Nitrile SUMO inhibitors and uses thereof
The present invention relates to cyano-containing compounds and compositions capable of acting as inhibitors of small ubiquitin-like modifier (SUMO) family of proteins. The compounds and compositions may be used in the treatment of cancer. There are disclosed, inter alia, methods of inhibiting an E1 enzyme, and compounds useful for inhibiting an E1 enzyme.
1 . A compound of the structure of Formula IV or Formula V:
wherein
R 1 is substituted or unsubstituted C 2 -C 6 alkenyl, or substituted or unsubstituted C 2 -C 6 alkynyl;
R 6 is selected from H, C 1-6 alkyl, C 2-4 alkynyl, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl, C 1-6 alkylamino-C 1-6 alkyl, C 1-6 alkylaminocarbonyl-C 1-6 alkyl, aminocarbonyl-C 1-6 alkyl, C 1-6 alkoxycarbonyl-C 1-6 alkyl, carboxy-C 1-6 alkyl, C 1-6 alkylcarbonylamino-C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 haloalkyl, C 1-6 alkylsulfonyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, aryl-C 1-6 alkyl, substituted or unsubstituted 5 or 6 membered heteroaryl-C 1-6 alkyl, substituted or unsubstituted 5 or 6 membered heterocyclyl and substituted or unsubstituted 5 or 6 membered heteroaryl;
R 7 is selected from H, carboxy, amino, C 1-6 alkyl, C 1-3 haloalkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylaminocarbonyl, and C 3-6 cycloalkyl;
R 8 is selected from H, carboxy, cyano, C 1-4 alkyl, C 1-3 haloalkyl, and C 1-6 alkylaminocarbonyl;
R 9 is selected from H, halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, cyano, amino, C 1-3 alkylcarbonylamino, C 1-3 alkylsulfonylamino, and C 1-3 alkylaminocarbonylamino;
R 10 is selected from H, halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, cyano, amino, C 1-3 alkylcarbonylamino, C 1-3 alkylsulfonylamino, and C 1-3 alkylaminocarbonylamino; and
R 11 is selected from H, halo, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, cyano, amino, C 1-3 alkylcarbonylamino, C 1-3 alkylsulfonylamino, and C 1-3 alkylaminocarbonylamino;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 1 is selected from ethenyl, fluoropropenyl, 3,3-difluoropropenyl, 3,3,3-trifluoropropenyl, 3,3,3-trifluoroprop-1-enyl, methoxypropenyl, ethoxypropenyl, aminopropenyl, 3-amino-butenyl, 3-methylamino-butenyl, 3-amino-4-hydroxy-butenyl, 3-methylamino-4-methoxy-butenyl, 3-amino-4-phenyl-butenyl, 3-amino-pentenyl, aminopropynyl, methoxypropynyl, dimethylaminopropenyl, di(d 1 ,d 2 ,d 3 -methyl)aminopropenyl, diethylaminopropenyl, 3-(N,N-dimethylamino)-3-phenyl-propenyl, 3-(N,N-dimethylamino)-3-cyclopropyl-propenyl, (cyclopropylamino)propenyl, bicyclo[1.1.1]pent-1-ylamino, (1-methylcyclopropylamino)propenyl, (3-methyloxetan-3-yl)aminopropenyl, (3-methyltetrahydrofur-3-yl)aminopropenyl, (4-methyl-tetrahydropyran-4-yl)aminopropenyl, methylaminopropenyl, N-benzyl-N-methylaminopropenyl, N-(tert-butyl)aminopropenyl, N-sec-butylaminopropenyl, N-butylaminopropenyl, N-(isopropyl)aminopropenyl, N-(d 2 -isopropyl)aminopropenyl, ethylaminopropenyl, N-[3,3-difluorocyclobutyl]aminopropenyl, 1-hydroxymethyl-1-methyl-ethylaminopropenyl, 3-dimethylamino-butenyl, 3-(N-methylamino)-butenyl, methylaminobutenyl, N,N-dimethylaminobutenyl, piperidin-2-ylpropenyl, pyrrolidin-1-ylpropenyl, 3-methyl-oxetan-3-ylpropenyl, 4-methyl-tetrahydropyran-4-ylpropenyl, piperidin-2-ylethenyl, pyrrolidin-2-ylethenyl, azetidin-2-ylethenyl, morpholin-3-ylethenyl, 1-methylpyrrolidin-2-ylethenyl, 3-methylpyrrolidin-5-ylethenyl, 3-ethylpyrrolidin-5-ylethenyl, 2-methylpyrrolidin-5-ylethenyl, 2,2-dimethylpyrrolidin-5-ylethenyl, 3-methoxypyrrolidin-5-ylethenyl, 3-fluoropyrrolidin-5-ylethenyl, 3,3-difluoropyrrolidin-5-ylethenyl, 5-azaspiro[2.4]heptan-6-ylethenyl, 2-azabicyclo [3.1.0]hexan-3-ylethenyl, 3,3-dimethylpyrrolidin-5-ylethenyl, 3-methylpyrrolidin-1-ylpropenyl, 2-methylpyrrolidin-1-ylpropenyl, 1-methylcarbonylpyrrolidin-3-ylethenyl, 2-carboxypyrrolidin-1-ylpropenyl, 3-carboxypyrrolidin-1-ylpropenyl, tetrahydrofur-3-ylpropenyl, dimethylaminopropynyl, methylaminopropynyl, 2-amino-2-methylbutynyl, 2-(1-amino-cyclopropyl)-ethynyl, 2-(1-amino-cyclobutyl)-ethynyl, 2-(1-amino-cyclopentyl)-ethynyl, azetidin-2-ylethynyl, pyrrolidin-2-ylethynyl, pyrrolidin-3-ylethynyl, 2-methyl-pyrrolidin-2-ylethynyl, 4-methyl-piperazin-1-ylpropynyl, and piperidin-3-ylethynyl; or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 , wherein R 6 is selected from H, ethyl, isopropyl, butyl, propyl, methyl, propynyl, 1-hydroxyethyl, 2-hydroxymethylethyl, 1-hydroxy-2,2-dimethylethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, methoxymethyl, methoxyethyl, dimethylaminoethyl, carboxymethyl, carboxyethyl, carboxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, dimethylaminocarbonylmethyl, dimethylaminocarbonyl-1-ethyl, methylaminocarbonyl-1-ethyl, methylaminocarbonylethyl, methylaminocarbonylmethyl, aminocarbonylmethyl, aminocarbonylethyl, 1-aminocarbonylethyl, aminocarbonyl-1,1-dimethylmethyl, methylcarbonylaminoethyl, 1-methylcarbonylamino-2,2-dimethylethyl, 2-cyano-2-methylethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, methylsulfonyl, cyclopropyl, cyclopropylmethyl, benzyl, 4-pyridinylethyl, 2-pyridinylethyl, 3-pyridinylmethyl, 2-pyridinylmethyl, 4-oxazolylmethyl, 1,3,4-oxadiazol-2-yl]methyl, 1,2,4-oxadiazol-2-yl]methyl 1-methylazetidin-3-yl, 1-methylpyrrolidin-3-yl, 1-methylpiperidin-4-yl, 1-methylpiperidin-3-yl, 5-methoxypyrimidin-4-yl, 2-amino-4-pyridyl, 3-chloro-5-fluoro-4-pyridyl, 3,5-difluoro-4-pyridyl, 3-fluoro-2-pyridyl, 3-methoxy-2-pyridyl, 3-fluoro-4-pyridyl, 3-chloro-4-pyridyl, 4-pyridyl and 2-pyridyl; or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 , wherein R 7 is selected from H, trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, methyl, ethyl, methoxy, amino, dimethylamino, carboxy, methylaminocarbonyl, dimethylaminocarbonyl, and cyclopropyl; or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 , wherein R 8 is selected from H, trifluoromethyl, methyl, ethyl, carboxy, cyano and methylaminocarbonyl; or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 , wherein R 9 is selected from H, fluoro, chloro, methyl, and cyano; or or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 , wherein R 10 is selected from H, fluoro, methylcarbonylamino, chloro, amino, hydroxy, methyl, difluoromethyl, methylsulfonylamino, and methylaminocarbonylamino; or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 , wherein R 11 is H or fluoro; or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 , wherein R 6 is ethyl; R 7 is trifluoromethyl; and R 8 is H; or
R 6 is methyl; R 7 is trifluoromethyl; and R 8 is H; or
R 6 is H; R 7 is trifluoromethyl; and R 8 is H; or
R 6 is 3,5-difluoropyridin-4-yl; R 7 is trifluoromethyl; and R 8 is H;
or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 , wherein R 1 is substituted ethenyl; or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 1 , wherein R 1 is dimethylaminopropenyl; or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 1 , wherein R 9 is fluoro; R 10 is H; and R 11 is H; or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 , wherein the compound is a specific isomer selected from:
or is a specific isomer selected from the group consisting of
14 . A pharmaceutical composition, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one carrier, excipient, or diluent.
15 . A method of treating cancer in a subject in need thereof, said method comprising administering to said subject a therapeutically effective amount of the compound of claim 1 .
16 . The compound of claim 13 , wherein the compound is the specific isomer
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 13 , wherein the compound is the specific isomer
or a pharmaceutically acceptable salt thereof.
18 . A compound having a structure selected from