Substituted urea neuropeptide Y Y5 receptor antagonists

Abstract

A novel class of compounds such as antagonists of the neuropeptide Y Y5 receptor, methods of making such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention or amelioration of one or more diseases associated with the neuropeptide Y Y5 receptor are disclosed.

Description

FIELD OF THE INVENTION

[0002] The present invention relates to neuropeptide Y Y5 receptor antagonists useful in the treatment of metabolic and eating disorders, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.

BACKGROUND OF THE INVENTION

[0003] Neuropeptide Y (NPY) is a 36 amino acid neuropeptide that is widely distributed in the central and peripheral nervous systems. NPY is a member of the pancreatic polypeptide family that also includes peptide YY and pancreatic polypeptide (Wahlestedt, C., and Reis, D., Ann. Rev. Toxicol., 32, 309,1993). NPY elicits its physiological effects by activation of at least six receptor subtypes designated Y1, Y2, Y3, Y4, Y5 and Y6 (Gehlert, D., Proc. Soc. Exp. Biol. Med., 218, 7, 1998; Michel, M. et al., Pharmacol. Rev., 50, 143,1998). Central administration of NPY to animals causes dramatically increased food intake and decreased energy expenditure (Stanley, B. and Leibowitz, S., Proc. Natl. Acad. Sci. USA 82: 3940,1985; Billington et al., Am J. Physiol., 260, R321, 1991). These effects are believed to be mediated at least in part by activation of the NPY Y5 receptor subtype. The isolation and characterization of the NPY Y5 receptor subtype has been reported (Gerald, C. et al., Nature, 1996, 382, 168; Gerald, C. et al. WO 96/16542). Additionally, it has been reported that activation of the NPY Y5 receptor by administration of the Y5—selective agonist [D-Trp32]NPY to rats stimulates feeding and decreases energy expenditure (Gerald, C. et al., Nature, 1996, 382,168; Hwa, J. et al., Am. J. Physiol., 277 (46), R1428,1999).

[0004] Published PCT patent application WO 00/27845 describes a class of compounds, characterized therein as spiro-indolines, said to be selective neuropeptide Y Y5 receptor antagonists and useful for the treatment of obesity and the complications associated therewith. Known urea derivatives indicated as possessing therapeutic activity are described in U.S. Pat. No. 4,623,662 (antiatherosclerotic agents) and U.S. Pat. No. 4,405,644 (treatment of lipometabolism). Provisional application, U.S. Serial No. 60/232,255 describes a class of substituted urea neuropeptide Y Y5 receptor antagonists.

SUMMARY OF THE INVENTION

[0005] The present invention relates to compounds represented by the structural formula I: 1

[0006] R1 is hydrogen or (C1-C6)alkyl;

[0007] R2 is hydrogen, (C1-C6)alkyl, (C3-C9)cycloalkyl or (C3-C7)cycloalkyl(C1-C6)alkyl; 2

[0008] where Z is OR10 or —N(R9)(R10);

[0009] j is 0, 1 or 2;

[0010] k is 1 or 2;

[0011] l is 0, 1 or 2;

[0012] m is 0, 1 or 2;

[0013] p is 1, 2 or 3;

[0014] r is 1, 2 or 3;

[0015] and s is 0, 1, 2, 3, 4, 5 or 6;

[0016] R4 is a subsituent independently selected from hydrogen, —OH, halogen, haloalkyl, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, —CN, (C1-C6)alkylO-, (C3-C7)cycloalkylO-, (C1-C6)alkyl(C3-C7)cycloalkylO-, (C1-C6)alkylS-, (C3-C7)cycloalkylS-, (C1-C6)alkyl(C3-C7)cycloalkylS-, —NR9R10, —NO2, —CONR9R10 and —NR2COR10;

[0017] R5 is a substituent independently selected from hydrogen, halogen, —OH, haloalkyl, haloalkoxy, —CN, —NO2, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, (C1-C6)alkylO-, (C3-C7)cycloalkylO-, (C1-C6)alkyl(C3-C7)cycloalkylO-, —CONH2 and —CONR9R10;

[0018] R6 is (C1-C6)alkylSO2—, (C3-C7)cycloalkylSO2—, (C1-C6)alkyl(C3-C7)cycloalkylSO2—, (C1-C6)haloalkylSO2—, hydroxy(C2-C6)alkyl)SO2—, (amino(C2-C6)alkyl)SO2—, alkoxy(C2-C6)alkyl)SO2—, alkylamino(C2-C6)alkyl)SO2—, dialkylamino(C2-C6)alkyl)SO2—, arylSO2—, heteroarylSO2—, aryl(C2-C6-alkylSO2—, R9R10NSO2—, (C1—. C6)alkylC(O)—, (C3-C7)cycloalkylC(O)—, (C3-C7)cycloalkyl(C1-C6)alkylC(O)—, arylC(O)—, heteroarylC(O)—, R9R10NC(O)—, —(S)CNR9R10, aryl, heteroaryl, —(CH2)nC(O)NR9R10, alkylS(NCN═)C—, R9R1ON(NCN═)C—, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, aryl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, or R9OC(O)—;

[0019] R7=hydrogen or alkyl;

[0020] R8 is hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, aryl, heteroaryl, (C1-C6)alkylSO2—, (C3-C7)cycloalkylSO2—, (C1-C6)alkyl(C3-C7)cycloalkylSO2—, (C1-C6)haloalkylSO2— or arylSO2—;

[0021] R9 is hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, aryl(C1-C6)alkyl, aryl, acyl or heteroaryl; and,

[0022] R10 is hydrogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, aryl(C1-C6)alkyl, aryl or heteroaryl;

[0023] or R9 and R10 taken together with the nitrogen atom form a 4-7 membered ring containing 1 or 2 heteroatoms selected from N, O or S with proviso that two O or S atoms are not adjacent to one another;

[0024] n=1 to 6;

[0025] or a pharmaceutically acceptable salt and/or hydrate thereof.

[0026] The present invention also relates to a method of treating metabolic and eating disorders, such as obesity and hyperphagia, and diabetes comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.

[0027] Another aspect of the invention is a pharmaceutical composition which comprises a compound of formula I in combination with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION

[0028] Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of “alkyl” applies to “alkyl” as well as to the “alkyl” portions of “alkoxy”, etc.

[0029] As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0030] “Patient” includes both human and other mammals.

[0031] “Mammal” means humans and other animals.

[0032] “Alkyl” means an aliphatic hydrocarbon group, which may be straight or branched and comprising 1 to 20 carbon atoms in the chain. Preferred alkyl groups contain 1 to 12 carbon atoms in the chain. More preferred alkyl groups contain 1 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.

[0033] “Lower alkyl” means a group having 1 to 6 carbon atoms in the chain, which may be straight or branched. The term “substituted alkyl” means that the alkyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)2, carboxy and alkylOC(O)—. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.

[0034] “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising 2 to 15 carbon atoms in the chain. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. “Lower alkenyl” means 2 to 6 carbon atoms in the chain, which may be straight or branched. The term “substituted alkenyl” means that the alkenyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, and alkoxy. Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, and 3-methylbut-2-enyl.

[0035] “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising 2 to 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to 12 carbon atoms in the chain; and more preferably 2 to 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. “Lower alkynyl” means 2 to 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, and 2-butynyl. The term “substituted alkynyl” means that the alkynyl group may be substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl. aryl and cycloalkyl.

[0036] “Aryl” means an aromatic monocyclic or multicyclic ring system comprising 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms. The aryl group can be unsubstituted or optionally substituted on the ring with one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, OCF3, alkylOC(O)—, arylOC(O)—, CF3, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, haloalkyl, haloalkoxy, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y1 and Y2 may be the same or different each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. Non-limiting examples of suitable aryl groups include phenyl and naphthyl. The “aryl” group can also be substituted by linking two adjacent carbons on its aromatic ring via a combination of one or more carbon atoms and one or more oxygen atoms such as, for example, methylenedioxy, ethylenedioxy, and the like.

[0037] “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain 5 to 6 ring atoms. The “heteroaryl” can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y. and Y2 may be the same or different, each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrrolyl, triazolyl, and the like.

[0038] “Aralkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthlenylmethyl. The bond to the parent moiety is through the alkyl.

[0039] “Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl. The bond to the parent moiety is through the aryl.

[0040] “Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms. Preferred cycloalkyl rings contain 5 to 7 ring atoms. The cycloalkyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y. and Y2 may be the same or different each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

[0041] “Halo” means fluoro, chloro, bromo, or iodo groups. Preferred are fluoro, chloro or bromo, and more preferred are fluoro and chloro.

[0042] “Halogen” means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine or bromine, and more preferred are fluorine and chlorine.

[0043] “Haloalkyl” means an alkyl as defined above wherein one or more hydrogen atoms on the alkyl is replaced by a halo group defined above. The preferred halogen is fluoride. Specific examples, but non-limiting examples include a halo(C1-C6)alkyl, —CF2CH3, —CH2F3 and CF3.

[0044] “Cycloalkenyl” means a non-aromatic mono or multicyclic ring system comprising 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain 5 to 7 ring atoms. The cycloalkenyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y1 and Y2 may be the same or different each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

[0045] “Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain 5 to 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y1 and Y2 may be the same or different each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic azaheterocyclenyl groups include 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridyl and the like. Non-limiting examples of suitable oxaheterocyclenyl groups include 3,4-dihydro-2H-pyran, dihydrofuranyl, and the like. Non-limiting example of a suitable multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitable monocyclic thiaheterocyclenyl rings include dihydrothiophenyl, dihydrothiopyranyl, and the like.

[0046] “Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to 10 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain 5 to 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y, and Y2 may be the same or different each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl and the like.

[0047] “Arylcycloalkyl” means a group derived from a fused aryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred arylcycloalkyls are those wherein aryl is phenyl and the cycloalkyl consists of 5 to 6 ring atoms. The arylcycloalkyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y1 and Y2 may be the same or different each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. Non-limiting examples of suitable arylcycloalkyls include 1,2,3,4-tetrahydronaphthyl, and the like. The bond to the parent moiety is through a non-aromatic carbon atom.

[0048] “Cycloalkylaryl” means a group derived from a fused arylcycloalkyl as defined herein by removal of a hydrogen atom from the aryl portion. Non-limiting examples of suitable cycloalkylaryls are as described herein for an arylcycloalkyl group, except that the bond to the parent moiety is through an aromatic carbon atom.

[0049] “Heteroarylcycloalkyl” means a group derived from a fused heteroaryl and cycloalkyl as defined herein by removal of a hydrogen atom from the cycloalkyl portion. Preferred heteroarylcycloalkyls are those wherein the heteroaryl thereof consists of 5 to 6 ring atoms and the cycloalkyl consists of 5 to 6 ring atoms. The prefix aza, oxa or thia before heteroaryl means that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heteroarylcycloalkyl can be optionally substituted on the ring by replacing an available hydrogen on the ring by one or more substituents which may be the same or different, each being independently selected from the group consisting of alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, Y1Y2N—, Y1Y2N-alkyl-, Y1Y2NC(O)— and Y1Y2NSO2—, wherein Y1 and Y2 may be the same or different each being independently selected from the group consisting of hydrogen, alkyl, aryl, and aralkyl. The nitrogen atom of the heteroaryl portion of the heteroarylcycloalkyl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroarylcycloalkyls include 5,6,7,8-tetrahydroquinolinyl, 4,5,6,7-tetrahydro-1H-benzimidazolyl, and the like. The bond to the parent moiety is through a non-aromatic carbon atom.

[0050] “Cycloalkylheteroaryl” means a group derived from a fused beteroarylcycloalkyl as defined herein by removal of a hydrogen atom from the heteroaryl portion. Non-limiting examples of suitable cycloalkylheteroaryls are as described herein for heteroarylcycloalkyl, except that the bond to the parent moiety is through an aromatic carbon atom.

[0051] “Aralkenyl” means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenethenyl and 2-naphthylethenyl. The bond to the parent moiety is through the alkenyl.

[0052] “Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

[0053] “Heteroaralkenyl” means an heteroaryl-alkenyl- group in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of suitable heteroaralkenyl groups include 2-(pyrid-3-yl)ethenyl and 2-(quinolin-3-yl)ethenyl. The bond to the parent moiety is through the alkenyl.

[0054] “Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

[0055] “Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, Alkynyl-C(O)—, cycloalkyl-C(O)—, cycloalkenyl-C(O)—, or cycloalkynyl-C(O)— group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, and cyclohexanoyl.

[0056] “Aroyl” means an aryl-C(O)— group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl. “Heteroaroyl” means a heteroaryl-C(O)— group in which the heteroaryl group is as previously described. Non-limiting examples of suitable groups include nicotinoyl and pyrrol-2-ylcarbonyl. The bond to the parent moiety is through the carbonyl.

[0057] “Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy. The alkyl group is linked to an adjacent moiety through the ether oxygen.

[0058] “Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

[0059] “Aralkyloxy” means an aralkyl-O— group in which the aralkyl groups is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

[0060] “Alkylamino” means an —NH2 group in which one or more of the hydrogen atoms on the nitrogen is replaced by an alkyl group as defined above.

[0061] “Arylamino” means an —NH2 group in which one or more of the hydrogen atoms on the nitrogen is replaced by an aryl group as defined above.

[0062] “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptylthio. The bond to the parent moiety is through the sulfur.

[0063] “Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.

[0064] “Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.

[0065] “Alkoxycarbonyl” means an alkoxy group defined earlier linked to an adjacent moiety through a carbonyl. Non-limiting examples of alkoxycarbonyl groups include —CH3C(O)—, CH3CH2C(O)— and the like.

[0066] “Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

[0067] “Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

[0068] “Alkylsulfonyl” means an alkyl-SO2— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

[0069] “Alkylsulfinyl” means an alkyl-S(O)— group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfinyl.

[0070] “Arylsulfonyl” means an aryl-SO2— group. The bond to the parent moiety is through the sulfonyl.

[0071] “Arylsulfinyl” means an aryl-S(O)— group. The bond to the parent moiety is through the sulfinyl.

[0072] The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

[0073] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0074] “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0075] “Effective amount” or “therapeutically effective amount” is meant to describe an amount of compound of the present invention effective to treat a mammal (e.g., human) having a disease or condition mediated by MCH, and thus producing the desired therapeutic effect.

[0076] “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0077] For compounds of the invention having at least one asymmetrical carbon atom, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and l isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by separating isomers of a compound of formula I or by synthesizing individual isomers of a compound of formula I.

[0078] Compounds of formula I can exist in unsolvated and solvated forms, including hydrated forms. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like, are equivalent to the unsolvated forms for purposes of this invention.

[0079] A compound of formula I may form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base forms for purposes of the invention.

[0080] In a preferred group of compounds of formula 1, Y is 3

[0081] including, in particular, those compounds in which R5 is a substitutent independently selected from hydrogen, halogen, haloalkyl and haloalkoxy and the sum of j and k is 1, 2 or 3.

[0082] In another preferred group of compounds of formula 1, Y is 4

[0083] including, in particular, those compounds in which R5 and R6 each independently is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, haloalkyl and haloalkoxy, preferably halo(C1-C6)alkyl or halo(C1-C6)alkoxy, more preferably CH3CF2—, CF3 and CF3O—, and the sum of j and k is 1, 2 or 3.

[0084] In another embodiment, Y is 5

[0085] and R5 is Cl, F, CF3, CF3O— and r is 1 or 2.

[0086] In another embodiment Y is 6

[0087] and R5 is CF3 and r is 1.

[0088] In another embodiment Y is 7

[0089] and R5 is F and r is 1 or 2.

[0090] In another embodiment R3 is 8

[0091] the sum of j and k is 1, 2 or 3 and R6 is (C3-C4)cycloalkyl or heteroaryl.

[0092] The symbols 9

[0093] respectively.

[0094] Compounds of formula I may be produced by processes known to those skilled in the art as shown in the following reaction schemes and in the preparations and examples below. 10

[0095] In Scheme 1, a 4-halophenyl isocyanate is condensed with an amino substituted cyclic amine derivative to give a 4-halophenyl urea derivative. Cleavage of the cyclic amine protecting group by methods known to those skilled in the art affords a cyclic amine derivative that can be derivatized, for example by alkylation (Path 1). Coupling of the product with, for example, an arylboronic acid, under palladium catalysis (Suzuki coupling) yields a biaryl urea derivative. Alternatively, the condensation product can be arylated, for example, by use of a Suzuki coupling reaction (Path 2). When A is a protecting group, deprotection affords an amine that can be derivatized by, for example, sulfonylation, acylation or alkylation. 11

[0096] In Scheme 2, reaction of an aryl lithium, for example, 5-thienyl lithium, with trimethylborate and coupling of the resultant boronate with a 4-haloaniline under palladium catalysis yields a biaryl amine derivative. Protection of the amine with, for example, trifluoroacetic anhydride gives a trifluoroacetamide derivative that can be halogenated with an appropriate halogenating agent, for example N-chlorosuccinimide. The protecting group can be cleaved and the resultant amine can be reacted with, for example, N,N′-disuccinimidyl carbonate and an amino substituted cyclic amine derivative, for example an amino piperidine derivative, to give a substituted urea. Cleavage of the piperidine nitrogen protecting group gives an amine that can derivatized, for example, by sulfonylation or acylation. 12

[0097] In Scheme 3, a 4-haloaniline or 4-halonitrobenzene derivative is arylated by use of, for example, a Suzuki coupling reaction. When X is a nitro group, the nitro group is subsequently reduced to an amine. The biaryl amine derivative can be converted to an isocyanate derivative, which can be condensed with an amino substituted cyclic amine derivative (Path 3). Alternatively, condensation with an amino substituted cycloalkyl derivative affords cycloalkyl urea derivatives (Paths 4 and 5). An appropriately functionalized cycloalkyl urea derivative can be further functionalized as shown, for example, in Path 5.

[0098] The compounds of formula I exhibit selective neuropeptide Y Y5 receptor antagonizing activity, which has been correlated with pharmaceutical activity for treating metabolic and eating disorders, such as obesity, hyperphagia, and diabetes.

[0099] Another aspect of this invention is a method of treating a mammal (e.g., human) having a disease or condition mediated by the neuropeptide Y Y5 receptor by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound to the mammal.

[0100] Another aspect of this invention is directed to a method of treating obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0101] Another aspect of this invention is directed to a method for treating metabolic and eating disorders such as bulimia and anorexia comprising administering to a mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0102] Another aspect of this invention is directed to a method for treating hyperlipidemia comprising administering to a mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0103] Another aspect of this invention is directed to a method for treating cellulite and fat accumulation comprising administering to a mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0104] Another aspect of this invention is directed to a method for treating Type II diabetes comprising administering to a mammal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound.

[0105] In addition to the “direct” effect of the compounds of this invention on the neuropeptide Y Y5 receptor subtype, there are diseases and conditions that will benefit from the weight loss such as insulin resistance, impaired glucose tolerance, Type II Diabetes, hypertension, hyperlipidemia, cardiovascular disease, gall stones, certain cancers and sleep apnea.

[0106] This invention is also directed to pharmaceutical compositions, which comprise an amount of a compound of Formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier therefor.

[0107] This invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of Formula, I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier therefor.

[0108] Compounds of Formula I can be produced by processes known to those skilled in the art using either solution phase or solid phase synthesis as shown in the following reaction schemes, in the preparations and examples below.

[0109] The compounds of formula I display pharmacological activity in test procedures designed to demonstrate neuropeptide Y Y5 receptor antagonist activity. The compounds are non-toxic at pharmaceutically therapeutic doses. Following are descriptions of the test procedures.

[0110] cAMP Assay

[0111] HEK-293 cells expressing the Y5 receptor subtype were maintained in Dulbecco's modified Eagles' media (Gico-BRL) supplemented with 10% FCS (ICN), 1% penicillin-streptomycin and 200 μg/ml Geneticin® (GibcoBRL #11811-031) under a humidified 5% CO2 atmosphere. Two days prior to assay, cells were released from T-175 tissue culture flasks using cell dissociation solution (1×; non-enzymatic [Sigma #C-5914]) and seeded into 96-well, flat-bottom tissue culture plates at a density of 15,000 to 20,000 cells per well. After approximately 48 hours, the cell monolayers were rinsed with Hank's balanced salt solution (HBSS) then preincubated with approximately 150 μl/well of assay buffer (HBSS supplemented with 4 mM MgCl2, 10 mM HEPES, 0.2% BSA [HH]) containing 1 mM 3-isobutyl-1-methylxanthine ([IBMX] Sigma #1-587) with or without the antagonist compound of interest at 37° C. After 20 minutes the 1 mM IBMX-HH assay buffer (antagonist compound) was removed and replaced with assay buffer containing 1.5 μM (CHO cells) or 5 μM (HEK-293 cells) forskolin (Sigma #F-6886) and various concentrations of NPY in the presence or absence of one concentration of the antagonist compound of interest. At the end of 10 minutes, the media were removed and the cell monolayers treated with 75 μl ethanol. The tissue culture plates were agitated on a platform shaker for 15 minutes, after which the plates were transferred to a warm bath in order to evaporate the ethanol. Upon bringing all wells to dryness, the cell residues were resolubilized with 250 μl FlashPlate® assay buffer. The amount of cAMP in each well was quantified using the [125I]-cAMP FlashPlate® kit (NEN #SMP-001) and according to the protocol provided by the manufacturer. Data were expressed as either pmol cAMP/ml or as percent of control. All data points were determined in triplicate and EC50's (nM) were calculated using a nonlinear (sigmoidal) regression equation (GraphPad Prism™). The KB of the antagonist compound was estimated using the following formula:

K B =[B }/(1−{[A′]/[A]})

[0112] where

[0113] [A] is the EC50 of the agonist (NPY) in the absence of antagonist,

[0114] [A′] is the EC50 of the agonist (NPY) in the presence of antagonist,

[0115] and [B] is the concentration of the antagonist.

[0116] NPY Receptor Binding Assay

[0117] Human NPY Y5 receptors were expressed in CHO cells. Binding assays were performed in 50 mM HEPES, pH 7.2, 2.5 mM CaCl2, 1 mM MgCl2 and 0.1% BSA containing 5-10 μg of membrane protein and 0.1 nM 125L-peptide YY in a total volume of 200 p. Non-specific binding was determined in the presence of 1 μM NPY. The reaction mixtures were incubated for 90 minutes at room temperature then filtered through Millipore MAFC glass fiber filter plates which had been pre-soaked in 0.5% polyethleneimine. The filters were washed with phosphate-buffered saline, and radioactivity was measured in a Packard TopCount scintillation counter.

[0118] For the compounds of this invention, a range of neuropeptide Y5 receptor binding activity from about 0.2 nM to about 500 nM was observed. Compounds of this invention preferably have a binding activity in the range of about 0.2 nM to 250 nM, more preferably about 0.2 to 100 nM, and most preferably about 0.2 to 10 nM.

[0119] Yet another aspect of this invention are combinations of a compound of Formula I or a pharmaceutically acceptable salt of said compound and other compounds as described below.

[0120] Accordingly, another aspect of this invention is a method for treating obesity comprising administering to a mammal (e.g., a female or male human)

[0121] a. an amount of a first compound, said first compound being a Formula I compound or a pharmaceutically acceptable salt of said compound; and

[0122] b. an amount of a second compound, said second compound being an anti-obesity and/or anorectic agent such as a 3 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist wherein the amounts of the first and second compounds result in a therapeutic effect.

[0123] This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising

[0124] a first compound, said first compound being a Formula I compound or a pharmaceutically acceptable salt of said compound

[0125] a second compound, said second compound being an anti-obesity and/or anorectic agent such as a β3 agonist, a thyromimetic agent, an anoretic, or an NPY antagonist; and/or optionally a pharmaceutical carrier, vehicle or diluent.

[0126] Another aspect of this invention is a kit comprising:

[0127] a. an amount of a Formula I compound or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;

[0128] b. an amount of an anti-obesity and/or anorectic agent such as a β3 agonist, a thyromimetic agent, an anoretic agent, or an NPY antagonist and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and

[0129] c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.

[0130] Preferred anti-obesity and/or anorectic agents (taken singly or in any combination thereof) in the above combination methods, combination compositions and combination kits are:

[0131] phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as sibutramine), a sympathomimetic agent, a serotonergic agent (such as dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist, a melanin concentrating hormone antagonist, the OB protein (hereinafter referred to as “leptin”), a leptin analog, a leptin receptor agonist, a galanin antagonist or a GI lipase inhibitor or decreaser (such as orlistat). Other anorectic agents include bombesin agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the glucagon-like peptide-1 receptor such as Exendin and ciliary neurotrophic factors such as Axokine.

[0132] Another aspect of this invention is a method treating diabetes comprising administering to a mammal (e.g., a female or male human)

[0133] a. an amount of a first compound, said first compound being a Formula I compound or a pharmaceutically acceptable salt of said compound; and

[0134] b. an amount of a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide wherein the amounts of the first and second compounds result in a therapeutic effect.

[0135] This invention is also directed to a pharmaceutical combination composition comprising: a therapeutically effective amount of a composition comprising

[0136] a first compound, said first compound being a Formula I compound or a pharmaceutically acceptable salt of said compound;

[0137] a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and optionally

[0138] a pharmaceutical carrier, vehicle or diluent.

[0139] Another aspect of this invention is a kit comprising:

[0140] a. an amount of a Formula I compound or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable carrier, vehicle or diluent in a first unit dosage form;

[0141] b. an amount of an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin (including orally bioavailable insulin preparations), an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage form; and

[0142] c. means for containing said first and second dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.

[0143] For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pa.

[0144] Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.

[0145] Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.

[0146] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

[0147] The compounds of the invention may also be deliverable transdermally. The transdermal composition can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

[0148] Preferably the compound is administered orally.

[0149] Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

[0150] The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, according to the particular application.

[0151] The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total dosage may be divided and administered in portions during the day as required.

[0152] The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 0.04 mg/day to about 4000 mg/day, in two to four divided doses.

[0153] The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures may be apparent to those skilled in the art.

[0154] In the preparations and examples, the following abbreviations are used: room temperature (R.T.), phenyl(Ph), -t-butyloxycarbonyl(-Boc), methylamine (MeNH2), sodium triacetoxyborohydride (NaBH(O Ac)3)), ethyl acetate (EtOAc), methanol (MeOH), triethylamine (Et3 N), ether (Et2O), tetrahydrofuran (THF), diisopropylethylamine (iPr2NEt), 1,2-dimethoxyethane (DME), ethanol (EtOH) and preparative thin layer chromatography (PTLC).

Preparation 1

[0155] 13

[0156] To a mixture of N-t-butoxycarbonyl4-piperidone (10.0 g, 50 mmol) and aqueous methylamine (40% w/w, 10 ml) in 1,2-dichloroethane (125 ml) was added NaBH(OAc)3 (16.0 g, 75 mmol). The reaction mixture was stirred overnight, then 1 M NaOH (250 ml) was added and the whole was extracted with ether (700 ml). The organic layer was washed with sat'd NaCl, dried (MgSO4), filtered, and concentrated to give the product (10.5 g, 97%) as an oil. 1H NMR (CDCl3, 400 MHz) δ 4.09 (2H, m), 2.86 (2H, m), 2.55 (1H, m), 2.50 (3H, s), 1.90 (2H, m), 1.51 (9H, s), 1.30 (2H, m).

Preparation 2

[0157] 14

[0158] Step 1 15

[0159] To a mixture of N-benzyloxycarbonyl-4-piperidone (10.70 g, 43.1 mmol) and aq. 40% MeNH2 (6.67 g, 85.8 mmol) in CH2Cl2 (200 ml) at R.T. was added NaBH(OAc)3 (27.25 g, 128.6 mmol). The reaction mixture was stirred at R.T. for 3 h then poured into sat'd NaHCO3 and extracted with CH2Cl2 (3×200 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated to give the product (10.63 g, 100%) that was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 7.34 (5H, m), 5.12 (2H, s), 4.19 (2H, b), 2.87 (2H, b), 2.72 (1H, m), 2.49 (3H, s), 1.92 (2H, b), 1.42 (2H, m). MS m/e 249 (M+H).

[0160] Step 2 16

[0161] To the product of Step 1 (10.63 g, 42.9 mmol) in anhydrous CH2Cl2 (200 ml) at R.T. was added di-tert-butyl dicarbonate (11.30 g, 51.8 mmol) in portions. The reaction mixture was allowed to stir at R.T. for 5 h then poured into 1 N NaOH (50 ml)/CH3OH (10 ml). The mixture was stirred for 15 min. and extracted with CH2Cl2 (3×200 ml). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was subjected to column chromatography (gradient 1:10 to 1:4 EtOAc/hexane) to give the product (13.00 g, 87%). 1H NMR (CDCl3, 400 MHz) δ 7.33 (5H, m), 5.10 (2H, s), 4.19 (3H, m), 2.87 (2H, b), 2.68 (3H, s), 1.60 (4H, m), 1.44 (9H, s). MS m/e 349 (M+H).

[0162] Step 3

[0163] A mixture of the product of Step 2 (12.90 g, 37.0 mmol) and 10% Pd/C (1.29 g) in MeOH (300 ml) was stirred under an H2 atmosphere. After 16 h the reaction mixture was filtered through celite and the filter pad was washed with MeOH. The combined filtrate and washings were concentrated to afford the product (7.80 g, 98.3%). 1H NMR (CDCl3, 400 MHz) δ 4.19 (1H, b), 3.15 (2H, b), 2.74 (3H, s), 2.66 (2H, m), 1.63 (4H, m), 1.46 (9H, s). MS m/e 215 (M+H).

Preparation 3

[0164] 17

[0165] To a stirred solution of Preparation 1 (21.0 g, 83.7 mmol) and Et3N (35 ml, 252 mmol) in CH2Cl2 (300 ml) was added benzyl chloroformate (18 ml, 126 mmol) dropwise. After 5 h, sat'd NH4Cl (200 ml) was added, and the organic layer was washed with H2O (150 ml) and sat'd NaCl (150 ml), dried (MgSO4), filtered and concentrated. To the residue (32 g) was added 4N HCl in 1,4-dioxane (300 ml), and the mixture was stirred for 4 h. The reaction mixture was concentrated, acetone was added, and the reaction mixture was again concentrated. The solid residue was dissolved in MeOH (40 ml) and Et2O was added. The resultant precipitate was collected, washed with Et2O, and dried to give the product as a white solid (20.2 g, 85%). MS m/e 249 (M+H, free base).

EXAMPLE 1

[0166] 18

[0167] Step 1 19

[0168] To a solution of Preparation 1 (7.0 g, 33 mmol) in CH2Cl2 (200 ml) was added 4-bromophenyl isocyanate (6.8 g, 35 mmol). The reaction mixture was stirred for 16 h, then H2O (200 ml) was added, and the organic layer was dried (MgSO4), filtered and evaporated. The residue was triturated with hexanes to give a white solid (11.0 g, 81%). MS (FAB) m/e 411 (M+H)+.

[0169] Step 2 20

[0170] To a solution of the product of Step 1 (400 mg, 0.97 mmol) and Pd(dppf)Cl2.CH2Cl2 (200 mg, 0.24 mmol) in toluene (10 ml) was added 2-fluorophenylboronic acid (250 mg, 1.43 mmol), Cs2CO3 (350 mg, 1.1 mmol), and H2O (0.3 ml). The reaction mixture was heated in a 90° C. oil bath under N2 for 1 h, then allowed to cool. The reaction mixture was partitioned between EtOAc (100 ml) and H2O (50 ml). The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography (3:7 acetone/hexane) of the residue afforded the product (400 mg, 97%). HRMS calc. for C24H31FN3O3 (M+H) 428.2349. Found 428.2343.

[0171] Coupling of the product of Step 1 with the appropriate boronic acid by essentially the same procedure gave: 21

[0172] HRMS calc. for C25H31F3N3O3 (M+H) 478.2318. Found 478.2313. 22

[0173] HRMS calc. for C25H31F3N3O3 (M+H) 478.2318. Found 478.2313. 23

[0174] HRMS calc. for C25H31F3N3O4 (M+H) 494.2260. Found 494.2267. 24

[0175] HRMS calc. for C24H31FN3O3 (M+H) 428.2343. Found 428.2349. 25

[0176] MS (FAB) m/e 478 (M+H)+. 26

[0177] MS (FAB) m/e 446 (M+H)+.

[0178] Step 3 27

[0179] To a solution of the product of Step 2 (100 mg, 0.23 mmol) in CH2Cl2 (5 ml) was added 4 M HCl in 1,4-dioxane (3 ml). After 16 h, the reaction mixture was concentrated. The residue was triturated with ether and the solid was collected, washed with ether, and air-dried to give the product (80 mg, 96%). HRMS calc. for C19H23FN3O (M+H) 328.1825. Found 328.1823.

[0180] Treatment of the other products from Step 2 by essentially the same procedure gave: 28

[0181] MS (ES) m/e 378 (M+H)+. 29

[0182] MS (FAB) m/e 378 (M+H)+. 30

[0183] HRMS calc. for C20H23F3N3O2 (M+H) 394.1742. Found 394.1747. 31

[0184] HRMS calc. for C19H23FN3O (M+H) 328.1825. Found 328.1823. 32

[0185] MS (ES) m/e 378 (M+H)+. 33

[0186] HRMS calc. for C19H22F2N3O (M+H) 346.1731. Found 346.1725.

[0187] Step 4

[0188] To a stirred solution of the product of Step 3 (20 mg, 0.055 mmol) and triethylamine (0.1 ml, 0.7 mmol) in CH2Cl2 (10 ml) was added methanesulfonyl chloride (0.1 ml, 0.1 mmol). After 16 h the reaction mixture was concentrated and the residue was subjected to PTLC (1:2 acetone/hexanes) to give a white solid (15 mg, 67%). HRMS calc. for C20H25FN3O3S (M+H)406.1601. Found 406.1599.

[0189] The following examples were prepared from the appropriate starting amine and sulfonyl chloride.

34
Y	R6	MS (M + H)	Example
35	—SO2CF3	460	1A
36	—SO2CH(CH3)2	434	1B
37	—SO2CH3	456	1C
38	—SO2CH3	456	1D
39	—SO2CH(CH3)2	484	1E
40	—SO2CF3	510	1F
41	—SO2CH3	472	1G
42	—SO2CH3	406	1H
43	—SO2CF3	460	1I
44	—SO2CH3	456	1J
45	—SO2CH3	424	1K

EXAMPLE 2

[0190] 46

[0191] Step 1 47

[0192] A stirred solution of 1 M 1-thienyllithium in THF (40 ml, 40 mmol) was cooled in a dry-ice/acetone bath under N2. Triethylborate (8.5 ml, 50 mmol) was added, and the reaction mixture was allowed to warm to R.T. After 20 min., 4-iodoaniline (6.6 g, 30 mmol), Na2CO3 (4.5 g), H2O (20 ml), and Pd(dppf)Cl2.CH2Cl2 (750 mg, 0.9 mmol) were added. The reaction mixture was stirred under N2 until the exotherm was complete, then partitioned between Et2O and H2O. The Et2O layer was washed with 1 N NaOH, dried (Na2CO3), and filtered through a pad of silica gel, eluting with Et2O. The resultant brown solid was dissolved in CH2Cl2 (100 ml) and a solution of trifluoroacetic anhydride (8 ml, 57 mmol) in CH2Cl2 (100 ml) was added in portions with stirring. To the resultant suspension was added CH2Cl2 (450 ml) and the reaction mixture was stirred for 20 min. Water (200 ml) was added, followed by NaHCO3 (7 g) in portions until CO2 evolution ceased. The organic layer was stirred with MgSO4 and DARCO, then filtered and concentrated to give a solid. The solid was dissolved in CH2Cl2 (50 ml) and to the stirred solution was added hexanes (100 ml). The solid was collected, washed with hexanes and dried to give the product (6.12 g, 75%). M.p. 213-216° C. Calcd for C12H8F3NOS: C, 53.14; H, 2.58; N, 5.17. Found: C, 53.06; H, 2.85; N, 4.90%.

[0193] Step 2 48

[0194] To a solution of the product of Step 1 (19.0 g, 70 mmol) in DMF (150 ml) was added N-chlorosuccinimide (10.1 g, 76 mmol) and trifluoroacetic acid (1.5 ml), and the reaction mixture was stirred under N2 for 2 days. Water (500 ml) was added and the resultant solid was collected, washed with water and dried to give the product (20.6 g, 96%). M.P. 198-200° C. Calcd for C12H7ClF3NOS: C, 47.12; H, 2.29; N, 4.58. Found: C, 47.19; H, 2.15; N, 4.47%.

[0195] Step 3 49

[0196] A mixture of the product of Step 2 (15.0 g, 49.1 mmol) and sodium hydroxide (19.6 g, 490 mmol) in MeOH (400 ml) and water (150 ml) was stirred at R.T. overnight. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried, and concentrated. The residue was purified by flash column (1:3 acetone/hexanes) to give the product (10.14 g, 98%). 1H-NMR (CDCl3, 400 MHz) δ 7.32 (2H, m), 6.90 (1H, d, J=4.8 Hz), 6.83 (1H, d, J=4.8 Hz), 6.67 (2H, m), 3.76 (2H, b).

[0197] Step 4 50

[0198] To a stirred, ice-cold solution of the product of Step 3 (2.0 g, 9.5 mmol) in THF (100 ml) was added pyridine (2.3 ml, 28 mmol) and N,N′-disuccinimidyl carbonate (2.44 g, 9.5 mmol). The reaction mixture was stirred at ice-bath temp. for 1.5 h, then Preparation 1 (2.04 g, 9.5 mmol) was added, and the reaction mixture was allowed to warm to R.T. After 16 h, the reaction mixture was concentrated, the residue was dissolved in EtOAc (200 ml) and washed with 2N HCl, sat'd NaHCO3 and sat'd NaCl. The organic layer was dried (Na2SO4), filtered, and evaporated to afford the product (4.21 g, 98%) that was used directly in Step 5. HRMS calc. for C22H29ClN3O3S (M+H) 450.1618. Found 450.1623.

[0199] Step 5 51

[0200] Reaction of the product of Step 4 (4.11 g, 9.13 mmol) with HCl by the procedure of Example 1, Step 3 afforded the product (3.71 g) that was used directly in Step 6. HRMS calc. for C17H21ClN3OS (M+H) 350.1094. Found 350.1100.

[0201] Step 6

[0202] To a suspension of the product of Step 5 (50 mg, 0.13 mmol) in CH2Cl2 (3 ml) was added Et3N (39 mg, 0.39 mmol) followed by n-propylsulfonyl chloride (20 mg, 0.14 mmol). The reaction mixture was stirred for 16 h. EtOAc (10 ml) was added and the mixture was washed with 2N HCl, sat'd NaHCO3 and sat'd NaCl, dried (MgSO4), filtered and concentrated. The residue was subjected to PTLC (3:97 MeOH/CH2Cl2) to give the product (37 mg, 62%). HRMS calc. for C20H27ClN3O3S2 (M+H) 456.1182. Found 456.1179.

[0203] Reaction of the product of Step 5, 2-5-1, with the appropriate sulfonyl chloride in the presence of Et3N gave the following examples.

52
	R6	MS (M + H)+	Example
	—SO2CH3	428	2A
	—SO2CH2CH3	442	2B
	—SO2CH(CH3)2	456	2C
	—SO2CF3	482	2D
	—SO2CH2CF3	496	2E

EXAMPLE 3

[0204] 53

[0205] Step 1 54

[0206] Using the procedure of Example 1, Step 1, Preparation 1 (2.3 g, 107 mmol) was reacted with 4-iodophenyl isocyanate (2.6 g, 107 mmol). Purification by flash chromatography (2:98 MeOH/CH2Cl2) afforded a white solid.

[0207] Step 2 55

[0208] A mixture of the product of Step 1 (3.0 g, 6.7 mmol), 4M HCl in 1,4-dioxane (15 ml) and THF (15 ml) was stirred at ambient temp. for 5 h. The reaction mixture was concentrated to dryness, and H2O (100 ml) and 3M NaOH (20 ml) was added to the residue. The whole was extracted with CH2Cl2 (3×100 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. Flash chromatography (2:98 MeOH/CH2Cl2 then 10:90 (2M NH3 in MeOH)/CH2Cl2) gave a white solid (2.4 g, 100%). HRMS calc. for C13H191N3O (M+H) 360.0573. Found 360.0576.

[0209] Step 3 56

[0210] To a stirred ice-cold mixture of the product of Step 2 (2.4 g, 6.7 mmol) and cyclopropane carboxaldehyde (0.8 ml, 11 mmol) in CH2Cl2 (20 ml) was added NaBH(OAc)3 (1.83 g, 10.8 mmol). The reaction mixture was allowed to warm to room temp. and stirred overnight. The reaction mixture was cooled in ice and 3M NaOH (5 ml) was added. After 0.5 h the mixture was extracted with CH2Cl2 (3×100 ml), dried (MgSO4), filtered and evaporated. The residue was triturated with CH2Cl2/hexanes (1:10) to afford a white solid (2.4 g, 87%). HRMS calc. for C17H25IN3O (M+H) 414.1038. Found 414.1042.

[0211] Step 4

[0212] A vessel charged with the product of Step 3 (200 mg, 0.48 mmol), 4-trifluoromethoxybenzeneboronic acid (250 mg, 1.21 mmol), tris(dibenzylideneacetone)dipalladium (0) (50 mg, 0.05 mmol), CsCO3 (0.8 g, 2.5 mmol) and toluene (10 ml) was refluxed under N2 for 3 h. The reaction mixture was allowed to cool, then EtOAc (50 ml) and H2O (25 ml) were added. Solids were removed by filtration and the EtOAc layer was dried (Na2SO4), filtered, and evaporated. The residue was subjected to PTLC (3:7 acetone/hexanes then 10:90 (2M NH3 in MeOH)/CH2Cl2) to give a pale yellow solid (50 mg, 23%). HRMS calc. for C24H29F3N3O2 (M+H) 448.2212. Found 448.2215.

[0213] Using appropriate starting materials and essentially the same procedure, the following compounds were prepared:

57
Y	MS (M + H)+	Example
58	364.1	3A
59	382	3B
60	404	3C
61	423	3D
62	400	3E
63	382	3F

EXAMPLE 4

[0214] 64

[0215] Step 1 65

[0216] To an N2-purged mixture of 4-bromonitrobenzene (20.0 g, 99.0 mmol), 3,5-difluorophenylboronic acid (23.4 g, 148 mmol) and Cs2CO3 (38.7 g, 119 mmol) in toluene (600 ml) and H2O (30 ml) was added Pd(dppf)Cl2.CH2Cl2 (4.04 g, 4.95 mmol). The reaction mixture was heated at 90° C. for 2 h, allowed to cool to R.T., then filtered through celite. The whole was extracted with EtOAc (3×500 ml). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give a solid. To a vigorously stirred ice-cold mixture of the solid in CH3OH (1 L) and NiCl2.6H2O (61.0 g, 257 mmol) was added NaBH4 (14 g, 370 mmol) in portions. After the addition was complete, the reaction mixture was poured into H2O (100 ml), then filtered through celite and extracted with EtOAc (3×500 ml). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was dissolved in EtOAc, and 1 N HCl/Et2O (300 ml) was added. The precipitate was washed with hexane, air-dried, and dissolved in H2O. The solution was neutralized by addition of 1 N NaOH, then extracted with CH2Cl2 (3×1 L). The combined organic layers were dried (Na2SO4), filtered, and concentrated to give the product (19.0 g, 94%). 1H NMR (CDCl3, 400 MHz) δ 7.38 (2H, m), 7.06 (2H, m), 6.75 (2H, m), 6.72 (1H, m), 3.81 (s, 2H). MS m/e 206 (M+H).

[0217] Using the appropriate substituted phenylboronic acid starting material and essentially the same procedure, the following compounds were prepared: 66

[0218] 1 H NMR (CDCl3, 400 MHz) δ 7.41-7.21 (5H, m), 7.33 (1H, m), 6.76 (2H, m), 3.76 (2H, b). 67

[0219] 1 H NMR (CDCl3, 400 MHz) δ 7.39 (2H, m), 7.24 (3H, m), 6.76 (2H, m), 3.80 (2H, b).

[0220] Additional arylamines were prepared from 4-iodoaniline according to the following procedure. 68

[0221] A mixture of 4-iodoaniline (1.00 g, 4.57 mmol), 3-trifluoromethylphenylboronic acid (1.30 g, 6.85 mmol) and Cs2CO3 (1.64 g, 5.02 mmol) in toluene (50 ml) and H20 (3 ml) was purged with N2 for 5 min. To the reaction mixture was added Pd(dppf)Cl2.CH2Cl2 (746 mg, 0.91 mmol). The reaction mixture was heated at 90° C. for 5 h, then allowed to cool to R.T. and poured into cold water. The whole was extracted with CH2Cl2 (3×100 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. Purification of the residue by PTLC (EtOAc/hexane 1:2) gave the product (216 mg, 20%). 1H NMR (CDCl3, 400 MHz) δ 7.77 (1H, m), 7.70 (1H, m), 7.51 (2H, m), 7.42 (2H, m), 6.78 (2H, m), 3.65 (2H, b).

[0222] Using the appropriate substituted phenylboronic acid starting material and essentially the same procedure, the following compounds were prepared. 69

[0223] 1 H NMR (CDCl3, 400 MHz) δ 7.54 (1H, m), 7.34 (3H, m), 7.15 (1H, t, J=8.8 Hz), 6.75 (2H, m), 3.76 (2H, b). 70

[0224] 1 H NMR (CDCl3, 400 MHz) δ 7.48 (2H, m), 7.35 (2H, d, J=6.4 Hz), 7.08 (2H, t, J=6.4 Hz), 6.76 (2H, d, J=6.4 Hz), 3.73 (2H, b). MS m/e 188 (M+H). 71

[0225] 1 H NMR (CDCl3, 400 MHz) δ 7.51 (1H, m), 7.41 (3H, m), 7.32 (1H, m), 7.23 (1H, m), 6.75 (2H, m), 3.78 (2H, b). MS m/e 204 (M+H).

[0226] Step 2 72

[0227] A stream of N2 was passed through a mixture of the product of Preparation 2 (2.00 g, 9.33 mmol), 3-bromopyridine (2.95 g, 18.7 mmol) and 2-(di-tert-butylphosphino)biphenyl (0.139 g, 0.467 mmol) and NaOtBu (1.80 g, 18.7 mmol) in anhydrous toluene (10 ml). Pd(OAc)2 (0.105 g, 0.467 mmol) was added and the reaction mixture was stirred at 110° C. for 24 h. The reaction mixture was allowed to cool to R.T. and poured into cold H2O. The whole was extracted with CH2Cl2 (3×50 ml) and the combined organic layers were dried (Na2SO4), filtered, and concentrated. Purification of the residue by PTLC (1:20 CH3OH/CH2Cl2) gave the product (1.47 g, 54%). 1H NMR (CDCl3, 400 MHz) δ 8.29 (1H, s), 8.07 (1H, b), 7.17 (2H, m), 4.2 (1H, b), 3.74 (2H, m), 2.82 (2H, m), 2.74 (3H, s), 1.70 (4H, m), 1.45 (9H, s). MS m/e 292 (M+H).

[0228] Step 3 73

[0229] To the product of Step 2 (1.47 g, 5.05 mmol) was added 4M HCl/1,4-dioxane (20 ml). The reaction mixture was stirred at R.T. for 1.5 h and concentrated to afford the product in quantitative yield. 1H NMR (CD3OD, 400 MHz) δ 8.46 (1H, s), 8.14 (2H, m), 7.86 (1H, s), 4.13 (2H, m), 3.40 (1H, b), 3.16 (2H, b), 2.75 (3H, s), 2.26 (2H, m), 1.76 (2H, m). MS m/e 192 (M+H).

[0230] Step 4

[0231] To a mixture of the product of Step 1 (4-1-1) (0.100 g, 0.487 mmol) and iPr2NEt (0.43 ml, 2.44 mmol) in anhydrous toluene (10 ml) was added triphosgene (0.051 g, 0.171 mmol). The mixture was stirred at 120° C. for 2 h, then allowed to cool to R.T., and the product of Step 3 (4-3-1) (0.133 g, 0.585 mmol) was added. The reaction mixture was stirred at R.T. for 16 h, then poured into cold H2O and extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by PTLC (1:20 CH3OH/CH2Cl2) to give the product (0.114 g, 56%). 1H NMR (CDCl3, 400 MHz) 68.33 (1H, d, J=2.4 Hz), 8.09 (1H, m), 7.49 (4H, m), 7.17 (2H, m), 7.06 (2H, m), 6.74 (1H, m), 6.51 (1H, s), 4.49 (1H, m), 3.77 (2H, m), 2.93 (3H, s), 2.91 (2H, m), 1.85 (4H, m). MS m/e 423 (M+H).

EXAMPLE 5

[0232] 74

[0233] Step 1 75

[0234] The product 5-1-1 was prepared in 57% yield from 2-bromopyridine and Preparation 2 by the procedure of Example 4, Step 2, except that 2-(di-tert-butylphosphino)biphenyl was replaced by 1,3-bis(diphenylphosphino)propane, and a reaction temperature of 80° C. instead of 110° C. was used. MS m/e 292 (M+H).

[0235] Step 2 76

[0236] Treatment of the product of Step 1 with 4 N HCl/dioxane by the procedure of Example 4, Step 3 gave the product. MS m/e 192 (M+H).

[0237] Step 3

[0238] To a stirred ice-cold mixture of 4-1-2 (0.063 g, 0.339 mmol) and pyridine (0.14 ml, 1.69 mmol) in anhydrous THF (10 ml) was added N,N′-disuccinimidyl carbonate (0.087 g, 0.339 mmol). The reaction was stirred in an ice-bath for 25 min. then the product of Step 2, 5-2-1(0.100 g, 0.508 mmol), was added. The reaction was allowed to warm to R.T., stirred for 16 h, then poured into cold H2O (20 ml). The whole was extracted with CH2Cl2 (3×20 ml), the combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was subjected to PTLC (1:20 CH3OH/CH2Cl2) to give the product (0.080 g, 58%). 1H NMR (CDCl3, 400 MHz) δ 8.19 (1H, m), 7.52 (5H, m), 7.37 (2H, m), 7.27 (1H, m), 6.99 (1H, m), 6.69 (1H, d), 6.62 (1H, m), 6.45 (1H, s), 4.56 (1H, m), 4.42 (2H, m), 2.92 (2H, m), 2.88 (3H, s), 1.78 (4H, m). MS m/e 405 (M+H).

EXAMPLE 6

[0239] 77

[0240] Reaction of 4-1-4, N,N′-disuccinimidyl carbonate and 5-2-1 by the procedure of Example 5, Step 3 afforded the product. MS m/e 455 (M+H).

EXAMPLE 7

[0241] 78

[0242] Reaction of 4-1-5, N,N′-disuccinimidyl carbonate and 5-2-1 by the procedure of Example 5, Step 3 afforded the product. MS m/e 473 (M+H).

EXAMPLE 8

[0243] 79

[0244] Reaction of 4-1-6, N,N′-disuccinimidyl carbonate and 5-2-1 by the procedure of Example 5, Step 3 afforded the product. MS m/e 405 (M+H).

EXAMPLE 9

[0245] 80

[0246] Reaction of 4-1-1, N,N′-disuccinimidyl carbonate and 5-2-1 by the procedure of Example 5, Step 3 afforded the product. MS m/e 423 (M+H).

EXAMPLE 10

[0247] 81

[0248] Reaction of 4-1-3, triphosgene and 5-2-1 by the procedure of Example 4, Step 4 afforded the product. MS m/e 455 (M+H).

EXAMPLE 11

[0249] 82

[0250] Reaction of 4-1-2, triphosgene and 4-3-1 by the procedure of Example 4, Step 4 afforded the product. MS m/e 405 (M+H).

EXAMPLE 12

[0251] 83

[0252] Reaction of 4-1-7, triphosgene and 4-3-1 by the procedure of Example 4, Step 4 afforded the product. MS m/e 421 (M+H).

EXAMPLE 13

[0253] 84

[0254] Step 1 85

[0255] A mixture of Preparation 3 (2.75 g, 9.7 mmol), 2-bromothiazole (1.98 g, 12.1 mmol), and K2CO3 (3.5 g, 25 mmol) in DMF (40 ml) was heated at 160° C. for 20 h. The reaction mixture was concentrated and partitioned between CH2Cl2 and H2O. The organic layer was washed with sat'd NaCl, dried (MgSO4), filtered and concentrated. Flash chromatography (gradient; CH2Cl2 to 2:98 MeOH/CH2Cl2) gave the product (2.0 g, 62%). MS m/e 332.1 (M+H).

[0256] Step 2 86

[0257] The product of Step 1 (2.0 g, 6.0 mmol) and 33% HBr in AcOH (40 ml) was stirred at R.T. for 2 h. The reaction mixture was evaporated and the residue was partitioned between 1 N NaOH and CH2Cl2. The organic layer was washed with sat'd NaCl, dried (MgSO4), filtered and evaporated. Flash chromatography (gradient; 2:98 (2M NH3 in MeOH)/CH2Cl2 to 15:85 (2M NH3 in MeOH)/CH2Cl2) gave the product (0.94 g, 79%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.04 (1H, d, J=4 Hz), 6.52 (1H, d, J=4 Hz), 3.96 (2H, m), 3.17 (1H, m), 2.99 (2H, m), 2.59 (3H, s), 2.16 (2H, m), 1.68 (2H, m). MS m/e 198 (M+H).

[0258] Step 3

[0259] Reaction of 4-1-2, triphosgene and 13-2-1 by the procedure of Example 4, Step 4 afforded the product. MS m/e 411 (M+H).

EXAMPLE 14

[0260] 87

[0261] Reaction of 4-1-1, triphosgene and 13-2-1 by the procedure of Example 4, Step 4 afforded the product. MS m/e 429 (M+H).

EXAMPLE 15

[0262] 88

[0263] Step 1 89

[0264] An N2-purged mixture of 2-bromopyrimidine (400 mg, 2.52 mmol), Preparation 3 (510 mg, 1.79 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), sodium tert-butoxide (516 mg, 5.37 mmol), and (1,3-bis-diphenylphosphino)propane (29 mg, 0.07 mmol) in toluene (6 ml) was stirred at 70° C. in a sealed vessel for 16 h. The reaction mixture was allowed to cool to R.T., and 1 N NaOH (20 ml) was added. The whole was extracted with CH2Cl2 (3×20 ml), and the combined CH2Cl2 extracts were dried (MgSO4), filtered, and evaporated. The residue was subjected to PTLC (2:98 MeOH/CH2Cl2) to give the product (464 mg, 79%). MS m/e 327 (M+H).

[0265] Step 2 90

[0266] The product of Step 1 (464 mg, 1.43 mmol) and 10% Pd/C (59 mg) in EtOH (20 ml) was stirred under 1 atm. of H2 for 16 h. The catalyst was removed by filtration through celite and the filter pad was washed with EtOH. The combined filtrate and washings were evaporated. The residue was subjected to PTLC (5:95 (2M NH3 in MeOH)/CH2Cl2) to give the product (464 mg, 79%). 1H NMR (CDCl3, 400 MHz) δ 8.28 (2H, m), 6.44 (1H, m), 4.66 (2H, m), 2.99 (2H, m), 2.65 (1H, m), 2.47 (3H, s), 1.96 (2H, m), 1.33 (2H, m). MS m/e 193 (M+H).

[0267] Step 3

[0268] Reaction of the product of Step 2 (15-2-1) with 4-1-2 with triphosgene by the procedure of Example 4, Step 4 gave the product. MS (m/e) 406 (M+H).

EXAMPLE 16

[0269] 91

[0270] Reaction of the product of Example 15, Step 2 (15-2-1) and 4-1-1 with triphosgene by the procedure of Example 4, Step 4 gave the product. MS (m/e) 424 (M+H).

EXAMPLE 17

[0271] 92

[0272] Step 1 93

[0273] Reaction of the product of Example 5, Step 2 with 4-bromo-2-fluorophenylisocyanate by the procedure of Example 1, Step 1 gave the product. 1H NMR (CDCl3, 400 MHz) δ 8.18 (1H, m), 7.47 (1H, m), 7.38 (2H, m), 7.30 (2H, m), 6.68 (1H, m), 6.61 (1H, m), 4.49 (1H, m), 4.43 (2H, m), 2.91 (2H, m), 2.85 (3H, s), 1.71 (4H, m). MS m/e 391 (M+H). Step 2

[0274] Reaction of the product of Step 1 with 3-fluorophenylboronic acid by the procedure of Example 4, Step 1 gave the product. MS m/e 423 (M+H).

EXAMPLE 18

[0275] 94

[0276] Step 1 95

[0277] A mixture of 4-biphenyl isocyanate (3.00 g, 15.4 mmol) and Preparation 1 (5.33 g, 25.0 mmol) in CH2Cl2 (100 ml) was stirred at R.T. for 16 h. The mixture was washed with water (25 ml), 3N HCl (25 ml), and brine (50 ml). The organic portion was dried (MgSO4), filtered, concentrated, and purified by column chromatography (gradient; CH2Cl2to 1:99 CH3OH/CH2Cl2) to give the product (6.11 g, 97%). MS (ES) m/e 410 (M+H)+.

[0278] Step 2 96

[0279] A mixture of the product of Step 1 (6.11 g, 14.9 mmol) and 4N HCl/dioxane (100 ml) was stirred at R.T. for 5 h. The volatiles were evaporated and the residue was triturated with ether. The precipitate was collected, dissolved in water (200 ml), basified to pH 14, and extracted with CH2Cl2 (300 ml). The organic portion was dried and concentrated to give the product (4.39 g, 92%). MS (ES) m/e 310 (M+H)+.

[0280] Step 3

[0281] A solution of the product of Step 2 (80 mg, 0.26 mmol), nicotinoyl chloride hydrochloride (54 mg, 0.30 mmol), and triethylamine (90 μl, 0.64 mmol) in CH2Cl2 (2 ml) was stirred at R.T. for 16 h. The mixture was diluted with CH2Cl2 (50 ml) and extracted with 3N NaOH (5 ml). The organic layer was washed with water (15 ml), dried, (MgSO4), filtered, and concentrated. The residue was subjected to PTLC (4:96 CH3OH/CH2Cl2) to give the product (90 mg, 84%). 1H NMR (CDCl3, 400 MHz) δ 8.68 (2H, m), 7.76 (1H, m), 7.2-7.6 (10H, m), 6.48 (1H, s), 4.85 (1H, m), 4.60 (1H, m), 3.80 (1H, m), 3.20 (1H, m), 2.91 (3H, s), 2.86 (1H, m), 1.4-2.0 (4H, m). MS (ES) m/e 415 (M+H)+.

[0282] Using the appropriate acid chloride and essentially the same procedure the following compounds were prepared.

97
R6	(M + H)+	Example
C(O)CH3	352	18B
98	378	18C
99	420	18D
100	414	18E
101	415	18F
102	415	18G

EXAMPLE 19

[0283] Reaction of Example 1, 1-3-5, with the appropriate acid chloride afforded the following compounds:

103
R6	(M + H)+	Example
C(O)—CH3	370	19A
104	396	19B
105	432	19C
106	433	19D
107	433	19E
108	433	19F
109	467	19G
110	501	19H
111	481	19I
112	497	19J

EXAMPLE 20

[0284] Reaction of the product of Example 1, 1-3-7, with the appropriate acid chloride afforded the following compounds:

113
R	(M + H)+	Example
C(O)—CH3	388	20A
114	414	20B
115	450	20C
116	451	20D
117	451	20E
118	451	20F

EXAMPLE 21

[0285] Reaction of the product of Example 2, Step 5, 2-5-1, with the appropriate acid chloride afforded the following compounds

119
R6	(M + H)+	Example
C(O)—CH3	392	21A
120	418	21B
121	454	21C
122	455	21D
123	455	21E
124	455	21F

EXAMPLE 22

[0286] 125

[0287] A mixture of Example 18 (45 mg, 0.11 mmol) and 3-chloroperoxybenzoic acid (40 mg) in CH2Cl2 (5 ml) was stirred at R.T. for 16 h. The mixture was diluted with CH2Cl2 (50 ml), then washed with 3N NaOH (2×5 ml) and water (10 ml). The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was subjected to PTLC (1:9 CH3OH/CH2Cl2) to give the product (34 mg, 73%). 1H NMR (CDCl3, 400 MHz) δ 8.20 (2H, m), 7.2-7.6 (11H, m), 6.56 (1H, s), 4.76 (1H, m), 4.59 (1H, m), 3.78 (1H, m), 3.22 (1H, m), 2.7-3.0 (4H, m), 1.4-2.0 (4H, m). MS (ES) m/e 431 (M+H)+.

EXAMPLE 23

[0288] 126

[0289] Step 1 127

[0290] A mixture of 4-piperidone ethylene ketal (0.64 ml, 5.0 mmol) and sulfamide (0.53 g, 5.5 mmol) in DME (20 ml) was refluxed for 16 h. The mixture was concentrated to ca. 3 ml, dissolved in EtOAc (175 ml), washed with sat'd NH4Cl (2×25 ml), water (2×25 ml), and brine (25 ml). The organic portion was dried, filtered, and evaporated to give the product (0.58 g, 52%). MS (ES) m/e 223 (M+H)+.

[0291] Step 2 128

[0292] A mixture of the product of Step 1 (560 mg, 2.52 mmol) and pyridinium 4-toluenesulfonate (190 mg, 0.756 mmol) in acetone (25 ml) and water (0.5 ml) was refluxed for 64 h. The mixture was evaporated to dryness and the residue was partitioned between CH2Cl2 (75 ml) and aq. NaHCO3 (2×20 ml). The aqueous layer was extracted with CH2Cl2 and EtOAc sequentially. The EtOAc layer was evaporated to give the product (140 mg). 1H NMR (CD3OD, 400 MHz) δ 3.47 (1H, t, J=6.4 Hz), 3.15 (3H, m), 2.54 (1H, t, J=6.4 Hz), 1.81 (3H, m).

[0293] Step 3 129

[0294] A mixture of the product of Step 2 (135 mg, 0.757 mmol), 40% aqueous methylamine (300 μ1,2.42 mmol), and sodium triacetoxyborohydride (375 mg, 1.77 mmol) in dichloroethane (5 ml) was stirred at R.T. for 19 h. The mixture was partitioned between 3N NaOH (5 ml) and EtOAc (3×50 ml). The organic layer was concentrated to give the crude product (40 mg). The aqueous layer was evaporated in vacuo to dryness and the residue was suspended in EtOAc. The suspension was filtered and the filtrate concentrated to give another batch of the product (70 mg). MS (FAB) m/e 194 (M+H)+.

[0295] Step 4

[0296] To an ice-cold solution of 4-1-2 (40 mg, 0.21 mmol) in anhydrous THF (3 ml) was added N,N′-disuccinimidyl carbonate (55 mg, 0.21 mmol) and pyridine (52 μl, 0.65 mmol). The mixture was stirred at 0° C. for 2 h and the product of Step 3 (70 mg, 0.36 mmol) was added. After stirring at R.T. for 2 h the reaction mixture was taken up in CH2Cl2 (50 ml), washed with 1N HCl (10 ml), dried, (Na2SO4), filtered and concentrated. The residue was subjected to PTLC (5:95 CH3OH/CH2Cl2) to give the product (62 mg, 71%).

[0297] 1 H NMR (CD3OD, 400 MHz) δ 7.56 (2H, m), 7.48 (2H, m), 7.40 (2H, m), 7.32 (1H, m), 7.02 (1H, m), 4.23 (1H, m), 3.75 (2H, m), 2.94 (3H, s), 2.72 (2H, m), 1.7-2.0 (4H, m). MS (ES) m/e 407 (M+H)+.

[0298] Using the appropriate starting materials and essentially the same procedure afforded the following compounds.

130
Y	(M + H)+	Example
131	389	23A
132	425	23B
133	429	23C

EXAMPLE 24

[0299] 134

[0300] A mixture of 1-3-5 (71 mg, 0.20 mmol), 2-bromoacetamide (32 mg, 0.23 mmol), and anhydrous potassium carbonate (170 mg, 1.20 mmol) in CH3CN (2 ml) in a sealed tube was heated to 45° C. for 6 h. The mixture was diluted with CH2Cl2 (75 ml), washed with water (50 ml), dried, and concentrated. The residue was subjected to PTLC (5:95 CH3OH/CH2Cl2) to give the product (37 mg, 49%). 1H NMR (CDCl3, 400 MHz) δ 7.48 (4H, m), 7.35 (2H, m), 7.23 (1H, m), 6.98 (2H, m), 6.56 (1H, s), 5.97 (1H, bs), 4.25 (1H, m), 2.8-3.0 (7H, m), 2.31 (2H, m), 1.6-1.8 (4H, m). MS (ES) m/e 385 (M+H)+.

EXAMPLE 25

[0301] 135

[0302] Step 1 136

[0303] To ethyl 4-oxocyclohexanecarboxylate (10 g, 59 mmol) in MeOH (75 ml) and water (50 ml) was added lithium hydroxide monohydrate (4.2 g, 100 mmol) at 0° C. The mixture was warmed up to R.T. and stirred for 3 h. The mixture was acidified to pH 2 with 3N HCl. The volatiles were evaporated and the residue was extracted with EtOAc (300 ml). The organic portion was dried and concentrated to give the product (8.01 g, 96%). MS (Cl) m/e 143 (M+H)+.

[0304] Step 2 137

[0305] 2M oxalyl chloride in CH2Cl2 (20 ml, 40 mmol) was added over 5 min to a solution of the product of Step 1 (3.0 g, 21 mmol) in anhydrous THF (50 ml). The solution was heated to 80° C. for 6 h and then evaporated to dryness. The residue was dissolved in THF (50 ml) at 0° C. and aq. NH4OH (6.0 ml, 89 mmol) was added. After stirring at R.T. for 16 h, the mixture was concentrated and the residue purified by column chromatography (gradient CH2Cl2 to 2:98 CH3OH/CH2Cl2) to give the product (762 mg, 26%). MS (Cl) m/e 142 (M+H)+.

[0306] Step 3 138

[0307] A mixture of the product of Step 2 (800 mg, 5.71 mmol), 40% aq. methylamine (4.0 ml, 52 mmol), and sodium triacetoxyborohydride (1.7 g, 8.0 mmol) in dichloroethane (20 ml) was stirred at R.T. for 16 h. The reaction was quenched with 3N NaOH and partitioned between brine and 1:1 CH3CN/CH2Cl2. The organic portion was concentrated and the residue purified by column chromatography (gradient CH2Cl2 to 1:4 2M NH3 in CH3OH/CH2Cl2) to give the product (450 mg, 51%). MS (Cl) m/e 157 (M+H)+.

[0308] Step 4

[0309] A mixture of the aniline 4-1-2 (100 mg, 0.534 mmol), N,N′-disuccinimidyl carbonate (137 mg, 0.535 mmol), and pyridine (0.13 ml, 1.6 mmol) in THF (3 ml) was stirred at 0° C. for 2 h. To this mixture was added the product of Step 3 (125 mg, 0.811 mmol) and the reaction was stirred at R.T. for 2 h. The mixture was diluted with CH2Cl2 (100 ml), washed with 1 N HCl (2×25 ml), water (2×25 ml), brine (25 ml), dried, and concentrated. The residue was subjected to PTLC (3:97 CH3OH/CH2Cl2) to give the cis-product (14 mg) and the trans-product (15 mg).

[0310] cis-Product 25A:

[0311] 1 H NMR (CD3OD, 400 MHz): δ 7.4-7.6 (4H, m), 7.33 (2H, m), 7.22 (1H, m), 6.95 (1H, m), 4.13 (1H, m), 2.86 (3H, s), 2.53 (1H, m), 2.13 (2H, m), 1.82 (2H, m), 1.5-1.75 (4H, m). MS (ES) m/e 370 (M+H)+.

[0312] trans-Product 25B:

[0313] 1 H NMR (CD3OD, 400 MHz): δ 7.4-7.5 (4H, m), 7.34 (2H, m), 7.23 (1H, m), 6.96 (1H, m), 4.07 (1H, m), 2.88 (3H, s), 2.14 (1H, m), 1.98 (2H, m), 1.81 (2H, m), 1.5-1.7 (4H, m). MS (ES) m/e 370 (M+H)+.

[0314] Reaction of the Product of Step 3, 25-3-1 with Aniline 4-1-1 by Essentially the Same Procedure Gave 25C and 25D: 139

[0315] 25C MS (ES) m/e 388 (M+H)+140

[0316] 25D MS(ES) m/e 388 (M+H)+

EXAMPLE 26

[0317] 141

[0318] Step 1 142

[0319] To a stirred mixture of 1,4-cyclohexanedione monoethylene ketal (4.68 g, 30 mmol) and 40% w/w aq. methylamine (6.0 mL) in 1,2-dichloroethane (75 mL), was added Na(OAc)3BH (9.6 g, 45 mmol) in portions. The reaction mixture was vigorously stirred for 16 h, then 1 N NaOH (75 mL) was added. The organic layer was washed with sat'd NaCl, dried (MgSO4), filtered, and evaporated to give an oil (4.60 g, 90%) that was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 3.97 (4H, s), 2.47 (1H, m), 2.46 (3H, s), 1.91 (2H, m), 1.80 (2H, m), 1.59 (2H, m), 1.45 (2H, m).

[0320] Step 2 143

[0321] To a stirred, ice-cold mixture of aniline 4-1-1 (1.00 g, 4.87 mmol) and pyridine (1.97 ml, 24.3 mmol) in anhydrous THF (50 ml) was added disuccinimidyl carbonate (1.25 g, 4.87 mmol). The reaction mixture was stirred at 0° C. for 1 h and the product of Step 1 (1.25 g, 7.31 mmol) was added. The reaction mixture was allowed to warm to R.T., stirred for 16 h, then poured into cold H2O (100 ml). The whole was extracted with CH2Cl2 (3×100 ml). The combined organic layers were dried (Na2SO4), filtered, and evaporated. Purification of the residue by column chromatography (1:20 CH3OH/CH2Cl2) afforded the product (1.40 g, 71%). 1H NMR (CDCl3, 400 MHz) δ 7.49 (4H, m), 7.10 (2H, m), 6.70 (1H, m), 6.60 (1H, s), 4.30 (1H, m), 3.90 (4H, s), 2.90 (3H, s), 1.75 (8H, m). MS m/e 403 (M+H).

[0322] Step 3 144

[0323] To the product of Step 2 (1.30 g, 3.23 mmol) in THF (30 ml) was added 5N HCl (20 ml). The reaction mixture was stirred at R.T. for 4.5 h, then extracted with CH2Cl2 (3×100 ml). The combined organic extracts were washed with sat'd NaHCO3, dried (Na2SO4), filtered and evaporated. The residue was purified by PTLC (1:20 CH3OH/CH2Cl2) to give the product (0.80 g, 69%). 1H NMR (CDCl3, 400 MHz) δ 7.50 (4H, m), 7.10 (2H, m), 6.80 (1H, m), 6.50 (1H, s), 4.80 (1H, m), 2.90 (3H, s), 2.48 (4H, m), 2.10 (2H, m), 1.90 (2H, m). MS m/e 359 (M+H).

[0324] Step 4 145

[0325] To a mixture of the product of Step 3 (0.43 g, 1.20 mmol) and benzylamine (0.257 g, 2.40 mmol) in 1,2-dichloroethane (10 ml) was added NaBH(OAc)3 (0.762 g, 3.60 mmol) in portions. The reaction mixture was stirred at R.T. for 4.5 h, then poured into sat'd NaHCO3 (20 ml) and extracted with CH2Cl2 (3×20 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by PTLC (1:20 (2M NH3/CH3OH):CH2Cl2) to produce the cis-isomer 26-4-1 (0.240 g, 44.5%) and the trans-isomer 26-4-2 (0.200 g, 37.0%). Cis isomer: 1H NMR (CDCl3, 400 MHz) δ 7.48 (4H, m), 7.30 (5H, m), 7.05 (2H, m), 6.70 (1H, m), 6.40 (1H, s), 4.20 (1H, m), 3.78 (2H, s), 2.90 (4H, m), 1.90 (4H, m), 1.55 (4H, m). MS m/e 450 (M+H). Trans-isomer: 1H NMR (CDCl3, 400 MHz) δ 7.48 (4H, m), 7.33 (5H, m), 7.05 (2H, m), 6.70 (1H, m), 6.37 (1H s), 4.20 (1H, m), 3.82 (2H, s), 2.88 (3H, m), 2.50 (1H, m), 2.10 (2H, m), 1.80 (2H, m), 1.20-1.70 (4H, m). MS m/e 450 (M+H).

[0326] Step 5 146

[0327] To the cis isomer 26-4-1 (0.600 g, 1.33 mmol) in 4.4% HCOOH/CH3OH (50 ml) was added 10% Pd/C (0.600 g). The reaction mixture was stirred at R.T. under argon for 16 h, then filtered through celite and concentrated. The residue was purified by PTLC (1:10 (2M NH3/CH3OH)/CH2Cl2) to afford the product (0.230 g, 85%). 1H NMR (CDCl3, 400 MHz) δ 7.50 (4H, s), 7.06 (2H, m), 6.70 (1H, m), 6.40 (1H, s), 4.20 (1H, m), 3.30 (1H), 3.00 (3H, s), 1.50-2.30 (10H, m). MS m/e 360 (M+H).

[0328] Step 6

[0329] To a mixture of the product of Step 5 (0.140 g, 0.390 mmol) and 1 M K2CO3 (1.2 ml, 1.2 mmol) in THF (5 ml) was added MeSO2Cl (0.178 g, 1.55 mmol). The reaction mixture was stirred at R.T. for 16 h then subjected to PTLC (1:10 CH3OH/CH2Cl2) to give the product (0.135 g, 79%). 1H NMR (CDCl3, 400 MHz) δ 7.53 (4H, m), 7.20 (2H, m), 6.90 (1H, m), 4.10 (1H, m), 3.60 (1H, m), 2.90 (6H, s), 1.50-2.10 (8H, m). MS m/e 438 (M+H).

EXAMPLE 27

[0330] 147

[0331] A mixture of 26-3-1 (0.21 g, 0.59 mmol), hydroxylamine hydrochloride (0.82 g, 12 mmol), and sodium acetate (0.97 g, 12 mmol) in absolute EtOH (10 ml) was stirred at R.T. for 64 h. The mixture was partitioned between CH2Cl2 (100 ml) and water (75 ml). The aqueous layer was extracted again with CH2Cl2 (50 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was subjected to PTLC (1:19 CH3OH/CH2Cl2) to give the product (210 mg, 95%). 1H NMR (CD3OD, 400 MHz) δ 7.4-7.6 (4H, m), 7.20 (2H, m), 6.85 (1H, m), 4.39 (1H, m), 3.45 (1H, m), 2.90 (3H, s), 2.45 (1H, m), 2.28 (1H, m), 1.6-2.0 (5H, m). MS (ES) m/e 374 (M+H).

[0332] Use of the appropriate starting material and essentially the same procedure afforded the following compound. 148

[0333] MS (ES) m/e 388 (M+H).

EXAMPLE 28

[0334] 149

[0335] Step 1 150

[0336] To a mixture of 1-3-5 (100 mg, 0.31 mmol), 1 M NaOH (0.5 ml), and 1 M Na2CO3 (0.5 ml) in CH2Cl2 (5 ml) was added 2-chloroethylsulfonyl chloride (100 mg, 0.61 mmol), and the reaction mixture was stirred for 16 hr. The reaction mixture was partitioned between water (25 ml) and CH2Cl2 (25 ml). The organic layer was dried (MgSO4), filtered, and concentrated. Subjection of the residue to PTLC (1:4 acetone/CH2Cl2) gave the product (40 mg, 31%). MS (ES) m/e 418 (M+H).

[0337] Step 2

[0338] To a stirred solution of the product of Step 1 (28-1-1) (50 mg, 0.12 mmol) in THF (10 ml) was added tetrabutylammonium hydroxide (0.5 g) in water (2 ml). After 16 hr, the reaction mixture was partitioned between water (25 ml) and CH2Cl2 (100 ml). The organic layer was dried (MgSO4), filtered, and concentrated. Subjection of the residue to PTLC (5:95 MeOH/CH2Cl2) gave the product (24 mg, 46%). HRMS calc. for C21H27FN3O4S (M+H) 436.1706. Found 436.1711.

EXAMPLE 29

[0339] 151

[0340] To a solution of 1-3-1 (400 mg, 1.22 mmol) in DMF (5 ml) was added EDCI (25 mg, 1.30 mmol) and 1-cyano-3-methylisothiourea sodium salt (175 mg, 1.27 mmol). The reaction mixture was stirred for 16 h, then diluted with EtOAc (50 ml). The mixture was washed with water (10 ml), sat'd NaHCO3 (20 ml) and water (10 ml). The organic layer was dried (MgSO4), filtered and concentrated. Subjection of the residue to flash chromatography (gradient; 3:97-7:93 MeOH/CH2Cl2) gave the product (250 mg, 50%). HRMS calc. For C22H26N6° F. (M+H) 409.2152. Found 409.2155.

EXAMPLE 30

[0341] 152

[0342] To a solution of 1-3-1 (500 mg, 1.53 mmol) in acetonitrile (10 ml) was added dimethyl-N-cyanodithioiminocarbonate (0.8 g, 5.5 mmol) and the reaction mixture was refluxed for 16 h. The reaction mixture was poured into water (50 ml) and extracted with EtOAc (50 ml). The organic layer was dried (MgSO4), filtered and concentrated. Subjection of the residue to flash chromatography (1:2 acetone/hexanes) gave the product (150 mg, 24%). MS m/e 426.1 (M+H).

[0343] Method for Screening Compound 14 of Example 14 for Y5 Antagonist Activity in vivo

[0344] Adult male Long-Evans or Sprague-Dawley rats (200-250 g, Charles River, Mass.) were maintained in individual cages at 22° C. on a 12 hr light/12 hr dark cycle with lights on at 0400. Rats had free access to food (Teklad Lab Rodent Chow, Bartonville, Ill.) and water. All studies were conducted in an AAALAC accredited facility following protocols approved by the Animal Care and Use Committee of the Schering-Plough Research Institute. The procedures were performed in accordance with the principles and guidelines established by the NIH for the care and use of laboratory animals.

[0345] Rats were anesthetized by intramuscular injection of a mixture of ketamine and xylazine (100 and 10 mg/kg, respectively). A 22 gauge stainless steel cannula was stereotaxically implanted into the lateral ventricle using the following coordinates: 1 mm posterior to bregma, 1.5 mm lateral to midline, 3.6 mm ventral to dura. After a three week recovery period, all animals were tested for correct cannula placement by intracerebroventricular (icv) infusion of human NPY (0.3 mmol). Only animals demonstrating a profound feeding effect (>2 g) within 60 min of the infusion were retained for the study. Four groups of twelve animals were used in each study. Each group was balanced such that the average baseline and NPY-induced food intake values were similar for each group. One group received an oral dose of vehicle while the other three groups received oral doses of the Y5 antagonist 14 one hour before icv administration of D-Trp34-NPY. D-Trp34-NPY was dissolved in 0.9% sterile saline (Sigma, St. Louis, Mo.) and were infused icv with a Hamilton infusion pump and syringe (Hamilton, Reno, Nev.) at a rate of 5 μl/min. The guide cannula remained inserted for an additional minute to prevent diffusion up the needle track. The chow-filled feeder was weighed during the infusion period and then returned to the home cage with the animal immediately following treatment. Food consumption was monitored at 60, 120 and 240 min after icv infusion of peptides. Differences in food intake between groups were determined by analysis of variance followed by Dunnett's multiple comparison test. Compound 14 (0.1, 0.3, 1, and 3 mg/kg) dose responsively inhibited D-Trp34-NPY stimulated food intake with an ID50 of 0.5 mg/kg.

[0346] It will be recognized that the following examples can be prepared by adapting appropriate procedures described in Examples 1-30, or by applying methods known to those skilled in the art:

Example	Structure	MSm/e (M + H)
31	153	483
32	154	449
33	155	483
34	156	467
35	157	440
36	158	483
37	159	483
38	160	457
39	161	457
40	162	449
41	163	449
42	164	440
43	165	483
44	166	483
45	167	422
46	168	410
47	169	424
48	170	438
49	171	438
50	172	436
51	173	472
52	174	374
53	175	388
54	176	402
55	177	402
56	178	400
57	179	442
58	180	414
59	181	428
60	182	396
61	183	403
62	184	431
63	185	414
64	186	423
65	187	360
66	188	374
67	189	388
68	190	388
69	191	410
70	192	424
71	193	422
72	194	424
73	195	386
74	196	404
75	197	356
76	198	370
77	199	392
78	200	406
79	201	420
80	202	418
81	203	420
82	204	384
83	205	384
84	206	382
85	207	388
86	208	466
87	209	531
88	210	452
89	211	467
90	212	452
91	213	428
92	214	402
93	215	416
94	216	416
95	217	430
96	218	456
97	219	456
98	220	430
99	221	442
100	222	480
101	223	444
102	224	467
103	225	465
104	226	465
105	227	428
106	228	465
107	229	422
108	230	410
109	231	424
110	232	438
111	233	438
112	234	436
113	235	472
114	236	374
115	237	400
116	238	388
117	239	402
118	240	402
119	241	442
120	242	414
121	243	428
122	244	408
123	245	431
124	246	338
125	247	352
126	248	428
127	249	396
128	250	368
129	251	395
130	252	435
131	253	437
132	254	407
133	255	443
134	256	449
135	257	381
136	258	450
137	259	388
138	260	402
139	261	416
140	262	417
141	263	450
142	264	464
143	265	416
144	266	389
145	267	442
146	268	356
147	269	370
148	270	403
149	271	371
150	272	389
151	273	449
152	274	385
153	275	449
154	276	449
155	277	511
156	278	449
157	279	519
158	280	465
159	281	467
160	282	501
161	283	511
162	284	466
163	285	467
164	286	466
165	287	449
166	288	449
167	289	447
168	290	531
169	291	448
170	292	448
171	293	452
172	294	466
173	295	467
174	296	468
175	297	440
176	298	452
177	299	450
178	300	422
179	301	434
180	302	434
181	303	448
182	304	449
185	305	459
186	306	487
187	307	409
188	308	420
189	309	436
190	310	401
191	311	435
192	312	485
193	313	449
194	314	523
195	315	463
196	316	450
197	317	442
198	318	420
199	319	438
200	320	427
201	321	387.1
202	322	388.1
203	323	387.1
204	324	386.1
205	325	393.1
206	326	323.1
207	327	465.1, 467.1
208	328	378.1
209	329	378.1
210	330	387.1
211	331	455.1
212	332	455.1
213	333	416.1
214	334	403.1
215	335	401.1
216	336	405.1
217	337	441.1
218	338	423.1
219	339	457.1
220	340	439.1
221	341	437.1
222	342	448.1
223	343	450.1
224	344	432.1
225	345	436.1
226	346	422.1
227	347	439.1
228	348	436.1
229	349	422.1
230	350	512.1
231	351	422.1
232	352	462.1
233	353	385
234	354	440.1
235	355	462.1
236	356	440.1
237	357	454.1
238	358	468.1
239	359	468.1
240	360	441
241	361	473
242	362	405
243	363	437
244	364	491
245	365	491
246	366	405
247	367	423
248	368	423
249	369	439
250	370	416
251	371	405
252	372	421
253	373	453
254	374	491
255	375	501
256	376	517
257	377	430
258	378	458
259	379	492
260	380	599
261	381	424
262	382	487
263	383	442
264	384	442
265	385	424
266	386	436
267	387	422
268	388	424
269	389	424
270	390	436
271	391	466
272	392	422
273	393	424
274	394	424
275	395	424
276	396	424
277	397	458
278	398	424
279	399	446
280	400	388
281	401	418
282	402	402
283	403	466
284	404	466
285	405	529
286	406	507
287	407	471
288	408	422
289	409	456
290	410	456
291	411	413
292	412	451
293	413	413
294	414	416
295	415	416
296	416	456
297	417	442
298	418	414
299	419	454
300	420	414
301	421	414
302	422	360
303	423	438
304	424	452
305	425	466
306	426	452
307	427	466
308	428	402
309	429	416
310	430	428
311	431	465
312	432	465
314	433	465
315	434	403
316	435	437
317	436	437
318	437	458
319	438	424
320	439	374
321	440	374
322	441	529
323	442	416
324	443	490
325	444	439
326	445	452
327	446	424
328	447	439
329	448	424
330	449	451
331	450	451
332	451	446
333	452	402
334	453	451
335	454	388
336	455	446
337	456	446
338	457	388
339	458	402
340	459	388
341	460	402
342	461	464

[0347] The preferred compounds of the present invention include the compounds of Examples: 29-59, 61-90, 95-216, 218-219, 221-262, 265, 267, 269-294, 296-297, 299-326, 328-337, 340-342 and their pharmaceutically acceptable addition salts and/or hydrates thereof, or where applicable, geometric or optical isomers or a racemic mixtures thereof.

Claims

1. A compound having the structural formula I:

2. A compound of claim 1 wherein

3. A compound of claim 2 wherein R5 is a substituent independently selected from hydrogen, halogen, haloalkyl, alkoxy and haloalkoxy and the sum of j and k is 1, 2 or 3.

4. A compound of claim 2 wherein R6 is (C1-C6)alkyl SO2—, hydroxy(C2-C6)alkylSO2—, (C3-C7)cycloalkylSO2—, R9R10NSO2— or NH2SO2—.

5. A compound of claim 1 selected from

6. A compound of claim 1, wherein the compound is

7. A compound of claim 2 wherein R6 is heterorarylC(O)—, (C1-C6)alkylC(O)— or (C3-C7)cycloalkyl C(O)—.

8. A compound of claim 1 selected from the group consisting of

9. A compound of claim 2 wherein R6 is heteroaryl.

10. A compound of claim 1 selected from the group consisting of

11. A compound of claim 1 wherein

12. A compound of claim 11 wherein R5 is a substituent independently selected from hydrogen, halogen, haloalkyl and haloalkoxy, r is 1 and the sum of j and k is 1, 2 or 3.

13. A compound of claim 11 wherein R6 is (C1-C6)alkylSO2—, (C3-C7)cycloalkylSO2—, or —SO2NR9R10.

14. A compound of the formula

15. A compound of claim 11 wherein R6 is heteroarylC(O)—, (C1-C6) alkylC(O)— or (C3-C7)cycloalkylC(O)—.

16. A compound of claim 1 selected from the group consisting of

17. A compound of claim 11 wherein R6 is heteroaryl.

18. A compound of claim 1 selected from the structural formulas set forth in the following table, and the pharmaceutically acceptable addition salts and/or hydrates thereof:

19. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 and a pharmaceutically acceptable carrier.

20. A method of treating metabolic or eating disorders comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 of said compound.

21. The method of claim 20 wherein said metabolic disorder is obesity.

22. The method of claim 20 wherein said eating disorder is hyperphagia.

23. A method of treating disorders associated with obesity comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt of said compound.

24. The method of claim 23 wherein said disorders associated with obesity are Type II Diabetes, insulin resistance, hyperlipidemia and hypertension.

25. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising: a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an anti-obesity and/or anorectic agent, a thryomimetic agent or an NPY antagonist; and a pharmaceutically acceptable carrier.

26. The pharmaceutical composition of claim 25 wherein the anorectic agent is a 3 agonist.

27. A method of treating a metabolic and eating disorder which comprises administering to a mammal in need of such treatment an amount of a first compound, said first compound being a compound of claim 1, or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an anti-obesity and/or anorectic agent, a thryomimetic agent or an NPY antagonist; wherein the amounts of the first and second compounds result in a therapeutic effect.

28. The pharmaceutical composition of claim 27 wherein the anorectic agent is a 3 agonist.

29. A pharmaceutical composition which comprises a therapeutically effective amount of a composition comprising: a first compound, said first compound being a compound of claim 1 or a pharmaceutically acceptable salt of said compound; a second compound, said second compound being an aldose reductase inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor, a protein tyrosine phosphatase 1B inhibitor, a dipeptidyl protease inhibitor, insulin, an insulin mimetic, metformin, acarbose, a PPAR-gamma ligand such as troglitazone, rosaglitazone, pioglitazone, or GW-1929, a sulfonylurea, glipazide, glyburide, or chlorpropamide; and a pharmaceutically acceptable carrier therefor.