MXPA05012483A - Guanidino-substituted quinazolinone compounds as mc4-r agonists - Google Patents

Abstract

A variety of small molecule, guanidine-containing moleculescapable 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 structure IA, IB, and IC where the values of the variables are defined herein.

Description

For iwo-letler codes and other abbreviations. Refer to the "Guidance Notes on Codes and Abbreviations" appearing at the be.gin-ning of the regular issue of the PCT Gazette.

COMPONENTS OF QUINAZOLINONE SUBSTITUTED WITH 6UANIDIN0 AS AGONISTS OF THE RECEPTOR OF MELANOCORTIN-4 (MC4-R) Field of the Invention This invention relates to melanocortin-4 receptor agonists (MC4-R) 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 Melanocortins are peptide products that result from the post-transductional processing of pro-opiomelanocortin and are known to have a broad array of physiological activities. Natural melanocortins include the different types of elanocyte stimulating hormone (a-MSH, β-MSH, -YMSH) and ACTH. Of these, -MSH and ACTH are considered to be the main endogenous melanocortins. 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 hair and skin. MC2-R mediates the effects of ACTH on steroidogenesis in the REF gland: (167256) adrenal. MC3-R and MC4-R are predominantly expressed in the brain. The MC5-R is considered to have a role in the exocrine gland system. The melanocortin-4 receptor (MC4-R) is a seven transmembrane receptor. The MC4-R can participate in the modulation of the flow of visual and sensory information, coordinates aspects of somatomotor control, and / or participate in the modulation of autonomic secretion to the heart. K. G. Mountjoy et al., Science, 257: 1248-125 (1992). Significantly, inactivation of this receptor by gene selection has resulted in mice developing an obesity syndrome of early maturity associated with hyperphagia, hyperinsulinemia, and hyperglycemia. D. Husznar et al., Cell, 88 (1): 131-41 (1997). MC4-R has 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. Hal-Lúevano, The proopiomelanocortin system, Ann. N. Y. Acad. Sci., 885: 1 (1999) -.'- ~ "- Additionally," observations with respect to endogenous MC4-R antagonists indicate that MC4-R has been implicated in endogenous energy regulation. For example, if it normally expresses an agouti protein in the skin and is an antagonist of the cutaneous MC receptor comprised in pigmentation, MCl-R. M. M. Ollmann et al., Science, 278: 135-138 (1997). However, overexpression of the agouti protein in mice leads to a yellow skin color due to antagonism of MCl-R and increased food intake and increased body weight due to antagonism of MC4-R. L. L. Kiefer et al., Biochemistry, 36: 2084-2090 (1997); D. S. Lu et al., Nature, 371: 799-802 (1994). The agouti-related protein (AGRP), a homolog of agouti protein, antagonist MC4-R but not MCl-R. T. M.

Fong et al., Biochem. Biophys. Res. Commun. 237: 629-631 (1997). The administration of AGRP in mice increases the ingestion of food and causes obesity but does not alter the pigmentation. M. Rossi et al., Endocrinology, 139: 4428-4431 (1998). Together, this research indicates that MC4-R participates in the regulation of energy, and therefore, - identifies this receptor as an objective for a rational design of drugs for the treatment of obesity. With respect to MC4-R and its undisclosed role in the etiology of obesity and food ingestion, the prior art includes reports of compounds and compositions that act as MC4-R agonists or antagonists. As examples, the United States Patent number. 6,060, 589 describes polypeptides that are capable of modulating the signaling activity of melanocortin receptors. Also, the United States Patent numbers. 6,054,556 and 5,731,408 describe families of agonists and antagonists for MC4-R receptors that are lactate heptapeptides having a cyclic structure. WO 01/10842 discloses MC4-R binding compounds having a multitude of structures and methods for using these compounds to treat disorders associated with MC4-R. Some of the disclosed compounds include ares and heteroarere containing amidino and guanidino. Several other classes of compounds with MC4-R agonist activity have been described. For example WO 01/70708 and WO 00/74679 describe MC4-R agonists which are piperidine compounds and derivatives, while WO 01/70337 and WO 99/64002 describe MC-R agonists which are derivatives of spiropiperidine. Other known agonists of the melanocortin receptor include aromatic amine compounds containing amino acid residues, particularly tryptophan residues, as described in WO 01/55106. Similar agonists are described in WO 01/055107 comprising 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 nitrogen-containing alkyl linker.

Guanidine-containing compounds having a variety of biological activities are also known in the prior art. For example, United States Patent number. 4,732,916 issued to Satoh et al., Describes guanidine compounds useful as anti-ulcer agents; the United States Patent number. 4,874,864, the United States Patent number. 4,949,891, and U.S. Patent number. 4,948,901 issued to Schnur et al. and EP 0343 894 discloses guanidino compounds useful as protease inhibitors and as anti-plasmin and anti-thrombin agents; and the United States Patent number. 5,352,704 issued to Okuyama et al., Describes a guanidino compound useful as an antiviral agent. Guanidine-containing compounds are also described in other references. For example, United States Patent number. 6,030,985 issued to Gentile et al., Describes guanidine compounds useful for treating and preventing conditions in which the inhibition of nitric oxide synthase such as attack, schizophrenia, anxiety, and pain is beneficial. The United States Patent number. 5,952,381 issued to Chen et al. Describes certain guanidine for 'use in the inhibition or selective antagonization of otvß3-integrins. A number of fully saturated, 5, 6 and 7 guanidine 1-azacarbocyclic-2-ylidene derivatives are described, with anti-secretory and hypoglycemic activities by U.S. Patent No. 4,211, 867 issued to Ras ussen. It is also taught that these compounds are useful for the treatment of cardiovascular disease. Other guanidine derivatives are described in U.S. Patent No. 5,885,985 issued to Macdonald et al. , as useful in therapy to treat inflammation. The various guanidinebenzamide compounds are described in WO 02/18327. Guanidinebenzamides are described as being useful for treating obesity and type II diabetes. The synthesis of various quinazolinone compounds is disclosed in United States Patent Application No. 10 / 444,495, published January 29, 2004 as US2004 / 0019049, international application number PCT / US03 / 16442, published on December 04 of 2003 as WO 03/099818, and US Provisional Applications 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 they were presented in the present. Despite the "recent discovery of the various compounds exhibiting MC4-R agonist activity, there is a need for new compounds and pharmaceutical compositions that can be used to treat diseases mediated by MC4-R and disease states. compounds exhibiting desirable pharmacological properties such as compounds having reduced bioaccumulation properties in subjects in which they are administered.

Brief Description of the Invention The present invention provides potent and specific MC4-R agonists which are small molecules. Thus, compounds of the formulas IA, IB, or IC have been provided according to one aspect of the invention: IA IB IC wherein Z1 is selected from the group consisting of CR4 and N; Z2 is selected from the group consisting of CR5 and N; Z3 is selected from the group consisting of CRS and N; R1 is selected from the group consisting of arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and substituted and unsubstituted alkyl groups, R2 is selected from the group consisting of H, and alkyl groups, unsubstituted alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl; R 3 is selected from the group consisting of H, and arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and substituted and unsubstituted alkyl; R4, R5, - and R6 are independently selected from the group consisting of H, Cl, T, F, BrH, NH2, CN, N02, and alkoxy, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino groups , cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and substituted and unsubstituted heterocarbylcarbonyl; W is B; It R1 || B 'is selected from the group consisting of H, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl substituted and unsubstituted, and heterocyclylalkyl groups; - R2 'is selected from the group consisting of H, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl substituted and unsubstituted, and hetersciclilalquilo groups; wherein at least one of R1 'and R2' is a substituted or unsubstituted heterocyclylalkyl group; R3 'is selected from the group consisting of H, and substituted and unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; and R4 is selected from the group consisting of H, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl and substituted and unsubstituted. According to a second aspect of the invention, the invention provides compounds of the formulas IA, IB, or IC in which: Z1 is selected from the group consisting of CR4 and N; Z2 is selected from the group consisting of CR5 and N; Z3 is selected from the group consisting of CR6 and N; R1 is selected from the group consisting of substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl groups; R2 is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, alkylcarbonyl, and arylcarbonyl groups; R3 is selected from the group consisting of H and unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and substituted and unsubstituted alkyl; R4, R5, and R6 are independently selected from the group consisting of H, Cl, I, F, Br, OH, NH2, CN, N02, and alkoxy, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl groups, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, "cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, substituted and unsubstituted heteroarylaminocarbonyl; W is a group of formula IIA or IIB, wherein R1 'and R2', together with the nitrogen to which they are joined, they are joined together to form a heterocyclic ring substituted with at least one group selected from the group consisting of arylalkyl groups -C (= 0) -alkyl, -alkyl-C (= 0) -O-alkyl, -C (= 0) -O-alkyl, -C (= 0) -NH2, -C (= 0) -NH (alkyl), -C (= 0) -N (alkyl) 2, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, aryl , heteroaryl, heterocyclyl, heteroarylalguyl, heterocyclylalkyl, and substituted alkylthioalkyl and unsubstituted gone; R3 'is selected from the group consisting of H, and substituted and unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, and cycloalkylalkyl groups; and R4 / is selected from the group consisting of H, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl and substituted and unsubstituted. The compounds provided by the invention further include prodrugs of the compound of the formula IA, IB, and IC, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, or solvates thereof. In some embodiments, the invention provides compounds of the formula IA, IB, "and IC in which W is a group of the formula IIA., the compound has the formula IA. The invention further provides compounds of the formula IA, IB, and IC in which at least one of R1 'and R2' is a pyrrolidinylalkyl group such as, but not limited to, a pyrrolidinylmethylethyl or pyrrolidinylethyl group. . The invention further provides compounds of the formula IA and IC in which R3 is H. The invention further provides compounds of the formula IA, IB, and IC in which Z1 is a CR4 group, Z2 is a group CR5, and Z3 is a CR6 group. In any of these embodiments, at least one of R4, R5, or Rs is an F. The invention further provides compounds of the formula IA, IB, and IC in which at least one of Z1, Z2, or Z3 is N. In some embodiments, Z1 is N. In other embodiments, Z2 is N. The invention further provides compounds of the formula IA, IB, and IC in which R3 'are selected from the group consisting of cycloalkyl, polycyclic cycloalkyl, alkenyl, alkyl, and substituted and unsubstituted aryl. In other embodiments of the compounds of the formula IA, IB, and IC, R3 is selected from the group consisting of cyclohexyl, 2-alkylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 5-dialquilciclohexilo, 2,6-dialquilciclohexilo, 3, 4-dialquilciclohexilo, 3-alkylcyclohexyl, 4-alkylcyclohexyl, 3,3,5-trialquilciclohexilo, cyclohexylmethyl, 2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl, 2,3 -diaminociclohexilo, 2, 4-diaminociclohexilo, 3,4-diaminociclohexilo, 2, 5-diaminociclohexilo, 2,6-diaminociclohexilo, 2, 2-diaminociclohexilo, 2-alcóxiciclohexilo, 3-alcoxiciclohexilo, 4-alcoxiciclohexilo, 2, 3-dialcoxiciclohexilo , 2, 4-dialcoxiciclohexilo, 3,4-dialcoxiciclohexilo, 2, 5-dialcoxiciclohexilo, 2,6-dialcoxiciclohexilo, 2, 2-dialcoxiciclohexilo, 2-alquiltiociclohexilo, 3-alquiltiociclohexilo, 4-alquiltiociclohexilo, 2, 3-dialquiltiociclohexilo, 2 , 4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohex xyl, 2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl, trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkyl-cyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocanphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and substituted and unsubstituted decalinyl. In still other embodiments of compounds of formula IA, IB, and IC, R3 is selected from the group consisting of, 2-methylcyclohexyl, 2, 2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2, 4-dimethylcyclohexyl ciciohexilo groups, 2,5-dimethylcyclohexyl, 2, 6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cyclohexenyl, 3, 3, 5-trimethylcyclohexyl, 4-t-butylcyclohexyl, cyclohexylmethyl, isopinocampheyl, 7,7 dimetinorbornilo, 4-isopropylcyclohexyl, 3-methylcycloheptyl groups, 2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluorometilciclohexilo, 2-methyl-4-trifluorometilciclohexilo, 2 -fluoromethylcyclohexyl, trifluoromethyl (polycyclic cycloalkyl), fluoromethyl (polycyclic cycloalkyl), and fluoro (polycyclic cycloalkyl) substituted and unsubstituted. The invention further provides compounds of the formula IA, IB, and IC in which R1 is a 2,4-disubstituted phenylethyl group. In still other embodiments of the compounds of formula IA, IB, and IC, R1 is selected from the group consisting of 2,4-dihalophenylethyl groups, and 2,4-dialkylphenylethyl. In still other embodiments of the compounds of formula IA, IB, and IC, R1 is selected from the group consisting of phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-etilfeniletilo, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-yodofeniletilo, 2-fluoro-4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromophenylethyl, 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, (phenyl) (hydroxymethyl) ethyl, (heteroaryl) (hydroxymethyl) substituted and unsubstituted ethyl groups (aryl) (hydroxymethyl) substituted and unsubstituted ethyl, (aryl) (alkoxymethyl) substituted and unsubstituted ethyl, (aryl) (aryloxymethyl) substituted and unsubstituted ethyl, (aryl) (arilalcoximetil) substituted and unsubstituted ethyl, (aryl) (heteroariloximetil) substituted and unsubstituted ethyl, (aryl) (heterocicliloximetil) substituted and unsubstituted ethyl, (heteroaryl) (alkoxymethyl) substituted and unsubstituted ethyl, (heteroaryl) (aryloxymethyl) substituted and unsubstituted ethyl, (heteroaryl) (arilalcoximetil) substituted and unsubstituted ethyl, (heteroaryl) (heteroariloximetil) substituted and unsubstituted ethyl, and groups (heteroaryl) (heterocicliloximetil) substituted ethyl and unsubstituted . In yet other embodiments of the compounds of formula IA, IB, and IC, R1 is selected from the group consisting of phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, -bromophenylelyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-etilfeniletilo, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl, 4-hydroxyphenylethyl, '3,4-dimethoxyphenylethyl, 2-chloro-4 -yodofeniletilo, 2-fluoro-4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromofeniletilo, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2, 4-difluorofeniletilo, 2 , -dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2-pyridyl) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl, and (phenyl) (hydroxymethyl) ethyl. In some embodiments where R1 'and R2', together with the nitrogen to which they are attached, are joined together to form a heterocyclic ring, the heterocyclic ring is a substituted piperazine and in other embodiments, the heterocyclic ring is a piperidine ring. In some embodiments, the piperazine or piperidine ring is substituted with a group selected from a phenylalkyl group, a substituted or unsubstituted phenyl group, an -alkyl-SCH3 group, an indolyalkyl group, a morpholinylaguyl group, a pyridyl group, an piperidinyl group, or a tetrahydrofuranylalkyl group. In still further embodiments, the invention provides compounds of formula IA, IB and IC in which R1 is a substituted or unsubstituted alkenyl group such as a substituted or unsubstituted allyl group or a substituted or unsubstituted vinyl group. The invention further provides compounds of the formula IB in which R2 is H. In still further embodiments, the invention provides compounds of the formula IA and IC in which R3 is a substituted or unsubstituted alkenyl group such as an allyl group substituted or unsubstituted or a substituted or a substituted or unsubstituted vinyl group. In some embodiments, the invention provides compounds in. which R3 is a substituted or unsubstituted heteroaryl group, heterocyclyl group, alkylamino group, or cycloalkylamino group. In some embodiments, R 3 is selected from substituted and unsubstituted 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazine, morpholinyl, piperazinyl, and cyclopropylamino groups. According to another aspect, the invention provides compounds of the formula VA, VB, and mixtures thereof wherein R1 is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R3 is selected from substituted or unsubstituted aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, or arylalkylamino groups; R4, -R5, and R6 are independently selected from H, Cl, 1, F, Br, OH, NH2, CN, N02, and substituted or unsubstituted alkoxy, and alkyl groups, -R1 'and R, together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclyl group; and R3 'is selected from substituted or unsubstituted cycloalkyl groups. In another aspect, the invention provides compounds of the formula VIA, VIB, and mixtures thereof.

VIA VIB wherein R1 is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R3 is selected from H or substituted or unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl-, or alkyl groups; -. , ---.-_-, R4 ^ R5 ^ - and R6 are independently selected from H, Cl, 1, F, Br, OH, NH2, CN, N02, and alkoxy, and alkenyl groups substituted or unsubstituted; 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 the formula which may be additionally substituted. In another aspect, the invention provides compounds of the formula and VIIA VIIB and mixtures thereof, VIIA VIIB wherein R is selected from substituted or unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R3 is selected from H or substituted or unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, aminocycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R4, R5, and R6 are independently selected from H, Cl, 1, F, Br, OH, NH2, CN, N02, and substituted or unsubstituted alkoxy, and alkyl groups; J is selected from H or substituted or unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or cycloalkylalkyl groups; And it is selected from a portion of the formula wherein R1 'is selected from substituted or unsubstituted alkyl groups; R2 ', R4', R5 'are independently selected from H or substituted or unsubstituted alkyl groups; R6 'is selected from substituted or unsubstituted alkyl groups; or R5 'and R6' together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; and R7 'is selected from CN, or substituted or unsubstituted alkyl, aryl, or arylalkyl groups. The compounds provided by the invention further include prodrugs of the compound of the formula VA, VB, VIA, VIB, VIIA, and VIIB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, or solvates thereof The invention further provides compounds of the formula VA, VB, VIA, VIB, VIIA, and VIIB in which R4, R5, and R6 are all H. The invention further provides compounds of the formula VA, VB, VIA , VIB, VIIA and VIIB in which R3 is selected from the group consisting of cyclohexyl groups, 22-aalqsuuiillcciicclloohheexxiilloo, 2,2-dialkyclocyclohexyl, 2,3-dialkyclohexyl, 2,4-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl, 3,4-dialkylcidiohexyl, 3-alkylcyclohexyl, 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-alkoxycyclohexyl, 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-dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl, trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl, cyclooctyl, 2-arylcyclohexyl, phenyl-cyclohexyl, 2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocanphenyl, carenyl, 7,7-dialkynorbornyl, bornyl, norbornyl, and substituted and unsubstituted decalinyl. In still other embodiments, R3 'is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl groups. , 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl, isopinocanphenyl, 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, trifluoromethyl (polycyclic cycloalkyl), fluoromethyl (polycyclic cycloalkyl), and fluoro (polycyclic cycloalkyl) substituted and unsubstituted. The invention further provides compounds of the formula VA, VB, VIA, VIB, VIIA, and VIIB in which R3 'is a substituted and unsubstituted polycyclic cycloalkyl group. In any of these embodiments, R3 is a substituted or unsubstituted polycyclic cycloalkyl group having the formula II The invention further provides compounds of the formula VA, VB, VIA, VIB, VIIA, and VIIB in which R1 is a substituted or unsubstituted arylalkyl group such as a substituted or unsubstituted phenylethyl group. In some 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 the groups 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- clors-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, and (phenyl) (hydroxymethyl) ethyl. In still other embodiments, R1 is selected from a group 2-fluoro-4-methoxyphenylethyl group, a 2-chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, a 4-chlorophenylethyl, a 4-chloro-2-fluorophenylethyl, a 2, 4-dichlorophenylethyl, a -bromophenylethyl, or a 4-bromo-2-fluorophenylethyl. The invention further provides compounds of the formula VA, VB, VIA, VIB, VIIA, and VIIB in which R3 is selected from substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted heteroaryl groups. In some embodiments, R3 is selected from pyridinyl, piperidinyl, piperazinyl, morpholinyl, thioorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl groups. , substituted or unsubstituted pyridazinyl, tetrazolyl, or pyridazinyl. In some embodiments, R3 is selected from heteroaryl or heterocyclyl groups of the formula which may be further substituted or may be unsubstituted.

In other embodiments of the compounds of the formula VIIA or VIIB, R3 is selected from heteroaryl or heterocyclyl groups of the formula ° which may be additionally substituted or may be unsubstituted. The invention further provides compounds of the formula VA, VB, VIA, and VIB in which R3 is selected from substituted or unsubstituted aryl or cycloalkyl groups. For example, in some embodiments, R3 is selected from aryl or cycloalkyl groups of the formula which may be additionally substituted or may be unsubstituted. The invention further provides compounds of the formula VIIA and VIIB in which R3 is selected from substituted or unsubstituted aryl, cycloalkyl, or aminocycloalkyl groups. For example in some embodiments, R3 is selected from aryl, cycloalkyl, or aminocycloalkyl groups of the formula which may be further substituted or may be unsubstituted. The invention further provides compounds of the formula VA, VB, VIA, VIB, VIIA, and VIIB in which R3 is selected from heterocyclylalkyl, or substituted or unsubstituted cycloalkylamino groups. For example, in some embodiments, R3 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 The invention further provides compounds of the formula VA and VB in which R1 'and R2', together with the nitrogen to which they are attached, form a substituted or unsubstituted piperazinyl group In some embodiments, R1 'and R2' , together with the nitrogen to which they are attached, form a piperazinyl group which is substituted with at least one group selected from, fluoromethyl, difluoromethyl, or trifluoromethyl groups In other embodiments, R1 'and R2', together with the nitrogen to which they are joined, forms a piperazinyl group substituted with at least one carbonyl group such that the piperazinyl group is a piperazinone which may be additional mind replaced. In some embodiments, R1 'and R2', together with the nitrogen to which they are attached, form a piperazinone of the formula which may be additionally substituted. In some embodiments of the compounds of formula IA and IB, R1 'and R2', together with the nitrogen to which they are attached form a piperazinone having the following formula and in some embodiments of the compounds of the formula VIA and VIB, Z is a piperazinone that has the following formula.

In some of these embodiments, R1 and R2 together with the nitrogen to which they are attached form a piperazinone having the following formula or Z is a piperazinone having the following formula The invention further provides compounds of the formula VA and VB, in which R1 'and R2', together with the nitrogen to which they are attached, form a piperazinyl group of the formula In some embodiments, the invention provides compounds in which the value t_./2 for the compound is less than 35, 30, 25, 15, 10 or 5 hours in a tissue with high blood perfusion such as brain, liver, kidney and heart. In some embodiments, the t_./2 is less than or about 4 hours and in some embodiments is less than or about 3 hours in a subject to whom the compound (s) has been administered. A composition such as a pharmaceutical formulation or medicaments comprising a compound according to the present invention and a pharmaceutically acceptable carrier has also been provided, according to another aspect of the invention. The invention further provides the use of the compounds of the invention when preparing a medicament or pharmaceutical formulation for use in treatment of a disease mediated by MC4-R. In some modalities, this disease is obesity or type II diabetes. It was also provided, according to another aspect of the invention, a method for treating a disease mediated by MC4-R, comprising administering to a subject in need thereof, or a compound or composition of the present invention. In some embodiments, the compounds of the invention exhibit reduced bioaccumulation in the tissue and plasma of the subject. In one embodiment, a disease to be treated by those methods of the present invention is obesity or type II diabetes. In one embodiment, a compound or composition of the invention is administered in intranasal form. In one embodiment, a compound or composition of the invention is administered to a human subject. Other objects, features and advantages of the present invention will become apparent from the following detailed description, however. It should be understood that the detailed description and the specific examples, insofar as they indicate 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. those skilled in the art from this detailed description.

Detailed Description of the Invention The present invention relates to different classes of small molecule melanocortin-4 (MC4-R) receptor agonists. These compounds can be formulated into compositions and are useful in activating MC4-R or in the treatment of diseases mediated by MC4-R, such as obesity, type II diabetes, erectile dysfunction, polycystic ovarian disease, complications that result from or are associated with -obesity and diabetes, and Syndrome X.

The following definitions are used from beginning to end in this specification. Alkyl groups include straight and branched chain 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 can be substituted one or more times with, for example, amino, thio, alkoxy, or halo groups such as F, Cl, Br, and I groups. The cycloalkyl groups are cyclic alkyl groups such as is enunciatively and without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. Cycloalkyl groups also include 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, camfenyl, isocamphenyl, and carenyl groups. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, such as, but not limited to, cyclohexyl groups 2,2-, 2,3-, 2,4-2,5- or 2,6 -disubstituted, or mono-, di- or tri-substituted norbornyl and cyclohexyl groups which may be substituted with, for example, alkyl, alkoxy, amino, thio, cyano, or halo groups. The alkenyl groups are cyclic, straight-chain or branched lower alkyl groups having from -2 to about 8 carbon atoms, and which further include at least one further bond, as exemplified for example by vinyl, propenyl, 2-butenyl groups , 3-butenyl, isobutenyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The alkynyl groups are straight or branched chain lower alkyl groups having from about 8 carbon atoms, and which further include at least one triple bond, as exemplified by the groups, including, without limitation, ethynyl groups , propynyl and butynyl. The aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. In this manner, the aryl groups include, without limitation and without limitation, 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 aromatic-aliphatic ring systems, it does not include aryl groups having other groups, such as alkyl or halo groups, attached 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, phenyl or benzyl groups 2-, 3-, 4-, 5- or 6-substituted, which may be substituted with groups including enunciatively and without limitation, amino, alkoxy, alkyl, cyano or halo. Cycloalkylalkyl groups are alkyl groups as defined above, a hydrogen or carbon bond of an alkyl group is replaced with a bond or a cycloalkyl group as defined above. 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. Heterocyclyl groups are non-aromatic ring compounds containing three or more ring members, of which, one or more is a heteroatom such as, without limitation, N, 0 and S. The phrase "heteroclic group" includes fused ring species including those comprising fused aromatic and non-aromatic 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 having other groups, such as alkyl or halo groups, attached to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, without limitation, piperazino, morpholino, thiomorpholino, pyrrolidino, piperidino and homopiperazino groups. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, without limitation, morpholino or piperazino groups, which are 2-, 3-, 4-, 5-, or 6-substituted or di-substituted with groups including, without limitation, amino, alkoxy, alkyl, cyano or halo. Heteroaryl groups are aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as without limitation and without limitation, N, O and S. Heteroaryl groups include without limitation and without limitation, groups such as furan, thiophene, pyrrole, isopirrolo, diazolo, imidazolo, isoimidazolo, triazolo, dithiolo, oxathiolo, isoxazolo, oxazole, thiazole, isothiazolo, oxadiazole, oxatriazolo, dioxazolo, oxatiazolo, pyran, dioxin, pyridine, pyrimidine, pyridazine, pyrazine, triazine, oxazine, isoxazine, oxathiazine, azepine, oxepin, tiepin, diazepine, benzofuran, and isobenzofuran. Although the phrase "heteroaryl groups" includes fused ring compounds, the phrase does not include heteroaryl groups having other groups attached to one of the ring members, such as alkyl groups. Also, heteroaryl groups with this substitution are referred to as "substituted heteroaryl" groups. Representative substituted heteroaryl groups may be substituted one or more times with groups including, without limitation, amino, alkoxy, alkyl, cyano or halo. The heterocyclylalkyl groups are alkyl groups as defined above in which a "hydrogen or carbon bond of the alkenyl group is replaced with a bond to a heterocyclyl group as defined above. The heteroarylalkyl groups are aligyl groups as defined above in which a hydrogen or carbon bond of the alkenyl group is replaced with a bond to a heteroaryl group as defined above. 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 alguilo groups, cicloalguilo, aryl, heterocyclyl or substituted heteroaryl and unsubstituted, as defined above. In general, "substituted" refers to a group as defined above in which one or more bonds to a nitrogen atom contained therein are replaced by a bond to a non-hydrogen or carbon atom such as, by way of example, , a halogen atom F, Cl, 'Br, and 1; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in the group such as thiol groups, algeryl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkyl amines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialguilsilyl groups, dialguylailsilyl groups, alkyldiarylsilyl and triarylsilyl groups; and other heteroatoms in several different groups. Substituted alkyl groups and also substituted cycloalkyl groups and others also include groups in which one or more bonds to a carbon or hydrogen atom are 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. Substituted cycloalkyl, substituted aryl, substituted heterocyclyl and substituted heteroaryl also include rings and fused ring systems in which a bond to a nitrogen atom is replaced as a bond to a carbon atom. Therefore, substituted cycloalkyl, substituted aryl, substituted heterocyclyl and substituted heteroaryl groups can also be substituted with alkyl groups as defined above. The pharmaceutically acceptable salts include a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic amino acid or acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium, alkaline earth metals such as calcium or 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 present invention includes, for example, hydrochloric acid, hydrobromic acid, nitric acid: sulfuric acid and phosphoric acid. As salts of organic acids, the present 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 present invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid. The term "protected" with respect to hydroxyl groups, amine groups and hydrogen sulfide groups refers to forms of these functionalities that are protected from undesirable reaction with a protecting group known to those skilled in the art as set forth in Protective Groups in Organic Synthesis , Greene, TW; Wuts, P. G. M., John Wiley & Sons, Naw York, NY,, (3rd Edition, 1999) which may be used or removed using the procedures set forth herein. Examples of protected hydroxyl groups include, but are not limited to, silicic ethers such as those obtained by the action of a hydroxyl group with such a reagent, without limitation, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl esters such as, but not limited to, methoxymethyl methoxy ether, methylthio methyl ester, benzyloxy methyl ether, t-butoxy methyl ether, 2-methoxyethoxy methyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ester; esters such as, but not limited to, formate of benzoyl, formate, acetate, trichloroacetate and trifluoroacetate. Examples of protected amine groups include, without limitation, and without limitation, amides such as formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include, without limitation, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemitium, dithio and aminothio-acetals; and others. Prodrugs, as used in the context of the present invention, include those derived from the present compounds undergoing metabolic biotransformation in vivo, by enzymatic or non-enzymatic processes, such as hydrolysis, to form a compound of the invention. The prodrugs can be used to improve the pharmaceutical or biological properties, such as solubility, melting points, stability and related physico-chemical properties, absorption, pharmacodynamics and other properties related to the distribution. The present invention provides potent and specific MC4-R agonists which are peptide molecules. According to one aspect of the invention, the invention provides a first and a second group of compounds of the formula IA, IB and IC. The compounds of the invention further include prodrugs of the compounds of formula LA, IB and IC, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof or solvates thereof. The compounds of formula IA, IB and IC have the following structure.

IA IB IC In the first and second groups of compounds of formula IA, IB and IC, Z1 is selected from the group consisting of CR4 and N. In some embodiments of the compounds of formula IA, IB and IC, Z1 is a CR4 group while in other embodiments, Z1 is an N. In the first and second groups of compounds of formula IA, IB and IC, Z2 is selected from the group consisting of CR5 and N. In some embodiments of the compounds of the formula IA, IB and IC, Z2 is a CR5 group whereas in other embodiments, Z2 is an N. In the first and second groups of compounds of the formula IA, IB and IC, Z3 is selected from the group consisting of CR6 and N. In some embodiments of the compounds of formula IA, IB and IC, Z3 is a CR6 group, while in other embodiments Z3 is an N. In some embodiments of the first and second group of compounds of formula IA, IB and IC, Z1 is a group CR4, Z2 is a group CR5, and Z3 is the group CR6. Thus, in some embodiments of the compounds of formula IA, IB and IC, the ring which includes Z1, Z2 and Z3 may be a carbocyclic aromatic ring. In some embodiments of the compounds of the formula IA, IB and IC, where Z1 is a group CR4, Z2 is a group CR5, and Z3 is a group CR6, at least one of R4, R5 and R6 is - a halogen such as Cl or F. In other embodiments, at least one of R4, R5 or R6 is an F. In some embodiments of the first and second group of compounds of the formula IA, IB and IC, at least one of Z1, Z2 or Z3 is one N. in the first and second groups of compounds of formula IA, IB and IC, R1 is selected from the group consisting of gue unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl substituted or unsubstituted. In some embodiments of the compounds of formula IA, IB and IC, R 1 is a 2,4-phenethyl group substituted by a group such as a 2,4-disubstituted phenylethyl group or a 4-substituted phenylethyl group. In other embodiments of the compounds of formula IA, IB and IC, R1 is selected from 2,4-dihalophenylethyl and 2,4-dialkylphenylethyl groups. In still other embodiments of the compounds of formula IA, IB and IC, R1 is selected from the group including phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4- chlorophenylethyl, 4-etilfeniletilo, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodofeniletilo, 2- fluoro-4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromofeniletilo, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2, 4-difluorofeniletilo, 2, 4 ~ dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2-pyridyl) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl, (phenyl) (hydroxymethyl) ethyl, (substituted heteroaryl) (hydroxyethyl) ethyl, unsubstituted (aryl) (hydroxymethyl) ethyl groups and unsubstituted (aryl). (substituted alkoxymethyl) ethyl and unsubstituted, (aryl) (aryloxymethyl) ethyl substituted and unsubstituted, (aryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (aryl) (heteroaryloxymethyl) ethyl substituted and unsubstituted, (Aryl) (heterocicliloximetil) substituted and unsubstituted ethyl, (heteroaryl) (alkoxymethyl) ethyl substituted and unsubstituted (heteroaryl) (aryloxymethyl) ethyl substituted and unsubstituted (heteroaryl) (arilalcoximetil) substituted and unsubstituted ethyl, (heteroaryl) (heteroaryloxymethyl) ethyl, and (heteroaryl) (heterocyclyloxymethyl) ethyl. In other embodiments, R1 is selected from phenylethyl, 2, 4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-fenoxifeniletilo, -bromofeniletilo, 4-methylphenylethyl, 4-chlorophenylethyl, 4-etilfeniletilo, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2 -fluorofeniletilo, 3 -metoxifeniletilo, 3 -fluorofeniletilo, thienylethyl, indolylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodofeniletilo, 2-fluoro-4-methylphenylethyl ', 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromophenylethyl, -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. In some embodiments of the first and second groups of compounds of the formula IA, IB and IC, R1 is a substituted and unsubstituted alkenyl group such as a substituted and unsubstituted allyl group or a substituted and unsubstituted vinyl group. In the first and second groups of compounds of formula IB, R2 is selected from the group consisting of H, and substituted alkenyl, alkenyl, alkynyl, cycloalguyl, aryl, heteroaryl, heterocyclyl, arylalguyl, heteroarylaguiloyl, cycloalguilaylguilo, alylcarbonyl, and arylcarbonyl groups and unsubstituted. In some embodiments of the compounds of formula IB, R2 is H. In the first and second groups of compounds of formula IA and IC, R5 is selected from the group consisting of H, and arylalguilo, heteroarylaguilo, alkoxy, alkylamino groups, alkyl, aryl, heteroaryl, heterocyclyl, cycloalguyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and substituted and unsubstituted alkyl. In some embodiments of the compounds of the formula IA and IC, R3 is H. In still further embodiments, the invention provides compounds of the formula IA and IC in which R3 is a substituted and unsubstituted alkenyl group such as an unsubstituted allyl group or replaced or a substituted and unsubstituted vinyl group. In some embodiments, the invention provides compounds wherein R3 is a substituted or unsubstituted heteroaryl group, heterocyclic group, alkylamino group, or cycloalkylamino group. In some embodiments, R 3 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazine, morpholinyl, piperazinyl, and substituted and unsubstituted cyclopropylamino groups. In the first and second groups of the compounds of the formula IA, IB and IC, R4, R5 and R6 is independently selected from the group consisting of H, Cl, 1, F, Br, OH, NH2, CN, N02, and alkoxy, alkenyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalguilo, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialguylaminocarbonyl, cycloalbumylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and substituted and unsubstituted heteroarylaminocarbonyl groups. In some embodiments of the compounds of the formula IA, IB and IC, R4, R5 and R6 are selected from H or a halogen such as Cl or F. In other embodiments of the compounds of the formula IA, IB and IC, at least one of R4, R5 and R6 is an F as in other embodiments of the compounds of the formula IA, IB or IC. R4, R5 and R6 are all H. In the first and second groups of compounds of formula IA, IB and IC, W is a group of formula IIA or IIB which has the following structure.

HA IIB In the first group of compounds of formula IA, IB and IC, R1 'is selected from H, or substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalguyl, heteroarylaguiloyl, cycloalkylalkyl, or heterocyclylalkyl group and unsubstituted, and R2 is selected from H, or substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalguylguan, and heterocyclylguiloyl groups. In some embodiments, at least one of R1 'and R2' is a heterocyclylalguilo group such as, but not limited to, a substituted and unsubstituted pyrrolidinylmethyl or pyrrolidinylethyl group. In some embodiments, the compounds have the formula IA or IC and W is a group of the formula IIA. In the second group of compounds of formula IA, IB and IC, R1 'and R2', together with the nitrogen to which they are attached, are joined together to form a heterocyclic ring. The heterocyclic ring is substituted by at least one group selected from the group consisting of arylalkyl groups, -C (= 0) -alkyl, -alkyl-C (= 0) -O-alkyl, -C (= 0) -O- alkyl, -C (= 0) -NH2, -C (= 0) -NH (alkyl), -C (= 0) -N (alken) 2, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, and alkylthioalguyl. replaced and unsubstituted. In some embodiments, the heterocyclic ring is a substituted piperazine and in other embodiments, the heterocyclic ring is a piperidine ring. In some embodiments, the piperazine or pyridine ring is substituted with a group selected from the group consisting of a phenylalkyl group, a substituted or unsubstituted phenyl group, an -alkyl-SCH3 group, an indolyl alkyl group, a morpholinylalkyl group, a group pyridyl, a pyridyl group and a tetrahydrofuranylguilo group. In the first and second groups of compounds of formula IA, IB and IC, R3 'is selected from the group consisting of H, and aryl, algeryl, alkenyl, alginyl, cycloalguyl, heteroaryl, heterocyclyl, heterocyclylaguyl, arylalguyl, heteroarylaguiloyl, and substituted and unsubstituted cycloalguilalguilo. In one embodiment of compounds of the formula IA, IB and IC, R3 'is selected from the group consisting of the cycloalkyl, cycloalkyl: polycyclic, alkenyl, alkenyl and aryl substituted and unsubstituted group. In yet other embodiments of compounds of the formula IA, IB and IC, R3 'is selected from the group consisting of cyclohexyl, 2-alkylcyclohexyl, 2,2-dialguylcyclohexyl, 2,3-dialkylcyclohexyl, 2,4-dialkylcyclohexyl, 2.5 groups. -dialkylcyclohexyl, 2,6-dialguylcyclohexyl, 3,4-dialguylcyclohexyl, 3-allylcyclohexyl, 4-allylcyclohexyl, 3,3,5-trialguylcyclohexyl, cyclohexylmethyl, 2-aminociclohexyl, 3-aminociclohexilo, 4-aminocic1ohexi1o, 2,3-diaminocyclohexyl , 2,4-diaminocyclohexyl, 3,4-diaminocyclohexyl, 2,5-diaminocyclohexyl, 2,6-diaminocyclohexyl, 2,2-diaminocyclohexyl, 2-alkoxycyclohexyl, 3-alkoxy cyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyclohexyl, , 4-dialcoxycyclohexyl, 3,4-dialcoxycyclohexyl, 2,5-dialkoxycyclohexyl, 2,6-dialcoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-allylthiocyclohexyl, 3-allylthiocyclohexyl, 4-allylthiocyclohexyl, 2,3-dial-guylthiocyclohexyl, 2,4 -dialguylthiocyclohexyl, 3,4-dialkylthiocyclohexyl, 2,5-dial-guylthiocyclohexyl, 2 , 6-dialkylthiocyclohexyl, 2,2-dial-guylthiocyclohexyl, fluorocycloalguyl, fluoroalguylcycloalguilo, trifluoromethylcycloalguilo, cyclopentyl, cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalguylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl , adamantyl, isocaphenyl, carenyl, 7,7-dialguylnorbornyl, bornyl, norbornyl, and substituted and unsubstituted dacalinyl. In one embodiment of compounds of the formula IA, IB, and IC, R3 'is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, , 5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cyclohexenyl, 3, 3, 5-trimethylcyclohexyl, 4-t-butylcyclohexyl, cyclohexylmethyl, isopinocamfeyl, 7,7-dimethylnorbornyl , 4-isopropylcyclohexyl, 3-methylcycloheptyl, 2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethyl-cyclohexyl, 2-methyl-4-trifluoromethyl-cyclohexyl, 2- fluoromethylcyclohexyl, trifluoromethyl (polycyclic cycloalguyl), fluoromethyl (polycyclic cycloalguyl), and fluoro (polycyclic cycloalguyl) substituted and unsubstituted. By way of non-limiting example, the R3 ', cycloalguyl and cyclohexyl and polycyclic cycloalguyl groups which include fluorine, include, but are not limited to, the following structures.

In the first and second group of compounds of the formula IA, IB and IC, R4 'is selected from the group consisting of H, and groups alguilo, alguenilo, alguinilo, cycloalguilo, heterocyclylaguilo, cycloalguilalguilo, arilo, heteroaryl, heterocyclyl, substituted and unsubstituted arylalguilo, and heteroarylalguilo. In one embodiment of the compounds of the formula IA, IB, IC, R4 'is H. In one embodiment of the first and second group of compounds of the formula IA, the compounds of the formula IA are selected from the group consisting of have the formula IIIA, IIIB, IIIC, IIID, IIIE, IIIF, and IIIG as shown below where R1, W, R1 ', R2', R3 ', and R4' have the same values as described above with respect to to the compounds and various modalities of the formulas IA, IB and IC.

IIIG In one embodiment of the first and second group, of compounds of the formula IB, the compounds of the formula IB are selected from the group consisting of compounds having the formula IVA and IVB as shown below where R1, W, R1 ', R2', R3 ', and R4' have the same values as described above with respect to the compounds of formula IA, IB and IC.

IVA IVB The present invention provides a third and fourth group of compounds which are MC4-R-specific potent agonists which are peptide molecules In this way, according to one aspect of the invention, the invention provides a third and fourth groups of compounds of the formula IA and IC The compounds of the invention further include prodrugs of the compound of the formula IA and IC, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof or solvates of the same. The compounds of formula IA and IC have the following structure.

IA? C In the third and fourth groups of compounds of the formula IA and IC, Z1 is selected from the group consisting of CR4 and N. In some embodiments of the second compounds of the formula IA ~ and "IC, Z1 is a group CR4 insofar as in other embodiments, Z1 is an N. In the third and fourth groups of the compounds of formula IA and IC, Z2 is selected from the group consisting of CR5 and N. In the same modalities the second group of compounds of the formula IA and IC, Z2 is a group CR5 insofar as in other embodiments, Z2 is an N. In the third and fourth groups of compounds of the formula IA and IC, Z3 is selected from the group which consists of CR6 and N In some embodiments, Z3 is a CR6 group in that in other embodiments, Z3 is an N. In some embodiments the third and fourth groups of compounds of formula IA and Cl, Z1 is a group CR4, Z2 is a group CR5 , and Z3 is a CR6 group.This way, in some modalities, the ring that includes Z1, Z2 and Z3 can be an arc ring. carbocyclic omático. In some embodiments of the third and fourth groups of compounds of the formula IA and IC, wherein Z1 is a group CR4, Z2 is a group CR5, and Z3 is a group CR6, at least one of R4, R5 or R6 is a halogen such as Cl or F. In other embodiments, at least one of R4, R5 or R6 is an F. In some embodiments of the third and fourth groups of compounds of the formula IA and IC, at least one of Z1, Z2 or Z3 is N. In the third and fourth groups of compounds of formula IA and IC, R1 is selected from the group consisting of H, groups, arylalguilo, heteroarylguilo, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, and alkyl substituted and unsubstituted. In some embodiments of the third and fourth groups of compounds of formula IA and IC, R1 is a 2,4-disubstituted phenylethyl group. In other embodiments, R1 is selected from 2,4-dihalophenylethyl and 2,4-dialkylphenylethyl groups. In still other embodiments, R1 is selected from the group 2,4-dianophenylethyl and 2,4-dialguylphenylethyl. In some other embodiments, R1 is selected from the group including phenylethyl,, 4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethylol, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl , thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromophenylethyl, 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, unsubstituted or substituted (phenyl) (hydroxymethyl) ethyl, unsubstituted or substituted (heteroaryl) (hydroxymethyl) ethyl, unsubstituted or substituted (aryl) (hydroxymethyl) ethyl, unsubstituted or substituted (aryl) (alkoxymethyl) groups ) ethyl, unsubstituted or substituted (aryl) (aryloxymethyl) ethyl, unsubstituted or substituted (aryl) (arylalkoxy) ethyl), unsubstituted or substituted (Aryl) (heterocicloloximetil) ethyl, unsubstituted or substituted (heteroaryl) (alkoxymethyl) ethyl, unsubstituted or substituted (heteroaryl) (aryloxymethyl) ethyl, unsubstituted or substituted (heteroaryl) (arilalcoximetil) ethyl, unsubstituted or substituted (heteroaryl) (heteroariloximetil) ethyl and unsubstituted or substituted groups (heteroaryl) (heterocyclyloxymethyl) ethyl. In other embodiments, R1 is an H or is an alkyl group having from one to eight carbon atoms. In some embodiments, R1 is H while in other embodiments, 'R1 is a methyl, ethyl or propyl group. In some embodiments, R1 is a methyl group. In still further embodiments, the invention provides compounds of formula IA and IC in which R1 is a substituted or unsubstituted alkenyl group such as a substituted or unsubstituted allyl group or a substituted or unsubstituted phenyl group. In the third and fourth groups of compounds of formula IA and IC, R3 is selected from the group gue consists of arilalguilo groups heteroarilalguilo, '- - alkoxy, alcoxialguilo, ariloxialguilo, alguilamino, dialguilamino, aryl, heteroaryl, heterocyclyl, cicloalguilo, heterociclilalguilo , cycloalguilalguilo, alguenilo, alguinilo, alguilo substituted or unsubstituted, and groups C (= NH) -heterocyclyl, and groups of the formula -LR7. In some embodiments of the third and fourth compound groups of the formula IA and IC, R3 is a 2,4-disubstituted phenylethyl group. In other embodiments, R 3 are selected from 2, 4-dihalophenylethyl and 2,4-dial-phenyl-phenyl-ethyl groups. In still other embodiments, R3 is selected from the group that includes phenylethyl, 2, 4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-fenoxifeniletilo, 4-bromofeniletilo, 4-methylphenylethyl, 4-chlorophenylethyl, 4-etilfeniletilo, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2- 'fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 2-fluoro-4 -clorofeniletilo, 2-fluoro-4-bromofeniletilo, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2, 4-difluorofeniletilo, 2,4-dimethylphenylethyl, "2, 4-dimethoxyphenylethyl, (2-pyridyl ) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl, groups (Phenyl) (hydroxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (hydroxymethyl) ethyl, substituted or unsubstituted groups (aryl) (hydroxymethyl) ethyl, substituted or unsubstituted (aryl) (alkoxymethyl) ethyl, substituted or unsubstituted (aryl) (aryloxymethyl ) ethyl, substituted or unsubstituted (aryl (arilalcoximetil) ethyl, substituted or unsubstituted (aryl) (heteroariloximetil) ethyl, substituted or unsubstituted (aryl) (heterocicliloximetil) ethyl, substituted or unsubstituted (heteroaryl) (alkoxymethyl) ethyl, substituted or unsubstituted ( heteroaryl) (aryloxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (arylalkoxymethyl) ethyl, and substituted or unsubstituted (heteroaryl) (heterocyclyloxymethyl) ethyl. In some embodiments of the third and fourth groups of compounds, R3 has any of the values described in this paragraph, and R1 is H or is a substituted or unsubstituted group. In some embodiments, R1 is H. In some aspects of the invention in the third and fourth compounds - groups of MC4-4-specific potent agonist compounds, the invention further provides compounds of the formula IA and IC in which R3 is a substituted or unsubstituted alkyl group such as a substituted or unsubstituted aryloxyalkyl group or a substituted or unsubstituted heteroaryloxyalkyl group. In some embodiments, R 3 is a substituted or unsubstituted aryloxymethyl group. In some embodiments, R3 is selected from the group consisting of -CH2-0-aryl groups wherein the aryl group is substituted with one or more halogen groups such as one or more Cl or F. In some embodiments, the aryl group is further substituted with an alkoxy group such as a methoxy or ethoxy group. In some modalities of the third and fourth group of compounds of the formula IA and IC, R3 is a group -CH2-0-aryl wherein the aryl group is selected from the group consisting of 2,4-difluorophenyl, 4-fluorophenyl, 2-fluorophenyl, 2-fluoro-4-methoxyphenyl, 2,4-dichlorophenyl, 4-chlorophenyl, 2-chlorophenyl, and 2-chloro-4-methoxyphenyl. In other embodiments, R 3 is a heterocyclylalkyl group. In some other embodiments of the compounds of formula IA and IC, R3 is a substituted or unsubstituted arylalkoxyalkyl group or a heteroarylalkoxyalipyl group. In some aspects of the invention of the compounds of the third and fourth groups of MC4-4-specific and potent agonist compounds, the invention further provides compounds of the formula IA and IC in which R3 is a. substituted or unsubstituted heterocyclylaylguilo group. In some embodiments, R3 is a substituted or unsubstituted heterocyclic ethyl group. In some embodiments, the heterocyclyl group is selected from the group consisting of 1H-tetrazole, piperazine, piperidine, imidazole groups and substituted or unsubstituted morpholines. In some embodiments, R3 is a -CH2-heterocyclyl group wherein the heterocyclyl group is a 1H-tetrazole, an imidazole, an N-methylpiperazine, and a 4-hydroxypiperidine, a 3-hydroxypiperidine, or a morpholine. In still other embodiments of the third and fourth groups of compounds of formula IA and IC, R 3 is a heterocyclyl group. In some embodiments of the third and fourth groups of the compounds of formula IA and IC, R3 is a substituted or unsubstituted piperazinyl group such as an N-methylpiperazinyl group, is a substituted or unsubstituted pyridine group, is a substituted or unsubstituted tetrazole group, is a substituted or unsubstituted group such as a 4-methylcyclohexyl group, or is a substituted or unsubstituted phenyl group. In still other embodiments, R 3 is an alkoxyalkyl group such as a methoxyalkyl group or an ethoxyalkyl group. In some embodiments, R3 is an alkoxyalkyl group such as an alkoxymethyl group such as a methoxymethyl group. In some other embodiments of the thirteenth and fourth groups of compounds of formula IA and IC, R 3 is a substituted or unsubstituted alkenyl group such as an aryl group substituted or unsubstituted by a substituted or unsubstituted vinyl group. In some embodiments, the invention provides compounds wherein R3 is a substituted or unsubstituted heteroaryl group, heterocyclyl group, alkylamino group, or cycloalkylamino group. In some embodiments, R 3 is selected from substituted or unsubstituted 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazine, morpholinyl, piperazinyl, and cyclopropylamino groups. In some embodiments of the third and fourth groups of compounds of formula IA and IC, R1 is an arylalkyl group such as those described above for R3. In some embodiments, R 1 is a substituted or unsubstituted phenylethyl group and R 3 is an alkyl group such as a methyl group. In other embodiments, R1 is an alkyl group such as a methyl group and R3 is selected from substituted aryloxyalkyl groups, phenylaminoalkyl groups or -LR7 groups wherein R7 is a group of the formula IIC. In the third and fourth groups of compounds of formula IA and IC, R4, R5 and R6 are independently selected from the group consisting of H, Cl, I, F, Br, OH, NH2, CN, N02, and alkoxy groups, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and substituted or unsubstituted heteroarylaminocarbonyl. In some embodiments of the third and fourth groups of compounds of the formula IA and IC, R4, R5 and R6 are selected from H or a halogen such as Cl or F. In other embodiments of the third and fourth groups of compounds of the formula IA and IC, at least one of R4, R5 and R6 is an F then in other embodiments of the third and fourth groups of compounds of the formula IA and IC, R4, R5 and R6 are all H. In the third and fourth groups of compounds of the formula IA and IC, W is a group of formula IIA or IIB which have the following structure.

HA || B In the third group of compounds of formula IA and IC, R1 'is selected from H, or alkenyl, alkenyl, alkynyl, cycloalguyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl groups, substituted or unsubstituted and R2 'is selected from H, or alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and substituted or unsubstituted groups. In some embodiments, at least one of R1 'and R2' is a heterocyclylalguilo group such as, without limitation, and pyrrolidinylmethyl or substituted or unsubstituted pyrrolidinylethyl groups. In some embodiments, W is a group of formula IIA. In the fourth group of compounds of formula IA and IC, R1 'and R2', together with the nitrogen to which they are attached, is joined together to form a heterocyclic ring. The heterocyclic ring is substituted with at least one group selected from the group consisting of arylalkyl groups, -C (= 0) -alguilo, -alguil- (C = 0) -0-alguilo, C (= 0) -0-alguilo , -C (= 0) -NH2, -C (= 0) -NH (alguilo), -C (= 0) -N (alguilo) 2, dialguilaminoalguilo, alylaminoalguilo, aminoalguilo, arilo, heteroaryl, heterocyclyl, heteroarylalguilo, heterocyclialguilo , and substituted or unsubstituted alguiltioalguilo. In some embodiments, the heterocyclic ring is a substituted piperazine and in other embodiments, the heterocyclic ring is a piperidine ring. In some embodiments, the piperazine or piperidine ring is substituted with ^ a group selected from a group consisting of a phenylalkyl group, a substituted or unsubstituted phenyl group, an -alkyl-SCH3 group, an indolylguiloyl group, a "morpholinylguiloyl group" , a pyridyl group, - - a piperidinyl group or a tetrahydrofuranylguilo group, -'--- "-. - In the third and fourth groups of compounds of formula IA and IC, R3 'is selected from the group consisting of H, and aryl, alkenyl, alkenyl, alkenyl, cycloalguyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl and cycloalkylalkyl, substituted or unsubstituted. In one embodiment, R3 'is selected from the group consisting of substituted or unsubstituted cycloalguyl, cycloalguyl polycyclic, alkenyl, alkenyl and aryl groups. In still other embodiments, R3 'is selected from the group consisting of cyclohexyl, 2-alkylcyclohexyl, 2,2-dialguylcyclohexyl, 2,3-dialguylcyclohexyl, 2,4-dialguylcyclohexyl, 2,5-dialguylcyclohexyl, 2,6-dialguylcyclohexyl, 3,4-dialguylcyclohexyl, 3-allylcyclohexyl, 4-allylcyclohexyl, 3,3,5-trialguylcyclohexyl, cyclohexylmethyl, 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-dialkoxycyclohexyl, 3, 4-dialcoxycyclohexyl, 2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-allylthiocyclohexyl, 3-allylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialguylthiocyclohexyl, 2,4-dialkylthiocyclohexyl, 3,4- dialkylthiocyclohexyl, 2,5-dialkylthiocyclohexyl, 2,6-dialguylthiocyclohexyl, 2,2-dialguilt cyclohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl, trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocaphenyl, carenyl, 7, 7-dialkinorbornyl, bornyl, norbomyl, and substituted or unsubstituted decalinyl. In still other embodiments, R3 is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl groups, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cyclohexenyl, 3, 3, 5-trimethylcyclohexyl, 4-t-butylcyclohexyl, cyclohexylmethyl, isopinocanphenyl, 7,7-dimethylnorbomyl, 4-isopropylcyclohexyl, 3-methylcycloheptyl, substituted or unsubstituted, 2-fluoro-4- groups methylcyclohexyl, 4-fluro-2-methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl, trifluoromethyl (polycyclic cycloalkyl), fluoromethyl (polycyclic cycloalkyl), and fluoro (polycyclic cycloalkyl). In the third and fourth groups of compounds of formula IA and IC, R 4 is selected from H, and substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalguyl, aryl, heteroaryl, heterocyclyl, arylalguyl or heteroarylalkyl groups. In one embodiment, R4 'is H. In the third and fourth groups of compounds of formula IA and IC, L is selected from the group consisting of a covalent bond, -CH2-, -O-, -S- and -NH -. In the third and fourth groups of compounds of the formula IA and IC, R7 is selected from the group consisting of substituted or unsubstituted arylaminoalkyl, aryl and aryloxyalkyl groups, or are selected from the group of the formulaIIC; IIC In the third and fourth groups of compounds of formula IA and IC, Y is selected from the group consisting of CH2 O, S and NR9, where NR9. In some embodiments, Y is a group NR9 and in some embodiments, m is 1. In some embodiments, R9 is an alkyl group such as a methyl group or is H. In the third and fourth groups of compounds of formula IA and IC , R8 is selected from the group consisting of H, or halogen, hydroxyl, carboxylic acid and alkyl, amino, alkylamino, dialkylamino, alkylaminoalguyl, heterocyclyl, alkoxy, carbonyl and aminocarbonyl groups, substituted or unsubstituted. In the third and fourth groups of compounds of formula IA and IC, m is an integer selected from the group consisting of 0, 1 and 2. In some embodiments, m is 1. The present invention provides a guinto and a sixth group of compounds that are MC4-4-specific potent agonists that are small molecules. Thus, according to one aspect of the invention, the invention provides a fifth and a sixth group of the compound of the formula ID. The compounds of the invention further include prodrugs of compounds of the formula ID, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, or solvates thereof. The compounds of the formula ID have the following structure In some embodiments of the fifth and sixth group of the compounds of the formula ID, at least one of R4, R5 or R6 is a halogen such as Cl or F. In at least one other embodiment, at least one of R4, R5 or R6 is F. In the guinto and sixth group of compounds of the formula ID, R1 is selected from the group consisting of H, arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alginyl and alkenyl substituted or unsubstituted In some embodiments, R1 is a 2,4-disubstituted phenylethyl group. In other embodiments, R1 is selected from 2,4-dihalophenylethyl and 2,4-dial-phenyl-phenylethyl groups. In still other embodiments, R1 is selected from the group including phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl. , 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, '"4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 2-fluoro 4-chlorophenylethyl, -2-fluoro-4-bromophenylethyl, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl, 2, -dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2- pyridyl) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl, groups (phenyl) (hydroxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (hydroxymethyl) ethyl, substituted or unsubstituted (aryl) (hydroxymethyl) ethyl, substituted or unsubstituted (aryl) (alkoxymethyl) ethyl, substituted or unsubstituted (aryl) (aryloxymethyl) groups ethyl, substituted or unsubstituted (aryl) (arylalkoxymethyl) ethyl, substituted or unsubstituted (aryl) (heteroaryloxymethyl) ethyl, substituted or unsubstituted (aryl) (heterocyclyloxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (alkoxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (aryloxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (arylalkoxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (heteroaryloxymethyl) ethyl, and substituted or unsubstituted groups (heteroaryl) (heterocyclyloxymethyl). In some embodiments of the fifth and sixth groups of compounds, R 1 is an H or is an alkyl group having from one to eight carbon atoms. In some embodiments, R 1 is H insofar as in other embodiments, R 1 is a methyl, ethyl or propyl group. In some embodiments, R1 is a methyl group. In still further embodiments, the invention provides compounds of the formula ID wherein R 1 is a substituted or unsubstituted alkenyl group such as a substituted or unsubstituted allyl group or a substituted or unsubstituted vinyl group.

In the guinto and sixth groups of compounds of the formula ID, R2 and R3 are independently selected from the group consisting of arylalguilo, heteroarylaguilo, alkoxy, alkoxyalguilo, aryloxyalguilo, alylamino, dialguilamino, aryl, heteroaryl, heterocyclyl, cycloalguilo, heterocyclylguilo, cycloalguilalguilo, alkenyl, alginyl, substituted or unsubstituted alguyl, and -C (= NH) -heterocyclyl groups, and groups of the formula -LR7. In some embodiments of the guinto and sixth groups of the compounds of the formula ID, R2 is -H or a substituted or unsubstituted algeryl group. In some embodiments, R3 is a 2,4-disubstituted phenylethyl group. In other embodiments, R3 is selected from 2,4-dihalophenylethyl and 2,4-dial-phenyl-phenylethyl groups. In still other embodiments, R 3 is selected from the group which includes phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl. , 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 2-fluoro-4 -chlorophenylethyl, 2-fluoro-4-bromophenylethyl, 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, groups (phenyl) (hydroxymethyl) ethyl substituted or unsubstituted (heteroaryl) (hydroxymethyl) ethyl, substituted or unsubstituted (aryl) (hydroxymethyl) ethyl, substituted or unsubstituted (aryl) (alkoxymethyl) ethyl, substituted or unsubstituted (aryl) (aryloxymethyl) groups ethyl, substituted or unsubstituted (aryl) (arylalkoxymethyl) ethyl, substituted or unsubstituted (aryl) (heteroaryloxymethyl) ethyl, substituted or unsubstituted (aryl) (heterocyclyloxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (alkoxymethyl) ethyl, substituted or unsubstituted ( heteroaryl) (aryloxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (arylalkoxymethyl) ethyl, substituted or unsubstituted (heteroaryl) (heteroaryloxymethyl) ethyl, and - groups (heteroaryl) (heterocyclyloxymethyl) ethyl substituted or unsubstituted. In some embodiments of the guinto and sixth groups of compounds, R3 has any of the values described in this paragraph, and R1 or R2 is H or is a substituted or unsubstituted alguyl group. In some embodiments, R1 is H. In other embodiments, R2 is H. In some aspects of the invention of the guinto compounds and sixth groups of potent and specific MC4-R agonists, the invention further provides compounds of the formula ID in wherein R3 is a substituted or unsubstituted aligyl group such as a substituted or unsubstituted aryloxyalipyl group or a substituted or unsubstituted heteroaryloxyalipyl group. In some embodiments, R 3 is a substituted or unsubstituted aryloxymethyl group. In some other embodiments, R3 is selected from the group consisting of -CH2-0-aryl groups, wherein the aryl group is substituted with one or more halogen groups such as one or more Cl or F. In some embodiments, the aryl group is further substituted with an alkoxy group such as a methoxy or ethoxy group. In some embodiments of the guinto and sixth groups of compounds of formula ID, R3 is a -CH2-0-aryl group in which the aryl group is selected from the group consisting of 2,4-difluorophenyl, 4-fluorophenyl, 2- groups fluorophenyl, 2-fluoro-4-methoxyphenyl, 2-dichlorophenyl, 4-chlorophenyl, 2-chlorophenyl, and 2-chloro-4-methoxyphenyl. In other embodiments, R 3 is a heterocyclylaylguilo group. In some other embodiments, R3 is a substituted or unsubstituted arylalkoxyalipyl group or a heteroarylalkoxyalipyl group. In some aspects of the invention of the guano compounds and sixth groups of MC4-R4-specific potent agonists, the invention further provides compounds of the formula ID in which R3 is a substituted or unsubstituted heterocyclylguiloyl group. In some modalities, R 3 is a substituted or unsubstituted heterocyclylmethyl group. In still other embodiments, the heterocyclyl group is selected from the group consisting of substituted or unsubstituted IH-tetrazole, piperazine, piperidine, imidazole and morpholine groups. In some embodiments, R3 is a -CH2-heterocyclyl group wherein the heterocyclyl group is a 1H-tetrazole, an imidazole, an N-methylpiperazine, a 4-hydroxypiperidine, a 3-hydroxypiperidine or a morpholino. In still other embodiments of the guinto and sixth groups of compounds of formula ID, R3 is a heterocyclyl group. In some embodiments R3 is a substituted or unsubstituted piperazinyl group such as a N-methylpiperazinyl group, is a substituted or unsubstituted pyridine group, is a substituted or unsubstituted tetrazole group, is a substituted or unsubstituted cycloalguyl group such as a 4-methylcyclohexyl group, or is a substituted or unsubstituted phenyl group. In still other embodiments, R 3 is an alkoxyalogyl group such as a methoxyalogyl group or an ethoxyalkyl group. - In some embodiments, R3 is an alkoxyalkyl group such as an alkoxymethyl group such as a methoxymethyl group. In some embodiments of the fifth and sixth groups of compounds of the formula ID, R3 is a substituted or unsubstituted alkenyl group such as a substituted or unsubstituted allyl group or a substituted or unsubstituted vinyl group.

In some embodiments, the invention provides compounds wherein R3 is a substituted or unsubstituted heteroaryl group, heterocyclyl group, alkylamino group, or cycloalkylamino groups. In some embodiments, R3 is selected from 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazine, morpholinyl, piperazinyl, and substituted or unsubstituted cyclopropylamino groups. In some embodiments of the fifth and sixth groups of compounds of formula ID, R 1 is an arylalkyl group such as those described above for R 3. In some embodiments, R3 is a substituted or unsubstituted phenylethyl group and R3 is an alkyl group such as a methyl group. In other embodiments of the fifth and sixth groups of compounds, R1 is an alkyl group such as a methyl group and R3 is selected from substituted aryloxyalkyl groups, substituted aryloxyalkyl groups, phenylaminoalkyl groups or -LR7 groups, wherein R7 is a group of the formula IIC. In the fifth and sixth groups of compounds of the formula ID, R4, R5 and R6 are independently selected from the group consisting of H, Cl, I, F, Br, OH, NH2, CN, N02 and alkoxy, alkyl, alkenyl groups alkynyl, alkynyl, alkylamino, dialkylamino, cycloalkyl, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, hetrocyclylaminocarbonyl and heteroarylaminocarbonyl, substituted or unsubstituted. In some embodiments of the guinto and sixth groups of the compounds of the formula ID, R4, R5 and R6 are selected from H or halogen or a halogen such as Cl or F. In other embodiments the guinto and sixth groups of compounds of the formula ID , at least one of R4, R5 and R6 is an F while in other embodiments, R4, R5 and R6 are all H. In the guinto and sixth groups of the compounds of the formula ID, W is a group of the formula IIA or IIB that has the following structure.

HA IIB In the fifth group of compounds of the formula ID, R1 'is selected from H, or substituted, unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl groups, and R2 is selected from H, or alkyl, alkenyl, alkynyl, cycloalkyl, ary, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and substituted and unsubstituted heterocyclylalkyl groups. In some embodiments, at least one of R1 'and R2' is a heterocyclylalkyl group, such as, but not limited to, a substituted and unsubstituted pyrrolidinylmethyl or pyrrolidinylethyl group. In some embodiments, W is a group of formula IIA. In the sixth group of compounds of the formula ID, R1 'and R2', together with the nitrogen to which they are attached, are joined together to form a heterocyclic ring. The heterocyclic ring is substituted with at least one group selected from the group consisting of arylalkyl groups, -C (= 0) -alkyl, -alkyl-C (= 0) -O-alkyl, -C (= 0) -O- alkyl, -C (= 0) -NH2, -C (= 0) -NH (alkyl), -C (= 0) -N (alkyl) 2, dialkylaminoalkyl, alkylaminoalguyl, aminoalguyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl, substituted and unsubstituted heterocyclylalguilo, and alguiltioalguilo. In some embodiments, the heterocyclic ring is a substituted piperazine and in other embodiments, the heterocyclic ring is a piperidine ring. In some embodiments, the piperazine or piperidine ring is substituted with a group selected from the group consisting of a phenylalkyl group, substituted and unsubstituted phenyl, an -alkyl-SCH3 group, an indolyalkyl group, a morpholinylaguyl group, a pyridyl group, an piperidinyl group, a tetrahydrofuranylguilo group. In a guinto and sixth groups of the compounds of the formula ID, E3 'is selected from the group consisting of H, and aryl, algeryl, alkenyl, alginyl, cycloalguyl, heteroaryl, heterocyclyl, heterocyclylaguyl, arylguiloyl groups, substituted and unsubstituted heteroarylalkyl, and cycloalkylalkyl. In one embodiment, R3 'is selected from the group consisting of cycloalguyl, polycyclic cycloalkeyl, alkenyl, alkenyl and aryl substituted and unsubstituted groups. In still other embodiments, R3 'is selected from the group consisting of cyclohexyl, 2-alkylcyclohexyl, 2,2-dial-keylcyclohexyl, 2,3-dial-guyl-cyclohexyl, 2,4-dial-keyl-cyclohexyl, 2,5-dial-keyl-cyclohexyl, 2,6-dial-keyl-cyclohexyl groups. , 3,4-dialguylcyclohexyl, 3-allylcyclohexyl, 4-allylcyclohexyl, 3,3,5-trialguylcyclohexyl, cyclohexylmethyl, 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-dialkoxycyclohexyl, 3, 4-dialkoxycyclohexyl, 2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-allylthiocyclohexyl, 3-allylthiocyclohexyl, 4-allylthiocyclohexyl, 2,3-dialguylthiocyclohexyl, 2,4-dialkylthiocyclohexyl, 3,4- dialguiltiocyclohexyl, 2,5-dialguiltiocyclohexyl, 2,6-dialguiltiocyclohexyl, 2,2-dialguil thiocyclohexyl, fluorocycloalguyl, fluoroalguylcycloalguilo, trifluoromethylcycloalguilo, cyclopentyl, cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalguylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocaphenyl, carenyl, 7, 7-dialkylnorbornyl, bornyl, norbornyl, and substituted and unsubstituted decalinyl. In still other embodiments, R3 'is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl groups. , 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cyclohexenyl, 3,3,5-trimethylcyclohexyl, 4,4-t-butylcyclohexyl, cyclohexylmethyl, isopinocamfeyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, 3- substituted and unsubstituted methylcycloheptyl, 2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethylcyhohexyl, 2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl, trifluoromethyl (cycloalkyl) polycyclic), fluoromethyl (polycyclic cycloalkyl), and fluoro (polycyclic cycloalkyl). By way of non-limiting example, suitable R3 'groups, cycloalkyl, cyclohexyl and polycyclic cycloalkyl including fluorine, include, without limitation, the structures set forth above with respect to the first group of compounds of formula IA, IB and IC. In the fifth and sixth groups of the compound of the formula ID, R4 'is selected from the group consisting of H, substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalguyl, aryl, heteroaryl, heterocyclyl, arylalguyl, and heteroarylalkyl groups. . In one embodiment of the guinto and sixth groups of the compound of the formula ID, R4 'is H. In the guinto and sixth group of the compounds of the formula ID, L is selected from the group consisting of a covalent bond, -CH2-, -0-, -S-, and -NH-. In the fifth and sixth group of the compounds of the formula ID, R7 is selected from the group consisting of substituted and unsubstituted arylaminoalkyl, aryl, and aryloxyalkyl groups or is selected from a group of the formula IIC; pc In the guinto and sixth groups of compounds of the formula ID, Y is selected from the group consisting of CH2, 0, S and NR9 where R9. In some embodiments, Y is a group NR9 and in some embodiments, m is 1. In some embodiments, R9 is an alkyl group such as a methyl group or is H. In the guinto and sixth groups of compounds of the formula ID, R8 it is selected from the group consisting of H, a halogen, hydroxyl, carboxylic acid, and substituted, unsubstituted algeryl, amino, alkylamino, dialkylamino, alkylaminoalguyl, heterocyclyl, alkoxy, carbonyl, and aminocarbonyl groups. In the guinto and sixth groups of compounds of the formula ID, m is an integer selected from the group consisting of 0, 1 and 2. In some embodiments, m is 1. The present invention provides a seventh and eighth group of compounds- what are strong and specific agonists of MC4-R that are small molecules. Thus, according to one aspect of the invention, the invention provides a seventh and eighth groups of compounds of the formula IE. The compounds of the invention further include -prodrugs of compounds of formula IE, pharmaceutically acceptable salts "thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, or solvates thereof. '" The - "Compounds of the formula IE have the following structure.

In some embodiments of the seventh and eighth groups of the compounds of the formula IE, at least one of R4, R5, or R6 is a halogen such as Cl or F. In other embodiments, at least one of R4, R5 or R6 is F In the seventh and eighth groups of compounds of the formula IE, R1 is selected from the group consisting of H, substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylguilo, alkenyl, alkynyl, and algeryl groups. . In some embodiments, R1 is a 2,4-disubstituted phenylethyl group. In other embodiments, R1 is selected from 2,4-dihalophenylethyl and 2,4-dialkylphenylethyl groups. In still other embodiments of the seventh and eighth groups of compounds of the formula IE, R 1 is selected from the group including phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl , 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, -hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro- 4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromophenylethyl, 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, (phenyl) (hydroxymethyl) ethyl, (heteroaryl) (hydroxymethyl) ethyl substituted unsubstituted, (aryl) (hydroxymethyl) ethyl substituted and unsubstituted, (aryl) (alkoxymethyl) ethyl substituted and unsubstituted, (a ril) (aryloxymethyl) ethyl substituted and unsubstituted, (aryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (aryl) (heteroaryloxymethyl) ethyl substituted and unsubstituted, (aryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (alkoxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (aryloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (substituted heteroaryl) unsubstituted and unsubstituted (heteroaryl) (heteroaryloxymethyl) ethyl, and (heteroaryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted. In some embodiments, R1 is an H or is an alkyl group having from one to eight carbon atoms. In some embodiments, R1 is H while in other embodiments, R1 is a methyl, ethyl or propyl group. In some embodiments, R1 is a methyl group. In still further embodiments of the seventh and eighth groups, the invention provides compounds of formula IE in which R 1 is a substituted and unsubstituted alkenyl group such as a substituted and unsubstituted allyl group or a substituted and unsubstituted vinyl group. In the seventh and eighth group of compounds of the formula IE, R1 is H or is a substituted and unsubstituted alkyl group. In some embodiments, R1 is H. In the seventh and eighth groups of compounds of the formula IE, R4, R5 and R6 are independently selected from the group consisting of H, Cl, I, F, Br, OH, NH2, CN, N02 and substituted and unsubstituted alkoxy, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalguilo, heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalbumylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, and heteroarylaminocarbonyl groups. In some embodiments, R4, R5 and R6 are selected from H or a halogen such as Cl or F. In other embodiments, at least one of R4, R5 or R6 is an F while in other embodiments, R4, R5 and R6 they are all H. In the seventh and eighth groups of compounds of the formula IE, W is a group of the formula IIA-or IIB have the following structure.

HA IIB In the seventh group of compounds of the formula IE, R1 'is selected from H, or substituted, unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl groups, and R2 is selected from H, or substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalguyl, and heterocyclylguiloyl groups. In some embodiments, at least one of R 1 'and R 2' is a heterocyclylayl group such as, but not limited to, a substituted or unsubstituted pyrrolidinylmethyl or pyrrolidinylmethyl group In some embodiments, W is a group of the formula II. In the eighth group of compounds of the formula IE, R1 'and R2', together with the nitrogen to which they are attached, are joined together to form a heterocyclic ring The heterocyclic ring is substituted with at least one group selected from the group consisting of of arylalkyl groups, -C (= 0) -alkyl, -alkyl-C (= 0) -O-alkyl, -C (= 0) -O-alkyl, -C (= 0) -NH2, -C (= 0) -NH (alkyl), -C (= 0) -N (alkyl) 2, dialkylaminoalkyl, alkylaminoalkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalguilo, heterocyclylalguilo, and substituted and unsubstituted alkylthioalkyl In some embodiments, the heterocyclic ring is a substituted piperazine and in other embodiments, the heterocyclic ring is a ring or piperidine. In some embodiments, the piperazine or piperidine ring is substituted with a group selected from the group consisting of a phenylalkyl group, a substituted and unsubstituted phenyl group, an -alkyl-SCH3 group, an indolyalkyl group, a morpholinylalkyl group, or a group pyridyl, a piperidinyl group, and a tetrahydrofuranylalkyl group. In the seventh and eighth groups of the compounds of formula IE, R3 'is selected from the group consisting of H, and aryl, alkyl, alkenyl, alkenyl, cycloalguyl, heteroaryl, heterocyclyl, heterocyclylaguyl, arylalguyl, heteroarylalkyl, -? substituted and unsubstituted cycloalkylalkyl. In an embodiment of the seventh and eighth groups of compounds of the formula IE, R3 'is selected from the group consisting of substituted and unsubstituted cycloalkyl, polycyclic, alkenyl, alkyl and aryl groups. In still other embodiments, R3 'is selected from the group consisting of cyclohexyl, 2-allylcyclohexyl, 2,2-dialguylcyclohexyl, 2,3-dial-guyl-cyclohexyl, 2-dialkylcyclohexyl, 2,5-dial-guyl-cyclohexyl, 2,6-dial-keyl-cyclohexyl groups, 3,4-dialguylcyclohexyl, 3-allylcyclohexyl, 4-allylcyclohexyl, 3,3,5-trialkylcyclohexyl, cyclohexylmethyl, 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-alkoxy-cyclohexyl, 3-alkoxycyclohexyl, 4-alkoxycyclohexyl, 2,3-dialkoxycyanohexyl, 2,4-dialkoxycyclohexyl, 3,4- dialcoxycyclohexyl, 2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-allylthiocyclohexyl, 3-alkylthiocyclohexyl, 4-allylthiocyclohexyl, 2,3-dialkylthiocyclohexyl, 2,4-dialkylthiocyclohexyl, 3,4-dialguylthiocyclohexyl, 2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl, 2,2-dialk ilthiocyclohexyl, fluorocycloalkyl, fluoroalkylcycloalkyl, trifluoromethylcycloalguyl, cyclopentyl, cycloheptyl, cyclohexenyl, isopropyl, n-butyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalguylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocaphenyl, carenyl, 7, 7-dialguilnorbornyl, bornyl, norbornyl, and substituted and unsubstituted decalinyl. In still other embodiments of the seventh and eighth groups of compounds of formula IE, R3 'is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl groups, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, cyclohexenyl, 3, 3, 5-trimethylcyclohexyl, 4-t-butylcyclohexyl, cyclohexylmethyl , isopinocampheyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, 3-methylcycloheptyl, 2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethyl-cyclohexyl, 2- methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl, trifluoromethyl (polycyclic cycloal-guyl), fluoromethyl (polycyclic cycloal-guyl), and fluoro (polycyclic cycloal-guyl) substituted and unsubstituted. By way of non-limiting example, the appropriate R3 'groups, cycloalguyl ,. cyclohexyl and polycyclic cycloalguyl which include fluorine, include, without limitation, the structures set forth above with respect to the first group of compounds of the formula IA, IB and IC.

In the seventh and eighth groups of compounds of the formula IE, R 4 'is selected from the group consisting of H, and substituted alkenyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, and heteroarylalkyl groups substituted unsubstituted In one embodiment, R4 'is H. In some embodiments of any of the compounds of the invention which includes a group W of formula IIA or IIB, where R1' and R2 'are joined together with the nitrogen to which they are attached to form a heterocyclic group, the heterocyclic group is substituted with a -CN group, a -OH group, a -CF3 group, a -CH2F group, a -CHF2 group, a -CH2CN group, a -CH20H group, a -CH2-O group -alkyl or a cycloalkyl group such as a cyclopropyl group. In some compounds, the heterocyclic compound is a piperidine or a piperazine. In some compounds, R1 'and R2' are joined together with the nitrogen to which they are attached to form a piperazine in which the N-atom in the piperazine ring which is not part of the guanidine group is substituted with a group -C = N , a -OH group, a -CH2CN group, or a cycloalkyl group. In some compounds in which R1 'and R2' are joined together to the nitrogen to which they are attached to form a heterocyclic ring, the heterocycle is a bicyclic structure that includes a spirocenter such that the heterocyclic ring is part of a spirocyclic structure. In some compounds, in which R1 'and R2' are joined together to the nitrogen to which they are attached to form a heterocyclic ring, the heterocyclic ring is substituted such that a ring carbon atom of the heterocyclic ring is a carbonyl carbon or the The carbon of the heterocyclic ring is replaced with a sulfur that binds to one or more oxygen atoms. For example, in some embodiments, R1 'and R2' are joined together with the nitrogen to which they are attached to form a piperazine ring in which one of the ring carbon atoms is a carbonyl carbon atom such that the compound of piperazine is a lactam which may be further substituted, for example, with an alkyl group such as a methyl group. The present invention provides for potent and specific MC4-R agonists that are small molecules and may exhibit reduced bio-accumulation properties when administered to mammalian subjects. According to one aspect of the invention, the invention provides compounds of the formula VA and VB. The compounds provided by the invention further include prodrugs of the compound of the formula VA and VB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof and solvates thereof. The compounds of the formula VA or VB have the following structures: VA VB In the compounds of the formula VA and VB, R1 is selected from substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alginyl, or algeryl groups. In some embodiments R1 is a substituted and unsubstituted arylalguilo group such as a substituted and unsubstituted phenylethyl group. In some embodiments R1 is a substituted and unsubstituted phenylethyl group such as a 4-substituted and unsubstituted phenylethyl group or a 2-disubstituted phenylethyl group such as 4-halophenylethyl, 2-halo-4-alkoxyphenylethyl, and 2,4-dihalophenylethyl groups . In some embodiments, R 1 is selected from phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, -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, and (phenyl) (hydroxymethyl) ethyl. In some embodiments, R1 is selected from a group 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. In still other embodiments, R 1 is selected from phenylethyl, 2-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl groups. , 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2 -fluoro-4-bromophenylethyl, 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, (phenyl) (hydroxymethyl) ethyl, substituted and unsubstituted, (heteroaryl) (hydroxymethyl) ethyl substituted and unsubstituted, (aryl) (hydroxymethyl) ethyl) substituted and unsubstituted, (aryl) (alkoxymethyl) ethyl substituted and unsubstituted, (aryl) (aryloxymethyl) ethyl substituted and in substituted, (aryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (aryl) (heteroaryloxymethyl) ethyl substituted and unsubstituted, (aryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (alkoxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (aryloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (substituted heteroaryl) unsubstituted and unsubstituted (heteroaryl) (heteroaryloxymethyl) ethyl, and (heteroaryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted. In the .-. compounds of the formula VA and VB, R3 is selected from substituted and unsubstituted aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, or cycloalkylamino groups. The compounds of the formula VA and VB. c n_., alores-, R3 such as those set forth above have been found to exhibit reduced bio-accumulation properties as evidenced by lower t? / 2 blood plasma values in test subjects to which they have been administered in the compounds . In general, these compounds also provide improved plasmatic Cmax values and can also provide improved Cmax brain values. In some embodiments, R 3 is selected from heterocyclyl groups substituted or unsubstituted by substituted and unsubstituted heteroaryl groups. In other embodiments, R3 is selected from pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl groups. , substituted or substituted pyridazinyl, tetrazolyl, or pyridazinyl. In some embodiments, R3 is selected from the heteroaryl or heterocyclyl group of the formula. which may be additionally substituted or may be unsubstituted. In some embodiments, the invention provides the compound of the formula VA and VB in which R3 is selected from heterocyclylalkyl, substituted and unsubstituted cycloalkylamino group. For example, in some embodiments, R3 is selected from a group such as substituted or unsubstituted cyclopropylamino group; a substituted and unsubstituted piperazinylalkyl group such as a piperazinylmethyl group or "an N-methylpiperazinylmethyl group, or a group that is piperidinylalkyl such as a piperidinylmethyl group or a piperidinylethyl group In some embodiments, R3 may be selected from an unsubstituted aryl or cycloalkyl group or substituted The examples include compounds of the following formula which may be additionally unsubstituted.

In the compounds of the formula VA and VB, R4, R5, and R6 is independently selected from H, Cl, I, F, Br, OH, NH2, CN, N02, substituted and unsubstituted alkoxy and alkyl groups. In some modalities, each of R4, R5, and R6 are H.

In the compounds of the formula VA and VB, R1 'and R2' together with the nitrogen to which they are attached form a substituted and unsubstituted heterocyclyl group. In some embodiments, R1 'and R2', together with the nitrogen to which they are attached, form a substituted and unsubstituted, saturated heterocyclyl group, such as, without limitation, a piperazinyl group or a piperidinyl group, or the like. In some embodiments, R1 'and R2', together with the nitrogen to which they are attached, form a substituted and unsubstituted piperazinyl group. In some embodiments, R1 'and R2', together with the nitrogen to which they are attached, form a piperazinyl group which is substituted with at least one group selected from fluoromethyl, difluoromethyl or trifluoromethyl groups. In other embodiments, R1 'and R2' together with the nitrogen to which they are attached form a piperazinyl group substituted with at least one carbonyl group such that the piperazinyl group is a piperazinone which may be further substituted. In some embodiments, R1 'and R2', together with the nitrogen to which they are attached, form a piperazinone of the formula which may be additionally substituted. In some embodiments, R1 'and R2', together with the nitrogen to which they are attached, form a piperazinone of the formula in some embodiments, R1 'and R2', together with the nitrogen to which they are attached form a piperazinone of the formula In some embodiments, the invention provides compounds of the formula VA and VB in which R1 'and R2', together with the nitrogen to which they are attached, form a piperazinyl group of the formula Compounds of formula VA and VB with R1 'and R2' values such as those set forth above have been found to exhibit reduced bioaccumulation properties as evidenced by lower blood plasma values of ti2 in test subjects to whom it has been administered the compounds. In general, these compounds also provide improved plasmatic Cmax values and also provide improved Cmax brain values and intracerebroventricular (icv) efficiency. Significant reductions were also observed in Fl (food intake) at 16 hours and 30 mpK (mg / kg) in some subjects for some compounds of the formula VA and VB. In the compounds in which R1 'and R2' are joined together with the nitrogen to which they are bound to form a piperazine, particularly a piperazine with reduced basicity in the distant NH group, they have been found particularly suitable since they possess reduced bioaccumulation properties. Examples of these compounds are disclosed in the various embodiments described above. The compounds of the formula VA and VB in which R1 'and R2' are joined to form a piperazine substituted with a monofluoroalkyl, difluoroalkyl, and / or trifluoroalkyl group, or a piperazinone such as an alkylpiperazinone, are only some examples of the compounds They exhibit reduced bioaccumulation properties as long as they have excellent efficiency. The compounds of the formula VA and VB, R3 'is selected from substituted and unsubstituted cycloalguyl group. In the same embodiments, R3 'is selected from the group consisting of cyclohexyl, 2-alkylcyclohexyl, 2,2-dial-keylcyclohexyl, 2,3-dial-keyl-cyclohexyl, 2,4-dial-keyl-cyclohexyl, 2,5-dial-guyl-cyclohexyl, 2,6-dial-keyl-cyclohexyl groups. , 3,4-dial uylcydohexyl, 3-allylcyclohexyl, 4-allylcyclohexyl, 3,3,5-trialguylcyclohexyl, 2-aminocyclohexyl, 3-aminociclshexyl, 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-dialkoxycyclohexyl, 3,4- dialcoxycyclohexyl, 2,5-dialkoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-alkylthiocyclohexyl, 3-allylthiocyclohexyl, 4-alkylthiocyclohexyl, 2,3-dialguylthiocyclohexyl, 2,4-dialkylthiocyclohexyl, 3,4-dialguylthiocyclohexyl, 2,5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, fl uorocicloalguilo, fluoroalquilcicloalguilo, trifluorometilcicloalguilo, cyclopentyl, cycloheptyl, cyclohexenyl, cyclooctyl, 2-arilciclohexilo, 2-phenylcyclohexyl, 2-arilalguilciclohexilo, 2-bencilciclohexilo, 4-phenylcyclohexyl, adamantyl, isocamfenilo, carenilo, 7,7-dialguilnorbornilo, bornyl, norbornyl, and substituted and unsubstituted decalinyl. In other embodiments, R3 is selected from the group consisting of cyclohexyl groups, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, , 4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl, isopinocampheyl, 7,7-dimethylnorbomyl, 4-isopropylcyclohexyl, 3-methylcycloheptyl, 2-fluoro-4-methylcyclohexyl , 4-fluoro-2-methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl, trifluoromethyl (polycyclic cycloal-guyl), fluoromethyl (polycyclic cycloal-guyl), and fluorine ( polycyclic cycloal-guyl) substituted and unsubstituted. In some embodiments, R3 'is a cycloalguyl, polycyclic, substituted and unsubstituted group. In some embodiments, R3 'is a substituted and unsubstituted polycyclic cycloalguyl group having the formula III In some embodiments, the compounds of formula VA and VB are selected from any of the following compounds: As described, the present invention provides potent and specific MC4-R agonists which are stick 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 the VIA and VIB formulas." Compounds provided with the invention further include prodrugs of the compounds of the formula VIA and VIB, pharmaceutically acceptable salts thereof, stereoisomers of the same, tautomers thereof, hydrates thereof, and solvates thereof The compounds of the formula VIA and VIB have the following structures: VIA VIB In the compounds of the formula VIA and VIB, R1 is selected from unsubstituted and unsubstituted arylalguilo, heteroarylaguilo, aryl, heteroaryl, heterocyclic, cycloalguilo, heterocyclylguilo, cycloalguilalguilo, alguenilo, alguinilo, or alguilo groups. In some embodiments, R1 'is a substituted or unsubstituted arylalguil group such as an unsubstituted or substituted phenylethyl group. In some embodiments R1 is a substituted phenylethyl group such as a 4-phenylethyl group substituted by a 2,4-disubstituted phenylethyl group such as 4-halophenylethyl, 2-halo-4-alkoxyphenylethyl, and 2,4-dihalophenylethyl. In some embodiments, R 1 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, and (phenyl) (hydroxymethyl) ethyl substituted and unsubstituted. In some other embodiments, R 1 is selected from a 2-fluoro-4-methoxyphenylethyl group, a 2-chloro-4-methoxyphenylethyl, 4-fluorophenylethyl group, 4-chlorophenylethyl nucleic acids, a 4-chloro-2-fluorophenylethyl group, , -dichlorophenylethyl, a 4-bromophenylethyl, or a 4-bromo-2-fluorophenylethyl substituted and unsubstituted. In still other embodiments, R 1 is selected from phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, -bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2- fluoro-4-bromophenylethyl, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2,4-difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4-di ethoxyphenylethyl, (2-pyridyl) ethyl, (3 -pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl, (phenyl) (hydroxymethyl) ethyl, substituted and unsubstituted (heteroaryl) (hydroxymethyl) ethyl, - groups (aryl) (hydroxymethyl) ethyl substituted and unsubstituted, (aryl) (alkoxymethyl) ethyl substituted and unsubstituted, (aryl) (aryloxymethyl) ethyl substituted and unsubstituted, (aryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (aryl) (heteroaryloxymethyl) ethyl substituted and unsubstituted, (aryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (alkoxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (aryloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (arylalkoxymethyl) methyl substituted and unsubstituted, (substituted heteroaryl) unsubstituted and unsubstituted (heteroaryl) (heteroaryloxymethyl) ethyl, and (heteroaryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted. In the compounds of the VIA and VIB, R3 is selected from H or unsubstituted or substituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups. Compounds of the formula VIA and VIB with R3 values such as those discussed above, have been found to exhibit reduced bioaccumulation properties as evidenced by lower blood plasma values of t and 2 in test subjects with which the compounds are administered. In general, these compounds also provide improved plasmatic Cmax values and also provide improved Cmax brain values. In some embodiments, R 3 is selected from substituted or unsubstituted heterocyclyl groups or substituted and unsubstituted heteroaryl groups. In other embodiments, R3 is selected from pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl groups. , substituted or unsubstituted pyridazinyl, tetrazolyl, or pyridazinyl. In some embodiments R3 is selected from the heteroaryl or heterocyclyl group of the formula which may be additionally substituted or unsubstituted. In some embodiments, the invention provides compounds of the formula VIA and VIB in which R3 is selected from heterocyclylalkyl or substituted cycloalkylamino or unsubstituted groups. For example, in some embodiments, R3 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 a N-methylpiperazinylmethyl group; or a piperidinylalkyl group such as a piperidinylmethyl group or a piperidinylmethyl group. In some embodiments, R3 may be selected from a substituted or unsubstituted aryl or cycloalkyl group. Examples include compounds of the following formula which may be further substituted.

In the compounds of the formula VIA and VIB, R4, R5, and R6 are independently selected from H, Cl, .1, F, Br, OH, NH2, CN, N02, and substituted and unsubstituted alkoxy and alkyl groups. In some embodiments, each of R4, R5, and R6 are H. In the compounds of the formula VIA and VIB, Z is a piperazinone of the formula which may be additionally unsubstituted. In some embodiments, Z is a piperazinone of the formula in some embodiments, Z is a piperazinone of the formula Compounds of the formula VIA and VIB with Z-values such as those discussed above have been found to exhibit reduced bioaccumulation properties as evidenced by lower blood plasma values of t? / 2 in test subjects at which has administered the compounds. In general, these compounds also provide improved plasmatic Cmax values and can also provide Cma? improved brain and intracerebroventricular efficiency (icv). Significant reductions were also observed in Fl (food intake) at 16 hours and 30 mpK (mg / kg) in some subjects for some compounds of the formula VIA and VIB. The compounds of the formula VIA and VIB have been found particularly suitable as having reduced bioaccumulation properties. Examples of these compounds are disclosed in the various embodiments described above. In the compounds of Formula VIA and VIB, R3 'is selected from H or substituted or unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or cycloalkylalguyl groups. In some embodiments, R3 'is selected from substituted or unsubstituted cycloalguyl groups. In some embodiments, R3 'is selected from the group consisting of cyclohexyl group, 2-allylcyclohexyl, 2,2-dialkylcyclohexyl, 2,3-dialguylcyclohexyl, 2-dialkylcyclohexyl, 2,5-dialkylcyclohexyl, 2,6-dialkylcyclohexyl, 3,4-dialkylcyclohexyl, 3-alkylcyclohexyl, 4-allylcyclohexyl, 3,3,5-trialguylcyclohexyl, 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-dialkoxycyclohexyl, 3,4-dialkoxycyclohexyl, , 5-dialcoxycyclohexyl, 2,6-dialkoxycyclohexyl, 2,2-dialkoxycyclohexyl, 2-allylthiocyclohexyl, 3-allylthiocyclohexyl, 4-allylthiocyclohexyl, 2,3-dialguylthiocyclohexyl, 2,4-dialkylthiocyclohexyl, 3,4-dialkylthiocyclohexyl, 2,5 -dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexyl, flu O-cycloalkyl, fluoroalkylcycloalkyl, trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocaphenyl, carenyl, 7,7-dialkylnorbornyl, bornyl, norbornyl, and substituted and unsubstituted decalinyl. In still other embodiments, R3 'is selected from the group consisting of cyclohexyl groups, 2-methylcyclhexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl, 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, , 3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl, isopinocampheyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, 3-methylcycloheptyl, 2-fluoro-4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl, 4, -difluoro- 2-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl, trifluoromethyl (polycyclic cycloalkyl), fluoromethyl (polycyclic cycloal-guyl), and fluoro (polycyclic cycloal-guyl) substituted and unsubstituted. In some embodiments, R3 'is a substituted or unsubstituted polycyclic cycloalguyl group. In some embodiments, R3 'is an unsubstituted or substituted polycyclic cycloalguyl group having the formula VIII.

VIII In accordance with one aspect of the invention, any of the compounds of Examples 113-390, tautomers are provided. thereof, salts thereof, mixtures thereof, or pharmaceutical formulations comprising the compounds, tautomers, salts or mixtures thereof. In some embodiments, the invention provides any of the compounds of Examples 113-343. In some embodiments, the invention provides any of the compounds of Examples 113-215. In other embodiments, the invention provides any of the compounds of Examples 216-343. In still other embodiments, the invention provides any of the compounds of Examples 344-390.

According to another aspect of the invention, the compound of formula VIIA and VIIB is provided. The compounds provided by the invention further include prodrugs of the compound of formula VIIA and VIIB, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, and solvates thereof. The compounds of formula VIIA and VIIB have the following structure.

VIIA VIIB In the compounds of formula VIIA and VIIB, R1 is selected from substituted or unsubstituted arylalguilo, heteroarylaguilo, aryl, heteroaryl, heterocyclyl, cycloalguilo, heterocyclylaguilo, 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 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-alkoxyphenylethyl, and 2,4-dihalophenylethyl. In some embodiments, R 1 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, -difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4-dimethoxyphenylethyl, (2-pyridyl) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl, and (phenyl) (hydroxymethyl) ethyl.

In still other embodiments, R1 is selected from a 2-fluoro-4-methoxyphenylethyl group,. . a. .group 2-fluoro-4-methylphenylethyl, a 2-chloro-4-methoxyphenylethyl, 4-fluorophenylethyl, a 4-chlorophenylethyl, a 4-chloro-2-fluorophenylethyl, a 2,4-dichlorophenylethyl, a 4-bromophenylethyl, or a -4-bromo-2-fluorophenylethyl group. In still other embodiments, R 1 is selected from phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxyphenylethyl, 2- groups. chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, 4-hydroxyphenylethyl, 3,4-dimethoxyphenylethyl, 2-chloro-4-iodophenylethyl, 2-fluoro-4-methylphenylethyl, 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromophenylethyl, 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, (phenyl) (hydroxymethyl) ethyl, substituted and unsubstituted (heteroaryl) (hydroxymethyl) ethyl, unsubstituted and substituted (aryl) (hydroxymethyl) ethyl groups, unsubstituted and substituted (aryl) (alkoxymethyl) ethyl groups, (aryl) (aryloxymethyl) ethyl substituted and unsubstituted, (aryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (aryl) (heteroaryloxymethyl) ethyl substituted and unsubstituted, (aryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (alkoxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (aryloxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (arylalkoxymethyl) ethyl substituted and unsubstituted, (heteroaryl) (heteroaryloxymethyl) ethyl substituted and unsubstituted, and (heteroaryl) (heterocyclyloxymethyl) ethyl substituted and unsubstituted. In the compounds of the formula VIIA and VIIB, R3 is selected from H or arylalguilo, heteroarylaguilo, alkoxy, alkylamino, dialguilamino, aryl, heteroaryl, heterocyclyl, cycloalguilo, aminocycloalguilo, heterocyclylguilo, cycloalguilalguilo, alguenilo, alguinilo, or alguilo substituted or unsubstituted groups. . Compounds of formula VIIA and VIIB with R3 values such as those discussed above and have been found to exhibit reduced bioaccumulation properties as evidenced by blood plasma values of t_./2 lower in test subjects to which they have been administered the compounds. In general, these compounds also provide improved plasmatic Cmax values and can also provide improved Cmax brain values. In some embodiments, R 3 is selected from substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted heteroaryl groups. In other embodiments, R3 is selected from pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, pyrazinyl, thiazolyl, pyrimidinyl, guinuclidinyl, indolyl, imidazolyl groups. Substituted or unsubstituted triazolyl, tetrazolyl, or pyridazinyl. In some embodiments, R3 is selected from the heteroaryl or heterocyclyl group of the formula. which may be additionally substituted or may be unsubstituted. In some embodiments, the invention provides compounds of the formula VIIA and VIIB in which R3 is selected from substituted or unsubstituted heterocyclylaylguilo or cycloalguilamino groups. For example, in some embodiments R3 is selected from a group such as a substituted or unsubstituted cyclopropylamino group; a substituted or unsubstituted piperazinylalguyl group such as a piperazinylmethyl group or an N-methylpiperazinylmethyl group; or a piperidinylalguilo group such as a piperidinylmethyl group or a piperidinylethyl group. In some embodiments, R 3 can be selected from a substituted or unsubstituted aryl, cycloalguyl or aminocycloalyl group. Examples include compounds of the following formula which may be further substituted.

In the compounds of formula VIIA and VIIB the, R4, R5 / Rs and they are independently selected from H, Cl, 1, F, Br, OH, NH2, CN, N02, and alkoxy and substituted and unsubstituted groups alguilo. In some embodiments, each of R, R5, and R6 are H. In the compounds of the formula VIIA and VIIB, Y is selected from a portion of the formula wherein R1 'is selected from substituted or unsubstituted algeryl groups: R2' and R4 ', R5' are independently selected from H or substituted or unsubstituted algeryl groups; R6 'is selected from substituted or unsubstituted alkyl groups; or R5 'and R6' together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; and R7 'is selected from CN, or substituted or unsubstituted algeryl, aryl or arylalguyl groups. In some modalities, Y is selected from a portion of the formula in other modalities, and is selected from Compounds of formula VIIA and VIIB with Y values such as those discussed above are found to exhibit reduced bioaccumulation properties as evidenced by lower blood plasma values of t and 2 in. test subjects to whom the compounds have been administered. In general, these compounds also provide improved plasmatic Cmax values and can also provide improved Cmax brain values and intracerebroventricular (icv) efficiency. Significant reductions were also observed in Fl (food intake) at 16 hours and 30 mpK (mg / kg) in some subjects for some compounds in formula VIIA and VIIB. The compounds of the formula VIIA and VIIB have been found particularly suitable as having reduced bioaccumulation properties. Examples of these compounds are disclosed in the various embodiments described above. In the compounds of formula VIIA and VIIB the R3 'substituted or unsubstituted cycloalkylalkyl aryl, alguilo, alguenilo, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or is selected from H or. In some embodiments, R3 'is selected from substituted and unsubstituted cycloalguyl groups. In some embodiments, R3 'is selected from the group consisting of gue, 2-alguilciclohexilo, 2, 2-dialguilciclohexilo, 2,3-dialguilciclohexilo, 2, 4-dialguilciclohexilo, 2,5-dialguilciclohexilo, 2, 6-dialguilciclohexilo ciciohexilo groups, 3,4-dialguilciclohexilo, 3-alguilciclohexilo, 4-alkylcyclohexyl, 3, 3, 5-trialquilciclohexilo, 2-aminocyclohexyl, 3-aminocyclohexyl, 4-aminocyclohexyl, 2,3-diaminociclohexilo, 2,4-diaminociclohexilo, 3,4- diaminociclohexilo, 2,5-diaminociclohexilo, 2,6-diaminocíclohexilo, 2, 2-diaminociclohexilo, 2-alcoxiciclohexilo, 3-alcoxiciclohexilo, 4 ~ alcoxiciclohexilo, 2,3-dialcoxiciclohexilo, 2, 4-dialcoxiciclohexilo, 3,4-dialcoxiciclohexilo, 2, 5-dialcoxiciclohexilo, 2,6-dialcoxiciclohexilo, 2, 2-dialcoxiciclohexilo, 2-alquiltiociclohexilo, 3-alquiltiociclohexilo, 4-alquiltiociclohexilo, 2, 3-dialquiltiociclohexilo, 2,4-dialquiltiociclohexilo, 3,4-dialquíltiociclohexilo, 2, 5-dialkylthiocyclohexyl, 2,6-dialkylthiocyclohexyl, 2,2-dialkylthiocyclohexy the, fluorocycloalkyl, fluoroalkylcycloalkyl, trifluoromethylcycloalkyl, cyclopentyl, cycloheptyl, cyclohexenyl, cyclooctyl, 2-arylcyclohexyl, 2-phenylcyclohexyl, 2-arylalkylcyclohexyl, 2-benzylcyclohexyl, 4-phenylcyclohexyl, adamantyl, isocaphenyl, carenyl, 7,7-dialkynorbornyl, bornyl, norbornyl , and substituted and unsubstituted decalinyl. In still other embodiments, R3 'is selected from the group consisting of cyclohexyl, 2-methylcyclohexyl, 2,2-dimethylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4-dimethylcyclohexyl, 2,5-dimethylcyclohexyl, 2,6-dimethylcyclohexyl groups. , 3,4-dimethylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 3,3,5-trimethylcyclohexyl, 4-t-butylcyclohexyl, isopinocamfeyl, 7,7-dimethylnorbornyl, 4-isopropylcyclohexyl, 3-methylcycloheptyl, 2-fluoro- 4-methylcyclohexyl, 4-fluoro-2-methylcyclohexyl, 4,4-difluoro-2-methylcyclohexyl, 4-trifluoromethylcyclohexyl, 2-methyl-4-trifluoromethylcyclohexyl, 2-fluoromethylcyclohexyl, trifluoromethyl (polycyclic cycloal-guyl), fluoromethyl (polycyclic cycloal-guyl), and fluoro (polycyclic cycloal-guyl) substituted and unsubstituted. In some embodiments, R3 'is a substituted or unsubstituted polycyclic cycloalguyl group. In some embodiments, R3 'is a substituted or unsubstituted polycyclic cycloalguyl group having the formula VIII VIII The compounds of the formula VA, VB, VIA, VIB, VIIA and VIIB may exhibit reduced bioaccumulation properties in the animal subjects to which they are administered. These subjects can include human and non-human animal subjects. Examples of mammalian subjects include, without limitation, rodents such as mice and rats, bovines, eguines, canines, felines, rabbits, guinea pigs, swine, primates such as humans and monkeys, and the like. In some embodiments, the invention provides compounds in which the t_./2 value for the compound is lower for 35, 30, -25, 20, 15, 10 or 5 hours between a tissue with high blood perfusion such as brain, liver, kidney and heart. In some embodiments, the t / 2 vapor for the compound is less than 4 hours and in some embodiments it is less than about 3 hours in a tissue of a subject to whom the compound has been administered. The invention also includes tautomers of the compounds, prodrugs, pharmaceutically acceptable salts of the compounds or tautomers, stereoisomers, hydrates and solvates thereof. One or more compounds of the invention can be included in pharmaceutical formulations or in medicaments. These compositions include at least one compound of the invention and at least one pharmaceutically acceptable carrier, but may also include mixtures of compounds of the invention. The compounds of the invention can be used in this way to prepare pharmaceuticals and pharmaceutical formulations for use in the treatment of an MC4-R mediated disease such as, but not limited to, obesity, type II diabetes, erectile dysfunction, . polyguistic ovarian disease, and syndrome X. In some modalities / the disease mediated by MC4-R is obesity or type II diabetes. Methods to treat diseases mediated by MC4-R include administering to a compound in need thereof, a compound or composition of the present invention. In some embodiments, the compounds of the invention describe reduced bioaccumulation in tissues such as in the brain or blood plasma of a subject. The administration of the compounds and compositions of the invention can be achieved using various methods such as those described herein. In one embodiment, the compound or composition is administered intranasally. In some embodiments, the compound or composition is administered intranasally to a human. The present compounds may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. In some cases, a stereoisomer may be more active and / or may exhibit beneficial effects compared to the other stereoisomers or when it is separated from the other stereoisomers. However, it is well within the skill of one skilled in the art to selectively separate and / or prepare the stereoisomers. Accordingly, "stereoisomers" of the present invention include. necessarily mixtures of stereoisomers, individual stereoisomers, or optically active forms. The present invention also provides compositions which can be prepared by mixing one or more compounds of the present invention, or pharmaceutically acceptable salts or tautomers thereof, with carriers, excipients, binders, pharmaceutically acceptable diluents, or the like to treat or ameliorate a variety of disorders. Examples of these disorders include, without limitation, obesity, erectile disorders, cardiovascular disorders, neuronal injuries or disorders, inflammation, fever, cognitive disorders, sexual behavior disorders. A therapeutically effective dose additionally refers to the amount of one or more compounds of the present invention sufficient to result in improvement of the symptoms of the disorder. The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art such as conventional granulation processes, mixed solution, encapsulation, lyophilization, emulsification or levigation, among others. The compositions may be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions and solutions. The present compositions can be formulated for various routes of administration, for example, by oral administration, by intranasal administration, by transmucosal administration, by rectal administration, or by subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection. . The compound or compounds of the present invention can also be administered in a local manner rather than in a systemic manner, 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 present invention. For oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel capsules and solid core capsules are acceptable as solid dosage forms. These can be prepared for example, by mixing one or more compounds of the present 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, guitines, guitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, caffeins, albumin, polymers or synthetic or semi-synthetic glycerides, methyl cellulose, hydroxypropyl cellulose, and / or polyvinyl pyrrolidone. Optionally, oral dosage forms may contain other ingredients to aid in administration, such as an inactive diluent, lubricants such as magnesium stearate, or preservatives such as paraben or ascorbic acid or antioxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfume agents. Additionally, colorants or pigments can be added for identification. Tablets and pills can be further treated with suitable coating materials known in the art. The 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. The pharmaceutical formulations can be prepared as suspensions of liquid solutions using sterile liquid, such as, without limitation, an oil, water, alcohol and combinations thereof. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents can be added for oral or parenteral administration. As noted above, suspensions may include oils. These oils include, without limitation, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. The suspension preparation may also contain fatty acid esters such as ethyl oleate, isopropyl ester, fatty acid glycerides and acetylated glycerides of fatty acids. 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 (ethylene glycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water can also be used in suspension formulations. For intranasal administration (eg, for distributing compounds to the brain), or administration by inhalation (eg, for distributing compounds through the lungs), the pharmaceutical formulations may be a solution, a spray, a dry powder, an aerosol that contains any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations thereof. Examples of formulations and methods of administration can be found in -in WO 01/41782, WO 00/33813, WO 91/97947, U.S. Patent No. 6,180,603, and U.S. Patent No. 5,624,898. A propellant for an aerosol formulation may include compressed air, nitrogen, "carbon dioxide, or a low boiling solvent" based on hydrocarbon The compound or compounds of the present invention may conveniently be distributed in the form of an aerosol presentation of a nebulizer or the like.

Injectable dosage forms generally include aqueous suspensions or suspensions of oil which can be prepared using a suitable dispersing wetting agent and suspending agent. The injectable forms may be in the solution phase or in the form of a suspension, which is prepared as a solvent or diluent. Solvents or acceptable vehicles include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile solvents can be used 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. For injection, the pharmaceutical formulation can be a suitable powder for reconstitution with an appropriate solution - as described above. Examples thereof include, without limitation, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates or particulate materials For injection, formulations 1 may optionally contain stabilizers, modifiers of pH, surfactants and bioavailability modifiers and combinations thereof Compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion A unit dose form for injection can be in ampoules or multi-dose containers 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 the compound in the intestines, sigmoid and / or rectus rectal suppositories are prepared by mixing one or more compounds of the present invention, or salts or ta pharmaceutically acceptable utomers of the compound, with acceptable carriers, for example, cocoa butter or polyethylene, which is present in a solid phase at normal storage temperatures, and present in a liquid phase at those temperatures suitable for releasing a drug within the body, just like in the rectum. Oils can also be used in preparations and formulations of the soft gelatine type and suppositories. After using water, saline, aqueous dextrose and related solutions of sugar, and glycerols 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 shock absorbers and conservators. In addition to those representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present invention. These excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. The formulations of the invention can be designed to be short acting, fast release, long acting and suspended release as described below. In this way, pharmaceutical formulations can also be formulated for controlled release or for slow release. The present compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or they may be administered in an extended release form to provide a prolonged storage and / or distribution effect. Therefore, the pharmaceutical formulations can be compressed into granules or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as endoprosthetics. These implants can use known inert materials such as silicones and biodegradable polymers. A therapeutically effective dose refers to that amount of the compound which results in improvement of the symptoms. Specific doses can be adjusted depending on the conditions of the disease, age and body weight, general health conditions, sex, subject's diet, dose intervals, administration routes, expression speed and drug combinations. Any of the above dosage forms containing effective amounts is well within the limits of routine experimentation and therefore, come within the scope of the present invention. A therapeutically effective dose may vary depending on the route of administration and the dosage form. The preferred compound or compounds of the present invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between the toxic and therapeutic effects that can be expressed as the ratio between LD50 and ED50. The LD50 is the lethal dose at 50% of the population and the ED50 is the therapeutically effective dose in 50% of the population. The LD5o and the. ED50 are determined by normal pharmaceutical procedures in cultures of animal or experimental animal cells. The present invention also provides methods for improving the activity of MC4-R in a human or non-human animal. The method comprises administering an effective amount of a compound, or composition, of the present invention to the mammal or non-human animal. The effective amounts of the compounds of the present invention include those amounts that activate MC4-R that are detectable, for example, by an assay described later in the illustrative examples, or any other assay known to those skilled in the art in which a detection signal transduction, a biochemical pathway, through the activation of receptors coupled to the G protein, for example, by measuring a high level of cAMP compared to a control model. Accordingly, "activation" means the ability of a compound to initiate a detectable signal. Effective amounts can also influence those amounts that alleviate the symptoms of a treatable MC4-R disorder by activating MC4-R. An MC4-R disorder, or an MC4-R-mediated disease, which can be treated by these methods provided, includes any biological disorder or disease in which MC4-R is involved or inhibition of MC4-R that enhances a pathway. biochemistry that is defective in the disorder or disease state. Examples of these diseases are obesity, erectile disorders, cardiovascular disorders, injuries - or neuronal disorders, inflammation, fever, cognitive disorders, type II diabetes, polycystic ovary disease, syndrome X, complications of obesity and diabetes, and sexual behavior In a preferred embodiment, the present invention provides effective compounds, compositions, and methods to reduce energy insertion and body weight; to reduce serum insulin and glucose levels; to relieve insulin resistance; and to reduce serum levels of free fatty acids. Accordingly, the present invention is particularly effective in the treatment of those disorders or diseases associated with obesity or type II diabetes. "Treatment" within the context of the present invention, therefore, means an improvement of the symptoms associated with a disorder or disease, or arrest of the progress or further worsening of these symptoms, or prevention or prophylaxis of the disease or disorder. For example, within the context of obesity, successful treatment may include an improvement in symptoms or detection of the progress of the disease, as measured by reduction in body weight, or a reduction in the amount of food or energy insertion. In this same sense, the successful treatment of type I or type II diabetes may include an improvement of the symptoms or arrest of the progress of the disease, as measured by a decrease in serum glucose or insulin levels, for example, in hyperinsulinemic or hyperglycemic patients. The Reaction Scheme illustrates a general synthetic route that can be used to synthesize various guanidinyl-substituted quinazolinone compounds As shown in the Reaction Scheme, the nutro and amino-quinazolinone compounds such as (d) and (e) can easily be converted to a plethora of guanidinyl quinazolinones by converting the amino functionality to an isothiocyanate functionality such as is possessed by the compound (f) This can be achieved by reacting the amine group with thiophosgene The isothiocyanate compounds such as (f) can then be easily converted to a thiourea such as the compound (g) by reaction with a suitable amine compound such as (1S, 2S, 3S, 5R) - (+) - isopinocamfeilamine. The preparation of the desired guanidinylamine such as compound (h) can then be achieved by reacting thiourea with a compound such as 1- [3- (dimethylamino) -propyl] -3-ethylcarbodiimide hydrochloride and then c on a suitable amine such as cis-2,6-dimethylpiperazine, (S) -2- (fluoromethyl) piperazine, or the like. Various fluorine substituted compounds can be prepared using the methodology shown in the Scheme the reaction using an appropriately substituted 4-nitroanthranilic acid. Other compounds can be prepared by using 5-nitroanthranilic acid instead of 4-nitroanthranilic acid.

Diagram of the Reaction Scheme Ib of Reaction illustrates another generally applicable method that can be employed to synthesize a large number of quinazolinone substituted with guanidinyl and heterocyclic derivatives of these compounds where a carbon of the benzene ring of the quinazolinone is replaced with a nitrogen atom. As shown in Reaction Scheme Ib, the conversion of a compound (d) to (e) can be achieved by initially adding trimethylphosphine to form a reactive intermediate of iminophosphorane, by adding a substituted isocyanate such as a cycloalkyl isocyanate, by example, a polycyclic isocycle 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.

Diagram Ib of Reaction Reaction enzyme 2a illustrates another general procedure which can be used to prepare a wide variety of guanzolinone compounds substituted with guanidinyl.

Reaction Run 2a R3 = H, Alkyl, Aryl, Arylalkyl, etc. Reaction run 2b shows yet another alternative route which can be used to prepare several compounds of formulas IA, IB, IIIA, IIIB, IVA, and IVB.

Reaction Run 2b Still another route that can be used to prepare the various compounds of the invention is shown in Reaction Run 2c.

Reaction Run 2c The invention provides several methods for synthesizing the compound of formula IA and IC, various intermediate compounds, and salts of the compounds and intermediates. For example, a method for producing a compound having the formula IXA is provided where R1, R3, Z1, Z2, Z3, R4, R5, and R6 have any of the values described above with respect to the compounds of the formula IA and the modalities of the compounds of formula IA, and Y1 is selected from the group consisting of N02, a protected amine group, a halogen such as Cl, F, Br, or I, a -NCS group, and a group N3 In some embodiments of the method., Rx is - a substituted or unsubstituted arylalguilo group. In some modalities of the method, R3 is 'H'. In some embodiments, Y1 is selected from F, N02, or a group N3. In some embodiments of the method, R1 is a substituted or unsubstituted arylalguil group, R3 is H, and Y1 is selected from an- F, -N02 or a group -N3.- E. some embodiments, Z1, Z2 and Z3 are each carbon atoms and R4, R5 and R6 are each H. The compounds of the formula IXA can be easily converted to compounds of the formula IA as shown in the Esguema la - of reaction and the procedures set forth herein. Typically, a compound of formula IXA where Y1 is a -NCS is reacted with a first amine and then reacted with a second amine as described in the Reaction Procedure. Any of the amines defined by R1 ', R2' and R3 'of the compounds of the formula IA can be used. The versatility of this method allows a wide variety of compounds of the formula IA to be prepared where W is a guanidine group prepared from the compounds of the formula IXA, where Y1 is a group -NCS. In another procedure which can be used to prepare the compounds of the formula IA of compounds of the formula IXA wherein Y1 is a group N3 is shown in the reaction sequence Ib where the nitrogen compounds with any of the groups R1 ', R2' and R3 'of the compounds of the formula IA can be used.

IXA A method for preparing a compound of the formula IXA typically includes cyclizing a compound of the formula IXB by reacting it with an electrophilic carbon having a R3 group such as a trialguilo ortoformate such as triethyl orthoformate, trimethyl orthoformate or the like where R3 is an H; Gold Reagent; a substituted or unsubstituted alkanoyl halide such as acetyl chloride wherein R3 is a methyl group; a substituted or unsubstituted alkanoic acid in the presence of an acid halide producing agent such as thionyl chloride, P0C13, various phosphorus halides, and the like (eg, an alkanoic acid of the formula R3C02H in combination with P0C13); a benzoyl chloride or an analogous heteroaryl chloride compound; or a substituted and unsubstituted benzoic acid or analogous heteroaryl carboxylic acid compounds and an acid halide producing agent. The reaction affords the compound of formula IXA. The compounds of formula IXB have the following formula.

IXB In the compounds of the formula IXB, the variables can have any of the same values as described above with respect to the compounds of the formula IXA. Methods for forming a compound of formula IXA can include reacting a compound of formula IXC with an amine of formula R1-NH2 to produce the compound of formula IXB using normal methods of amide formation and where R1 has any of the values of the compounds of the formula IXA and IXB and the variables in the IXC compound have the values of the compounds of the formula IXA and IXB and Y2 is a hydroxyl group or is an equivalent thereof. The compounds of formula IXC have the following formula.

IXC An alternative method for synthesizing compounds of formula IA is shown in Reaction Scheme 2a. This method generally includes reacting a compound of the formula IXC with an amine of the formula R1-NH2, and an electrophilic carbon having a group R3 such as a carboxylic acid of the formula R3-C02H. The compounds of the formula IA can be further prepared according to the procedure in the reaction enzyme 2b by reacting a compound of the formula IXC or in an amide of the formula R1-N (H) -C (= 0) -R3 in the presence of P0C13 or an analogous compound. Compounds of the formula IE can be prepared from the compounds of the formula IXB wherein Y1 is a group N02 by reacting the compound with NaN02 as described in Method 6 to produce the analogs of the compounds of the formula IXA which are then they can convert to the compounds of the compounds of the formula IE of the compounds wherein Y1 is a group -N3 or is a group -NCS. The compounds of the formula IB can be produced from the compounds of the formula IXB by reacting the compound of the formula IXB with phosgene or an eguivalent thereof as described in Step 2 of Example 2 and the subsequent conversion to the compounds of the formula guanidine of the compounds N3 or -NCS using the normal procedures.

Finally, the compounds of formula ID can be prepared using the procedures described in Method 7 (Steps 1 and 2) using the fragments with the variables described above with respect to the compounds of the formula ID. As noted above, the invention also provides methods for synthesizing the compound of the formula IC, various intermediate compounds, and salts of the compounds and intermediates. For example, a method for producing a compound having the formula XA is provided where R 1, R 3, Z 1, Z 2, Z 3, R R 5, and R 6 have any of the values described above with respect to the compounds of the formula IC and embodiments of the compounds of formula I, and Y1 is selected from the group consisting of N02, a protected amine group, a halogen such as Cl, F, Br, or I, a -NCS group, and a N3 group. In some embodiments of the method, R1 is a substituted or unsubstituted arylalkyl group. In some embodiments of the method, R3 is H. In some embodiments, Y1 is selected from an F, N02 / or a group ~ N3. In some embodiments of the method, R1 is a substituted or unsubstituted arylalkyl group, R3 is H, and Y1 is selected from a group F, N02 or N3. In some embodiments, Z1, Z2 and Z3 are each carbon atoms and R4, R5 and R6 are each H. The compounds of the formula XA can be easily converted to compounds of the formula IC as shown in the Scheme of reaction and the procedures set forth herein. Typically, a compound of the formula XA is reacted where Y1 is a -NCS with a first_amine and then reacted with a second amine as described in the Reaction Procedure. Any of the amines defined by the R1 ', R2' and R3 'of the compounds of the formula IC can be used. The versatility of this method allows a wide variety of compounds of the formula IC to be prepared where W is a guanidine group prepared from the compounds of the formula XA, where Y1 is a group -NCS.Another method that can be used for preparing the compounds of the formula IC of compounds of the formula IXA wherein Y1 is a group N3 is shown in Reaction Scheme Ib where the nitrogen compounds with any of the groups R1 ', R2' and R3 'of the compounds of the XA A method for preparing a compound of formula XA typically includes cyclizing a compound of formula XB by reacting it with an electrophilic carbon having a R3 group such as a trialguilous orthoformate such as triethyl orthoformate, trimethyl orthoformate or the like where R3 is an H; Gold reagent; a substituted or unsubstituted alkanoyl halide such as acetyl chloride wherein R3 is a methyl group; a substituted or unsubstituted alkanoic acid in the presence of an acid halide producing agent such as thionyl chloride, P0C13, various phosphorus halides, and the like (for example, an alkanoic acid of the formula R3C02H in combination with P0C13); benzoyl chloride or an analogous heteroaryl chloride compound, or a substituted and unsubstituted benzoic acid or an analogous heteroaryl carboxylic acid compound and an acid halide producing agent The reaction provides the compound of formula XA. the formula XB has the following formula, XB In the compounds of the formula XB, the variable may have any of the same values as described above with respect to the compounds of the formula XA. The method for forming a compound of the formula XA can include reacting a compound of the formula XC with an amine of the formula R1 -! ^ To produce the compound of the formula XB using normal methods of amide formation and where R1 has any of the values of the compounds of the formula XA and XB and the variables in the XC compound have the values of the compounds of the formula XA and XB and Y2 is a hydroxyl group or is an eguivalent thereof. The compounds of formula C have the following formula.

XC An alternative method for synthesizing the compounds of the formula IC is shown for analogous compounds of the formula IA in the reaction 2a. This method generally includes reacting a compound of the formula XC with an amine of the formula R1-NH2, and an electrophilic carbon having a group R3 such as a carboxylic acid of the formula R3-C02H. The compounds of the formula IC can be further prepared according to an analogous procedure to agly shown in reaction enzyme 2b by reacting a compound of the formula XC or in an amide of the formula R.sub.H) -C (= 0 ) -R3 in the presence of P0C13 or an analogous compound. The present invention, generally described in this manner, will be more readily understood with reference to the following examples, which are provided by way of illustration and are not intended to limit the present invention.

Examples The following abbreviations and terms from beginning to end of the Examples are used: Boc: t-Butyl carbamate protecting group Celite®: Diatomaceous earth filter agent DAST: (Dimethylamino) sulfur trifluoride DCM: DIBAL dichloromethane: Diisobutylaluminum hydride DIEA: N, N-Diisoproylethylamine DMF: N, N-Dimethylformamide DMSO: - Dimethylmisulfoxide EDCI: 1- (1- Hydrochloride 3-Dimethylaminopropyl) -3-ethylcarbodiimide EtOAc: Ethyl acetate EtOH: Ethanol Reagent of (Dimethylaminomethylene-Gold's chloride: aminomethylene) di-methyl-ammonium HOBt: Hydroxybenzotriazole HPLC: High performance liquid chromatography HCl: Hydrochloric acid HBTU: O-Benzotriazol-1-yl- N, N, N ', N' -tetramethyluronium hexafluorophosphate KOH: Potassium hydroxide LC: Liquid chromatography MS: MeOH Mass Spectroscopy: Methanol mL: Milliliter NMO: Oxide of N-Morpholine NMP: l-Methyl-2-pyrrolidinone NMR: Nuclear magnetic resonance spectroscopy TFA: Trifluoroacetic acid THF: Tetrahydrofuran Synthesis of 6-methylpiperazin-2-one 6-Methylpiperazin-2-one Step 1: Synthesis of N-Boc-alanine-N '-benzyl-glycine methyl ester (1) To a stirred solution of N-Boc-L-alanine (1 equivalent) and N-benzylglycine methyl ester (1 equivalent) in dichloromethane. add-TEA (1 equivalent) and HOBt (1 equivalent), followed by EDCl (1 equivalent). The solution is allowed to stir at room temperature under N2 for 48 hours. The reaction was diluted with 10% HCl, and the organic layer was separated and dried over MgSO4. The crude product is chromatographed. in silica (30% EtOAc / hexanes) giving the desired product (1) as a clear oil (75%).

Step 2. Synthesis of [benzyl- (2-terbutoxycarbonylamino-propyl) -amino] -acetic acid methyl ester (2) To a stirred solution of BH3 in THF (1 M, 2 equivalents), a solution was added dropwise. of dipeptide (1) in THF. The reaction was then maintained at room temperature for 24 hours and then diluted with methylene chloride, washed with NaHCO 3, and dried over MgSO 4. The crude product is chromatographed on silica eluting with 20% EtOAc / hexanes to give the desired product (2) as a colorless oil (40%).

Step 3. Synthesis of l-benzyl-5- (S) -methyl-3-oxo-piperazine (3) The ester (2) was stirred in a 50:50 solution of TFA: CH2C12 for 1 hour. The solvent was then stirred, and the residue was redissolved in methylene chloride and washed with a saturated solution of Na 2 CO 3. The organic layer was then separated and dried over MgSO4 to give the desired piperazine compound (3) as a white solid (87%).

Step 4. Synthesis of 6- (S) -methylpiperazin-2-one (4) 3 eguivalents of chloroethylchloroformate and Hunig's base (3 eguivalents) were added to a dichloroethane solution of 3 at room temperature. The solution was stirred overnight, and the reaction was then loaded directly onto a column of silica gel and chromatographed eluting with EtOAc / hexanes (4: 6). The isolated carbamate intermediate was dissolved in methanol and heated to reflux for 2 hours. The methanol removal provided the desired piperazin-2-one (4) as a blanquecino solid (the yield was not optimized, but it was approximately 60% for the 2 steps). The 6 (S) -methyl-piperazin-2-one compounds of the invention were made according to the following methods by activation with EDC of the thiourea intermediate to the carbodiimide followed by coupling with 6 (S) -methyl-piperazine. -2-ona.

Synthesis of 6- (S) -methylpiperazin-2-one-guanidine compounds The compounds of 6- were prepared. { S) ~ methylpiperazin-2-one-guanidine of the invention according to the methods described herein by EDC activation of the -thiourea intermediate to provide the corbodiimide followed by coupling with 6 (S) -Methyl-piperazin-2 -one Synthesis of 2- (R) -Fluoromethylpiperazine and 2- (R) -Difluoromethylpiperazine Synthesis of 2- (R) -Fluoromethylpiperazine Synthesis of 2- (R) -Difluoromethylpiperazine Step 1. Synthesis of N-benzyl-serine methyl ester To a stirred solution of the 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 eguivalent), followed by 2 g of anhydrous MgSO. The mixture was stirred at room temperature in a sealed flask for 20 hours, and then the solids were filtered, the filtrate was evaporated. The residue was redissolved in methanol (50 mL) and sodium borohydride (1 eqivalent) was added carefully. The mixture was stirred for 30 minutes, diluted with methylene chloride, washed with NaHCO 3 and then dried with magnesium sulfate. The desired title product was obtained as a yellow oil and crude was used. The N-4-methoxybenzyl-serine methyl ester was made in a similar manner using anisaldehyde instead of benzaldehyde.

Step 2. Synthesis of N-benzyl-N-chloroacetyl-serine methyl ester To an ice-cooled solution of the crude benzyl amino acid prepared as described in Step 1 and triethylamine (1 eqivalent) in methylene chloride, chloride was added of chloroacetyl (1 equivalent) drop by drop. After 1 hour, the reaction was washed with 10% HCl, and the organic layer was separated and dried over sodium sulfate. The 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 di-N-benzyl-cyclo-serine-glycine The chloride prepared in Step 2 was dissolved in acetonitrile, and benzyl amine (3 eguivalents) was added. The solution was heated to 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, washed with 10% HCl and dried over MgSO4. The crude product was passed through a plug of silica gel (100% EtOAc, Rf = 0.5) giving a white solid (80%). Di-N-4-methoxybenzyl-cyclo-serine-glycine was prepared in a similar manner using p-methoxybenzylamine and the p-methoxybenzyl derivative of the starting material.

Step 4. Synthesis of l, 4-dibenzyl-2- (R) -piperazine-methanol To an ice-cooled mixture of LiAlH4 (10 eguivalents) in anhydrous THF under N2 was added the cyclic dipeptide produced in Step 3 in THF drop a drop.

The resulting gray mixture was heated to reflux for 16 hours. The reaction was carefully quenched with H20, NaOH, H20 (1: 1: 3), and the resulting white mixture was cooled through celite. The filtrate was dried over MgSO4 and concentrated, giving the desired product as a colorless oil. (93%).

Step 5. Synthesis of 1, 4-dibenzyl-2- (R) -fluoromethylpiperazine To an ice-cooled solution of DAST (2 eguivalents) in methylene chloride under N 2 was added the alcohol prepared in Step 4 in methylene chloride drop a drop. The yellow solution was stirred at 0 ° C at room temperature for 20 hours. The reaction was diluted with NaHCO 3 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 to give the desired title compound as a yellow oil (40%).

Step 6. Synthesis of 2- (R) -fluoromethylpiperazine 1,4-Dibenzylfluoromethylpiperazine was dissolved from Step 5 in dichloromethane, and α-clsroethyl chloroformate (3 eguivalents) was added. The resulting solution was heated to reflux for 16 hours. The reaction was loaded directly onto a column of silica gel 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 completely removed giving the desired deprotected piperazine as a white solid (90% for 2 steps).

Synthesis of l, 4-di-p-methoxybenzyl-2- (R) -piperazine-carboxaldehyde 1,4-di-p-methoxybenzyl-2- (R) -difluoromethylpiperazine To a dry flask containing an oxalyl chloride solution in methylene chloride (2.0 M, 1.2 eguivalents) at -78 ° C, DMSO (2.4 eguivalents) was added dropwise under a stream of nitrogen. After stirring for 15 minutes, a solution of 1,4-di-p-methoxybenzyl-2- (R) -piperazine ethanol (1 eqivalent) was added dropwise and the resulting solution was stirred for 1 hour, added TEA (5 equivivalents) and the mixture was added to NaHCO3 (aqueous), separated and dried over MgSO4. After filtration, the filtrate was cooled to -78 ° C, and DAST (1.2 eguivalents) was added dropwise. 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 on silica (10% EtOAc / hexanes) giving the desired difluoro compound of the title as a light brown oil (33%). The deprotection of the difluoro was carried out in the same manner as described in Step 6 using a-chloroethyl chloroformate giving a white solid (85%).

Synthesis of compounds of 2- (R) -fluoromethylpiperazine and 2- (R) -difluorome-1-piperazine-guanidine The compounds of 2- (R) -Fluoromethylpiperazine and (R) -difluoromethylpiperazine-guanidine 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-methylpiperazin-2-one) Step 1. Synthesis of (2R) -2-. { [(benzyloxy) carbonyl] -aminojpropanothioate of S-ethyl A 250 mL round bottom flask was charged with benzyloxycarbonyl-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 cooled 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 DCC is highly exothermic so that the reaction will bubble up in the reaction, and the reaction must be kept well ventilated. 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. Chromatography on silica gel using hexanes with polarization to hexanes / ethyl acetate 8: 1 gave 93% yield (18.0 g, 62.5 mmol) of the desired product as a colorless oil.

Step 2. Synthesis of (IR) -l-methyl-2-oxoethylcarbamate To a stirred solution containing (2R) -2-. { [(benzyloxy) carbonyl] amino} S-ethyl propanethioate (18.-9 g, 62.5 mmol), 10% Pd / wet C (1.89 g), and acetone (347 mL) at 0 ° C triethylsilane (29.9 mL, 187.5 mmol) was added. .

The resulting mixture was stirred for 30 minutes at 0 ° C and then filtered through celite using ethyl acetate to thoroughly wash the celite. The filtrate was concentrated and partitioned between acetonitrile (500 mL) and hexanes (150 mL).

The layers were separated, and the acetonitrile phase was added 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 N- ((2R) -2- { [(Benzyloxy) carbonyl] aminojpropyl) methyl glycinate A 1000 mL round bottom flask was charged with benzyl (IR) -l-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 concentrated, redissolved in diethyl ester (200 mL) and placed in a separatory funnel. The organic phase was washed with saturated NaHCO3 (200 L) 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 NaS04 and concentrated. Chromatography on silica gel using hexanes / ethyl acetate 2: 1 with gradual polarization to hexanes / ethyl acetate 1 • - 1 gave the desired product as a clear solid in 75% yield (12.5 g, 44.6 mmol).

To a solution of N- ((2R) -2 - { [(Benzyloxy) carbonyl] -aminojpropyl) methyl glycinate (12.5 g, 44.6 mmol) in anhydrous methanol (446 mL) under an atmosphere of N2 was added Pd at 10% / C (1.25 g). The flask was then placed in 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. After completion (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. 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 the product can be further crashed with the addition of ethyl acetate.If any starting material remains, it will be in the filtrate.

Synthesis of (3R, R) -3,4-pyrrolidinediol hydrochloride (3R, 4R) -1- (Phenylmethyl) -3,4-pyrrolidinediol (250 mg, 1.30 mmol) was dissolved in ethyl acetate and a suspension of 10% Pd in carbon in ethyl acetate was added. The mixture was hydrogenated in a Parr hydrogenator at 4.00 kg / cm2 (57 pounds / square inch) for 12 hours. The reaction was then filtered through celite to remove the catalyst. Excess 4N HCl was added in dioxane and then concentrated to give the title compound as a brown oil which was used without further purification.

Synthesis of (3S, 4S) -3,4-pyrrolidinediol HO OH CiH t NH NH (3S.4S) -1- (Phenylmethyl) -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 tiomorpholine 1,1-dioxide hydrochloride 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-methyl (2R, 4R) -4-hydroxy-1,2-pyrrolidinedicarboxylate carboxylate HO > Trimethylsilyl-diazomethane (3.89 mmol) was added slowly to an ice-cooled solution (4R) -1-. { [(1,1-dimethylethyl) oxy] carbonyl} -4-hydroxy-D-proline (0.75 g, 3.25 mmol), 60 mL of toluene and 20 mL of methanol. The reaction was stirred for 2 hours in an ice bath, warmed to room temperature, concentrated to give 0.89 g of the title compound as a light yellow oil. NMR- ^? (400 MHz, DMS0-D6) d ppm 1.4 (, 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 (2R, 4R) -4-hydroxy-2- (hydroxymethyl) -1-pyrrolidinecarboxylate 1,1-dimethylethyl ester LiBH (6.46 mmol as a solution in THF) was added to an ice-cooled solution of 2-methyl (2R, 4R) -4-hydroxy-1,2-pyrrolidinedicarboxylate of (1,1-dimethylethyl) (0.36 g, 1.47 g. mmol) in THF. The reaction was heated at 70 ° C for 48 hours. The reaction was quenched with isopropanol and then saturated NaHCO3. The mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with 1N NaOH, dried over MgSO4 and concentrated to give 0.185 g of the title compound.

RMN-1 !! (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 trifluoroacetate (salt) (2R, 4R) -4-hydroxy-2- (hydroxymethyl) -1-pyrrolidinecarboxylate 1,1-dimethylethyl ester (0.185 g, 0.852 mmol) in a 1: 1 solution of methylene chloride: TFA was stirred for 14 hours. The reaction was concentrated, and the crude material was used without further purification. NMR ^ H (400 MHz, DMSO-D6) d 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-l-carbonitrile hydrochloride Step 1. Synthesis of 4-cyano-cis-3,5-dimethyl-piperazine-l-carboxylic acid tert-butyl ester 4. 00 g of the cis-3,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (prepared according to the method of E. Jon Jacobson et al., J. Med. Chemistry, 1999, Vol. 42, 1123-144 ) in 91 mL of dichloromethane was treated with sodium bicarbonate (4.7 g) followed by the addition of cyanogen bromide (7.5 mL). The reaction mixture was refluxed overnight, filtered and purified by column chromatography (0 to 50% ethyl acetate / hexanes) to give 3.9 g of the title compound as a white solid. XH NMR (CDC13, 300 MHZ) d ppm 1J33 (d.6H, J = 6.5 Hz), 1.44 (s 9H), 2.54 (m, 2H), 3.09 (m, 2H), 4.09 (m, 2H); 13 C NMR (CDC13 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-piperazine-1-carbonitrile hydrochloride The tert-butyl ester of 4-cyano-cis-3,5-dimethylpiperazine-l-carboxylic acid (1.0 g) in 10 mL of THF was treated with 4.0 N HCl / dioxane (25 mL), stirred for 5 hours and concentrated to provide 1.1 g of the title compound. XH NMR (DMSO-D6, 300 MHz): d 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 (, 2H); 13C (DMSO, 75 MHz) and 16.73 (2C), 46.81 (2C), 50.80 (2C), 104.20.

Synthesis of cis-2, 6-dimethyl-piperazin-l-ol hydrochloride Step 1. Synthesis of cis-3, 5- dimethyl-4- (3-oxo-butyl) -piperazine-1-carboxylic acid tert-butyl ester The cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (3.00 g, prepared according to the method of E. Jon Jacobson et al., J. Med. Chemistry, 1999, Vol. 42, was treated. 1123-144) in 47 mL of chloroform with methyl vinyl ketone (1.7 mL) at room temperature and was heated to reflux for two days. The reaction was then concentrated, diluted with THF and heated to reflux for 1 day before purification by column chromatography (0 to 10% MeOH / DCM) to give 0.865 g of the title compound as a clear, colorless oil. XH NMR (CDC13, 300 MHz) d 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); RMN 13C (CDC13, 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 The cis-3,5-dimethyl-4- (3-oxo-butyl) -piperazine-1-carboxylic acid tert-butyl ester (1.00 g) in chloroform (40 mL) was treated with m-chloroperbenzoic acid (77%) , 0.97 g) 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 the precipitates, washed with saturated aqueous sodium bicarbonate, filtered through a plug of silica gel and concentrated. The residue was taken in a 1: 1 mixture of DCM and MeOH and treated with an excess of 4.0 M HCl / 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-acetin-3-ol hydrochloride H • Cl Step 1. Synthesis of l-benzhydril-azetidin-3-ol A solution of 1- (diphenylmethyl) -3- (methanesulfonyloxy) azetidine (1.0 g) in THF (17 mL) was treated with 3.0 M methylmagnesium bromide (1.2 mL) in diethyl ester 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 taken 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 light, yellow oil. ESMS: 240.19 (M + 1), 1.22 minutes, Method D.

Step 2. Synthesis of l-benzhydryl-azetidin-3-one To a solution of l-benzhydryl-azetidin-3-ol (640 mg) in methylene chloride (6.0 mL) were added 4Á molecular sieves. The reaction vessel was purged with nitrogens followed by addition of NMO (800 mg) and then TPAP (42 mg). The reaction was stirred overnight and then filtered through a plug of silica to yield 335 mg of the title compound as a clear, colorless oil. XH NMR (CDC13, 300 MHz) d 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 l-benzh? Dfil-3-methyl-azetidin-3-ol L-benzhydryl-l-acetidin-3-one (335 mg) in diethyl ether (6.0 mL) with 3.0 M methyl magnesium bromide in diethyl ether (0.52 mL) at 0 ° C, stirred for 10 minutes and then it was quickly cooled with saturated aqueous sodium bicarbonate. The solution was then extracted with methylene chloride (x3), and the combined organics were dried over magnesium sulfate, and concentrated to provide 363 mg of the title compound as a clear, colorless oil. X H NMR (CDC13 300 MHz) d ppm 1.53 (s 3 H), 196 (s, 1 H), 1.96 (d, 2 H, J = 8.42 Hz), 3.19 (d, 2 H, J = 8.42 Hz), 4.34 (s 1 H ), 7.17 (m, 2H), 7.26 (m.2H), 7.31 (m, 2H), 7.40 (, 4H).

Step 4. Synthesis of 3-methyl-azetin-3-ol hydrochloride To a suspension of l-benzhydryl-3-methyl-azetidin-3-ol (363 mg) in MeOH (10 mL) was treated with 4.0 N HCl / dioxane (1.0 mL) followed by an excess of palladium hydroxide in carbon (humid, Degusa type). The solution was then reacted with hydrogen in a Parr hydrogenator overnight at 3.16 kg / cm 2 (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 A solution of tert-butyl 4-oxo-l-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 (x 3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to give 2.12 g of the title compound. -, which was used in additional purification. XH NMR (CDC13.300 MHz) d ppm 1.49 (s 9H), 2.34 (t, 2H, J = 6.07 Hz), 257 (t, 2H, J = 6.07 Hz), 351 (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 The tert-butyl ester of 4-methoxyimino-piperidine-1-carboxylic acid in MeOH (10 mL) was treated with 4.0 M HCl / dioxane (1.0 mL) and stirred at room temperature overnight. The solution was concentrated to yield 213 mg of the title compound without further purification. X H NMR (DMSO, 300 MHz) d 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 A solution of tert-butyl 4-oxo-l-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 rapidly quenched with sodium bicarbonate, diluted with saturated Rocket Salt, and extracted with methylene chloride (x 3). The combined organics were filtered through Celite, concentrated, and purified by column chromatography (0 to 40% EtOAc / hexanes). The impure residue was then taken in MeOH (5 L) and treated with 4.0 M HCl / dioxane (4 mL), stirred for 30 minutes and concentrated to give the crude title compound.

Synthesis of ethyl (3S) -3-hydroxy-l-proline hydrochloride Acetyl chloride (10.8 mL, 153 mmol) was added slowly to 100% ethanol cooled with ice (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. NMR XH (400 MHz, DMSO-D6) d ppm 1.2 (t, J = 8.1 Hz, 3 H) 1.9 (, 2H), 3.3 (m, 2H), 4.1 (m, 1H), 4.2 (g, J = 7.1 Hz, 2H) 4.4 (m, 1H), 9.0 (s 1H), 10.4 (s 1H).

Synthesis of [(2S, 3S) -3-methyl-2-pyrrolidinyl] methanol hydrochloride Step 1. Synthesis of ethyl (3S) -3-methyl-L-proline The title compound was prepared from (3S) -3-methyl-L-proline, using the methods used to prepare ethyl (3S) -3-hydroxyl-L-proline hydrochloride. XH NMR (400 MHz, DMS0-D6) d ppm 1.1 (d, J = 6.8 Hz, 3H) 1.2 (t, J = 6.8 Hz, 3H) 1.6 (m, 1H), 2.1 (m, 1H), 2.3 ( m, 1H), 3.2 (m, 2H), 3.8 (m, 1H), 4.2 (m, 2H), 4.7 (m, 1H), 9.0 (s 1H), 10.4 (s 1H).

Step 2_. Synthesis of 2-ethyl (2S, 3S) -3-methyl-l, 2- -_- _ Warm (3S) -3-methyl-L-proline (0.837 gf 4.32 mmol), bis (1, 1-dimethylethyl) sodium bicarbonate (0.942 g, 4.32 mmol), and triethylamine (1.5 mL, 10.8 mmol) in a mixture of approximately 2: 1 THF and ethanol at 75 ° C for 16 hours. The reaction was allowed to cool to room temperature, diluted with water. The crude mixture was extracted 2X with ethyl acetate. The organic layers were washed with NaOH, IN, dried over MgSO 4 and concentrated under reduced pressure to give the title compound (855 mg, 3.3 mmol) as a clear oil. NMR? (400 MHz, DMSO-D6) d ppm 1.1 (d, J = 6.8 Hz, 3H), 1.2 (m 3H), 1.3 (m, 9H), 1.5 (m, 1H), 1.9 (m, 1H), 2.2 (m, 1H), 3.2 (, 1H), 3.4 (m, 1H), 3.6 (m, 1H), 4.1 (m, 2H).

Step 3. Synthesis of (2S, 3S) -2- (hydroxymethyl) -3-methyl-l- Lithium borohydride was added dropwise. { 6 6 mmol, 3.31 mL of a 2 M in THF solution) to an ice-cold THF solution of 2-ethyl (2S, 3S) -3-methyl-l, 2- (1,1-dimethylethyl) pyrrolidinedicarboxylate. ) (850 mg, 3.3 mmol) and methanol (0.133 mL, 3.3 mmol). The reaction was cooled to room temperature and then stirred for 4 hours. The reaction was quenched with i-propanol then with saturated NaHCO 3. The reaction mixture was extracted 3 x with ethyl acetate. The organic layers were dried over MgSO4 and concentrated under reduced pressure to give the title compound, which was used without further purification. X H NMR (400 MHz, DMSO-D6) d ppm 0.9 (t, J = 7.0 Hz, 3H), 1.3 (m, 9H), 1.9 (, 1H), 2.2 (m, 1H), 3.1 (m, 2H) , 3.3 (m, 2H), 3.5 (m, 1H), 4.7 (m, 1H).

Step 4. Synthesis of [(2S, 3S) -3-methyl-2-pyrrolidinyl] methanol hydrochloride In 1,1-dimethylethyl (2S, 3S) -2- (hydroxymethyl) -3-methyl-1-pyrrolidinecarboxylate from step 3 was dissolved in a 1: 1 mixture of methylene chloride: methanol.

Excess 4N HCl was added in dioxane, and the reaction was dried at room temperature for 1 hour, concentrated under reduced pressure, and then used in the final step (see Reaction Escape (g). ) a (h)). NMR XH (400 MHz, DMSO-D6) d ppm 1.1 (d, J = 6.2 Hz, 3H), 1.5 (m, 1H), 2.1 (, 2H), 3.1 (m, 1H), 3.3 (m, 1H) , 3.4 (m, 1H), 4.5 (dd, J = 12.1, 8.1 Hz, 1H), 4.7., (Dd, J = 12.:3, 3.1 Hz, 1H).

Synthesis of ethyl (3S) -3-hydroxy-L-proline hydrochloride Acetyl chloride (10.8 mL, 153 mmol) was added slowly to 100% ethanol cooled with ice (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. X H NMR (400 MHz, DMSO-D6) d ppm 1.2 (t, J = 8.1 Hz, 3H) 1.9 (m, 2H), 3.3 (m, 2H), 4. 1 (m, 1H), 4.2 (g, J = 7.1 Hz, 2H), 4.4 (m, 1H), 9.0 (s) 1H), 10.4 (s 1H).

Synthesis of (2R, 3S) -2-methyl-3-pyrrolidinol hydrochloride Step 1. Synthesis of 1- (1,1-dimethylethyl) 2-ethyl (2S, 3S) -3-hydroxy-1,2-pyrrolidinecarboxylate The title compound was prepared from (3S) -3-hydroxy- Ethyl L-proline using the methods used to prepare 1- (1,1-dimethylethyl) -2-ethyl- (2S, 3S) -3-methyl-1,2-pyrrolidinecarboxylate. NMR - "(400 MHz, DMSO-D6) d ppm 1.2 (m, 3H), 1.3 (m, 9H), 1.7 (m, 1H), 1.9 (m, 1H), 3.3 (m, 2H), 4.1 (m, 4H), 5.5 (s 1H).

Step 2_. Synthesis of 2-ethyl (2S, 3S) -3 - ([(1, 1-dimethylethyl) (dimethyl) silyl] oxy} -l, 2-pyrrolidinecarboxylate The following were filtered at room temperature for 16 hours: 2-ethyl (2S, 3S) -3-hydroxy-l, 2-pyrrolidinecarboxylate. 1- (1,1-dimethylethyl) (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) the reaction was diluted with water and IN HCl to make the mixture acidic. The mixture was extracted three times with methylene chloride. The organic layer was washed with 1M HCl, dried over MgSO4 to give the title compound as a light brown oil (10.88 g, 29.1 mmol). NMR XH (400 MHz, DMSO-D6) d ppm 0.0 (m, 6H), 0.8 (, 9H), 1.2 (m 3H), 1.3 (m, 9H), 1.7 (m, 1H), 1.9 (m, 1H) ), 3.4 (m, 2H), 3.9 (m, 1H), 4.1 (m, 2H), 4.4 (m, 1H). ES + = 374.30.

Step 3 ^ Synthesis of (2R.3S) -3-f ([1,1-dimethylethyl) dimethyl) silyl] oxy} -2- (hydroxymethyl) -1-pyrrolidinecarboxylate 1,1-dimethylethyl ester The title compound was prepared from 2-ethyl (2S, 3S) -3-. { [(1,1-dimethylethyl) (dimethyl) silyl] oxy} -1,1-pyrrolidinecarboxylic acid 1- (1,1-dimethylethyl) using the methods used for the preparation of (2S, 3S) -2- (hydroxymethyl) -3-methyl-1-pyrrolidinecarboxylate 1,1-dimethylethyl. X H NMR (400 MHz, DMSO-D6) d ppm -0.0 (m, 6H), 0.8 (m, 9H), 1.0 (m, 1H), 1.4 (m, 9H), 1.6 (, 1H), 3.1 (m , 1H), 3.2 (m, 2H), 3.5 (m, 2H), 4.3 (m, 1H), 4.8 (m, 1H).

Step 4. Synthesis of (2R, 3S) -3-. { [(1,1-dimethylethyl) (dimethyl) silyl] oxy} 2-. { [(methylsulfonyl) oxy] methyl} 1,1-dimethylethyl-1,1-pyrrolidinecarboxylate Methanesulfonyl chloride (3.85 mL, 39.29 mmol) was added to an ice-cold methylene chloride solution of (2R, 3S) -3-. { [(1,1-dimethylethyl) (dimethyl) silyl] oxy} -2- (hydroxymethyl) -1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester (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 NaHCO3, dried over MgSO4 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). XH NMR (400 MHz, DMSO-D6) d ppm 0.1 (s 6H), 0.8 (s 9H), 1.4 (m, 9H), 1.7 (m, 1H), 2.0 (m, 1H), 3.2 (s, 3H) ), 3.3 (m, 2H), 3.7 (m, 1H), 4.0 (m, 1H), 4.2 (m, 1H), 4.3 (m, 1H). ES + = 410.16.

Step 5_. Synthesis of (2R, 3S) -3-. { [(1,1-dimethylethyl) (dimethyl) silyl] oxy} -1,1-dimethylethyl methyl-1-pyrrolidinecarboxylate Superhydride (45.8 mL, 1 M, 45.8 mmol) was added dropwise to an ice-cooled solution of ((2R, 3S) -3-. {[[(1,1-dimethylethyl) (dimethyl) silyl] oxy]} 2- { [(methylsulfonyl) oxy] methyl] -1-pyrrolidinecarboxylate 1,1-dimethylethyl (4.69 g, 11.47 mmol) in THF. The reaction was cooled to room temperature and stirred for 16 hours. the reaction was quenched with i-propanol until the gas evolution was completed. the reaction was diluted with saturated NaHC03, then extracted with ethyl acetate, dried with MgS04 and concentrated under reduced pressure. the crude material was purified by column chromatography on silica gel to yield the title compound (2.69 g, 8.5 mmol) XH NMR (400 MHz, DMSO-D6) d ppm 0.0 (s 6H), 0.8 (s 9H), 1.0 (m, 3H), 1.4 (s 9H), 1.6 (m, 1H), 2.0 (m, 1H), 3.3 (m, 2H), 3.5 (m, 1H), 4.0 (m, 1H), ES + = 316.22.

Step 6. Synthesis of 1,1-dimethylethyl (2R, 3S) -3-hydroxy-2-methyl-1-pyrrolidinecarboxylate Tetrabutylammonium fluoride (16.7 mL, 1N in THF, 16.73 mmol) was added to a solution of (2R, 3S) -3-. { [(1,1-dimethylethyl) (dimethyl) silyl] oxy} -1,1-dimethylethyl 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 (1.55 g, 7.8 mmol). X H NMR (400 MHz, DMSO-D6) d ppm 1.0 (m, 3H), 1.4 (s 9H), 1.6 (m, 1H), 1.9 (m, 1H), 3.3 (m, 2H), 3.5 (m, 1H), 3.8 (, 1H), 4.9. (S 1H). ES + = 202.15.

Step 7. Synthesis of (2R, 3S) -2-methyl-3-pyrrolidinol hydrochloride The title compound was prepared from (2R, 3S) -3-hydroxy-2-methyl-l-pyrrolidinecarboxylate 1,1-dimethylethyl using the methods used for preparing hydrochloride [(2S, 3S) -3 -methyl-2-pyrrolidinyl] methanol. NMR XH (400 MHz, DMSO-D6) d ppm 1.2 (d, J = 7.0 Hz, 3H), 1.7 (, 1H), 2.1 (m, 1H), 3.2 (m, 2H), 3.3 (m, 1H) 3.9 (m, 1H), 5.5 (m, 1H), 9.0 (s 1H), 9.4 (m, 1H). 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) -1-pyrrolidinecarboxylate The title compound was prepared from 2-ethyl (2S.3S) -3-hydroxy-l, 2-pyrrolidinecarboxylic acid 1- (1,1-dimethyl) ethyl ester, using the methods used to prepare (2S, 3S) -2- (Hydroxymethyl) -3-methyl-1-pyrrolidinecarboxylic acid 1,1-dimethylethyl ester. 2 H NMR (400 MHz, DMSO-D6) d ppm 1.4 (s 9H), 1.6 (, 1H), 1.9 (m, 1H), 3.1 (m, 1H), 3.2 (m, 2H), 3.4 (m, 2H) ), 4.1 (m, 1H). ES + = 218.24, 117.97 (-Boc).

Step 2. Synthesis of (2R, 3S) -2- (hydroxymethyl) -3-pyrrolidinol hydrochloride The title compound was prepared from (2R, 3S) -3-hydroxy-2- (hydroxymethyl) -1-pyrrolidinecarboxylate 1,1-dimethylethyl using the methods used to prepare [(2S, 3S) -3 hydrochloride -methyl-2-pyrrolidinyl] methanol. X H NMR (400 MHz, DMSO-Dβ) d ppm 1.8 (m, 1H), 2.0 (m, 1H), 2.5 (m, 2H), 3.2 (m, 2H), 3.3 (m, 1H), 3.5 (m , 1H), 3.6 (m, 1H), 4.1 (m, 1H), 8.7 (s 1H), 9.5 (m, 1H). ES + = 117.97 Synthesis of N-3-azetidinyl-methanesulfonamide Step Synthesis of N- [1- (diphenyl-ethyl) -3- [azetidinyl] methanesulfonamide A solution of 1- (diphenylmethyl) -3-azetidinamina (synthesis according to methods Arimoto et al., J. of Antibiotics 29A9), 1243-1256, 1986) (197 mg, 0.83 mmol) in dichloromethane (10 L ) was treated with excess triethylamine at 0 ° C followed by methanesulfonyl chloride (71 μL, 0.91 mmol). The reaction was stirred for 30 minutes and then cooled 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 to 0.31 minutes. Method D. Step 2. Synthesis of N-3-azetidinylmethanesulfonamide A solution of N- [1- (diphenylmethyl) -3-azetidinyl] -methanesulfonamide (185 mg, 0.585 mmol) in MeOH (10 mL) was treated with 1 mL 4.0 N HCl / dioxane and then reacted overnight with hydrogen gas at 3.51 kg / cm2 (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-o-methyloxime Step 1. Synthesis of 1,1-dimethylethyl 3-methyl-4-oxo-l-piperidinecarboxylate 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 HCl / dioxane (2.2 mL), followed by palladium hydroxide. The mixture was then reacted overnight with hydrogen gas at 3.51 kg / cm2 (50 psi). The reaction was then filtered through Celite, concentrated and then taken in THF (20 mL). The crude reaction mixture was then treated with triethylamine (2.3 mL), followed by di-tert-butyl bicarbonate (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-l-piperidinecarboxylate as a white solid. X H NMR (400 MHz, CDCl 3) d 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, 1H), 4.2 (m, 2H).

Step 2. Synthesis of (4E) -3-methyl-4- [(methyloxy) imino] -1-piperidinecarboxylate 1,1-dimethylethyl ester A solution of 1,1-dimethylethyl 3-methyl-4-oxo-l-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 hydrogen carbonate (506 mg, 6.02 mmol) in water (3 mL). The reaction was vigorously stirred 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. NMR aH (400 MHz, CDC13) d ppm 1.1 (d, J = 6.8 Hz, 3 H) 1.5 (s 9H), 2.5 (m, 1H), 2.6 (m, 2H), 3.5 (m, 4H), 3.8 (s, 3H).

Step 3. Synthesis of (4E) -3-methyl-4-piperidinone-0-methyloxime (4E) -3-Methyl-4- [(methyloxy) imino] -1-piperidinecarboxylate 1,1-dimethylethyl ester (197 mg) in methanol, treated with 4.0 N HCl / dioxane (4 mL) and stirred overnight. The reaction was then concentrated to give the product as a white solid (170 mg). The crude material was used without further purification.

Synthesis of 4, 4-dimethylcyclohexanone The title compound was synthesized using the following literature procedure which is incorporated herein by reference and for all purposes as if disclosed in its entirety. Liu, Hsing-Jang; Bro ne, Eric N.C. and Chew, Sew Yeu. Dog. J. Chem. 66.2345-2347 (1988).

Synthesis of (4,4-dimethylcyclohexyl) amine The title compound was synthesized using the following literature procedure which is incorporated herein by reference and for all purposes as if disclosed in its entirety. Faller, A., MacPherson, D.T., Ner P. H., Stan ay, S. J. and Trouw, L. S. WO04 / 5913A1 (2003).

Synthesis of N- (3- (2- [2-fluoro-4- (methyloxy) phenyl] ethyl.} -4-oxo-3,4-dihydro-7-guinazolinyl) -N '- [(SS, 2S , 3S, 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] carbodiimide (Carbodiimide A) N- (3- {2- [2-fluoro-4- (methyloxy) phenyl] ethyl} -4-oxo-3,4-dihydro-7-guinazolininyl-N '- [(1S) was gently stirred. , 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] thiourea with PS-Carbodiimide Argonaut (1.5 eguivalent) for 15 hours in THF The resin was completely filtered 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-dihydro-7-guinazolinyl} -N '- [(1S, 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3.1. l] hept-3-yl] carbodiimide (Carbodiimide B) N- was gently stirred. { 3- [2- (2,4-Dichlorophenyl) ethyl] -4-oxo-3,4-dihydro-7-guinazolinyl} -N '- [(1S, 2S, 3S, 5R) -2,6,6-trimethylbicyl [3.1. l] hept-3-yl] thiourea with PS-Carbodiimide Argonaut (1.5 eguivalent) for 15 hours in THF. The resin was filtered and the carbodiimide solution 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) -quinazolinone Step 1. Synthesis of 2-amino-N- [2- (2,4- dichlorophenyl) ethyl] -4-nitrobenzamide To a stirred solution of 4-nitro-isatoic anhydride (10.0 g, 0.048 mol) in CH2C12 (100 mL) was added 2,4-dichlorophenylethylamine (10.08 g, 0.053 mol) followed by DMF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was then dissolved in 1.0 L CH2C12 and washed with 1.0 M NaOH. The combined organic layers were concentrated under reduced pressure and purified by flash chromatography on silica gel (0-100% EtOAc / hexanes as 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).

Step 2, Synthesis of 3- [2- (2,4-dichlorophenyl) ethyl] -7-nitro-2,4 (1H, 3H) -quinazolinadione 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 1.1 solution in toluene (30 mL was added to 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 CHC12 was added to the residue. The precipitate was collected via vacuum filtration and washed with CH2C12 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-dichlorophenyl) ethyl] -7-nitro-4 (3H) -quinazolinone 3- [2- (2,4-dichlorophenyl) ethyl] -7-nitro-2,4 (1H, 3H) -quinazolinadione (2.0 g, 5.26 mmol) and PC15 (1.2 g, 5.79 mmol) were added to a flask containing POCl3 (20 mL) and the resulting solution was refluxed with stirring for 6 hours. The reaction is allowed to cool to room temperature and is stirred overnight at this temperature. The POCl3 was removed under reduced pressure and CH2C12 was added to the residue. The unreacted starting material was removed via vacuum filtration and the product was purified by flash chromatography with silica gel (eluent of 100% CH2C12) to give the product (0.96 g, 46% yield) as a white solid. 1 H NMR (DMS0-D6) 400 MHz d ppm 8.35-8.25 (m, 3H), 7.58 (d, J = 2.2 Hz, 1H), 7.41-7.34 (, 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-3,4-dihydro-7-guinazolinyl} -N '- [(1S, 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3.1. l] hept-3-yl] -1-azetidinecarboximidamide Step 1. Synthesis of 1-dimethylethyl [1- (diphenylmethyl) -3-azetidinyl] carbamate} To a solution of 1- (diphenylmethyl) -3-azetidinamine (232 mg, 0.97 mmol) in THF (6 mL) at 0 ° C was added a solution of di-tert-butyl bicarbonate (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 give 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-dimethylethyl 3-azetidinyl carbamate A solution of 1,1-dimethylethyl [1- (diphenylmethyl) -3-azetidinyl] carbamate in MeOH (10 mL) was treated with 4.0 N HCl / dioxane (1 mL) and then reacted overnight with hydrogen gas at 3.51 kg / cm2 (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) ethyl] -4-oxo-3,4-dihydro-7-guinazolinyl} -N '- [(SS, 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3, .1.1] ept-3-yl] -1-azetidinecarboximidamide 1, 1-Dimethylethyl [1- ((Z) - (. {3- [2- (4-fluorophenyl) ethyl] -4-oxo-3 was treated, 4-dihydro-7-quinazolinyl} Not me) -. { [(1S, 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] -imino} 1, 1-dimethylethyl methyl) -3-azetidinyl] carbamate (synthesized using 1,1-dimethylmethyl 3-azetidinyl-carbamate by the methods described above) with 4.0 N HCl / dioxane (4 mL) and stirred overnight. The reaction was then purified by preparative HPLC to provide 3-amino-N-. { 3- [2- (4-fluorophenyl) ethyl] -4-oxo-3,4-dihydro-7-quinazolinyl} -N '- [(1S, 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3.1.l] hept-3-yl] -1-azetidinecarboximidamide as a white solid. LC / MS: M + H 517.20 to 2.19 minutes. Method D.

General method for the preparation of C-2 analogs bound to nitrogen. Step 1. Synthesis of 2-Amino Analogs To a stirred solution of 2-chloro-3- [2- (2,4-dichlorophenyl) ethyl] -7-nitro-4 (3H) -quinazolinone (1 equivalent) in acetonitrile (1.0 M) was added the corresponding amine ( 2 equivalents) and the reaction mixture was heated to reflux until the reaction was finished as monitored by HPLC (approximately 30 minutes). The reaction mixture was then cooled to room temperature and the solvent was removed in vacuo. The crude product was purified via flash chromatography on silica gel (eluents of 0-5% MeOH / CH2Cl2).

Step 2. Reduction of Nitro to Aniline To a stirred solution of the nitro compound (1 equivalent) in absolute ethanol (1.0 M) was added iron powder (2.5 eguivalents) and acetic acid (14 eguivalents). The reaction mixture was heated to reflux until the reaction was finished as monitored by HPLC. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and washed with saturated NaHCO 3. The aqueous layer was re-extracted with Et05Ac (x2) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was used in the next step without further purification.

Step 3. Conversion of Aniline to Thiourea To a stirred solution of crude aniline (1 equivivalent) in acetone (1.0 M) at 0 ° C was added Na 2 CO 3 (2 eguivalents) followed by thiophosgene (3 eguivalents) dropwise via syringe. The reaction mixture was stirred at 0 ° C for 10 minutes and then allowed to warm to room temperature. A solid precipitated in the 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. Sodium chloride dissolved. The aqueous layer was re-extracted with EtOAc (x2) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude material was then dissolved in THF (1.0 M) and (1S, 2S, 3S, 5R) - (+) - isopinocanphenylamine (1.3 eguivalent) was added via syringe. The reaction mixture was stirred at room temperature for 30 minutes then concentrated in vacuo. The crude material was purified via flash chromatography on silica gel (eluent of 0-5% MeOH / CH2Cl2).

Step 4. Conversion of Thiourea to Guanidine To a stirred solution of thiourea (1 eqivalent) in THF (1.0 M) was added EDC (1.5 eguivalents) 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 room temperature and then the corresponding amine (2 eguivalents) and Et3N (2 eguivalents) were added * The reaction mixture was stirred at room temperature for 1 hour then concentrated in vacuo. The crude material was purified by reverse phase HPLC comparative (eluent MeCN / water) and lyophilized to produce the TFA salt.

General procedure for the synthesis of aryl-guanidines. Unless stated otherwise, a THF solution of a carbodiimide such as carbodiimide A or carbodiimide was stirred with. approximately 1.5 equivivalents 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 eguivalents of triethylamine were added). The reaction was concentrated under a stream of nitrogen, dissolved in methanol and purified by preparative HPLC.

Synthesis of trifluoroacetate N-3- (2- [2-fluoro-4- (methyloxy) phenyl] ethyl.} -4-oxo-3,4-dihydro-7-guinazolinyl) -N ' 4H-1, 2,4-triazol-4-yl-N "- [(IR, 2S, 3S, 5S) -2,6,6-trimethylbicyclo [3 .1.1] hept-3-yl] guanidine N- (3-. {2- 2- [2-fluoro-4- (methyloxy) phenyl] ethyl], -4-sxo were stirred., 3,4-dihydro-7-guinazolinyl) -N '- [(1S, 2S, 3S, 5R) -2,6,6-trimetibicyclo [3.1.1] ept-3-yl] carbodiimide (4 mL, solution 23 mM in THF), 4H-1,2,4-triazol-4-amine (49 mg) and excess NaH together and heated at 50 ° C for 30 minutes. The reaction was quenched with 1 mL of H20 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 MgSO4 and concentrated. The material was dissolved in 1 mL of methanol, purified by preparative HPLC and lyophilized to give the TFA salt of the title compound.

Synthesis of cis-4-fluorocyclohexylamine Step 1. Synthesis of trans- (t-butoxy) -N- (4-hydroxycyclohexyl) -carboxamide A suspension of trans-4-aminocyclohexanol (1 eqivalent) in THF (0.1 M) was treated with (Boc) 20 (1 eqivalent). The mixture was stirred at room temperature overnight, dissolved in chloroform, and washed with water to yield the solid which was used without further purification.

Step 2. Synthesis of cis- (t-butoxy) -N- (4-fluorocyclohexyl) carboxamide To a solution of (t-butoxy) -N- (4-hydroxylohexyl) carboxamide (1 eqivalent) in CH2C12 (1 M) cooled to -78 ° C was added dropwise a solution of DAST (1 equivalent) in CH2C12 ( 0.5 M). The mixture was stirred at -78 ° C for 4 hours, and then the temperature was allowed to rise. The solution was poured into saturated NaHCO 3 and extracted with chloroform, dried and evaporated. The resulting crude product was purified on silica gel, eluting with 5:95 ethyl acetate / hexane.

Step 3. Synthesis of cis-4-fluorocyclohexylamine A solution of cis- (t-butoxy) -N- (4-fluorocyclohexyl) carboxamide (6.51 mmol) in CH2C12 (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 aqueous acid phase was cooled to 0 ° C and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2C12, dried and filtered, yielding the title compound which was used without further purification and as a 0.3M solution in CH2C12.

Synthesis of 4,4-difluorocyclohexylamine Step 1. Synthesis of N- (4,4-difluorocyclohexyl) (t-butoxy) -carboxamide A solution of (t-butoxy) -N- (4-oxocyclohexyl) carboxamide (2.5 g, 11.7 mmol) in CH2C1 (45 mL) was treated with a solution of DAST (2.63 mL, 19.93 mmol) in CH2C12 (6 mL) at room temperature. EtOH (141 μL, 2.3 mmol, was added and the mixture was stirred at room temperature overnight.) The solution was poured into saturated NaHCO 3 and extracted with chloroform, dried, and evaporated with producing the mixture at 1: 1 of the compound of the title and (t-butoxy) -N- (4-fluorocyclohexyl-3-enyl) carboxamide This mixture was dissolved in CH2C12 (40 mL) and MeOH (14 mL) and cooled to -78 [deg.] C. Ozone was diluted in the solution for 50 minutes until it turned green and Me2S (3 eguivalents) was added.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 produce the title compound which was used without further purification.

Step 2. Synthesis of 4, 4-difluorocyclohexylamine A solution of N- (4,4-difluorocyclohexyl) (t-butoxy) carboxamide (6.51 mmol) in CH2C12 (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 aqueous acid phase was cooled to 0 ° C and made basic by the addition of solid KOH. The resulting mixture was extracted with CH2C12, dried, and filtered to yield the title compound which was used without further purification as the 0.3M solution in CH2C12.

Procedure 1. Synthesis of 6-fluoro analog of 7-azido-guinazolin-4-one (1) Step 1. Synthesis of (2-amino-4,5-difluorophenyl) -N- [2- (4-fluorophenyl) ethyl] -carboxamide To a stirred solution of 4,5-difluoroanthranilic acid (2.0 g, 11.6 mmol) in anhydrous THF (30 mL) was added hydroxybenzotriazole hydrate (HOBt) (1.56 g, 11.6 mmol), diisopropylethylamine (2.01 mL). , 11.6 mmol), and 4-flusrophenylethylamine (1.52 mL, 11.6 mmol). After all the HOBt had completely dissolved, EDCl (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 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) ethyl] -3-hydroguinazolin-4-one 2 3 The starting benzamide (2) was dissolved in trimethyl orthoformate (20 mL) and heated to 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 were collected by filtration, washed with hexanes, dried in the pump. The formamide intermediate was isolated as a white solid and confirmed by NMR. This intermediate compound was suspended in POCl3 (10 mL) and heated at 140 ° C for 3 minutes. The reaction was cooled, poured on crushed ice, made lightly alkaline with saturated sodium bicarbonate solution, and extracted, with EtOAc. The organic layer was collected and dried over magnesium sulfate. The product (3) was isolated as a white solid (1.94 g, 6.38 mmol, 75% for 2 steps).

. He passed. 3. Synthesis of 7- (azadiazomvinyl) -6-fluoro-3- [2- (4- f luorofenyl) ethyl] -3-hydroguinazolin-4-one 3 1 Difluoroguinazoline (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 resulting precipitate was collected by filtration and washed with water.

The solid was dissolved in methylene chloride and dried (MgSO4) in order to remove the trace of water. The product (1) was isolated as a white solid (1.43 g, 4.37 mmol, 95%). After the formation of compound 1, the final guanidine guinazolinones were formed following the synthesis method described below (Method IA).

Procedure 1A To a solution of (1) (1 equivalent) in THF was added trimethylphosphine (1.5 eguivalents), 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. l] hept-3-yl-isocyanate (1.6 equivalents). The solution was heated at 70 ° C overnight. To half of the carboimide solution was added a THF solution of (6S, R) -2,6-dimethylpiperazine (2 equivalents). After being heated at 70 ° C for 2 hours, the residue is subjected to purification by HPLC to give the guanidine product as its TFA salt. The analogs of 2-fluoro-4-methoxy, 2,4-difluoro and 2,4-dichloro were synthesized via the same route described above. The compounds of the group synthesized via the route described above include Examples 42, 44 and 45.

Example 1. Synthesis of (3R, 5S) -N- (3- {2- (12-fluoro-4- (methyloxy) -phenyl} ethyl} - 4-OXO-3,, 4-- dihydroquinazolin • 7-yl) - 3,5-dimeti 1-N '- [(1S, 2SJr 5 R) -2,6,, 6-trimethylbicyclo tee. l.l] hept-3-yl] piperazine-1-carboximidamide Step 1. Synthesis of (c): 2-amino-N- [2- (2-fluoro-4-methoxy-phenyl) -ethyl] -4-nitro-benzamide. 2-Fluoro-4-methoxyphenylethylamine ((a ): eguivalent), 4-nitroantranilic acid ((b): 1 eguivalent), HBTU (1.5 eguivalent), and dry THF (0.5 M in (a)) to a round, dry bottom flask. The mixture was allowed to stir for 10 hours at room temperature. The reaction was then charged dry on 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-guinazolin-4-one The pure product ((c): 1 eguivalent) from Step 1, the Gold reagent and dioxane (0.5 M in (c)) were added to a dry round bottom flask, adapted with a condenser, and heated to reflux for 16 hours. Once the complete conversion of the product by LC / MS was verified, acetic acid (1 equivalent) and sodium acetate (1 equivalent) were added to the reaction. The subsequent mixture was heated to reflux for 3 hours. So, 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 mixture of the product was purified via flash chromatography using a mixture of CH2Cl2 / 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-guinazolin-4-one To a solution of (d), prepared as described in Step 2, in MeOH (0.25 M in (d)) was added Pd at 10 ° C.

% / C (0.1 equivalent). The mixture was sealed with a septum and degassed with nitrogen for 10 minutes. The hydrogen was then bubbled through the solution for 20 minutes. Once the completion of the reaction was verified by LC / MS, the reaction was degassed with nitrogen for 10 minutes. The mixture was filtered through Celite "11 and concentrated in vacuo to yield the product ((e): 7-amino-3- [2- (2-fluoro-4-methoxy-phenyl) -ethyl] -3H- guinazolin-4-one) The product was used in the next reaction and without further purification.

Step 4. Synthesis of (f): 3- [2 - (2-fluoro-4-methoxy-phenyl) -ethyl] -7-isothiocyanato-3H-guinazolin -one To a mixture of (e), prepared as described in Step 3, (1 eguivalent) and NaHCO 3 (3 eguivalents) in acetone (0.1 M in (e)), thiophosgene (3 eguivalents) was added dropwise. The resulting slurry was stirred at room temperature for three hours. Once the completion of the reaction was verified by LC / MS, the reaction was concentrated in vacuo to remove the solvent and excess thiophosgene. The mixture was taken in ethyl acetate and washed with water. After the organic layer was isolated, the aqueous layer was extracted with two more portions of acetate. of ethyl. 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-guinazolin-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-quinazolin-7-yl}. 3- (2,6,6-trimethyl-bicyclo [3.1.1] ept-3-yl) -thiourea To a solution of (f), prepared as described in Step 4, (1 equivalent) in THF (0.5 M in (f)) was added (IS, 2S, 3S, 5R) - (+) - isopinocanphenylamine (1.5 eguivalents). The reaction was stirred at room temperature for 10 hours. The crude mixture of the product was then concentrated in vacuo, dissolved in methylene chloride, and purified via flash chromatography using hexanes / ethyl acetate. The crude fractions were combined and concentrated in vacuo to yield the crude product ((g): l-. {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) -thiourea).

Step 6. Synthesis of (h): (3R, 5S) -N- (3- (2- [2-fluoro-4- (methoxyloxy) phenyl] ethyl} -4-oxo-3,4-dihydroquinazolin- 7-yl) -3,5-dimethyl-N '- [(1S.2S.5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] piperazine-1-carboximidamide 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 i- [3- (dimethylamino ) -propyl] -3-ethylcarbodiimide (2 eguivalents). The reaction was adapted with a condenser and heated at 80 ° C for 1 hour. The resulting solution was allowed to cool to room temperature for 20 minutes. A solution of cis-2,6-dimethylpiperazine (2 eguivalents, 0.5 M in CH 2 Cl 2) 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 most of the acetonitrile. Then sodium carbonate (15 equivalents) was added to the resulting aqueous solution and the slurry was left sitting at room temperature for 1 hour with occasional stirring. 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 the product (h) as a free base. The resulting solid was then dissolved in aqueous HCl solution (1M, 15 equivalents) and concentrated in vacuo. The resulting mixture was dissolved in a water / acetonitrile 1: 1 mixture and lyophilized to yield the product of the pure Bis-HCl salt ((h): (3R, 5) S) -N- (3-. { 2- [2-fluoro-4- (methoxy) phenyl] ethyl.} -4-oxo-3,4-dihydroguinazolin-7-yl) -3,5-dimethyl-N'- [(1S.2S. 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] piperazine-1-carboximidamide.

Synthesis of compounds of structures IIIA, IIIB, IIIF and IIIG The compounds of formula IIIA, IIIB, IIIF and IIIG were prepared using the methodology described above using an appropriately substituted pyridine, pyrazine, or pyrimidine benzoic acid, instead of acid 4-nitroanthranilic (b) in Step 1. Then steps 2-6 can be carried out to give the final product. One skilled in the art will also recognize that the pyridine may be further substituted to produce substituted compounds in a variety of ways wherein R4, R5 and / or R6 are any of the groups described herein such as, without limitation, fluoro, chlorine, algane and alkaryl.

Synthesis of compounds of structure IIIC, IIID, and IIIE The compounds of formula IIIC, IIID, and IIIE are prepared using the methodology described above using a 4-nitroanthranilic acid appropriately substituted with fluorine in place of 4-nitroanthranilic acid (b) in Step 1. Steps 2-6 can be carried out to give the final product. One skilled in the art will recognize that a fluorinated substituted 4-nitroanthranilic acid may be used which includes additional substituents to produce variously substituted compounds wherein R4, R5 and / or R6 are any of the groups described herein, such as enunciative and without limitation, fluoro, chloro, alguilo and alkaryl.

Synthesis of compounds of structure IC The compounds of formula IC are prepared using the methodology described above using an appropriately substituted 5-nitroanthranilic acid in place of 4-nitroanthranilic acid (b) in Step 1. Steps 2-6 are then can carry out to give the final product. One skilled in the art will recognize that a 5-nitroanthranilic acid substituted with fluorine can be used which additionally includes substituents - 'to produce variously substituted compounds where R4, R? and / or R6 are any of the groups described herein, such as, without limitation, fluoro, chloro, alkyl and alkaryl.

Example 2_ Synthesis of 7-. { [1- ((5S, 3R) -3,5-dimethylpiperazinyl) -2- ((2S, 3S, IR, 5R) -2,6,6-trimethylbicyclo [3.1.1] ept-3-yl) (1Z ) -2-azavinyl] amino} 3- [2- (2,4-dichlorophenyl-D-ethyl] -1,3-dihydroquinazoline-2,4-dione Step 1. Synthesis of (c): 2-amino-N- [2- (2, 4 -dichlorophenyl) To a dry round bottom flask were added 2,4-dichlorophenylethylamine ((a): 1 equivalent), 4-nitroanthranilic acid ((b): 1 eguivalent), HBTU (1.5 eguivalent), and dry THF (0.5 M in ( to)). The mixture was allowed to stir for 10 hours at room temperature. The reaction was then charged dry on 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-dichlorophenyl) ethyl] -7-nitro-l, 3-dihydroguinazoline-2,4-dione (c) To a 0.3 M 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% solution of phosgene in toluene, followed by 15 mL of triethylamine. After stirring for 1 hour at room temperature, the 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 sulphate and rotary evaporation, an orange-brown solid ((d): 3- [2- (2,4-dichlorophenyl) ethyl] -7-nitro-l was obtained with more than 90% yield , 3-dihydroguinazoline-2,4-dione) Step Synthesis of (e): 7-amino-3- [2- (2,4-dichlorophenyl) ethyl] -l, 3-dihydroguinazoline-2,4-dione (d) 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 eguivalents). 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 the completion of the reaction was verified by LC / MS, the reaction was degassed with nitrogen for 10 minutes. The mixture was filtered through Celite "1 * and concentrated in vacuo to yield the product ((e)) 7-amino-3- [2- (2,4-dichlorophenyl) ethyl] -1,3-dihydroguinazoline- 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-dihydroguinazolin-7-isothiocyanate. (and) To a mixture of (e), prepared as described in Step 3, (1 equivalent) and NaHCO 3 (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 the completion of the reaction was verified by LC / MS, the reaction was concentrated in vacuo to remove excess solvent and thiophosgene. The mixture was then taken 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 compound ((f): 3- [2- (2,4-dichlorophenyl)). ethyl] -2,4-dioxo-l, 3-dihydroguinazolin-7-isothiocyanate). The crude product was used in the next reaction without further purification.

Step 5. Synthesis of (g): 7- ( { [((2S, 3S, IR, 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl) amino] thioxomethyl. amino) -3- [2- (2,4-dichlorophenyl) ethyl] -1,3-dihydroguinazoline-2,4-dione (f) 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) - (+) - isopinocanphenylamine (1.5 The reaction was stirred at room temperature for 10 hours.The mixture of the crude product was then concentrated in vacuo, dissolved in methylene chloride, and purified via flash chromatography using hexanes / ethyl acetate. Combine and concentrate in vacuo to yield the pure product ((g 7- ( { [((2S, 3S, IR, 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl) amino] thioxomethyl.}. amino) -3- [2- (2,4-dichlorophenyl) ethyl] -1,3-dihydroguinazoline-2,4-dione.

Step 6. Synthesis of (h): [7- ((5S, 3R) -3,5-dimethylpiperazinyl) -2- ((2S, 3S, IR, 5R) -2,6,6-trimethylbicyclo [3.1.1 ] hept-3-yl) (1Z) -2-azavinyl] amino} -3- [2- (2,4-Dichlorophenyl) ethyl] -1,3-dihydroquinazoline-2,4-dione (9) 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-bottomed flask was added 1- [3- ( dimethylamino) -propyl] -3-ethylcarbodiimide (2 eguivalents). The reaction flask was quenched with a condenser cooled with water and heated at 80 ° C for 1 hour under a nitrogen atmosphere. The resulting solution was cooled to 0 ° C for 20 minutes. Then a solution of cis-2,6-dimethylpiperazine (2 equivalents; 0.5 M in CHCl 2) was 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 via preparative HPLC using water (0.1% TFA) / acetonitrile (0.1% TFA). The pure fractions were combined and concentrated in vacuo to remove most of the acetonitrile. Then sodium hydroxide (10 equivalents) was added to the resulting aqueous solution and the slurry was allowed to settle at room temperature for 1 hour with occasional stirring. 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 the product (h) as a free base. The resulting solid was then dissolved in an aqueous solution of HCl (1 M, eguivalents) and concentrated in vacuo. The resulting mixture was dissolved in a 1: 1 water / acetonitrile mixture and lyophilized to yield the product of the pure Bis-HCl salt ((h): 7-. {1- ((5S, 3R) - 3, 5-dimethylpiperazinyl) -2- ((2S, 3S, 1R, 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl) (1Z) -2-azavinyl] amino.}. 3- [2- (2,4-dichlorophenyl) ethyl] -1,3-dihydroquinazoline-2,4-dione).

Synthesis of compounds of the IVA and IVB structure The compounds of the formula IVA and IVB are prepared using the methodology described above using an appropriately substituted pyridine in place of a 4-nitroanthranilic acid (b) in Step Ib. The procedure IA can then be carried out to give the final product.

One skilled in the art will also recognize that pyridine can be further substituted to produce substituted compounds in a variety of ways wherein R4, R5 and / or R6 are any of the groups described herein, such as, without limitation, fluoro, chloro , alguilo and alkaryl. The compounds are prepared using the methodology described above in Process A. The process IA can then be carried out to give the final product. One skilled in the art will recognize that a fluorinated substituted 4-nitroanthranilic acid including additional substituents can be used to produce variously substituted compounds wherein R4, R5 and / or R6 are any of the groups described herein such as, enunciatively and without limitation fluoro, chloro, alkyl and alkaryl.

Example 3. Synthesis of 7-. { [1- ((3S) -3-methylpiperazinyl) (1Z) -2-aza-2- (4,4-difluorocyclohexyl) vinyl] amino} -3- [2, (2-fluoro-4-methoxyphenyl) ethyl] -3-hydroquinazolin-4-one Step Synthesis of (b): 7- ( { [(4.4-difluorocyclohexyl) amino] -thioxomethyl}. Amino) -3- [2- (2-fluoro-4-methoxyphenyl) ethyl] -3-hydroquinazolin- 4-one (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 mixture of the crude product 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 crude product ((b): 7- ( { [(4,4-difluorocyclohexyl) amino] -thioxomethyl). Amino) -3 -. [2- ( 2-fluoro-4-methoxyphenyl) ethyl] -3-hydroquinazolin-4-one).

Step 2. Synthesis of (c): 7- ([l - ((3S) -3-methylpiperazinyl) (1Z) -2-aza-2 .-- (4,4-difluorocyclohexyl) vinyl] amino.} - 3- [2- (2-fluoro-4-methoxyphenyl) -ethyl] -3-hydroquinazolin-4-one To a solution of (b), prepared as described in Step 1 (1 eguivalent) in dry THF (0.1 M in (b)) in a dry round-bottomed flask was added 1- [3- (dimethylamino) -propyl] -3-ethylcarbodiimide hydrochloride (2 equivalents) The reaction was run with a condenser and heated to 80 ° C. for 1 hour The resulting solution was allowed to cool to room temperature for 20 minutes, then a solution of (S) -2-methylpiperazine (2 eguivalents, 0.5 M in CH2C12) was added to the reaction, and the resulting mixture was stirred at 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. they combined and concentrated in vacuo. The aqueous mixture was dissolved in DMSO and purified via preparative HPLC using water (0.1% TFA / acetonitrile (TFA / 0.1%) .The pure fractions were combined and concentrated in vacuo to remove most of the acetonitrile, then carbonate was added. of sodium (15 eguivalents) to the resulting aqueous solution and the slurry was allowed to settle at room temperature for 1 hour with occasional stirring.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 (c) as a free base.The resulting solid was then dissolved in aqueous HCl solution (1M; equivalents) and concentrated in vacuo The resulting mixture was dissolved in a 1: 1 water / acetonitrile mixture and lyophilized to yield the pure Bis-HCl salt product ((c): 7-. - ((3S) -3-methylpiperazinyl) (1Z) -2-aza-2- (4,4-difluorocyclohexyl) inyl] amino} -3- [2- (2-Fluoro-4-methoxyphenyl) -ethyl] -3-hydrohydroquinazolin-4-one).

Method 1 Synthesis of 3- [2- (4-fluorophenyl) ethyl] ~ 7-nitro-2- (4-pyridyl) -3-hydroguinazolin-4-one Pyridine-4-carboxylic acid was stirred in P0C13 at room temperature during approximately 5 minutes. To the stirred solution were added 0.9 equivivalents 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 microwave tube, which was then heated to 165 ° C in a microwave for 10 minutes. LC / MS indicated completion of the reaction. P0C13 was evaporated and the residue was dissolved in CH2C12 and washed with saturated sodium bicarbonate solution. The combined organic layers were dried over MgSO4 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-pyridyl) -3-hydroguinazolin-4-one, was then converted to Example 77 using the procedures described in the Esguema Reaction Method 2 Synthesis of 2- [2- (2-fluoro-4-methoxyphenyl) ethyl] -3-methyl-7-nitro-3-hydroguinazolin-4-one 3- (2-fluoro-4-methoxy-phenyl) was synthesized ) -N-methyl-propionamide using an EDCI-mediated coupling of 3- (2-fluoro-4-methoxy-phenyl) -N-methyl-propionic acid and methylamine (2M solution in THF). The amine was then taken at P0C13 in a microwave vessel and the mixture was stirred for about 3 minutes. To the stirred solution was added about 1 equivivalent of 4-nitroanthranilic acid. The well-sealed flask was stirred for 10 minutes until there was a change in color from red to yellow. The bottle was then sealed and reacted in a microwave unit at 165 ° C for 600 seconds. The completion of the reaction was verified with LC / MS. Then 2- [2- (2-fluoro-4-methoxyphenyl) ethyl] -3-methyl-7-nitro-3-hydroguinazolin-4-one was purified with column chromatography, eluting with EtOAc in hexanes. Then 2- [2- (2-fluoro-4-methoxyphenyl) ethyl] -3-methyl-7-nitro-3-hydroguinazolin-4-one was converted to Example 90 using the procedures described above through the corresponding thiourea ( Reaction scan).

Method 3 Synthesis of 3- [2- (2-fluoro-4-methoxyphenyl) ethyl] -2- (4-methylpiperazinyl) -7-nitro-3-hydroguinazolin-4-one (B) and 3- [2- ( 2-fluoro-4-methoxyphenyl) ethyl] -2- [imino (4-methylpiperazinyl) -methyl] -7-nitro-3-hydroguinazolin-4-one B c The synthesis of nitrile A was carried out first as described in J. Heterocyclic Chem., 35, 659 (1998)). Nitrile A was heated in an excess of N-methylpiperazine at 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 and silica gel. eluting with 10% MeOH in CH2C12. Compound B was the first to leave the column. Compounds B and C were then converted respectively to Examples 99 and 71 using the methods described herein.

Method 4: Synthesis of 3- [2- (2-fluoro-4-methoxyphenyl) ethyl] -7-nitro-2- (1,2,3,4-tetrazol-5-yl) -3-hydroguinazolin-4-one The nitrile 1 shown above (0.9 g, 2.4 mmol) was dissolved in dry DMF (5 mL). Sodium azide (0.8 g, 12.2 mmol) 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 dissolved in THF / EtOAc 1: 1 (25 L), washed with water (25 mL), and dried over MgSO4. Filtration and removal of the solvent gave 650 of a brown solid. The XH NMR (DMSO-D6, 300 MHz) was consistent with the desired formation of the product. The product was converted to Example 78 using the methods described herein.

Method 5 Synthesis of 3- [2 - (4-fluorophenyl) ethyl] -2- [(4-methylpiperazinyl) -methyl] -7-nitro-3-hydroguinazolin-4-one Step 1 Synthesis of 2- sloro-N- [2- (4-fluoro-phenyl) -ethyl] -acetamide (1) 1 To a solution of 4-fluorophenylethylamine (1.0 eguivalent) in dry THF was added Hunig's base (DIEA) (1 equivalent). The mixture was then stirred for 3 minutes at 0 ° C. Later, 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 Na2SO4. After in va cuo concentration, compound 1 shown above was obtained, which was further carried without further purification. LC / MS = M + H 216.1 to 2.18 minutes.

Step 2 Synthesis of 2-chloromethyl-3- [2- (4-fluoro-phenyl) -ethyl] -7-nitro-3H-quinazolin-4-one (2) 2 Compound 1 (1.2 equivalents) was dissolved in pure P0C13 and allowed to stir under N2 for 5 minutes. Then 4-nitroanthranilic acid (1.0 equivalent) was added, and the mixture was allowed to stir at room temperature for 10 minutes until the color changed to yellow from red. Further, the reaction mixture was refluxed at 100 ° C for 2 hours, followed by removal of P0C13 in vacuo (addition of triethylamine to the rotoevaporation condenser). The crude product obtained in this way was neutralized with a saturated solution of NaHCO 3, extracted with ethyl acetate (3 times), dried over Na 2 SO, and condensed in vacuo. Purification of the crude product was carried out by column chromatography on several batches using a gradient of EtOAc in hexanes. LC / MS = M + H 3.62 to 3.5 minutes.

Step 3 Synthesis of 3- [2- (4-fluorophenyl) ethyl] -2- [(4-methylpiperazinyl) -methyl] -7-nitro-3-hydroquinazolin-4-one A solution of 2 (1 eguivalent) and 4-methylpiperazine (3 eguivalents) in 2 mL of NMP was heated to 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 in the next step without further purification. Compound 3 was then converted to Example 69 using the methods described herein. This procedure produced a dark oil, and small amounts of NMP can remain in the product. The formation of some analogous compounds resulted in the addition of three equivivalents of diisopropyl ethyl amine. Similar guímica 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-hydroguinazolin-4-one 2,4-difluorophenol (2.5 eguivalents) was added to 2- (chloromethyl) -3-methyl-7-nitro-3-hydroguinazolin-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 into sodium sulfate and concentrated in vacuo to give 2- [(2-4, -difluorophenoxy) methyl] -3- methyl-7-nitro-3-hydroguinazolin-4-one in quantitative yields. Compound 3a was then converted to Example 88 using the methods described herein. Similar guímica 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-f-luoro-4-methoxy-enyl) -ethyl] -7-nitrobenzo [d] 1,2,3-triazin-4-one 1 A mixture of benzamide (1) (3.42 mmol), water (40 mL), and concentrated HCl (12 mL) was cooled in an ice bath, and a solution of NaN02 (3.6 mmol) in water was added dropwise. (5 mL). The mixture was stirred for 1 hour, and 20 mL of 10 N NaOH were added. Stirring was continued for another hour, and the reaction was neutralized with AcOH, extracted with methylene chloride, and dried over MgSO4. The crude product was chromatographed on silica (30%) EtOAc / hexanes) which produces the desired product as a yellow solid. The purified compound was then converted to Example 102 using the methods described herein.

Method 7 Synthesis of 6-amino-2- [2- (2-fluoro-4-methoxyphenyl) ethyl] -2-hydroisoguinolin-l-one Step 1 B C The diacid A (1 equivalent) was added to an eguipated flask with a reflux condenser and a 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 eqivalent) was added. The reaction was refluxed overnight, and then stirred in toluene by rotary evaporation. Purification by flash chromatography using ethyl acetate / hexanes gave product C in 30% yield.

The imide (C) was dissolved in CH2C12 and cooled to -78 ° C. 3 equivivalents of DIBAL (1M in CH2C12) were added, and the reaction was stirred at -78 ° C for 1 hour then when LC / MS indicated completion of the reaction. The solution was then diluted with ether and 10 equiv alents of NaF and 4 equiv alents of water were added. The reaction was then stirred for one hour. The reaction was then filtered through Celite "11 to produce the crude pyridone-amine (D) Compound D was then converted to Example 103 using the procedures described herein. Similar guímica was used to prepare Example 104 as described. identifies in the final table As noted below, the compounds in the following tables were prepared using the methodology described herein from commercially available starting materials that are readily recognizable to those skilled in the art or by using methods of For example, Example 11 was prepared using the methodology described in the Reaction Escape and in appropriate amino-indanol Examples 14 and 18 also include arylalguilo groups substituted with hydroxymethyl were also prepared using the general methodology of the Esguema la with the appropriate amino alcohol.The piperazine compound substituted with N-cyano, Example 36, was prepared by: first, protecting with mono-Boc 2,6-trans-dimethylpiperazine; second / treat the protected compound with cyanogen bromide (2.5 eguivalents) and Hunig base (1.1 eguivalent); third, purify the resulting nitrile-piperazine compound on silica gel; fourth, check out "the" product - purified; and in turn, reacting the purified nitrile-trans-dimethyl-piperazine compound, resulting using the methods described herein to produce Example 36. Compounds such as Examples 73 and 76 were prepared using the method of Method 2 with the appropriate amides of methacrylic acid and acetic acid. The compounds of the formula IB wherein R 2 is a group) alkyl such as Example 59 wherein R 2 is a methyl group can be prepared by alkylating a dione wherein R 2 is H prepared as described in the present. For example, Example 59 was prepared using the mutilation method shown below (reaction of dione with methyl iodide and potassium carbonate (1: 2: 2) in DMF at 60 ° C to produce the nitro compound which then became to Example 59 using the normal procedures described herein.

The compounds in the following tables are prepared using the methodology described in the above methods, methods and examples. The starting materials used in the synthesis are recognizable by one skilled in the art and are commercially available or can be prepared using known methods. The synthesis of the various guanidine compounds is known in the art. This synthesis information can be found in the following references each of which is incorporated herein by reference in its entirety as if fully set forth herein: PCT Publication WO 02/18327; PCT publication WO 03/099818; U.S. Patent Application Serial No. 09 / 945,384; U.S. Patent Application Serial No. 10 / 444,495; US Provisional Patent Application Serial No. 60 / 230,565; provisional application of United States Patent Serial No. 60 / 245,579; US Provisional Patent Application Serial No. 60 / 282,847; US Provisional Patent Application Serial No. 60 / 353,183; US Provisional Patent Application Serial No. 60 / 353,188; US Provisional Patent Application Serial No. 60 / 382,762; US Provisional Patent Application Serial No. 60 / 441,019; U.S. Provisional Patent Application Serial No. 60/473, 317, U.S. Provisional Application Serial No. 60 / 523,336, and U.S. Provisional Application Serial No. 60 / 524,491. twenty Table of Examples 67-101 No. Structure Name MH + (3R, 5S) -N- (3- (2-fluoro-4-methyloxy) phenyl] ethyl} -2-. {(4- methyl-piperazin-1- il) methyl] -4-oxo-67 3,4-dihydroquinazolin-7-yl) -3,5-701.9 dimethyl-N- [(SS, 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3.1 .1] hept-3-yl] piperazin-1-carboximidamide Table of Examples 113-215 10 fifteen twenty 10 fifteen twenty 10 fifteen twenty 10 fifteen twenty 10 fifteen twenty 10 fifteen twenty HPLC methods HPLC Method A - Semi-Polar Method This method was developed by injecting 3 μL of sample onto a SynergiMax-RP column (50 x 2.0 mm) (particle size 4 μm). The elution was with 15% methanol to 100% methanol for 3.5 minutes, then 1 minute to 100% methanol. The column was heated to 50 ° C and the flow rate was 1.5 mL / minute. Water contained 0.1% formic acid, and methanol contained 0.075% by volume formic acid. DAD scans were collected from 220 to 400 n.

HPLC Method B - Semipolar Method This method was achieved by injecting a 3 μl sample onto a SynergiMax-RP column (50 x 2.0 mm) (particle size 4 μm). The elution was with 15% methanol to 100% methanol for 5 minutes, then 1 minute to 100% methanol. The column was at room temperature and the flow rate was 1 mL / minute. Water contained 0.1% formic acid, and methanol contained 0.075% by volume formic acid. DAD scans were collected from 220 to 400 nm.

HPLC Method C - Polar Method This method was achieved by injecting 3 μl of sample onto a SynergiHydro-RP column (50 x 2.0 mm) (particle size 4 μm). The elution was with 2% methanol to 100% methanol for 5 minutes, then 1 minute to 100% methanol. The column was at room temperature and the flow rate was 1 mL / minute. Water contained 0.1% formic acid, and methanol contained 0.075% by volume formic acid. The DAD scans were collected from 220 to 400 nm.

HPLC Method D - Polar Method This method was achieved by injecting 3 μl of a sample onto a SynergiHydro-RP column (50 x 2.0 mm) (particle size 4 μm). The elution was with 2% methanol with 100% methanol for 3.5 minutes, then 0.5 minutes with 100% methanol. The 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% by volume formic acid. The DAD scans were collected from 220 to 400 nm.

E HPLC Method - Polar Method This method was achieved by injecting 3 μl of sample onto a SynergiHydro-RP column (50 x 2.0 mm) (particle size 4 μm). The elution was with 2% methanol with 100% methanol for 5 minutes, then 1 minute with 100% methanol. The column was at room temperature and the flow rate was 0.8 mL / minute. Water contained 0.1% formic acid, and methanol contained 0.075% by volume formic acid. The DAD scans were collected from 220 to 400 nm.

HPLC Method F - Normal Method This method was achieved by injecting 3 μl of sample onto a SynergiHydro-RP column (50 x 2.0 mm) (particle size 4 μm). The elution was with 10% methanol to 100% methanol for 3 minutes, then 1 minute to 100% methanol. The column was at room temperature and the flow rate was 2.0 mL / minute. Water contained 0.1% formic acid, and methanol contained 0.075% by volume formic acid. The DAD scans were collected from 220 to 400 nm. The EC50 values of the test compounds were determined by treating cells expressing MC4-R with the test compound and using the cells and measuring the intercellular concentration of cAMP with a Scintillation Proximity Assay kit from cAMP (SPA) Amersham -Pharmacy RPA-559. The EC50 values of the test compounds were also determined using the following reporter method by Goetz, et al., Which is incorporated herein by reference in its entirety and for all purposes as if the present were fully disclosed. Goetz, A.G.; Andrews J.L .; Littleton, T.R.; Ignar, D.M. DEVELOPMENT OF A FACILE METHOD FOR HIGH THROUGHPUT SCREENING WITH REPÓRTER GENE ASSAYS J. Biomolec. Screening, 5 pp. 377-384 (2000). CHO-6xCRE-luc + indicator cell lines expressing human MC1R, MC3R, MC4R and MC5R (Accession numbers of GenBank X65634, L06155 S77415 and U08353) and the CHO cell line of host indicator gene were prepared in complete medium in flasks T225 48 hours before the assay, the cells were harvested with 2 mL trypsin of 0.05%, washed with complete medium and plated at a concentration of 4000 cells / well in complete medium.

Sixteen hours before the assay, the medium was removed from the cells and replaced with 90 μL / serum free DMEM / F12 cavity. At the time of the assay, agonists were added in one volume in 10 μL and the plates were incubated for 4 hours at 37 ° C in a cell culture incubator. The medium was aspirated followed by the addition of 50 μL of a 1: 1 mixture of LucLite "11 and dPBS containing 1 mM CaCl 2 MgCl 2 The plates were then sealed and subjected to dark adaptation at room temperature for 10 minutes before of luciferase activity being quantified using a Top Count "11 microplate scintillation counter (Packard) using a count time of 3 seconds / well. The data of the concentration-response curve of NDP-aMSH were expressed as a percentage of the stimulation at times in the control of NDP-aMSH for each receptor subtype. The control value is the average of the duplicate cavities treated with NDP-aMSH lxlO "7 M. The compounds described above were synthesized and tested according to the test procedures described above, Each of the examples exhibited values of -log EC50 above about 3. For this reason, each of the example compounds is individually preferred and is preferred as a group.The nomenclature for these compounds was provided using a program version 5.07 of ACD Yam (November 14, 2001) available of Advanced Chemistry Development, and the Chemnnnovation NamExpert + Nomenclaton "11 brand program available from Chemlnnovation Software, Inc. Some of the starting materials were named using normal IUPAC nomenclature. The exemplary compounds are illustrative and should not be construed as limiting the present invention in any way.

In vivo studies of MC4-R agonists in energy uptake, body weight, hyperinsulinemia and glucose levels. In vivo studies were conducted to observe the effect of MCR-4 agoniosts on energy uptake, body weight, hyperinsulinemia and glucose levels. All studies were carried out with ob-ob mice from 9-10 weeks of age males who exhibited early onset of obesity, insulin resistance and diabetes due to leptin deficiency. The mice were acclimatized at the facility for a week before the studies and individually caged. Studies with mice treated with drug and treated with vehicle (control) were always run in parallel. In the multi-day studies, the mice (8-15 per group) were 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 pm) with 3 mg / kg of an MC4-R agonist of the present invention for 4 weeks. The body weight as well as the ingestion of water and food are monitored daily. Animals fasted overnight for measurements of fasting levels of glucose, insulin and lipids once a week until the end of the study. The energy expenditure (metabolic rate at rest, ie, consumption of 02 and production of C02) is monitored in air-tight chambers at the end of the study in the animals fed. The consumption of 02 and the production of C02 are measured using the Oxymax systems (Columbus Instruments). The oral glucose tolerance test (OGTT - glucose tolerance oral test (OGTT - a routine test for diabetes and glucose intolerance) is performed in fasted mice overnight at the end of the study. oral tolerance to glucose using a glucose monitor (Onetouch sold by Lifescan) Free fatty acids are measured using a non-esterified free fatty acid enzymatic assay (Aco Chemicals) Serum insulin levels are measured by immunoassay (Alpco).

Results The effect of the compounds of the present invention on the ingestion of food it is determined by measuring grams / mouse / day throughout a 4-week study. The food is monitored every morning. Cumulative food intake represents the total amount of grams that mice consume during the study. A significant reduction in food ingestion is demonstrated in those IP treated mice with the compounds of the present invention. The effect of the compounds of the present invention on body weight is determined by measuring grams / mouse from beginning to end of a 4 week study. The mice are weighed each morning. A significant reduction in body weight is demonstrated in those IP treated mice with the compounds of the present invention. The effect of the compounds of the present invention on blood glucose levels is determined by measuring blood glucose levels as represented by mg of glucose / dL of blood. The mice fasted overnight and measured the glucose levels the following morning. The vehicle treated mice show an increase in blood glucose consistent with the rapid progression of diabetes in this breed of mice while, diabetes is significantly reduced in mice treated with the drug. A significant reduction in fasting glucose levels is demonstrated in those IP treated mice with the compounds of this invention.

The effect of the compounds of the present invention on glucose levels during the oral glucose tolerance test (OGTT) is determined by measuring blood glucose in mice nested overnight. Blood glucose is represented as mg of glucose / dL of blood. Glucose levels are measured the next morning. Orally administered glucose raises blood glucose similarly to a meal, and the response to this hexogenic glucose gives a measure that the body also regulated glucose homeostasis. The vehicle-treated mice showed an elevated glucose response consisting of their diabetic status, while the drug-treated mice showed a greatly improved glucose clearance. The effect of the compounds of the present invention on the levels of free fatty acids (FFA) is determined by measuring the mmoles of serum FFA / L. The mice fasted overnight and measured free fatty acid levels the next morning. The vehicle-treated mice show high levels of FFA from beginning to end of the study consistent with their obese state, while diabetes of the drug-treated mice show a dramatic decrease. The effect of the compounds of the present invention on serum insulin levels is determined by measuring serum insulin levels one hour after individual IP dosing of 1 and 3 mg / kg in fasted ob / ob mice overnight. The serum insulin levels are represented as ng of insulin / ml of serum. The drug-treated mice show a depressing dose decrease relative to the vehicle.

Determination of t _, / 2 Cmax, Fl, Bioavailability, Cl, VSS and Nocturnal Efficiency In vivo studies were carried out to observe the effects of the compounds of formula IA, IB, IIA and IIIB on the subject animal. Male CD-1 mice, body weight of 20 grams on arrival, were used in these studies. The mice were given 30 mg / kg of the compound in HPMC / Tween solution or suspension via oral priming. Plasma, brain and liver samples were collected at time periods of 1, 2, 4, 8 and 24 hours after dosing. A mouse was used for a "time point", thus, a total of 5 mice were used for each compound tested.For the collection of samples, the mice were sacrificed by euthanasia with C02.The blood samples were taken for cardiac function and The blood and liver samples were collected immediately after bleeding and the samples were kept on dry ice.For the calculation of tissue half-lives (t? / 2s), the terminal velocity constant k was estimated by the absolute value of the slope of a logarithmic-linear regression of the terminal phase of the tissue-time concentration profile.The tissue half-life t_./2 is In (2) / k Male mice C57BL / 6J of 6- 9 weeks of age were used in these studies.The mice were housed individually at least 5 days before the study.Two and a half hours before the start of the dark cycle, the food was removed from the upper part of the cage.The mice were dosed with a compound of the invention (in HPMC / Tween, as a vehicle) or the vehicle via oral priming two hours before the beginning of the dark cycle. Immediately before the beginning of the dark cycle, pre-weighed food was given to each mouse. The food is weighed at 16 and 24 hours after the introduction of the food to obtain cumulative values of food ingestion. The mice were sacrificed by euthanasia with C02 followed by cervical dislocation. The following table includes t? / 2 data for plasma, brain, kidney and liver obtained after oral administration.

All references cited herein are hereby incorporated by reference in their entirety and for all purposes as if fully set forth herein. It is understood that the invention is not limited to the embodiments set forth herein for illustration, but encompasses all these forms thereof as come within the scope of the following claims. It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention.

Claims (80)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula IA, IB, or IC IA IB IC characterized in that: Z1 is selected from CR4 or NZ2 is selected from CR5 or NZ3 is selected from CR6 or NR1 is selected from the group consisting of arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, substituted and unsubstituted alkenyl, alkynyl, or alkyl; R 2 is selected from the group consisting of H, or substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, alkylcarbonyl, or arylcarbonyl groups; R3 is selected from the group consisting of H, and substituted and unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; ? A? A and R6 alkoxy groups are independently selected from the group consisting of H, Cl, I, F, Br, OH, NH2, CN, N02, and alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl, unsubstituted and substituted heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, or heteroarylaminocarbonyl; W is a group of the formula HA; HA R1 'is selected from the group consisting of H, and substituted, unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocyclylalkyl groups; R2 'is selected from the group consisting of H, and alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl substituted and unsubstituted, or heterocyclylalkyl groups; wherein at least one of R1 'and R2' is a substituted or unsubstituted heterocyclylalkyl group; R3 is selected from the group consisting of H, and aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or substituted and unsubstituted; R4 'is selected from the group consisting of H, or alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl or substituted and unsubstituted; and pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, hydrates thereof, or solvates thereof.
2. 2. The compound according to claim 1, characterized in that R1 'or R2' is a substituted or unsubstituted pyrrolidinylethyl group.
3. 3. The compound according to claim 2, characterized in that R1 'or R2' is a substituted or unsubstituted pyrrolidinylmethyl group or is a substituted or unsubstituted pyrrolidinylethyl group.
4. 4. The compound according to claim 1, characterized in that R3 is H.
5. The compound according to claim 1, characterized in that Z1 is a group CR4, Z2 is a group CR5, and Z3 is a group CR6.
6. 6. The compound according to claim 1, characterized in that R3 'is selected from substituted or unsubstituted cycloalguilo, polycyclic, alkenyl, alkyl, or aryl cycloalkyl groups.
7. 7. The compound according to claim 1, characterized in that R1 is a 2,4-disubstituted phenylethyl group.
8. 8. The compound according to claim 1, characterized in that R1 is selected from phenylethyl, 2,4-dichlorophenylethyl, -methoxyphenylethyl, 4-phenoxyphenylethyl, 4-b-isophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexenylethyl groups. , 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, 2-fluoro-4-chlorophenylethyl, 2-fluoro -4-bro-ofhenylethyl, 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.
9. 9. A composition, characterized in that it comprises the compound according to any of claims 1-8 and a pharmaceutically acceptable carrier.
10. 10. A compound of the formula IA, IB, or IC IA IB IC characterized in that: Z1 is selected from CR4 or N; Z2 is selected from CR5 or N; Z3 is selected from CR6 or N; R1 is selected from the group consisting of substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R 2 is selected from the group consisting of H, and substituted and unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, alkylcarbonyl, or arylcarbonyl groups; R3 is selected from the group consisting of H, and substituted and unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R4, R5, and R6 are independently selected from the group consisting of H, Cl, I, F, Br, OH, NH, CN, NQ_, and alkoxy, alkyl, alkenyl, alkynyl, alkylamino, dialkylamino, cycloalkyl groups, unsubstituted and substituted heterocyclylamino, heteroarylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocyclylaminocarbonyl, or heteroarylaminocarbonyl; is HA IIB wherein R1 'and R2' together with the nitrogen to which they are attached, are joined together to form a heterocyclic ring substituted with at least one group selected from arylalkyl groups, -C (= 0) -alkyl, -alkyl-C (= 0) -O-alkyl, -C (= 0) -0-alkyl, -C (= 0) -NH2, -C (= 0) -Mí (alkyl), -C (= 0) -N ( alkyl) 2, (± alkyl, aminoalkyl, alkylaminoalkyl, aminoalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, and substituted and unsubstituted alkylthioalkyl; R 3 'is selected from the group consisting of H, and aryl, alkyl, alkenyl, alkynyl, cycloalkyl groups unsubstituted and substituted, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or cycloalkylalkyl; R4 'is selected from the group consisting of H, and alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, arylalkyl, or substituted and unsubstituted heteroarylalkyl, and pharmaceutical salts of the same, stereoisomers thereof, tautomers thereof, hydrates thereof, or solvates thereof.
11. 11. The compound according to claim 10, characterized in that the heterocyclic ring formed by R1 'and R2' and the nitrogen to which they are attached is a substituted piperazine.
12. 12. The compound according to claim 11, characterized in that the piperazine is substituted with a group selected from a phenylalkyl group, a substituted or unsubstituted phenyl group, an -alkyl-SCH3 group, an indolyalkyl group, a morpholinylalkyl group, a group pyridyl, a piperidinyl group, or a tetrahydrofuranylalkyl group.
13. 13. The compound according to claim 10, characterized in that the heterocyclic ring formed by R1 'and R2' and the nitrogen to which they are attached is a substituted piperidine.
14. 14. The compound according to claim 13, characterized in that the piperidine is substituted with a group selected from a phenylalkyl group, a substituted or unsubstituted phenyl group, an -alkyl-SCH3 group, an indolyalkyl group, a morpholinylalkyl group, a pyridyl group, a piperidinyl group, or? n tetrahydrofuranylalkyl group.
15. 15. The compound according to claim 10, characterized in that R3 is H.
16. 16. The compound according to claim 10, characterized in that Z1 is a group CR4, Z2 is a group CR5, and Z3 is a group CRS.
17. 17. The compound according to claim 10, characterized in that R3 'is selected from substituted or unsubstituted cycloalkyl, polycyclic, alkenyl, alkyl, or aryl cycloalkyl groups.
18. 18. The compound according to claim 10, characterized in that R1 is a 2,4-disubstituted phenylethyl group.
19. 19. The compound according to claim 10, characterized in that R1 is selected from phenylethyl, 2,4-dichlorophenylethyl, 4-methoxyphenylethyl, 4-phenoxyphenylethyl, 4-bromophenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl, 4-ethylphenylethyl, cyclohexylethyl, 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, 2-fluoro-4-chlorophenylethyl, 2-fluoro-4-bromophenylethyl, 2-fluoro-4-methoxyphenylethyl, 2-trifluoromethyl-4-fluorophenylethyl, 2, -difluorophenylethyl, 2,4-dimethylphenylethyl, 2,4-dimethoxyphenylethyl , (2-pyridyl) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl or (phenyl) (hydroxymethyl) ethyl.
20. 20. A composition, characterized in that it comprises the compound according to any of claims 10-19 and a pharmaceutically acceptable carrier.
21. 21. The use of a compound of any of claims 1-8 in the preparation of a medicament for treating the disease mediated by MC4-R.
22. 22. The use according to claim 21, wherein the disease mediated by MC4-R is obesity or type II diabetes.
23. 23. The use of a compound according to any of claims 10-19 in the preparation of a medicament for treating the disease mediated by MC4-R.
24. 24. The use according to claim 23, wherein the disease mediated by MC4-R is obesity or type II diabetes.
25. 25. O compound according to the formula VA, VB, mixtures thereof, or pharmaceutically acceptable salts of the compound, VA VB wherein R1 is selected from arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl substituted or unsubstituted; R 3 is selected from substituted or unsubstituted aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, or cycloalkyl, substituted or unsubstituted groups; R4, R5, and R6 are independently selected from H, Cl, 1, F, Br, OH, NH2, CN, N0_, and substituted or unsubstituted alkoxy, and alkyl groups; R1 'and R2', together with the nitrogen to which they are attached, form a substituted or unsubstituted heterocyclyl group; and R3 is selected from substituted or unsubstituted cycloalkyl groups.
26. 26. The compound according to claim 25, characterized in that R4, R5, and R6 are all H.
27. 27. The compound according to claim 25, characterized in that R3 'is a substituted or unsubstituted polycyclic cycloalkyl group.
28. The compound according to claim 27, characterized in that R3 is a substituted or unsubstituted polycyclic cycloalkyl group of the formula VIII
29. 29. The compound according to claim 25, characterized in that R1 is a substituted or unsubstituted arylalkyl group. _ _.
30. 30. The compound according to claim 29, characterized in that R1 is a substituted phenylethyl group.
31. 31. The compound according to claim 30, characterized in that R1 is a 4-substituted phenylethyl group or is a 2-disubstituted phenylethyl group. 20
32. 32. The compound according to claim 30, wherein R1 is selected from groups 2-f luoro-4 -metoxifeniletilo, 2-chloro-4 - metilf eniletilo, 4 -fluorofeniletilo, 4 -clorofeniletilo, 4 - chloro-2 -f luorofeniletilo , 2, 4-dichlorofenylethyl, 4-25 bromofenilethyl, or 4-bromo-2-fluorophylethyl.
33. 33. The compound according to claim 25 wherein R1 is selected from, 2,4-dichlorophenylethyl, 4-metcxifeniletilo, 4-fenaxifeniletilo, 4-brcmofeniletilo, 4-methylphenylethyl, 4-chlorophenylethyl, 4-fluorophenylethyl, 4- phenylethyl groups etilfeniletilo, ciclchexeniletilo, 2-metcxifeniletilo, 2-chlorophenylethyl, 2-fluorophenylethyl, 3-methoxyphenylethyl, 3-fluorophenylethyl, thienylethyl, indolylethyl, 4-hidrc? ifeniletilo, 3,4-dimetaxifeniletilo, 2-chloro-4-yodofeniletilo, 2- fluoro-4-methylphenylethyl, 4-chloro-2-fluorophenylethyl, 4-brcmo-2-fluorophenylethyl, 2-fluoro-4-methoxyphenylethyl, 2-trifl? orcmetil-4-fluorophenylethyl, 2,4-difluorofeniletilo 2,4- dimethylphenylethyl, 2,4-dimethaxyphenylethyl, (2-pyridyl) ethyl, (3-pyridyl) ethyl, (4-pyridyl) ethyl, (pyridyl) (hydroxymethyl) ethyl or (phenyl) (hydraxymethyl) ethyl.
34. 34. The compound according to claim 25, characterized in that R3 is selected from substituted or unsubstituted heterocyclyl groups, or substituted or unsubstituted heteroaryl groups.
35. 35. The compound according to claim 34, wherein R3 is selected from pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, drofuranilo tetra, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiophenyl, pyranyl, tetrahidrqpiranilo, tetrahydrothiopyranyl, pyrazinyl, thiazolyl , substituted or unsubstituted pyrimidinyl, quipuclidinyl, indolyl, imidazolyl, triazolyl, tetrazolyl, or pyridazinyl.
36. 36. The compound according to claim 25, characterized in that R3 is selected from heteroaryl or heterocyclyl groups of the formula which may be additionally substituted or may be unsubstituted.
37. 37. The compound according to claim 25, characterized in that R3 is selected from aryl or cycloalkyl groups of the formula which may be additionally substituted or may be unsubstituted.
38. 38. The compound according to claim 25, characterized in that R1 'and R2', together with the nitrogen to which they are attached, form a substituted or unsubstituted piperazinyl group.
39. 39. The compound according to claim 38, characterized in that R1 'and R2', together with the nitrogen to which they are attached, form a piperazinyl group which is substituted with at least one group selected from fluoromethyl, difluoromethyl or trifluoromethyl groups.
40. 40. The compound according to claim 38, characterized in that R1 'and R2P together with the nitrogen to which they are attached, form a piperazinyl group comprising at least one carbonyl group such that the piperazinyl group is a piperazinone which may be further substituted.
41. 41. The compound according to claim 40, characterized in that R1 'and R2P together with the nitrogen to which they are attached form a piperazinone of the formula which may be additionally substituted.
42. 42. The compound according to claim 41, characterized in that R1 'and R2P together with the nitrogen to which they are attached, form a piperazinone of the formula
43. 43. The compound according to claim 42, characterized in that R1 'and together with the nitrogen to which they are bound, form a piperazinone of the formula
44. 44. The compound according to claim 38, characterized in that R1 'and R2P together with the nitrogen to which they are attached form a piperazinyl group of the formula
45. 45. The compound according to claim 25, characterized in that it is a compound of the formula
46. 46. The compound according to claim 25, characterized in that it is a compound of the formula
47. 47. The compound according to claim 25, characterized in that it is a compound of the formula
48. 48. The compound according to claim 25, characterized in that it is a compound of the formula
49. 49. The compound according to claim 25, characterized in that it is a compound of the formula
50. 50. The compound according to claim 25, characterized in that it is a compound of the formula
51. 51. The compound according to claim 25, characterized in that it is a compound of the formula
52. 52. The compound according to claim 25, characterized in that it is a compound of the formula
53. 53. The compound according to claim 25, characterized in that the compound is a compound of the formula
54. 54. The compound according to claim 25, characterized in that it is a compound of the formula
55. 55. The compound according to claim 25, characterized in that it is a compound of the formula
56. 56. The compound according to claim 25, characterized in that it is a compound of the formula
57. 57. The compound according to claim 25, characterized in that it is a compound of the formula
58. 58. The compound according to claim 25, characterized in that it is a compound of the formula
59. 59. The compound according to claim 25, characterized in that it is a compound of the formula
60. 60. The compound according to claim 25, characterized in that it is a compound of the formula
61. 61. The compound according to claim 25, characterized in that it is a compound of the formula
62. 62. A pharmaceutical formulation, characterized in that it comprises the compound according to any of claims 25-61 and a pharmaceutically acceptable carrier.
63. 63. A compound of the formula VIIA, VIIB, mixtures thereof, or pharmaceutically acceptable salts of the compound VIIA VIIB characterized in that R1 is selected from the group consisting of substituted and unsubstituted arylalkyl, heteroarylalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R3 is selected from the group consisting of H, or substituted and unsubstituted arylalkyl, heteroarylalkyl, alkoxy, alkylamino, dialkylamino, aryl, heteroaryl, heterocyclyl, cycloalkyl, aminocycloalkyl, heterocyclylalkyl, cycloalkylalkyl, alkenyl, alkynyl, or alkyl groups; R4, R5, and Rs are independently selected from H, Cl, I, F, Br, OH, NH2, CN, N02, or substituted and unsubstituted alkoxy or alkyl groups; R3 'is selected from H, and unsubstituted and unsubstituted aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, or cycloalkylalkyl groups; and Y is selected from a portion of the formula wherein R1 'is selected from substituted or unsubstituted algeryl groups; R2 ', R4', and R5 'are independently selected from H or substituted or unsubstituted algeryl groups; R6 'is selected from substituted or unsubstituted alkyl groups; or R5 'and R6', together with the nitrogen to which they are attached form a heterocyclyl or heteroaryl group; and R7 'is selected from CN, or substituted or unsubstituted alkyl, aryl or arylalkyl groups.
64. 64. The compound according to claim 63, characterized in that R4, R5, and R6 are all H.
65. 65. The compound according to claim 63, characterized in that R3 is a substituted or unsubstituted polycyclic cycloalkyl group.
66. 66. The compound according to claim 65, characterized in that R3 'is a substituted or unsubstituted polycyclic cycloalkyl group of the formula VIII VIII
67. 67. The compound according to claim 63, characterized in that R1 is a substituted or unsubstituted arylalkyl group.
68. 68. The compound according to claim 67, characterized in that R1 is a substituted phenylethyl group.
69. 69. The compound according to claim 68, characterized in that R1 is a 4-substituted phenylethyl group or is a 2,4-disubstituted phenylethyl group.
70. 70. The compound according to claim 67, characterized in that R1 is selected from 2-fluoro-4-methoxyphenylethyl, 2-chloro-4-methoxyphenylethyl, 4-f-fluorophenylethyl, 4-chlorophenylethyl, 4-chloro-2-fluorophenylethyl groups. , 2, 4-dichlorofenylethyl, 4-bromofethylethyl, or 4-bromo-2-f luorofethylethyl.
71. 71. The compound according to claim 70, characterized in that R3 is selected from substituted or unsubstituted heterocyclyl groups or substituted or unsubstituted heteroaryl groups.
72. 72. The compound according to claim 71, characterized in that R3 is selected from pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, furanyl, pyrrolidinyl, pyrrolyl, thiophenyl, tetrahydrothiopyl, pyranyl, tetrahydropyranyl, trahydrotiopyr ayl pyrazinyl, thiazolyl, pyrimidinyl, quinuclidinyl, indolyl, imidazolyl, triazolyl, tetrazolyl, or substituted or unsubstituted pyridazinyl.
73. 73. The compound according to claim 63, characterized in that R1 is selected from phenylethyl, 2,4-dichlorofenylethyl, 4-methoxy-phenylethyl, 4-phenoxy-phenylethyl, 4-bromo-phenylethyl, 4-methylphenylethyl, 4-chlorophenylethyl groups, 4-f luorofethylethyl, 4-ethylphenylethyl, cyclohexenylethyl, 2-methoxy-phenylethyl, 2-chloro-phenylethyl, 2-f-lorofenylethyl, 3-methoxy-phenylethyl, 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.
74. 74. The compound according to claim 63, characterized in that R3 is selected from heteroaryl or heterocyclyl groups of the formula which may be additionally substituted or may be unsubstituted.
75. 75. The compound according to claim 63, characterized in that R3 is selected from aryl, cycloalkyl, or aminocycloalkyl groups of the formula which may be additionally substituted or may be unsubstituted.
76. 76. The compound according to claim 63, characterized in that Y is selected from
77. 77. The compound according to 76, characterized in that Y is selected from
78. 78. A pharmaceutical formulation, characterized in that it comprises a pharmaceutically acceptable carrier and the compound according to any of claims 63-77.
79. 79. The use of a compound according to any of claims 25-62 or 63-77 in the preparation of a medicament for treating a disease mediated by MC4-R.
80. 80. The use according to claim 79, wherein the disease mediated by MCR-4 is obesity or type II diabetes.