17 R 18 , —COR 19 , —CN, -L 8 -carbocyclyl, -L 8 -aryl, -L 8 -heterocyclyl, and -L 8 -heteroaryl, wherein the carbocyclyl in -L 8 -carbocyclyl, the aryl in -L 8 -aryl, the heterocyclyl in -L 8 -heterocyclyl, and the heteroaryl in -L 8 -heteroaryl are each optionally substituted with one or more R 20 ;
each L 8 is independently selected from a bond and C 1-6 alkylene;
R 17 and R 18 are each independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and C 3-7 cycloalkyl-C 1-6 alkyl;
R 19 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl; and
each R 20 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, —OH, —NR 17 R 18 , —COR 19 , and —CN.
2 . The compound of claim 1 , wherein the compound has formula (IIIa) or (IIIb), or a salt thereof
wherein one of Z 1 , Z 2 , and Z 3 is R 3 or H, and the others are independently selected from H and R 2 .
3 . The compound of claim 1 , wherein the compound has formula (IVa), or a salt thereof
wherein one of Z 1 , Z 2 , Z 3 , and Z 4 is selected from R 2 , R 3 , and H, and the others are independently selected from H and R 2 , with the proviso that only up to two of Z 1 , Z 2 , Z 3 , and Z 4 are R 2 , or
the compound has formula (IVb), or a salt thereof
wherein one of Z 1 , Z 2 , Z 3 , and Z 4 is selected from R 2 , R 3 , and H, and the others are independently selected from H and R 2 , with the proviso that only up to two of Z 1 , Z 2 , Z 3 and Z 4 are R 2 .
4 . The compound of claim 1 , wherein m is 0.
5 . The compound of claim 1 , wherein R 3 is selected from -L 1 -R 5 , -L 2 -OR 6 , -L 3 -NR 7 R 8 , —CONR 9 R 10 , —NR 11 COR 12 , and —Y-L 7 -NR 7 R 8 .
6 . The compound of claim 1 , wherein R 3 is —CONR 9 R 10 or —NR 11 COR 12 .
7 . The compound of claim 1 , wherein each R 2 is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, and —(C 1-4 alkylene)-OR 4 .
8 . The compound of claim 1 , which is a compound selected from:
3-(2-(1-Butyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
1-Butyl-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
1-Butyl-N-ethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
3-(2-(3-(Piperidin-1-ylmethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
4-((1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methyl) morpholine,
3-(2-(1-(Tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
N,N,1-Trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
3-(2-(1-Propyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
1-Butyl-N,N-diethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(2-(4,4-Difluoropiperidin-1-yl)ethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
(1-Propyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol,
3-(2-(3-(Methoxymethyl)-1-propyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c] pyridin-3-yl)methanol,
3-(2-(1H-Pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(Pyridin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(1-(2,2,2-Trifluoroethyl)piperidin-4-yl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Methyl-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Butyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
1-(1-Butyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-N,N-dimethylmethanamine,
3-(2-(1H-Pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
1-(2-Methoxyethyl)-N,N-dimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide,
3-(2-(1-(2-Methoxyethyl)-3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(2-Methoxyethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(Pyridin-3-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(Pyridin-2-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1H-Pyrazolo[3,4-b]pyridin-1-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(2-Methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-Ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
3-(2-(1-(2-(1-Methyl-1H-imidazol-2-yl)ethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, and
3-(2-(1-((1-Methyl-1H-pyrazol-4-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole,
or a salt thereof.
9 . A pharmaceutical composition which comprises a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10 . A method for treating a disease associated with HDAC6, comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
11 . A method for treating a disease selected from cancer, an autoimmune or inflammatory disease, transplant rejection, a ciliopathy, a disease of the nervous system, a mental or behavioral disorder, an infectious disease, a cardiovascular disease, muscle atrophy and cachexia, comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
12 . The method of claim 10 , wherein the patient to be treated is a human.
13 . The method of claim 10 , wherein said disease is a disease of the nervous system.
14 . The method of claim 13 , wherein said disease is a peripheral neuropathy.
15 . The method of claim 13 , wherein said disease is a chemotherapy-induced peripheral neuropathy.
16 . The method of claim 13 , wherein said disease is Charcot-Marie Tooth Disease.
17 . The method of claim 13 , wherein said disease is amyotrophic lateral sclerosis.
18 . The compound of claim 1 , wherein the compound has formula (IIIa), or a salt thereof
wherein one of Z 1 , Z 2 , and Z 3 is R 3 or H, and the others are independently selected from H and R 2 .
19 . The compound of claim 18 , wherein Z 2 is R 3 , wherein Z 1 and Z 3 are independently selected from H and R 2 , and wherein R 3 is —CONR 9 R 10 .
20 . The compound of claim 1 , which is N,N,1-trimethyl-5-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-yl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide, or a salt thereof.
21 . The compound of claim 1 , which is 3-(2-(1-(2-methoxyethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, or a salt thereof.
22 . The compound of claim 1 , which is 3-(2-(1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-4-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole, or a salt thereof.