Methods of administering apo B-secretion/MTP inhibitors

Claim 2

The use as claimed in claim 1 wherein said apolipoprotein B-secretion/microsomal triglyceride transfer protein inhibitor is selected from: (i) a compound of formula (I) the stereoisomers, and hydrates thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers and hydrates, wherein L represents: X-Y-Z, wherein: X is.a.moiety selected from the group consisting of CH 2 , CO, CS, or SQ 2 ; Y is a moiety selected from the group consisting of a direct link, aliphatic hydrocarbylene radicals having up to 20 carbon atoms, which radical may be monosubstituted by hydroxy, (C 1 -C 10 )alkoxy, (C 1 -C 10 )acyl, (C 1 -C 10 )acyloxy, or (C 6 -C 10 )aryl, NH, and O, provided that if X is CH 2 , Y is a direct link; and Z is a moiety selected from the group consisting of: (1) hydrogen, halogen, cyano, (2) hydroxy, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, (C 1 -C 10 )acyl, thiophenylcarbonyl, (C 1 -C 10 )alkoxycarbonyl, (3) (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 6 -C 10 )aryl(C 1 -C 10 )alkylamino, provided that Y is not O or NH, (4) unsubstituted vinyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl and fused benz derivatives thereof, (C 7 -C 10 )Polycycloalkyl, (C 4 -C 8 )cycloalkenyl, (C 7 -C 10 )polycycloalkenyl, (5) (C 6 -C 10 )aryloxy, (C 6 -C 10 )arylthio, (C 6 -C 10 )aryl(C 1 -C 10 )alkoxy, (C 6 -C 10 )aryl(C 1 -C 10 )alkylthio, (C 3 -C 8 )cycloalkyloxy, (C 4 -C 8 )cycloalkenyloxy, (6) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5 to 14 ring atoms, wherein said radicals contain a total of from 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur, and wherein the individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, provided that if X is CH 2 , Z is H or is selected from groups (4) and (6), wherein, when Z contains one or more rings, said rings may each independently bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylamino(C 1 -C 10 )alkoxy, (C 1 -C 3 )perfluoroalkyl, (C 1 -C 3 )perfluoroalkoxy, (C 1 -C 10 )acyl, (C 1 -C 10 )acyloxy, (C 1 -C 10 )acyloxy(C 1 -C 10 )alkyl, and pyrrolidinyl; or G, wherein G is selected from the group consisting of: (a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen, and sulfur, wherein the individual rings of said heterocyclic ring may be independently saturated, partially saturated or aromatic, and wherein each of said phenyl or heterocyclic rings may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acyloxy, (C 1 -C 6 )acylamino and (C 1 -C 6 )perfluoroacylamino; (b) -CH 2 CN, (c) (d) (C 2 -C 12 )alkyl or (C 2 -C 12 )perfluoroalkyl wherein each of said (C 2 -C 12 )alkyl and (C 2 -C 12 )perfluoroalkyl is substituted optionally with from 1-3 substituents selected independently from: (1) phenyl, halogen, nitro, cyano, hydroxy, -NR 1 R 2 , -OCOR 3 , (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 4 )thioalkoxy or (C 1 -C 4 )perfluorothioalkoxy, where R 1 and R 2 in the definition of -NR 1 R 2 are each selected independently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )perfluoroacyl, aminocarbonyl, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, aminosulfonyl, (C 1 -C 4 )alkylaminosulfonyl, di(C 1 -C 4 )alkylaminosulfonyl, (C 1 -C 4 )perfluoroalkylaminosulfonyl, di(C 1 -C 4 )perfluoroalkylaminosulfonyl, (C 1 -C 4 )alkylsulfonyl, and (C 1 -C 4 )perfluoroalkylsulfonyl, or where R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a saturated, partially-saturated or aromatic heterocyclic ring, wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms and incorporates optionally an additional 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, and (C 1 -C 10 )acyloxy, where R 3 in the definition of -OCOR 3 is selected from -NR 1 R 2 , phenyl, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )perfluoroalkoxy, (2) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy, and (3) a saturated, partially-saturated or aromatic heterocyclic ring containing a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy; (e) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 - C 8 )cycloalkyl and (C 3 -C 8 )cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy; and (f) -(CH 2 ) n COR 4 , where R 4 in the definition of -(CH 2 ) n COR 4 is selected from hydroxy, phenyl, -NR 1 R 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkenyl, where n is an integer from 1 to 4; (ii) a compound of formula (Ia) the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers, and prodrugs, wherein each R a and R b is independently hydrogen or C 1 -C 8 alkyl; each n is independently 0, 1, 2 or 3; each X is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substitited heterocycloalkyl; R 1 is hydrogen or C 1 -C 8 alkyl; and R 2 is hydrogen, -(CR a R a ) n -X, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a 3 to 7 membered heterocycloalkyl ring comprising from 1 to 3 heteroatoms; and (III) a compound selected from the group consisting of: 9-[4-[4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide, and the pharmaceutically acceptable salts thereof; 2-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-one, and the pharmaceutically acceptable salts thereof; 9-[4-(4-[2-4-bifluoromethylphenyl)benzoylamino]piperidin-1-yl)butyl]-N-2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, and the pharmaceutically acceptable salts thereof; 9-[4-[4-(2-benzothiazol-2-yl-benzoylamino)-piperidin-1-yl]-butyl]-9H-fluorene-9-carboxylic acid-{2,2,2-trifluoroethyl)-amide, and the pharmaceutically acceptable salts thereof; [11a-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione; [11a-R]-cyclopentyl-7-(prop-2-enyl)-8[(pyridin-2-yl)methoxy]-2,3,11,11a-tetrahydro-6H-pyrazino-[1,2b]-isoquinoline-1,4-dione; 2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido[2,3b]indol-9-ylmethyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)-acetamide; and 2-cyclopentyl-N-(2-hydroxy-1-phenyl-ethyl)-2-[4-(quinoin-2-ylmethoxy)-phenyl]-acetamide.

Claim 3

The use as claimed in claim 2 wherein said inhibitor is a compound of formula (I) the stereoisomers and hydrates thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers and hydrates, wherein L represents: X-Y-Z, wherein: X is a moiety selected from the group consisting of CH 2 , CO, CS, or SO 2 ; Y is a moiety selected from the group consisting of a direct link, aliphatic hydrocarbylene radicals having up to 20 carbon atoms, which radical may be monosubstituted by hydroxy, (C 1 -C 10 )alkoxy, (C 1 -C 10 )acyl, (C 1 -C 10 )acyloxy, or (C 6 -C 10 )aryl, NH, and O, provided that if X is CH 2 , Y is a direct link; and Z is a moiety selected from the group consisting of: (1) hydrogen, halogen, cyano, (2) hydroxy, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio, (C 1 -C 10 )acyl, thiophenylcarbonyl, (C 1 -C 10 )alkoxycarbonyl, (3) (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 6 -C 10 )aryl(C 1 -C 10 )alkylamino, provided that Y is not O or NH, (4) unsubstituted vinyl, (C 6 -C 10 )aryl, (C 3 -C 8 )cycloalkyl and fused benz derivatives thereof, (C 7 C 10 )polycycloalkyl, (C 4 -C 8 )cycloalkenyl, (C 7 -C 10 )polycycloalkenyl, (5) (C 6 -C 10 )aryloxy, (C 6 -C 10 )arylthio, (C 6 -C 10 )aryl(C 1 -C 10 )alkoxy, (C 6 -C 10 )aryl(C 1 -C 10 )alkylthio, (C 3 -C 8 )cycloalkyloxy, (C 4 -C 8 )cycloalkenyloxy, (6) heterocyclyl selected from the group consisting of monocyclic radicals and fused polycyclic radicals, wherein said radicals contain a total of from 5 to 14 ring atoms, wherein said radicals contain a total of from 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur, and wherein the individual rings of said radicals may be independently saturated, partially unsaturated, or aromatic, provided that if X is CH 2 , Z is H or is selected from groups (4) and (6), wherein, when Z contains one or more rings, said rings may each independently bear 0 to 4 substituents independently selected from halo, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, halophenylthio, benzyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylamino(C 1 -C 10 )alkoxy, (C 1 -C 3 )perfluoroalkyl, (C 1 -C 3 )perfluoroalkoxy, (C 1 -C 10 )acyl, (C 1 -C 10 )acyloxy, (C 1 -C 10 )acyloxy(C 1 -C 10 )alkyl, and pyrrolidinyl; or G, wherein G is selected from the group consisting of: (a) a phenyl or heterocyclic ring wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen, and sulfur, wherein the individual rings of said heterocyclic ring may be independently saturated, partially saturated or aromatic, and wherein each of said phenyl or heterocyclic rings may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acyloxy, (C 1 -C 6 )acylamino and (C 1 -C 6 )perfluoroacylamino; (b) -CH 2 CN, (c) (d) (C 2 -C 12 )alkyl or (C 2 -C 12 )perfluoroalkyl wherein each of said (C 2 -C 12 )alkyl and (C 2 -C 12 )perfluoroalkyl is substituted optionally with from 1-3 substituents selected independently from: (1) phenyl, halogen, nitro, cyano, hydroxy, -NR 1 R 2 , -OCOR 3 , (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 4 )thioalkoxy or (C 1 -C 4 )perfluorothioalkoxy, where R 1 and R 2 in the definition of -NR 1 R 2 are each selected independently from hydrogen, formyl, phenyl, benzyl, benzoyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkenyl, (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 6 )acyl, (C 1 -C 6 )perfluoroacyl, aminocarbonyl, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, aminosulfonyl, (C 1 -C 4 )alkylaminosulfonyl, di(C 1 -C 4 )alkylaminosulfonyl, (C 1 -C 4 )perfluoroalkylaminosulfonyl, di(C 1 -C 4 )perfluoroalkylaminosulfonyl, (C 1 -C 4 )alkylsulfonyl, and (C 1 -C 4 )perfluoroalkylsulfonyl, or where R 1 and R 2 , taken together with the nitrogen atom to which they are attached, form a saturated, partially-saturated or aromatic heterocyclic ring, wherein said heterocyclic ring contains a total of from 3 to 14 ring atoms and incorporates optionally an additional 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, and (C 1 -C 10 )acyloxy, where R 3 in the definition of -OCOR 3 is selected from -NR 1 R 2 , phenyl, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 6 )alkoxy and (C 1 -C 6 )perfluoroalkoxy, (2) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C4)perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy, and (3) a saturated, partially-saturated or aromatic heterocyclic ring containing a total of from 3 to 14 ring atoms, wherein said heterocyclic ring incorporates a total of from 1 to 4 ring heteroatoms selected independently from oxygen, nitrogen and sulfur, wherein said heterocyclic ring may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkylthio, (C 1 -C 10 )alkflamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy; (e) (C 3 -C 8 )cycloalkyl or (C 3 -C 8 )cycloalkenyl wherein each of said (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )cycloalkenyl may have optionally from 1 to 4 substituents selected independently from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, benzyl, benzoyl, benzyloxy, (C 1 -C 10 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 10 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 1 -C 10 )alkoxycarbonyl, (C 1 -C 10 )alkythio, (C 1 -C 10 )alkylamino, di(C 1 -C 10 )alkylamino, (C 1 -C 10 )alkylaminocarbonyl, di(C 1 -C 10 )alkylaminocarbonyl, (C 1 -C 10 )acyl, (C 1 -C 10 )perfluoroacyl, (C 1 -C 10 )acylamino, (C 1 -C 10 )perfluoroacylamino, (C 1 -C 10 )acyloxy; and (f) -(CH 2 ) n COR 4 , where R 4 in the definition of -(CH 2 ) n COR 4 is selected from hydroxy, phenyl, -NR 1 R 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )perfluoroalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )perfluoroalkoxy, (C 3 -C 8 )cycloalkyl, and (C 3 -C 8 )cycloalkenyl, where n is an integer from 1 to 4.

Claim 4

The use as claimed in claim 3 wherein said compound of formula (I) is selected from the group consisting of: 4'-trifluoromethyl-biphenyl-2-carboxylic acid-(2-(1H-(1,2,4-triazol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide; 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2-acetylaminoethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl amide; 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2-methoxyethyl)-1,2,3,4-tetrahydroisoquinlin-6-yl]-amide; 4'-trifluoromethyl-biphenyl-2-carboxylic acid-[2-(2,2-diphenylethyl)-1,2,3,4-tetrahydroisoquinlin-6-yl]-amide; 2-(6-(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl)-carbamic acid methyl ester; 4'-trifluoromethyl-biphenyl-2-catoxylic acid-[2-(thiophen-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinlin-6-yl]-amide; 4'-trifluoromethyl-biphenyl-2-carboxyic acid-(2-pyridin-2-ylmethyl)-1,2,3,4-tetralhydroisoquinlin-6-yl)-amide; and 6-[(4'-trifluoromethyl-biphenyl-2-cabonyl)-amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic add [(R)-1-phenyl-ethyl]-amide; the stereoisomers and hydrates thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers, and hydrates.

Claim 5

The use as claimed in claim 2 wherein said inhibitor is a compound of formula (la) the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers, and prodrugs, wherein each R a and R b is independently hydrogen or C 1 -C 8 alkyl; each n is independently 0, 1, 2 or 3; each X is independently aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substitited heterocycloalkyl; R 1 is hydrogen or C 1 -C 8 alkyl; and R 2 is hydrogen, -(CR a R a ) n -X, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a 3 to 7 membered heterocycloalkyl ring comprising from 1 to 3 heteroatoms.

Claim 6

The use as claimed in claim 5 wherein said compound of formula (la) is selected from the group consisting of: 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-(diphenylpyridin-2-yl-methyl)-amide; 7-[(4'-triluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-(phenylpyridin-2-yl-methyl)-amide; 7-((4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (1 -methyl-1-phenyl-ethyl)-amide; 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid(1-phenyl-propyl)-amide; (R)-7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-(1-phenyl-ethyl)-amide; 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-(1-pyridin-2-yl-propyl)-amide; 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-(2-pyridin-2-yl-ethyl)-amide; 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-ethylamide; 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-isopropylamide; and 7-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid-diethylamide; the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers and prodrugs.

Claim 7

The use as claimed in claim 2 wherein said inhibitor is a compound selected from the group consisting of: 9-[4-(4-(2,3-dihydro-1-oxo-1H-isoindol-2-yl)-1-piperidinyl]butyl]-N-propyl-9H-fluorene-9-carboxamide, and the pharmaceutically acceptable salts thereof; 2-[1-(3,3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-1H-isoindol-1-one, and the pharmaceutically acceptable salts thereof; 9-[4-(4-[2-(4-trifluoromethylphenyl)benzoylamino]piperidin-1-yl)butyq-N-2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide, and the pharmaceutically acceptable salts thereof; 9-(4-[4-(2-benzothiazol-2-yl-benzoylamino)-piperidin-1-yl]-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide, and the pharmaceutically acceptable salts thereof; [11 a-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-(prop-2-enyl)-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]isoquinoline-1,4-dione; [11a-R]-Cyclopentyl-7-(prop-2-enyl)-8-[(pyridin-2-yl)methoxy]-2,3,11,11a-tetrahydro-6H-pyrazino[1,2b]-isoquinoline-1,4-dione; 2-cyclopentyl-2-[4-(2,4-dimethyl-pyrido[2,3b]indol-9-ylmethyl)-phenyl]-N-(2-hydroxy-1-phenyl-ethyl)-acetamide; and 2-cyclopentyl-N-(2-hydroxy-1-phenyl-ethyl)-2-[4-(quinolin-2-ylmethoxy)-phenyl]-acetamide.

Claim 8

The use as claimed in claim 1 wherein said medicament is intended for oral administration.

Claim 9

The use as claimed in claim 1 wherein said medicament is intended for parenteral administration.

Claim 10

The use as claimed in claim 1 wherein said medicament is intended for transdermal administration.