METHODS FOR TREATING COGNITIVE DISORDERS USING INHIBITORS OF HISTONE DEACETYLASE
This disclosure relates to compounds for the inhibition of histone deacetylase and treatment of a cognitive disorder or deficit. More particularly, the disclosure provides for compounds of formula (I) wherein (I), Q, J, L and Z are as defined in the specification.
1 - 65 . (canceled)
66 . A method of treating a cognitive disorder or deficit comprising administering a compound of Formula (IV) or a pharmaceutically acceptable salt thereof:
wherein
R 140 is selected from the group consisting of H, —OH, halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2 ;
xa and xb denote numbers that are each independently selected from 0, 1 and 2; and
R 150 and R 160 are independently selected from the group consisting of H, halo, —CN, —CF 3 , —OCF 3 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxyl, —O—C 2 -C 6 alkyl-O—R 53 , —OR 53 , —C 0 -C 6 alkyl-S(O) 0-2 —R 53 , —C 0 -C 6 alkyl-C(O)—R 53 , —C 0 -C 6 alkyl-C(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)—R 53 , —C 0 -C 6 alkyl-S(O) 2 NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 S(O) 2 —R 53 , —C 0 -C 6 alkyl-OC(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)O—R 53 , —C 0 -C 6 alkyl-NR 52 C(O)NR 50 R 51 , —C 0 -C 6 alkyl-C(O)O—R 53 , —C 0 -C 6 alkyl-OC(O)—R 53 , —C 0 -C 6 alkyl-aryl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-cycloalkyl, —C 0 -C 6 alkyl-heterocyclyl, —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 , —O—C 2 -C 6 alkyl-NR 50 R 51 , —NR 53 —C 2 -C 6 alkyl-NR 50 R 51 and —O-heterocyclyl-R 53 , wherein each alkyl and heteroalkyl is optionally substituted with one or three substituents independently selected from the group consisting of F, —OH and oxo, and wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2 ;
R 50 and R 51 are independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 2 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 7 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;
or
R 50 and R 51 , together with the N atom to which they are attached, optionally form a 3-10 membered heterocyclic ring, wherein the heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;
R 52 is independently selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 7 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;
R 53 is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 0 -C 4 alkyl-C 3 -C 7 cycloalkyl, —C 0 -C 4 alkyl-aryl, —C 0 -C 4 alkyl-heteroaryl and —C 0 -C 4 alkyl-heterocyclyl, wherein each alkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or three substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl.
67 . The method according to claim 66 , wherein the compound has Formula (V):
wherein
R 140 is selected from the group consisting of H, —OH, halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2 ;
xb denotes a number selected from 0, 1 and 2; and
R 150 and R 160 are independently selected from the group consisting of H, halo, —CN, —CF 3 , —OCF 3 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxyl, —O—C 2 -C 6 alkyl-O—R 53 , —OR 53 , —C 0 -C 6 alkyl-S(O) 0-2 —R 53 , —C 0 -C 6 alkyl-C(O)—R 53 , —C 0 -C 6 alkyl-C(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)—R 53 , —C 0 -C 6 alkyl-S(O) 2 NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 S(O) 2 —R 53 , —C 0 -C 6 alkyl-OC(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)O—R 53 , —C 0 -C 6 alkyl-NR 52 C(O)NR 50 R 51 , —C 0 -C 6 alkyl-C(O)O—R 53 , —C 0 -C 6 alkyl-OC(O)—R 53 , —C 0 -C 6 alkyl-aryl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-cycloalkyl, —C 0 -C 6 alkyl-heterocyclyl, —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 , —O—C 2 -C 6 alkyl-NR 50 R 51 , —NR 53 —C 2 -C 6 alkyl-NR 50 R 51 and —O-heterocyclyl-R 53 , wherein each alkyl and heteroalkyl is optionally substituted with one or three substituents independently selected from the group consisting of F, —OH and oxo, and wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2 ;
xc is 0 or 1; and
R 170 is selected from the group consisting of H, halo, —CN, —CF 3 , —OCF 3 , —C 1 -C 6 alkyl, —C 1 -C 6 alkoxyl, —O—C 2 -C 6 alkyl-O—R 53 , —OR 53 , —C 0 -C 6 alkyl-S(O) 0-2 —R 53 , —C 0 -C 6 alkyl-C(O)—R 53 , —C 0 -C 6 alkyl-C(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)—R 53 , —C 0 -C 6 alkyl-S(O) 2 NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 S(O) 2 —R 53 , —C 0 -C 6 alkyl-OC(O)NR 50 R 51 , —C 0 -C 6 alkyl-NR 52 C(O)O—R 53 , —C 0 -C 6 alkyl-NR 52 C(O)NR 50 R 51 , —C 0 -C 6 alkyl-C(O)O—R 53 , —C 0 -C 6 alkyl-OC(O)—R 53 , —C 0 -C 6 alkyl-aryl, —C 0 -C 6 alkyl-heteroaryl, —C 0 -C 6 alkyl-cycloalkyl, —C 0 -C 6 alkyl-heterocyclyl, —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 , —O—C 2 -C 6 alkyl-NR 50 R 51 , —NR 53 —C 2 -C 6 alkyl-NR 50 R 51 and —O-heterocyclyl-R 53 , wherein each alkyl and heteroalkyl is optionally substituted with one or three substituents independently selected from the group consisting of F, —OH and oxo, wherein each aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of halo, —CN, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxyl, —O—C 2 -C 4 alkyl-O—C 1 -C 4 alkyl, —CF 3 , —OCF 3 , —NO 2 , —C 1 -C 6 alkyl-S(O) 0-2 R 53 , —NH 2 , —NR 50 R 51 , —C 1 -C 6 alkyl-NR 50 R 51 and —N(C 1 -C 6 alkyl) 2
R 50 and R 51 are independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 2 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 7 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;
or
R 50 and R 51 , together with the N atom to which they are attached, optionally form a 3-10 membered heterocyclic ring, wherein the heterocyclyl is optionally substituted with one to three substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;
R 52 is independently selected from the group consisting of —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkyl-O—C 1 -C 6 alkyl, —C 0 -C 6 alkyl-C 3 -C 7 cycloalkyl, wherein each alkyl and cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;
R 53 is independently selected from the group consisting of —C 1 -C 6 alkyl, —C 0 -C 4 alkyl-C 3 -C 7 cycloalkyl, —C 0 -C 4 alkyl-aryl, —C 0 -C 4 alkyl-heteroaryl and —C 0 -C 4 alkyl-heterocyclyl, wherein each alkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or three substituents independently selected from the group consisting of halo, —OH, amino, —CN or —C 1 -C 4 alkyl;
68 . The method according to claim 67 , wherein the compound has Formula (VI):
69 - 70 . (canceled)
71 . A method for treating a cognitive disorder or deficit comprising administering a compound selected from the group consisting of:
(Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(dibenzo[b,f][1,4]thiazepin-11-yl)-N-hydroxybenzamide,
4-(10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
N-hydroxy-4-(10-methyl-10,11-dihydrodibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(benzo[b]pyrido[3,2-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide,
(Z)-4-(2-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(2-methoxydibenzo[b,f][1,4]oxazepin-1′-yl)benzamide,
(Z)-4-(benzo[b]pyrido[4,3-f][1,4]oxazepin-5-yl)-N-hydroxybenzamide,
(Z)-4-(2-(2-(dimethylamino)ethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-2-fluoro-N-hydroxybenzamide,
(Z)-5-(4-(hydroxycarbamoyl)phenyl)benzo[b]pyrido[4,3-f][1,4]oxazepine 2-oxide,
(Z)-N-hydroxy-4-(3-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-3-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(8-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(9-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(7-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(7-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(2-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(8-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(4-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(3-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(benzo[b]thieno[2,3-f][1,4]oxazepin-10-yl)-N-hydroxybenzamide,
(Z)-4-(3-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(8-chlorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(3-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(6-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(7-cyanodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(4-hydroxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(1-methoxydibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(4-(2-methoxyethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(1-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(2-(trifluoromethyl)benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)benzamide,
(Z)-4-(1-cyclopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide,
(Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(4-(2-morpholinoethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(benzo[f]pyrido[2,3-b][1,4]oxazepin-6-yl)-N-hydroxybenzamide,
(Z)-4-(2-fluoro-4-methoxydibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(4-(methylthio)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(4-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(4-(methylsulfinyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-4-(5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(4-(methylsulfonyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(E)-4-((dibenzo[b,f][1,4]oxazepin-11-ylamino)methyl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(4-methoxy-8-(trifluoromethyl)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(3-morpholinodibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(4-propyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(4-(trifluoromethoxy)dibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(Z)-N-hydroxy-4-(6-methyldibenzo[b,f][1,4]oxazepin-11-yl)benzamide,
(E)-4-(dibenzo[b,f][1,4]oxazepin-11-yl)-3-fluoro-N-hydroxybenzamide,
(E)-6-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxynicotinamide,
(E)-5-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxyfuran-2-carboxamide,
(E)-5-(dibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxythiophene-2-carboxamide,
(Z)-4-(5-ethyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,
(Z)-4-(5-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxy-N-methylbenzamide,
(Z)-N-hydroxy-4-(5-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzamide,
(E)-4-45-cyclopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamino)methyl)-N-hydroxybenzamide,
(Z)-4-(4-fluorodibenzo[b,f][1,4]oxazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(5-(2-methoxyethyl)-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzamide,
(E)-4-(2-(dibenzo[b,f][1,4]oxazepin-11-ylamino)ethyl)-N-hydroxybenzamide,
(Z)-4-(11-ethyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide,
(Z)-4-(5-cyclopropyl-2-fluoro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(11-isopropyl-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide,
(Z)-4-(benzo[f]thieno[2,3-b][1,4]oxazepin-5-yl)-N-hydroxybenzamide,
(Z)-6-(4-(dibenzo[b,f][1,4]oxazepin-11-yl)benzamidooxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid,
(Z)-N-hydroxy-4-(11-(3-morpholinopropyl)-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide,
(Z)-N-hydroxy-4-(11-(2-morpholinoethyl)-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)benzamide,
(Z)-4-(11-(cyclopropylmethyl)-11H-benzo[b]pyrido[2,3-e][1,4]diazepin-5-yl)-N-hydroxybenzamide,
(Z)-N-hydroxy-4-(5-(2-morpholinoethyl)-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzamide,
or a pharmaceutically acceptable salt thereof.
72 - 96 . (canceled)
97 . The method of claim 66 wherein the cognitive disorder is Alzheimer's Disease.