Title of Invention	QUINAZOLINONE COMPOUNDS WITH REDUCED BIOACCUMULATION
Abstract	A variety of small molecule, guanidine-containing molecules capable of acting as MC4-R agonists are provided, The compounds are useful in treating MC4-R mediated diseases when administered to subjects. The compounds have the formula IA and IB, IA and IB have the following structure where Z has the formula shown below and the rest of the variables are defined herein.

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QUINAZOLINONE COMPOUNDS WITH REDUCED BIOACCUMULATION Field of the Invention [0001] This invention relates to melanocortin-4 receptor (MC4-R) agonists and methods of their preparation. More specifically, the invention relates to quinazolinone compounds that exhibit reduced bioaccumulation properties when administered to a subject. Background of the Invention [0002] Melanocortins are peptide products resulting from post- translational processing of pro-opiomelanocortin and are known to have, a broad array of physiological activities. The natural melanocortins include the different types of melanocyte stimulating hormone (α-MSH, p-MSH, y-MSH) and ACTH. Of these, a-MSH and ACTH are considered to be the main endogenous melanocortins. [0003] The melanocortins mediate their effects through melanocortin receptors (MC-Rs), a subfamily of G-protein coupled receptors. There are at least five different receptor subtypes (MC1-R to MC5-R). MC1-R mediates pigmentation of the hair and skin. MC2-R mediates the effects of ACTH on steroidogenesis in the adrenal gland. MC3-R and MC4-R are predominantly expressed in the brain. MC5-R is considered to have a role in the exocrine gland system. [0004] The melanocortin-4 receptor (MC4-R) is a seven- transmembrane receptor. MC4-R may participate in modulating the flow of visual and sensory information, coordinate aspects of somatomotor control, and/or participate in the modulation of autonomic outflow to the heart. K. G. Mountjoy et al., Science, 257:1248-125 (1992). Significantly, inactivation of this receptor by gene targeting has resulted in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. D. Husznar et al„ Cell, 88(1): 131-41 (1997). MC4-Rhas. also been implicated in other disease states including erectile disorders, cardiovascular disorders, neuronal injuries or disorders, inflammation, fever, cognitive disorders, and sexual behavior disorders. M. E. Hadley and C. Haskell-Luevano, The proopiomelanocortin system. Ann. N. Y. Acad. Sci., 885:1 (1999). [0005] Furthermore, observations in connection with endogenous MC4- R antagonists indicate that MC4-R is implicated in endogenous energy regulation. For example, an agouti protein is normally expressed in the skin and is an antagonist of the cutaneous MC receptor involved in pigmentation, MC1-R. M. M. Ollmann et al., Science, 278:135-138 (1997). However, overexpression of agouti protein in mice leads to a yellow coat color due to antagonism of MC1-R and increased food intake and body weight due to antagonism of MC4-R. L. L. Kiefer et al., Biochemistry, 36: 2084-2090 (1997); D. S. Lu et a/., Nature, 371:799-802 (1994). Agouti related protein (AGRP), an agouti protein homologue, antagonizes MC4-R but not MC1-R. T. M. Fong et al., Biochem. Biophys. Res. Commun. 237:629-631 (1997). Administration of AGRP in mice increases food intake and causes obesity but does not alter pigmentation. M. Rossi et al., Endocrinology, 739:4428-4431 (1998). Together, this research indicates that MC4-R participates in energy regulation, and therefore, identifies this receptor as a target for a rational drug design for the treatment of obesity. [0006] In connection with MC4-R and its uncovered role in the etiology of obesity and food intake, the prior art includes reports of compounds and compositions that act as agonists or antagonists of MC4-R. As examples, U.S. Patent No. 6,060,589 describes polypeptides that are capable of modulating signaling activity of melanocortin receptors. Also, U.S. Patent Nos. 6,054,556 and 5,731,408 describe families of agonists and antagonists for MC4-R receptors that are lactam heptapeptides having a cyclic structure. WO 01/10842 discloses MC4-R binding compounds having a multitude of structures and methods of using such compounds to treat MC4-R associated disorders. Some of the compounds described include amidino- and guanidino- containing arenes and heteroarenes. [0007] Various other classes of compounds have been disclosed as having MC4-R agonist activity. For example, WO 01/70708 and WO 00/74679 disclose MC4-R agonists that are piperidine compounds and derivatives, while WO 01/70337 and WO 99/64002 disclose MC-R agonists that are spiropiperidine derivatives. Other known melanocortin receptor agonists include aromatic amine compounds containing amino acid residues, particularly tryptophan residues, as disclosed in WO 01/55106. Similar agonists are disclosed in WO 01/055107 which comprise aromatic amine compounds containing tertiary amide or tertiary amine groups. Finally, WO 01/055109 discloses melanocortin receptor agonists comprising aromatic amines which are generally bisamides separated by a nitrogen-containing alkyl linker. [0008] Guanidine-containing compounds having a variety of biological activities are also known in the prior art. For example, U.S. patent No. 4,732,916 issued to Satoh et al. discloses guanidine compounds useful as antiulcer agents; U.S. Patent No. 4,874,864, U.S. Patent No. 4,949,891, and U.S. Patent No. 4,948,901 issued to Schnur et al. and EP 0343 894 disclose guanidino compounds useful as protease inhibitors and as anti-plasmin and anti-thrombin agents; and U.S. Patent No. 5,352,704 issued to Okuyama et al. discloses a guanidino compound useful as an antiviral agent.^jjanjdjne- containing compounds are also disclosed in other references. For example, U.S. Patent No. 6,030,985 issuedto Gentile et al. discloses guanidine compounds useful for treating and preventing conditions in which inhibition of nitric oxide synthetase is beneficial such as stroke, schizophrenia, anxiety, and pain. U.S. Patent No. 5,952,381 issued to Chen al discloses certain guanidine compounds for use in selectively inhibiting or antagonizing αvβ3 integrins. [0009] Various 5-, 6-, and 7- membered fully saturated 1- azacarbocyclic-2-ylidene derivatives of guanidine are disclosed as having anti-secretory and hypoglycemic activities by U.S. Patent No. 4,211,867 issued to Rasmussen. Such compounds are also taught as useful for the treatment of cardiovascular disease. Other guanidine derivatives are disclosed by U.S. Patent No. 5,885,985 issued to Macdonald et al. as useful in therapy to treat inflammation. Various guanidinobenzamide compounds are disclosed in WO 02/18327. The guanidinobenzamides are disclosed as useful for treating obesity and type II diabetes. [0010] The synthesis of various quinazolinone compounds is set forth in U.S. Patent Application No. 10/444,495, published on January 29, 2004 as US 2004/0019049, international application number PCT/US03/16442, published on December 4, 2003 as WO 03/099818, U.S. Patent Application No. 10/850,967, filed on May 21, 2004; international application no. PCT/US04/15959; and U.S. Provisional Application Nos. 60/382,762, 60/441,019, 60/473,317, 60/523,336, and 60/524,492 each of which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein. [0011] Despite the recent disclosure of various compounds that exhibit MC4-R agonist activity, a need remains for new compounds and pharmaceutical compositions that may be used to treat MC4-R mediated diseases and disease states. A need also remains for compounds that exhibit desirable pharmacological properties such as compounds that have reduced bioaccumulation properties in subjects to which they are administered. Summary of the Invention [0012] The instant invention provides potent and specific agonists of MC4-R that are small molecules. Thus, there has been provided, in accordance with one aspect of the invention, compounds of formula IA, IB, mixtures thereof, or pharmaceutically acceptable salts thereof where R1 is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R2 is selected from H or substituted or unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R3, R4, and R5 are independently selected from H, CI, I, F, Br, OH, NH2, CN, NO2, or substituted or unsubstituted alkoxy or alkyl groups; R3 is selected from H or substituted or unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or cycloalkylalkyl groups; and Z is selected from a piperazinone of formula which may be additionally substituted. [0013] Compounds provided by the invention further include prodrugs of the compounds of formula IA and IB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, or solvates thereof. [0014] The invention further provides compounds of formula IA and IB in which R3, R4, and R6 are all H. [0015] The invention further provides compounds of formula IA and IB in which R3' is selected from the group consisting of substituted and unsubstituted cyclohexyl, 2-alkylcyciohexyl, 2,2-dialkylcyclohexyl, 2,3- dialkylcyclohexyl, 2,4-dialkylcyclohexyi, 2,5-dialkylcyclohexyl, 2,6- dialkylcyclohexyl, 3,4-diaikylcyclohexyl, 3-alkylcyclohexyl, 4-alkylcyclohexyl, 3,3,5-trialkyIcyclohexyl, 2-aminocyclohexyl, 3-aminocyclohexyl, 4- aminocyclohexyl, 2,3-diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4- diaminocyclohexyl, 2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2- diaminocyclohexyl, 2-alkoxycyclohexyl, 3-alkoxycyclohexyl, 4- alkoxycyclohexyl, 2,3-dialkoxycyclohexyl, 2,4-dialkoxycycIohexyl, 3,4- dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2- dialkoxycyclohexyl, 2-alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4- alkylthiocyclohexyl, 2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl, 3,4- dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocycloh'exyl, 2,2- dialkylthiocyclohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl, trifluoromethyicycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl, cyclooctyl, 2- arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and decalinyl groups. In still other embodiments, R3' is selected from the group consisting of substituted and unsubstituted cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3- dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6- dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4- methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 4-f-butylcyclohexyl, isopinocampheyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, 3- methylcycloheptyl groups, 2-fluoro-4-methylcyclohexyl, 4-fluoro-2- methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl, trifIuoromethyl(polycyclic cycloalkyl), fluoromethyl(polycyclic cycloalkyl), and fluoro(polycyclic cycloalkyl) groups. [0016] The invention further provides compounds of formula IA and IB in which R3' is a substituted or unsubstituted polycyclic cycloalkyl group. In some such embodiments, R3' is a substituted or unsubstituted polycyclic cycloalkyl group having the formula II [0017] The invention further provides compounds of formula IA and IB in which R1 is a substituted or unsubstituted arylalkyl group such as a substituted or unsubstituted phenylethyl group. In some such embodiments, R1 is a substituted phenylethyl group such as a 4-substituted phenylethyl group or a 2,4-disubstituted phenylethyl group. In some embodiments, R1 is selected from phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4- phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4- chlorophenylethyi, 4-fluorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3- methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl, 4- hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2- fluoro-4-methylphenylethyl, 4-chloro-2-fluorophenylethyl, 4-bromo-2- fluorophenylethyl, 2-fluoro-4-methoxyphenylethyl, 2-trifIuoromethyl-4- fluorophenylethyir2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4- dimethoxyphenylethyl, (2-pyridyl)ethyl, (3-pyridyl)ethyl, (4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, and (phenyl)(hydroxymethyl)ethyl groups. In still other embodiments, R1 is selected from 2-fluoro-4~methoxyphenylethyl, 2- chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, 4-chlorophenyIethyl, 4- chloro-2-fluorophenylethyl, 2,4-dichlorophenylethyl, 4-bromophenylethyl, or 4- bromo-2-fluorophenylethyl groups. [0018] The invention further provides compounds of formula IA and IB in which R2 is selected from substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted heteroaryl groups. In some embodiments, R2 is selected from substituted or unsubstituted pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrrmidinyl, quinuclidiny!, indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl groups. In some such embodiments, R2 is selected from heteroaryl or heterocyclyl groups of formula which may be additionally substituted or may be unsubstituted. [0019] The invention further provides compounds of formula IA and IB in which R2 is selected from substituted or unsubstituted aryl or cycloalkyl groups. For example, in some embodiments, R2 is selected from aryl or cycloalkyl groups of formula which may be additionally substituted or may be unsubstituted. [0020] The invention further provides compounds of formula IA and IB in which R2 is selected from substituted or unsubstituted heterocyclylalkyl, or cycloalkylamino groups. For example, in some embodiments, R2 is selected from a group such as a substituted or unsubstituted cyclopropylamino group; a substituted or unsubstituted piperazinylalkyl group such as a. piperazinylmethyl group or an N-methyipiperazinylmethyl group; or a piperidinylalkyl group such as a piperidinylmethyl group or a piperidinylethyl group. [0021] The invention further provides compounds of formula IA and IB in which Z is a piperazinone having the following formula In some such embodiments, Z is a piperazinone having the following formula [0022] In some embodiments, the invention provides compounds in which the Un value for the compound is less than 35, 30, 25, 20, 15, 10, or 5 hours in a tissue with high blood perfusion such as brain, liver, kidney, and heart. In some such embodiments, the tm is less than or about 4 hours and in some embodiments is less than or about 3 hours in a subject to which the compound(s) have been administered. [0023] There has also been provided, in accordance with another aspect of the invention, a composition such as a pharmaceutical formulation or medicament comprising a compound according to the instant invention and a pharmaceutical^ acceptable carrier. The invention further provides the use of the compounds of the invention in preparing a medicament or pharmaceutical formulation for use in treating an MC4-R mediated disease. In some embodiments, such a disease is obesity or type II diabetes. [0024] There has also been provided, in accordance with another aspect of the invention, a method of treating an MC4-R mediated disease, comprising administering to a subject in need thereof, a compound or composition of the instant invention. In some such embodiments, the compounds of the invention exhibit reduced bioaccumulation in the tissue and plasma of the subject. [0025] In one embodiment, a disease to be treated by those methods of the instant invention is obesity or type II diabetes. [0026] In one embodiment, a compound or composition of the invention is intranasally administered. [0027] In one embodiment, a compound or composition of the invention is administered to a human subject. [0028] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. Detailed Description [0029] The instant invention relates to novel classes of small molecule meIanocortin-4 receptor (MC4-R) agonists. These compounds can be formulated into compositions and are useful in activating MC4-R, or in the . treatment of MC4-R-mediated diseases, such as obesity, type II diabetes, erectile dysfunction, polycystic ovary disease, complications resulting from or associated with obesity and diabetes, and Syndrome X. [0030] The following definitions are used throughout this specification. [0031] Alkyl groups include straight chain and branched alkyl groups having from 1 to about 8 carbon atoms. Examples of straight chain alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl groups. Examples of branched alkyl groups, include, but are not limited to, isopropyl, sec-butyl, t-butyl, and isopentyl groups. Representative substituted alkyl groups may be substituted one or more times with, for example, amino, thio, alkoxy, or halo groups such as F, CI, Br, and I groups. [0032] Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyi, cycloheptyl, and cyclooctyl groups. Cycloalkyl groups also includes rings that are substituted with straight or branched chain alkyl groups as defined above, and further include cycloalkyl groups that are substituted with other rings including fused rings such as, but not limited to, decalinyl, tetrahydronaphthyl, and indanyl. Cycloalkyl groups also include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups. Representative substituted cycloalkyl groups may be mono- substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbornyl or cycloheptyl groups, which may be substituted with, for example, alkyl, alkoxy, amino, thio, cyano, or halo groups. [0033] Alkenyl groups are straight chain, branched or cyclic lower alkyl groups having 2 to about 8 carbon atoms, and further including at least one double bond, as exemplified, for instance, by vinyl, propenyl, 2-butenyl, 3- butenyl, isobutenyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl groups among others. [0034] Alkynyl groups are straight chain or branched lower alkyl groups having 2 to about 8 carbon atoms, and further including at least one triple bond, as exemplified by groups, including, but not limited to, ethynyl, propynyl, and butynyl groups. [0035] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus aryl groups include, but are not limited to, phenyl, azulene, heptalene, biphenylene, indacene, fluorene, phenanthrene, triphenylene, pyrene, naphthacene, chrysene, biphenyl, anthracenyl, and naphthenyl groups. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems, it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once, such as, but not limited to, 2- , 3-, 4-, 5-, or 6-substituted phenyl or benzyl groups, which may be substituted with groups including, but not limited to, amino, alkoxy, alkyl, cyano, or halo. In some embodiments, aryl groups have from 6 to 14 ring member carbon atoms. [0036] Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloaikyl group as defined above. [0037] Arylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. [0038] Heterocyclyl groups are nonaromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and nonaromatic groups. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, but are not limited to, piperazino, morpholino, thiomorpholino, pyrrolidino, piperidino and homopiperazino groups. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, morpholino or piperazino groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups including, but not limited to, amino, alkoxy, alkyl, cyano, or halo. [0039] Heteroaryl groups are aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such asfuran, thiophene, pyrrole, isopyrrole, diazoie, imidazole, isoimidazole, triazole, dithiole, oxathiole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, oxatriazole, dioxazole, oxathiazole, pyran, dioxin, pyridine, pyrimidine, pyridazine, pyrazine, triazine, oxazine, isoxazine, oxathiazine, azepin, oxepin, thiepin, diazepine, benzofuran, and isobenzofuran. Although the phrase "heteroaryl groups" inclu'des fused ring compounds, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups". Representative substituted heteroaryl groups may be substituted one or more times with groups including, but not limited to, amino, alkoxy, alkyl, cyano, or halo. In some embodiments, heteroaryl groups include from 5 to 14 ring members. [0040] Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. [0041] Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. [0042] Aminocarbonyl groups are groups of the formula RR'NC(O)-, wherein R or R' may be the same or different, and each is independently selected from H, or substituted or unsubstituted alkyl, cycloalkyl, aryl, heterocyclyl or heteroaryl groups, as defined above. [0043] In general, "substituted" refers to a group as defined above in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms such as, but not limited to, a halogen atom such as F, CI, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, diaikylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups and also substituted cycloalkyl groups and others also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. [0044] Substituted cycloalkyl, substituted aryl, substituted heterocyclyl and substituted heteroaryl also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, substituted aryl, substituted heterocyclyl and substituted heteroaryl groups may also be substituted with alkyl groups as defined above. [0045] Pharmaceutically acceptable salts include a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali met als such as sodium or potassium, alkali earth met als such as calcium and magnesium or aluminum, and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid. [0046] The term "protected" with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M." John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlo'rosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2- methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetater Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4- picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acet als; and others. [0047] Prodrugs, as used in the context of the instant invention, includes those derivatives of the instant compounds which undergo in vivo metabolic biotransformation, by enzymatic or nonenzymatic processes, such as hydrolysis, to form a compound of the invention. Prodrugs can be employed to improve pharmaceutical or biological properties, as for example solubility, melting point, stability and related physicochemical properties, absorption, pharmacodynamics and other delivery-related properties. [0048] The instant invention provides potent and specific agonists of MC4-R that are small molecules and may exhibit reduced bioaccumulation properties when administered to animal subjects. In accordance with one aspect of the invention, the invention provides compounds of formula IA, IB, mixtures thereof, and pharmaceutical^ acceptable salts thereof. Compounds provided by the invention further include prodrugs of the compound of formula IA and IB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, and solvates thereof. Compounds of formula IA or IB have the following structures: [0049] In compounds of formula IA and IB, R1 is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups. In some embodiments, R1 is a substituted or unsubstituted arylalkyl group such as a substituted or unsubstituted phenylethyl group. In some such embodiments, R1 is a substituted phenylethyl group such as a 4- substituted phenylethyl group or a 2,4-disubstituted phenylethyl group such as 4-halophenylethyl, 2-halo-4-alkoxypheny!ethyl, and 2,4-dihalophenylethy! groups. In some embodiments, R1 is selected from phenylethyl, 2,4- diehlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4- bromophenylethyl, 4-methy!pheny!ethyl, 4-chlorophenylethyl, 4- fluorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2- methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3- methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl, 4- hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-ch!oro-4-iodophenylethyl, 2- fluoro-4-methylphenylethyl, 4-chloro-2-fiuorophenylethyl, 4-bromo-2- fluorophenylethyl, 2-fiuoro-4-methoxyphenylethyi, 2-trifluoromethyl-4- fiuorophenylethyl, 2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4- dimethoxyphenylethyl, (2-pyridyl)ethyI, (3-pyridyl)ethyl, (4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, and (phenyl)(hydroxymethyl)ethyl groups. In still other embodiments, R1 is selected from 2-fluoro-4-methoxyphenylethyl, 2- chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, 4-chlorophenylethyl, 4- chloro-2-fluorophenylethyl, 2,4-dichlorophenylethyl, 4-bromophenylethyl, or 4- bromo-2-fluorophenylethyl group. In still other embodiments, R1 is selected from phenylethyl,-2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4- phenoxyphenylethyl, 4-bromopheny!ethyl, 4-methylphenylethyl, 4- chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2- methoxyphenylethyi, 2-chlorophenylethyl, 2-fIuorophenylethyl, 3- methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyI, 2-chloro-4-iodophenylethyl, 2-fluoro-4- methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2-f!uoro-4-bromophenylethyl, 2-fluoro-4-methoxyphenyIethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2,4- difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2- pyridyl)ethyl, (3-pyridyl)ethyl, (4-pyridyl)ethyl, (pyridyl)(hydroxymethyl)ethyl, (phenyl)(hydroxymethyl)ethyl, substituted and unsubstituted (heteroaryl)(hydroxymethyI)ethyl, substituted and unsubstituted (aryl)(hydroxymethy!)ethy! groups, substituted and unsubstituted (aryl)(aikoxymethyl)ethyl, substituted and unsubstituted (aryl)(aryloxymethyl)ethyl, substituted and unsubstituted (aryl)(arylalkoxymethyl)ethyl, substituted and unsubstituted (aryl)(heteroaryioxymethyl)ethyl, substituted and unsubstituted (aryl)(heterocyclyloxymethyl)ethyl, substituted and unsubstituted (heteroaryl)(alkoxymethyl)ethyl, substituted and unsubstituted (heteroaryl)(aryloxymethyl)ethyl, substituted and unsubstituted (heteroaryl)(arylalkoxymethy!)ethyl, substituted and unsubstituted (heteroaryl)(heteroaryloxymethyl)ethyl, and substituted and unsubstituted (heteroaryl)(heterocyclyloxymethyl)ethyl groups. [0050] In compounds of formula IA and IB, R2 is selected from H or substituted or unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, oralkyl groups. Compounds of formula IA and IB with R2 values such as those set forth above have been found to exhibit reduced bioaccumulation properties as evidenced by lower ty2 blood plasma values in test subjects to which the compounds have been administered. Generally, such compounds also provide improved plasma Cmax values and may also provide improved brain Cmax values. In some embodiments, R2 is selected from substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted heteroaryl groups. In other embodiments, R2 is selected from substituted or unsubstituted pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl groups. In some such embodiments, R2 is selected from heteroaryl or heterocyclyl group of formula which may be additionally substituted or may be unsubstituted. In some embodiments, the invention provides compounds of formula IA and IB in which R2 is selected from substituted or unsubstituted heterocyclylalkyl, or cycloalkylamino groups. For example, in some embodiments, R2 is selected from a group such as a substituted or unsubstituted cyclopropylamino group; a substituted or unsubstituted piperazinylalkyl group such as a piperazinylmethyl group or an N-methylpiperazinylmethyl group; or a piperidinylalkyl group such as a piperidinylmethyl group or a piperidinylethyl group. In some embodiments, R2 may be selected from a substituted or unsubstituted aryl or cycloalkyl group. Examples include compounds of the following formula which may be additionally substituted. [0051] In compounds of formula IA and IB, R3, R4, and R5 are independently selected from H, CI, I, F, Br, OH, NH2, CN, NO2, or substituted or unsubstituted alkoxy or alkyl groups. In some embodiments, each of R3, R4, and R5 are H. [0052] In compounds of formula IA and IB, Z is a piperazinone of formula which may be additionally substituted. In some embodiments, Z is a piperazinone of formula In some such embodiments, Z is a piperazinone of formula [0053] Compounds of formula IA and IB with Z values such as those set forth above have been found to exhibit reduced bioaccumulation properties as evidenced by lower U/2 blood plasma values in test subjects to which the compounds have been administered. Generally, such compounds also provide improved plasma Cmax values and may also provide improved brain Cmax values and intracerebroventricular (icv) efficacy. Significant reductions in Fl (food intake) at 16 hours and 30 mpK (mg/kg) were also observed in some subjects for some compounds of formula IA and IB. Compounds of formula IA and IB have been found particularly suitable as possessing reduced bioaccumulation properties. Examples of such compounds are set forth in the various embodiments described above. [0054] In compounds of formula IA and IB, R3' is selected from H or substituted or unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, orcycloalkylalkyl groups. In some embodiments, R3' is selected from substituted or unsubstituted cycloalkyl groups. In some embodiments, R3' is selected from the group consisting of substituted and unsubstituted cyclohexyl, 2- alkylcyclohexyl, 2,2-diaikylcyclohexyl, 2,3-dialkylcyclohexyl, 2,4- dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl, 3,4- dialkylcyclohexyl, 3-aIkylcyclohexyl, 4-alkylcyclohexyl, 3,3,5-trialkylcyclohexyl, 2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl, 2,3- diaminocyclohexyl, 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5- diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2- alkoxycyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycycIohexyl, 2,3- dialkoxycyclohexyl, 2,4-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, 2,5- dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2- alkylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3- dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl, 2,5- dialkylthiocyclohexyl, 2,6-dialkylthiocycIohexyI, 2,2-dialkylthiocycIohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl, trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl, cyclooctyl, 2-arylcyclohexyl, 2-phenyIcyclohexyl, 2- arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocamphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl, norbomyl, and decalinyl groups. In still other embodiments, R3' is selected from the group consisting of substituted and unsubstituted cyclohexyl, 2-methylcyc!ohexyl, 2,2- dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5- dimethylcyclohexyl, 2,6-dimethyicyclohexyl, 3,4-dimethylcyclohexyl, 3- methylcyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 4-f- butylcyclohexyl, isopinocampheyl, 7,7-dimethylnorbornyl, 4- isopropylcyclohexyl, 3-methylcycloheptyl groups, 2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl, 4,4-difluoro-2-methyIcyclohexyl, 4- trifluoromethylcyclohexyl, 2-methyl-4-trifluoromethylcyclohexyl, 2- fluoromethylcyclohexyl, trifluoromethyl(polycyclic cycloalkyl), fIuoromethyl(polycyclic cycloalkyl), and fluoro(polycyclic cycloalkyl) groups. In some embodiments, R3' is a substituted or unsubstituted polycyclic cycloalkyl group. In some such embodiments, R3' is a substituted or unsubstituted polycyclic cycloalkyl group having the formula II [0055] Compounds of formula IA and IB may exhibit reduced bioaccumulation properties in animal subjects to which they are administered. Such subjects may include human and non-human animal subjects. Examples of mammalian subjects include, but are not limited to, rodents such as mice and rats, bovines, equines, canines, felines, rabbits, guinea pigs, porcines, primates such as humans and monkeys, and the like. In some embodiments, the invention provides compounds in which the fa value for the compound is less than 35, 30, 25, 20, 15, 10, or 5 hours in a tissue with high blood perfusion such as brain, liver, kidney, and heart. In some such embodiments, the fa value for the compound is less than 4 hours and in some embodiments is less than or about 3 hours in a tissue of a subject to which the compound has been administered. [0056] One or more compounds of the invention may be included in pharmaceutical formulations or medicaments. Such compositions include at least one compound of formula IA and/or IB and a pharmaceutically acceptable carrier. Therefore, the compounds of formula IA and IB may be used to prepare medicaments and pharmaceutical formulations for use in treating an MC4-R mediated disease such as, but not limited to, obesity, type II diabetes, erectile dysfunction, polycystic ovary disease, and Syndrome X. In some embodiments, the MC4-R mediated disease is obesity or type II diabetes. [0057] Methods for treating MC4-R mediated diseases include administering to a subject in need thereof, a compound or composition of the instant invention. In some such embodiments, the compounds of the invention exhibit reduced bioaccumulation in the tissues such as in the brain or blood plasma of a subject. Administration of the compounds and compositions of the invention may be accomplished using various methods such as those described herein. In one embodiment, the compound or composition is administered intranasally. [0058] The instant compounds may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. In some cases, one stereoisomer may be more active and/or may exhibit beneficial effects in comparison to other stereoisomer(s) or when separated from the other stereoisomer(s). However, it is well within the skill of the ordinary artisan to separate, and/or to selectively prepare said stereoisomers. Accordingly, "stereoisomers" of the instant invention necessarily includes mixtures of stereoisomers, individual stereoisomers, or optically active forms. [0059] The instant invention also provides for compositions which may be prepared by mixing one or more compounds of the instant invention, or pharmaceutical^ acceptable salts or tautomers thereof, with pharmaceutical^ acceptable carriers, excipients, binders, diluents or the like, to treat or ameliorate a variety of disorders. Examples of such disorders include, but are . not limited to obesity, erectile disorders, cardiovascular disorders, neuronal injuries or disorders, inflammation, fever, cognitive disorders, sexual behavior disorders. A therapeutically effective dose further refers to that amount of one or more compounds of the instant invention sufficient to result in amelioration of symptoms of the disorder. The pharmaceutical compositions of the instant invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others. The compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral administration, by intranasal administration, by . transmucosal administration, by rectal administration, or subcutaneous administration as well as intrathecal, intravenous, intramuscular,. intraperitoneal, intranasal, intraocular or intraventricular injection. The compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation. The following dosage forms are given by way of example and should not be construed as limiting the instant invention. [0060] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient such as a starch or other additive. Suitable additives or excipients are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein,'albumin, synthetic or semi-synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, a thickeners, buffers, a sweeteners, flavoring agents or perfuming agents, Additionally, dyestuffs or pigments may be added for identification. Tablets and pills may be further treated with suitable coating materials known in the art. [0061] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration. [0062] As noted above, suspensions may include oils. Such oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations. [0063] For intranasal.administration (e.g., to deliver compounds to the brain), or administration by inhalation (e.g., to deliver compounds through the lungs), the pharmaceutical formulations may be a solution, a spray, a dry powder, or aerosol containing any appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Examples of intranasal formulations and methods of administration can be found in WO 01/41782, WO 00/33813, WO 91/97947, U.S. Patent No. 6,180,603, U.S. Patent No. 5,624,898; Published U.S. Patent Application No. 2003/0229025 (U.S. Serial No." 10/374,507); and WO 03/072056 each of which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein. A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent. The compound or compounds of the instant invention are conveniently delivered in the form of an aerosol spray presentation from a nebulizer or the like. [0064] Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides. [0065] For injection, the pharmaceutical formulation may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi-dose containers. 10066] For rectal administration, the pharmaceutical formulations may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutical^ acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives. [0067] Besides those representative dosage forms described above, pharmaceutical^ acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. [0068] The formulations of the invention may be designed for to be short-acting, fast-releasing, iong-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release. [0069] The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers. [0070] A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms. Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective-amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention. A therapeutically effective dose may vary depending upon the route of administration and dosage form. The preferred compound or compounds of the instant invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective'in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals. [0071] The present invention also provides methods of enhancing MC4-R activity in a human or non-human animal. The method comprises administering an effective amount of a compound, or composition, of the instant invention to said mammal or non-human animal. Effective amounts of the compounds of the instant invention include those amounts-that activate MC4-R which are detectable, for example, by an assay described below in the illustrative Examples, or any other assay known by those skilled in the art that a detect signal transduction, in a biochemical pathway, through activation of G-protein coupled receptors, for example, by measuring an elevated cAMP level as compared to a control model. Accordingly, "activating" means the ability of a compound to initiate a detectable signal. Effective amounts may also include those amounts which alleviate symptoms of a MC4-R disorder treatable by activating MC4-R. [0072] An MC4-R disorder, or MC4-R-mediated disease, which may be treated by those methods provided, include any biological disorder or disease in which MC4-R is implicated, or which inhibition of MC4-R potentiates a biochemical pathway that is defective in the disorder or disease state. Examples of such diseases are obesity, erectile disorders, cardiovascular disorders, neuronal injuries or disorders, inflammation, fever, cognitive disorders, type II diabetes, polycystic ovary disease, Syndrome X, complications from obesity and diabetes, and sexual behavior disorders. In a preferred embodiment, the instant invention provides compounds, compositions, and methods effective for reducing energy intake and body weight; reducing serum insulin and glucose levels; alleviating insulin resistance; and reducing serum levels of free fatty acids. Accordingly, the instant invention is particularly effective in treating those disorders or diseases associated with obesity or type II diabetes. [0073] "Treating" within the context of the instant invention, therefore, means an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. For example, within the context of obesity, successful treatment may include an alleviation of symptoms or halting the progression of the disease, as measured by reduction in body weight, or a reduction in amount of food or energy intake. In this same vein, successful treatment of type I or type II diabetes may include an alleviation of symptoms or halting the progression of the disease, as measured by a decrease in serum glucose or insulin levels in, for example, hyperinsulinemic or hyperglycemic patients. [0074] Scheme 1a illustrates a general synthetic route that may be used to synthesize various guanidinyl-substituted quinazolinone compounds. As shown in Scheme 1a, nitro and amino quinazolinone compounds such as (d) and (e) may be readily converted into a plethora of guanidinyl quinazolinones by converting the amino functionality to an isothiocyanate functionality such as possessed by compound (f). This may be accomplished reacting the amine group with thiophosgene. Isothiocyanate compounds such as (0 may then be readily converted into a thiourea such as compound (g) by reaction with a suitable amine compound such as (1S,2S,3S,5R)-(+)- isopinocampheylamine. Preparation of the desired guanidinylamine such as compound (h) may then be accomplished by reacting the thiourea with a compound such as 1-[3-(dimethyIamino)-propyl]-3-ethylcarbodiimide hydrochloride and then with a suitable amine such as cis-2,6- dimethylpiperazine, (S)-2-(fluoromethyl)piperazine, or the like. Various fluorine-substituted compounds may be prepared using the methodology shown in Scheme 1a using an appropriately substituted 4-nitroanthranilic acid. Other compounds may be prepared by using 5-nitroanthranilic acid in place of 4-nitroanthranilic acid. [0075] Scheme 1b illustrates another generally applicable method that may be employed to synthesize a large number of guanidinyl-substituted quinazolinones and heterocyclic derivatives of such compounds where a carbon of the benzene ring of the quinazolinone is replaced with a nitrogen atom. As shown in Scheme 1b, conversion of compound (d) to (e) may be accomplished by initially adding trimethylphosphine to form a reactive iminophosphorane intermediate, adding a substituted isocyanate such as a cycloalkyl isocyanate for example, a polycyclic isocyanate to produce a carbodiimide, and finally forming (e) by addition of and reaction with an amine such as, but not limited to a substituted piperazine. Scheme 1b [0076J Scheme 2a illustrates another general procedure that may be used to prepare a wide variety of guanidinyl-substituted quinazolinone compounds. SCHEME 2a R3= Hi Alkyl, Aryl, Arylalkyl, etc. [0077] Scheme 2b shows yet another alternative route that may be used to prepare various compounds of of the invention. SCHEME 2b [0078] Still another route that may be used to prepare various compounds of the invention is depicted in Scheme 2c. SCHEME 2c [0079] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention. EXAMPLES [0080] The following abbreviations and terms are used throughout the Examples: Boc: t-Butyl carbamate protecting group Celite®: Diatomaceous earth filter agent DAST: (Dimethylamino)sulfur trifluoride DCM: Dichloromethane DIBAL: Diisobutylaluminum hydride D1EA: A/,A/-Diisoproylethylamine DMF: . A/,/V-Dimethylformamide (DMSO: Dimethylsulfoxide EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc: Ethyl acetate EtOH: Ethanol Gold's Reagent: (Dimethylaminomethyleneaminomethylene)di- methyl ammonium chloride HOBt: Hydroxybenzotriazole HPLC: High perfomance liquid chromatography HCI: Hydrochloric acid HBTU: O-Benzotriazol-l-yl-N.N.N'.N'-tetramethyluronium hexafluorophosphate KOH: Potassium hydroxide LC; Liquid Chromatography MS: Mass Spectroscopy MeOH: Methanol mL: Milliliter NMO: N-Morpholine oxide NMP: 1-Methyl-2-pyrrolidinone NMR: Nuclear magnetic resonance spectroscopy PS-CDI: Polymer supported carbodiimide resin TFA: Trifluoroacetic acid THF: Tetrahydrofuran SYNTHESIS OF 6-METHYLPIPERAZIN-2-ONE Step 1: Synthesis of N-Boc-alanine-N'-benzyl glycine methyl ester (D [0081] To a stirred solution of N-Boc-L-alanine (1 equivalent) and N- benzyl glycine methyl ester (1 equivalent) in dichioromethane was added TEA (1 equivalent) and HOBt (1 equivalent)', followed by EDCI (1 equivalent). The solution was allowed to stir at room temperature under N2 for 48 hours. The reaction was diluted with 10% HCI, and the organic layer was separated and dried over MgS04. Crude product was chromatographed on silica (30% EtOAc/hexanes) giving the desired product (1) as a clear oil (75%). Step 2. Synthesis of [benzyI-(2-tertbutoxycarbonylamino-propyl)- amino]-acetic acid methyl ester (2) [0082] To a stirred solution of BH3 in THF (1 M, 2 equivalents), was added dropwise a solution of dipeptide (1) in THF. The reaction was then maintained at room temperature for 24 hours and then diluted with methylene chloride, washed with NaHC03, and dried over MgS04. Crude product was chromatographed on silica eluting with 20% EtOAc/hexanes giving the desired product (2) a colorless oil (40%). Step 3. Synthesis of 1-benzyl-5-(S)-methyI-3-oxo-piperazine (3) [0083] Ester (2) was stirred in a 50:50 solution of TFA:CH2CI2 for 1 hour. The solvent was then removed, and the residue was redissolved in methylene chloride and washed with a saturated solution of Na2C03. The organic layer was then separated and dried over MgS04 giving desired piperazine compound (3) as a white solid (87%). Step 4. Synthesis of 6-(S)-methylpiperazin-2-one (4) [0084] To a dichloroethane solution of 3 at room temperature was added 3 equivalents of chloroethylchloroformate and Hunig's base (3 equivalents). The solution was stirred overnight, and the reaction was then directly loaded onto a silica gel column and chromatographed eluting with EtOAc/hexanes (4:6). The isolated carbamate intermediate was dissolved in methanol and heated at reflux for 2 hours. Removal of methanol provided the .. desired piperazin-2-one (4) as an off white solid (yield was not optimized, but was approximately 60% for the 2 steps). 6(S)-methyl piperazin-2-one compounds of the invention were made according to the following methods by EDC activation of the thiourea intermediate to the carbodiimide followed by coupling with 6(S)-methyl piperazin-2-one. Synthesis of 6-(S)-methylpiperazin-2-one guanidine compounds [0085] 6(S)-Methyl piperazin-2-one guanidine compounds of the invention were prepared according to the methods described herein by EDC activation of the thiourea intermediate to provide the carbodiimide followed by coupling with 6(S)-Methyl piperazin-2-one. SYNTHESIS OF 2-(R)-FLUOROMETHYLPIPERAZINE AND 2-(R)-DIFLUOROIWETHYLPIPERAZINE Synthesis of 2-(R)-Fiuoromethylpiperazine Step 1. Synthesis of N-benzyl serine methyl ester [0086] To a stirred solution of serine methyl ester hydrochloride (3.0 g, 19.28 mmol) and triethylamine (2.7 mL, 19.28 mmol) in methylene chloride (30 mL) was added benzaldehyde (1 equivalent), followed by 2 g anhydrous MgS04. The mixture was stirred at room temperature in a sealed flask for 20 hours, and then the solids were filtered away, and the filtrate was evaporated. The residue was redissolved in methanol (50 mL), and sodium borohydride (1 equivalent) was carefully added. The mixture was stirred for 30 minutes, was diluted with methylene chloride, was washed with NaHC03, and was then dried over magnesium sulfate. The desired title product was obtained as a yellow oil and was used crude. N-4-methoxybenzyl serine methyl ester was made in a similar fashion using anisaldehyde in place of benzaldehyde. Step 2. Synthesis of N-benzyl-N-chloroacetyl serine methyl ester [0087] To an ice cooled solution of the crude benzyl amino acid prepared as described in Step 1 and triethylamine (1 equivalent) in methylene chloride, was added chloroacetyl chloride (1 equivalent) dropwise. After 1 hour, the reaction was washed with 10% HCI, and the organic layer was separated and dried over sodium sulfate. Crude product was chromatographed on silica gel eluting with 60% EtOAc/hexanes (Rf = 0.3) giving the desired title compound as a colorless oil (67%). Step 3. Synthesis of df-N-benzyl cyclo serine glycine [0088] The chloride prepared in Step 2 was dissolved in acetonitrile, and benzyl amine was added (3 equivalents). The solution was heated at reflux for 20 hours, during which time a solid formed in the flask. The reaction was cooled, and the solvent was removed. The residue was dissolved in methylene chloride, was washed with 10% HCI, and was dried over MgS04. Crude product was passed through a silica gel plug (100% EtOAc, Rf = 0.5) giving a white solid (80%). Di-N-4-methoxybenzyl cyclo serine glycine was made in a similar fashion using p-methoxybenzyl amine and the p- methoxybenzyl derivative of the starting material. Step 4. Synthesis of 1,4-dibenzyl-2-(R)-piperazinemethanol [0089] To an ice cooled mixture of LiAIH4 (10 equivalents) in anhydrous THF under N2 was added the cyclic dipeptide produced in Step 3 in THF dropwise. The resulting grey mixture was heated to reflux for 16 hours. The reaction was carefully quenched with HaO, NaOH, H2O (1:1:3), and the resulting white mixture was filtered through celite. The filtrate was dried over MgS04 and concentrated, giving the desired product as a colorless oil (93%). Step 5. Synthesis of 1,4-dibenzyF-2-(R)-fluoromethylpiperazine [0090] To an ice cooled solution of DAST (2 equivalents) in methylene chloride under N2 was added the alcohol prepared in Step 4 in methylene - chloride dropwise. The yellow solution was stirred at 0°C to room temperature for 20 hours. The reaction was diluted with NaHC03, and the organic layer was separated and dried over sodium sulfate. The crude product was chromatographed on silica gel eluting with 10-50% EtOAc/hexanes giving the desired title compound as a yellow oil (40%). Step 6 Synthesis of 2-(R)-fluoromethylpiperazine [0091] 1,4-DibenzyIfluoromethylpiperazine from Step 5 was dissolved in dichloroethane, and oc-chloroethyl chloroformate (3 equivalents) was added. The resulting solution was heated to reflux for 16 hours. The reaction was directly loaded onto a silica gel column and chromatographed eluting with 10- 20% EtOAc/hexanes. The intermediate dicarbamate was isolated as a clear oil. The intermediate dicarbamate oil was dissolved in methanol and heated at reflux for 2 hours. The solvent was then thoroughly removed giving the desired deprotected piperazine as a white solid (90% for 2 steps). Synthesis of 1,4-di-p-methoxybenzyl-2-(R)-piperazine- carboxaidehyde 1,4-di-p-methoxybenzyl-2-(R)- difluoromethylpiperazine [0092] To a dry flask containing a solution of oxalyl chloride in methylene chloride (2.0 M, 1.2 equivalents) at -78°C was added DMSO (2.4 equivalents) dropwise under a stream of nitrogen. After stirring for 15 minutes, a solution of 1,4-di-p-methoxybenzyl-2-(R)-piperazinemethanol (1 equivalent) in methylene chloride was added dropwise, and the resulting solution was stirred for 1 hour. TEA (5 equivalents) was added, and the mixture was added to NaHCOs(aq), separated, and dried over MgS04. After filtering, the filtrate was cooled to -78°C, and DAST was added dropwise (1.2 equivalents). The resulting orange solution was stirred for 12 hours. The reaction was then diluted with aqueous sodium bicarbonate, and the organic layer was separated and chromatographed in silica (10% EtOAc/hexanes) giving the desired title difluoro compound as a light brown oil (33%). Deprotection of the difluoride was carried out in the same manner as described in Step 6 using a-chloroethyl chloroformate giving a white solid (85%). Synthesis of 2-(R)-fluoromethyIpiperazine and 2-(R)- difluoromethylpiperazine guanidine compounds [0093] 2-(R)-Fluoromethylpiperazine and 2-(R)- difluoromethylpiperazine guanidine compounds of the invention were prepared according to the methods described herein by EDC activation of the thiourea intermediate to provide the carbodiimide followed by coupling with 2- (R)-fluoromethylpiperazine or 2-(R)-difluoromethylpiperazine. SYNTHESIS OF (6S)-6-METHYLP!PERAZIN-2-ONE) Step 1. Synthesis of S-ethyl (2R)-2-{[(benzyloxy)carbonyi]- amino}propanethioate [0094] A 250 mL round bottom flask was charged with benzyloxy- carbonyl-L alanine (15.0 g, 67.2 mmol) and 67.2 mL of dichloromethane. To this mixture was added DMAP (0.82 g, 6.72 mmol) and chilled EtSH (0°C, 5.46 mL, 73.9 mmol) followed by the addition of DCC (15.2 g, 73.9 mmol) in one portion. The addition of the DCC is highly exothermic so the reaction will bubble upon addition, and the reaction should be kept well vented. The resulting mixture was stirred for 30 minutes at 22°C. The resulting white solid was then removed by vacuum filtration, and the filtrate was concentrated. Silica Gel chromatography using hexanes with polarization to 8:1 hexanes/ethyl acetate afforded 93% yield (18.0g, 62.5 mmol) of the desired product as a colorless oil. Step 2. Synthesis of Benzyl (1R)-1-methyI-2-oxoethylcarbamate [0095J To a stirred solution containing S-ethyl (2R)-2- {[(benzyloxy)carbonyljamino}- propanethioate (18.9 g, 62.5 mmol), wet 10% Pd/C (1.89 g), and acetone (347 mL) at 0°C was added triethylsilane (29.9 mL, 187.5 mmol). The resulting mixture was stirred for 30 minutes at 0°C and then filtered through celite using ethyl acetate to wash the celite thoroughly. The filtrate was concentrated and partitioned between acetonitrile (500 mL) and hexanes (150 mL). The layers were separated, and the acetonitrile phase was washed once with hexane (150 mL) and then concentrated to provide the desired product (59.4 mmol, 95%) which was used in the next step without further purification. Step 3. Synthesis of Methyl N-((2R)-2-{[(benzyloxy)carbonyl]- amino}propyl)glycinate [0096J ,'A 1000 mL round bottom flask was charged with benzyl (1 R)-1- methyl-2-oxoethylcarbamate (59.4 mmol) and 347 mL of anhydrous methanol. The resulting mixture was cooled to 0°C and glycine methyl ester hydrochloride (29.3 g, 237.6 mmol) was added. After 10 minutes, 1.0 M NaCNBH4 in THF (95 mL, 95.0 mmol)was added and the reaction was allowed to warm'to 22"C overnight. The reaction mixture was then concentrated, redissolved in diethyl ether (200 mL) and placed in a separatory funnel. The organic phase was washed with saturated NaHC03 (200 mL) and separated. The basic aqueous layer was washed twice with diethyl ether (2 x 200 mL), and the combined organic layers were washed with brine (2 x 200 mL), dried with Na2SC>4 and concentrated. Silica gel chromatography using 2:1 hexanes/ethyl acetate with gradual polarization to 1:1 hexanes/ethyl acetate provided the desired product as a clear oil in 75% yield (12.5 g, 44.6 mmol). Step 4. Synthesis of (6S)-6-Methylpiperazin-2-one) [0097] To a solution of methyl N-((2R)-2-{[(benzyloxy)carbonyi]- amino}propyl)glycinate (12.5 g, 44.6 mmol) in anhydrous methanol (446 mL) under an atmosphere of N2 was added 10% Pd/C (1.25 g). The flask was then placed on a Buchi hydrogenator and purged three times with N2 followed by 3 times with H2. The reaction was allowed to stir under hydrogen (2.2 L, 98.12 mmol) until no more hydrogen was consumed. Once complete (24 hours), the reaction mixture was poured through Celite and the filtrate was concentrated. Ethyl acetate(5-10 mL) was added causing a white solid to crash out. This white solid was dried and collected to provide the desired product in 95% yield (4.8 g, 42.37 mmol). (The filtrate can be concentrated and more of the product can be crashed out by addition of ethyl acetate. If any starting material remains, it will be in the filtrate. SYNTHESIS OF (3R,4R)-3,4-PYRROLIDINEDIOL HYDROCHLORIDE [0098] (3R,4R)-1-(Phenylmethyl)-3,4-pyrrolidinedio! (250 mg, 1.30 mmo!) was dissolved in ethyl acetate and added to a suspension of 10% Pd on carbon in ethyl acetate. The mixture was hydrogenated on a Parr hydrogenator at 57 PSI for 12 hours. The reaction was then filtered through Celite to remove catalyst. Excess 4N HCI in dioxane was added and then concentrated give the title compound as a brown oil which was used without further purification. SYNTHESIS OF (3S,4S)-3,4-PYRROLIDJNEDIOL HYDROCHLORIDE [0099] (3S,4S)-1-(Pheny!methyl)-3,4-pyrrolidinediol was converted to the title compound using the procedure described above for the synthesis of (3R,4R)-3,4-pyrrolidinediol hydrochloride. SYNTHESIS OF THIOMORPHOLINE 1,1-DIOXIDE HYDROCHLORIDE [0100] 4-(Phenylmethyl)thiomorpholine 1,1-dioxide was converted to the title compound using the procedure described above for the synthesis of (3R,4R)-3,4-pyrrolidinediol hydrochloride. SYNTHESIS OF (3R,5R)-5-(HYDROXYMETHYL)-3-PYRROLIDINOL TRIFLUOROACETATE (SALT) Step 1. Synthesis of 1-(1,1-Dimethylethyl) 2-methyf (2R,4R)-4- hydrdxy-1,2-pyrrolidinedicarboxylate [0101] Trimethylsilyl.diazomethane (3.89 mmol) was slowly added to an ice cooled solution of (4R)-1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-hydroxy-D- proline (0.75 g, 3.25 mmol), 60 mL toluene and 20 mL of methanol. The reaction was stirred for 2 hours on the ice bath, was warmed to room temperature, and was concentrated to give 0.89 g of the title compound as a clear yellow oil. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.4 (m, 9 H), 1.8 (dt, J=12.8,4.9 Hz, 1 H), 2.4 (m, 1. H), 3.1 (m, 1 H), 3.5 (dd, J=10.8, 5.7 Hz, 1 H), 3.6 (s, 3 H), 4.2 (m, 2 H). Step 2. Synthesis of 1,1-Dimethylethyl (2R,4R)-4-hydroxy-2- (hydroxymethyl)-l-pyrrolidinecarboxylate [0102] L1BH4 (6.46 mmol as a solution in THF) was added to an ice cooled solution of (1,1-dimethylethyl) 2-methyl (2R,4R)-4-hydroxy-1,2- pyrrolidinedicarboxylate (0.36 g, 1.47 mmol) in THF. The reaction was heated at 70°C. for 48 hours. The reaction was quenched with isopropanol and then saturated NaHC03. The mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with 1N NaOH, dried over MgS04 and concentrated to give 0.185 g of the title compound. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.4 (m, 9 H), 1.8 (m, 1 H), 2.0 (m, 1 H), 3.0 (m, 1 H), 3.4 (m, 1 H), 3.5 (m, 2 H), 3.7 (m, 1 H), 4.1 (m, 1 H), 4.9 (dd, J=5.3, 5.3 Hz, 1 H), 5.1 (m, 1 H). Step 3. Synthesis of (3R,5R)-5-(Hydroxymethyl)-3-pyrrolidinol trifiuoroacetate (salt) [0103] 1,1 -Dimethylethyl (2R,4R)-4-hydroxy-2~(hydroxymethyl)-1 - pyrrolidinecarboxyiate (0.185 g, 0.852 mmol) was stirred in a 1:1 solution of, methylene chloride:TFA for 14 hours. The reaction was concentrated, and the crude material was used without further purification. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.5 (m, 1 H), 2.2 (m, 4 H), 3.0 (m, 1 H), 3.1 (m, 1 H), 3.6 (m, 3 H), 4.3 (m, 1 H), 5.3 (s,br, 2 H), 8.6 (s,br, 1 H>, 9.2 (s,br, 1 H). SYNTHESIS OF CIS-2,6-DIMETHYL-PIPERAZINE-1-CARBONITRILE HYDROCHLORIDE Step 1. Synthesis of 4-Cyano-cis-3,5-dimethyIpiperazine-1- carboxylic acid tert-butyl ester [0104] 4.00 g of cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (prepared according to the method E. Jon Jacobson et. a!. J. Med. Chemistry. 1999, Vol.42, 1123-144) in 91 mLof dichloromethane was treated with sodium bicarbonate (4.7 g) followed by addition of cyanogen bromide (7.5 mL). The reaction mixture was heated at reflux overnight, was filtered, and was purified by column chromatography (0 to 50% ethyl acetate/hexanes) to afford 3.9 g of the title compound as a white solid. 1H NMR (CDCI3, 300 MHz) 6 ppm 1.33 (d, 6H, J = 6.5 Hz), 1.44 (s, 9H), 2.54 (m, 2H), 3.09 (m, 2H), 4.09 (m, 2H); 13C NMR (CDCI3, 75 MHz) 16.70 (2C), 28.54 (3C), 53.86 (4C), 80.86, 114.10,154.22. Step 2. Synthesis of cis-2,6-Dimethyl-piperazme-1-carbonitrile hydrochloride [0105] 4-Cyano-cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (1.0 g) in 10 mL THF was treated with 4.0 N HCI/dioxane (25 mL), stirred for five hours and concentrated to provide 1.1 g of the title compound. 1H NMR (DMSO-D6, 300 MHz) 5 ppm 1.24 (d, 6H, J = 6.6 Hz), 2.65 (q, 2H, J = 11.1 Hz), 3.27 (d, 2H, J = 12.2 Hz), 3.63 (m, 2H); 13C (DMSO, 75 MHz) 16.73 (2C), 46.81 (2C), 50.80 (2C), 104.20. SYNTHESIS OF CIS-2,6-DIMETHYL-PIPERAZIN-1-OL HYDROCHLORIDE Step 1. Synthesis of cis-3,5-Dimethyl-4-(3-oxo-butyl)-piperazine-1 - carboxylic acid tert-butyl ester [0106] Cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.00 g; prepared according to the method E. Jon Jacobson et. al.: J. Med. Chemistry. 1999, Vol. 42, 1123-144) in 47 mL chloroform was treated with methylvinylketone (1.7 mL) at room temperature and heated at reflux for two days. The reaction was then concentrated, diluted with THF and heated at reflux for 1 day before purifying by column chromatography (0 to 10% MeOH/DCM) to afford 0.865g of the title compound as a clear, colorless oil. 1H NMR (CDCI3, 300 MHz) 5 ppm 1.08 (d, 2H, J=6.07 Hz), 1.47 (s, 9H), 2.17 (s, 3H), 2.52 (m, 6H), 3.10 (m, 2H), 2.86 (bs, 2H); 13C NMR (CDCI3, 75 MHz) 17.6 (2C), 28.62 (5C), 30.8, 37.34, 42.46, 53.57 (4C), 79.85, 154.49, 208.29. Step 1. Synthesis of cis-2,6~Dimethyl-piperazin-1-ol hydrochloride [0107] Cis-3,5-Dimethyl-4-(3-oxo-butyl)-piperazine-1-carboxyIicacid tert-butyl ester (1.00 g) in chloroform (40 mL) was treated with m-chloroperbenzoic acid (77%, 0.97g) at 0° C. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then cooled to 0° C, filtered to remove precipitates, washed with saturated aqueous sodium bicarbonate, filtered through a plug of silica gel and concentrated. The residue was taken up in a 1:1 mixture of DCM and MeOH and treated with an excess of 4.0 M HCI/dioxane. The reaction mixture was stirred overnight and then purified by column chromatography (0 to 10% MeOH:DCM) to yield 50 mg of the title compound. ESMS (0.41 minutes, (M+1) 131.13, Method E). SYNTHESIS OF 3-METHYL-AZETIN-3-OL HYDROCHLORIDE Step 1. Synthesis of 1-benzhydryl-azetidin-3-oI [0108] A solution of 1-(diphenylmethyI)-3-(methanesulphonyloxy) azetidine (1.0 g) in THF (17 mL) was treated with 3.0 M methylmagnesium bromide (1.2 mL) in diethyl ether at 0" C. The reaction was stirred for 1.5 hours at 0° C and then quenched with saturated aqueous sodium bicarbonate, filtered through Celite, and concentrated. The residue was then take up in methylene chloride and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried over magnesium sulfate, filtered, concentrated and purified by column chromatography (0 to 60% EtOAc/hexanes) to provide 640 mg of the title compounds as a clear, yellow oil. ESMS: 240.19 (M+1), 1.22 minutes, Method D. Step 2. Synthesis of 1-Benzhydryl-azetidin-3-one [0109] To a solution of 1-benzhydryl-azetidin-3-ol (640 mg) in methylene chloride (6.0 mL) was added 4A molecular sieves. The reaction vessel was purged with nitrogen followed by addition of NMO (800 mg) and then TPAP (42 mg). The reaction was stirred over night and then filtered through a plug of silica to yield 335 mg of the title compound as a clear, colorless oil. 1H NMR (CDCI3, 300 MHz) 5 ppm 4.03 (s, 4H), 4.61 (s, 1H), 7.25 (m, 2H), 7.32 (m, 4H), 7.50 (m, 4H). Step 3. Synthesis of 1-Benzhydryl-3-methyl-azetidin-3-ol [0110] 1-Benzhydryl-azetidin-3-one (335 mg) in diethyl ether (6.0 mL) was treated with 3.0 M methylmagnesium bromide in diethyl ether (0.52 mL) at 0° C, stirred for 10 minutes and quenched with saturated aqueous sodium bicarbonate. The solution was then extracted with methylene chloride (*3), and the combined orgahics were dried over magnesium sulfate, and concentrated to provide 363 mg of the title compound as a clear, colorless oil. 1H NMR (CDCI3, 300 MHz) 5 ppm 1.53 (s, 3H), 1.96 (s, 1H), 1.96 (d, 2H, J = 8.42 Hz), 3.19 (d, 2H, J = 8.42 Hz), 4.34 (s, 1H), 7.17 (m, 2H), 7.26 (m, 2H), 7.31 (m, 2H), 7.40 (m, 4H). Step 4. Synthesis of 3-Methyl-azetin-3-ol hydrochloride [0111] A suspension of 1-benzhydryl-3-methyl-azetidin-3-oI (363 mg) in MeOH (10 mL) was treated with 4.0 N HCI/dioxane (1.0 ml_) followed by an excess of palladium hydroxide on carbon (wet, Degusa type). The solution was then reacted with hydrogen on a Parr hydrogenator over night at 45 psi. The reaction mixture was then filtered through Celite, concentrated, diluted to a known concentration and used without further purification. SYNTHESIS OF PIPERIDIN-4-ONE O-METHYL-OXIME HYDROCHLORIDE Step 1. Synthesis of 4-Methoxyimino-piperidine-1 -carboxylic acid tert-butyl ester [0112] A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) and methoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated with sodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasic mixture was stirred vigorously for 10 minutes, diluted with water, and extracted with ethyl acetate (x3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 2.12 g of the title compound, which was used without further purification. 1H NMR (CDCI3, 300 MHz) 5 ppm 1.49 (s, 9H), 2.34 (t, 2H, J = 6.07 Hz), 2.57 (t, 2H, J = 6.07 Hz), 3.51 (t, 2H, J = 6.07 Hz), 3.56 (t, 2H, J = 6.07 Hz), 3.85 (s, 3H). Step 2. Synthesis of Piperidin-4-one O-methyl-oxime hydrochloride [0113] 4-Methoxyimino-piperidine-l-carboxylic acid tert-butyl ester in MeOH (10 mL) was treated with 4.0 M HCI/dioxane (1.0 mL) and stirred at room temperature over night. The solution was concentrated to yield 213 mg of the title compound without further purification. 1H NMR (DMSO, 300 MHz) 5 ppm 2.47 (t, 2H, J = 6.62 Hz), 2.68 (t, 2H, J = 6.07 Hz), 3.17 (m, 4H), 3.77 (s, 3H), 9.08 (bs, 1H). SYNTHESIS OF 4-METHYL-PIPERIDIN-4-OL HYDROCHLORIDE [0114] A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (500 mg) in THF (6 mL) at 0° C was treated with 3.0 M methylmagnesium bromide/diethyl ether (0.80 mL). The solution was allowed to warm to room temperature and stirred for 48 hours. The reaction was quenched with sodium bicarbonate, diluted with saturated Rochele's Salt, and extracted with methylene chloride (x3). The combined organics we're filtered through Celite, concentrated, and purified by column chromatography (0 to 40% EtOAc/hexanes). The impure residue was then taken up in MeOH (5 mL) and treated with 4.0 M HCI/dioxane (4 mL), stirred for 30 minutes and concentrated to provide the crude title compound. SYNTHESIS OF ETHYL (3S)-3-HYDROXY-L-PROLlNATE HYDROCHLORIDE [0115] Acetyl chloride (10.8 mL, 153 mmol) was slowly added to ice cold .100% Ethanol (100 mL). (3S)-3-hydroxy-L-proline (5 g, 38.2 mmol) was added and heated at 100°C for 16 hours. The ester was concentrated to a solid and used without purification. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.2 (t, J=8.1 Hz, 3 H) 1.9 (m, 2 H) 3.3 (m, 2 H) 4.1 (m, 1 H) 4.2 (q, J=7.1 Hz, 2 H) 4.4 (m, 1 H) 9.0 (s, 1 H) 10.4 (s, 1 H). SYNTHESIS OF [(2S,3S)-3-METHYL-2-PYRROLIDINYL]METHANOL HYDROCHLORIDE Step 1. Synthesis of Ethyl (3S)-3-methyl-L-proIinate [0116] The title compound was prepared from (3S)-3-methyl-L-proline, using the methods used to prepare ethyl (3S)-3-hydroxy-L-prolinate hydrochloride. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.1 (d, J=6.8 Hz, 3 H) 1.2 (t, J=6.8 Hz, 3 H) 1.6 (m, 1 H) 2.1 (m, 1 H) 2.3 (m, 1 H) 3.2 (m, 2 H) 3.8 (m, 1 H) 4.2 (m, 2 H) 4.7 (m, 1 H) 9.0 (s, 1 H) 10.4 (s, 1 H). Step 2. Synthesis of 1 -(1,1 -Dimethylethyl) 2-ethyl (2S,3S)-3-methyl- 1,2-pyrroIidinedicarboxyIate [0117] Ethyl (3S)-3-methyl-L-prolinate (0.837 g, 4.32 mmol), bis(1,1- dimethylethyl) dicarbonate (0.942 g, 4.32 mmol), and triethylamine (1.5 mL, 10.8 mmol) were heated in an approximately 2:1 mixture of THF and ethanol at 75°C for 16 hours. The reaction was allowed to cool to room temperature, then diluted with water. The crude mixture was extracted 2 X with ethyl acetate. The organic layers were washed with 1N NaOH, dried over MgS04, and concentrated under reduce pressure to give the title compound (855 mg, 3.3 mmol) as a clear oil. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.1 (d, J=6.8 Hz, 3 H) 1.2 (m, 3 H) 1.3 (m, 9 H) 1.5 (m, 1 H) 1.9 (m, 1 H) 2.2 (m, 1 H) 3.2 (m, 1 H) 3.4 (m, 1 H) 3.6 (m, 1 H) 4.1 (m, 2H). Step 3. Synthesis of 1,1 -Dimethylethyl (2S,3S)-2-(hydroxymethyl)-3- methyl-1 -pyrrolidinecarboxylate [0118] Lithium borohydride (6.6 mmol, 3.31 mL of a 2M in THF solution) was added dropwise to an ice cold THF solution of 1-(1,1- dimethylethyl) 2-ethyl (2S,3S)-3-methyl-1,2-pyrrolidinedicarboxylate (850 mg, 3.3 mmol) and methanol (0.133 mL, 3.3 mmol). The reaction was warmed to room temperature and then stirred for 4 hours. The reaction was quenched with i-propanol then with saturated NaHC03. The reaction mixture was extracted 3 x with ethyl acetate. The organic layers were dried over MgS04 and concentrated under reduced pressure to give the title compound, which was used without further purification. 1H NMR (400 MHz, DMSO-D6) 5 ppm 0.9 (t, J=7.0 Hz, 3 H) 1.3 (m, 9 H) 1.9 (m, 1 H) 2.2 (m, 1 H) 3.1 (m, 2 H) 3.3 (m, 2 H) 3.5 (m, 1 H) 4.7 (m, 1 H). Step 4. Synthesis of [(2S,3S)-3-Methyl-2-pyrrolidinyl]methanol hydrochloride [0119] The crude 1,1-dimethylethyl (2S,3S)-2-(hydroxymethyl)-3- methyl-1-pyrrolidinecarboxylate from step 3 was dissolved in a 1:1 mixture of methylene chloride:methanoI. Excess 4N HCI in dioxane was added, and the reaction stirred at room temperature for 1 hour, concentrated under reduced pressure, and then used in the final step (see Scheme 1a (g) to (h)). 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.1 (d, J=6.2 Hz, 3 H) 1.5 (m, 1 H) 2.1 (m, 2 H) 3.1 (m, 1 H) 3.3 (m, 1 H) 3.4 (m, 1 H) 4.5 (dd, J=12.1, 8.1 Hz, 1 H) 4.7 (dd, J=12.3, 3.1 Hz, 1 H). SYNTHESIS OF ETHYL (3S)-3-HYDROXY-L-PROLINATE HYDROCHLORIDE [0120] Acetyl chloride (10.8 mL, 153 mmol) was slowly added to ice cold 100% Ethanol (100 mL). (3S)-3-hydroxy-L-proline (5 g, 38.2 mmol) was added and heated at 100°C for 16 hours. The ester was concentrated to a solid and used without purification. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.2 (t, J=8.1 Hz, 3 H) 1.9 (m, 2 H) 3.3 (m, 2 H) 4.1 (m, 1 H) 4.2 (q, J=7.1 Hz, 2 H) 4.4 (m, 1 H) 9.0 (s, 1 H) 10.4 (s, 1 H). SYNTHESIS OF (2R,3S)-2-METHYL~3-PYRROLIDlNOL HYDROCHLORIDE Step 1. Synthesis of 1-(1,1-Dimethylethyl) 2-ethyl (2S,3S)-3- hydroxy-1,2-pyrrolidinedicarboxyIate [0121] The title compound was prepared from ethyl (3S)-3-hydroxy-L- prolinate using the methods used to prepare 1-(1,1-dimethylethyl) 2-ethyl (2S,3S)-3-methyl-1,2-pyrrolidinedicarboxylate. 1H NMR (400 MHz, DMSO- D6) 5 ppm 1.2 (m, 3 H) 1.3 (m, 9 H) 1.7 (m, 1 H) 1.9 (m, 1 H) 3.3 (m, 2 H) 4.1 (m, 4 H) 5.5 (s, 1 H). Step 2. Synthesis of 1-(1,1-Dimethylethyl) 2-ethyl (2S,3S)-3-{[(1,1- dimethylethyl)(dimethyl)siIyl]oxy}-1,2- pyrrolidinedicarboxylate [0122] 1-(1,1-dimethylethyI) 2-ethyl (2S,3S)-3-hydroxy-1,2- pyrrolidinedicarboxylate (8.98 g, 34.7 mmol), imidazole (2.36 g, 34.7 mmol), dimethylaminopyridine (50 mg, catalytic) and chloro(1,1- dimethylethyl)dimethylsilane (4.96 g, 32.9 mmol) were stirred at room temperature for 16 hours. The reaction was diluted with water and 1N HCI to make the mixture acidic. The mixture was extracted three times with methylene chloride. The organic layer was washed with 1M HCI, dried over MgSC*4 to give the title compound as a clear brown oil (10.88 g, 29.1 mmol). 1H NMR (400 MHz, DMSO-D6) 5 ppm 0.0 (m, 6 H) 0.8 (m, 9 H) 1.2 (m, 3 H) 1.3 (m, 9 H) 1.7 (m, 1 H) 1.9 (m, 1 H) 3.4 (m, 2 H) 3.9 (m, 1 H) 4.1 (m, 2 H) 4.3 (m, 1 H). ES+ = 374.30. dimethylethyl) (dimethyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (6.05 g, 26.19 mmol) and triethylamine (7.28 mL, 52.38 mmol). The reaction was warmed to room temperature, stirred for 16 hours then concentrated under reduced pressure. The crude material was dissolved in ethyl acetate and washed with saturated NaHCQ3, dried over MgS04 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to give the title compound as a yellow oil. (4.69 g, 11.4 mmol). 1H NMR (400 MHz, DMSO-D6) 5 ppm 0.1 (s, 6 H) 0.8 (s, 9 H) 1.4 (m, 9 H) 1.7 (m, 1 H) 2.0 (m, 1 H) 3.2 (s, 3 H) 3.3 (m, 2 H) 3.7 (m, 1 H) 4.0 (m, 1 H) 4.2 (m, 1 H) 4.3 (m, 1 H). ES+ = 410.16. Step 5. Synthesis of 1,1-Dimethylethyl (2R,3S)-3-{[(1,1- dimethylethyl)(dimethyI)silylJoxy}-2-methyl-1- pyrrolidinecarboxylate [0125] Superhydride (45.8 mL, 1M, 45.8 mmol) was added dropwise to an ice cold solution of 1,1-dimethylethyl (2R,3S)-3-{[(1,1- dimethyIethyl)(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}-1- pyrrolidinecarboxylate (4.69 g, 11.47 mmol) in THF. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was quenched with i-propanol until gas evolution ceased. The reaction was diluted with saturated NaHC03 then extracted with ethyl acetate, dried over MgS04 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to yield the title compound (2.69g, 8.5 mmol). 1H NMR (400 MHz, DMSO-D6) 5 ppm 0.0 (s, 6 H) 0.8 (s, 9 H) 1.0 (m, 3 H) 1.4 (s, 9 H) 1.6 (m, 1 H) 2.0 (m, 1 H) 3.3 (m, 2 H) 3.5 (m, 1 H) 4.0 (m, 1 H). ES+ = 316.22. Step 6. Synthesis of 1,1-Dimethylethyl (2R,3S)-3-hydroxy-2-methyI- 1 -pyrrolidinecarbbxylate [0126] Tetrabutyl ammonium fluoride (16.7 m!_, 1N in THF, 16.73 mmoi) was added to a solution of 1,1-dimethylethy! (2R,3S)-3-{[(1,1- dimethylethyl)(dimethyl)silyl]oxy}-2-methyl-1-pyrrolidinecarboxylate in THF and stirred for 16 hours at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to yield the title compound (1.55g, 7.8 mmol). 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.0 (m, 3 H) 1.4 (s, 9 H) 1.6 (m, 1 H) 1.9 (m, 1 H) 3.3 (m, 2 H) 3.5 (m, 1 H) 3.8 (m, 1 H) 4.9 (s, 1 H). ES+ = 202.15. Step 7. Synthesis of (2R,3S)-2-Methyl-3-pyrrolidinol hydrochloride [0127] The title compound was prepared from 1,1-dimethyiethy! (2R,3S)-3-hydroxy-2-methyl-1-pyrrolidinecarboxylate using the methods used for preparation of [(2S,3S)-3-methyl-2-pyrrolidinyl]methanol hydrochloride. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.2 (d, J=7.0 Hz, 3 H) 1.7 (m, 1 H) 2.1 (m, 1 H) 3.2 (m, 2 H) 3.3 (m, 1 H) 3.9 (m, 1 H) 5.5 (m, 1 H) 9.0 (s, 1 H) 9.4 (m, 1 H). ES+= 101.82. SYNTHESIS OF (2R,3S)-2-(HYDROXYMETHYL)-3-PYRROLIDINOL HYDROCHLORIDE Step 1. Synthesis of 1,1-Dimethylethyl (2R,3S)-3-hydroxy-2- (hydroxymethyl)-l-pyrrolidinecarboxylate [0128] The title compound was prepared from 1-(1,1-dimethylethyl) 2- ethyl (2S,3S)-3-hydroxy-1,2-pyrrolidinedicarboxylate using the methods used to prepare 1,1-dimethylethyl (2S,3S)-2-(hydroxymethyl)-3-methyl-1- pyrrolidinecarboxylate. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.4 (s, 9 H) 1.6 (m, 1 H) 1.9 (m, 1 H) 3.1 (m, 1 H) 3.2 (m, 2 H) 3.4 (m, 2 H) 4.1 (m, 1 H). ES+ = 218.24,117.97 (-Boc). Step 2. Synthesis of (2R,3S)-2-(Hydroxymethyl)-3-pyrroIidinol hydrochloride [0129] The title compound was prepared from 1,1-dimethylethyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)-1 -pyrrolidinecarboxylate using the methods used to prepare [(2S,3S)-3-methyl-2-pyrrolidinyl]methanol hydrochloride. 1H NMR (400 MHz, DMSO-D6) 5 ppm 1.8 (m, 1 H) 2.0 (m, 1 H) 2.5 (m, 2 H) 3.2 (m, 2 H) 3.3 (m, 1 H) 3.5 (m, 1 H) 3.6 (m, 1 H) 4.1 (m, 1 H) 8.7 (s, 1 H) 9.5 (m, 1 H). ES+ = 117.97. SYNTHESIS OF N-3-AZETIDINYLMETHANESULFONAMIDE Step 1. Synthesis of N-[1-(diphenylmethyl)-3- azetidinyljmethanesulfonamide [0130] A solution of 1-(diphenylmethyl)-3-azetidinamine (synthesized according to the methods of Arimoto et. al., J. of Antibiotics 39 (9), 1243-56, 1986)(197 mg, 0.83 mmol) in'dichloromethane (10 mL) was treated with excess triethylamine at 0°C followed by methanesulfonyl chloride (71 uL, 0.91 mmol). The reaction was stirred for 30 minutes and then concentrated and purified on silica gel (0 - 10% methanol/dichloromethane) to provide 185 mg of the desired product as a white solid. LC/MS: M+H 317.19 at 0.31 minutes, Method D. Step 2. Synthesis of N-3-azetidinylmethanesulfonamide [0131] A solution of N-[1-(diphenylmethyl)-3-azetidinyI]- .methanesulfonamide (185 mg, 0.585 mmol) in MeOH (10 mL) was treated with 1 mL of 4.0 N HCI/dioxane and then reacted overnight with hydrogen gas at 50 psi. The reaction mixture was then filtered through a pad of Celite and used without further purification. SYNTHESIS OF (4E)-3-METHYL-4-PIPERIDINONE-0-METHYLOXIME Step 1. Synthesis of 1,1-DimethylethyI 3-methyl-4-oxo-1- piperidinecarboxylate [0132] A solution of 3-methyl-1-(phenylmethyl)-4-piperidinone (1.5 g, 7.4 mmol) in methanol (10 mL) was treated with 4.0 N HCI/dioxane (2.2 mL), followed by palladium hydroxide. The mixture was then reacted overnight with hydrogen gas at 50 psi. The reaction was then filtered through Celite, concentrated, and then taken up in THF (20 mL). The crude reaction mixture was then treated with triethylamine (2.3 mL), followed by di-tert-butyi dicarbonate (1.9 g, 8.9 mmol). The reaction was stirred for two hours, concentrated, taken up in dichloromethane and washed with saturated aqueous ammonium hydroxide, followed by brine. The organic layer was dried over magnesium sulfate and purified by column chromatography to provide 734 mg of 1,1-dimethylethyl 3-methyl-4-oxo-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCI3) 5 ppm 1.0 (d, J=6.69, 3 H) 1.5 (s, 9 H) 2.4 (m, 2 H) 2.5 (m, 1 H) 2.8 (m, 1 H) 3.2 (m, 1 H) 4.2 (m, 2 H). Step 2. Synthesis of 1,1 -Dimethylethyl (4E)-3-methyl-4- [(methyloxy)imino]-1-piperidinecarboxylate [0133] A solution of 1,1-dimethylethyl 3-methyl-4-oxo-1- piperidinecarboxylate (367 mg, 1.72 mmol) in THF (10 mL) was treated with methylhydroxylamine hydrochloride (503 mg, 6.02 mmol) followed by a solution of sodium hydrogencarbonate (506 mg, 6.02 mmol) in water (3 mL). The reaction was stirred vigorously overnight. The reaction was then filtered, .diluted with water, and extracted with dichloromethane. The crude material was purified by column chromatography (0 - 10% ethyl acetate/hexanes) to provide 197 mg of the desired product as a white solid. 1H NMR (400 MHz, CDCI3) 5 ppm 1.1 (d, J=6.8 Hz, 3 H) 1.5 (s, 9 H) 2.5 (m, 1 H) 2.6 (m, 2 H) 3.5 (m, 4 H) 3.8 (s, 3 H). Step 3. Synthesis of (4E)-3-methyl-4-piperidinone O-methyloxime [0134] 1,1 -Dimethylethyl (4E)-3-methyl-4-[(methyloxy)imino]-1 - piperidinecarboxylate (197 mg) was dissolved in methanol, treated with 4.0 N HCI/dioxane (4 mL) and stirred overnight. The reaction was then concentrated to provide the product as a white solid (170 mg). The crude material was used without further purification. SYNTHESIS OF 4,4-DIMETHYLCYCLOHEXANONE [0135] The title compound was synthesized using the following literature procedure which is hereby incorporated by reference and for all purposes as if fully set forth in its entirety. Liu, Hsing-Jang; Browne, Eric N.C. and Chew, Sew Yeu. Can. J. Chem. 66, 2345-2347 (1988). SYNTHESIS OF (4,4-DIMETHYLCYCLOHEXYL)AMINE [0136] The title compound was synthesized using the following literature procedure which is hereby incorporated by reference and for all purposes as if fully set forth in its entirety. Faller, A., MacPherson, D.T., Ner, P. H., Stanway, S. J. and Trouw, L. S. WO04/5913A1 (2003). SYNTHESIS OF N-(3-{2-[2-FLUORO-4-(METHYLOXY)PHENYL]ETHYL}-4- OXO-S^-DIHYDRO-Z-QUINAZOLINYLJ-N'-KIS^S^S^R)^^^- TRIMETHYLBICYCLO[3.1.1]HEPT-3-YL]CARBODIIMIDE (CARBODIIMIDE A) [0137] A/-(3-{2-[2-fluoro-4-(methyloxy)phenyl]ethyI}-4-oxo-3,4-dihydro- 7-quinazolinyl)-A/'-[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- y!]thiourea was gently stirred with Argonaut PS-Carbodiimide (1.5 eq) for 15 hours in THF. The resin was filtered off and the solution of carbodiimide A was diluted to a known volume to give a solution of known molarity. SYNTHESIS OF N-{3-[2-(2,4-DICHLOROPHENYL)ETHYL]-4.-OXO-3,4- DJHYDRO-7-QUINAZOLINYL}-N'-[(1S,2S,3S,5R)-2,6,6- TRIMETHYLBICYCLO[3.1.1JHEPT-3-YL]CARBODIIMIDE (CARBODIIMIDE B) [0138] A/-{3-[2-(2,4-dichlorophenyI)ethyl]-4-oxo-3,4-dihydro-7- quinazolinyl^Ar-tCIS^S.SS.SR^.e.e-trimethyibicyclotS.I.IJhept-S-yOthiourea was gently stirred with Argonaut PS-Carbodiimide (1.5 eq) for 15 hours in THF. The resin was filtered off and the solution of carbodiimide B was diluted to a known volume to give a solution of known molarity. SYNTHESIS OF 2-CHLORO-3-[2-(2,4-DICHLOROPHENYL)ETHYL]-7- NITRO-4(3H)-QUINA20LINONE Step 1. Synthesis of 2-Amino-N-[2-(2,4-dichlorophenyl)ethyl]-4- nitrobenzamide [0139] To a stirred solution of 4-nitro-isatoic anhydride (10.0 g, 0.048 mol) in CH2CI2 (100 mL) was added 2,4-dichlorophenethylamine (10.08 g, 0.053 mol) followed by DMF (10 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was then dissolved in 1.0 L CH2CI2 and washed with 1.0 M NaOH. The combined organic layers were concentrated under reduced pressure and purified by silica gel flash chromatography (0-100% EtOAc/hexanes eluent) to give the product (16.5 g, 97% yield) as a yellow solid. HPLC retention time: 3.04 min; Method A; LRMS (ESI) m/z 354 (M+1). SYNTHESIS OF 2-CHLORO-3-[2-(2,4-DICHLOROPHENYL)ETHYL]-7- NITRO-4(3H)-QUINAZOLINONE Step 1. Synthesis of 2-Amino-N-[2-(2,4-dichlorophenyl)ethyl]-4- nitrobenzamide [0139] To a stirred solution of 4-nitro-isatoic anhydride (10.0 g, 0.048 mol) in CH2CI2 (100 mL) was added 2,4-dichlorophenethylamine (10.08 g, 0.053 mol) followed by DMF (10 mL). The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was then dissolved in 1.0 L CH2CI2 and washed with 1.0 M NaOH. The combined organic layers were concentrated under reduced pressure and purified by silica gel flash chromatography (0-100% EtOAc/hexanes eluent) to give the product (16.5 g, 97% yield) as a yellow solid. HPLC retention time: 3.04 min; Method A; LRMS(ESI)m/z354(M+1). Step 2. Synthesis of 3-[2-(2,4-DichlorophenyI)ethyl]-7-nitro- 2,4(1 H,3H)-quinazolinedione [0140] To a stirred solution of 2-amino-N-[2-(2,4-dichlorophenyl)ethyl]- 4-nitrobenzamide (1.0 g, 2.82 mmol) in toluene (30 mL) was added a 1.9 M solution of phosgene in toluene (4.5 mL, 8.5 mmol). The reaction mixture was heated to 60°C and stirred for 4 hours. The solvent was removed under reduced pressure and CH2CI2 was added to the residue. The precipitate was collected via vacuum filtration and washed with CH2CI2 to give the product (0.92 g, 86% yield) as a white solid. HPLC retention time: 3.28 min; Method A; LRMS (ESI) m/z 378 (M-1). Step 3. Synthesis of 2-Chloro-3-[2-(2,4-dichlorophenyJ)ethyI]-7- nitro-4(3H)-quinazofinone [0141] 3-[2-(2,4-Dichlorophenyl)ethyl]-7-nitro-2,4(1H,3H)- quinazolinedione (2.0 g, 5.26 mmol) and PCI5 (1.2 g, 5.79 mmol) were added to a flask containing POCI3 (20 mL) and the resulting solution was refluxed with stirring for 6 hours. The reaction was allowed to cool to RT and stirred overnight at this temp. The POCI3 was removed under reduced pressure and CH2CI2 was added to the residue. The unreacted starting material was removed via vacuum filtration and the product was purified by silica gel flash chromatography (100% CH2CI2 eluent) to give the product (0.96 g, 46% yield) as a white solid. 1H NMR (DMSO- D6) 400 MHz 5 ppm 8.35-8.25 (m, 3H), 7.58 (d, J=2.2 Hz, 1H), 7.41-7.34 (m, 2H), 4.41 (t, J=7.5 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H) ppm. SYNTHESIS OF 3-AMINO-N-{3-[2-(4-FLUOROPHENYL)ETHYL]-4-OXO- S^-DIHYDRO-Z-QUINAZOLINYLy-N'-KIS^S^S^R)-^^- TRIMETHYLBICYCLO[3.1.1]HEPT-3-YLJ-1- AZETIDINECARBOXIMIDAMIDE Step 1. Synthesis of 1 -Dimethylethyl [1 -(diphenylmethyl)-3- azetldinyl]carbamate [0142] To a solution of 1-(diphenylmethyl)-3-azetidinamine (232 mg, 0.97 mmol) in THF (6 mL) at 0°C was added a solution di-tert-butyl dicarbonate (255 mg, 1.17 mmol) in THF (4 mL). The reaction was warmed to room temperature and dichloromethane (4 mL) was added to bring the slurry into solution. The reaction was stirred overnight, concentrated and then purified by column chromatography (0 - 30% ethyl acetate/hexanes) to afford 211 mg of the desired product, as a white solid. LC/MS: M+H 339.19 at 1.20 minutes, Method D. Step 2. Synthesis of 1,1-DimethylethyI 3-azetidinylcarbamate [0143] A solution of 1,1-dimethylethyl [1-(diphenylmethyl)-3- azetidinyl]carbamate in MeOH (10 mL) was treated with of 4.0 N HCI/dioxane (1 mL) and then reacted overnight with hydrogen gas at 50 psi. The reaction mixture was then filtered through a pad of Celite, concentrated and the crude residue was used without further purification. Step 3. Synthesis of 3-Amino-N-{3-[2-(4-fluorophenyl)ethyI]-4-oxo- 3,4-dihydro-7-quinazoHnyl}-N4(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximidamide [0144] 1,1-dimethylethyl [1-((Z)-({3-[2-(4-fluorophenyl)ethyl]-4-oxo-3,4- dihydro-7-quinazolinyl}amino){[(1S,2S,3S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl]imino}methyl)-3-azetidinyl]carbamate (synthesized using 1,1-dimethylethyl 3-azetidinylcarbamate by the methods described previously) was treated with 4.0 N HCI/dioxane (4 mL) and stirred overnight. The reaction was then purified by preparatory HPLC to provide 3- amino-N-{3-[2-(4-fluorophenyi)ethyl]-4-oxo-3,4-dihydro-7-quinazolinyl}-N'- [(1S,2S,3S,5R)-2,6,6-trimethyIbicyclo[3.1.1]hept-3-yl]-1- azetidinecarboximidamide as a white solid. LC/MS: M+H 517.20 at 2.19 minutes, Method D. GENERAL METHOD FOR THE PREPARATION OF NITROGEN-BOUND C-2 ANALOGS Step 1. Synthesis of 2-Amino Analogs [0145] To a stirred solution 2-chIoro-3-[2-(2,4-dichlorophenyl)ethyI]-7- nitro-4(3H)-quinazolinone (1 equivalents) in acetonitrile (1.0 M) was added the corresponding amine (2 equivalents) and the reaction mixture was heated to reflux until the reaction was completed as monitored by HPLC (ca. 30 min). The reaction mixture was then cooled to RT and the solvent was removed in vacuo. The crude product was purified via silica gel flash chromatography (0- 5% MeOH/CH2CI2 eluent). Step 2. Reduction of Nitro to Aniline [0146] To a stirred solution of the nitro compound (1 equiv) in absolute ethanol (1.0 M) was added iron powder (2.5 equivalents) and acetic acid (14 equivalents). The reaction mixture was heated to reflux until the reaction was complete as monitored by HPLC. The reaction mixture was then cooled to RT, diluted with EtOAc, and washed with sat. NaHC03. The aqueous layer was re-extracted with EtOAc (x2) and the combined organic layers were dried over Na2S04l filtered, and concentrated in vacuo. The crude solid was used in the next step without purification. Step 3. Conversion of Aniline to Thiourea [0147] To a stirred solution of crude aniline (1 equiv) in acetone (1.0 M) at 0° C was added Na2C03 (2 equivalents) followed by thiophosgene (3 equivalents) dropwise via syringe. The reaction mixture was stirred at 0° C for 10 minutes then allowed to warm to room temperature. A solid precipitated from solution as the reaction progressed. When the starting material was completely consumed as monitored by HPLC, the reaction mixture was concentrated in vacuo, diluted with acetone, and then concentrated again to remove excess thiophosgene. The material was then diluted with EtOAc and washed with water. All of the solid was dissolved. The aqueous layer was re- extracted with EtOAc (x2) and the combined organic layers were dried over Na2S04) filtered, and concentrated in vacuo. The crude material was then dissolved in THF (1.0 M) and (1S,2S,3S,5R)-(+)-isopinocampheylamine (1.3 equiv) was added via syringe. The reaction mixture was stirred at RT for 30 min then concentrated in vacuo. The crude material was purified via silica gel flash chromatography (0-5% MeOH/CH2CI2 eluent). Step 4. Conversion of Thiourea to Guanidine [0148] To a stirred solution of thiourea (1 equivalents) in THF (1.0 M) was added EDC (1.5 equivalents) and the reaction mixture was heated to reflux. When the starting material was completely consumed as monitored by HPLC, the reaction mixture was cooled to RT and then the corresponding amine (2 equivalents) and Et3N (2 equivalents) were added. The reaction mixture was stirred at room temperature for 1 hour then concentrated in vacuo. The crude material was purified via preparative reversed-phase HPLC (MeCN/water eluent) and lyophilized to produce the TFA salt. GENERAL PROCEDURE FOR THE SYNTHESIS OF ARYL GUANIDINES. [0149] Unless otherwise noted, a THF solution of a carbodiimide such as Carbodiimide A or Carbodiimide B was stirred with approximately 1.5 equivalents of primary or secondary amine at room temperature for 10 minutes. (In cases where the amine was in a salt form, the amine was dissolved in minimal methanol and 2 equivalents of triethylamine was added.) The reaction were concentrated under a stream of nitrogen, dissolved in methanol and purified by preparative HPLC. SYNTHESIS OF N-(3-{2-[2-FLUORO-4-(METHYLOXY)PHENYL]ETHYL}-4- OXO-S^-DIHYDRO-T-QUINAZOLINYLJ-N'^H-I^^-TRIAZOL^-YL-N"- [(IR^S.SS.SSJ^.e.e-TRIWlETHYLBICYCLOtS.I.IJHEPT-S-YgGUANIDINE TRIFLUOROACETATE [0150] N-(3-{2-[2-fluoro-4-(methyioxy)phenyl]ethyl}-4-oxo-3,4-dihydro- 7-quinazolinyl)-N'-[(1 S,2S,3S,5f?)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yljcarbodiimide (4 mL, 23 mM solution in THF), 4H-1,2,4-triazol-4~amine (49 mg) and excess NaH were stirred together and heated at 50° C for 30 minutes. The reaction was quenched with 1 mL H2O and 5 mL of ethyl acetate. The mixture was passed through a Varian Chem Elut cartridge followed by 50 mL of ethyl acetate. The ethyl acetate solution was dried over MgS04 and concentrated. This crude material was dissolved in 1 mL of methanol, purified by preparative HPLC and freeze-dried to give the TFA salt of the title compound. SYNTHESIS OF c/s-4-FLUOROCYCLOHEXYLAMINE Step 1. Synthesis of frans-(f-butoxy)-N-(4-hydroxycyclohexyI)- carboxamide [0151] A suspension of frans-4-aminocyclohexanoI (1 equivalent) in THF (0.1 M) was treated with (Boc)20 (1 equivalent). The mixture was stirred at room temperature overnight, dissolved in chloroform, and washed with water to yield a solid that was used without further purification. Step 2. Synthesis of c/s-(f-butoxy)-N-(4- fluorocyclohexyl)carboxamide [0152] To a solution of (f-butoxy)-N-(4-hydroxycyclohexyl)carboxamide (1 equivalent) in CH2CI2 (1 M) cooled to -78°C was added dropwise a solution of DAST (1 equivalent) in CH2CI2 (0.5 M). The mixture was stirred at -78°C for 4 hours, and then allowed to rise to room temperature. The solution was poured into saturated NaHCCb and extracted with chloroform, dried, and evaporated. The resulting crude product was purified on silica gel, eluting with ethyl acetate/hexane 5:95. Step 3. Synthesis of c/s-4-fluorocycIohexylamine [0153] A solution of c/s-(f-butoxy)-N-(4-fluorocyclohexyl)carboxamide (6.51 mmol) in CH2CI2 (20 ml_) was treated with TFA (10 ml_) at room temperature. The reaction mixture was stirred for 2 hours, the solvent was removed in vacuo, and the crude product was dissolved in water and washed ^ with chloroform. The acidic aqueous phase was cooled at 0°C and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2Ci2, dried and filtered, yielding the title compound which was used without further purification and as a 0.3 M solution in CH2CI2. SYNTHESIS OF 4,4-DIFLUOROCYCLOHEXYLAMINE Step 1. Synthesis of N-(4,4-difluorocyclohexyl)(f- butoxy)carboxamide [0154] A solution of (£-butoxy)-N-(4-oxocyclohexyl)carboxamide (2.5 g,11.7 mmol) in CH2CI2 (45 mL) was treated with a solution of DAST (2.63 mL, 19.93 mmol) in CH2CI2 (6 mL) at room temperature. EtOH (141 uJ, 2.3 mmol) was added, and the mixture was stirred at room temperature overnight. The solution was poured into saturated NaHCC>3 and extracted with chloroform, dried, and evaporated to yield a 1:1 mixture of the title compound and (f-butoxy)-N-(4-fluoroclyclohex-3-enyl)carboxamide. This mixture was dissolved in CH2CI2 (40 mL) and MeOH (14 mL) and cooled to -78°C. Ozone was bubbled into the solution for 50 minutes until it turned green and Me2S was added (3 equivalents). The reaction mixture was allowed to warm to room temperature, chloroform was added and the organic phase was washed with water, dried, and evaporated to yield the title compound which was used without further purification. Step 2. Synthesis of 4,4-difluorocyclohexylamine [0155] A solution of N-(4,4-difluorocycIohexyl)(£-butoxy)carboxamide (6.51 mmol) in CH2CI2 (20 mL) was treated with TFA (10 mL) at room temperature. The reaction mixture was stirred for 2 hours, the solvent was removed in vacuo, and the crude product was dissolved in water and washed with chloroform. The acidic aqueous phase was cooled at 0°C and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2CI2, dried, and filtered yielding the title compound which was used without further purification as a 0.3 M solution in CH2CI2. Procedure 1 Synthesis of 6-fluoro analog of 7-azido-quinazoline-4- one (1) Step 1: Synthesis of (2-amfno-4,5-difIuorophenyl)-N-[2-(4- fluorophenyI)ethyl]-carboxamide [0156] To a stirred solution of 4,5-difluoro anthranilic acid (2.0 g, 11.6 mmol) in anhydrous THF (30 mL) was added hydroxybenzotriazole hydrate (HOBt) (1.56 g, 11.6 mmol), diisopropylethyl amine (2.01 mL, 11.6. mmol), and 4-fluorophenylethyl amine (1.52 mL, 11.6 mmol). After all of the HOBt had completely dissolved, EDCI (2.21 g, 11.6 mmol) was added and the resulting orange solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue was chromatographed on silica eluting with 15% EtOAc in hexanes giving the desired benzamide (2) as white crystals (3.07 g, 10.4 mmol, 90%). Step 2: Synthesis of 6,7-difluoro-3-[2-(4-fluorophenyl)ethyI]-3- hydroquinazolin-4-one [0157] The starting benzamide (2) was dissolved in trimethyl orthoformate (20 mL) and heated at 120°C under a stream of nitrogen for 3 hours. The solution was cooled, and the solvent was removed by rotary evaporation. The residue was triturated with hexanes, and the solids collected by filtration, washed with hexanes, and dried on the pump. The formamide intermediate was isolated as a white solid and confirmed by NMR. This intermediate was suspended in POCI3 (10 mL) and heated to 140°C for 3 minutes. The reaction was cooled, poured over crushed ice, made slightly alkaline with saturated sodium bicarbonate solution, and extracted with EtOAc. The organic layer was collected and dried over magnesium sulfate. Product (3) was isolated as a white solid (1.94 g, 6.38 mmol, 75% for 2 steps). Step 3: Synthesis of 7-(azadiazomvinyI)-6-fluoro-3-[2-(4- fluorophenyl)ethyl]-3-hydroquinazo!in-4-one [0158] Difluoroquinazoline (3) (1.46 g, 4.6 mmol) was dissolved in DMSO (10 mL), and sodium azide (3 g, 46.0 mmol) was added. The resulting mixture was heated to 70°C with stirring for 4 hours. The reaction was monitored by NMR. The reaction was cooled and diluted with water, and the resuitingprecipitate collected by filtration and washed with water. The solid was dissolved in methylene chloride and dried (MgSC>4) in order to remove trace water. Product (1) was isolated as an off-white solid (1.43 g, 4.37 mmol, 95%). [0159] Following the formation of compound 1, final guanidine quinazolinones were formed following the synthetic method described below (Procedure 1A): Procedure 1A [0160] To a solution of (1) (1 equivalent) in THF was added trimethylphosphine (1.5 equivalents), and the mixture was stirred at room temperature for 10 minutes. To the iminophosphorane solution was added (1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylisocyanate(1.6 equivalents). The solution was heated at 70°C overnight. To half of the carboimide solution was added a THF solution of (6S,2R)-2,6- dimethylpiperazine (2 equivalents). After being heated at 70°C for 2 hours, the residue was subjected to HPLC purification to give the guanidine product as its TFA salt. [0161] The 2-fluoro-4-methoxy, 2,4-difluoro and 2,4-dichloro analogs were synthesized via the same pathway described above. Compounds of the group synthesized via the pathway described above include Examples 42, 44, and 45'. EXAMPLE 1. Synthesis of (3R,5S)-N-{3-{2-[2-fIuoro-4-(methyloxy)- phenyl]ethyI}-4-oxo-3,4-dihydroquinazoIin-7-yl)-3,5- dimethyl-N'-[(1 S,2S,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yI]piperazine-1 - carboximidamide Stepl. Synthesis of (c): 2-amino-N-[2-(2-fIuoro-4-methoxy-phenyl)- ethyI]-4-nitro-benzamide [0162] 2-Fluoro-4-methoxyphenylethylamine ((a):1 equivalent), 4- nitroanthranilic acid ((b): 1 equivalent), HBTU (1.5 equivalents), and dry THF (0.5 M in (a)) were added to a dry round bottom flask. The mixture was allowed to stir for 10 hours at room temperature. The reaction was then dry loaded onto silica gel and purified via flash chromatography using hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo to yield the product ((c): 2-amino-N-[2-(2-fluoro-4-methoxy-phenyl)- ethyl]-4-nitro-benzamide) as a pure solid. Step 2. Synthesis of (d): 3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-7- nitro-3H-quinazolin-4-one [0163] The pure product ((c): 1 equivalent) of Step 1, Gold's reagent, and dioxane (0.5 M in (c)) were added to a dry round bottom flask, fitted with a condenser, and heated to.refluxfor 16 hours. Once complete product conversion was verified by LC/MS, acetic acid (1 equivalent) and sodium acetate (1 equivalent) were added to the reaction. The subsequent mixture was heated to reflux for 3 hours. Then, the reaction was concentrated in vacuo, taken up in ethyl acetate, and washed with water. After the organic layer was isolated, the aqueous layer was extracted with two more portions of ethyl acetate. The organic layers were then combined, dried over sodium sulfate, filtered through a cotton plug, and concentrated. The crude product mixture was purified via flash chromatography using a mixture of CH2CI2/MeOH. The pure fractions were combined and concentrated in vacuo to yield the pure product ((d): 3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-7-nitro-' 3H-quinazolin-4-one) as a pure solid. Step 3. Synthesis of (e): 7-amino-3-[2-(2-fluoro-4-methoxy-phenyl)- ethyl]-3H-quinazo!in-4-one [0164] To a solution of (d), prepared as described in Step 2, in MeOH (0.25 M in (d)) was added 10% Pd/C (0.1 equivalent). The mixture was sealed with a septum and degassed with nitrogen for 10 minutes. Hydrogen was then bubbled through the solution for 20 minutes. Once reaction completion was verified by LC/MS, the reaction was degassed with nitrogen for 10 minutes. The mixture was filtered through Celite® and concentrated in vacuo to yield the product ((e): 7-amino-3-[2~(2-fluoro-4-methoxy-phenyI)- ethyl]-3H-quinazolin-4-one). The product was used in the next reaction without further purification. Step 4. Synthesis of (f): 3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]-7- isothiocyanato-3H-qiiinazolin-4-one [0165] To a mixture of (e), prepared as described in Step 3, (1 equivalent) and NaHC03 (3 equivalents) in acetone (0.1 M in (e)) was added thiophosgene (3 equivalents) dropwise. The resulting slurry was stirred at room temperature for three hours. Once reaction completion was verified by LC/MS, the reaction was concentrated in vacuo to remove solvent and excess thiophosgene. The mixture was then taken up in ethyl acetate and washed with water. After the organic layer was isolated, the aqueous layer was extracted with two more portions of ethyl acetate. The organic layers were then combined, dried over sodium sulfate, filtered through a cotton plug, and concentrated in vacuo to yield the product ((f): 3-[2-(2-fluoro-4-methoxy- phenyl)-ethyl]-7-isothiocyanato-3H-quinazolin-4-one). The crude product was used in the next reaction without further purification. Step 5. Synthesis of (g): 1-{3-[2-(2-fluoro-4-methoxy-phenyl)-ethyl]- 4-oxo-3,4-dihydro-quinazoIin-7-yl}-3-(2,6,6-trimethyI- bicyclo[3.1.1]hept-3-yl)-thiourea [0166] To a solution of (f), prepared as described in Step 4, (1 equivalent) in THF (0.5 M in (f)) was added (1S,2S,3S,5R)-(+)- isopinocampheylamine (1.5 equivalents). The reaction was stirred at room temperature for 10 hours. The crude product mixture was then concentrated in vacuo, dissolved in methylene chloride, and purified via flash chromatography using hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo to yield the pure product ((g): 1-{3-[2-(2- fluoro-4-methoxy-phenyl)-ethyl]-4-oxo-3,4-dihydro-quinazolin-7-yl}-3-(2,6,6- trimethyl-bicyclo[3.1.1 ]hept-3-yl)-th iourea). Step 6. Synthesis of (h): (3R,5S)-N-(3-{2-[2-fluoro-4- (methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquInazolin-7-yI)- S.S-dimethyl-N'-KIS^S^R^.e.e- trimethylbicyc!o[3.1.1]hept-3-yl]piperazine-1- carboximidamide [0167] To a solution of (g), prepared as described in Step 5, (1 equivalent) in dry THF (0.1 M in (g)) in a dry round bottom flask was added 1- [3-(dimethyIamino)-propyl]-3-ethylcarbodiimide hydrochloride (2 equivalents). The reaction was fitted with a condenser and heated to 80°C for 1 hour. The resulting solution was allowed to cool to room temperature for 20 minutes. A solution of c/s-2,6-dimethylpiperazine (2 equivalents; 0.5 M in CH2CI2) was then added to the reaction, and the resulting mixture was stirred at room temperature for 10 minutes. The mixture was then diluted with ethyl acetate and washed with water. After the organic layer was isolated, the aqueous layer was extracted with two more portions of ethyl acetate. The organic layers were then combined and concentrated in vacuo. The crude mixture was dissolved in DMSO and purified via preparative HPLC using water (0.1% TFA)/acetonitrile (0.1% TFA). The pure fractions were combined and concentrated in vacuo to remove the majority of acetonitrile. Sodium carbonate (15 equivalents) was then added to the resulting aqueous solution and the slurry was allowed to sit at room temperature for 1 hour with occasional swirling. The basic aqueous solution was then extracted with 3 separate portions of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered through a cotton plug, and concentrated in vacuo to yield product (h) as a free base. The resulting solid was then dissolved in an aqueous HCI solution (1 M; 15 equivalents) and concentrated in vacuo. The resulting mixture was dissolved in a 1:1 water/acetonitrile mixture and lyophilized to yield the pure Bis-HCI salt product ((h): (3R,5S)-N-(3-{2-[2- fluoro-4-(methyloxy)phenyl]ethyl}-4-oxo-3,4-dihydroquinazolin-7-yl)-3,5- dimethyl-N'-[(1S,2Sl5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]piperazine-1- carboximidamide. [0168] Compounds where one of R3, R4, and/or R5 is fluorine are prepared using the methodology described above using an appropriately fluorine-substituted 4-nitroanthranilic acid in place of 4-nitroanthranilic acid (b) in Step 1. Steps 2-6 may then be carried out to give the final product. One skilled in the art will recognize that a fluorine-substituted 4-nitroanthranilic acid may be used which includes further substituents to produce variously substituted compounds where R3, R4, and/or R5 are any of the groups herein described such as, but not limited to, fluoro, chloro, alkyl, and alkaryl. EXAMPLE 2. Synthesis of 7-{[1-((5S,3R)-3,5-dimethyIpiperazinyl)-2- ((2S,3S,1 R,5R)-2,6,6-trimethylbicycio[3.1.1]hept-3- yl)(1Z)-2-azavinyl]amino}-3-E2-(2,4- dich!orophenyI)ethyl]-1,3-dihydroquinazoline-2,4- dione Step 1. Synthesis of (c): 2-amino-N-[2-(2,4-dichIorophenyl)-ethyl]-4- nitro-benzamide i [0169] 2,4-Dichlorophenyiethylamine ((a):1 equivalent), 4- nitroanthranilic acid ((b): 1 equivalent), HBTU (1.5 equivalents), and dry THF (0,5 M in (a)) were added to a dry round bottom flask. The mixture was allowed to stir for 10 hours at room temperature. The reaction was then dry loaded onto silica gel and purified via flash chromatography using hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo to yield the product ((c): 2-amino-N-[2-(2,4-dichloro-phenyl)ethyl]-4- nitrobenzamide) as a pure solid. Step 2. Synthesis of (d): 3-[2-(2,4-dichlorophenyI)ethyl]-7-nitro-1,3- dihydroquinazoline-2,4-dione [0170] To a 0.3M solution of (c), prepared as described in Step 1 ,(2.5 g, 7.5 mmol (c)) in dioxane was added 40 mL of a 20% phosgene solution in toluene, followed by 15 mL triethylamine. After stirring for 1 hour at room temperature, solvent was removed by rotary evaporation followed by high vacuum. The residue was dissolved in ethyl acetate and washed three times with water. After drying with sodium sulfate and rotary evaporation, an orange-brown solid ((d): 3-[2-(2,4-dichlorophenyl)ethyl]-7-nitro-1,3- dihydroquinazoline-2,4-dione) was obtained in over 90% yield. Step 3. Synthesis of (e): 7-am[no-3-[2-(2,4-dichIorophenyl)ethyl]-1,3- dihydroquinazoline-2,4-dione [0171] To a solution of (d), prepared as described in Step 2, in MeOH (0.25 M in (d)) was added 10% Pd/C (0.1 equivalents). The mixture was sealed with a septum and degassed with nitrogen for 10 minutes. Hydrogen was then bubbled through the solution for 20 minutes. Once reaction completion was verified by LC/MS, the reaction was degassed with nitrogen for 10 minutes. The mixture was filtered through Celite® and concentrated in vacuo to yield the product ((e)) 7-amino-3-[2-(2,4-dichlorophenyl)ethyl]-1,3- dihydroquinazoline-2,4-dione). The product was used in the next reaction without further purification. Step 4. Synthesis of (f): 3-[2-(2,4-dichlorophenyl)ethyl]-2,4-dioxo- 1,3-dihydroquinazolin-7-isothiocyanate [0172] To a mixture of (e), prepared as described in Step 3, (1 equivalent) and NaHC03 (3 equivalents) in acetone (0.1 M in (e)) was added thiophosgene (3 equivalents) dropwise. The resulting slurry was stirred at room temperature for three hours. Once reaction completion was verified by LC/MS, the reaction was concentrated in vacuo to remove solvent and excess thiophosgene. The mixture was then taken up in ethyl acetate and washed with water. After the organic layer was isolated, the aqueous layer was extracted with two more portions of ethyl acetate. The organic layers were then combined, dried over sodium sulfate, filtered through a cotton plug, and concentrated in vacuo to yield the product ((f): 3-[2-(2,4-dichlorophenyl)ethyl]- 2,4-dioxo-1,3-dihydroquinazolin-7-isothiocyanate). The crude product was used in the next reaction without further purification. Step 5. Synthesis of (g): 7-({[((2S,3S,1 R,5R)-2,6,6- trimethyIbicyclo[3.1.1]hept-3-y[)amino]thioxomethyl}amino)- 3-[2-(2,4-dichlorophenyI)ethyl]-1,3-dihydroquinazoline-2,4- dione [0173] To a solution of (f), prepared as described in Step 4, (1 equivalent) in THF (0.5 M in (f)) was added (1S,2S,3S,5R)-(+)- isopinocampheylamine (1.5 equivalents). The reaction was stirred at room temperature for 1G hours. The crude product mixture was then concentrated in vacuo, dissolved in methylene chloride, and purified via flash chromatography using hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo to yield the pure product ((g 7- ({[((2S.3S.1 R,5R)-2,6,6-frimethylbicyclo[3.1.1]hept-3- yl)amino]thioxomethyl}amino)-3-[2-(2,4-dichlorophenyI)ethyl]-1,3- dihydroquinazoline-2,4-dione). Step 6. Synthesis of (h): 7-{[1-((5S,3R)-3,5-dfmethylpiperazinyl)-2- ((2S,3S,1 R,5R)-2,6,6-trimethylbicyclo[3.1.1 Jhept-3-yI)(1Z)-2- azavinyl]amino}-3-[2-(2,4-dichlorophenyI)ethyl]-1,3- dihydroquinazoline-2,4-dione [0174] To a solution of (g), prepared as described in Step 5, (1 equivalent) in dry THF (0.1 M in (g)) in a dry round bottom flask was added 1- [3-(dimethylamino)-propyI]-3-ethylcarbodiimide hydrochloride (2 equivalents). The reaction flask was fitted with a water-cooled condenser and heated to 80°C for 1 hour under a nitrogen atmosphere. The resulting solution was cooled to 0°C for 20 minutes. A solution of c/s~2,6-dimethylpiperazine (2 equivalents; 0.5 M in CH2CI2) was then added to the reaction, and the resulting mixture was stirred at 0°C for 10 minutes. The mixture was then diluted with ethyl acetate and washed with water. After the organic layer was isolated, the aqueous layer was extracted with two more portions of ethyl acetate. The organic layers were then combined and concentrated in vacuo. The crude mixture was dissolved in DMSO/acetonitrile and purified via preparative HPLC using water (0.1% TFA) /acetonitrile (0.1% TFA). The pure fractions were combined and concentrated in vacuo to remove the majority of acetonitrile. Sodium hydroxide (10 equivalents) was then added to the resulting aqueous solution and the slurry was allowed to sit at room temperature for 1 hour with occasional swirling. The basic aqueous solution was then extracted with 3 separate portions of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered through a cotton plug, and concentrated in vacuo to yield product (h) as a free base. The resulting solid was then dissolved in an aqueous HCI solution (1 M; 15 equivalents) and concentrated in vacuo. The resulting mixture was dissolved in a 1:1 water/acetonitrile mixture and lyophilized to yield the pure Bis-HCI salt product ((h): 7-{[1 -((5S,3R)-3,5-dimethylpiperazinyl)-2-((2S,3S, 1 R,5R)-2,6,6- trimethylbicyclo[3.1.1]hept-3-yl)(1Z)-2-azavinyl]amino}-3-[2-(2I4- dichlorophenyl)ethyl]-1,3-dihydroquinazoline-2,4-dione). EXAMPLE 3. Synthesis of 7-{[1-((3S)-3-methylpiperazinyO(1Z)-2- aza-2-(4,4-difIuorocyclohexyI)vinyl]amino}-3-[2-(2- fIuoro-4-methoxyphenyI)ethyI]-3-hydroquinazolin-4- one Step 1. Synthesis of (b): 7-({[(4,4-difIuorocyclohexyl)amino]- thioxomethyl}amino)-3-[2-(2-fluoro-4-methoxyphenyl)ethyI]- 3-hydroquinazolin-4-one [0175] To a solution of (a), prepared as (f) described in Step 4 of Example 1, (1 equivalent) in THF (0.5 M in (a)} was added 4,4- difluorocyclohexylamine prepared as described above (1.5 equivalents). The reaction was stirred at room temperature for 10 hours. The crude product mixture was then concentrated in vacuo, dissolved in methylene chloride, and purified via flash chromatography using hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo to yield the puM product ((b): 7-({[(4,4-difluorocycIohexyl)amino]-thioxomethyl}amino)-3-[2-(2-fluoro-4- methoxyphenyl)ethylj-3-hydroquinazolin-4-one). | Step 1. Synthesis of (b): 7-({[(4,4-difluorocyclohexyl)amino]- thioxomethyl}amino)-3-[2-(2-fluoro-4-methoxyphenyf)ethy!]- 3-hydroquinazolrn-4-one [0175] To a solution of (a), prepared as (f) described in Step 4 of Example 1, (1 equivalent) in THF (0.5 M in (a)) was added 4,4- difiuorocyclohexylamine prepared as described above (1.5 equivalents). The reaction was stirred at room temperature for 10 hours. The crude product mixture was then concentrated in vacuo, dissolved in methylene chloride, and purified via flash chromatography using hexanes/ethyl acetate. The pure fractions were combined and concentrated in vacuo to yield the pure product ((b): 7-({[(4,4-difluorocyclohexyl)amino]-thioxomethyl}amino)-3-[2-(2-fluoro-4- methoxyphenyl)ethyl]-3-hydroquinazolin-4-one). separate portions of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered through a cotton plug, and concentrated in vacuo to yield product (c) as a free base. The resulting solid was then dissolved in an aqueous HCI solution (1 M; 15 equivalents) and concentrated in vacuo. The resulting mixture was dissolved in a 1:1 water/acetonitrile mixture and iyophilized to yield the pure Bis-HCI salt product ((c): 7-{[1-((3S)-3- methylpipera2inyl)(1Z)-2-aza-2-(4,4-difluorocyclohexyl)vinyl]amino}-3-[2-(2- fluoro-4-methoxyphenyl)-ethyl]-3-hydroquinazolin-4-one). Method 1 Synthesis of 3-[2-(4-fluorophenyl)ethyl]-7-nitro-2-(4-pyrrdyl)- 3-hydroquinazplin-4-one [0177] Pyridine 4-carboxylic acid was stirred in POCfe at room temperature for about 5 minutes. To the stirred solution was then added 0.9 equivalents of (2-amino-4-nitrophenyl)-N-[2-(4- fluorophenyl)ethyl]carboxamide. The resulting mixture was then stirred for about 15 minutes at room temperature in a mjerowave tube, which was then heated to 165°C in a microwave for 10 minutes. LC/MS indicated completion of the reaction. The POCb was evaporated, and the residue was dissolved in CH2CI2 and washed with saturated sodium bicarbonate solution. The combined organic layers were dried over MgS04 and concentrated in vacuo and chromatographed on silica gel, eluting with a gradient of EtOAc in Hexanes. The resulting product, 3-[2-(4-fluorophenyl)ethyl]-7-nitro-2-(4- pyridy!)-3-hydroquinazolin-4-one, was then converted to Example 77 using the procedures described in Scheme 1a. Method 2 Synthesis of 2-[2-(2-fluoro-4-methoxyphenyI)ethyl]-3- methyl-7-nitro-3-hydroquinazolin-4-one [0178] 3-(2-Fluoro-4-methoxy-phenyl)-N-methyl-propionamide was synthesized using an EDCI mediated coupling of 3-(2-fluoro-4-methoxy- phenyl)-N-methyl-propionic acid and methylamine (2M solution in THF). The amide was then taken up in POCb in a microwave vessel and the mixture was stirred about 3 minutes. To the stirred solution was added about 1 equivalent of 4-nitroanthranilic acid. The unsealed vial was stirred for 10 minutes until there was a color change from red to yellow. The vial was then sealed and reacted in a microwave unit at 165°C for 600 seconds. Reaction completion was checked with LC/MS. 2-[2-(2-Fluoro-4-methoxyphenyl)ethyl]-3-methyl-7- nitro-3-hydroquinazo!in-4-one was then purified by column chromatography, eluting with EtOAc in hexanes. 2-[2-(2-Fluoro-4-methoxyphenyl)ethyl]-3- methyl-7-nitro-3-hydroquinazolin-4-one was then converted to Example 90 using the procedures described above through the corresponding thiourea (Scheme 1a). Method 3 Synthesis of 3-[2-(2-fluoro-4-methoxyphenyI)ethyll-2-(4- methylpiperazinyI)-7-nitro-3-hydroquinazolin-4-one (B) and 3-[2-(2-fluoro-4-methoxyphenyl)ethyI]-2-[imino(4- methyIpiperazinyl)-methyl]-7-nitro-3-hydroquinazolrn-4-one (C) [0179] The synthesis of nitrile A was first conducted as described in J. Heterocyclic Chem., 35, 659 (1998)). Nitrile A was heated in an excess of N- methylpiperazine to 110°C in a microwave for 600 seconds and analyzed by LC/MS to provide B and C. Products B and C were separated by column chromatography on silica gel eluting with 10% MeOH in CH2CI2. Compound B was the first to come off the column. Compounds B and C were then respectively converted to Examples 99 and 71 using the procedures described herein. Method 4 Synthesis of 3-[2-(2-fluoror4-methoxyphenyl)ethyl]-7-nitro-2- (1,2,3,4-tetraazol-5-yl)-3-hydroquinazolin-4-one [0180] Nitrile 1 shown above (0.9 g, 2.4 mmoles) was dissolved in dry DMF (5 mL). Sodium azide (0.8 g, 12.2 mmoles) was added and the mixture was heated at 125°C for 1 hour. The reaction was cooled, diluted with water (25 mL), and filtered. The collected solid was redissolved in THF/EtOAc 1:1 (25 mL), washed with water (25 mL), and dried over MgSCU. Filtration and solvent removal afforded 650 mg of a brown solid. The 1H NMR (DMSO-D6, 300 MHz) was consistent with desired product formation. The product was converted to Example 78 using the procedures described herein. Method 5 Synthesis of 3-[2-(4-fIuorophenyI)ethyl]-2-[(4- methylpiperazinyl)-methyl]-7-nitro-3-hydroquinazoIin-4-one (3) Step 1 Synthesis of 2-chloro-N-[2-(4-fluoro-phenyI)-ethyl]- acetamide (1) [0181] To a solution of 4-fluorophenylethylamine (1.0 equivalent) in dried THF was added Hunig's base (DIEA)(1 equivalent). The mixture was then stirred for 3 minutes at 0°C. Thereafter, a solution of chloroacetylchloride (1.0 equivalent) in THF was added via a syringe over a period of 7 minutes. The reaction mixture was then stirred at room temperature for 1 hour after which time the reaction mixture was condensed in vacuo, quenched with water, extracted with ethyl acetate (3X) and dried over Na2S04. After concentration in vacuo, compound 1 shown above was obtained, which was carried on further without further purification. LC/MS= M+H 216.1 at 2.18 minutes. Step 2 Synthesis of 2-chloromethyl-3-[2-(4-fluoro-phenyI)-ethyl]-7- nitro-3H-quinazolin-4-one (2) [0182] Compound 1 (1.2 equivalents) was dissolved in neat POCU and allowed to stir under N2 for 5 minutes. Solid 4-nitroanthranilic acid (1.0 equivalent) was then added, and the mixture was allowed to stir at room temperature for 10 minutes until the color changed to yellow from red. Thereafter, the reaction mixture was refluxed at 100°C for 2 hours, followed by removal of POCI3 in vacuo (addition of triethylamine to the rotovap condenser). The crude product so obtained was neutralized with a saturated solution of NaHCC-3, extracted with ethyl acetate (3 times), dried over Na2S04, and condensed in vacuo. Purification of the crude product was carried out with column chromatography in several batches using a gradient of EtOAc in hexanes. LC/MS = M+H 3.62 at 3.5 minutes. Step 3 Synthesis of 3-[2-(4-fluorophenyl)ethyl]-2-[(4- methyIpiperazinyl)-methyl]-7-nitro-3-hydroquinazolin-4-one (3) [0183] A solution of 2 (1 equivalent) and 4-methylpiperazine (3 equivalents) in 2 mL NMP were heated at 80°C. After stirring for 18 hours, the dark brown solution was diluted with ethyl acetate and washed twice with water. The organic phase was then dried with sodium sulfate, filtered and concentrated in vacuo, and taken on to the next step without further purification. Compound 3 was then converted to Example 69 using the procedures described herein. This procedure yielded a dark oil, and small amounts of NMP may remain in the product. Formation of some analogous compounds required the addition of three equivalents of diisopropyl ethyl amine. Similar chemistry was used to prepare Examples 67, 70, 72, 74, 75, 79, and 81 as identified in the following tables. Step 3a Synthesis of 2-[(2,4-difluorophenoxy)methyl]-3-methyl-7- nitro-3-hydroquinazolin-4-one [0184] 2,4-Difluorophenol (2.5 equivalents) was added to 2- (ch!oromethyl)-3-methyl-7-nitro-3-hydroquinazolin-4-one (2a) in acetone and refluxed for 8 hours. The solution was then cooled to room temperature, washed with saturated sodium bicarbonate, dried and filtered over sodium sulfate and concentrated in vacuo to afford 2-[(2,4-difluorophenoxy)methyl]-3- methyl-7-nitro-3-hydroquinazolin-4-one in quantitative yields. Compound 3a was then converted to Example 88 using the procedures described herein. Similar chemistry was used to prepare Examples 68, 89, 92, 93, 94, 95, 96, 97, 98, and 100 as identified in the following tables. METHOD 6 Synthesis of 3-[2-(2-fIuoro-4-methoxyphenyI)ethyl]-7- nitrobenzo[d]1,2,3-triazin-4-one [0185] A mixture of benzamide (1) (3.42 mmol), water (40 mL), and concentrated HCI (12 mL) was cooled in an ice bath', and a solution of NaNC>2 (3.6 mmol) in water (5 mL) was added drop wise. The mixture was stirred for 1 hour, and 20 mL 10 N NaOH was added. The stirring was continued for another hour, and the reaction was neutralized with AcOH, extracted with methylene chloride, and dried over MgS04. The crude product was chromatographed on silica (30%) EtOAc/hexanes) yielding the desired product as a yellow solid. The purified compound was then converted to Example 102 using the procedures described herein. Method 7 Synthesis of 6-amino-2-[2-(2-fluoro-4-methoxyphenyl)ethyl]- 2-hydroisoquinoIin-1-one Step 1 [0186] The diacid A (1 equivalent) was added to a flask equipped with a reflux condenser and dean stark trap and charged with dry toluene. The mixture was heated to reflux and then 2-(2-fluoro-4-methoxy-phenyl)- ethylamine B (1 equivalent) was added. The reaction was kept at reflux overnight, and then the toluene was removed by rotary evaporation. Purification by flash chromatography using ethyl acetate/hexanes provided the product C in 30% yield. Step 2 [0187] The imide (C) was dissolved in CH2CI2 and cooled to -78°C. 3 equivalents of D1BAL (1M in CH2CI2) were added, and the reaction was stirred at -78°C for 1 hour when LC/MS indicated completion of the reaction. The solution was then diluted with ether and 10 equivalents of NaF and 4 equivalents water were added. The reaction was then stirred for an hour. The reaction was then filtered through Celite® to yield the crude pyridone amine (D). Compound D was then converted to Example 103 using the procedures described herein. Similar chemistry was used to prepare Example 104 as identified in the final table. EXAMPLE COUPLING OF PIPERAZINONE WITH THIOUREA Synthesis of (3S)-N-{3-[2-(2-fluoro-4-methoxyphenyl)ethyl]-4-oxo- 2-pyridin-3-yl-3,4-dihydroquinazolin-7-yl}-3-methyl-5-oxo-N'- [(IS^S.SSjSRJ-a.e.e-trimethylbicyclotS.l.ljhept-S-yllpiperazine-l- carboximidamide (Example 216) [0188] A solution of thiourea (1) (1.796 g, 3.07 mmol) and 6- methylpiperazin-2-one (0.525 g, 4.60 mmol) in THF (50 mL) was treated with PS-CDI (6.5 mmol, 5.0 g of 1.3 mmol/g resin) and heated at 80°C for 13 hours. The reaction was filtered, and the resin was washed with THF. The crude product was then concentrated in vacuo and purified by column chromatography (0-5 % 2.0 N NH3 in MeOH/CH2CI2) to provide 1.55 g of the title compound (Example 216) as a tan solid. [0189] As noted below, the compounds in the following tables were prepared using the methodology described herein from commercially available starting materials which are readily recognizable by those skilled in the art or by using known synthetic methods. For example, Example 11 was prepared using the methodology described in Scheme 1a and the appropriate amino indanol. Examples 14 and 18 which include hydroxymethyl-substituted arylalkyl groups were also prepared using the general methodology of Scheme 1a with the appropriate amino alcohol. N-cyano substituted piperazine compound Example 36 was prepared by: first, mono-Boc protecting 2,6-trans dimethylpiperazine; second, treating the mono-Boc protected compound with cyanogen bromide (2.5 equivalents) and Hunig's base (1.1 equivalent); third, purifying the resulting nitrile piperazine compound on silica gel; fourth, deprotecting the purified compound; and fifth, reacting the resulting purified nitrile trans dimethyl piperazine compound using the methods described herein to produce Example 36. Compounds such as Examples 73 and 76 were prepared using the procedure of Method 2 with the appropriated amides of methacrylic acid and acetic acid. [0190] The compounds in the following tables were prepared using the methodology described in the above procedures, methods, and examples. The starting materials used in the syntheses are recognizable to one of skill in the art and are commercially available or may be prepared using known methods. The synthesis of various guanidine compounds is known in the art. Such synthesis information may be found in the following references each of which is hereby incorporated by reference in its entirety as if fully set forth herein: PCT publication WO 02/18327; PCT publication WO 03/099818; United States Patent Application Serial No. 09/945,384; United States Patent Application Serial No. 10/444,495; United States Provisional Patent Application Serial No. 60/230,565; United States Provisional Patent Application Serial No. 60/245,579; United States Provisional Application Serial No. 60/282,847; United States Provisional Application Serial No. 60/353,183; United States Provisional Application Serial No. 60/353,188; United States Provisional Application Serial No. 60/382,762; United States Provisional Application Serial No. 60/441,019; United States Provisional Application Serial No. 60/473,317; United States Provisional Application Serial No. 60/523,336; and United States Provisional Application Serial No. 60/524,491. HPLC Methods HPLC Method A Semi-Polar Method [0191] This method was accomplished by injection of 3 pL of sample onto a SynergiMax-RP (50 x 2.0 mm) column (4 pm particle size). Elution was with 15% methanol to 100% methanol over 3.5 minutes, then 1 minute at 100% methanol. Column was heated at 50°C and the flow rate was 1.5 mL/minute. The water contained 0.1% formic acid, and the methanol contained 0.075% formic acid by volume. DAD scans were collected from 220 to 400 nm. HPLC Method B Semi-Polar Method [0192] This method was accomplished by injection of 3 uL of sample onto a SynergiMax-RP (50 x 2.0 mm) column (4 urn particle size). Elution was with 15% methanol to 100% methanol over 5 minutes, then 1 minute at 100% methanol. Column was at room temperature and the flow rate was 1 mL/minute. The water contained 0.1% formic acid, and the methanol contained 0.075% formic acid by volume. DAD scans were collected from 220 to 400 nm. HPLC Method C Polar Method [0193] This method was accomplished by injection of 3 uL of sample onto a SynergiHydro-RP (50 x 2.0 mm) column (4 urn particle size). Elution was with 2% methanol to 100% methanol over 5 minutes, then 1 minute at 100% methanol. Column was at room temperature and the flow rate was 1 mL/minute. The water contained 0.1% formic acid, and the methanol contained 0.075% formic acid by volume. DAD scans were collected from 220 to 400 nm. HPLC Method D Polar Method [0194] This method was accomplished by injection of 3 |JL of sample onto a SynergiHydro-RP (50 x 2.0 mm) column (4 urn particle size). Elution was with 2% methanol to 100% methanol over 3.5 minutes, then 0.5 minutes at 100% methanol. Column was at room temperature and the flow rate was 1.5 mL/minute. The water contained 0.1% formic acid, and the methanol contained 0.075% formic acid by volume. DAD scans were collected from 220 to 400 nm. HPLC Method E Polar Method [0195] This method was accomplished by injection of 3 uL of sample onto a SynergiHydro-RP (50 x 2.0 mm) column (4 urn particle size). Elution was with 2% methanol to 100% methanol over 5 minutes, then 1 minute at 100%o methanol. Column was at room temperature and the flow rate was 0.8 mL/minute. The water contained 0.1% formic acid, and the methanol contained 0.075% formic acid by volume. DAD scans were collected from 220 to 400 nm. HPLC Method F Standard Method [0196] This method was accomplished by injection of 3 fjL of sample onto a SynergiHydro-RP (50 x 2.0 mm) column (4 urn particle size). Elution was with 10% methanol to 100% methanol over 3 minutes, then 1 minute at 100% methanol. Column was at room temperature and the flow rate was 2.0 mL/minute. The water contained 0.1% formic acid, and the methanol contained 0.075% formic acid by volume. DAD scans were collected from 220 to 400 nm. [0197] EC50 values of test compounds were determined by treating cells expressing MC4-R with test compound and lysing the cells and measuring intercellular cAMP concentration with an Amersham-Pharmacia RPA-559 cAMP Scintillation Proximity Assay (SPA) kit. EC50 values of test . compounds were also determined using the following method reported by Goetz, et al. which is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein. Goetz, A.G.; Andrews J.L.; Littleton, T.R.; Ignar, D.M. DEVELOPMENT OF A FACILE METHOD FOR HIGH THROUGHPUT SCREENING WITH REPORTER GENE ASSAYS J. Biomolec. Screening, 5, pp. 377- 384 (2000). CHO-6xCRE-luc+ reporter cell lines expressing human MC1R, MC3R, MC4R, and MC5R (GenBank accession numbers X65634, L06155, S77415 and U08353) and the CHO host reporter gene cell line were propagated in complete medium in T225 flasks. Forty-eight hours prior to 1 assay, cells were harve'sted with 2 mL of 0.05% trypsin, washed with complete medium and plated at a concentration of 4000 cells/well in complete medium. Sixteen hours prior to the assay, the medium was removed from the cells and replaced with 90 uL/well of serum-free DMEM/F12. At the time of the assay, agonists were added in a 10 uL volume and plates were incubated for 4 hours at 37°C in a cell culture incubator. The medium was aspirated followed by the addition of 50 uL of a 1:1 mixture of LucLite™ and dPBS containing 1 mM CaCb and 1 mM MgCI2. The plates were then sealed and subjected to dark adaptation at room temperature for 10 minutes before luciferase activity was quantitated using a TopCount™ microplate scintillation counter (Packard) using 3 second/well count time. The NDP-aMSH concentration-response curve data were expressed as a percentage of the fold stimulation in the NDP-aMSH control for each receptor subtype. The control value is the average of duplicate wells treated with 1 *1 Q"7 M NDP- aMSH. [0198] The compounds described above were synthesized and tested according to the assay procedures described above. Each of the Examples exhibited -log EC5o values above about 3. For this reason, each of the exemplary compounds is individually preferred and is preferred as a group. Nomenclature for these compounds was provided using ACD Name version 5.07 software (November 14, 2001) available from Advanced Chemistry Development, Inc and Chemlnnovation NamExpert + Nomenclator™ brand software available from Chemlnnovation Software, Inc. Some of the starting materials were named using standard IUPAC nomenclature. The Example compounds are illustrative and should not be construed as limiting the instant invention in any manner. In Vivo Studies of MC4-R Agonists on Energy Intake, Body Weight, Hyperinsulinemia, and Glucose Levels [0199] In vivo studies are conducted to observe the effect of MCR-4 agonists on energy intake, body weight, hyperinsulinemia, and glucose levels. All studies are conducted with male 9-10 week old ob/ob mice which display early onset of obesity, insulin resistance and diabetes due to leptin deficiency. Mice are acclimated in the facility for 1 week before studies and are caged individually. Vehicle-treated (control) and drug treated mice studies are always run in parallel. In multi-day studies, mice (8-15 per group) are monitored for baseline body weight, fasting levels of glucose, insulin, blood lipids and energy expenditure and then injected twice daily (9 a.m. and 5 p.m.) with 3 mg/kg of a MC4-R agonist of the present invention for 4 weeks. Body weight as well as food and water intake are monitored daily. Animals are fasted overnight for measurements of fasting levels of glucose, insulin, and lipids once a week until the end of the study. Energy expenditure (resting metabolic rate, i.e., 02 consumption and C02 production) are monitored in air tight chambers at the end of the study on fed animals. 02 consumption and C02 production are measured using Oxymax systems (Columbus Instruments). Oral glucose tolerance test (OGTJ - a routine test for diabetes and glucose intolerance) is performed on overnight fasted mice at the end of the study. Blood glucose and oral glucose tolerance are measured using a glucose monitor (Onetouch sold by Lifescan). Free fatty acids are measured using an non-esterified free fatty acids enzymatic assay (Waco Chemicals). Serum insulin levels are measured by immunoassay (Alpco). Results [0200] The effect of the compounds of the present invention on food intake is determined by measuring grams/mouse/day throughout a 4 week study. Food is monitored every morning. Cumulative food intake represents the total amount of grams the mice consume during the study. A significant reduction in food intake is demonstrated in those mice treated IP with the compounds of the present invention. [0201] The effect of the compounds of the present invention on body weight is determined by measuring grams/mouse throughout a 4 week study. Mice are weighed every morning. A significant body weight reduction is demonstrated in those mice treated IP with the compounds of the present invention. [0202] The effect of the compounds of the present invention on blood glucose levels is determined by measuring blood glucose levels as represented as mg of glucose/dL of blood. Mice are fasted overnight and glucose levels are measured the following morning. Vehicle treated mice show an increase in blood glucose consistent with the rapid progression of diabetes in this mouse strain whereas, diabetes is slowed down considerably in drug treated mice. A significant reduction in fasting glucose levels is demonstrated in those mice treated IP with the compounds of this invention. [0203] The effect of the compounds of the present invention on glucose levels during oral glucose tolerance test (OGTT) is determined by measuring blood glucose in overnight fasted mice. Blood glucose is represented as mg of glucose/dL of blood. Glucose levels are measured the following morning. Orally administered glucose quickly elevates blood glucose, similar to a meal, and the response to this exogenous glucose gives a measure of how well the body regulated glucose homeostasis. Vehicle treated mice show an elevated response to glucose consistent with their diabetic state, whereas drug treated mice show a very much improved glucose disposal. [0204] The effect of the compounds of the present invention on free fatty acid (FFA) levels is determined by measuring mmoles of FFA/L of serum. Mice are fasted overnight and free fatty acid levels are measured the following morning. Vehicle treated mice show elevated levels of FFA throughout the study consistent with their obese state, whereas the drug treated mice diabetes show a dramatic decrease. [0205] The effect of the compounds of the present invention on serum insulin levels is determined by measuring serum insulin levels one hour after single IP dosing of 1 and 3 mg/kg in overnight fasted ob/ob mice. .Serum insulin levels are represented as ng of insulin/mL of serum. Drug treated mice . show a dose dependent decrease relative to vehicle. Determination of tm, Cmax, Fl, Bioavailability, CI, Vss, and Nocturnal Efficacy [0206] In vivo studies were conducted to observe the effect of the compounds of the invention in the subject animal. Male CD-1 mice, body weight of 20 grams at arrival, were used in these studies. Mice were given 30 mg/kg of compound in HPMC/Tween solution or suspension via oral gavage. Plasma, brain, and liver samples were collected at time periods of 1, 2, 4, 8, and 24 hours post dosing. One mouse was used per time point. Thus, a total of 5 mice were used for each compound tested. For sample collection, mice were euthanized with C02. Blood samples were taken by cardiac puncture and kept on ice. Brain and liver samples were collected immediately after bleeding and the samples were kept on dry ice. For calculation of tissue half- lives (U12S), the terminal rate constant k was estimated by the absolute value of the slope of a log-linear regression of the terminal phase of the tissue concentration-time profile. The tissue half-life ty2 is ln(2)//c. [0207] Male C57BL/6J mice of 6-9 weeks age were used in these studies. The mice were singly housed at least 5 days prior to the study. Two and a half hours before the onset of the dark cycle, food was removed from the cage top. Mice were dosed with a compound of the invention (in HPMC/Tween, as vehicle) or vehicle via oral gavage two hours before the . onset of the dark cycle. Immediately before the onset of the dark cycle, pre- weighed food was given to each mouse. Food was weighed at 16 and 24 hours after the introduction of food to obtain cumulative food intake values. Mice were then euthanized with C02 followed by cervical dislocation. [0208] The following table includes tV2 data for plasma, brain, kidney, and liver obtained after oral administration. Tissue Half-Life Data for Various Quinazolinone Compounds (PO) [0209] All references cited herein are hereby incorporated by reference in their entirety and for all purposes as if fully set forth herein. [0210] It is understood that the invention is not limited to the embodiments set forth herein for illustration, but embraces all such forms thereof as come within the scope of the following claims. WE CLAIM: 1. A compound of formula IA, IB, or mixtures thereof, or pharmaceutical acceptable salts of the compound, wherein R1 is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R2 is selected from H or substituted or unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R3, R4, and R5 are independently selected from H, Cl, I, F, Br, OH, NH2, CN, NO2, or substituted or unsubstituted alkoxy or alkyl groups; R3' is selected from H or substituted or unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or cycloalkylalkyl groups; and Z is selected from a piperazinone of formula which may be additionally substituted. 2. The compound as claimed in claim 1, wherein R3, R4, and R5 are all H. 3. The compound as claimed in claim 1, wherein R3' is a substituted or unsubstituted polycyclic cycloalkyl group. 4. The compound as claimed in claim 3, wherein R3' is a substituted or unsubstituted polycyclic cycloalkyl group of formula II 5. The compound as claimed in claim 1, wherein R1 is a substituted or unsubstituted arylalkyl group. 6. The compound as claimed in claim 5, wherein R1 is a substituted phenylethyl group. 7. The compound as claimed in claim 6, wherein R1 is a 4- substituted phenylethyl group or is a 2,4-disubstituted phenylethyl group. 8. The compound as claimed in claim 5, wherein R1 is selected from 2-fluoro-4-methoxyphenylethyl, 2-chloro-4- methoxyphenylethyl, 4- fluorophenylethyl,4-chlorophenylethyl,4- chloro-2-fluorophenylethyl,2,4-dichlorophenylethyl, 4- bromophenylethyl, or 4-bromo-2-fluorophenylethyl groups. 9. The compound as claimed in claim 1, wherein R1 is selected from phenylethyl, 2, 4-dichlorophenylethyl, 4-methoxyphenylethyl, 4- phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4- chlorophenylethyl, 4-fluorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2- fluorophenylethyl, 3- methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl, 4- hydroxyphenylethyl, 3, 4- dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2- fluoro-4- methylphenylethyl, 4-chloro-2-fluorophenylethyl, 4-bromo-2- fluorophenylethyl,2-fluoro-4-methoxyphenylethyl,2-trifluoromethyl -4-fluorophenylethyl,2,4-difluorophenylethyl,2,4- dimethylphenylethyl, 2,4- dimethoxyphenylethyl, (2-pyridyl) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl, or (phenyl) (hydroxymethyl) ethyl groups. 10. The compound of claim 1, wherein R is selected from substituted or unsubstituted heterocyclyl groups, or substituted or unsubstituted heteroaryl groups. 11. The compound as claimed in claim 10, wherein R2 is selected from substituted or unsubstituted pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl groups. 12. The compound as claimed in claim 1, wherein R2 is selected from heteroaryl or heterocyclyl groups of formula which may be additionally substituted or may be unsubstituted. 13. The compound as claimed in claim 1, wherein R2 is selected from aryl or cycloalkyl groups of formula which may be additionally substituted or may be unsubstituted. 14. The compound as claimed in claim 1, wherein Z is a piperazinone of formula 15. The compound as claimed in claim 14, wherein Z is a piperazinone of formula 16. A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and the compound as claimed in claim 1. ABSTRACT TITLE: QUhINAZOLINONE COMPOUNDS WITH REDUCED BIOACCUMULATION A variety of small molecule, guanidine-containing molecules capable of acting as MC4-R agonists are provided, The compounds are useful in treating MC4-R mediated diseases when administered to subjects. The compounds have the formula IA and IB, IA and IB have the following structure where Z has the formula shown below and the rest of the variables are defined herein.

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