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US 8,524,711 B2Granted
Amino-derivatives as novel inhibitors of histone deacetylase
AssigneeJanssen Pharmaceutica NV
InventorsPatrick René Angibaud, Kristof Van Emelen, Virginie Sophie Poncelet, Bruno Roux
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Abstract
This invention comprises the novel compounds of formula (I) wherein n, m, t, R1, R2, L, Q, X, Y, Z and have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
Claims10
A compound of formula (I),
- the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
- n is 0;
- m is 2;
- t is 0 or 1 and when t is 0 then a direct bond is intended;
- Q is C;
- X is nitrogen;
- Y is nitrogen;
- Z is —O—;
- R1 is —C(O)NR3R4, —N(H)C(O)R7, —C(O)—C1-6alkanediylSR7, —NR8C(O)N(OH)R7, —NR8C(O)C1-6alkanediylSR7, or —NR8C(O)C═N(OH)R7 wherein R3 and R4 are each independently hydrogen, hydroxy, C1-6alkyl, hydroxyC1-6alkyl, aminoC1-6alkyl or aminoaryl;
- R7 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, arylC1-6alkyl, C1-6alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;
- and R8 is hydrogen or C1-6alkyl;
- R2 is hydrogen, hydroxy, amino, hydroxyC1-6alkyl, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl, aminocarbonyl, hydroxycarbonyl, aminoC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonylC1-6alkyl, hydroxyaminocarbonyl, C1-6alkyloxycarbonyl, C1-6alkylaminoC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl;
- -L- is a bivalent radical that is C1-6alkanediyl, carbonyl, sulfonyl, or C1-6alkanediyl substituted with phenyl;
- is a radical that is
- wherein each s is independently 0, 1, 2, 3, 4, or 5, as allowed;
- each R5 and R6 are independently hydrogen;
- halo;
- hydroxy;
- amino;
- nitro;
- trihaloC1-6alkyl;
- trihaloC1-6alkyloxy;
- C1-6alkyl;
- C1-6alkyl substituted with aryl and C3-10cycloalkyl;
- C1-6alkyloxy;
- C1-6alkyloxyC1-6alkyloxy;
- C1-6alkylcarbonyl;
- C1-6alkyloxycarbonyl;
- C1-6alkylsulfonyl;
- cyanoC1-6alkyl;
- hydroxyC1-6alkyl;
- hydroxyC1-6alkyloxy;
- hydroxyC1-6alkylamino;
- aminoC1-6alkyloxy;
- di(C1-6alkyl)aminocarbonyl;
- di(hydroxyC1-6alkyl)amino;
- (aryl)(C1-6alkyl)amino;
- di(C1-6alkyl)aminoC1-6alkyloxy;
- di(C1-6alkyl)aminoC1-6alkylamino;
- di(C1-6alkyl)aminoC1-6alkylaminoC1-6alkyl;
- arylsulfonyl;
- arylsulfonylamino;
- aryloxy;
- aryloxyC1-6alkyl;
- arylC2-6alkenediyl;
- di(C1-6alkyl)amino;
- di(C1-6alkyl)aminoC1-6alkyl;
- di(C1-6alkyl)amino(C1-6alkyl)amino;
- di(C1-6alkyl)amino(C1-6alkyl)aminoC1-6alkyl;
- di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)amino;
- di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl;
- aminosulfonylamino(C1-6alkyl)amino;
- aminosulfonylamino(C1-6alkyl)aminoC1-6alkyl;
- di(C1-6alkyl)aminosulfonylamino(C1-6alkyl)amino;
- di(C1-6alkyl)aminosulfonylamino(C1-6alkyl)aminoC1-6alkyl;
- cyano;
- thiophenyl;
- thiophenyl substituted with di(C1-6alkyl)aminoC1-6alkyl(C1-6alkyl)aminoC1-6alkyl, di(C1-6alkyl)aminoC1-6alkyl, C1-6alkylpiperazinylC1-6alkyl, hydroxyC1-6alkylpiperazinylC1-6alkyl, hydroxyC1-6alkyloxyC1-6alkylpiperazinylC1-6alkyl, di(C1-6alkyl)aminosulfonylpiperazinylC1-6alkyl, C1-6alkyloxypiperidinyl, C1-6alkyloxypiperidinylC1-6alkyl, morpholinylC1-6alkyl, hydroxyC1-6alkyl(C1-6alkyl)aminoC1-6alkyl, or di(hydroxyC1-6alkyl)aminoC1-6alkyl;
- furanyl;
- furanyl substituted with hydroxyC1-6alkyl;
- benzofuranyl;
- imidazolyl;
- oxazolyl;
- oxazolyl substituted with aryl and C1-6alkyl;
- C1-6alkyltriazolyl;
- tetrazolyl;
- pyrrolidinyl;
- pyrrolyl;
- piperidinylC1-6alkyloxy;
- morpholinyl;
- C1-6alkylmorpholinyl;
- morpholinylC1-6alkyloxy;
- morpholinylC1-6alkyl;
- morpholinylC1-6alkylamino;
- morpholinylC1-6alkylaminoC1-6alkyl;
- piperazinyl;
- C1-6alkylpiperazinyl;
- C1-6alkylpiperazinylC1-6alkyloxy;
- piperazinylC1-6alkyl;
- naphtalenylsulfonylpiperazinyl;
- naphtalenylsulfonylpiperidinyl;
- naphtalenylsulfonyl;
- C1-6alkylpiperazinylC1-6alkyl;
- C1-6alkylpiperazinylC1-6alkylamino;
- C1-6alkylpiperazinylC1-6alkylaminoC1-6alkyl;
- C1-6alkylpiperazinylsulfonyl;
- aminosulfonylpiperazinylC1-6alkyloxy;
- aminosulfonylpiperazinyl;
- aminosulfonylpiperazinylC1-6alkyl;
- di(C1-6alkyl)aminosulfonylpiperazinyl;
- di(C1-6alkyl)aminosulfonylpiperazinylC1-6alkyl;
- hydroxyC1-6alkylpiperazinyl;
- hydroxyC1-6alkylpiperazinylC1-6alkyl;
- C1-6alkyloxypiperidinyl;
- C1-6alkyloxypiperidinylC1-6alkyl;
- piperidinylaminoC1-6alkylamino;
- piperidinylaminoC1-6alkylaminoC1-6alkyl;
- (C1-6alkylpiperidinyl)(hydroxyC1-6alkyl)aminoC1-6alkylamino;
- (C1-6alkylpiperidinyl)(hydroxyC1-6alkyl)aminoC1-6alkylaminoC1-6alkyl;
- hydroxyC1-6alkyloxyC1-6alkylpiperazinyl;
- hydroxyC1-6alkyloxyC1-6alkylpiperazinylC1-6alkyl;
- (hydroxyC1-6alkyl)(C1-6alkyl)amino;
- (hydroxyC1-6alkyl)(C1-6alkyl)aminoC1-6alkyl;
- hydroxyC1-6alkylaminoC1-6alkyl;
- di(hydroxyC1-6alkyl)aminoC1-6alkyl;
- pyrrolidinylC1-6alkyl;
- pyrrolidinylC1-6alkyloxy;
- pyrazolyl;
- thiopyrazolyl;
- pyrazolyl substituted with two substituents selected from C1-6alkyl or trihaloC1-6alkyl;
- pyridinyl;
- pyridinyl substituted with C1-6alkyloxy, aryloxy or aryl;
- pyrimidinyl;
- tetrahydropyrimidinylpiperazinyl;
- tetrahydropyrimidinylpiperazinylC1-6alkyl;
- quinolinyl;
- indolyl;
- phenyl;
- phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, C1-6alkyl, C1-6alkyloxy, hydroxyC1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC1-4alkyloxy, C1-4alkylsulfonyl, C1-4alkyloxyC1-4alkyloxy, C1-4alkyloxycarbonyl, aminoC1-4alkyloxy, di(C1-4alkyl)aminoC1-4alkyloxy, di(C1-4alkyl)amino, di(C1-4alkyl)aminocarbonyl, di(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkylaminoC1-4alkyl, di(C1-4alkyl)amino(C1-4alkyl)amino, di(C1-4alkyl)amino(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)amino, di(C1-4alkyl)aminoC1-4alkyl(C1-4alkyl)aminoC1-4alkyl, aminosulfonylamino(C1-4alkyl)amino, aminosulfonylamino(C1-4alkyl)aminoC1-4alkyl, di(C1-4alkyl)aminosulfonylamino(C1-4alkyl)amino, di(C1-4alkyl)aminosulfonylamino(C1-4alkyl)aminoC1-6alkyl, cyano, piperidinylC1-4alkyloxy, pyrrolidinylC1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC1-4alkyl, di(C1-4alkyl)aminosulfonylpiperazinyl, di(C1-4alkyl)aminosulfonylpiperazinylC1-4alkyl, hydroxyC1-4alkylpiperazinyl, hydroxyC1-4alkylpiperazinylC1-4alkyl, C1-4alkyloxypiperidinyl, C1-4alkyloxypiperidinylC1-4alkyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinyl, hydroxyC1-4alkyloxyC1-4alkylpiperazinylC1-4alkyl, (hydroxyC1-4alkyl)(C1-4alkyl)amino, (hydroxyC1-4alkyl)(C1-4alkyl)aminoC1-4alkyl, di(hydroxyC1-4alkyl)amino, di(hydroxyC1-4alkyl)aminoC1-4alkyl, furanyl, furanyl substituted with —CH═CH—CH═CH—, pyrrolidinylC1-4alkyl, pyrrolidinylC1-4alkyloxy, morpholinyl, morpholinylC1-4alkyloxy, morpholinylC1-4alkyl, morpholinylC1-4alkylamino, morpholinylC1-4alkylaminoC1-4alkyl, piperazinyl, C1-4alkylpiperazinyl, C1-4alkylpiperazinylC1-4alkyloxy, piperazinylC1-4alkyl, C1-4alkylpiperazinylC1-4alkyl, C1-4alkylpiperazinylC1-4alkylamino, C1-4alkylpiperazinylC1-4alkylaminoC1-6alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC1-4alkyl, piperidinylaminoC1-4alkylamino, piperidinylaminoC1-4alkylaminoC1-4alkyl, (C1-4alkylpiperidinyl)(hydroxyC1-4alkyl)aminoC1-4alkylamino, (C1-4alkylpiperidinyl)(hydroxyC1-4alkyl)aminoC1-4alkylaminoC1-4alkyl, pyridinylC1-4alkyloxy, hydroxyC1-4alkylamino, hydroxyC1-4alkylaminoC1-4alkyl, di(C1-4alkyl)aminoC1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC1-4alkyloxy, or thiophenylC1-4alkylamino;
- each R5 and R6 can be placed on the nitrogen in replacement of the hydrogen;
- wherein aryl in the above is phenyl, or phenyl substituted with one or more substituents that is each independently halo, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.
118 more elements
A compound of formula (I),
- the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein
- n is 0;
- m is 2;
- t is 0;
- Q is C;
- X is nitrogen;
- Y is nitrogen;
- Z is —O—;
- R1 is —C(O)NR3R4, —C(O)—C1-6alkanediylSR7, —NR8C(O)N(OH)R7, —NR8C(O)C1-6alkanediylSR7, —NR8C(O)C═N(OH)R7 wherein R3 and R4 are each independently selected from hydrogen, hydroxy, hydroxyC1-6alkyl or aminoC1-6alkyl;
- R2 is hydrogen, hydroxy, amino, hydroxyC1-6alkyl, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl, aminocarbonyl, aminoC1-6alkyl, C1-6alkylaminoC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl;
- -L- is a bivalent radical selected from C1-6alkanediyl, carbonyl or sulfonyl;
- is a radical selected from
- wherein each s is independently 0, 1, 2, 3, or 4, as allowed;
- R5 is hydrogen;
- halo;
- hydroxy;
- amino;
- nitro;
- trihaloC1-6alkyl;
- trihaloC1-6alkyloxy;
- C1-6alkyl;
- C1-6alkyloxy;
- C1-6alkylcarbonyl;
- C1-6alkyloxycarbonyl;
- C1-6alkylsulfonyl;
- hydroxyC1-6alkyl;
- aryloxy;
- di(C1-6alkyl)amino;
- cyano;
- thiophenyl;
- furanyl;
- furanyl substituted with hydroxyC1-6alkyl;
- benzofuranyl;
- imidazolyl;
- oxazolyl;
- oxazolyl substituted with aryl and C1-6alkyl;
- C1-6alkyltriazolyl;
- tetrazolyl;
- pyrrolidinyl;
- pyrrolyl;
- morpholinyl;
- C1-6alkylmorpholinyl;
- piperazinyl;
- C1-6alkylpiperazinyl;
- hydroxyC1-6alkylpiperazinyl;
- C1-6alkyloxypiperidinyl;
- pyrazolyl;
- pyrazolyl substituted with one or two substituents selected from C1-6alkyl or trihaloC1-6alkyl;
- pyridinyl;
- pyridinyl substituted with C1-6alkyloxy, aryloxy or aryl;
- pyrimidinyl;
- quinolinyl;
- indolyl;
- phenyl;
- or phenyl substituted with one or two substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl;
- and
- R6 is hydrogen;
- halo;
- hydroxy;
- amino;
- nitro;
- trihaloC1-6alkyl;
- trihaloC1-6alkyloxy;
- C1-6alkyl;
- C1-6alkyloxy;
- C1-6alkylcarbonyl;
- C1-6alkyloxycarbonyl;
- C1-6alkylsulfonyl;
- hydroxyC1-6alkyl;
- aryloxy;
- di(C1-6alkyl)amino;
- cyano;
- pyridinyl;
- phenyl;
- or phenyl substituted with one or two substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl
- each R5 and R6 can be placed on the nitrogen in replacement of the hydrogen;
- wherein aryl in the above is phenyl, or phenyl substituted with one or more substituents that is each independently halo, C1-6alkyl, C1-6alkyloxy, trifluoromethyl, cyano, or hydroxycarbonyl.
74 more elements
Dependencies are inferred from the claim text.