	US 7,501,417 B2
	Aminocarbonyl-derivatives as novel inhibitors of histone deacetylase
Kristof Van Emelen, Sint-Niklaas (Belgium); Hans Louis Jos De Winter, Schilde (Belgium); Alexey Borisovich Dyatkin, Ambler, Pa. (US); Marc Gustaaf Celine Verdonck, Gierle (Belgium); Lieven Meerpoel, Beerse (Belgium); and Jimmy Arnold Viviane Van heusden, Oelegem (Belgium)
Assigned to Janssen Pharmaceutica, N.V., Beerse (Belgium)
Appl. No. 10/507,271 PCT Filed Mar. 11, 2003, PCT No. PCT/EP03/02511 § 371(c)(1), (2), (4) Date Sep. 09, 2004, PCT Pub. No. WO03/076421, PCT Pub. Date Sep. 18, 2003.
Claims priority of provisional application 60/363799, filed on Mar. 13, 2002.
Prior Publication US 2005/0222414 A1, Oct. 06, 2005
Int. Cl. C07D 239/42 (2006.01); C07D 295/20 (2006.01); A61K 31/506 (2006.01); A61P 35/00 (2006.01)

U.S. Cl. 514—252.14 [514/275; 544/295; 544/330]

10 Claims

1. A compound of formula (I),

N-oxide forms, pharmaceutically acceptable salts stereo-chemically isomeric forms thereof, wherein

n is 0, 1, 2 or 3 and when n is 0 then a direct bond is intended;

each Q is

each X is nitrogen;

each Y is nitrogen;

each Z is nitrogen; or

R¹is —C(O)NR⁷R⁸, —N(H)C(O)R⁹, —C(O)—C_1-6alkanediylSR⁹, —NR¹⁰C(O)N(OH)R⁹, —NR¹⁰C(O)C_1-6alkanediylSR⁹, or —NR¹⁰C(O)C═N(OH)R⁹wherein R⁷and R⁸are each independently selected from hydrogen, hydroxy, C_1-6alkyl, hydroxyC_1-6alkyl, aminoC_1-6alkyl or aminoaryl;

R⁹is independently selected from hydrogen, C_1-6alkyl, C_1-6alkylcarbonyl, arylC_1-6alkyl, C_1-6alkylpyrazinyl, pyridinone, pyrrolidinone or methylimidazolyl;

R¹⁰is independently selected from hydrogen or C_1-6alkyl;

R²is hydrogen, halo, hydroxy, amino, nitro, C_1-6alkyl, C_1-6alkyloxy, trifluoromethyl, di(C_1-6alkyl)amino, hydroxyamino or naphtalenylsulfonylpyrazinyl;

R³is hydrogen, hydroxy, amino, hydroxyC_1-6alkyl, C_1-6alkyl, C_1-6alkyloxy, arylC_1-6alkyl, aminocarbonyl, hydroxycarbonyl, aminoC_1-6alkyl, aminocarbonylC_1-6alkyl, hydroxycarbonylC_1-6alkyl, hydroxyaminocarbonyl, C_1-6alkyloxycarbonyl, C_1-6alkylaminoC_1-6alkyl or di(C_1-6alkyl)aminoC_1-6alkyl;

when Z is equal to nitrogen, then -L- is a direct bond;

when Z is equal to

then -L- is —NH— or the bivalent radical —C_1-6alkanediylNH—;

R⁴is hydrogen, C_1-6alkyl, C_3-10cycloalkyl, hydroxyC_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl or aryl;

is a radical selected from

wherein each s is independently 0, 1, 2, 3, 4 or 5;

each R⁵and R⁶are independently selected from hydrogen; halo; hydroxy; amino; nitro; trihaloC_1-6alkyl; trihaloC_1-6alkyloxy; C_1-6alkyl; C_1-6alkyl substituted with aryl and C_3-10cycloalkyl; C_1-6alkyloxy; C_1-6alkyloxyC_1-6alkyloxy; C_1-6alkylcarbonyl; C_1-6alkyloxycarbonyl; C_1-6alkylsulfonyl; cyanoC_1-6alkyl; hydroxyC_1-6alkyl; hydroxyC_1-6alkyloxy; hydroxyC_1-6alkylamino; aminoC_1-6alkyloxy; di(C_1-6alkyl)aminocarbonyl; di(hydroxyC_1-6alkyl)amino; (aryl)(C_1-6alkyl)amino; di(C_1-6alkyl)aminoC_1-6alkyloxy; di(C_1-6alkyl)aminoC_1-6alkylamino; di(C_1-6alkyl)aminoC_1-6alkylaminoC_1-6alkyl; arylsulfonyl; arylsulfonylamino; aryloxy; aryloxyC_1-6alkyl; arylC_2-6alkenediyl; di(C_1-6alkyl)amino; di(C_1-6alkyl)aminoC_1-6alkyl; di(C_1-6alkyl)amino(C_1-6alkyl)amino; di(C_1-6alkyl)amino(C_1-6alkyl)aminoC_1-6alkyl; di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)amino; di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl; aminosulfonylamino(C_1-6alkyl)amino; aminosulfonylamino(C_1-6alkyl)aminoC_1-6alkyl; di(C_1-6alkyl)aminosulfonylamino(C_1-6alkyl)amino; di(C_1-6alkyl)aminosulfonylamino(C_1-6alkyl)aminoC_1-6alkyl; cyano; thiophenyl; thiophenyl substituted with di(C_1-6alkyl)aminoC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl, C_1-6alkylpiperazinylC_1-6alkyl, hydroxyC_1-6alkylpiperazinylC_1-6alkyl, hydroxyC_1-6alkyloxyC_1-6alkylpiperazinylC_1-6alkyl, di(C_1-6alkyl)aminosulfonylpiperazinylC_1-6alkyl, C_1-6alkyloxypiperidinyl, C_1-6alkyloxypiperidinylC_1-6alkyl, morpholinylC_1-6alkyl, hydroxyC_1-6alkyl(C_1-6alkyl)aminoC_1-6alkyl, or di(hydroxyC_1-6alkyl)aminoC_1-6alkyl; furanyl; furanyl substituted with hydroxyC_1-6alkyl; benzofuranyl; imidazolyl; oxazolyl; oxazolyl substituted with aryl and C_1-6alkyl; C_1-6alkyltriazolyl; tetrazolyl; pyrrolidinyl; pyrrolyl; piperidinylC_1-6alkyloxy; morpholinyl; C_1-6alkylmorpholinyl; morpholinylC_1-6alkyloxy; morpholinylC_1-6alkyl; morpholinylC_1-6alkylamino; morpholinylC_1-6alkylaminoC_1-6alkyl; piperazinyl; C_1-6alkylpiperazinyl; C_1-6alkylpiperazinylC_1-6alkyloxy; piperazinylC_1-6alkyl; naphtalenylsulfonylpiperazinyl; naphtalenylsulfonylpiperidinyl; naphtalenylsulfonyl: C_1-6alkylpiperazinylC_1-6alkyl; C_1-6alkylpiperazinylC_1-6alkylamino; C_1-6alkylpiperazinylC_1-6alkylaminoC_1-6alkyl; C_1-6alkylpiperazinylsulfonyl; aminosulfonylpiperazinylC_1-6alkyloxy; aminosulfonylpiperazinyl; aminosulfonylpiperazinylC_1-6alkyl; di(C_1-6alkyl)aminosulfonylpiperazinyl; di(C_1-6alkyl)aminosulfonylpiperazinylC_1-6alkyl; hydroxyC_1-6alkylpiperazinyl; hydroxyC_1-6alkylpiperazinylC_1-6alkyl; C_1-6alkyloxypiperidinyl; C_1-6alkyloxypiperidinylC_1-6alkyl; piperidinylaminoC_1-6alkylamino; piperidinylaminoC_1-6alkylaminoC_1-6alkyl; (C_1-6alkylpiperidinyl)(hydroxyC_1-6alkyl)aminoC_1-6alkylamino; (C_1-6alkylpiperidinyl)(hydroxyC_1-6alkyl)aminoC_1-6alkylaminoC_1-6alkyl; hydroxyC_1-6alkyloxyC_1-6alkylpiperazinyl; hydroxyC_1-6alkyloxyC_1-6alkylpiperazinylC_1-6alkyl; (hydroxyC_1-6alkyl)(C_1-6alkyl)amino; (hydroxyC_1-6alkyl)(C_1-6alkyl)aminoC_1-6alkyl; hydroxyC_1-6alkylaminoC_1-6alkyl; di(hydroxyC_1-6alkyl)aminoC_1-6alkyl; pyrrolidinylC_1-6alkyl; pyrrolidinylC_1-6alkyloxy; pyrazolyl; thiopyrazolyl; pyrazolyl substituted with two substituents selected from C_1-6alkyl or trihaloC_1-6alkyl; pyridinyl; pyridinyl substituted with C_1-6alkyloxy, aryloxy or aryl; pyrimidinyl; tetrahydropyrimidinylpiperazinyl; tetrahydropyrimidinylpiperazinylC_1-6alkyl; quinolinyl; indolyl; phenyl; phenyl substituted with one, two or three substituents independently selected from halo, amino, nitro, C_1-6alkyl, C_1-6alkyloxy, hydroxyC_1-4alkyl, trifluoromethyl, trifluoromethyloxy, hydroxyC_1-4alkyloxy, C_1-4alkylsulfonyl, C_1-4alkyloxyC_1-4alkyloxy, C_1-4alkyloxycarbonyl, aminoC_1-4alkyloxy, di(C_1-4alkyl)aminoC_1-4alkyloxy, di(C_1-4alkyl)amino, di(C_1-4alkyl)aminocarbonyl, di(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)amino(C_1-4alkyl)amino, di(C_1-4alkyl)amino(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-4alkyl)amino, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-4alkyl)aminoC_1-4alkyl, aminosulfonylamino(C_1-4alkyl)amino, aminosulfonylamino(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminosulfonylamino(C_1-4alkyl)amino, di(C_1-4alkyl)aminosulfonylamino(C_1-4alkyl)aminoC_1-6alkyl, cyano, piperidinylC_1-4alkyloxy, pyrrolidinylC_1-4alkyloxy, aminosulfonylpiperazinyl, aminosulfonylpiperazinylC_1-4alkyl, di(C_1-4alkyl)aminosulfonylpiperazinyl, di(C_1-4alkyl)aminosulfonylpiperazinylC_1-4alkyl, hydroxyC_1-4alkylpiperazinyl, hydroxyC_1-4alkylpiperazinylC_1-4alkyl, C_1-4alkyloxypiperidinyl, C_1-4alkyloxypiperidinylC_1-4alkyl, hydroxyC_1-4alkyloxyC_1-4alkylpiperazinyl, hydroxyC_1-4alkyloxyC_1-4alkylpiperazinylC_1-4alkyl, (hydroxyC_1-4alkyl)(C_1-4alkyl)amino, (hydroxyC_1-4alkyl)(C_1-4alkyl)aminoC_1-4alkyl, di(hydroxyC_1-4alkyl)amino, di(hydroxyC_1-4alkyl)aminoC_1-4alkyl, furanyl, furanyl substituted with —CH═CH—CH═CH—, pyrrolidinylC_1-4alkyl, pyrrolidinylC_1-4alkyloxy, morpholinyl, morpholinylC_1-4alkyloxy, morpholinylC_1-4alkyl, morpholinylC_1-4alkylamino, morpholinylC_1-4alkylaminoC_1-4alkyl, piperazinyl, C_1-4alkylpiperazinyl, C_1-4alkylpiperazinylC_1-4alkyloxy, piperazinylC_1-4alkyl, C_1-4alkylpiperazinylC_1-4alkyl, C_1-4alkylpiperazinylC_1-4alkylamino, C_1-4alkylpiperazinylC_1-4alkylaminoC_1-6alkyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylpiperazinylC_1-4alkyl, piperidinylaminoC_1-4alkylamino, piperidinylaminoC_1-4alkylaminoC_1-4alkyl, (C_1-4alkylpiperidinyl)(hydroxyC_1-4alkyl)aminoC_1-4alkylamino, (C_1-4alkylpiperidinyl)(hydroxyC_1-4alkyl)aminoC_1-4alkylaminoC_1-4alkyl, pyridinylC_1-4alkyloxy, hydroxyC_1-4alkylamino, hydroxyC_1-4alkylaminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkylamino, aminothiadiazolyl, aminosulfonylpiperazinylC_1-4alkyloxy, or thiophenylC_1-4alkylamino;

each R⁵and R⁶can be placed on the nitrogen in replacement of the hydrogen;

aryl in the above is phenyl, or phenyl substituted with one or more substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy, trifluoromethyl, cyano or hydroxycarbonyl.