Title of Invention

BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE FOR THE TREATMENT OF PREVENTION OF DIABETES

Abstract

The present invention is directed to compounds which are inhibitors of rhe dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Full Text

BETA-AMINO HETEROCYCLIC DIPEPTIDYL PEPTIDASE INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES BACKGROUND OF THE INVENTION Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or af:er administration of glucose durins an oral glucose tolerance rest. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations oi the lipid. lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular -disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important m the ciinical management and treatment of diabetes mellitus. There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NEDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance. Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver. The available treatments for type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide. which stimulate the pancreaticβ—cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meelitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secre'tagogues *,sulfonylureas or rr.eglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The bisuanides increase insulin sensitivitv resulting in some correction of hyperglycemia. However, the two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea. Metformin has fewer side effects than phenformin and is often prescribed for the treatment of Type 2 diabetes. The glitazones (i.e. 5-benzylthiazolidine-2.4-ciones) are a more recently described class of compounds with potential for ameliorating many symptoms of type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes resulting in partial or complete correction of tfie elevated plasma levels of glucose without occurrence of hypoglycemia. The glitazones that are currently marketed are agonists of the peroxisome proliferator activated receptor (PPAR). primarily the PPAR-gamma subtype. PPAR-gamma agonism is generally believed to be responsible for the improved insulin sensititization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of Type II diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from the glitazones (i.e., they are not thiazolidinediones). Serious,side effects (e.g. liver toxicity) have occurred with some of the glitazones, such as troglitazone. Additional methods of treating the disease are still under investigation. New biochemical approaches that have been recently introduced or are still under development include treatment with alpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosine phosphatase-lB (PTP-1B) inhibitors. Compounds that are inhibitors of the dipeptidyl peptidase-IV ("DP-IV" or "DPP-IV") enzyme are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly type 2 diabetes. See for example WO 97/40832, WO 98/19998. U.S. Patent No. 5.939.560, Bioorg. Med. Chem. Lett., 6: 1163-1166 (1996): and Bioorg. Med. Chem. Lett.. 6: 2745-274S (1996). The usefulness of DP-IV inhibitors in the treatment of type 2 diabetes is based on the fact that DP-IV in vivo readily inactivates glucagon like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1 and GIP are incretins and are produced when food is consumed. The incretins stimulate production of insulin. Inhibition of DP-IV leads to decreased inactivation of the incretins, and this in turn results in increased effectiveness of the incretins in stimulating production of insulin by the pancreas. DP-IV inhibition therefore results in an increased level of serum insulin. Advantageously, since the incretins are produced by the body only when food is consumed, DP-TV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low hiood sugar (hypoglycemia). Inhibition of DP-IV is therefore expected :o increase insulin without increasing the risk of hypoglycemia, which is a dangerous side effect associated with the use of insulin secretagogues. DP-IV inhibitors also have other theraoeutic utilities, as discussed herein. DP-Pv" inhibitors have not been studied extensively to date, especially for utilities other than diabetes. New compounds are needed so that improved DP-TV inhibitors can be found for the treatment of diabetes and potentially other diseases and conditions. The therapeutic potential of DP-IV inhibitors for the treatment of type 2 diabetes is discussed by DJ. Drucker in Exp. Opin. Invest. Drugs, 12; S7-I00 (2003) and by K. Augustyns, et al., in Exp. Opin. Ther. Patents. 13: 499-510 (2003). - ■ SUMMARY OF THE INVENTION The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in, which the dipeptidyl peptidase-IV enzyme is involved. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to hexahydrodiuzepinone compounds useful as inhibitors of dipeptidyl peptidase-TV. Compounds of the present invention are described by structural formula I: Dr a pharmaceuticallyacceptable salt thereof; wherein each n is independently 0, J, or 2; Ar is phenyl substituted with one to five RP substituents; R1 is selected from the group consisting of hydrogen, C1-10 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkoxy, carboxy, Ci-6 alkyloxycarbonyl, and phenyl-C1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with* one to five halogens, (CH2)n-aryl wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, CN. hydroxy, R2, OR2, NHS02R2, NR-SO2R2, SOoR2, CO2H, and C1-6 alkyloxycarbonyl, (CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen, C1-6alkyl, and Ci-f alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to fivi halogens, (CH2)n-heterocyclyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, Cj-6 alkyl and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, (CH2)rrQ3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxv. C1-6 alkyl and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; and wherein any methylene (CH2) carbon atom in R I is .msubstituted or substituted with one to two groups independently selected from halogen.aydrox\\ and C 1-4 alkyl unsubstituted or substituted with one to five halogen; each R3 is independently selected from the group consisting of hydrogen, halogen, cyano. hydroxy, C1-6 alkyl, unsubstituted or substituted with one to five halogens, C1-6alkoxy, unsubstituted or substituted with one to five halogens. carboxy, alkoxycarbonyL amino, NHR2, NR2R2, NHS02R2, NR2S02R2, NHCOR2, NR2COR2, NHC02R2, NR2C02R2, S02R2, SO2NH2, S02NHR2, and S02NR2R2; each R- is independently Cl-6 alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, CO2H, and C1-6 aJkyloxycarbonyl; R4 and R5 are independently selected from the group consisting of: hydrogen. cyano, carboxy, C1-6 alkyloxycarbonyl, C1-10 alkyl, unsubstituted or substituted with one to five substituents independently selected from halosen, hvdroxw C1-6 alkoxv. carboxv, C1-6 alkyloxycarbonyl, and phenyl-C1-_3 alkoxy, wherein alkoxy is unsubstituied or substituted with one to five halogens, lCH2)n-aryl, wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy. C1-6 alkyl, and C1-6 alkoxy. wherein alkyl and alkoxy are unsubstituted or substituted with one to five halosens. (CH2)n-heteroaryl. wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen. C 1_6 alkyl, and C 1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, (CH2)n-heterocycIyl* wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, Q-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halosens, (CH2)n-C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, Ci-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halosens. (CH2)nCONR6R7, wherein R6 and R7 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CEbWphenyl, (CH2)n-C3-6 cycloalkyl, and C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, Ci-6 alkyl, and Ci-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; or wherein R^ and R? together with the nitrogen atom to which they are attached form a heterocyclic ring selected from azetidine, pyrrolidine, piperidine. piperazine, and morpholine: and wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C[-6 alkyl, and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; and wherein any methylene (CH2) carbon atom in R4 or R5 is unsubstituted or substituted with one to twc groups independently selected from halogen. hydrow. ar.d C1-4 aikyl unsubstituted or substituted with one to five halogens; and R8and R9 are each independently hydrogen or C1-6 alky!. In one embodiment of the compounds of the ^resent invention, the carbon atc.v. marked with an ':: has the R configuration as depicted in formula la wherein Ar, R1R4. R5R8 and R9 are as defined herein. In a second embodiment of the compounds of the present invention, R-2 is selected from the group consisting of hvdrogen. halogen, cyano, hydroxy. C1-6 alkyl. unsubstituted or substituted with one to five halogens, and C1-6 alkoxy, unsubstituted or substituted with one to five halogens. In a class of this embodiment, R3 is selected from the group consisting of hydrogen, fluoro. chloro, bromo, trifluoromethyl, and methyl. In a subclass of this class, R3 is selected from the group consisting of hydrogen, fluoro, and chloro. In a third embodiment of the compounds of the present invention. R* is selected from the group consisting of: hydrogen, C1-6 alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-5 alkoxy. carboxy. C1.5 alky loxycarbonyl, and phenyI-C1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens, lCH2)n-C3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C i_6 alkyl. and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens; and wherein any methylene (CH2) carbon atom in Rl is unsubstituted or substituted with om to two groups independently selected from halogen. Hydroxy, and C 1-4 alkyl unsubstituted or substituted with one to five halogens. In a class of this embodiment of the compounds of the present invention. R ^ :s selected from the group consisting of hvdroeen, C1-4 alkyl, 2,2,2-trifluoroethyl, methoxvcarbonvlmethvl, carboxymethyl, hydroxyethyl, benzvloxvmethvl, « .j * benzyloxyethyl, and cyclopropyl. ■ In a subclass of this class, Rl is selected from the group consisting of hydrogen. methyl, te/Y-butyl, and cyclopropyl. In a fourth embodiment of the compounds of the present invention. R-* and R»- ure independently selected from the group consisting of: hydrogen, Ci-io alkyl, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, Ci-6 alkoxy, carboxy, C[-6 alkyloxycarbonyk and phenyl-Ci-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens, (CH2)n-ary'» wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, Ci-6 alkyl, and Ci-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five haloeens, (CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three . - substituents independently selected from hydroxy, halogen. Ci-g alkyi\ and Cw6 alkoxv. wherein alkvl and alkoxv are unsubstituted or substituted with one to five haloeens. In a subclass of this class, R4 and R5 are independently selected from the group consisting of. hydrogen, CH3, CH2CH3, CH2CH(CHs)2, CH2-cyclopropyl. CHo-cyclohexyl, CH20CH2Ph, CH2OH CH2Ph, CH2(3-OCF3-Ph), CH2(4-OCF3-Ph), CH2(3-CF3,5-CF3-Ph), CH2(2-CF3-Ph). CH2(2-Cl-Ph), CH2(2-Me-Ph), CH?(2-Me,5-Me-Ph), CH2(2-Ph-Ph), CH2(2-F,5-F-Ph), CH2(2-F-Ph). CH2(2-F,3-F-Ph). CH2(2-pyridinyl), CH2(3-pyridinyl), CH2(4-pyridinyl), CH2( 1 -oxidopyridin-2-yl), CH2(l-oxidopyridin-3-yl), CH2(l//-pyrazoI-l-yl), CH2(2-F,6-F-Ph), and ^H2CF3. 1 In a further subclass of this class, R5 is hydrogen. In a fifth embodiment 01 me compounds of the present invention, R§ and R9 are independently selected from hydrogen and methyl. In a class of this embodiment, RS and R9 are hydrogen. In a sixth embodiment of the present invention are compounds of formula la wherein Rl is selected from the group consisting of hydrogen, C1-4 alkyl, 2,2.2-trifluoroethyl, methoxycarbonyi methyl, earboxymethyl, hydroxyethyl, benzyloxymethyl. benzyloxyethyl, and cyclopropyl; R-"1 is hydrogen, chloro. or fluoro; R4 is selected from the group consisting of: hydrogen, CH3) CH2CH3, CH2CH(CH3)2, CH2-cyclopropyI. CFb-cyclohexyl, CH20CH2Ph, CH2OH CH2Ph, CH2(3-OCF3-Ph), CH2(4-OCF3-Ph), and CH2(3-CF3,5-CF3-Ph) CH2(2-CF3-Ph), CH2(2-Cl-Ph), CH2(2-Me-Ph), CH2(2-Me,5-Me-Ph), CH2(2-Ph-Phj. - • CH2(2-F,5-F-Ph), CH2(2-F-Ph). CH2(2-F,3-F-Ph), CH2(2-pyridinyl). CH2(3-pyridinyl), CH2(4-pyridinyl), CH2(l-oxidopyridin-2-yl), CH2(l-oxidopyridin-3-yl), CH2(l//-pyrazol-l-yH, CH2(2-F,6-F-Ph). and CH2CF3; and RS and R9 are hvdroaen. In a class of this embodiment, R5 is hydrogen. Dlustrative, but nonlimiting examples, of compounds of the present invention that are useful as inhibitors of dipeptidyl peptidase-IV are the following: or a pharmaceutically acceptable salt thereof. As used herein the following definitions are applicable. . "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means carbon chains which may be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl. butyl, sec- and tort-butyl, pentyl, hexyl. heptyl, octyl, nonyl. and the like. Where the specified number of carbon atoms permits, e.g., from C3-10, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified. Ci-6 is intended. "Cycloalkyl" is a subset of alkyl and means a saturated carbocyclic ring having a specified number of carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl. cyclopentyl. cyclohexyl, cycloheptyl, cyclooctyl, and the like. A cycloalkyl group generally is monocyclic unless stated other.vise. Cycloalkyl groups are saturated unless otherwise defined. The term "alkoxv" refers to straight or branded chain alkoxides ^f the number of carbon atoms specified i.e.g., C}-6 alkoxy), or any number -. ithin this range [i.e.. merhov. MeO-). ethoxy, isopropoxy. etc.]. The term fc'alkyIthio*" refers to straight or branched chain aikyisulfides of :he number or" carbon atoms specified • e.g., C1-6 alkylthio), or .m\ number within this range r:.e.. rr.erhylthio (MeS-). ethylthio, isopropylthio, etc.]. The term "alkylamino" refers to straight or branched aikylamir.es of the number of carbon atoms specified (e.g., Cj-6 alkylarnino), or any number vv:th:n this range [i.e.. mcthylamino. ethylamino, isopropylamino. t-butylamino, e'.cj. The term "alkylsult'onyi" refers to straight or branched chain aik\;su!fones of ::-number of carbon atoms specified ie.g.? C 1-6 alkylsulfony; ■- or any number within this range [i.e., methylsLilfony] (MeS02-), ethylsulfonyk isopropylsulfonyl. eic.j. The term "alkvloxvcarhonvl" refers to straight or branched chum esters o'\ a carhoxylic acid derivative of the present invention of the number of carbon atoms specified =e.g.. C1-6 alkvloxycarbonvH, or anv number within this ranee [i.e., me(hvK>.\vcarbonvl (MeOCO- . emyloxycarbonyl. or butyloxycarhonyl]. "Aryi" means a mono- or poJycyclic aromatic nng system containing carbon nng atoms. The preferred aryls are monocyclic or bicyclic 6-10 memhered aromatic nng systems. Phenyl and naphthyl are preferred aryls. The most preferred aryi is phenyl. "Heterocycle" and "heterocyclyl" refer to saturated or unsaturated non-aromatic nmzs or ring systems containing at least one heteroatom selected from 0. S and N. further including the oxidized forms of sulfur, namely SO and SO:- Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholme, 1.4-dithiane. piperazine. piperidine, 1,3-dioxoIane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran. dihydropyran, oxathiolane, dithiolane, 1.3-dioxane, L,3-dithiane, oxathiane. thiomoipholine. and the like. "Heteroaryl" means an aromatic or partially aromatic hererocycle that contains at least one nng heteroatom selected fromO, S and N. Heteroaryls thus includes heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles that are nc> aromatic. Examples of heteroaryl groups include: pyrrolyl, isoxazolyl. isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyh triazolyl, tetrazolyh furyk triazinyk thienyl, pyrimidyL benzisoxazolyl, benzoxazolyl, benzothiazolyh benzothiadi^.oly!. dihvdrobenzofuranyl, indolinyk pyridazinyl, indazolyk isoindolyl. dihydrober/othienyl. indolizinyl. cinnoliny 1, phthaluzinyl, quinazolinyl, naphthyridinyl. carbazolyk benzodioxolyl. quinoxalinyk purinyl, furazanyl, isobenzyifuranyl, benzimidazolyl. benzofuraryl. benzothienyl. quinolyl, indolyl, isoquinolyl, dibenzofuranyl, and the like. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 atoms are included, forming 1-3 rings. "Halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred. Fluorine is most preferred when the halogens are substituted on an alkyl or alkoxy group (e.g. CF3O and CF3CH2O). The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers. diastereomeric mixtures and individual diastereomers. The compounds of the present invention have one asymmetric center at the carbon atom marked with an * in formula la. Additional asymmetric centers may be present depending upon the nature of the various subsiituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this inventien.- The present invention is meant to comprehend all such isomeric forms of these compounds. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. Some of the compounds described herein may exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of the present invention.— Formula I shows the structure of the class of compounds without preferred stereochemistry. Formula la shows the preferred sterochemistry at the carbon atom to which is attached the amino group of the beta amino acid from which these compounds are prepared. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantionierically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The' coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods arc well known in the art. Alternatively, any enantiomer of a compound may he obtained by szereosdective synthesis using optically pure starting materials or reagents of known configuration by me:hecs well known in the art. It will be understood that, as used herein, references to the compounds of structural formula I are meant to also include the pharmaceutical!} acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutical!}' acceptable salts or in other synthetic manipulations. The compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt'1 refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases £nd inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the following: acetate, benzenesulfonate, benzoate, bicarbonate, btsuifate. bitartrate, borate, bromide, camsylate. carbonate, chloride, clavulanate. citrate, di hydrochloride. edetate, edisylate, estolate, esylate^fumarate, gluceptate, gluconate, glutamate. glycollylarsanilatc, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate. maieate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate. pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate. sulfate, subacetate. succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutical!}' acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines. and basic ion-exchange resins, such as arginine, bctaine, caffeine, choline. N.X-dibenzylethylenediamine, diethylamine. 2-diethylaminoethanol, 2-dimethylaminoethanoI, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine. histidine, hydrabamine, isopropylamine, lysine, methyiglucamine, morpholine. piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine. tnpropylamine, tromethamine, and the like. Also, in the case of a carboxylic acid (-COOH) or alcohol group being present in the compounds of the present invention, pharmaceutical!}' acceptable esters of carboxylic acid derivatives, such as methyl ethyl or pivaloyloxymethyl, or acy[ derivatives of alcohols, such as acetate or maleate, can be employed. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Solvates, and in particular, the hydrates of the compounds of structural formula I are included in the present invention as well. Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. The subject compounds are useful in a method o[ inhibiting the dipeptidyl peptidase-IV enzyme in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as inhibitors of dipeptidyl peptidase-IV enzyme activity. In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). The present invention is further directed to a method for the manufacture of a medicament for inhibiting dipeptidyl peptidase-IV enzyme activity in humans and animals comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The subject treated in the present methods is generally a mammal preferably a human being, male or female, in whom inhibition of dipeptidyl peptidase-IV enzyme activity is desired. The term "therapeutically effective amount'1 means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. The term "composition" as used herein 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. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient! s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, ccmplexation or aggregation of any two or more of the ingredients, or from, dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical!} acceptable carrier. By f,pharmaceutically acceptable" it is meant the carrier, diluent or exeipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of" and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment. The utility.of.the compounds in accordance with the present invention as . inhibitors of dipeptidyl peptidase-IV enzyme activity may be demonstrated by methodology known in the art. Inhibition constants are determined as follows. A continuous tluorometric assay is employed with the substrate Gly-Pro-AMC, which is cleaved by DP-FV to release the fluorescent AMC leaving group. The kinetic parameters that describe this reaction are as follows: Km = 50μM; kcal = 75 s_i; kcat/Km = 1.5 x 106 M'V1. A typical reaction contains approximately 50 pM enzyme, 50 jiM Gly-Pro-AMC. and buffer (100mM HEPES, pH 7.5, 0.1 mg/ml BSA) in a total reaction volume of 10CTμl. Liberation of AMC is monitored continuously in a 96-well plate fluorometer using an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Under these conditions, approximately 0.8μM AMC is produced in 30 minutes at 25 degrees C. The enzyme used in these studies was soluble (transmembrane domain and cytoplasmic extension excluded) human protein produced in a baculovirus expression systerr (Bac-To-BacT Gibco BRL). The kinetic constants for hydrolysis of Gly-Pro-AMC and GLP-1 were found to be in accord with literature values for the native enzyme. To measure the dissociation constants for compounds, solutions of inhibitor in DMSO were added to reactions containing enzyme and substrate (final DMSO concentration is 1%). All experiments were conducted at room temperature using the standard reaction conditions described above. To determine the dissociation constants (Kj)? reaction rates were fit by non-linear regression to the Michaelis-Menton equation for competitive inhibition. The errors in reproducing the dissociation constants are typically less than two-fold. In particular, the compounds of the foIIowing examples had activity in inhibiting the dipeptidyl peptidase-IV enzyme in the aforementioned assays, generally v.ith an IC50 of less than about 1 μM. Such a result is indicative of the intrinsic activity of theTompounds in use as inhibitors the dipeptidyl peptidase-IV enzyme activity. Dipeptidyl peptidase-IV enzyme (DP-IV) is a cell surface protein that has been implicated in a wide range of biological functions. It has a broad tissue distribution (intestine, kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells, vascular endothelium, lymphoid and myeloid cells, serum), and distinct tissue and cell-type expression levels. DP-IV is identical to the T ceil activation marker CD26, and it can cleave a number of immunoregulatory, endocrine, and neurological peptides in vitro. This has suggested a potential roie for this peptidase in a variety of disease processes in humans or other species. Accordingly, the subject compounds are useful in a method for the prevention or treatment of the following diseases, disorders and conditions. Tvpe n Diabetes and Related Disorders: It is well established that the incretins GLP-1 and GIP are rapidly inactivated in vivo by DP-TV. Studies with DP-IV-deficient mice and preliminary clinical trials indicate that DP-IV inhibition increases the steady state concentrations of GLP-1 and GIP, resulting in improved glucose tolerance. By analogy to GLP-l and GIP. it is likely that other glucagon family peptides involved in glucose regulation are also inactivated by DP-IV (eg. -PACAP). Inactivation of these peptides by DP-IV may also play a role in glucose homeostasis. The DP-IV inhibitors of the present invention therefore have utility in the treatment of Type II diabetes and in the treatment and prevention of the numerous conditions that often accompany Type II diabetes, including Syndrome X (also known as Metabolic Syndrome), reactive hypoglycemia, and diabetic dyslipidemia. Obesity, discussed below, is another condition that is often found with Type II diabetes that may respond to treatment with the compounds of this invention. The following diseases, disorders and conditions are related to Type 2 diabetes, and therefore may be treated, controlled or in some cases prevented, by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance. (3) insulin resistance. (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipidemia, (S) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12) atherosclerosis and its sequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, (16) other inflammatory conditions, (17) pancreatitis, (18) abdominal obesity, (19) neurodegenerative disease. (20) retinopathy, (21) nephropathy, (22) neuropathy, (23)-Syndrome X, (24) ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component. In Syndrome X. also known as Metabolic Syndrome, obesity is thought to promote insulin resistance, diabetes. dyslipidemia, hypertension, and increased cardiovascular risk. Therefore, DP-IV inhibitors may also be useful to treat hypertension associated with this condition. Obesity: DP-IV inhibitors mav be useful for the treatment of obesitv. This is based on the observed inhibitory effects on food intake and gastric emptying of GLP-1 and GLP-2. Exogenous administration of GLP-1 in humans sianificantlv decreases food intake and slows gastric emptying (Am. J. PhvsioL 277: R910-R916 (1999)). ICV administration of GLP-1 ir. rats and mice also has profound effects on food intake (Nature Medicine. 2: 1254-1258 (1996". This inhibition of feeding is not observed in GLP-1 Rc"'~) mice, indicating that these effects arc mediated through brain GLP-1 receptors. By analogy to GLP-i, it is likely that GLP-2 is also regulated by DP-IV. ICV administration of GLP-2 also inhibits food intake, analogous to the effects observed with GLP-1 (Nature Medicine. 6: S02-807 (2000)). In addition, studies with DP-IV deficient mice suggest that these animals are resistant to diet-induced obesity and associated pathology (e.g. hyperinsulinonemia). Growth Hormone Deficiency. DP-IV inhibition mav be useful for the treatment of growth hormone deficiency, based on the hypothesis that growth-hormone releasing factor (GRF). a peptide that stimulates release of growth hormone from the anterior pituitary, is cleaved by the DP-IV enzyme in vivo (WO 00/56297). The following data provide evidence that GRF is an endogenous substrate: (1) GRF is efficiently cleaved in vitro to generate the inactive product GRF[3-44] (BBA 1122: 147-153 (1992)): (2) GRF is rapidly degraded in plasma to GRF[3-44V. this is prevented by the DP-IV inhibitor diprotin A; and (3) GRF[3-44] is found in the plasma of a human GRF transgenic pig (J. Clin. Invest., 83: 1533-1540 (1989)). Thus DP-IV inhibitors may be useful for the same spectrum of indications which have been considered for growth hormone secretasosues. Intestinal Injury: The potential for using DP-IV inhibitors for the treatment of intestinal injury is suggested by the results of studies indicating that glucagon-like peptide-2 (GLP-2), a likely endogenous substrate for DP-IV, may exhibit trophic effects on the intestinal epithelium (Regulatory Peptides, 90: 27-32 (2000)). Administration of GLP-2 results in increased small bowel mass in rodents and attenuates intestinal injury in rodent models of colitis and enteritis. Immunosuppression: DP-IV inhibition may be useful for modulation of the immune response-based upon studies implicating the DP-IV enzyme in T cell activation and in ehemokine processing, and efficacy of DP-IV inhibitors in in vivo models of disease. DP-IV has been shown to be identical to CD26, a cell surface marker for activated immune cells. The expression o\ CD26 is regulated by the differentiation and activation status of immune cells. It is generally-accepted that CD26 functions as a co-stimulatory molecule in in vitro models of T ceil activation. A number of chemokjnes contain proline in the penultimate position, presumably to protect them from degradation by non-specific aminopeptidases. Many of these have been shown to be processed in vitro by DP-IV. In several cases (RANTES. LD"S-beta, MDC, eotaxin, SDF-lalpha), cleavage results in an altered activity in chemotaxis and signaling assays. Receptor selectivity also appears to be modified in some cases (RANTES). Multiple N-terminally truncated, forms of a number of chemokjnes have been identified in in vitro cell culture systems, including the predicted products of DP-IV hydrolysis. DP-IV inhibitors have been shown to be efficacious immunosuppressants in animal models of transplantation and arthritis. Prodipine t,Pro-Pro-diphenyl-phosphonate). an irreversible inhibitor of DP-IV, was shown to double cardiac allograft survival in rats from day 7 to day 14 (Transplantation, 63: 1495-1500 (1997)). DP-IV inhibitors have been tested in collagen and alkvldiamine-induced arthritis in rats and showed a statistically significant attenuation of hind paw swelling in this model flnt, J. Immunopharmacologv. 19:15-24 (1997) and Immunopharmacologv, 40: 21-26(1998)]. DP-IV is upregulated in a number of autoimmune diseases including rheumatoid arthritis, multiple sclerosis. Graves' disease, and Hashimoto's thyroiditis (Immunology Todav, 20: 367-375 (1999)). HTV Infection: DP-IV inhibition may be useful for the treatment or prevention of HIV infection or AIDS because a number of chemokines which inhibit HTV' cell entry are potential substrates for DP-IV (Immunology Today 20: 367-375 (1999)). In the case of SDF-lalpha, cleavage decreases antiviral activity (PNAS, 95: 6331-6 (1993)). Thus, stabilization of SDF-lalpha through inhibition of DP-IV would be expected to decrease HTV infectivity. Hematopoiesis: DP-IV inhibition may be useful for the treatment or prevention of hematopoiesis because DP-IV may be involved in hematopoiesis. A DP-IV inhibitor, Val-Boro-Pro, stimulated hematopoiesis in a mouse model of cyclophosphamide-induced neutropenia (WO 99/56753). Neuronal Disorders: DP-rv inhibition may be useful for the treatment or prevention of various neuronal or psychiatric disorders because a number of pepiides implicated in a variety of neuronal processes are cleaved in vitro by DP-IV. A DP-IV inhibitor thus may have'a therapeutic benefit in the treatment of neuronal disorders. Endomorphin-2. beta-casomorphin, and substance P have all been shown to be in vitro substrates for DP-IV. In all cases, in vitro cleavage is highly efficient, with kcal/Km about 106 M'Y1 or greater. In an electric shock jump test model of analeesia in rats, a DP-IV inhibitor showed a significant effect that was independent of the presence o^exogenous endomorphin-2 Neuroptotective and neuroregenerative effects of DP-IV inhibitors were also evidenced by the inhibitors' ability to protect motor neurons from excitotoxie cell death, to protect striatal innervation of dopaminergic neurons when administered concurrently with MPTP, and to promote recovery of striatal innervation density when given in a therapeutic manner following MPTP treatment [see Yong-Q. Wu, et a;.. 'Neuroprotective Effects of Inhibitors of Dipeptidyl Peptidase-IY In Vitro and In Vivo.'* Int. Conf. On Dipentidvl Ammopeptidases: Basic Science and Clinical Applications. September 26-29. 2002 (Berlin. Germany)]. Tumor Invasion and Metastasis: DP-IV 'inhibition may be useful for the treatment or prevention of tumor invasion and metastasis because an increase or decrease in expression of several ectopeptidases including DP-IV has been observed during the transformation of normal cells to a malignant phenotype (J. Exp. Med., 190: 301-305 (1999)). Up- or down-regulation of these proteins appears to be tissue and cell-type specific. For example, increased CD26/DP-IV ..expression has been observed on T cell lymphoma, T cell acute lymphoblastic leukemia, cell-derived thyroid carcinomas, basal cell carcinomas, and breast carcinomas. Thus. DP-IV inhibitors may have utility in the treatment of such carcinomas. Benign Prostatic Hypertrophy: DP-TV inhibition may be useful for the treatment of benign prostatic hypertrophy because increased DP-IV activity was noted in prostate tissue from patients with BPH (Eur. J. Clin. Chem. Clin. Biochem.. 30: 333-33S (1992)). Sperm motilitv/male contraception: DP-IV inhibition may be useful for the altering sperm motility and for male contraception because in seminal fluid, prostatosomes. prostate derived organelles important for sperm motility, possess very high levels of DP-TV activity (Eur. J. Clin. Chem. Clin. Biochem., 30: 333-338 (1992)). Gingivitis,: DP-IV inhibition may be useful for the treatment of gingivitis he:ause DP-IV activity was found in gingival crevicular fluid and in some studies correlated with periodontal disease seventy (Arch. Oral Biol.. 37: 167-173 (1992)). Osteoporosis: DP-TV inhibition may be useful for the treatment or prevention of osteoporosis because GIP receptors are present in osteoblasts. The compounds of the present invention have utility in treating or preventing one or more of the following conditions or diseases: (1) hyperglycemia, (2) low glucose tolerance. 1.5) insulin resistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7) hyperlipemia, i S) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels. (11) high LDL levels. (' 12) atherosclerosis and its sequelae, (13) vascular restenosis. (14) irritable bouel s;. ndrome. i 15) inflammatory bowel disease, including Crohn's disease and ulcerative colitis, ('16: ether inflammatory conditions, (17) pancreatitis, (18) abdominal obesity. (\9) neurodegenerative disease, (20) retinopathy, (21) nephropathy, (22) neuropathy, (23) Syndrome X. (.24 J ovarian hyperandrogenism (polycystic ovarian syndrome), (25) Type II diabetes, (26) grow;!-, hormone deficiency. (27) neutropenia, (28) neuronal disorders, (29) tumor metastasis, (30) benign. prostatic hypertrophy, (32) gingivitis, (33) hypertension, (34) osteoporosis, and other conditions that may be treated or prevented by inhibition of DP-P/. The subject compounds are further useful in a method for the prevention or treatment of the-aforementioned diseases, disorders and conditions in combination with other agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of Formula I or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor. contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred. However, the combination therapy may also include therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a "compound of Formula I. Examples of other acrive ingredients that may be administered in combination with a compound of Formula L and either administered separately or.in the same pharmaceu:.:ui composition, include, but are not limited to: (a) other dioentidvl oentidase IV I'DP-IVI miuhuors; (b) insuhn sensitizers including (i) PPARy -gomsrs such as the giirazones it.z. ivogliiazone. pioglitazone, englitazone, MCC-555, rosigiirazonc. and the like; and other PP.-.R ligands, including PP A Reefy dual agonists, such as KRP-2°~\ ana PPARa agonists such as fenofibric acid derivatives (gemfibrozil, elofibrate. fenofibrate and bezafihrare ?. • U ) bicuamiro such as metformin and phenformin, and t iii) protein tyros me phosphatase-1 B (c) insuhn or insulin mimetics; (d) sulfonylureas and other insulin secretagogues. such as tolbutamide g!ybun:c-:. glipizide, glimepiride, and meglitinides, such as repaglinide; (e) o/'izlucosidase inhibitors (such as acarbose and mielitoIV. «_ •— (f) glucagon receptor antagonists such as those disclosed m WO 9S/0452S, WO - 99/01423, WO 00/390SS, and WO 00/69S10; (g) GLP-1. GUM mimetics, and GLP-l receptor agonists such as those disclosed in W'OOO/42026 and WOOO/598S7: (h) GIP and GIP numerics such as those disclosed in"WOOO/5S360, and GIF receptor agonists: (i) PACAP, PACAP mimetics, and PACAP receptor agonist- such as those disclosed in WO 01/23420; (j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin. itavastatin. and rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPARa asonists such as fenofibric acid derivatives ('gemfibrozil, elofibrate. fenofibrate and bezafibrate), (v) PPARa/ydual agonists, such as KRP-297. i'vi> inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoAmhoIesterel acykransferase inhibitors, such as avasimibe, and (viii) antioxidants, such as probucol; (k) PPAR5 agonists, such as those disclosed in W097/28149: (I.i amiobesity compounds such as fenfluramine, dexfenfiurammc, phen'jrmin:* sibutramine. orlistat. neuropeptide Y] or Y1 or antagonists-- CB-I receptor im.er.e agonists-atid antagonists.Δ 3 adrenergic receptor agonists, melanocortm receptor agonists. :n particular rnelanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone MCH) receptor antagonists; (m) ileal bile acid transporter inhibitors; (n) agents intended for use in inflammatory condition* >v>ch as aspirm. nonsteroidal anti-inflammatory drugs, glucocorticoids, azultidine. and selective e;.oieox\genasc-2 inhibitors; (o) antihypertensive agents such as ACE inhibitors (enalapril. ksinoprii. captc^riL quinapril, tandolapril). A-H receptor blockers (losartan, candesartan. irbesartar.. vaisartam teimisartan, eprosartan), beta blockers and calcium channel blockers and (p) glucokinase activators (GKAs). Dipeptidyl peptidase-IV inhibitors that can be combined with compounds or structural formula I include those disclosed in WO 03/004498 (16 January 20)3 r. WO 05/004496 (16 January 2003); EP 1 25S 476 (20 November 2002); WO 02/0>3 12S 124 October 2002); WO 02/062764 (15 August 2002); WO 03/000250 13 January 2003 r. ^'0 03/0(>253r; ■ January 2003); WO 03/002531 (9 January 2003); WO 03/002553 (9 January 2^03 »: WO 05/002593 (9 January 2003); WO 03/000LS0 (3 January 2003); and WO 03/0001 SI (3 Januar 2003). Specific DP-IY inhibitor compounds include isoleucine thiazolidide: NVP-DPP72S: P32/9S; P93/01; and LAP 237. Annobesity compounds that can be combined with compounds of structural formula I include fenfluramine, dexfenfluramine, phentermine, sibutramme. oriistat, neuropeptide Yi or Y5 antagonists. cannabinoiCBl receptor antagonists or inverse agonists. melanocortin receptor agonists, in particular, melanocortin-4 receptor agonists, ghrelin antagonists, and melanin-concentrating hormone (MCH) receptor antagonists. For a review of anti-obesity compounds that can be combined with compounds of structural formula I, see S. Chaki et al., 'Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity," Expert Opin. Ther. Patents, 11: 1677-1692 (2001 j and D. Spanswick and K. Lee, "Emerging antiobesity drugs/1 Expert Opin. Emerging Drugs. S: 217-237 '2003). Neuropeptide Y5 antagonists that can be combined with compounds of structural formula 1 include those disclosed in U.S. Patent No. 6,335,345 Cannabinoid CBl receptor antagonists thai can be combined v.-rn compound- - :' formula ^include those disclosed in PCT Publication WO 03/007SS7: U.S. Patent No. 5.624.9-1. such as rimonabant; PCT Publication WO 02/076949, such as SLV-319: U.S. Patent No. o.02S,084; PCT Publication WO 95/41519; PCT Public;;::on WO 00/I096S; PCT Publication WO 99/02499: U.S. Patent No. 5.552.237; and U.S. Pare:;: No. 5/2^2.736. Meianocortin receptor agonists that can be combined-with compounds of structural formula I include chose disclosed in WO 03/0C°S47 (6 February 200? >: WO 02.voS3S8 ;.h September 2002); WO 99/64002 t 16 December 1999c WO 00/74679 I'U December 20O' : WO 01/70708 (27 September 2001 c and WO 01/70337 27 September 200 h as well as ihac disclosed in J.D. Speake et al. "Recent advances in the development of me!anocortm-4 receptor agonists/' Expert Ooin. Ther. Patents, 12: 1631-1638(20:2'). The potential utility of safe and effective activators of giuco-dnase iGKAs : :r the treatment of diabetes is discussed-in J. Grimsby et ah. "A'.losteric Activators of Glucolvinc.-.: Potential Role in Diabetes Therapw Science, 301: 370-J~3 (2003). The above combinations include combinations of a compound of the preser.: invention not only with one other active compound, but also with two or more other active compounds. Non-limiting examples include combinations of compounds having Formula [ with two or more active compounds selected from biguanides. sulfonylureas, KMG-CoA reductase inhibitors. PPAR agonists, PTP-IB inhibitors, other DP-IV inhibitors, and anti-obesity compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of the present invention are useful. Such-other drugs may be administered, bv a route and-in an amount commonlv used therefor, contemroraneouslv or sequentially with a compound of the present invention. When a compound oi the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention. The weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will he used. Thus, for example, when a compound of the present invention is combined with another a2ent. the weight ratio of the compound of the oresent invention to the other agent will generally range from about 1000: t to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the present ire cntion and other-active ingredients will generally also be within the aforementioned range, hut in each case, an effective dose of each active ingredient should be used. [n such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one eiement may he prior to, concurrent to. or subsequent to :he administration of other agentt: . The compounds of the oreseru invention mav be'administered bv oral, parenteral • e.g.. intramuscular, intraperitoneal, intravenous. ICV, intracistemai injection or infusion. subcutaneous injection, or impIanO. by inhalation spray, nasal, vaginal, rectal, sublingual, c: topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutical!} acceptable carriers, adju". anrs and vehicles appropriate for each route of administration. In addition to the treatment of warmblooded animals such as mice. rats, horses, cattle, sheeo. does. cats, monkevs. etc.. the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds e: this invention may conveniently be presented in dosage unit form and may be prepared by any o: the methods well known in the an of pharmacy. All methods include the step of bringing the active ingredient into association with the earner which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both. and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. 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. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions. dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaeeutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaeeutically acceptable excipients 'which are suitable for the manufacture of tablets. These exeipients may be for example, inert diluents, such as calcium carbonate.-sodium carbonate. lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch. or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal trac: and thereby provide a sustained action over a longer period. For example, a time delay matenal such as alvcervl monos-.earate or slvcervl distearate may be emoloved. Thev mav also be coated by the techniques described in the U.S. Patents 4,256,108; 4.1t56,452: and 4.265.$74 to form osmotic therapeutic tablets for control release. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed u ith water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethx [cellulose. sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products lof ethylene oxide with partial esters derived from-fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate. one or more coloring asents, one or more flavoring agents, and one or more sweetening a2ents. such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil. olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax. hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable di>persing-»'irweuir.g agents and suspending agents are exemplified by those already mentioned above. Additional excipients. for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil. for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacantb. naturaily-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate. and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known att using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent ov solvent, for example as a solution in l.3-hutane diol. Among the acceptable vehicles and solvents that may be employed are water. Rinser's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions. In the treatment or prevention of conditions which require Inhibition of dipeptfdyi peptidase-IV enzyme activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably ab^ut 0.5 to about LOO mg/kg per day. A suitable dosage level may be about 0.0 i to d:!- mg/kg per day. about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg'kg per cay. Withm this ramie tc_ cosaee mav be 0.05 to 0.5, 0.5 to 5 or 5 to 50 rrnz/ks per da*.. For oral administration, toe compositions are preferably provided in the form of tablets containing i.O :o \\)C\\ mg or the active ingredient, particularly 1.0. 5.0, 10.0. 15.0. 20.0, 25. When treating or preventing diabetes meihtus and/or h;.pcrga . ciraa or hypertriglyceridemia or other diseases for which compounds of the present im.ention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 mg to about I1 0 r:g per kilogram of animal body weight, preferably given as a single daily dose or in divided d It will be understood, however, that the specific dose ieve! and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length ■; f action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and ' the host undergoing therapy. Several methods for preparing the compounds of this invention are illustrated in the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The compounds of the present invention can be prepared from beta amino acid intermediates such as those of formula II and substituted hexahydrodiazepinone intermediates such as those of formula III, using standard peptide coupling conditions followed by deprotection. The preparation of these intermediates is described in the following Schemes. where Ar, Rl. R^. R^, RS. and R? are as defined above and P is a suitable nitrogen protecting group such as tert-butoxycavbonyl t'BOC), benzyloxycarbonyl (Chz). or 9-fiaorenylmethoxycarbonyl ( Fmoc). Compounds of formula II are commercially available, known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One common route is illustrated in Scheme 1. Protected alpha-amino acid_K which may be commercially available or readily prepared from the corresponding amino acta by protection using, for example, di-f«?rf-butyl dicarbonate (for P = BOC). carbobenzyloxy chloride ('for P = Cbz), or iV-(9-fluorenylmethoxycarbonyloxy)succinimide (for P = Fmoc). is treated with isobu:yl chloroformate and a base such as triethylamine orA^V-diisopropylethylarrune, followed by diazomethane. The resultant diazoketone is then treated with silver benzoate in a solvent such as methanol or aqueous dioxane and may be subjected to sonication following the procedure of Sewald et al., Synthesis, 837 (1997) in order to provide the beta amino acid n. As will be understood by those skilled in the art, for the preparation of enantiomericaily pure beta amino acids n, enantiomericaily pure alpha amino acids I may be used. Alternate routes to the protected beta-amino acid intermediates II can be found in the following reviews: E. Juarisii. Enantioselective Synthesis of fl-Amino Acids, Ed., Wiley-VCH, New York: 1997; Juaristi et aL AldrichimicaActa.27: 3 (1994); and Cole et al.. Tetrahedron. 32: 9517 (1994). Compounds of formula 1U are commercially available, known in the literature or may be conveniently prepared by a variety of methods familiar to those skilled in the art. One convenient method wherein Rl is hydrogen is shown in Scheme 2. Ammo ester.2« conveniendy used as its hydrochloride salt, is condensed with acrylonitrile 3 and the amino group of the product formed is protected, for example, as its terr-butoxylcarbonyl (Boc) derivative, to pro*, ide 4. which is reduced to the primary amine 5. Cyclization of 5 to iV-proteered hexahydrodiazepinone 7 can be conducted by using trimethylaluminum. Alternatively, the amino ester 5 can be hydrolyzed to the acid 6 and cyclized bv usins amino acid coupling reasents such as EDC to provide intermediate 7. Deprotection, for example, in the case of Boc. by treatment with acid such as hvdrosen chloride in dioxane or trifluoroacetic acid in dichloromethane. provides Intermediate DJa. An alternate method of preparing hexahydrodiazepinone Ulb (wherein R-. R$. and R9 are hvdrosen) is shown in Scheme 3. a-Ketoaeids S, such as pvruvic acid, can be condensed with an aminopropionitrile 9 to provide the cyanoethyl oxopropanamides 10, which can be reductively cyclized to hexahydrodiazepinone Ulb with a reducing agent such as platinum oxide and hydrogen. Hexafiydrodiazepinone intermediates HI and intermediates for their synthesis can be modified in various ways. For example, the amide nitrogen of intermediate 7. prepared as outlined in Scheme 2, can be alkylated by deprotonation with a base such as sodium hydride followed bv treatment with an alkvl halide as shown in Scheme 4. Deorotection of the resulting intermediate _U provides intermediate HI. Another such example is illustrated in Scheme 5. Protected hexahydrodiazepinone JJ2, which may be prepared as described for Intermediate JJ_ in Scheme 4 wherein R-* and R$ are hydrogen, or by protection of intermediate Ola from Scheme 3 \\ herein R5 is hvdroaen, can be alkylated bv using bases such as LDA followed bv treatment with various alkyl halides. The process may be repeated to install a second alkyl group. RS. Deprotection provides Intermediate m. Intermediates II and HI are coupled under standard peptide coupling conditions, for example, using l-ethyI-3-(3-dimethylaminopropyl)carbodiimide and l-hydro\ybenzotria;:ole (EDC/HOBT) or 0-(7-azabenzotriazol-I-yl)-NwVfyV'jV'-tetramethyIuromum hexafluorophosphate and l-hydroxy-7-azabenzotriazole (HATU/HOAT) in a solvent such as N,N-dimethylformamide (DMF) or dichloromethane for 3 to 4S hours at ambient temperature to provide Intermediate 13_ as shown in Scheme 6. In some cases, Intermediate HI may be a salt. such as a hydrochloride or trifluoroacetic acid salt, and in these cases it is convenient to add a. base, generally iV.N-diisopropylethylamine, to the coupling reaction. The protecting group is then removed with, for example, trifluoroacetic acid or methanolic hydrogen chloride in the case of Boc to give the desired amine I. The product is purified, if necessary, by recrystallization, trituration, preparative thin layer chromatography, flash chromatography on silica gel. such as with a Biotage® apparatus, or HPLG. Compounds that are purified by HPLC may be isolated as the corresponding salt. Purification of intermediates is achieved'in the same manner. In some cases the product I or synthetic intermediates illustrated in the above schemes may be further modified, for example, by manipulation of suhstituents on Ar. RK P^4, or RA These manipulations may include, but are not limited to, reduction, oxidation, alleviation, .icvlation. and hydrolysis reactions that are commonly known to those skilled in the art. In some cases the order of carrying out the foregoing reaction schemes may '^e ■■ aned to facilitate the reaction or to avoid unwanted reaction products. The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. i"3/?V3T(^^-Butoxvcai^onvl)amino1--4-(2.5-dinuorophenvr>butanoic acid Step A: i7^,5')-iV-f^77-Buto\vcarbonvn-2.5-dinuorophenvlalanine To a solution of 0.5 g(2A9 mmol) of 2,5-difluoro-DL-phen\lalanif>e in 5 mL of /crr-butanol were added sequential!}' 1.5 mL of 2N aqueous sodium hydroxide solution and 54? ms of di-/e/'f-butvl dicarbonate. The reaction was stirred at ambient temperature for 16 h and diluted with ethyl acetate. The organic phase was washed sequentially with IN hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 97:2:1 dichloromethane:methanol:acetic acid) to afford the title compound. MS302(M + 1). Step B: ('/?.5')-3-r(fgrr-Butoxvcarbonvnamino]'l-diazo-4-('2.5-diflu(^ro-phenvl ibutan-2-one To a solution of 2.23 g (7.4 mmol) of (7?,5)-AT-(/tfrr-butoxycarbonyl)-2.5-difluorophenylalanine in 100 mL of diethyl ether at 0 °C were added sequentially 1.37 mL'o.l mmob of triethyiamine and 0.931 mL (7.5 mmol) of isobutyl chloroformatc and the reaction v. as stirred at this temperature for 15 min. A cooled ethereal solution of diazomethane v. as then - -added until the yellow color persisted and stirring was continued for a further 16 h. The exec. ■, diazomethane was quenched by dropwise addition of acetic acid, and the reaction was diluted with ethyl acetate and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification bv flash chrorciatosraohv (silica izel, 4:1 hexane:ethvi ace'ate; afforded :;v d i azo ketone. lH NMR (500 MHz, CDCI3) 5 7.03-6.95 im, IH). 6.95-0. SS • -. IH:. 5.45 ■ -,. IK'. :.IS -S. IH), 4.45 (bs, IH). 3.19-3.12 (m. IH), 2.97-2.SO (m. 1H\ 1.3S is. 9H>. Sten C: nvl)aminoM^^ acid To a solution of 2.14 2 (6.5S mmol) of (R.S':-}J- :V":-V:to\ ■■ ;a:^on\'. -amir...V-duizo-442,5-difiuorophenyi)butan-2-one dissolved m luO mL or' memanoi at-30 C were ,.d.ied sequentially 3.3 mL (19 mmol) of diisopropylethylamine and 302 ma f 1.32 rranol) ■:•; siiver benzoate. The reaction was stirred for 90 min before diluting with ethyl acetate and washma sequentially with 2N hydrochloric acid, saturated aqueous sodium bicarbonate, and Vine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and the enantiomers were separated by preparative chiral HPLC (Chiralpak AD column. 5v erhanol in hexanes- ■-".» give 550 mg of the desired (/?)-enantiomer, which eluted first. Tins material was d:sived m 50 mL of a mixture of tetrahydrofuran:methanol:lN aqueous lithium hydroxide (3:1:1' and surred at 50 °C for 4 h. The reaction was cooled, acidified with 5cc dilute hydrochloric acid and extracted with ethyl acetate. The combined organic phases were washed with brine, dried o'. er magnesium sulfate and concentrated in vacuo to give the title compound as a white foamy sVid. lHNMR (500 MHz, CDCl^'o 7.21 (m. IH), 6.9S (m. 2H), b.iOibs. IH). 5.^5 tm.lH). 4.21 -m. IH), 2.98 (m. 2H). 2.60 (m, 2H), 1.38 (s, 9H). r (3/?)-3~[(rerf-Butoxvcarbonvr)amiraQ]-442-fluoro-4-{'trifluorometh'.i :-r?hen-.i'--buianoic acid Step A: (2^.55)-2.5-Dihvdroo.6-dimethoxvO-(2^-nuoro-4'^trii1tiuiva^eth\i/oeiizvl ;-5- isonropvlpvrazine To a solution of 3.52 g (IS mmol) of commercially available '25v'-2.5-dihycro-3.6-dimethoxy-2-isopropylpyrazme in 100 mL of tetrahydrofuran at -7() JC vw;> added 12 mL (19 mmoh of a 1.6M solutionof butyllithium in hexanes. After -di-ring at -.m- :emrerarure wr 20 mm, 5 g (19.5 mrnoi'i of 2-fIuor->4-trifliioromethylbenzvi hn.-mide in 20 mL of tetrahydrofuran was added and stirring was continued for 3 h before v. aiming me reaction :■; ambient temperature. The reaction was quenched with water, concentrated in vacuo, and extracted with ethyl acetate. The combined organic phase was washed with brne, cried, and concentrated in vacuo. Purification by flash chromatography (silica gel. 0-5'" ethyl acemtc ;n hexanes) afforded the title compound. !K NMR (500 MHc.CDCh) 6 ".35-7.25 (m,3H), 4.35-4.31 im. 1H-. }"5 >•$.}[]).}.65 -. 5H,>. 3.60 ft, IH, J = 3.4 Hz). 3.33 (dd. IH. J = 4.6, 13.5 Hz). 3.03 tdd. 1H. J = 7. I}.5: Hzv 2.25-2.15 i.m, IH). 1.0 (d, 3H. J = 7 Hz), 0.66 id, 3H, J = 7 Hz). Step B: (7^-.V-(rcjrr-Butoxvcarhonvr)-2-nuoro-4-irinLioromethT. i-phenylalanine nicth-.i ester To a solution of 5.5 g (15 mmol) of (2A\55)-2c5-dihydro-3.6-dimethoxy-2-f2"-fluoro-4'-(tnfluoromethynbenzyr)-5-isopropylpyrazine in 50 mL of a mixture of acetonitrilcrdichloromethane (10:1 > was added SO mL of IN aqueous influcroacetie acid. The reaction was stirred for 6 h and the organic solvents were removed in vacuo. Sodium carbonate was added until the solution was basic (>pH S), and then the reaction was diluted with 100 mL of tetrahydrofuran and 10 g (46 mmol 3H), 3.32-3.25 (m. IH), 3.13-3.05 'm. IH), 1.40 (s, 9H). Step C: f/?')-:V-(re/t-ButoxvcarbonvlV2-nuoro-4-trifluoromethvT'Dhenvl-alanine A solution of 5.1 g (T4 mmol) of (/?,5)-iV-(r?t-butoxycarbonyr)-2-fluoro-4-trifluoromethyljphenylalanine methyl ester in 350 mL of a mixture of tetrahydrofuran: methanol:IN lithium hydroxide (3:1:1) was stirred at 50 °C for 4 h. The reaction was cooled. acidified with 5^ hydrochloric acid and extracted with ethyl acetate. The iwmhinec organ-J phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to gL e~ the title compound. lH NMR (500 MHz, CD3OD) 5 7,45-7.38 (m, 3PI), 4.44-4.40 \m. I FT), 3.38-3.33 -.m. UL. 2.9S M:1U. 1H.J = 9.6. 13.5 HZ), 1.44 Step D: (3/?V3-[(rcr:4>utOAVcarbonvnamino]-4-r2-ni;or(>--l-'tr;niioroniotiv--; --»he: = '-'/- butanoic acid To a solution of 3.4 2 ('9.7 mmol) of the product from Step C in 60 mL o>' tetralv-drofuran at 0 °C were added sequentially 2.3 mL (13 mmol"' of diisoprapyietm.iamir.e 2nd 1.7 mL f 13 mmol) of isobutyl chioroformate and the reaction was snrred at this temperature for 30 mm. A cooled ethereal solution of diazomethane v\ as then added until the yei'iw. er-.or persisted and stirring was continued for a further 16 h. The excess diazomethane w^s quemmed by dropwise addition of acetic acid, and the reaction was diluted wirh ethyl acetate and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated in vacuo. Purification bv flash chromatography (silica gel, 9:1 hexane:ethyl acetate) afforded 0.5 g o( diazoketone. To a solution of 0.5 g (1.33 mmol) of the diazoketone dissolved in 100 mL ^' methanol ai 0 ;C ■•-ere added sequentially 0.7 mL *4 mmol) of diisopropylethylamme and 32 mg (0.13 mm^n of sm.er benzoate. The reaction was stirred for 2 h before diluting with ethyl acetate and washing sequentially'with 2N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The organic phase was dried over magnesium sulfate, concentrated in vacuo and dissolved in 50 mL of a mixture of tetrahydrofuran:methanol:IN aqueous lithium hydroxide (3:1:1) and stirred at 50 °C for 3 h. The reaction was cooled, acidified with 5'-7- hydrochloric acid and extracted \vi:n ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound as a white foamy solid. *H NMR (500 MHz, CD3OD): 3 7.47-7.33 (m, 3H), 4.SS (bs, 1HL 4.26-3.93 (m. IHL 3.06-3.01 f3J?V3-f(>t'rf-Bu[Q\vcar(x)nv|fo acid StejLA: US. 5/\V2.5-Dihvcro-3.6-dimethoxv-2MSopropvl-5-C\4\5'tnr1uorobenZ'-l - pvrazine The title compound >3.S1 g) was prepared from 3.42 g ( IS.5 mmol'i of * 2.S --2.5-dihyciro-3.6-dimethoxy-2-isopropy!pyrazine and 5 g (22.3 mmol) of 2.4.5-trifluoroben//. i bromide using the procedure described for Intermediate 2. Step A. lH NMR (500 MHz, CDCI3); 5 7.01 (m, IH), 6.85 (m. 1H). 4.22 (m. 1H>. 3.7S (m. 3H.«. 3.64 (m, 3H), 3.61 (m. IH), 3.20 (m, IHK 2.9S (m, 1H), 2.20 im, IH). 0.99 (d. 3H. J = 8HT^. 0.62 (d, 3H,J = SHz). Step B: f/?')-.'V"(r^/'r--Butoxvcarbonvl')-2.4.5-trifluorophenvla!anine methvl ester To a solution of 3.SI g(li.6 mmol) of (25. 5/?)-2,5-dihydro-3,6-dimethox}-2-isopropyl-5-(2'.4\5'trifluorobenzyl)pyrazine in 20 mL of acetonitnle was added 20 mL ot 2N hydrochloric acid. The reaction was stirred for 72 h and concentrated in vacuo. The residue was dissolved in 30 mL of dichloromethane and 10 mL (72 mmol) of triethyJamrtte and 9.68 g (44.S mmol) of di-terr-butyl dicarbonate were added. The reaction was stirred for 16 h, diluted with ethyl acetate and washed sequentially with IN hydrochloric acid and brine. The organic phase was dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography (silica gel, 9:1 hexanes:ethyl acetate) to afford the title compound. lH NMR (500 MHz. CDCI3): 5 6.99 (m, IH), 6.94 (m, IH), 5.0S (m, IHK 4.5S (m, IHi. 3.7S (m, 3H), 3.19 (m. IH), 3.01 (m, IH;, 1.41 (s, 9H). Steo C: i7\t?-:V-(rfgrr--Butoxvcarbonvri*2.415-trifluorophenvlalarine The title compound t.2.01 g) was prepared from 2.41 g (7.5 moil :f ■ "\'>-.V- Step D: G/?')o-f(fcf/':-Buto.\vcarbonvl)amino1-4-. 2.4.5-'nf1uoroohenvi '-:"u:aroic acic To a solution of 0.37 g (1.16 mmol) of KR)-:\:-\ IT-dmieehyLihou; -carbon;. N 2,4.5-influorophenylaIanme in 10 mL of diethyl ether at -20 :C were added seaacaualiy 0.193 mL(l.3 mmol) of tnethylamme and 0.1 S mL(1.3 mmoPi or' ;sr-but\! clvioromrnuue. and the reaction was stirred at this lemcerarure i'or 15 min. A cooled ethereal solution of diazomemane was then added until the yellow color persisted and stirring was continued ror a farmer 1 h. The excess diazomethane was quenched by dropwise addition of acetic acid, and the reacuon '-;.as diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate solutiona\nxl brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography (silica gel. 5:1 hexane:ethyl acetate) afforded '136 g of diazoketone. To a solution of 0.35 g (1.15 mmol") of the diazoketone dissolved in 12 mL oi 1.4-dio \ane: water (5:1) was added 26 nag (0.113 mmol) of silver benzoate. The resultant solution was sonicated for 2 h before diluting with ethyl acetate and washing sequentially with IN hydrochloric acid and hrine, drvins over magnesium sulfate and concentrating in vacuo. Purification bv flash chromatography (silica-gel. 97:2:1 dichIoromethane:methanol:aeetic acid) afforded the title compound. *H NMR (500 MHz, CDCI3) 0 7.06 (m, IH), 6.95 (m. 1H). 5.06 2H), 2.61 (m,2H), 1.39 (s.9H). (3/?V4-(2-Bromo-4.5 To a solution of 2.4- g (10 mmol) of'2-brcmo-4,5-difluorobenzoic acid [prerared according to the procedure of Braish et al., Svn. Co mm.. 3067-307-1 Essentially following the procedures outlined for the preparation of Intermediates 1-4. the Intermediates in Table 1 were prepared. (_3/?V4-f(3/?y3-Amino-4-('2A5-tri^ 2-one hydrochloride StetvAl Methvl N-: rc/?T-buioxvcurbonvI)^V-(2-c\ anoethvi i-D^MiQJJg. To a stirred suspension of D-alanine methyl ester hydrochloride ■ 3.0 gi ur.d 5.'-" aqueous sodium hydroxide solution (2.9 mL) in water i '.5 mL> at 0 1(A acr; iomtriie ■' 1. hr.L. ".as added. The resultant mixture was stirred at 70 °C for 3.5 a ami cooied to rr-orr. "empe:,:;^;r:. Di-:tjrt bury! dicarbonate 130 mL) was added and the reaction mixture sirred for ~x\ <_> davs. The reaction mixture was diluted with saturated aqueous secuim bicarbonate solution ando:-:::x:;:ed with ethy! acetate. The organic la;.er was separated, washed with brine, dried over anhydrou sodium sulfate and concentrated. The residue was purified by flash column ohromatog:arr. i silica, ethyl ucetate/hexane 2:3) to yield methyl A-i;eT--;n!rovycarbonyi)-Y- Step B: Methvl ,V-(3-aminoorooviV:V-i7^?7-buto\\ carbon vlTD-al an in ate To a solution of me:hyl iV-(^rNbutoxycarhonylVA'-f2-eyanoethyiVD-alan!nav (1.5 g) in ethanol (SO mL) and chloroform (1.4 mL) was added platinum oxide '• 350 mg\ xxcsxe reaction mixture was stirred over an atmosphere of hydrogen for 16 hr. The mixture was ::x_-x;d through Celite, and the Celite washed with methanol and dichloromethane. The nitrate v.--concentrated to give methyl ;V-(3-aminopropyl)wV-(VtV7-butoxycarb('ny[VD-alaninate as an . x; residue. Step C: r't'rr-Butvl (2/?)-Hexahvdro-2-methvl-?-oxo-lf/-L4-dia7.epine- 1-carhoxviatc To a 2M solution of tnmethylaluminum in dichloromethane '30 mLi was adcex siowly a solution of methyl AV3-arranopropyl)wV-(ferr-butoxycarbonyl")-D-alaninate (11.5 c ■". dichloromethane. The reaction mixture was stirred at room temperature for four days and -her* poured into a flask containing 30 g of Celite. The mixture was stirred and quenched by the -x-xx addition of-10 mL of saturated aqueous ammonium chloride solution. Sodium sulfate (20 g and methanol (50 mL) were added. The mixture was stirred for L h, then filtered. The solids were washed with 5% methanol/dichloromethane. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel, eluting sequentially with 4. 6. 7 and 12rc or 10:1 methanol/aqueous concentrated ammonium hydroxide in dichloromethane) to provide xhe title compound containing less than 3% of the (3S)-isomer. LC/MS22S.9(M+1). Ste2_E>i • ■ tert-Butyl (2^)-Hexahydro-2-methyl-3-oxo-lH-\ .4-diazepuvj- L-carbo\y]ate (obtained in the previous-step was dissolved in AM hydrogen chloride in diox^ne and xvapoixx:. after 2.5 h to yield the hydrochloride salt of" the desired compound. Step E: (3/?V4-rr3/?V3-fto^ButoxvcarbQnvl)aminol-4-(2,4.5- tnfluorophenvnbutanovnhexahvdro-3-methv]-2tf"l.4-diazenin-2-one ■ ~ ■■■.»! — ' ' " ■» ' —i - '* ' — ■ ■ I. — —- — ■ , — - I — — I I. , ■ -, . —I— -~ To a solution of A-methylmorphoIine (0.3S mL) and (3/?)-3-[(ajn-butoxycarbonyl)amino]-4-(2>4,5-trifluovophenyI)butanoic acid (1.0 g) in 20 mL of dichloromethane at -20 °C was added isobutyl chloroformate (0.39 mL). The resultant mixture was stirred for 1 h. (3/?)-he.\ahydro-3-methyl-2//-l,4-diazepin-2-one hydrochloride (500 mg) and A'-methylmorphoIine (0.40 mL) in dichloromethane (5 mL") and DMF (S mL.* were added. The mixture was stirred for 2S h. initially at -20 °C and then with slow warming to ambient temperature. The reaction was quenched by the addition of saturated ammonium chloride solution and extracted sequentially with dichloromethane and ethyl acetate. The combined organic layer was washed sequentially with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by -chromatography (silica gel, 3 to 7% 10:1 methanol/concentrated ammonium hydroxide in dichloromethane) to afford the coupled product. This was further purified by dissolving the product in a mixture of ethanol (7.5 mL) and hexane (16 mL) at 50 °C. The solution was allowed to cool to ambient temperature overnight, and then placed in the refrigerator for 3 h. The solid was collected and washed with cold 5% ethanol/hexane to give the title compound. Step F: (3/?)-4T(3/?V3-Amino-4-(2.4,54rifluorophenvl)butanovnhexahvdm-3-methvl-2// -L4-diazepin-2-bne hydrochloride (3/?)-4-[(3/?)-3-[(terr-ButoxycarbonyI)aminoH-(2,4,5-trifluorophenyl)butanoyl]hexahydro-3-methyl-2//-l,4-diazepin-2-one from Step £ was treated with AN hydrogen chloride in dioxane, stirred for 2.5 h and evaporated to yield the title compound. LC/MS 344.1 (M+l). ^^3^V3iArnino^^ hydrochloride Step A: Methvl iV-f3*AminQpropvlVjV-(fgrr-buto\vcarbonvn^lvcinate The title compound was prepared from glycine methyl ester hydrochloride following the methods described in Example 1, Steps A-B. LC/MS 241.0 (M+i). Step B: fcrr-Butvl Hexahvdro-3-oxo-l//-1.4-diazepine-l'Carboxvlate To a solution of methyl iV-(3-aminopropyl)-iV-('/'^rr-btitox\carbonvl)glycinate (10.2 g) in tetrahydrofuran (THFVmethanol (2/1, 300 mL) was added 1.1/ aqueous lithium hydroxide solution (60 mJL). The resultant mixture was stirred at room temperature overnight. An additional 20 mL ot IM aqueous lithium hydroxide solution was added and the mixture was stirred for 6 h. Solvent was removed under reduced pressure, and the residue was dissolved in 50 mL of methanol and 200 mL of toluene and concentrated in vacuo. To the residue in dichloromethane (300 mL) was added Lethyl-3-(3-dimethyiaminopropyl tearbodiimide (EDC. 9.6 g) and 1-hydroxybenzotriazole (HOBT, 6.8 g). The mixture was stirred at room temperature for three days, then treated with saturated aqueous ammonium chloride solution and extracted _ with three portions of ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, 4 to 5% methanol/aqueous ammonium hydroxide (10:1) in dichloromethane i to yield the title compound. LS/MS 215.0 (M+l). " . . . - ; i .....--■■ ."'"'"" Step C: fm-Buiyl Hexahvdro-4-methvl-3-oxo-lH-L4-diazeDine-l-carboxvlate Sodium hydride (103 mg) was added to a stirred solution of ren-buiy\ hexahydro-3-oxo-l/M,4-diazepine-l-carboxylate in DMF (5 mL) at 0 °C. After 1 h. iodomethane (0.15 mL) was added, and the resultant mixture was stirred at 0 °C, then room temperature overnight. It was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was separated, washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and concentrated to give the product, which was used without further purification. Step D: Hexahvdro-l-methvl-2ff-L4~diazepin-2-one hydrochloride ten-Butyl hexahydro-4-methyl-3-oxo-l/Y-1.4-diazepine-I-carboxylate obtained in Example 2, Step C.was dissolved in AM hydrogen chloride in dioxane and -jvuporated'after 2.5 h to yield the title compound. Step E: 4-rf3/?V3-f(r^/t-ButoxvcarbQnvnamino1-4-(2,5- difluorophenvnbutanovnhexahvdro-l-mcthvU2tf-I.4-diazepin-2*OTie To a stirred mixture of (3R)-3-[(fe?*r-butoxycarbonyl)aiTiino]-4-f 2.5-difluoropheny])butanoic acid (40 mg), EDC (29 mg), and HOBT (21 mg) in dichloromethane was added triethylamine (0.042 mL) and hexahydro-l-methyI-2#-L4-diazepin-2-one hydrochloride (33 mg). The resultant mixture was stirred at ambient temperature overnight and then concentrated. The residue was purified by preparative TLC (silica gel, S% 10:1 methanol/concentrated ammonium hydroxide in dichlcromethane) to yield the title compound. StepD: 4-[(3/?)o-Amino^42.5-dinuorophenv!')butanovnhexahvdro-l-methv!-2/j-1.4- diazepin-2-one (3/?)-4-[(3R)-3-[(rerr-ButoxycarbonyI)amino]-4-(2.5-tnfluorophenyl)butanoyl]hexahydro-3-methyl-2//-1.4-diazepin-2-one from StepE was treated with 4iV hydrogen chloride in dioxane, stirred for 4 h and evaporated to yield the title compound. LC/MS 326.0 (M+L). (^RV4-[(3/?V3-Amino-4-(2,4.5-trifluorophenvl>butanovll-3-benzvlhexahvdro4-methvl-2/7-1.4-diazepin-3-one hydrochloride Step A: ferf-Butvl 2-BenzvIhexahvdro-4-methvl-3-oxo-If/-L4-diazepine-l-cai-hoxviate To a stirred solution of terf-butyl hexahydro-4-methyl-3-oxo-lH-l,4-diazepine-l-carboxylate, prepared as described in Example 2, Step C (180 mg), in THF (8 mL) at -78 °C was added a solution of lithium diisopropylamide (LDA) (1.5M in cyclohexane, 0.53 mU. After the mixture stirred for 40 min, benzyl bromide (0.28 mL) was added. The resultant mixture continued to be stirred at -78 °C for 6 h. Then the reaction mixture was diluted with saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate solution and brine, dried o\er anhydrous sodium sulfate and concentrated. The residue was purified by chromatography (silica gel, 2% methanol/dichloromethane) to yield the title compound. Step B: 3-Benzvlhexahvdro-l*methvl-2//-L4-diazepin-2-one hydrochloride terr-Butvl 2-benzyIhexahvdro-4-methv!-3-oxo-l/:^l,4-diaz.eDir.e-l-carboxv:ate obtained in Step A was dissolved in 4M hydrochoride in dioxane and evaporated after 2.5 h to yield the hydrochloride salt of the desired compound. Step C: (3/?V4-fG/?y3-[(7err-butoxv^^ 3-benz\lhexahvdro--l-methvl-2W-1.4-diazepin-2-one /V-Methylmoipholine (0.04S mL) and isobutyl chiorofo'rmare (0.026 mL) were added to a stirred solution of (3/?)-3-[(tert-butoxycarbonyI)amino]-4-(2-4.5-trifluorophcnyI)butanoic acid (67 mg) in THF (I mL) at-20 °C and the resultant mixture was stirred for I h. 3-Bcrizy1hexahydro-l-methyl-2//-l,4-diazepin-2-onc hydrochloride obtained in Step B above (4S mg) and /V-methylmorpholine (0.024 mL) in DNfF (I mLi were added. The mixture was stirred for 30 min at -20 °C and for 36 h at ambient temperature, and then evaporated. The residue was treated with saturated aqueous ammonium chloride solution. extracted with ethyl acetate, and the organic extract evaporated. The product obtained was purified by preparative TLC (silica gel, methanol/concentrated ammonium hydroxide/dichloromethane 4.4:0. l:95.5Xto obtain the coupled product as a mixture of diastereomers. The isomers were resolved by HPLC (ChiralPAK AD, 14 Step D: (3/?)-4-l'f3/?V3-Amino-4-(2,4.5-trifluorophenvnbutanovl]-3- benzvlhexahvdro-1- methvl-2ff-1.4-diazepin-2-one hydrochloride The title compound from Step C was dissolved in 4Af hydrogen chloride in dioxane and evaporated after 2.5 h to yield the desired product. LC/MS 434.1 (M+i). (3/^)-4-rG/\V3-amino-4-i2.4.>-tnfluorophenvl)biitano\i]hc:valv dro-3-[4--ftri"Fluoromethoxv'ibenzvl1-2f/-1.4-diazepin-2-one Step A: /yrr-Butvl 4-f^BenzvIoxv)methvl1hcxahvdro-3-o\o-l/;/'-l.4--diazeoine-1- carboxvlate The title compound was prepared from rert-hutyl hexahydro-3-oxo-lf/-[.4-diazepine-1-carboxylate (Example 2. Step B) and benzyl chloromethyl ether essentially following the method described in Example 2, Step C. Step B: /grr-Butvl 4-f(Benzvloxv)methvnhevXahvdro-3-oxo-2-f4- (tnfluQromethoxv')benzvn-l//-l,4-diazepine-l-carboxvlate The title compound was prepared from rert-bntyl 4- l(benzyIoxy')methyI]hexahydro-3-oxo-l/-/-l,4-diazepine-L-carboxylate and4- (trifluoromethoxy)benzylbromide essentially following the procedure described in Example 3, Step 1. Step C: rgrr-Butvl Hexahvdro-3-oxO"2-['4-(trifluorometho\v')benzvl]-l//-1.4-diazepine-l- carboxvlate To a solution of terr-butyl 4-[(benzyloxy)methyl]hexahydro-3-oxo-2-f4-(trifluoromethoxy)benzyl]-lf/-l,4-diazepine-l-carboxylate (520 mg) in ethanol (17 mLj was added 10% palladium on carbon (300 mg). The reaction mixture was stirred for 22 h under an atmosphere of hydrogen. A few drops of water were added and stirring continued for an additional 20 h. The mixture was filtered through Celite, and the Celite washed v-.ith ethyl acetate. The filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on a BiotagelD apparatus (silica gel: methanol/concentruted aqueous ammonium hydroxide solution/dicholoromethane 1.5:0.1:98.4). The product obtained was dissolved in toluene and refluxed for 3 h. Evaporation under vacuum yielded the title eomp^und. whtch was used in the next step without further purification. Seen D: HexahvdrQo*r4-tLr:fluornrnethoxv')her.:vll-2/Y-; .-l-dia/.^m^-^r.e hydrochloride tdrt-Butyl hexahydro-3-cxo-'2-[4-(trinuv^rometho\y ibcnz;- ij-' r:~ 1.4-diaze?ine- i-carboxylate was dissolved in 4A/hydrogen chloride in dioxane and after 2.5 h evaporated :o vieid the desired product. Step E: i3/iV4-[G/?'i-3-f|-4-' 2A5- tnfluorophenvl^bi:tanov]lhexahvdroo-r--' trifiU'^omerh*\v.v 'He:i//.:"!-2tf- '■ .--diazepin-2-one /Y-Methylmorpholine (0.072 mL) and ssobutyl chlorotormaie i 0.039 mL> v.ere added to a stirred solution of (3/?V3-[(/^/t-butoxycarbon\T)amino]-4-C.4.5- trifiuorophcnyObutanoie acid (95 mg) in dichioromethane (5 mL/ at -20 C and the resultant mixture was stirred for 30 min. Hexah\dro-3-l4-(trinuoronKth^xyjber,z;dj-2/-/-I.4-diazepiri-2- one hydrochloride obtained in Step D (91 mg) and /v'-methylrnorpholine '0.03o nolo were added. The reaction mixture was stirred for 30 min at -20 °C and 2 h at ambient temperature and then evaporated. The residue was purified by preparative TLC (silica gel, methanol/saturated aqueous ammonium hydroxide/diehioromethane 4.4:0.1:95.5). and the isomers were subseuuentaly resolved by HPLC (ChiralPAK OD, 7% ethanol/hexane) to provide the slower elating (7v.i?»- isomer. ; Step F: (3/?)-4T(3/?V3-Airdno-4-(2,4.54nnuorophenvl^butanovlihexahvdro-3-[4- Orifiuoromethoxv')benzvl1-2#-L4-diazepin-2-one hydrochloride (3/?H-[(3/?)-3-[(r^rr-ButoxycarbonyI)amino]-4-i 2.4.5- trifluorophenyl)butanoyl]hexahydro-3-[4-(trifluoromethoxy)benzyl]-2f/-L4-diazepin-2-or:e v. as dissolved in 4A/ hydrogen chloride in dioxane and evaporated after 2.5 h to yield the desired product. LC/MS 504.2 (M+i). G/?M-f('3KV3-Amino-4-i'2.4^ 1.4-diazepin-2-one hydrochloride Step A: /V- A solution oi benzotriazole (2.4 g, 20 mmol) and thionyl chloride i 1.5 mL' in dichloromethane (10 mU was added dropwise toa stirred solution of pyruvic acid m dichloromethane (10 mL) and the mixture was stirred for ten min. The precipitate formed was filtered and washed with dichloromethane. The filtrate was treated with magnesium sulfa*.:. filtered, and the filtrate was stirred overnight with a solution of 3-Uc^-butyiumino propionunie dissolved in dichloromethane (10 mL). The reaction mixture was treated with saturated acuenus ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated and purified by Biotage® flash chromatography (silica gel, ethyl acetate/hexane 1:1) to yield the desired product as an' oil. 1H NMR (400 MHz, CDC13) 5 1.49 (s, 9H), 2.45 is. 3H). 2.74 (t, J = 7.4ft:. 2Hi. 3.6 (broad. 2H). StepB: l-re;t-Butvl-hexahvdro-3-methvl-2f/-1.4-diazepin-2-one JV-(r lHNMR(400MHz,CDCI3)o 1.23 (d, J = 6.6,3H)? 1.43(s,9H), 1.5 (mi. 1H). 1.7-m, IH .2.9 (m, iH),3.2(m, IH), 3.4 (m, IH.}. 3.6 (m, 2H). LC/MS 185.2 (M+li. Steo_C (3/?)-4-fG/?V3-umino-4-{2A54rifluoro^ 3-methvl-2tf-1.4-diazepin-2-one The title compound was prepared from ;3/?V3-[(/kc7r-butoxycar:.^oiv.i.arri:r.o;-4-12,4,5-trifluorophenyi>butanoic acid and l-^rNbiityI-hexahydro-3-methyl-2i7-1 .-—d;u2e~;::-2-one bv [ho method described in Examnie 3, Sizv C and D. LC/MS 400.! iM~i K 4JIl/\Lh2^AlI^^ hydrochloride Step A: Hexahvdro-5-methvi-2f/-L4-dia7.epm-2-onc The title compound was prepared from croiononkrile essentially foilowinc the procedures out lined in Example 2. Steps A and B. Step B: 44(3/\)-3-amino-4-0.4,5-trinuorophenvl)bLifanovnhexahvcro-^-me:nvl-2f/-1.4- .. diazepin-2-one The title compound was prepared from (3R)-3~[\ tdrt-buiox\carbonyl 'ammoj-4-(2,4.5-trifluorophenyI)butanoic acid hexahydro-5-methyI-2/:/-i.4-diazepin-2-one by the method described in Example 3, Step C and D. LC/MS 344.1 (M+l). j3/?V4-[f3J?V?-Amino-4-f2A5-triruorophenvlMxitanovllhexahvdro-3-fU-' ■xidopvr:din-2-yOmethvlL2//-L4-diazepin-2-one. influoroacetic acid salt Step A: (3/?V4-r(3/?y3-fufg7?-Buto^^ trifluorophenvlM?utam:>vl1hexahvdro^ diazeoin-2-one The title compound was prepared essentially following the procedures desc^bed in Example 4, Steps A to E. Step B: (3ffy4-f(3/?^'-?-An^no-4-f2A5-trifluo^ 1- oxidoovndin-2--1'inethvn-2//-L4-diaiepin-2-iMie. tnfluonKicetu acid sal: To a solution ot ■. 3/?)-4-[('3/?)-3-[(re:r/,-butoxycarbon> l'iair:ino]-4- 2.4.5- trirluorophenyl)butanoyl]hexahydro^^ (20 mg, 0.038 mmol) in dichloromerhane (2.5 mL) at 0 CC was added mCPBA (2S mg. 0.09f; mmol'i and the reaction mixture was stirred overnight at ambient temperature. The soiudon was :reated . _ with saturated aqueous sodium bicarbonate solution and extracted with dichloroiricihane. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (silica, 1 l:S9 10% ammonia in methanol/dichloromethane) to yield the iV-BOC protected pyridine ;V-oxide. Depi'otecuon with trifiuoroacetic acid-dichloromethane (1:1) at ambient temperature for 1 h followed by concentration gave the desired product. MS 437.2 (M+l). p/^)-4-r(3flV3-Amino-4M'24.5-mfluoroph^^ vnmethvl]-2f/r-L4-diazepin-2-one. trifiuoroacetic acid salt The title compound was prepared essentially following the procedures described in Example 7. MS 437.2 (M+U i3/v>)-4-fr3/?)-3-Amino-4-Q4.5-:rfluorophenvnbutano'-1 lhexam.dro-3-' \ /V-p*. ra/el- i-■■ Imcthvl'*-27M.4-diazepin-2-one. trifluoroacetic acid salt Slep A: /yrr-Butvl 4-r('henzvloxv)methvl1hexahvdro-3H).\o-l7/-1.4-dia7.cpine-L- carboxvlatc The title compound was prepared from :ert~bi\vA hexah;.dro-3-oxo-I7M,4-diazepine-1-carboxylate (Example 2. Step B) and benzyl ehioromethyi ether essentially following the method described in Example 2, Step C. Step B: /e'rr-Butvl 4-[Ybenzvloxv)methvrihexah\,dro--2-methvlene--::-oxo-1.4--diu7.epine-l- carboxvlate The title was prepared from tert-biayl 4-[(benzyloxy)mer.hyijhexahydro-3-oxo-1/7-1,4-diazepine-l-carboxyiate and benzyl ehioromethyi ether essentially following the procedure described in Example 3. Step 1. Steo C: rirr-Butvl 4-r(benzvloxv)methvl"lhexahvdro-2-( 17/-pvrazol-i-vlmethvi)-3~oxo- 1.4-diazepine-l-carhoxvlate To a solution of pyrazole (25S mg, 3.78 mmol) in 10 mL of DMF at 0 °C was added sodium hydride (60%, 91 mg). The resultant mixture was stirred for 30 min and then the product from Step B (655.4, 1.S9 mmol) was added. The reaction was stirred at ambient temperature overnight and quenched by the addition of water. The aqueous mixture was extracted with three portions of ethyl acetate. The combined organic phases were concentrated. Purification by flash chromatography on a Biotage!1 apparatus ('silica ge!. 40 - 80rc ethyl acetate/hexane gradient) gave the title compound. Step D: ?-' !7/-pvrazol-l-vl.Tiethvr)-1.4-diazeDan-2-one The product from Step C was treated with trifluoroacetic acid. Tr.t reaction was stirred at ambient temperature overnight and then concentrated. The residue war dissolved :n toluene and heated at reflux for 3 h. Purification by flash chromatojiraphv on a 3:o:aec,:!' apparatus (silica gel. 5 - 15 v- of 10:1 methanol/amrnomum [\- droxide in dichic::me:ha"ei ^a\e the title compound. Stcv E: (f3/?V4-rr3/?%i-j-Amino-4-(,2,4,5-trifluorophenv;. ■huian^ynheNah;.d-'",-3-' \ f7- pvrazol-l-vlmethvr)-2tf-1.4-diazepin-I-one. trir'iuoroaceric acid ■■„]{ The title compound was prepared from the product from Step D a:x - 3T\! -~2--'j :<: acid essentially folic.. :r.g ihe coupling method described in example step e. purification by preparative tlc ethanol gave the a-boc product as a mixture of diastereomei kplc fchiralcell os column provided individual diustereome: deprotection with trifluoroacctic aciddichloromethane for i h at ambient temperature foiic-v.ed concentration diastereomers title compound. ms>. Essentially following the procedures outlined for the preparation :f Examples 1-9. the compounds in Table 2 were prepared. EXAMPLE OF A PHARMACEUTICAL FORMULATION As a specific embodiment of an oral pharmaceutical composition, a 100 nig potency tablet is composed of ICO mg of any of the compounds of the present invention. 26S mg microcrystalline cellulose. 20 mg of croscanrrcllose sodium, and 4 mg of magnesium stearate. The active, microcrystalline-cellulose, and croscarmellosc are blended first. The mixture is then lubricated by magnesium stearate and pressed into tablets. While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations. changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosases other than the particular dosages as set forth herein above mav be aoolicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. The specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical earners, as well as the type of formulation and mode of administration employed, and such expected v-ari-ations or c:t\cvcr,ca in the results are contemplated in accordance v.iih the objects and practices of the present invention, it is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims he interpreted as broadly as is reasonable. WHAT IS CLAMED IS: or a pharmaceuticals acceptable salt thereof; wherein each n is independently 0. 1. or 2; Ar is phenyl substituted with one to five RP substituents; Rl is selected from the aroup consisting of *_ » ~ «—- hydrogen, C1-10 alkyl. wherein alkyl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy. C1-6 aikoxy. carboxy, C i _(S alkyloxycarbonyl. and phenyl-Ci-3 aikoxy, wherein aikoxy is unsubstituted or substituted with one to five halogens, (CH2)n-aryl- wherein aryi is unsubstituted or substituted with one to five substituer.r.s independently selected from halogen, CN, hydroxv, R-. OR-, N"KSO>R-. NR-SO2R2, SCbR2, CO2H, and C1-6 alkyloxycarbonyl. (CH2)n"heteroaryI, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen. C1-6 alkyl, and C1-6 aikoxy, wherein alkyl and aikoxy are unsubstituted or substituted with one to five halogens, (CH2)n-heterocycIyl, wherein heterocyclyl is unsubstituted or substituted with one to three substituents independently selected from oxo, hydroxy, halogen, Ci-6 alkyl, and C1-6 aikoxy, wherein alkyl and aikoxy are unsubstituted or substituted with one to five halosens, (CH2)n-C3-6 cycloalkyl, wherein cycloalkyi is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy. C1-6 alkyl. and C1-6 aikoxy, wherein alkyl and aikoxy are unsubstituted or substituted with one to five halogens; and wherein any methylene (CH2) carbon atom in Rl is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alky: unsubstituted or substituted with one to five halogens; each R-1 is independently selected from the group consisting of hvdrosen, halogen, cvano. hvdroxv. C1-6 alky L unsubstituted or substituted with one to five halogens, C1-6 alkoxy, unsubstituted or substituted with one to five halogens, carboxy, alkoxvcarbonvl. amino, NHR2. NTR2R2, NHSO0R2, NR2S02R2, NHCOR2, • NR2COR2, iNTICOoR2, NR2C02R2, S02R2, SO2NH2, S02NHR2, and S02NR2R2; each R- is independently C16 alkyi, unsubstituted or substituted with one to five substituents independently selected from halogen, CO2H, and C1-6 alkyloxycarbonyl; R4 and R5 are independently selected from the group consisting of: hydrogen, cyano, carboxy, C1-6 alkyloxycarbonyl, C1-10 alkyi, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 aiko\y. earboxy, C 1-6 alkyloxycarbonyl, and phenyi-C1-3 alkoxy. wherein a!kox\ > unsubstituted or substituted with one to five halogens. (CH2)n-aryl' wherein aryl is unsubstituted or substituted with one to fi\e substituents independently selected from halogen, hydroxy.C1-6 alkyi. and Cw^ alkoxy. wherein alkyi and aikoxy are unsubstituted or substituted with ore :o five haloecns. • ■ (CH2)n-beteroarv'l. wherein heteroaryl is unsubstituted or substituted wi'.r. ?-ne :^ :hree substituents independently selected from hydroxy, halogen. C1-6 uikyl. and Ci_o alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to fi\e halogens, (CHh )n-heterocvclvl. wherein heterocvclvl is unsubstituted or substituted with cnc to —.11 v « J J three substituents independently selected from oxo. hydroxy, halci-en. Ci_h aikyl. and C1-6 alkoxy, wherein alkyi and alkoxy are unsubstituted or substituted with one to five halogens. (CH2)n-C"3-6 cycloalkyl. wherein cycloalkyl is unsubstituted ov substituted with one to threesubstituents independently selected from halogen, hydroxy. Ci_g alkyi. and C1-6 alkoxv. wherein alkvl and alkoxv are unsubstituted or substituted with one to five halogens, (CH2)TICONR6R7? wherein R6 and R7 are independently selected from the group consisting of hydrogen, tetrazolyl, thiazolyl, (CH2')n-?henyk to five halogens and wherein phenyl and cycloalkyl are unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, Cj_6 alkyi, and C1-6alkoxy, wherein alkyi and alkoxy are unsubstituted or substituted with one to five halogens; or wherein R° and R7 together with the nitrosen atom to which thev are attached form a heterocyclic nng selected from azetidine, pyrrolidine, piperidine, piperazine. and morpholine; and wherein said heterocyclic ring is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy. C1-6alky!, and C1-6 'alkoxy, wherein alkyi and alkoxy are unsubstituted or substituted with ore to five halogens: and wherein any methylene (CH2) carbon atom in R4 or R5.substituted or substituted with one to two groups independently selected from halogen, hvdroxy. and C1-4 alky I unsubstituted or substituted with one to five halogens: and RS and R.9 are each independently hydrogen orCl-6 alkyi. wherein the carbon atom marked with an * has the R configuration and Ar. RK R~K R-, RS, and R9 are as defined in Claim 1. 3. The compound of Claim 1 wherein RJ is selected from the zvouv consisting of hydrogen, halogen, cyano, hydroxy, C1-6 alkyl, unsubstituted or substituted with one to five halogens, and C1-6 alkoxy, unsubstituted or substituted with one to five halogens. 4. The compound of Claim 3 wherein R3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, trifluoromethyl, and methyl. 5. The compound of Claim 4 wherein R3 is hydrogen, chloro, or fluoro. 6. The compound of Claim 1 wherein R* is selected from the group consisting of: hydrogen. C1-6 alky!, wherein alkyl is unsuhstituted*or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkoxy, carboxy, C[-6 alkyloxycarbonyl. and phenyl-C1-3 alkoxy, wherein alkoxy' is unsubv.iuited or substituted with one to five haloeens. (CH2)n"-3-6 cycioalkyl. wherein cycloalkyi is unsaturated or substituted v-.tth ore to three substitueras independently selected from halogen, hydroxy. C...- aikyi. and C1-6 alkoxy. wherein alky! and alkox;. are unsubstituted or substituted with one to five halogens: and wherein any methylene (CH21 carbon atom in Rl is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 alky 1 unsubstituted :r substituted with one to five halogens. 7. The compound of Claim 6 wherein Rl is selected from the gnup consisting of - - hvdrogien. C 1-4 alky 1, 2,2,2-irifluoroethyI. methoxycarbonylmethyl. curboxymethyl, hvdroxvethvl, benzyloxymethyl, benzvloxvethyl, and v J J cyclopropyl. 8. The compound of Claim 7 wherein R^ is selected from the group consisting of hydrogen, methyl, terr-butyl, and cyclopropyl. 9. The compound of Claim 1 wherein R4 and R5 are independently selected from the group consisting of: hydrogen, C1-10 alky!, unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkoxy, carboxy, C1-6 alkyloxycarbonyl. and phenyl-C1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens, (CH2)n-aryl. wherein aryHs unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl. und Ci-6 alkoxy. wherein alkvl and aikoxv are unsubstituted or substituted with one r_o five halogens. (CHo)n-heteroaryl- wherein heteroaryi is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen. C [^ aikyi, arc C{_6 alkoxy, wherein alkyl and alkoxy are unsubstituted or .substituted with ore to five halogens. (CH2Jn-heterocyc!yI. wherein heterocyciyl is unsubstituted or substituted with one to three substituents independently selected from oxo. hydroxy, halogen. C{-6 alkyl, and C:.(5 alkoxy. therein alky! and alkoxy are unsubstituted or substituted with one to five haiocens. (CH'2)n-C3-6 cycloalkyl. wherein cycloalkyl is unsubstituted or substituted with one to three substituems independently selected from halogen, hydroxy, Ci_6 alkyi, and C1-6 aikoxv, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, wherein any methylene (CHh.1 carbon atom in R4 or R5 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C1-4 aikyi unsubstituted or substituted with one to five halogens. 10. The compound of Claim 9 wherein R4and R5are independently selected from the group consisting of: hydrogen. C1-6 alkyl. unsubstituted or substituted with one to five substituems independently selected from halogen, hydroxy, C1-6 alkoxy, carboxy. C1-6 alkyloxycarbonyl. and phenyl-C1-3 alkoxy, wherein alkoxy is unsubstituted or substituted with one to five halogens, (CH2)n-a^yk wherein aryl is unsubstituted or substituted with one to five substituents independently selected from halogen, hydroxy, C1-6 alkyl, and C1-6 alkoxy. wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, (CH2)n-heteroaryl, wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from hydroxy, halogen. C1-6 alkyl, andC1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five . . haloaens, - - ' i'CH2)n-C3-6 cyyoalkyk v..herein cycloalky I is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C1-6 alkyl and C1-6 alkoxy, wherein alkyl and alkoxy are unsubstituted or substituted with one to five halogens, and wherein any methylene (CH2) carbon atom ir. R4 or R5 is unsubstituted - substituted with one to two groups independently selected from halogen, hydroxy, arc C ;u a'.kvl unsubstituted or substituted with one to five halosens. 11. The compound of Claim 10 wherein R4and R5 are independently selected ~om the group consisting of: hvdrocen. CH3, CH2CH3, CH2CH(CH3.)2, CFh-cyclopropyl. CHb-cyclohexyl. CH20CH2Ph. CH2OH CH2Ph, CH2(3-OCF3-Ph), CH2(4-OCF3-Ph). CH2(3-CF3,5-CF3-Phl CH2(2-CF3-Ph), CH2(2-Cl-Ph), CH2(2-Me-Ph), CH2(2-Me,5-Me-Ph). CH2(2-Ph-Ph), CH2(2-F.5-F-Ph). CH2(2-F-Ph), CH2(2-F,3-F-Ph), CH2(2-pyridinyl), CH2(3-pyridinyI), CH2(4-pyridinyI). CH2(l-oxidopyndin-2-yli, CH2(l-oxidopyridin-3-yl;, CH2n//-pyrazoI-l-yl), CH2(2-F,6-F-Ph;, and CH2CF3- 12. The compound of Claim II wherein R" Is hydrogen. 13. The compound of Claim 1 wherein R$ and R° are independent;.' se'.ecied from hydrogen and methyl. * .>* 14. The compound of Claim 13 wherein R^ and R9 are hydrogen. [5. The compound of Claim 1 wherein Rl is selected rroir. the crcur- consisting of hydrogen. C1-4 alkyL 2.2,2-trifluoroethyI. methoxvcarbonvlmethvi. .■J carhoxymethyl, hydroxyethyl. benzvloxvmethvi. benzvloxvethvl, and cyclopropyl; R3 is hydrogen, chloro, or fluoro; R4 is selected from the group consisting of: hvdrosen, CH3. CH2CH3, CH2CH(CH3)2, CH2-cyclopropyl. CH2-cyclohexyl, CH20CH2Ph, CH2OH CH2Ph, CH2(3-OCF3-Ph). CH2(4-OCF3-Ph), and CH2(3-CP'3,5-CF3-Ph) CH2(2-CF3-Ph). CH2(2-CI-Ph), CH2(2-Me-Ph). CH2(2-Me.5-Me-Ph ) CH2(2-Ph-Ph), CH2(2-F,5-F-Ph) CH2(2-F-Ph), CH2(2-F,3-F-Ph). CH2(2-pyridinyl). CH2(3-pyridinyn. CH2(4-pyridinyI). CH2(l-oxidopyndin-2-yl), CH2(l-oxidopyridin-3-yl), CH2(l/H-pyrazol-l-yl), CH2(2-F,6-F-Ph). and CH2CF3: and RS and R9 are hydrogen. 16. The compound of Claim 15 wherein R^ is hydrogen. 17. The compound of Claim 15 which is selected from the group consisting of The pharmaceutical composition of Claim 19further comprising one or more additional active ingredients selected from the group consisting ci. (a1 a second dioeDf.dvl peptidase IV inhibitor: » 1 J i. V (b1 an insulin sensitizer selected from the group consisting of a PPARy agonist, a PPARa v dual agonist, a PPARa aconist, a biguanide, and a orotein r.-rosir.e phosphatase-IB inhibitor. (c) an insuiin or insulin mimetic; (d) a sulfonylurea or other insulin secretogogue: (,e) an a-giucosidase inhibitor: if) a glucagon receptor antagonist; (2) GLP-1. a GLP-1 mimetic, or a GLP-l reeemor asor.ist: (h) GIP. a GIF mimetic, or a GIP receptor agonist; (i) PACAP. a PACAP mimetic, or a PACAP receptor agonist: f) a cholesterol lowering agent such as (i) HMG-CoA reductase inhibitor, (ii) sequestrant, (iii) nicotmyl alcohol, nicotinic acid or a salt thereof, fiv) PPARa agonist, (v) PPARa/y dual agonist, (vi) inhibitor of cholesterol absorption, (vii'j acyl CoA:choles:eroi acyltransferase inhibitor, and (y'ni) anti-oxidant; (k) a PPAR5 agonist: (]) an antipbesity compound; (m) an ileiil bile acid transporter inhibitor; (n) an anti-inflammatory agent; and (0) an antihypertensive agent.

Documents:

963-chenp-2005-abstract.pdf

963-chenp-2005-assignement.pdf

963-chenp-2005-claims.pdf

963-chenp-2005-correspondnece-others.pdf

963-chenp-2005-correspondnece-po.pdf

963-chenp-2005-description(complete).pdf

963-chenp-2005-form 1.pdf

963-chenp-2005-form 18.pdf

963-chenp-2005-form 26.pdf

963-chenp-2005-form 3.pdf

963-chenp-2005-form 5.pdf

963-chenp-2005-pct.pdf