MX2008005670A - Hydrazone derivatives and uses thereof - Google Patents

Abstract

The present invention is directed to the use of a compound having the formula (I) wherein R1, R2, R3, R4, L1, and L2are defined herein. The compounds of the present invention are useful as inhibitors of certain taste perceptions and functions. The invention is also directed to compositions comprising a compound according to the above formula.

Description

HIDRAZONE DERIVATIVES AND USES OF THE SAME FIELD OF THE INVENTION The present invention relates to the use of compounds of Formula I to inhibit certain functions and taste perceptions and related uses. The invention is also directed to, among other things, compositions comprising a compound of Formula I which can be used in pharmaceuticals, foods and others, to inhibit certain functions and taste perceptions.

BACKGROUND OF THE INVENTION Taste perception plays a critical role in both the nutritional status of humans and the basic survival of animals. Margolskee, R.F., J. Biol. Chem. 277: 1-4 (2002); Avenet, P. and Lindemann, B., J. Membrane Biol. 112: 1-8 (19889). Taste perception task is performed by taste receptor cells (TRC). CRTs have the ability to perceive the multitude of compounds that are associated with a given flavor and then convert that perception to a signal that is deciphered by the brain, resulting in the sensation of taste (tasty) sweet, bitter, sour, salty or umami CRTs are polarized epithelial cells, meaning that they have basolateral and apical membranes Ref. : 192074 specialized. A palate contains approximately 60 to 100 CRT. Each CRT has a portion of its membrane exposed on the mucosal surface of the tongue. Kinnamon, S.C., TINS 11: 491-496 (1988). Sensory transduction is initiated by sapid molecules, or "tasters" that interact with microvillus processes in the apical TRC membrane. The tasters bind to specific membrane receptors, resulting in a voltage change across the cell membrane. Instead, this depolarizes, or changes the electrical potential, of the cell, causing release of transmitters and excitation of primary gustatory nerve fibers. A recently discovered transmembrane protein, TRPM5, has been shown to be essential for flavor transduction. Pérez et al., Nature Neuroscience 5: 1169-1176 (2002); Zhang et al, Cell 112: 293-301 (2003). This protein is a member of the potential receptor potential family (TRP) of ion channels, forms a channel through the membrane of the taste receptor cell, and is believed to be activated by stimulation of a receptor pathway coupled to phospholipase C and by release of Ca2 + mediated by IP3. The opening of this channel is dependent on an elevation in Ca2 + levels. Hofmann et al, Current Biol. 13: 1153-1158 (2003). The activation of this channel leads to depolarization of the CRT, which, in turn, leads to transmitter release and excitation of the primary gustatory nerve fibers. Because TRPM5 is a necessary part of the perception-taste machinery, its inhibition prevents an animal from perceiving particular flavors. Although this perception of taste is a vital function, the inhibition of undesirable flavors is beneficial under certain circumstances. For example, many pharmaceutical active ingredients for medicines produce undesirable flavors, such as a bitter taste. The inhibition of the bitter taste produced by the medicine can lead to improved acceptance by the patient. Traditionally, sweeteners and flavorings have been used to mask the bitter taste of pharmacists. The sweetener or flavoring is known to activate other flavor trajectories and at sufficiently high concentrations, this serves to mask the bitter taste of the pharmacist. However, this procedure has proved ineffective in masking the taste of very bitter compounds. Microencapsulation in a cellulose derivative has also been used to mask the bitter taste of pharmacists. However, this procedure prevents the rapid oral absorption of the pharmacist. A number of other methods have been suggested to inhibit, alter or mask undesirable flavors, which include the use of 5'-adenosine carboxylic acid (AMP) and 5'-inosine carboxylic acid (IMP) as potential inhibitors of bitterness. See, U.S. Patent No. 6,540,978. However, the compounds currently available are lacking in desirable characteristics. Another aspect of the flavor is its role in the absorption of food. Studies have shown increased absorption of food as palatability increases. Sorensen, et al., Int. J. Obes. Relat. Metab. Disord. 27 (10): 1152-66 (2003). For example, certain drugs, such as antihypertensives and antihyperlipidemics, have been reported to produce adverse taste alterations and may result in reduced feed absorption. Doty, et al., J. Hypertens. 21 (10): 1805-13 (2003). The taste deterioration has also been associated with radiation treatments for head and neck cancer and this taste deterioration has been considered to be one of the factors associated with reduced appetite and altered patterns of food absorption. Vissink, et al., Cri. Rev. Oral Biol. Med. 14 (3): 213-25 (2003). The reduced consumption of food has also been correlated with the loss of taste sensations in the elderly. Shiftman, S. S., J Am. Med. Ass'n. 278 (16): 1357-1362 (1997). Currently, while there are a number of agents that are or have been in the market to reduce the absorption of food and appetite, such as derivatives of amphetamines and fenfluramine, many have serious side effects. More selective procedures, for example, neuro-regulation via mimetics / peptide antagonists, are still in development stages. Therefore, there is a need for compounds that can effectively inhibit an undesired taste without exhibiting one or more of the side effects of the prior art taste masking agents.

BRIEF DESCRIPTION OF THE INVENTION A first aspect of the present invention is directed to a method for inhibiting a flavor-modulating protein, the method comprising contacting the protein with a compound of Formula I, or a physiologically acceptable salt thereof. A further aspect of the present invention is directed to a method for inhibiting the depolarization of a taste receptor cell, the method comprising contacting the cell with a compound of Formula I or a physiologically acceptable salt thereof. A further aspect of the present invention is directed to a method of inhibiting the taste of a pharmacist, which comprises administering one or more compounds of Formula I, or a physiologically acceptable salt thereof, in conjunction with the administration of the pharmacist to a subject.

A further aspect of the present invention is directed to a method for inhibiting the flavor of a food product, comprising administering one or more compounds of Formula I, or a physiologically acceptable salt thereof, in conjunction with administration of the pharmaceutical to a subject . A further aspect of the present invention is directed to a pharmaceutical composition comprising an active agent, optionally one or more pharmaceutically acceptable carriers, and one or more compounds of Formula I or a physiologically acceptable salt thereof. A further aspect of the present invention is directed to a food product comprising one or more compounds according to Formula I or a physiologically acceptable salt thereof. A further aspect of the present invention is directed to a method for reducing the palatability of the food and its absorption comprises administering one or more compounds of Formula I to a subject in need of such treatment. These and additional aspects of the present invention are described in detail below.

BRIEF DESCRIPTION OF THE FIGURES The accompanying figures, which are incorporated in this document and form a part of the specification, serve to explain the principles of the invention and allow a person skilled in the pertinent art to make and use the invention. Figure 1 illustrates the generation of the FLIPR response of TRPM5. Figure 2 illustrates electrophysiology results of inhibition of TRP 5 with the compound of Example 3 as described in Example 24. Figure 3 illustrates a summary of 14 experiments demonstrating the inhibition of the Ca2 + activated current of TRPM5 by the compound of Example 3. Figures 4A and 4B illustrate the TRPM5-dependent fluorescent signal in HEK293 cells, as explained in Example 67.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds and compositions that are employed, for example, to inhibit the activity of a flavor-modulating protein. Other aspects of the present invention are described in detail in this document.

Methods of Use A first aspect of the present invention is directed to a method for inhibiting a flavor-modulating protein, the method comprising contacting the protein with a compound of Formula I: 1 or a physiologically acceptable salt thereof, wherein R1 is C6-4 aryl, 5-14 elements heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and Ci-6 alkyl, each of which is optionally substituted; R2 is H, Ci-6 alkyl, C6-10 aryl or arylC6-ioalkyl (Ci-e); R3 is H, Ci_6 alkyl, C6-io aryl or cyano; R4 is C1-6 alkyl, C6-I4 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl or 3-14 membered cycloheteroalkenyl, each of which is optionally replaced, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted; or R3, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from C6-14 aryl, 5-14 elements heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted. In one embodiment, R1 is optionally substituted C6-io aryl, such as phenyl or naphthyl. In another embodiment, R1 is optionally substituted with 5-10 elements, or preferably, 5-7-element heteroaryl, such as but not limited to pyridyl, pyrimidinyl, imidazolyl, tetrazolyl, furanyl, thienyl, indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl and benthiazolyl, each of which is optionally substituted. In other cases, the heteroaryl group is a heteroaryl containing nitrogen or an heteroaryl containing oxygen. Another subset of R1 includes a substituted aryl, preferably C6-10 aryl group, or heteroaryl having 1 -3 substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci_6 alkyl, C2-6 alkenyl , C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 1-6 alkylenedioxy, C 1-6 alkoxy (Ci-6), C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, monoalkylamino (C1-4), dialkylamino (Ci-4), alkylcarbonylamino C2-6 / alkoxycarbonylamino C2-6, alkoxycarbonyl C2-6, carboxy, alkoxy (Ci-6) alkoxy (C2-6), carboxyalkoxy C2-6 and carboxyalkyl C2 -6. Another preferred heteroaryl group is carbazolyl, which is optionally substituted. In another embodiment, R1 is optionally substituted C3-10 cycloalkyl, or optionally substituted C3-10 cycloalkenyl. In another embodiment, d R1 is optionally substituted cycloheteroalkyl of 3-10 elements or optionally substituted cycloheteroalkenyl of 3-10 elements. Suitable R1 groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. Cycloalkyl groups also include bicycloalkyl and polycycloalkyl groups, preferably having 7-10 carbon atoms, such as bicyclo [4.1.0] heptanil and adamantyl. Another subset of R1 includes a substituted C3-10 cycloalkyl or C3-10 cycloalkenyl having 1-3 substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci_6 alkyl, C2-6 alkenyl, haloalkyl Ci-6, C 1-6 alkoxy, C 3-6 alkenyloxy, C 1-6 alkylenedioxy, C 1-6 alkoxy (Ci-6), C 1-6 aminoalkyl, Ci-6 aminoalkoxy, Ci-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, monoalkylamino (C1-4), dialkylamino (Ci-4), alkylcarbonylamino C2-6, alkoxycarbonylamino C2-6, alkoxycarbonyl C2-6, carboxy, alkoxy (Ci-6) alkoxy (C2-6), carboxyalkoxy C2-6 and carboxyalkyl C2 -6, each of which is optionally substituted. In yet a further embodiment, R1 is optionally substituted Ci-6 alkyl, such as methyl, ethyl and propyl. R1 can be a straight or branched chain alkyl group. Suitable substituted alkyls include haloalkyl, hydroxyalkyl, aminoalkyl and the like. Suitable groups for R1 include, 2-benzo [d] thiazol-2-yl, 1-naphthalenyl, 4-methoxyphenyl, 2-carboxyphenyl, 3-methylphenyl, 3-bromobenzyl, bicyclo [4. 1 . 0] heptanil, 4-nitrophenyl, 4- (trifluoromethylthio) phenyl, tricyclo [3. 3 . 1 . 1.3 7] decanyl; N-ethyl-N-2-hydroxyethylaminophenyl, 5-chloro-3- (trifluoromethyl) pyridin-2-yl, 3, -dimethylphenyl, 2-nitro-5- (pyrrolidin-1-yl) phenyl, 3-cyclohexenyl, and 1H-benzo [d] imidazol-2-yl Other suitable groups for R1 include, 4- (dimethylamino) phenyl, 4 - (diethylamino) phenyl, 1-hydroxycyclopentyl, 4-nitrophenyl, 2-bromo-4-methoxyphenyl, lH- indol-3-yl, 4-t-butyl-2-methylphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 8-dimethylquinolin-2-yl and 9H- carbazole-9-yl. In another embodiment, R2 is H. Alternatively, R2 is Ci-6 alkyl, such as methyl, ethyl or propyl. R2 can be a straight or branched chain alkyl group. In other embodiments, R 2 is a C 6 -ioalkyl aryl (Ci-6), such as benzyl, phenethyl or phenylpropyl group. Preferably, R 2 is a C 6 -ioalkyl aryl (Ci-4). In a further embodiment, R3 is H.

Alternatively, R3 is Ci-6 alkyl, such as methyl, ethyl or propyl. R3 can be a straight or branched chain alkyl group. In yet another embodiment, R3 is cyano (-CN). In another embodiment, R 4 is optionally substituted C 1 -aryl, such as phenyl or naphthyl. In another embodiment, R 4 is 5-10 elements heteroaryl or preferably 5-7 elements optionally substituted, such as but not limited to pyridyl, pyrimidinyl, imidazolyl, tetrazolyl, furanyl, thienyl, indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl and benzothiazolyl, each of which is optionally substituted. In other cases, the heteroaryl group is a heteroaryl containing nitrogen. In other cases, the heteroaryl group is an heteroaryl containing oxygen. Another preferred heteroaryl group is carbazolyl, which is optionally substituted. Another subset of R4 includes a substituted aryl or heteroaryl group having 1-3 substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C 2-6 alkenyl, Ci-6 haloalkyl , Ci-6 alkoxy, C3-6 alkenyloxy, Ci-6 alkylenedioxy, Ci-6alkyloxy (Ci-6), Ci-6 aminoalkyl, Ci-6 aminoalkoxy, Ci-6 hydroxyalkyl, C2-6 hydroxyalkoxy, monoalkylamino (C1-6) 4), dialkylamino (C1-4), alkylcarbonylamino C2 ~ 6 / alkoxycarbonylamino C2-6, alkoxycarbonyl C2-6 carboxy, alkoxy (Ci-6) alkoxy (C2-6) carboxyalkoxy C2-6 and carboxyalkyl C2-6- In another embodiment, R4 is optionally substituted C3-10 cycloalkyl, or optionally substituted C3-10 cycloalkenyl. In another embodiment, R 4 is optionally substituted cycloheteroalkyl of 3-10 elements or optionally substituted 3-10 cycloheteroalkenyl groups. Suitable R4 groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. Cycloalkyl groups also include bicycloalkyl groups, such as bicyclo [4.1.0] heptanil. In yet a further embodiment, R 4 is optionally substituted C 1-6 alkyl, such as methyl, ethyl and propyl. R 4 can be a straight or branched chain alkyl group. Suitable substituted alkyls include, haloalkyl, hydroxyalkyl, aminoalkyl, and the like. In another embodiment, R 4 is a phenyl substituted with 1-4 groups independently selected from the groups consisting of halo, C 1-4 alkoxy such as methoxy, and C 1-4 alkylthio. Other suitable R4 groups include, 6-bromobenzo [d] [1,3] dioxol-5-yl, 4-hydroxy-3-iodo-5-methoxybenzylidene, 4-hydroxy-3-methoxyphenyl, 3,4,5-trimethoxyphenyl , 4- (diethylamino) -2-hydroxyphenyl, 5-bromo-2-oxoindolin-3-ylidene, 2-oxoindolin-3-ylidene, 3,4-dimethoxyphenyl and 3-trifluoromethylphenyl. Additional suitable groups for R 4 include 4-methoxyphenyl, 4- (allyloxy) -3-methoxyphenyl, 4-isopropylphenyl, 1,3-indolinylidene, 4- (diethylamino) -2-hydroxyphenyl, 1,5-dimethyl-2- oxoindolin-3-ylidene, l-butyl-lH-indol-3-yl, 4-pyridinyl, lH-pyrrol-2-yl, 2,4-dihydroxyphenyl, 4- (4-morpholino) -3-nitrophenyl, quinuclidinylidene and 2-hydroxy-4-diethylaminophenyl. In one modality, L1 is absent. Thus, in accordance with this embodiment, R1 is directly attached to the nitrogen atom by a single bond. In another embodiment, L1 is a linker containing 1-10, preferably 1-7, carbons and / or heteroatoms, and which is optionally substituted. The linker is a divalent moiety that connects R1 to nitrogen. The linker may be any suitable divalent moiety containing 1-10 carbons and / or heteroatoms. Suitable linkers will contain, for example, 1,2,3,4,5 or 6 carbons and / or heteroatoms. For example, the linker can be a divalent carbon linker with 1-10, preferably 1-7, carbon atoms, such as but not limited to, methylene (-CH2), ethylene (-CH2CH2), propylene (e.g. -CH2-CH2-CH2), butylene and the like. Alternatively, L1 may be a C3-10 cycloalkylene linker, such as methylenecyclopropylene. A divalent carbon linker can be substituted with suitable substituents as described herein. In another subseries, a preferred group of substituents includes amino, hydroxy, halogen, cyano, thiol, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy / C 1-6 alkylenedioxy, C 1-6 alkoxy 6 (C 1-6) alkyl, C 1-6 aminoalkyl, Ci-6 aminoalkoxy, Ci-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, (C 1-4) monoalkylamino, (C 1-4) dialkylamino, C 2-6 alkoxycarbonylamino, C 2-6 alkoxycarbonylamino , C2-6 alkoxycarbonyl, carboxy, (C1-6) alkoxy (C2-6) alkoxy, C2-6 carboxyalkoxy and C2-6 carboxyalkyl. L1 could also be a divalent linker containing 2-10, preferably 2-6, carbons and heteroatoms. Such linkers include, by way of non-limiting examples, alkyleneoxy, alkylene, alkylenethio, alkylenedioxy. Other suitable examples include -CH2CH2C (0), -OCH2-, NHCH2-, -OCH2CH2-, -NHCH2CH2-, and -OCH2CH2CH2-. It is understood that a preferred linker containing both carbon and heteroatoms will be one in which the heteroatom is not directly attached to the nitrogen atom of Formula I.

The linker L1 may also contain 1-10 heteroatoms, preferably 1, 2 or 3 heteroatoms. Suitable heteroatom linkers include, -O-, -S-, -NH-, -N = N-, and the like. For example, a suitable L1 group is -SCH2C (0) -. In other embodiments, linker L1 is an alkylene, alkenylene or alkynylene portion of 1-6 elements. In another embodiment, the linker L1 is a heteroalkylene, heteroalkenylene or heteroalkynylene portion of 1-6 elements. The linker L1 can be substituted as described herein. In one embodiment, the linker L1 is a divalent moiety containing 1-6 carbon atoms and substituted with 1, 2 or 3 substituents selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, oxo, Ci alkyl -6, C2-6 alkenyl, Ci_6 haloalkyl, Ci_6 alkoxy, C3-6 alkenyloxy, C1-6 alkylenedioxy, Ci-6alkyl alkoxy (Ci-β), C1-6 aminoalkyl, Ci-6 aminoalkoxy, C1-6 hydroxyalkyl, hydroxyalkoxy C2-6 monoalkylamino (C1-4), dialkylamino (C1-4), alkylcarbonylamino C2-6, alkoxycarbonylamino C2-6, alkoxycarbonyl C2-6 carboxy, alkoxy (Ci-β) alkoxy (C2-6), carboxyalkoxy C2.6 and C2-6 carboxyalkyl. In another embodiment, L1 is a linker selected from the group consisting of ?? In another embodiment, R1 and L1 together as a whole form a selected group of the following: In one modality, L2 is absent. Thus, in accordance with this embodiment, R4 is directly attached to the carbon atom to which it is attached to the nitrogen atom by a double bond. L2 may also be a divalent linker containing 2-10, preferably 2-6 carbons and heteroatoms. Such linkers include, by way of non-limiting examples, alkyleneoxy, alkyleneamino, alkylenethio, alkylenedioxy. Other suitable examples include -CH2CH2C (0), -OCH2-, -NHCH2-, -OCH2CH2-, -NHCH2CH2- and -OCH2CH2CH2. It is understood that a preferred linker containing both carbon and heteroatoms will be one in which a heteroatom is not directly attached to the nitrogen atom of Formula I. The linker L2 can also be a linker having 1-10 hetero-atoms, preferably 1, 2 or 3 heteroatoms. Suitable heteroatom linkers include -O-, -S-, -NH-, -N = N, and the like. For example, a suitable group L1 is -SCH2C (0) -. In a further embodiment, R4 and L2 together form a group selected from -N = N-aryl and -N = N-heteroaryl. Suitable examples of -N = N-aryl include but are not limited to, -N = N-phenyl, in which, the phenyl is optionally substituted, and -N = N-naphthyl, in which, the naphthyl is optionally substituted . In a further embodiment, R4 and L2 together form a group selected from In a first subclass, the present invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I wherein: R1 is aryl Ce- ?? optionally substituted; R 2 is H or C 1-6 alkyl, preferably C 1-4 alkyl; R3 is H or C1-6 alkyl, preferably alkyl C1-4; And R4 is aryl Ce- ?? optionally substituted. In a modality, within this first subclass, R1 is unsubstituted phenyl. In other cases, the C6-io aryl group such as a phenyl group, is substituted with 1, 2, or 3 groups independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 3-6 cycloheteroalkyl, C 3-6 cycloheteroalkenyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 1-6 alkylthio, Ci-6 alkylenedioxy, Ci-6alkoxy (Ci-6) alkoxy, Ci-6 aminoalkyl, Ci-6 aminoalkoxy, Ci-6 hydroxyalkyl, C2-6 hydroxyalkoxy, (C1-4) monoalkylamino, (C1-4) dialkylamino, alkylcarbonylamino C2-6, C2-6 alkoxycarbonylamino, alkoxycarbonyl 2-6, carboxy, alkoxy (Ci-6) alkoxy (C2-6), monoalkylamino (C1-4) alkoxy (C2-6), dialkylamino (C1-4) alkoxy ( C2-6), mono (carboxyalkyl) amino C2-10 bis (carboxyalkyl C2-io) amino, aminocarbonyl, C 2-6 alkynylcarbonyl C 1-6 alkylsulfonyl, C 2-6 alkynylsulfonyl C 1-6 alkylsulfinyl, C 1-6 alkylsulfonamido, C 6-10 arylsulfonamido C 1-6 alkyl iminoamino, formyliminoamino, C 2-6 carboxyalkoxy C 2-6 carboxycarboxylamino (Ci-) 6). In still further cases, the substituents of the aryl group are selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C 2-6 alkenyl, Ci-6 haloalkyl, Ci-6 alkoxy, C 3 alkenyloxy -6, C 1-6 alkylenedioxy, C 1-6 alkoxy (C 1-6) alkyl, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy # (C 1-4) monoalkylamino, dialkylamino (C 1-4) ), C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino / C 2-6 alkoxycarbonyl, carboxy, C 1-6 alkoxy (C 2-6) alkoxy carboxyalkoxy C 2-6 and C 2-6 carboxyalkyl- In another embodiment, the substituents on R 1 are independently selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy ,. trifluoromethyl, morpholinyl and pyrrolidinyl. In another embodiment within this first subclass, L1 is a linker containing 1-6 carbons and / or heteroatoms and which are optionally substituted. In another embodiment within this first subclass, L2 is a linker containing 1-6 carbons and / or heteroatoms and which are optionally substituted. In another embodiment within this first subclass, R 4 is phenyl, optionally substituted with 1 to 3 substituents selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In a second subclass, the present invention is directed to a method for inhibiting a flavor-modulating protein, the method comprising contacting the protein with a compound of Formula I wherein R 1 is optionally substituted 5-10-element heteroaryl; R2 is H or Ci-6 alkyl; R3 is H or Ci-6 alkyl; and R4 is optionally substituted C6-io aryl. In one embodiment within this second subclass, R 1 is an unsubstituted 5-10 element heteroaryl, such as indolyl, pyridyl, benzothiazolyl, benzimidazolyl or qunolinyl. Alternatively, R1 is a heteroaryl of 5-10 elements substituted with one or more substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C2-6 alkenyl / C2- alkynyl 6 # haloalkyl Ci-6, cycloalkyl C3-6 cycloalkenyl C3-6, cycloheteroalkyl C3-6, cycloheteroalkenyl C3-6, alkoxy Ci-6, alkenyloxy C3-6, alkylthio Ci_6, alkylenedioxy Ci-6, alkoxy Ci-6alkyl (Ci -6), C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy / (C 1-4) monoalkylamino, dialkylamino (C 1-4), C 2-6 alkylcarbonylamino, C 2-6 alkoxycarbonylamino, C 2 alkoxycarbonyl -6 carboxy, alkoxy (Ci-6) alkoxy (C2-6). (C 1-4) monoalkylamino (C 2-6) alkoxy, dialkylamino (C 1-4) alkoxy (C 2-6), mono (carboxyalkyl) amino C 2 -io, bis (carboxyalkyl C 2-7) amino, aminocarbonyl, alkynylcarbonyl C 2-6 , C 1-6 alkylsulfonyl, C 2-6 alkynylsulfonyl, Ci-6 alkylsulfinyl, C 1-6 alkylsulfonamido, C 6 -io arylsulfonamido, C 1-6 alkyliminoamino, formyliminoamino, C 2-6 carboxyalkoxy C 2-6 carboxyalkyl and carboxyalkylamino (Ci-e) Still further cases, the heteroaryl substituents are selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 alkenyloxy. , C 1-6 alkylenedioxy, C 1-6 alkoxy (Ci-6), C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, C 1-4 monoalkylamino, dialkylamino (C 1-4), C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl / carboxy, (Ci_6) alkoxy (C2-6) alkoxy, C2-6 carboxyalkoxy and C2-6 carboxyalkyl.

In another embodiment, the substituents on R 1 are independently selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In another embodiment within this first subclass, L1 is a linker containing 1-10, preferably 1-4 carbons and / or heteroatoms and which is optionally substituted. In another embodiment within this first subclass, L2 is a linker containing 1-10, preferably 1-4 carbons and / or heteroatoms and which are optionally substituted. In a third subclass, the present invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein: R1 is optionally substituted C6-yl aryl; R2 is H or Ci-6 alkyl; R 3 s h or C 1-6 alkyl; and R 4 is optionally substituted 5-10 element heteroaryl; In one embodiment within this third subclass, R1 is unsubstituted phenyl. In other cases, the aryl group Ce-10 / such as a phenyl group, is substituted with 1, 2 or 3 groups independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 3-6 cycloheteroalkyl, C 3-6 cycloheteroalkenyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 1-6 alkylthio, C 1-6 alkyndiioxy, Ci-6alkoxy (C 1-6) alkoxy, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, (C 1-4) monoalkylamino, (C 1-4) dialkylamino, alkylcarbonylamino C2-6, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, (C1-6) alkoxy (C2-6) alkoxy, (C1-4) monoalkylamino (C2-6) alkoxy, dialkylamino (C1-4) alkoxy ( C2-6), mono (carboxyalkyl) amino C2-io, bis (C2-io) aminocarbonyloxy, aminocarbonyl, C2-6 alkynylcarbonyl, Ci-6 alkylsulfonyl, C2-6 alkynylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, arylsulfonamido Ce-10, Ci_6 alkyliminoamino, formyliminoamino, C2-6 carboxyalkoxy C2-6 carboxyalkyl and carboxyalkylamino (C6-6). In still further cases, the substituents of the aryl group are selected from a group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C 2-6 alkenyl, Ci-6 haloalkyl, Ci-6 alkoxy, C 3-6 alkenyloxy, C 1-6 alkynedioxy, C 1-6 alkoxy (C 1-6) alkyl, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, C 1-6 monoalkylamino, C 1-6 alkylamino 4), C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, (Ci-6) alkoxy (C2-6) alkoxy C2-6 carboxyalkoxy and C2-6 carboxyalkyl. In another embodiment, the substituents on r1 are independently selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and purrolidinyl. In another embodiment within this first subclass, L1 is a linker containing 1-10, preferably 1-4 carbons and / or heteroatoms and which are optionally substituted. In another modality within this first subclass, L2 is a linker containing 1-10, preferably 1-4 carbons and / or heteroatoms and which are optionally substituted. In one embodiment within this third subclass, R 4 is a heteroaryl of 5-10 unsubstituted elements such as indolyl, pyridyl, benzothiazolyl, benzimidazolyl, or quinolinyl. Alternatively, R1 is 5-10 elements heteroaryl substituted with one or more substituents independently selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In a fourth subclass, the present invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein R 1 is 5-10 elements heteroaryl optionally substituted; R2 is H or Ci-6 alkyl; R3 is H or Ci-6 alkyl; and R 4 is optionally substituted 5-10 element heteroaryl. In one embodiment within this fourth subclass, R1 is an unsubstituted 5-10 element heteroaryl, such as indolyl, pyridyl or quinolinyl. Alternatively, R1 is 5-10 elements heteroaryl, substituted with one or more substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl Ci-6 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 3-6 cycloheteroalkyl, C 3-6 cycloheteroalkenyl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 1-6 alkylthio, C 1-6 alkylenedioxy, C 1-6 alkoxy ( Ci-β, Ci-6 aminoalkyl, Ci-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, (C 1-4) monoalkylamino, dialkylamino (Ci-4), C 2-6 alkylcarbonylamino / C 2-6 alkoxycarbonylamino, C 2 alkoxycarbonyl -6, carboxy, alkoxy (Ci-.6) alkoxy (C2-6), monoalkylamino (C1-4) alkoxy (C2-6) dialkylamino (C1-4) (C2-6) alkoxy, mono (carboxyalkyl) amino C2-i0, bis (C2-io) aminocarboxylamino, aminocarbonyl, C2-6 alkynylcarbonyl, Ci-6 alkylsulfonyl, C2-6 alkynylsulfonylC1-6 alkylsulfinyl; C 1-6 alkylsulfonamido, C 6 -io arylsulfonamido, Ci-6 alkyliminoamino, formyliminoamino, C 2-6 carboxyalkoxy C 2-6 carboxyalkyl and carboxyalkylamino (Ci-6). In still further cases, the heteroaryl substituents are selected from a group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, C 1-6 alkyl, C 2-6 alkenyl, Ci-6 haloalkyl, C 1-6 alkoxy, C 3 alkenyloxy -6, Ci-6-alkylenedioxy, Ci-6alkoxy (C 1-6) alkoxy, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, Ci.sub.6 hydroxyalkyl, C 2-6 hydroxyalkoxy, (C 1-4) monoalkylamino, dialkylamino (C 1-4) ), C2-6 alkoxycarbonylamino C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, alkoxy (Ci-β) (C2-6) alkoxy, C2-6 carboxyalkoxy and C2-6 carboxyalkyl. In another embodiment, the substituents on R1 are independently selected from the group consisting of nitro, bromo, chloro, -carboxi, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In one embodiment within this fourth subclass, R 4 is an unsubstituted 5-10 element heteroaryl, such as indolyl, pyridyl, benzothiazolyl, benzimidazolyl or quinolinyl. Alternatively, R1 is a heteroaryl of 5-10 elements, substituted with one or more substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C2-6 alkenyl, C2- alkynyl 6, Ci-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 cycloheteroalkyl, C3-6 cycloheteroalkenyl, C1-6 alkoxy, C3-6 alkenyloxy, Ci-6-alkylthio, C1-6-alkylenedioxy, Ci-alkoxy, 6alkyl (Ci-6), aminoalkyl Ci-6, aminoalkoxy C1-6, hydroxyalkyl C1-6, hydroxyalkoxyC2-6 monoalkylamino (C1-4), dialkylamino (C1-4), alkylcarbonylaminoC2-6, alkoxycarbonylaminoC2-6alkoxycarbonyl C2-6, carboxy, alkoxy (Ci-β) (C2-6) alkoxy, (C1-4) monoalkylamino (C2-6) alkoxy dialkylamino (C1-4) alkoxy (C2-6), mono (carboxyalkyl) amino C2 -io, bis (C2-io-carboxy) amino, aminocarbonyl, C2-6 alkynylcarbonyl, Ci-6 alkylsulfonyl, C2-6 alkynylsulfonyl, Ci-6 alkylsulfinyl, C1-6 alkylsulfonamido, arylsulfonamido C6-io alkylimin oamino Ci-6, formyliminoamino, carboxyalkoxy C2-6 carboxyalkyl C2-6 and carboxyalkylamino (Ci-6). In still further cases, the heteroaryl substituents are selected from a group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C 2-6 alkenyl, Ci_6 haloalkyl, Ci-6 alkoxy, C 3-6 alkenyloxy , Ci-6alkylenedioxy, Ci-6alkyloxy (Ci-β), C 1-6 aminoalkyl, C 1-6 aminoalkoxy, Ci-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, (C 1-4) monoalkylamino, (C 1-4) dialkylamino, C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, (Ci-6) alkoxy (C2-6) alkoxy, C2-6 carboxyalkoxy and C2-6 carboxyalkyl. In another embodiment, the substituents on R4 are independently selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In a fifth subclass, the present invention is directed to a method for inhibiting a flavor-modulating protein, the method cosing contacting the protein with a compound of Formula I wherein R1 is optionally substituted C6-10 aryl; R2 is H or Ci-β alkyl; and R3 is H or Ci-6 alkyl; and R4 is optionally substituted C3-10 cycloalkyl. In one embodiment within this fifth subclass, R1 is unsubstituted phenyl. In other cases, the aryl group C6-io # such as a phenyl group, is substituted with 1, 2 or 3 groups independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C2-6 alkenyl C2-6 alkynyl, Ci-6 haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 cycloheteroalkyl, C3-6 cycloheteroalkenyl, Ci-6 alkoxy, C3-6 alkenyloxy, Ci-6-alkylthio, C1-6-alkylenedioxy, Ci-6-alkyloxy (Ci-β) , C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy (C 1-4) monoalkylamino, dialkylamino (C 1-4), C 2-6 alkylcarbonylamino C 2-6 alkoxycarbonylamino, C 2-6 alkoxycarbonyl, carboxy, alkoxy (C 1-6) Ci-6) (C2-6) alkoxy, (C1-4) monoalkylamino (C2-6) alkoxy, (C1-4) dialkylamino (C2-6 >alkoxy); , mono (carboxyalkyl) amino C2-io / bis (C2-io-carboxy) amino, aminocarbonyl, C2-6 alkynylcarbonyl C1-6 alkylsulfonyl, C2-6 alkynylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonamido, C6-10 arylsulfonamido alkyliminoamino C1-6, formyliminoamino, C2-6 carboxyalkoxy C2-6 carboxyalkyl and carboxyalkylamino (Ci-6). In still further cases, the aryl substituents are selected from a group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, C 1-6 alkyl, C 2-6 alkenyl, Ci-6 haloalkyl, Ci-6 alkoxy, C 3 alkenyloxy -6, C 1-6 alkylenedioxy, C 1-6 alkoxy (C 1-6) alkyl, C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, C 1-4 monoalkylamino, dialkylamino (C 1-4) ), C2-6 alkylcarbonylamino, C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, (C1-6) alkoxy (C2-6) alkoxy / C2-6 carboxyalkoxy and C2-6 carboxyalkyl- In another embodiment, the substituents in R1 they are independently selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In a sixth subclass, the present invention is directed to a method for inhibiting a flavor-modulating protein, the method comprising contacting the protein with a compound of Formula I wherein R 1 is optionally substituted 5-10-element heteroaryl; R2 is H or Ci-6 alkyl; R3 is H or Ci_6 alkyl; and R4 and L2 together form -N = N-aryl. In one embodiment within this sixth subclass, R1 is an unsubstituted 5-10 element heteroaryl, such as indolyl, pyridyl or quinolinyl. Alternatively, R1 is a 5-10 element heteroaryl substituted with one or more substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C2-6 alkenyl C2-6 alkynyl haloalkyl Ci_6, C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 cycloheteroalkyl, C3-6 cycloheteroalkenyl, Ci-6 alkoxy, C3-6 alkenyloxy, Ci-6 alkylthio, Ci-6-alkylenedioxy, Ci-6alkoxy-alkoxy (Ci-β ), C 1-6 aminoalkyl, C 1-6 aminoalkoxy, C 1-6 hydroxyalkyl, C 2-6 hydroxyalkoxy, (C 1-4) monoalkylamino, (C 1-4) dialkylamino, C 2-6 alkylcarbonylamino, C 2-6 alkoxycarboni, C 2-6 alkoxycarbonyl. 6, carboxy, (C 1-6) alkoxy (C 2-6) alkoxy, (C 1-4) monoalkylamino (C 2-6) alkoxy, dialkylamino (C 1-4) alkoxy (C 2-6) / mono (carboxyalkyl) amino C 2- 10 bis (C2-io carboxyalkyl) amino, aminocarbonyl, C2-6 alkynylcarbonyl, Ci_6 alkylsulfonyl, C2-6 alkynylsulfonyl, Ci-6 alkylsulfinyl, Ci_6 alkylsulfonamido, arylsulfonamido C6-10 »alkyl C 1-6 monoamino, formyliminoamino, C 2-6 carboxyalkoxy C 2-6 carboxyalkyl and C 1-6 carboxyalkylamino. In another embodiment, the substituents on R 1 are independently selected from the group consisting of nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy , diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In this sixth subclass, R4 and L2 together form a -N = N-aryl, wherein aryl is an optionally substituted C6-10 aryl group, such as phenyl or naphthyl. Suitable substituents on the aryl group include, but are not limited to, nitro, bromo, chloro, carboxy, methoxycarbonyl, methoxy, diethylamino, hydroxymethyl, methyl, allyloxy, trifluoromethylthio, hydroxy, trifluoromethyl, morpholinyl and pyrrolidinyl. In a seventh subclass, the present invention is directed to a method for inhibiting a flavor-modulating protein, the method comprising contacting the protein with a compound of Formula I wherein R 1 is optionally substituted 5-10-element heteroaryl, such as pyridyl , quinolinyl, benzothiazolyl, benzimidazolyl and indoline; R4 is optionally substituted C6-io aryl, such as phenyl and naphthyl; and L1 and L2 are absent. In an eighth subclass, the present invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I wherein R1 is C6-10 aryl; heteroaryl of 5-10 elements, C3-10 cycloalkyl, C3-10 cycloalkenyl, cycloheteroalkyl of 3-10 elements, cycloheteroalkenyl of 3-10 elements, and C1-6alkyl, each of which is optionally substituted; R2 is H, C1-6 alkyl or arylC6-ioalkyl (Ci-6); L1 is absent, or is a linker containing 1-10, preferably 1-6, carbons and / or heteroatoms and which are optionally substituted; R3, R4 and L2 together with the carbon atom form a group selected from aryl e-io, heteroaryl of 5-10 elements, cycloalkyl C3-10, cycloalkenyl C3-10, cycloheteroalkyl of 3-10 elements, cycloheteroalkenyl of 3- 10 elements, each of which is optionally substituted. In an eighth subclass, the present invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I wherein R1 is optionally substituted indolinyl; R2 is H, C1-6 alkyl, or arylC6-ioalkyl (C1-6); L1 is absent, or is a linker containing 1-10, preferably 1-6, carbons and / or heteroatoms and which are optionally substituted; R3, R4 and L2 together with the carbon atom form a group selected from C6-io aryl heteroaryl of 5-10 elements, C3-10 cycloalkyl, C3-10 cycloalkenyl, cycloheteroalkyl of 3-10 elements, cycloheteroalkenyl of 3-10 elements, each of which is optionally substituted. In a further subclass, the invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein R 1 is heteroaryl; R2 is H; R 4 is hteroaryl; L1 is absent; and L2 is N = N. In a further subclass, the invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein R 1 is a bicycloalkyl; R2 is H; R3 is H; R 4 is aryl or heteroaryl; L1 is absent; and L2 is absent. In a further subclass, the invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein R 1 is aryl; R2 is H; R3 is H; R 4 is aryl or heteroaryl; L1 is an optionally substituted linker containing 2-4 carbons or heteroatoms; and L2 is absent. In a further subclass, the invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein R 1 is cycloalkenyl; R2 is H; R3 is H; R 4 is aryl or heteroaryl; L1 is an optionally substituted linker containing 2-4 carbons or heteroatoms; and L2 is absent. In a further subclass, the invention is directed to a method for inhibiting a flavor modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein R 1 is optionally substituted aryl; R2 is H; R3 is H; R 4 is optionally substituted aryl or heteroaryl; L1 is - (CH2) 1-6-C (0) -; and L2 is absent. In a further subclass, the invention is directed to a method for inhibiting a flavor-modulating protein, the method comprising contacting the protein with a compound of Formula I, wherein R 1 is optionally substituted naphthyl; R2 is H; R3 is H; R 4 is optionally substituted aryl; L1 is - (CH2) -C (0) -; and L2 is absent. Other compounds suitable for use in the methods of the invention include a compound of Formula I, wherein R 1 is phenyl substituted with amino, alkylamino, or dialkylamino, and R 2 is a benzo [d] [1,3] [dioxol-5 ilo optionally substituted; wherein R 1 is C 3-6 cycloalkyl optionally substituted with hydroxy, and R 2 is phenyl optionally substituted with one or more hydroxy and / or C 1-4 alkoxy; wherein R1 is phenyl and R4 is phenyl optionally substituted with one or more groups selected from hydroxy, amino, alkylamino and dialkylamino; or wherein R1 is 3-indolyl and R4 is phenyl optionally substituted with 1-4 C1-4 alkoxy groups. In a further subclass, the invention is directed to the use of a compound according to Formula I, wherein R 1 is optionally substituted phenyl; R2 is optionally substituted phenyl; L1 is a C3-5 linker, such as one containing a cyclopropyl group; and L2 is absent. A subset of compounds within this subclass, compounds in accordance with the following Formula II wherein Ri is hydrogen or halogen; R2 is hydrogen or Ci-4 haloalkyl; R3 is hydrogen, haloalkyl Ci-4; C 1-4 alkoxy or C 1-4 alkylthio; and R 4 is hydrogen, Ci-4 haloalkyl, Ci-4 alkoxy or Ci-4 alkylthio. In another embodiment, Ri is hydrogen or halogen; R2 is CF3; R3 is hydrogen, haloalkyl Ci-, alkoxy Ci-4, or alkylthio Ci-4; and R 4 is hydrogen, Ci-4 haloalkyl, Ci-4 alkoxy or Ci-4 alkylthio. Suitable alkoxy groups include methoxy. Suitable haloalkyl groups include trifluoromethoxy. Suitable alkylthio groups include -SCH3. Preferably, the compounds are trans-cyclopropyl compounds. Examples of compounds of the present invention are described herein, for example, in the Examples. Examples of suitable compounds for use in the method of the present invention include: 4- ((E) - ((Z) -l- (2- (benzo [d] thiazol-2-yl) hydrazone) -2-methyl- methyl propyl) diazenyl) benzoate; (E) -2- (4-Bromo-2- ((2- (quinolin-8-1) hydrazono) methyl) phenoxy) -acetic acid; (E) -N '- (3,4-dimethoxybenzylidene) -2- (naphthalene-1 acetohydrazide; (E) -N' - (3,4-dimethoxybenzylidene) -2-phenylcyclopropane-carbohydrazide; (E) -3- cyclohexenyl-4-hydroxy- '- (4-methoxybenzylidene) -butanhydrazide; (E) -N' - (3,4-dimethoxybenzylidene) -4-hydroxyhexanhydrazide; 2- ((Z) -2- (phenyl) ( ) -phenyldiazenyl) methylene) hydrazinyl) benzoic acid (E) -? '- (3,4-dimethoxybenzylidene) -2- (m-tolyloxy) acetohydrazide; (E) -N' - (4- (allyloxy) -3- methoxybenzylidene) -2- (3-bromobenzylthio) -acetohydrazide; (E) - '- (4-isopropylbenzylidene) bicyclo [4.1.OJheptan-7-carbohydrazide; (Z) -1,3,3-trimethyl-2- ((E) -2- (2- (4-nitrophenyl) hydrazono) -ethylidene) indoline; (E) - '- (4- (diethylamino) -2-hydroxybenzylidene) -2-phenylcyclopropanecarbohydrazide; (4-trifluoromethylthio ) phenyl) carbonhydrazonoidicianide; N- ((E) -3- ((Z) -2- (1, 5-dimethyl-2-oxoindolin-3-ylidene) hydrazinyl) -3-oxo-l-phenylprop-1-en-2-yl) benzamide; (Z) -2- (2- ((l-Butyl-lH-indol-3-yl) methylene) hydrazinyl) benzoic acid; (E) -4- ((2-benzyl-2-phenylhydrazono) methyl) pyridine; (Z) -? ' - ((lH-pyrrol-2-yl) methylene) tricyclo [3.3.1. I3'7] decan-3-carbohydrazide; (Z) -1- (2- (4- (ethyl (2-hydroxyethyl) amino) phenyl) hydrazono) -naphthalen-2- (1H) -one; (E) -4- ((2- (5-chloro-3- (trifluoromethyl) pyridin-2-yl) -2-2-methyl-hydrazono) methyl) benzene-1,3-diol; (E) -2- (3,4-dimethylphenylamino) - '(4-morpholino-3-nitrobenzylidene) acetohydrazide; (Z) -3- (2-Nitro-5- (pyrrolidin-1-yl) phenyl) hydrazono) quinuclidine; (E) -2- ((2- (lH-benzo [d] imidazol-2-yl) hydrazono) methyl) -5- (diethylamino) phenol; and physiologically acceptable salts thereof. Examples of suitable compounds for use in the method of the present invention include: N- (3- (2- ((6-Bromobenzo [d] [1,3] dioxol-5-yl) methylene) hydrazinyl) -1- ( 4- (dimethylamino) phenyl) -3-oxoprop-1-en-2-yl) benzamide; N- (1- (4- (diethylamino) phenyl) -3- (2- (4-hydroxy-3-iodo-5-methoxybenzylidene) hydrazinyl) -3-oxoprop-1-en-2-yl) benzamide; '- (4-Hydroxy-3-methoxybenzylidene) -3- (1-hydroxycyclopentyl) -propanhydrazide; 4-Nitro-N '- (3, 4, 5-trimethoxybenzylidene) enzohydrazide; N '- (4- (diethylamino) -2-hydroxybenzidine) phenylcyclopropanecarboxyhydrazide; 1- (5-Bromo-2-oxoindolin-3-ylidene) -2- (2-bromo-4-methoxyphenoxy) acetohydrazide; 3- (1H-indol-3-yl) -N '- (3,4,5-trimethoxybenzylidene) propanhydrazide; N '- (2-oxoindolin-3-ylidene) -2- (2-methyl-4- (1,1-dimethylethyl) -phenoxy) acetohydrazide; 2- (4-Chlorophenyl) -N '- (3,4-dimethoxy-benzylidine) -cyclopropane-carboxyhydrazide; 2- (2-chlorophenyl) -? ' - (3,4-dimethoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) - '- (3,4-dimethoxybenzidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (3,4-dimethoxybenzylidene) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) - '- (3,4-dimethoxybenzidin) cyclopropanecarboxyhydrazide; 2- (4- fluorophenyl) -? ' - (3,4-dimethoxybenzidine) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) - '- (3-tri fluoromethylbeni1idin) cyclopropane-carboxyhydrazide; 2- (3-chlorophenyl) - '- (3-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) -N '- (3-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (3-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -N '- (3-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) - '- (3-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) - '- (3-methoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) - '- (3-methoxybenylidin) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) -N '- (3-methoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (3-methoxy-benzylidine) -cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -N '- (3-methoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) -N '- (3-methoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) - '- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) -1- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) -N '- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -? ' - (3-methylthiobenzylidene) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -? ' - (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) -? ' - (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) -? ' - (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) - '- (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) -N '- (2-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) - '- (2-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) - '- (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) - '- (4-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) - '- (4-trifluoroinethylbenylidene) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) - '- (4-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (4-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -N '- (4-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) -? ' - (4-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; '- (3,4-dimethoxybenzylidene) -2- (4,8-dimethylquinolin-2-ylthio) -acetohydrazide; 3- (9H-carbazol-9-yl) - '- (3,4-dimethoxybenzylidene) propan-hydrazide; and physiologically acceptable salts thereof. The methods of the present invention also include the use of a physiologically acceptable salt of a compound according to Formula I. The term "physiologically acceptable salt" refers to an acid and / or base addition salt of a compound in accordance with Formula I. The acid addition salts can be formed by adding an appropriate acid to the compound according to Formula I. The base addition salts can be formed by adding an appropriate base to the compound according to Formula I. The bases or acids do not substantially degrade, decompose or destroy the compound according to Formula I. Examples of physiologically suitable salts include, salts of hydrochloride, hydrobromide, acetate, fumarate, maleate, oxalate, and succinate. Other suitable salts include sodium, potassium, carbonate and tromethamine salts. It is also understood that the present invention is considered to encompass the use of stereoisomers, as well as optical isomers, for example, mixtures of enantiomers, as well as individual enantiomers and diastereomers, which originate as a consequence of the structural asymmetry in the selected compounds of the present series. It is further understood that the present invention encompasses the use of tautomers of a compound of Formula I. Tautomers are well known in the art and include keto-enol tautomers. It is also understood that the compounds of Formula I include both the E and Z isomers, in varying proportions of the hydrazone. As is known in the art, the hydrazone portion can isomerize between the E and Z isomers, as shown in the following schematic: While the specific compounds listed above may indicate a particular stereochemistry of the hydrazone portion, ie, E or Z, the present invention explicitly includes both isomers. The compounds of Formula I can also be solvated, including hydrated. Hydration can occur during the manufacture of the compounds or compositions comprising the compounds, or hydration can occur over time, due to the hygroscopic nature of the compounds. Certain compounds within the field of Formula I can be derivatives referred to as "prodrugs". The term "prodrug" denotes a derivative of a known direct acting agent, wherein the derivative has therapeutic value that may be similar to, greater than or less than that of the agent. In general, the prodrug is transformed into the active agent by an enzymatic or chemical process when supplied to the subject, cell or test medium. In certain cases, the prodrugs are derivatives of the compounds of the invention which have metabolically unfoldable groups and come to be by solvolysis or under physiological conditions, the compounds of the invention, which are pharmaceutically active in vivo. For example, ester derivatives of compounds of this invention are often active in vivo, but not in vi tro. Other derivatives of the compounds of this invention have activity in both their acid and acid-derivative forms, but the acid-derived form often offers solubility, tissue compatibility, or delayed release benefits in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters prepared by reaction of the precursor acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with an amine. Simple aliphatic or aromatic esters derived from pendant acidic groups in the compounds of this invention are preferred prodrugs. In some cases, it is desirable to prepare prodrugs of the double ester type such as alkyl esters (acyloxy) or alkyl ester ((alkoxycarbonyl) oxy). When any variable occurs more than once in any constituent or in Formula I, its definition in each case is independent of its definition in each other case, unless indicated otherwise. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. The term "alkyl" as used herein by itself or as part of another group, refers to straight or branched chain radicals of up to 10 carbons, unless the chain length is limited to this, such as methyl ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl, 1-methylbutyl, isobutyl, pentyl, t-amino, (CH3CH2 (CH3) 2C-), hexyl, isohexyl, heptyl, octyl or decyl.

The term "alkenyl" as used herein by itself or as part of another group, refers to a straight or branched chain alkyl radical of 2-10 carbon atoms, unless the chain length limits it. to this, which includes but is not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, pentenyl, 1-hexenyl, and 2- hexenyl. The term "alkynyl" as used herein in itself or as part of another group, refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length limits it to this. , wherein there is at least one triple bond between two of the carbon atoms in the chain, including but not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-methyl- 2-butynyl, l-methyl-3-butynyl, 2-methyl-3-pentynyl, hexynyl and heptinyl. In cases where there is an alkenyl or alkynyl portion as a substituent group, the unsaturated bond is preferably not directly attached to a portion of nitrogen, oxygen or sulfur. The term "cycloalkyl", as used herein in its own right or as part of another group; it refers to cycloalkyl groups containing 3 to 14, preferably 3 to 10, carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl also includes bicycloalkyl, polycycloalkyl and other bridged cycloalkyl groups. The term "cycloalkenyl" as used herein in its own right or as part of another group; it refers to cycloalkenyl groups containing 3 to 10 carbon atoms and 1 to 3 carbon-carbon double bonds. Typical examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclohexadienyl. Cycloalkenyl also includes bicycloalkenyl, polycycloalkenyl and other bridged cycloalkenyls. The term "cycloheteroalkyl" as used herein by itself or as part of another group, refers to a group having 3 to 14 atoms in the ring containing carbon and 1, 2, 3 or 4 heteroatoms of oxygen, nitrogen or sulfur. Typical examples include but are not limited to, 2-tetrahydrofuranyl, 2-tetrahydrothienyl, 2-pyrrolidinyl, 3-isoxazolidinyl, 3-isothiazolidinyl, 1,3,4-oxazolidin-2-yl, 2,3-dihydrothien-2-yl. , 4, 5-isoxazolin-3-yl, 3-piperidinyl, 1,3-dioxan-5-yl, 4-piperidinyl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperazinyl , quinuclidinyl and morpholinyl. The term "cycloheteroalkenyl" as used by itself or as part of another group, refers to a group containing 3 to 14 atoms in the ring containing carbon atoms and 1, 2, 3 or 4 oxygen atoms, nitrogen or sulfur, and 1, 2 or 3 double bonds. Typical examples preferably include the cycloheteroalkyl groups mentioned above, specifically pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, piperazinyl, quinuclidinyl and morpholinyl, and thus modified to contain 1 or 2 double bonds. The term "alkylene" as used herein by itself or as part of another group, refers to a diradical of a saturated, unbranched hydrocarbon chain having, unless otherwise indicated, from 1 to 15 atoms carbon, preferably 1 to 10 carbon atoms and more preferably, 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms and more preferably, 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene and the like. The term "alkenylene" as used herein by itself or as part of another group, refers to a diradical of a saturated, unbranched hydrocarbon chain having, unless otherwise indicated, from 2 to 15 atoms carbon, preferably 1 to 10 caratoms, more preferably, 1 to 6 caratoms, and having at least 1 and preferably 1 to 6 sites of vinyl unsaturation. This term is exemplified by groups such as ethylene (-CH = CH-), propylene (-CH2CH = CH-, CH = CHCH2-), and the like. The term . "alkynylene" as used herein by itself or as part of another group, refers to a diradical of a saturated, unbranched hydrocarchain having, unless otherwise indicated, from 2 to 15 caratoms , preferably 1 to 10 caratoms, more preferably, 1 to 6 caratoms, and having at least 1 and preferably 1 to 6 sites of acetylene unsaturation (triple ). Examples include alkynylene groups such as ethylene (-C = C-), propargylene (-CH2-C = C-), and the like. The term "heteroalkylene", as used herein by itself or as part of another group, means alkylene, as defined above, wherein 1 to 5 of the caratoms indicated, are replaced by a heteroatom selected from N , O u S (e.g., amino, oxo, thio, aminomethylene (-NHCH2-), oxymethylene (-OCH2-), etc.). Examples include alkylenoxy, alkyleneamino and alkylenethio. Preferably, the oxygen, nitrogen and sulfur atoms contained therein do not form s with other heteroatoms. Suitable groups include ethyleneoxy, propyleneoxy, butyleneoxy, pentylenyloxy, hyperoxyxy, ethyleneamino, heptyleneamino and octyleneamino. Additional examples include CH2CH2-SCH2CH2- and -CH2-S-CH2CH2-NH-CH2-. In a heteroalkylene group mode, heteroatoms may also occupy any but not both of the chain terms. The term "heteroalkenylene", as used herein by itself or as part of another group, means alkenylene, as defined above, wherein 1 to 5 of the caratoms indicated are replaced by a heteroatom selected from N, O u S. Examples include alkenyleneoxy, alkenyleneamino, and alkenylenethio.

Preferably, the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. Suitable groups include ethenyleneoxy, propenyihenoxy, butylennoxy, pentenyleneoxy, hexenyleneoxy, ethenyleneamino, propenyleneamino, butylene-benzoyl, pentenyleneamino, and hexenylamino. In a heteroalkenylene group mode, heteroatoms can also occupy any, but not both, of the chain terms. Additionally, in another embodiment, the heteroatom is not part of the vinyl bond. The term "heteroalkynylene", as used herein by itself or as part of another group, means alkynylene as defined above, wherein 1 to 5 of the indicated carbon atoms is replaced by a heteroatom chosen from N, O u S. Examples include alkynyloxy, alkynylamino and alkynynthio.

Preferably, the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. In one embodiment of the heteroalkylene groups, the heteroatoms may occupy any, but not both, terms of the chain. Additionally, the heteroatom is not part of the vinyl bond. The term "cycloalkylene", as used herein by itself or as part of another group, refers to a non-aromatic alicyclic divalent hydrocarbon radical, having from 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms. . Examples of "cycloalkylene" as used herein include, but are not limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl , cyclohexyl-1,4-diyl and the like. Additional examples include divalent groups which also contain an alkylene group such as methylenecyclopropylene (ie, -CH2-cyclopropylene), ethylenecyclopropylene (ie, -CH2CH2-cyclopropylene) and methylenecyclohexylene (ie, -CH2-cyclohexylene). The term "cycloalkenylene", as used herein by itself or as part of another group, refers to a substituted alicyclic divalent hydrocarbon radical having from 3 to 15 carbon atoms, preferably 3 to 10, and at least one carbon-carbon double bond. Examples of "cycloalkenylene" as used herein include, but are not limited to, 4,5-cyclopentenyl, 3-diyl, 3,4-cyclohexen-1, 1-diyl, and the like. Cycloalkenylene further refers to a divalent hydrocarbon radical as defined by cycloalkenylene and having at least one single bond replaced with a double bond. The double bond can be contained in the structure of the ring. Alternatively, when possible, the double bond can be located in an acyclic portion of the cycloalkenylene moiety. The term "cycloheteroalkylene", as used herein by itself or as part of another group, refers to a cycloalkylene group as described above, wherein 1 to 5 of the indicated carbon atoms is replaced by a selected heteroatom of N, O or S. In one embodiment, the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. Suitable examples include the piperidine, piperazine, morpholine, and pyrrolidine diradicals. Other suitable examples include methylene piperidyl, ethylene piperidyl, methylene piperazinyl, ethylene piperazinyl and methylenemorpholinyl. The term "cycloheteroalkenylene", as used herein by itself or as part of another group, refers to a cycloalkenylene group as described above, wherein 1 to 5 of the indicated carbon atoms is replaced by a selected heteroatom of N, 0 or S. In one embodiment, the oxygen, nitrogen and sulfur atoms contained therein do not form bonds with other heteroatoms. The term "alkoxy," as used herein by itself or as part of another group, refers to any of the above alkyl groups linked to an oxygen atom. Typical examples are methoxy, ethoxy, isopropoxy, sec-butyloxy and t-butyloxy. The term "alkenyloxy", as used herein by itself or as part of another group, refers to any of the above alkenyl groups linked to an oxygen atom. Typical examples include ethenyloxy, propenyloxy, butenyloxy, pentenyloxy, and hexenyloxy. The term "aryl", as used herein by itself or as part of another group, refers to monocyclic or bicyclic aromatic groups containing from 6 to 14 carbons in the ring portion, preferably 6-10 carbons in the portion of the ring. Typical examples include phenyl, naphthyl, anthracenyl or fluorenyl. The term "aralkyl" or "arylalkyl", as used herein by itself or as part of another group, refers to Ci-6 alkyl groups as defined above, which have an aryl substituent, such as benzyl, phenylethyl or -naphthylmethyl.

The term "heteroaryl", as used herein by itself or as part of another group, refers to groups having 5 to 14 ring atoms, 6, 10 or 14 p-electrons carried in a cyclic array; and containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur atoms. Examples of heteroaryl groups are: thienyl, benzo [b] thienyl, naphtho [2, 3-b] thienyl, thiantrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxythiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl groups , pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl , fenantridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, and tetrazolium. Additional heteroaryls are described in A. R. Katritzky and C. W. Rees, eds. , Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, NY (1984). The term "alkylenedioxy", as used herein by itself or as part of another group, refers to a ring and is especially C 1 -4 alkylenedioxy. Alkylene dioxy groups can optionally be substituted with halogen (especially fluorine). Typical examples include methylenedioxy (-OCH20-) or difluoromethylenedioxy (-OCF20). The term "halogen" or "halo", as used herein by itself or as part of another group, refers to chlorine, bromine, fluorine or iodine. The term "monoalkylamine" or "monoalkylamino", as used herein by itself or as part of another group, refers to the group NH2, wherein a hydrogen has been replaced by an alkyl group, as defined above. The term "dialkylamine" or "dialkylamino", as used herein by itself or as part of another group, refers to the NH2 group, wherein both hydrogens have been replaced by alkyl groups, as defined above. The term "hydroxyalkyl", as used herein by itself or as part of another group, refers to the above alkyl groups, wherein one or more hydrogens thereof are substituted by one or more hydroxyl portions. The term "acylamino", as used herein, refers to a portion of the formula -NRaC (0) Rb, wherein Ra and Rb are independently hydrogen or alkyl groups are defined above. The term "haloalkyl", as used herein by itself or as part of another group, refers to any of the above alkyl groups, wherein one or more hydrogens thereof are substituted by one or more halo moieties. Typical examples include fluoromethyl, trifluoromethyl, trichloroethyl and trifluoroethyl. The term "haloalkenyl", as used herein by itself or as part of another group, refers to any of the above mentioned uenyl groups, wherein one or more hydrogens thereof are substituted by one or more halo portions. Typical examples include fluoroethenyl, difluoroethenyl and trichloroethenyl. The term "carboxyalkyl", as used herein by itself or as part of another group, refers to any of the above alkyl groups, wherein one or more hydrogens thereof are substituted by one or more carboxylic acid moieties. The term "heteroatom" is used herein to mean an oxygen atom ("O"), a sulfur atom ("S"), or a nitrogen atom ("N"). It will be recognized that when the heteroatom is nitrogen, it can form a portion NRaRb, where Ra and Rb are, independently of each other, hydrogen or alkyl, or together with the nitrogen to which they are attached, form an unsaturated ring of 5, 6 or 7. elements. The term woxi "means an oxygen atom (O) .The term wtio" means a sulfur atom (S). In general and unless otherwise defined, the phrase "optionally substituted", used herein, refers to a group or groups being optionally substituted with one or more substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, Ci-6 alkyl, C 2-6 alkenyl, C 2 alkynyl - 6, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 3-6 cycloheteroalkyl, C 3-6 cycloheteroalkenyl, aryl, 5-10 membered heteroaryl, C 1-6 alkoxy, C 3-6 alkenyloxy, C 1-6 alkylthio, C 1-6 alkylenedioxy 6, Ci_6alkoxy (Ci-6) alkoxy, arylC6-ioalkyl (Ci-6), arylC6-ioalkenyl (C2-6), arylC6-ioalkoxy (Ci-6), aminoalkyl C1-6, aminoalkoxy C1-6, hydroxyalkyl C1-6 6, C2-6 hydroxyalkoxy, benzamido, monoalkylamino (C1-4), dialkylamino (C1-4), alkylcarbonylamino C2 ~ 6 alkoxycarbonylamino C2-6, alkoxycarbonyl C2-6, carboxy, alkoxy (C1-6) alkoxy (C2-6) ) monoalkylamino (C1-4) alkoxy (C2-6), dialkylamino (C1-4) alkoxy (C2-6), mono (carboxyalkyl) amino C2-io, bis (C2-io) aminocarbonyloxy, aminocarbonyl, arylC6-4-alkoxycarbonyl (Ci-6>, C2-6 alkynylcarbonyl, C1-6 alkylsulfonyl, C2-6 alkynylsulfonyl, C6-arylsulfonyl / arylC6-ioalkylsulfonyl (C1 -6), C 1-6 alkynylsulfinyl, C 1-6 alkylsulfonamido, C 6 -aryl arylsulfonamido # arylC 6 -ioalkylsulfonamido (Ci-6>, C 1-6 alkyliminoamino, formyliminoamino, C 2-6 carboxyalkoxy C 2-6 carboxyalkyl and carboxyalkylamino (Ci-6) When the phrase "optionally substituted" is used with reference to an alkyl, alkenyl or alkynyl group, the phrase "optionally substituted" herein, refers to the group or groups being optionally substituted with one or more substituents independently selected from the group that consists of amino, hydroxy, nitro, halogen, cyano, thiol, C3-6 cycloalkyl, C3-6 cycloalkenyl, C3-6 cycloheteralkyl, C3-6 cycloheteroalkenyl, C6-thio aryl / 5-10 membered heteroaryl, C1-6 alkoxy , C 3-6 alkenyloxy, C 1-6 alkylthio, C 1-6 alkylenedioxy, coxy, arylCe-ioalkyl (Ci-6), arylC6-ioalkenyl (C2-e), arylC6-ioalkoxy (Ci-6), aminoalkyl C1-6, aminoalkoxy Ci-6, hydroxyalkyl Ci-6, hydroxyalkoxyC2-6 benzamido, monoalkylamino (C1-4), dialkylamino (C1-4), alkylcarbonylamino C2-6 / alkoxycarbonylamino C2-6 / alkoxycarbonyl C2-6, carboxy, alkoxy (C1-6) alkoxy (C2-6), monoalkylamino (C1-4) (C2-6) alkoxy, (C1-4) dialkylamino (C2-6) alkoxy, mono (carboxyalkyl) amino C2-io, bis (C2-yO) carboxylamino, arylC6-y4alkoxycarbonyl (Ci-6), C2-6 alkynylcarbonyl, Ci-6 alkylsulfonyl, C2-6 alkynylsulfonyl / C6-10 arylsulfonyl / arylC6-ioalkylsulfonyl (C1-6) , C 1-6 alkynylsulphinyl, C 1-6 alkylsulfonamido, C 6 -io arylsulfonamido, arylC 6 -ioalkylsulfonamido (Ci-d), C 1-6 alkyliminoamino, formyliminoamino, C 2-6 carboxyalkoxy C 2-6 carboxyalkyl and carboxyalkylamino (Ci-6). Although detailed definitions for each term previously used have not been provided, each term is understood to be one of ordinary skill in the art. As defined above in certain embodiments, linkers L1 and L2 can be a linker containing 1-10 carbons and / or heteroatoms and which are optionally substituted. This is understood as meaning that the linkers can contain any combination of carbon atoms and heteroatoms, such as the sum of the carbon number and heteroatoms, excluding any of the optional substituents, equal to an integer from 1 to 10. Thus, according to the invention, suitable linkers may include, but are not necessarily limited to: a linker containing 1 carbon atom (eg, CH2); a linker containing a heteroatom (for example, O); a linker containing 3 carbon atoms and 2 heteroatoms (for example, OCH 2 CH 2 NHCH 2); a linker containing 10 carbon atoms; or a linker containing a new carbon atom and 1 heteroatom. As mentioned above, the compounds described above can be used to inhibit a flavor modulating protein. Such inhibition can be in vitro or ex vivo. The amount of the compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, used to inhibit the flavor-modulating protein, may not necessarily be the same when used in vivo as compared to in vi tro. Factors such as pharmacokinetics and pharmacodynamics of the particular compound may require that a larger or smaller number of the Compound of Formula I, or any of the subgroups, specific subclasses or specific compounds described above, be used when a protein modulating the protein is inhibited. taste in vivo. Accordingly, one aspect of the present invention is a method for inhibiting a taste-inhibiting protein comprising, contacting the flavor-modulating protein with a compound according to Formula I, or any of the specific subgroups., subclasses or specific compounds described above. In one embodiment of the first aspect of the present invention, the method comprises contacting a cell with a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, wherein the cell expresses the protein that modulates the taste. . In another embodiment of the present invention, the method comprises administering a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to a subject in an amount sufficient to inhibit a flavor modulating protein, wherein the subject has or expresses the protein that modulates the taste. In addition, when administered orally, the compound can be dispersed or diluted by saliva. By way of example, the present invention is directed to a method for inhibiting a flavor modulating protein, which comprises contacting the protein with a compound of Formula I, or any of the specific subclasses and specific compounds listed above, and inhibiting the protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% or from about 50% to about 99%. In another embodiment, the method comprises contacting the protein with a compound of Formula I, or any of the specific subclasses and specific compounds listed above, and inhibiting the protein by about 10% to about 50%. In another embodiment, the present invention is directed to a method of inhibiting a flavor modulating protein, which comprises contacting the protein with a compound of Formula I, or any of the specific subclasses and specific compounds listed above, and inhibiting the protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% to about 99%, or alternatively from about 10 % up to about 50% and wherein the protein that modulates the flavor is a protein that modulates the flavor that originates naturally. In another embodiment, the present invention is directed to a method for inhibiting a flavor modulating protein, which comprises contacting the protein with a compound of Formula I, or any of the specific subclasses and specific compounds listed above, and inhibiting the protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% to about 99%, or alternatively from about 10 % up to about 50% and wherein the flavor-modulating protein is a human protein that modulates the naturally occurring flavor. Any amount of the compound of Formula I that provides the desired degree of inhibition can be used. For example, a compound of Formula I can be used at a concentration of about 0.1 uM to about 1,000 uM, to inhibit a protein that modulates taste. Alternatively, concentrations of about 1, 10 or 100 uM of a compound of Formula I can be used to inhibit a flavor-modulating protein. In certain embodiments, a single dose or two to four divided daily doses, provided based on approximately 0.001 to 100 mg / kg of body weight per day, is appropriate. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes, or any other suitable delivery system, such as intranasal or transdermal routes, can be used. As used herein, the term "inhibition", and grammatical variants thereof, refer to interfering with normal activity. For example, inhibition of a flavor-modulating protein means interfering with the normal activity of a flavor-modulating protein. Inhibition includes but is not necessarily limited to modulate, modify, inactivate and the like. As used in this document, the phrase "protein that modulates flavor", refers to a TRPM5 protein, and includes TRPM5 proteins naturally and recombinantly produced; natural, synthetic and recombinant, biologically active polypeptide fragments of the protein; biologically active polypeptide variants of the proteins or fragments thereof, including hybrid fusion proteins and dimers; biologically active polypeptide analogs of the protein or fragments or variants thereof, including substituted cysteine analogs. The protein that modulates the taste may be a non-human protein, for example, a non-human mammalian protein, or in other embodiments, a non-human protein such as but not limited to protein that modulates the taste of cow, horse, sheep , pork, chicken, turkey, donkey, cat, dog, mouse, rat, rabbit, monkey, or guinea pig. The protein that modulates the taste can be generated and / or isolated by any means known in the art. An example of a protein that modulates flavor and methods for producing the protein are described in, for example, Liu and Liman, Proc. Nat '1 Acad. Sd. USA 100: 15160-15165 (2003); D. Prawitt, et al., Proc. Nat'l Acad. Sd. USA 100: 15166-71 (2003); and Ulrich, N.D., et al, Cell Calcium 37: 267-278 (2005); each of which is fully incorporated by reference in this document. A homologue is a protein that can include one or more substitutions, deletions or amino acid additions, either from natural mutations of human manipulation. Thus by way of example, a flavor modulating protein may include one or more amino acid substitutions, deletions or additions, either from natural mutations or human manipulation. As indicated, changes are preferably of a minor nature, such as conservative amino acid substitutions, which do not significantly affect the fold or activity of the protein. Variants of flavor-modulating proteins which can be inhibited according to the present invention comprise non-conservative modifications (eg, substitutions). By "non-conservative" modification herein, it means a modification in which the native-type residue and the mutant residue differ significantly in one or more physical properties, including hydrophobicity, charge, size and shape. For example, modifications of a polar waste to a non-polar waste or vice-versa, modifications of positively charged waste to negatively charged waste or vice-versa, and modifications of large waste to small waste or vice-versa, are non-conservative modifications. For example, substitutions can be made which affect more significantly: the structure of the polypeptide skeleton in the area of alteration, for example, the alpha-helical or beta-sheet structure; the charge or hydrophobicity of the molecule at the target site; or the volume of the side chain. Substitutions which are generally expected to produce the largest changes in polypeptide properties are those in which (a) a hydrophilic residue, eg seryl or threonyl, is replaced by (or by) a residue hydrophobic, for example, leucine, isoleucine, phenylalanine, vally or alanyl; (b) a cysteine or proline is substituted by (or by), any other residue; (c) a residue having an electropositive side chain for example, lysyl, arginyl or histidyl, is replaced by (or by), an electronegative residue, for example, glutamyl or aspartyl; or (d) a residue having a bulky side chain; for example, phenylalanine is substituted by (or by) one having a side chain, for example, glycine. In one embodiment, flavor-modulating proteins used in accordance with the present invention have at least one non-conservative modification. In other embodiments, the method of the invention comprises inhibiting a flavor-modulating protein that is a non-human protein, such as but not limited to a protein that modulates the taste of cow, horse, sheep, pig, chicken, turkey, donkey, cat, dog, mouse, rat, rabbit, monkey or guinea pig. A further aspect of the present invention is a method for inhibiting the depolarization of a taste receptor cell comprising contacting the flavor receptor cell with a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above. For example, a compound of Formula I can inhibit the depolarization of a taste receptor cell, be a different mechanism, or in addition, the mechanism of inhibition of a flavor receptor protein. In one embodiment of this aspect of the present invention, the method comprises contacting a flavor receptor cell with a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, wherein the taste receptor cell can detect a flavor, sweet, bitter, sour, salty, or umami. In another embodiment of the present invention, the method comprises administering a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to a subject in an amount sufficient to inhibit depolarization of a flavor receptor cell. In addition, when administered orally, the compound can be dispersed or diluted by saliva. By way of example, the present invention is directed to a method for inhibiting the depolarization of a taste receptor cell comprising contacting the taste receptor cell with a compound according to Formula I, or any of the specific subclasses. and specific compounds described above; and inhibiting the depolarization of the taste receptor cell by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% up to about 99%, or alternatively from about 30% to about 75%. In another embodiment, the present invention is directed to a method for inhibiting the depolarization of a flavor receptor cell, which comprises contacting the protein with a compound of Formula I, or any of the specific subclasses and specific compounds listed above, and inhibiting the depolarization of the taste receptor cell by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% to about 99%, or alternatively from about 20% to about 60% and wherein the taste receptor cell is a protein that modulates the naturally occurring taste. In another embodiment, the present invention is directed to a method for inhibiting the depolarization of a taste receptor cell, which comprises contacting the protein with a compound of Formula I, or any of the specific subclasses or specific compounds listed above, and inhibiting the flavor receptor cell by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 50% to about 99%, or alternatively from about 40% to about 80% and wherein the taste receptor cell is a human taste receptor cell. Any amount of the compound of Formula I that provides the desired degree of inhibition can be used. For example, a compound of Formula I can be used at a concentration of about 0.1 uM to about 1,000 uM to inhibit a taste receptor cell. Alternatively, concentrations of about 1 uM, 50 uM or 100 uM, of a compound of Formula I, can be used to inhibit the depolarization of a taste receptor cell. In certain embodiments, a single dose or two to four daily divided doses provide a base of about 0.001 to 100 mg per kilogram of body weight per day, preferably about 0.01 to about 25 mg / kg of body weight per day, is appropriate. When a flavor receptor cell is inhibited in vivo, the compound of Formula I is preferably administered orally. In one embodiment of this aspect of the present invention, the method comprises contacting a flavor receptor cell with a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, wherein the taste receptor cell can detect a flavor, sweet, bitter, sour, salty, or umami. In another embodiment of the present invention, the method comprises administering a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to a subject in an amount sufficient to inhibit depolarization of a flavor receptor cell. In addition, when administered orally, the compound can be dispersed or diluted by saliva. In another embodiment, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, is employed to inhibit a taste, such as an undesirable flavor of a food product. Examples of food products having an undesired taste include, but are not necessarily limited to, citrus fruits such as grapefruit, orange and lemon; vegetables such as tomato, pepper, celery, melon, carrot, leg and asparagus, seasonings or flavoring materials, such as soy sauce and red pepper; soy products; fish products; meats and processed meats; dairy products such as cheese; breads and cakes; and confectionery such as sweets, chewing gums and chocolates. Other examples of food products contemplated in accordance with the present invention, are described below and through the specification. The method can be performed in such a way that the flavor of the food product being limited by the compound of Formula I, is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70% 80%, 90%, or 95%, or from about 60% to about 99%, or alternatively from about 20% to about 50%. Thus, in a more specific embodiment, the method comprises administering a food product comprising one or more food ingredients and one or more compounds according to Formula I, wherein one or more compounds according to Formula I, are present in an amount sufficient to inhibit a bitter taste produced by the food product by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% , or from about 60% to about 99%, or alternatively from about 30% to about 70%. Of course, in other modalities, a bitter taste can be inhibited at different magnitudes. Any amount of the compound of Formula I that provides the desired degree of taste inhibition can be used. For example, a compound of Formula I can be used at a concentration of about 0.1 uM to about 5,000 uM to inhibit a bitter taste. Alternatively, concentrations of about 1 uM, 100 uM or 500 uM, of a compound of Formula I, can be used to inhibit a sweet taste. A food product could also include drinks and soft drinks. Examples of beverages that have an undesirable or unwanted taste include but are not limited to citrus and vegetable juices, soy, milk, coffee, cocoa, black tea, green tea, fermented tea, semi-fermented tea, soft drinks, soft drinks and milk. In certain embodiments, the effective amount that inhibits the taste of a compound according to Formula i, or any of the specific subgroups, subclasses or specific compounds described above, ranges from about 0.01 to about 5.0 grams per 100 ml. In other embodiments, the effective amount that inhibits the taste of a compound according to Formula I, or any of the specific subgroups, subclasses, or specific compounds described above, ranges from about 0.5 to about 2 grams per 100 ml. Alternatively, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, is administered in an amount of about 1 gram per 100 ml. The method of the present invention in its various forms can be used to inhibit one or more flavors selected from the group consisting of sweet, bitter, sour, salty or umami. Preferably, the method of the present invention inhibits a bitter and / or sweet flavor. As used herein, the phrase "inhibits a flavor", and grammatical variants thereof, such as "inhibit flavor" and "inhibit a flavor", refers to interfering with the perception of a flavor. The taste may be perceived to a lesser degree or not perceived by all by the application of the present invention. A further aspect of the present invention is a method for inhibiting a flavor of a pharmaceutical composition comprising, administering a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to a subject receiving the pharmaceutical composition. The compound of Formula I can be administered together with the pharmaceutical composition as separate compositions, for example, either concurrently or sequentially. The compound of Formula I can be administered or caused to be administered, before the pharmaceutical agent that produces the taste to be inhibited. Alternatively, the compound of Formula I can be administered as a component of the pharmaceutical composition. By means of the example, the method can be performed in such a way that the taste being inhibited by the compound of Formula I, is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80 %, 90%, or 95%, or from about 60% to about 99%, or alternatively from about 25% to about 50%. Thus, in a more specific embodiment, the method comprises administering a food product comprising a pharmaceutically active agent, optionally one or more excipients and one or more compounds according to Formula I, wherein one or more compounds in accordance with Formula I, are present in an amount sufficient to inhibit a bitter taste produced by the pharmaceutically active agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, or alternatively from about 30% to about 60%. In another embodiment, the compound of Formula I is administered in a ratio of from about 10: 1 to about 1:10 relative to the pharmaceutical agent. By means of further examples, the method for inhibiting a flavor of a pharmaceutical composition may comprise inhibiting a flavor produced by one or more agents selected from the group consisting of antipyretics, analgesics, laxatives, appetite suppressants, antiacid, antiasthmatics, antidiuretics, agents active against flatulence, anti-migraine agents, psychopharmacological agents, spasmolytics, sedatives, antihyperkinetics, tranquilizers, antihistamines, decongestants, beta-receptor blockers, agents for alcohol withdrawal, antitussives, fluoride supplements, local antibiotics, corticosteroid supplements, anticancer agents goiter formation, antiepileptics, anti-dehydration agents, antiseptics, NSAIDs, gastrointestinal active agents, alkaloids, microelement supplements, ion exchange resins, cholesterol suppressing agents, lipid reducing agents, antiarrhythmics and ctorantes. Additional specific examples of the pharmaceutical compositions according to the method of the invention are described below. Additionally, the method for inhibiting a flavor of a pharmaceutical composition may comprise inhibiting a flavor produced by a pharmacist against terrorism. Due to the increased risk of terrorist attacks, such as chemical, nuclear or biological attacks, the use of pharmaceutical agents against terrorism is expected to increase in the future. A pharmaceutical agent against terrorism includes those pharmaceutical agents that are used in counter-acting agents that can be used in a terrorist attack. Agents that can be used in terrorist attacks, or considered as employees for future terrorist acts include, ricin, sarin, radioactive agents and materials, and anthrax. The pharmaceutical agents that attack these agents are employed as a pharmacist against terrorism. Such anti-terrorism pharmaceuticals include, but are not limited to, antibiotics such as ciproflaxin and doxycycline; potassium iodide and antiviral agents. Thus, in one embodiment of the present invention, the method can be carried out in such a way that the taste of a pharmacist against terrorism, such as an antibiotic such as ciprofloxacin and doxycycline; potassium iodide; or an antiviral agent, is inhibited by the compound of Formula I by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, or alternatively from about 25% to about 50%. In another embodiment, the compound of Formula I is administered at a ratio of from about 10: 1 to about 1:10 relative to the counter-terrorism agent. In another embodiment, a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, is employed to inhibit an undesirable taste of a nutritional composition. Examples of nutritional compositions having undesirable taste include, but are not necessarily limited to, enteral nutrition products for nutritional deficit treatment, trauma, surgery, Crohn's disease, kidney disease, hypertension, obesity and the like, to promote athletic performance, muscular improvement or general well-being or inborn errors of metabolism such as phenylketonuria. In particular, such nutritional formulations may contain one or more amino acids which have a bitter or metallic taste or after taste. Such amino acids include, but are not limited to, essential amino acids selected from the group consisting of L isomers of leucine, isoleucine, histidine, lysine, methionine, phenylalanine, threonine, tryptophan, tyrosine, and valine. Additional specific examples of nutraceutical compositions according to the method of the invention are described below. By way of example, the method can be performed such that the taste being inhibited by the compound of Formula I is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, or alternatively from about 20% to about 50%. Thus, in a more specific embodiment, the method comprises administering a nutraceutical composition comprising a nutraceutical agent, optionally one or more excipients and one or more compounds according to Formula I, wherein one or more compounds in accordance with Formula I, are present in an amount sufficient to inhibit an undesired taste, produced by the pharmaceutically active agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95%, or from about 60% to about 99%, or alternatively from about 10% to about 50%. A compound according to Formula I can be incorporated into medical and / or dental compositions. Certain compositions used in diagnostic procedures have an unpleasant taste, such as contrast materials and local oral anesthetics. The inhibitors of the invention can be used to improve the comfort of the subjects who undergo such procedures by improving the taste of the compositions. In addition, inhibitors of the invention can be incorporated into pharmaceutical compositions including tablets and liquids, to improve their taste and improve patient comfort, particularly where the patient is a child or a non-human animal). In another embodiment, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, is used to inhibit a flavor of a cosmetic product. For example, but not by way of limitation, a compound according to Formula I can be incorporated into facial creams, lipstick, lip gloss and the like. Also, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, can be used to inhibit an unpleasant taste of lip balm, such as Chapstick® or Lip Balm Burt's Beeswax®. In addition, a compound in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above, may be incorporated into compositions that are not traditional, pharmaceutical or cosmetic foodstuffs, but which may contact taste membranes. . Examples include, but are not limited to, soaps, shampoo, toothpaste, denture adhesive and glue on the surfaces of stamps and envelopes. Thus, the present invention also covers a process of preparing a composition that is not a traditional, pharmaceutical or cosmetic food, but which can contact flavor membranes, in accordance with conventional methods, wherein the improvement comprises adding a compound of Formula I to the composition. In another embodiment, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, are used to inhibit a bitter taste associated with one or more of the following: bitter pharmaceutical alkaloids such as acetaminophen, ampicillin, chlorpheniramine, clarithromycin, doxylamine, guaifenesin, ibuprofen, pseudoephedrine hydrochloride and ranitidine, bitter pharmaceutical metal salts such as zinc containing bioadhesives (denture adhesive), bitter vitamins, bitter components of foods such as creatine, limonin, naringin, quinizolate , and bitter components of beverages such as caffeine and humulone. In one embodiment, the concentration of the compound according to Formula I used in the range of 0.01 mM to 20 mM and may vary depending on the amount of the bitter compound used in its bitterness.

In another embodiment, the present invention is directed to a method of inhibiting the flavor of a veterinary product, such as veterinary medicines, veterinary food products, veterinary supplements and the like, which are administered to domesticated animals. In a preferred embodiment, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, are used to inhibit the taste of a veterinary product administered to a dog or cat. In one embodiment, in each of the methods for inhibiting a flavor described herein, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, is administered in an amount effective to inhibit flavor. As a non-limiting example, the amount effective to inhibit the taste of a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, administered in one embodiment is from about 0.01 to about 5.0 grams per 100 mi. In other embodiments, the methods for inhibiting the flavor described herein, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above is administered in an amount that is sufficient, in combination with the administration of one or more agents that inhibit the additional flavor, to inhibit the taste. For example, in a method for inhibiting the bitter taste of a liquid pharmaceutical composition, the composition comprises a compound according to Formula I and another flavor inhibiting agent, wherein the amount of the compound of Formula I is about 25% up to about 75% of the compound required to inhibit the bitter taste in the absence of another flavor-inhibiting agent. In another embodiment, the present invention is directed to a method for reducing the palatability and / or absorption of the food, which comprises administering to a subject in need of such treatment, one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, in an amount sufficient to reduce the palatability and / or absorption of food. Agronic protein-modulating taste mice have been shown to have decreased flavor preference for sucrose, artificial sweeteners and umami flavors, and decreased taste aversion for bitter solutions. See Zhang et al., Cell 112: 293-301 (2003). Thus, in accordance with the present invention, a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, can be administered to a subject so that the palatability of the food, as experience for the subject, it is reduced. Without being bound by theory, it is believed that a lower palatability of the food can lead to lower absorption of food by the subject. Thus, in certain embodiments, by administering a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to a subject, the subject will consume a decreased amount of food compared to the food intake. of the subject when a compound of Formula I is not administered, or any of the specific subgroups, subclasses or specific compounds described above. In other embodiments, by administering a compound a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to a subject, the subject will have a lower caloric intake compared to the caloric intake of the subject when not a compound of Formula I, or any of the specific subgroups, is administered, subclasses or specific compounds described above. In other embodiments, by administering a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, a subject may be a means of dieting to facilitate or assist in losing weight. In each of the embodiments of the methods described above, the objective of the method, unless otherwise limited, can be any animal that needs the particular treatment or effect of the method. Such animals include but are not limited to cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, monkey or coballo protein that modulates the taste. In other modalities, the animal is a livestock animal, a domestic animal or an animal kept as a pet. In particular embodiments, the objective of the claimed method is a human. In addition, in each of the embodiments of the methods described herein, a compound of Formula I may be used in varying proportions for the agent that is believed to cause the undesired taste, such as a bitter or sweet flavor. For example, a compound of Formula I can be administered in a molar ratio of about 1000: 1 to about 1: 1000, or alternatively administered in a molar ratio of about 500: 1, about 200: 1, about 10: 1, about 1: 1, about 1:10, about 1: 200 or about 1: 500, in relation to the agent that is believed to cause the unwanted taste. In another example, the present invention is directed to a method for inhibiting the bitter taste of a pharmaceutical composition, comprising administering to a subject in need of such a method a pharmaceutical composition and a compound according to Formula I, wherein the composition The pharmaceutical comprises a pharmaceutically active agent and optionally one or more excipients, and wherein the compound according to Formula I is administered as either a component of the pharmaceutical composition or as a separate dosage form, and wherein the molar proportion of the compound of Formula I for the pharmaceutically active agent from about 1000: 1 to about 1: 1000, or alternatively administered in a molar ratio of about 500: 1, about 200: 1, about 10: 1, about 1: 1, about 1: 10, about 1: 200, or about 1: 500. As will be appreciated, ranges and varying amounts of the compound of Formula I may be used, with modifications if preferred, in each of the embodiments described herein.iCA Compositions The present invention is also directed to various useful compositions comprising a compound of Formula I or a physiologly acceptable salt thereof.

In another aspect, the present invention is directed to a pharmaceut composition comprising a compound of Formula I, as defined above, which includes any of the embodiments, subclasses or specific species described above, and one or more pharmaceutly acceptable carriers. Preferred compositions of the present invention are pharmaceut compositions comprising a compound selected from one or more embodiments listed above, and one or more pharmaceutly acceptable excipients. Pharmaceutly acceptable compositions comprising one or more compounds of Formula I, or any of the specific groups, subclasses or specific compounds described above, can be used to formulate pharmaceut drugs containing one or more active agents that exert a biolog effect other than the inhibition of flavor and / or inhibition of a protein that modulates the taste. The pharmaceut composition preferably further comprises one or more active agents that exert a biolog effect. Such active agents include pharmaceut and biolog agents that have an activity other than taste inhibition. Such active agents are well known in the art. See, for example, The Physician's Desk Reference. Such compositions can be prepared according to procedures known in the art, for example, as described in Remington's Pharmaceut Sciences, Mack Publishing Co., Easton, Pa., USA. In one embodiment, such active agent includes bronchodilators, anorexiants, antihistamines, nutritional supplements, laxatives, analgesics, anesthetics, antacids, H2 receptor antagonists, anticholinergic, antidiarrheal, demulcent, antitussive, antinauseous, antimicrobial, antibacterial, antifungal, antiviral, expectorant, anti-inflammatory agents, antipyretics and mixtures thereof. The pharmaceut composition according to the present invention may comprise one or more compounds according to Formula I, as described above, or any of the specific subgroups, subclasses or specific compounds described above; an active agent that have a bitter taste; and optionally one or more pharmaceutly acceptable carriers. In another embodiment, the active agent is selected from the group consisting of antipyretics and analgesics, for example, ibuprofen, acetaminophen, or aspirin; laxatives, for example, phenolphthalein dioctyl sulfosuccinate sodium; appetite depressants, for example, amphetamines, phenylpropanolamine, phenylpropanolamine hydrochloride, or caffeine; antacids, for example, calcium carbonate; antiasthmatics, for example, theophylline; antidiuretics, for example, diphenoxylate hydrochloride; agents active against flatulence, for example, simetecone; migraine agents, for example, ergotamintartrate; psychopharmacolog agents, for example, haloperidol; spasmolytic or sedative, for example, phenobarbitol; antihyperkinetics, for example, methyldopa or methylphenidate; tranquilizers, for example, benzodiazepines, hydroxymeprobamates or phenothiazines; antihistamines, for example, astemizole, chlorpheniramine maleate, pyridamine maleate, doxlamin succinate, bromopheniramine maleate, phenyltoloxaminq citrate, chlorocyclizine hydrochloride, feniramin maleate, and fenindamin tartrate; decongestants, for example, phenylpropanolamine hydrochloride, phenylephrine hydrochloride, pseudoephedrine hydrochloride, pseudoephedrine sulfate, phenylpropanolamine bitartrate and ephedrine; receptor blockers, for example, propranolol; agents for abstinence from alcohol, for example, disulfiram; antitussives, for example, benzocaine, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentan citrate, and clofedianol hydrochloride; fluorine supplements, for example, sodium fluoride; local antibiotics, for example, tetracycline or cleocin; corticosteroid supplements, for example, prednisone or prednisolone; agents against goiter formation, for example, colchicine or allopurinol; anti-epileptics, for example, sodium phenytoin; anti-dehydration agents, for example, electrolyte supplements; antiseptics, for example, cetylpyridinium chloride; NSAIDs, for example, acetaminophen, ibuprofen, naproxen, or salts thereof; gastrointestinal active agents, for example, loperamide and famotidine; various alkaloids, for example, codeine phosphate, codeine sulfate, or morphine; supplements for remains of elements, for example, sodium chloride, zinc chloride, calcium carbonate, magnesium oxide, and other alkali metal salts and alkaline earth metal salts; vitamins; ion exchange resins, for example, cholestyramine; cholesterol depressants and substances that decrease lipid; antiarrhythmics, for example, N-acetylprocainamide; and expectorants, for example, guaifenesin. Active substances which have a particularly undesirable taste which include bacterial agents such as ciprofloxacin, ofloxacin and pefloxacin; antiepileptics such as zonistamide; macrolide antibiotics such as erythromycin; beta-lactam antibiotics such as penicillins and cephalosporins; active psychotropic substances such as chlorpromazine; active substances such as sulpirin; and people active against ulcers, such as cimetidine. In other embodiments, the pharmaceutical composition comprises one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, and at least one amino acid selected from the group consisting of glycine, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-guthamic acid, L-glutamine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-amitin, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, creatine and mixtures thereof. In another embodiment, the pharmaceutical composition comprises one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above; a biologically active agent that exhibits a different flavor inhibition activity; and at least one amino acid, such as one selected from the group consisting of glycine, L-alanine, L-arginine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, L-histidine, L-isoleucine , L-leucine, L-lysine, L-methionine, L-ornithine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, creatine and mixtures of same. The pharmaceutical compositions of the present invention may be in any suitable form to achieve its intended purpose. Preferably, however, the composition is one which can be administered buccally or orally. Alternatively, the pharmaceutical composition can be an oral or nasal spray.

The pharmaceutical compositions of the invention may be in any form suitable for administration to any animal that may experience the beneficial effects of one or more compounds in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above. Most important among such animals are humans, although the invention is not intended to be limited. Other suitable animals include canines, felines, dogs, cats, cattle, horses, cattle, sheep and the like. A veterinary composition, as used herein, refers to a pharmaceutical composition suitable for non-human animals. Such veterinary compositions are known in the art. The pharmaceutical preparations of the present invention can be manufactured using known methods; for example, by conventional mixing, granulating, dragee-making, solvent or lyophilization processes. In this way, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores. Pharmaceutical excipients are well known in the art. Suitable excipients include fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose and / or calcium phosphate preparations, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste. , using, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinyl pyrrolidone. If desired, disintegrating agents may be added, such as the aforementioned starches and also carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Auxiliary, all the above, flow regulating agents and lubricants are, for example, silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. Dragee cores with adequate coating are provided which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. To produce gastric juice resistant coatings, solutions of suitable cellulose preparations are used, such as acetylcellulose phthalate or hydroxypropylmethyl cellulose phthalate. Suitable dyes or pigments can be added to the coated tablets, for example, for identification or for combinations characterized by doses of active compounds. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, atyl acetate, alcohol benzyl, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

In a preferred embodiment, the invention is directed to a chewable tablet comprising one or more compounds according to Formula I and one or more biologically active agents. Chewable tablets are known in the art. See, for example, U.S. Patent Nos. 4,684,534 and 6,060,078, each of which is incorporated by reference in its entirety. Any kind of medication can be contained in the chewable tablet, preferably a bitter-tasting medicine, natural plant extract and other organic compounds. More preferably, vitamins such as vitamin A, vitamin B, vitamin Bl, vitamin B2, vitamin B6, vitamin C, vitamin E and vitamin K; natural plant extracts such as Sohgunjung-tag extracts, Sipchundaebo-tang extracts and extracts of Eleutherococcus senticosus; organic compounds such as dimenhydrinate, meclazine, acetaminophen, aspirin, phenylpropanolamine and cetylpyridinium chloride; or gastrointestinal agents such as dry aluminum hydroxide gel, domperidone, soluble azulene, L-glutamine and hydrotalcite can be contained in the core. In another embodiment, the present invention is directed to an orally disintegrating composition, wherein the orally disintegrating composition further comprises one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above. Orally disintegrating tablets are known in the art. See, for example, U.S. Patent Nos. 6,368,625 and 6,316,029, each of which is incorporated by reference in its entirety. In another embodiment, the present invention is further directed to a nasal composition further comprising one or more compounds in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above. Nasal sprays are known in the art. See, for example, U.S. Patent No. 6,187,332. In addition to one or more compounds according to Formula I for a nasal spray can reduce the experience of an unpleasant taste associated with the composition of a nasal spray. By way of a non-limiting example, a nasal spray composition according to the present invention comprises water (such as 95-98 weight percent), a citrate (such as 0.02 M citrate anion up to 0.06 M citrate anion) , a compound according to Formula I, and optionally phosphate (such as 0.03 M phosphate to 0.09 M phosphate). In another embodiment, the present invention is directed to a solid dosage form comprising an effervescent granule activated by water and / or saliva, such as one having a controllable rate of effervescence, and a compound in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above. The effervescent composition may further comprise a pharmaceutically active compound. Effervescent pharmaceutical compositions are known in the art. See, for example, U.S. Patent No. 6,649,186, which is incorporated by reference in its entirety. The effervescent composition can be used in pharmaceutical, veterinary, horticultural, domestic, food, culinary, pesticide, agricultural, cosmetic, herbicide, industrial, cleaning, confectionery and flavoring applications. Formulations that incorporate the effervescent composition comprising a compound according to Formula I may further include one or more additional adjuvants and / or active ingredients which may be selected from those known in the art to include flavorings, diluents, colors, binders, fillers, surfactants, disintegrants, stabilizers, compaction vehicles and non-effervescent disintegrants. In another embodiment, the present invention is directed to a pharmaceutical composition in the form of a film or wafer form comprising a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, and is capable of disintegrating. Such a pharmaceutical composition in the form of a film or wafer form can be configured, for example, as rapidly disintegrating administration forms, for example, administration forms that disintegrate within a period of 1 second to 3 minutes, or as administration forms. slowly disintegrating, for example, administration forms that disintegrate within a period of 3 to 15 minutes. The indicated disintegration times can be shown at the aforementioned ranges using, for example, matrix forming polymers which have different disintegration or solubility characteristics. In this way, by mixing the corresponding polymer components, the disintegration time can be adjusted. In addition, disintegrants are known which "absorb" water in the matrix and cause the matrix to open by bursting from the inside. As a consequence, certain embodiments of the invention include such disintegrants for the purpose of adjusting the disintegration time. Polymers that are suitable for use in the pharmaceutical composition in the form of film or wafer form include cellulose derivatives, polyvinyl alcohol (e.g., MOWIOL ™), polyacrylates, polyvinyl pyrrolidone, cellulose ethers, such as ethyl cellulose, as well as polyvinyl alcohol, polyurethane, polymethacrylates, polymethyl methacrylates and derivatives, and copolymers of the aforementioned polymers.

In certain embodiments, the total thickness of the pharmaceutical composition in the form of a film or wafer form according to the invention is preferably 5 μp to 10 mm, preferably 30 to 2 mm, and particularly preferably 0.1 mm to 1 mm. . The pharmaceutical preparations may be round, oval, elliptical, triangular, quadrangular or polygonal, but may also have any rounded shape. In another embodiment, the present invention is directed to a composition comprising a medicament or agent contained in a coating that surrounds a gum-based formulation and further comprises an amount of flavor inhibition of a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above.

Preferably, the coating comprises at least 50% by weight of the complete product. Since the nucleus is chewable, the drug or agent is released into the saliva. For example, U.S. Patent No. 6,773,716, which is incorporated herein by reference in its entirety, discloses a suitable medicament or agent contained in a coating surrounding a gum-based formulation. One or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, can be used in the preparation of the coating. Optionally, the composition may also comprise high intensity sweeteners and appropriate flavors. It has been found that with respect to certain medicaments or agents that may have a bitter or strong flavor that by adding an inhibiting agent to the formulation, a much tastier formulation can be provided, including the medicament. In this respect, still nevertheless the medicament in, for example, its powdered form may be bitter or have an unpleasant taste, the matrix used as the coating of the present invention, which includes the inhibiting agent, will provide a product having acceptable medical properties. The compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, may be present in various amounts, such as about 30%, 50%, 75% or 90%. In another embodiment, the compound according to Formula I may be present in about 30% to about 99%. In other embodiments, the compound according to Formula I is present at about 1% to about 30%. In still another embodiment, the present invention is directed to a process for preparing an improved composition comprising a medicament or agent contained in a coating surrounding a gum-based formulation, wherein the method comprises adding a compound in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to the coating surrounding the gum-based formulation. The compound according to Formula I can be added in various amounts, such as about 30%, 50%, 75%, 80% or 90%, or from about 10% up to 90%. In other embodiments, the compound according to Formula I is present at about 1% to about 30%. In still another embodiment, the present invention is directed to a process for preparing an improved composition comprising a medicament or agent contained in a coating surrounding a gum-based formulation, wherein the improvement comprises adding a compound according to the Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to the coating surrounding the gum-based formulation. The compound according to Formula I can be added in various amounts, such as about 30%, 50%, 75%, 80% or 90%, or from about 10% to about 90%. In other embodiments, the compound according to Formula I is present at about 1% to about 30%.

In a further embodiment, the invention is directed to a pharmaceutical composition suitable for aerosol administration, comprising a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, and a suitable carrier. The aerosol composition may further comprise a pharmaceutically active agent. Aerosol compositions are known in the art. See, for example, U.S. Patent No. 5,011,678, which is incorporated by reference in its entirety. As a non-limiting example, an aerosol composition according to the present invention can comprise a medically effective amount of a pharmaceutically active substance, one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, and a biocompatible propellant, such as a (hydro / fluoro) carbon impeller. In certain embodiments, the pharmaceutical compositions of the invention comprise about 0.001 mg to about 1000 mg of a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above. In another embodiment, the compositions of the invention comprise about 0.01 mg to about 10 mg of a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above. In another embodiment, the composition of the invention comprises a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, in an amount sufficient to inhibit a flavor-modulating protein. By way of example, the present invention is a pharmaceutical or veterinary composition, comprising a compound of Formula I, or any of the specific subclasses and specific compounds listed above in an amount sufficient for a flavor-modulating protein of at least about 10. %, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% or from about 50% to about 99%, or alternatively from about 10% to about 40%. In another embodiment, the present invention is directed to a method for inhibiting a flavor-modulating protein, comprising contacting the flavor-modulating protein with a compound of Formula I, or any of the specific subclasses and specific compounds listed above. , and inhibiting the protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or from about 50% up to about 99%, or alternatively from about 20% to about 60%, and wherein the flavor-modulating protein is a protein that modulates the naturally occurring taste. In another embodiment, the present invention is directed to a method that inhibits taste-modulating protein, which comprises contacting the protein with a compound of Formula I, or any of the above. specific subclasses and specific compounds listed above, and inhibit the protein by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or about 50 % up to about 99%, or alternatively from about 20% to about 40%, and wherein the protein is a protein that modulates the naturally occurring taste. In another embodiment, the present invention is directed to a nutrient composition, one or more compounds in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above, and optionally one or more carriers. Examples of nutritional compositions that have an undesirable taste include, but are not necessarily limited to, enteric nutritional products for treatment of nutritional deficit, trauma, surgery, Crohn's disease, kidney disease., hypertension, obesity and the like, to promote athletic performance, strengthen muscle or general well-being or inborn errors of metabolism such as phenylketonuria. In particular, such nutraceutical formations may contain one or more amino acids which have a bitter or metallic taste or flavor. Such amino acids include, but are not limited to, essential amino acids selected from the group consisting of L isomers of leucine, isoleucine, histidine, lysine, methionine, phenylalanine, threonine, tryptophan, tyrosine and valine. Additionally, the invention is directed to a process for preparing an improved nutritional composition, wherein the improvement comprises adding one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, for a composition nutraceutical In certain embodiments, one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, are added to a nutraceutical composition in an amount of about 1% to about 50% or about 5%. , 10% or 15% by weight. In another embodiment, the present invention is directed to a dental hygienic composition comprising one or more compounds in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above. Dental hygiene compositions are known in the art and include but are not necessarily limited to toothpaste, mouthwash, scale rinse, dental floss, dental analgesic (such as Anbesol ™) and the like. For example, the invention includes a dental bleaching composition, which comprises one or more compounds of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, in an amount sufficient to inhibit a bitter taste. Dental bleaching compositions are known in the art. See for example, U.S. Patent No. 6,485,709, which is incorporated herein by reference in its entirety. A dental bleaching composition of the present invention intended for use with dental trays may be used an adhesive carrier formed from a fluid and a thickener. The adhesive carrier may therefore comprise finely divided silica, such as silica fume, dispersed in a liquid, such as polyol. Examples of suitable polyols include propylene glycol, glycerin, propylene glycols, sorbitol, polyethylene glycols and the like. While the carrier preferably includes thickeners, the carrier may also be solely a liquid such as water or any of the liquid polyols are any thickeners. Additionally, the invention is directed to a process for preparing an improved dental hygienic composition, wherein the improvement comprises adding one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, for a dental bleaching composition. In certain embodiments, one or more compounds according to Formula I are added to a dental hygienic composition in an amount of from about 1% to about 20%, preferably about 1% to about 5%, or about 5%, 10% or 15% by weight. In another embodiment, the present invention is directed to a cosmetic product comprising one or more compounds in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above. For example, but not by way of limitation, the cosmetic product comprising a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, may be a face cream, lipstick, lip gloss and Similary. Other suitable compositions of the invention include lip balm such as Chapstick® or Beeswax® Lip Balm by Burt, further comprises one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above. Additionally, the invention is directed to a process for preparing an improved cosmetic product, wherein the improvement comprises adding one or more compounds according to Formula I, or any of the specific groups, subclasses or specific compounds described above, to a product. cosmetic. In certain embodiments, one or more compounds according to Formula I, or any of the specific groups, subclasses or specific compounds described above, are added to a cosmetic product in an amount of about 1% to about 20%, preferably about 1. % up to about 5%, or about 1%, 2% or 3% by weight. In another embodiment, the present invention is directed to a food product comprising one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above. Preferably, the food product is one which exhibits an undesired taste, such as a bitter taste, which can be inhibited by a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above. In addition, in a preferred embodiment, the food product comprises a compound according to Formula I, or any of the specific groups, subclasses or specific compounds described above in an amount sufficient to inhibit an unpleasant taste. Specific food products and food ingredients to which one of more compounds of formula I, or any of the specific subgroups, subclasses or specific compounds described above, which may be added include, but are not necessarily limited to, potassium chloride, ammonium chloride , sodium chloride (eg, table salt), magnesium chloride, halide salts, naringin, caffeine, urea, magnesium sulfate, saccharin, acetosulfan, aspirin, potassium benzoate, potassium bicarbonate, potassium carbonate, nitrate potassium, potassium nitrate, potassium sulfate, potassium sulfite, potassium glutamate, food preservatives themselves physiologically acceptable salts, antibiotics, sugar-free chocolates, cocoa bean, yogurt, preservatives, flavor improvers, diet supplements, gelling agents, pH control agents, nutrients, processing aids, thickening agents, dispersing agents, stabilizer is, dyes, dye thinners, anti-hardening agents, antimicrobial agents, formulation aids, yeast agents, surface active agents, anti-hardening agents, nutritional supplements, alkali, acids, sequestrants, denudation agents, general purpose buffers, thickeners, agents retention of stew juice, color fixatives in meat and meat products, color fixatives in poultry meat and poultry meat products, pasta conditioners, ripening agents, yeast foods, mold retardants , emulsifiers, binders, miscellaneous aqueous correctors and food additives for general purpose, tableting aids, alkaline peeling agents, aqueous washing agents, oxidants, antioxidants, enzymes, spreaders, fungicides, paste preparations, coffee, tea, dry preparations, non-dairy cream substitute, salts, animal glue adjuvants, cheese, nuts , meat and meat products, poultry meat and poultry meat products, pork and pork products, fish and fish products, vegetable and vegetable products, fruit and fruit products, smoked products such as meat , cheese, fish, poultry meat and vegetables, shake agents, chewing substances in chewable gums, pasta enhancer, animal feed, poultry feed, fish feed, pork feed, defoaming agents, juices, liquors, alcohol-containing substances or beverages, beverages including but not limited to alcoholic beverages and non-alcoholic soft drinks carbonated and / or non-carbonated, whipping ingredients, bulking agents used in comestibles including but not limited to starches, corn solids, polysaccharides and other polymeric carbohydrates, ice creams, as well as substances containing potassium or containing metal with undesirable flavors and the like. In addition, the present invention contemplates the preparation of comestibles such as bread, muffin, pancake, cake, sponge cake, snack foods, baked goods etc., prepared using for example potassium bicarbonate or potassium carbonate instead of the sodium salts as fermentation agents together with a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, in an amount sufficient to eliminate one or more undesirable flavors. The compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, may typically be present in an amount ranging from about 0.001% to about 50% by weight, preferably about 0.1% to about 10% by weight. % by weight, or alternatively, from 0.1% to about 1% by weight, of the material with the undesirable taste. The present invention also contemplates the preparation of condoms for foodstuffs comprising the potassium salts of benzoate, nitrate, nitrite, sulfate and sulfite and successively, together with an appropriate concentration of a compound according to Formula I, or any of the subgroups specific, subclasses or specific compounds described above, to eliminate undesirable flavors in food products. In this way, the invention is directed to a process for preparing an improved food product, wherein the improvement comprises adding one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to a food product In certain embodiments, one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, are added to a food product in an amount of from about 1% to about 20%, preferably about 1. % up to about 5%, about 1%, 3% or 4% by weight. In another embodiment, the present invention is directed to an animal food product comprising one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above. One or more compounds are preferably in an amount sufficient to inhibit one or more undesirable flavors associated with the animal food product. Animal food products are well known in the art, see for example, U.S. Patent No. 6,403,142, and which includes dog food, cat food, rabbit feed and the like. The animal food product may also be useful food products for feed cattle, such as cattle, bison, pig, chicken and the like. In another embodiment, the animal feed composition of the present invention is a solid hypoallergenic pet food comprising a component containing proteins and protein fragments, wherein all of the component is partially hydrolyzed and further comprises one or more compounds in accordance with Formula I, or any of the specific subgroups, subclasses or specific compounds described above. Additionally, the invention is directed to a process for preparing an improved animal food product., wherein the improvement comprises adding one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, to an animal food product. In certain embodiments, one or more compounds according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, are added to an animal food product in an amount from about 1% to about 25%, about 1. % up to about 10%, or about 5%, 10% or 15% by weight. In additional embodiments of the present invention, any of the compositions described herein and containing a compound according to Formula I may further comprise one or more additional taste masking agents. Such masking agents include but are not limited to the group consisting of sucralose; zinc gluconate; ethyl maltol; glycine; acesulfame-k; aspartame; saccharin; fruitful xylol; mannitol; isomalt; Salt; licorice root dried atimizada; glycyrrhizin; dextrose; sodium gluconate, sucrose; glucon-delta-lactone; ethyl vanillin; and vanillin. In another embodiment, the present invention is directed to a composition comprising a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, and a carrier, wherein the carrier is suitable for an assay. Such carriers may include solid carriers and / or liquid carriers. A composition suitable for an assay may, but not necessarily be sterile. Examples of suitable carriers for assays include dimethyl sulfoxide, ethanol, dichloromethane, methanol and the like. In another embodiment, a composition comprises a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, and a carrier, wherein the compound is in an amount suitable to inhibit a flavor-modulating protein. In each of the embodiments of the compositions described herein, a compound of Formula I, or any of the specific subgroups, subclasses or specific compounds described above, may be used in proportions that change for the agent believed to cause the taste. unwanted, such as bitter or sweet flavor. For example, a composition of the invention may comprise a compound of Formula I in a molar ratio of from about 1000: 1 to about 1: 1000, or alternatively administered, in a molar ratio of about 500: 1, about 200: 1, about 10: 1, about 1: 1, about 1:10, about 1: 200, or about 1: 500, in relation to the agent that is believed to cause the undesired taste, such as bitter or sweet flavor. In another example, the present invention is directed to a food product comprising one or more food ingredients and a compound according to Formula I, wherein the molar ratio of the compound of Formula I to the food agent that causes, or is believed to be causes a bitter taste of about 1000: 1 to about 1: 1000, or alternatively administered in a molar ratio of about 500: 1, about 200: 1, about 10: 1, about 1: 1, about 1:10, about 1 : 200 or about 1: 500. As will be appreciated, the varied ranges and amounts of the compound of Formula I may be used, with modifications if preferred, in each of the embodiments described herein. The activity of a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above can be determined by testing the compound using a number of methods known in the art. For example, one can evaluate the ability of a compound to inhibit a bitter taste by using an in vivo taste assay. This in vivo assay identifies bitter blockers by testing their activity using human subjects. A concentration of the bitter quinine compound in water was found to be the substantial proportion as 5 for bitterness on a scale of 0 to 10, where 0 is not bitter and 10 is the most intense bitterness that the substantial proportion has ever encountered. This concentration of quinine is then made by containing a concentration of a compound according to Formula I to be tested, and the substantial proportion of bitterness of this solution on the same scale. The activity of a compound according to Formula I, or any of the specific subgroups, subclasses or specific compounds described above, can also be determined by assay means described in Example 23. The assay is described in full detail in the application Copendent Serial No. (Attorney's Document No. 2305.0170001), filed on November 3, 2006, which is incorporated by reference in this document in its entirety.

Compounds A further aspect of the present invention is directed to novel compounds according to Formula I. New compounds according to Formula I are useful in the methods and compositions as described herein. Varied modalities of the compounds include any and all of the specific genres, subgenres, subgroups and specific compounds described herein. In a further embodiment, the invention is directed to a compound in accordance with the following formula wherein R1 is hydrogen or halogen; R2 is hydrogen or Ci_4 haloalkyl; R3 is hydrogen, haloalkyl, Ci-4 alkoxy or Ci-C4 alkylthio; and R 4 is hydrogen, Ci-4 haloalkyl, Ci-4 alkoxy or Ci-4 alkylthio. In another embodiment, R1 is hydrogen or halogen; R2 is CF3; R3 is hydrogen, Ci-4 haloalkyl, Ci-4 alkoxy or C1-4 alkylthio; and R 4 is hydrogen, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 alkylthio. Suitable alkoxy groups include methoxy. Suitable haloalkyl groups include trifluoromethoxy. Suitable alkylthio groups include -SCH3. Preferably, the compounds are trans-cyclopropyl compounds. Examples of compounds of the present invention are described herein, for example in the Examples.

Methods of Preparation of Compounds A compound according to Formula I can be synthesized in accordance with the methods summarized in the following descriptions. The compounds for use in the present invention can be synthesized using methods known in the art. The following general reaction schemes illustrate synthetic methods used to prepare compounds of the present invention. In one process, a compound of Formula I can be prepared by condensing a suitable acylated hydrazide with a suitable ketone or aldehyde in a suitable organic solvent, such as ethanol, 2-propanol, tetrahydrofuran, toluene, etc., and mixtures thereof, as shown in Reaction Scheme 1 (wherein R1, R2, R3, R4, L1 and L2 are defined above). The presence of a quenching agent with water such as molecular sieves or dry potassium carbonate may be useful in the process. Acid or basic catalysts can be used to facilitate condensation. Acid catalysts include, but are not limited to, p-toluenesulfonic acid, methylsulfonic acid and phosphoric acid, and sulfuric acid. Basic catalysts include, but are not limited to, trimethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate, and sodium carbonate.

Reaction Scheme 1 I Condensation In an alternative process, certain compounds according to Formula I, wherein R2 is H, can be prepared as shown in Reaction Scheme 2 (wherein R1, R2, R3, R4, L1 and L2 are defined above) . In accordance with this process, a suitable carboxylic acid is treated with a hydrazone of a suitable aldehyde or ketone to provide a compound according to Formula I. Carbonyldiimidazole and triethylamine can be used as condensation agents in this reaction, although they can use other suitable condensation agents.

Reaction Scheme 2 As a further example, the compounds Formula I, wherein R1 and R2 are aryl groups, can be prepared by condensing an acylated hydrazide (such as compound 1) with an aldehyde (such as compound 2) in a suitable organic solvent, such such as ethanol, 2-propanol, tetrahydrofuran, toluene, etc., and mixtures thereof, and in the presence of a quenching agent with water such as molecular sieves or dry potassium carbonate (Reaction Scheme 1). Acidic or basic catalysts can be used to facilitate condensation. Acid catalysts include, but are not limited to, p-toluenesulonic acid, methylsulphonic acid, phosphoric acid, and sulfuric acid. Basic catalysts include, but are not limited to, triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate and sodium carbonate. An example of this process is shown in Reaction Scheme 3. Reaction Scheme 3 I The variation of this method may include treating a carboxylic acid (such as compound 3) with hydrazone of a suitable aldehyde (such as compound 4) to provide I. Carbonyldiimidazo and triethylamine are usually employed as condensation agents in this reaction . An example of this process is shown in Reaction Scheme 4.

Reaction Scheme 4 The reaction can also be carried out pure (for example, without a solvent). After the reaction is complete, the product can be isolated by crystallization of solvents such as ethanol, dichloromethane, ethyl acetate and toluene, etc. Other similar compounds of this invention can be obtained from commercial sources and prepared by those skilled in the art. Starting materials are commercially available or can be prepared by ordinary persons skilled in the art. For example, compound I shown above can be prepared by reacting a carboxylic acid (such as compound 3) with a protective hydrazine (such as compound 5) in the presence of carbonyldiimidazole / triethylamine to provide a protected acidic hydrazine (such as compound 6). After the reaction is complete, the acidic hydrazine protecting group (such as compound 6) can be removed under standard conditions (such as acidic conditions, eg, trifluoroacetic acid) to provide a compound of formula 1. An example of this process is shown in Reaction Scheme 5.

Reaction Scheme 5 Carbonyl diimidazole Triethylamine Other compounds of this invention can be prepared by slight variations of the methods described herein. These documents and others are described in the literature, such as Wyrzykiewicz and Prukala, Polish J.

Chem. 72: 694-702 (1998); and Elderfield and Wood, J. Org. Chem. 27: 2463-2465 (1962), each of which is incorporated by reference in its entirety. Of course, other methods and methods known in the art can be used to prepare certain compounds of Formula I. The following examples are illustrative, but not limiting, of the method, compounds and compositions of the present invention. Each of the compounds listed below is obtained from commercially available catalogs of companies, such as Aldrich RarechemLib, Aldrich Sigma, AlsInEx, Biotech Corp., Brandon / Berlex, Calbiochem, ChemBridge, Comgenex West, Foks H, G. & J. Research, IBS, ICN Biochemicals, Institute for Chemotherapy, Kodak, Lederle Labs, Ligand-CGX, Maybridge PRI, Menai Organics, Enai / Neurocrine, MicroSource, MPA Chemists, Mybrgd / ONYX, PRI- Peakdale, RADIAN, Receptor Research, RGI, Rhone-Poulenc, SPECS / BioSPECS / SYNTHESIA, T. Glinka, Tripos Modern, VWR, Zaleska, Zelinksy / Berlex, Eros, and Chemica. The compounds are purified using conventional purification methods, such as CLAR. The identity of the compound was confirmed using HPLC and mass spectrometry. Analytical LC-MS was performed on a 75 x 4.6 mm Atlantis DCie column using a solvent system of Shock Absorber A (100% water with 0.1% formic acid) and Shock Absorber B (100% acetonitrile). At a flow rate of 1.0 ml / min, 1.5 ml of 70% B-cushion was passed into the column, followed by a linear gradient of 1.5 ml for 95% buffer B, followed by a washed isocratic with 1.5 ml of B shock absorber 95%. As is known in the art and noted above, the hydrazone portion can exist in any of the E or Z conformations. Thus, while a particular stoichiometry can be indicated for particular compounds described herein, it will be understood that the invention includes all stereoisomers, and in particular all the E and Z isomers. Other modifications and suitable adaptations of the variety of conditions and parameters normally encountered and are obvious to those skilled in the art are within the spirit or scope of the invention.

EXAMPLES EXAMPLE 1 4 - ((E) - ((Z) - 1- (2- (Benzo [d] thiazol-2-yl) hydrazono) -2-methylpropyl) diazenyl) methyl benzoate Molecular Formula: Ci9H19 502S: Molecular Weight: 381.5 (calculated).

EXAMPLE 2 Acid (E) -2- (4-Bromo-2- ((2- (quinolin-8-yl) hydrazone) methyl) phenoxy) acetic acid Molecular Formula: Ci8Hi4Br 303; Molecular Weight: 400 (calculated).

EXAMPLE 3 (E) -N- (3,4-Dimethoxybenzylidene) -2- (naphthalen-1-yl) acetohydrazide Molecular Formula: C21H20 2O3; Molecular Weight: 348 (calculated), 348 (found).

EXAMPLE 4 (E) - '- (3, 4-dimethoxybenzylidene) -2- phenylcyclopropanecarbohydrazide Molecular Formula: C19H20 2O3; Molecular Weight: 324 (calculated), 324 (found).

EXAMPLE 5 (E) -3-Cyclohexenyl-4-hydroxy-N '- (4-methoxybenzylidene) butanhydrazide Molecular Weight: C18H24 2O3; Molecular Weight: 316.40 (calculated).

EXAMPLE 6 (E) -N '- (3,4-Dimethoxybenzylidene) -4-hydroxyhexanhydrazide Molecular Formula: C20H30N2O4; Molecular Weight (calculated), 364 (found).

EXAMPLE 7 2- ((Z) -2- (phenyl- ((E) -phenyldiazenyl) -methylene) hydrazinyl) benzoic acid Molecular Formula: C2oHi6 402; Molecular Weight: 344.7 (calculated).

EXAMPLE 8 (E) -N- (3,4-Dimethoxybenzylidene) -2- (m-tolyloxy) acetohydrazide Molecular Formula: Ci8H20N2O4; Molecular Weight: 328 (calculated), 328 (found).

EXAMPLE 9 (E) -N '- (4- (Allyloxy) -3-methoxybenzylidene) -2- (3-bromobenzylthio) acetohydrazide Molecular Formula: C2oH2iBrN203S; Molecular Weight: 449 (calculated), 447.9 (found).

EXAMPLE 10 (E) - '- (4-Isopropylbenzylidene) bicyclo [4.1.0] heptan-7-carbohydrazide Molecular Formula: Ci8H24 20; Molecular Weight: 284 (calculated), 284 (found).

EXAMPLE 11 (Z) -1,3, 3-Trimethyl-2- ((E) -2- (2- (4-trophenyl) hydrazono) ethylidene) indoline Molecular Formula: Ci9H2oN402; Molecular Weight: 336 (calculated), 336 (found).

EXAMPLE 12 (E) -N '- (4- (Diethylamino) -2-hydroxybenzylidene) -2- phenylcyclopropanecarbohydrazide Molecular Formula: C21H25N3O2; Molecular Weight: (calculated), 351 (found).

EXAMPLE 13 4- (Trifluoromethylthio) phenyl) carbonhydrazonoidicide General Formula: C10H5F3N4S; Molecul Weight (calculated).

EXAMPLE 14 N- ((E) -3- ((Z) -2- (1, 5-Dimethyl-2-oxoindolin-3-ylidene) hydrazinyl) -3-oxo-1-phenylprop-1-en-2 il) enzamide General Formula: C26H22 4O3; Molecular Weight (calculated).

EXAMPLE 15 do (Z) -2- (2- ((1-Butyl-lH-indolyl) methylene) hydrazinyl) benzoic acid General Formula: C20H21N3O2; Molecular Weight: 335.4 (calculated) EXAMPLE 16 ((2-Benzyl-2-phenylhydrazono) methyl) iridine Molecular Formula: C19H17N3; Molecular Weight (calculated), 287.2 (found).

EXAMPLE 17 (Z) - '- ((lH-Pyrrol-2 -i 1) methylene) tricyclo [3.3.1.13'7] decan-3-carbohydrazide Molecular Formula: C16H21N3O; Molecular Weight: 271 (calculated).

EXAMPLE 18 (Z) -1- (2- (4- (Ethyl- (2-hydroxyethyl) amino) phenyl) hydrazone) naphthalene-2 (1H) Molecular Formula: C20H21N3O2; Molecular Weight (calculated), 333.2 (found).

EXAMPLE 19 (E) -4- ((2- (5-Chloro-3- (trifluoromethyl) pyridin-2-yl) -2-methylhydrazono) methyl) benzene-1,3-diol Molecular Formula: C14H11CIF3N3O; Molecular Weight: 345.7 (calculated), 344.9 (found).

EXAMPLE 20 (E) -2- (3,4-Dimethylphenylamino) - '- (4-morpholino-3-nitrobenzylidene) acetohydrazide Molecular Formula: C21H25 5O4; Molecular Weight: 411.4 (calculated), 411.3 (found).

EXAMPLE 21 (Z) -3- (2-Nitro-5- (pyrrolidin-1-yl) phenyl) hydrazone) quinuclidine Molecular Formula: C17H23 5O2; Molecular Weight: 329.4 (calculated).

EXAMPLE 22 (E) -2- ((2- (lH-Benzo [d] imidazol-2-yl) hydrazone) methyl) -5- (diethylamino) phenol G Molecular Formula: Ci8H2i 50; Molecular Weight: 323.4 (calculated).

EXAMPLE 23 N- (3- (2- ((6-Bromobenzo [d] [1,3] dioxol-5-yl) methylene) hydrazinyl) -1- (4- (dimethylamino) phenyl) -3-oxoprop- l-en il) enzamide Molecular Formula: C26H23Br 404; Molecular Weight: 535.4 (calculated) EXAMPLE 24 N- (1- (4- (Diethylamino) phenyl) -3- (2- (4-hydroxy-3-iodo-5-methoxybenzylidene) hydrazinyl) -3-oxoprop-1- en-2-yl) benzamide Molecular Formula: C28H29I 4O; Molecular Weight (calculated).

EXAMPLE 25 N '- (4-Hydroxy-3-methoxybenzylidene) -3- (1-hydroxy-cyclopentyl) propanhydrazide Molecular Formula: C16H22N2O4; Molecul Weight (calculated).

EXAMPLE 26 4-Nitro-N '- (3,4,5-trimethoxybenzylidene) benzo idrazide Molecular Formula: C17H17 3O6; Molecular Weight: 359.3 (calculated).

EXAMPLE 27 N '- (4- (diethylamino) -2-hydroxybenzidine) phenylcyclopropanecarboxyhydrazide Molecular Formula: C2iH25 302; Molecular Weight EXAMPLE 28 '- (5-Bromo-2-oxoindolin-3-ylidene) -2- (2-bromo-4-methoxyphenoxy) acetohydrazide Molecular: 483. 1 (calculated).

EXAMPLE 29 3- (lH-indol-3-yl) -N '- (3,4,5-trimethoxybenzylidene) propanhydrate? Molecular Formula: C21H23 3O4; Molecular Weight: 381.4 (calculated).

EXAMPLE 30 N '- (2-Oxoindolin-3-ylidene) -2- (2-methyl-4- (1, 1-dimethylethyl) phenoxy) acetohydrazide Molecular Formula: C21H23 3O3; Molecular Weight (calculated).

EXAMPLE 31 A mixture of 4-chlorobenzaldehyde (10 g, 71 mmol), malonic acid (8.1 g, 78 mmol), piperidine (0.70 ml) and pyridine (60 ml) was refluxed for 4 hours. The reaction mixture was cooled to 0 ° C and acidified with 6N hydrochloric acid to form a precipitate. The precipitate was collected by filtration and dried to provide 4-chlorocinnamic acid.

Thionyl chloride (12: 4 ml, 0.167 mmol) was added dropwise over a period of 20 minutes to a solution at 0 ° C of a portion of the preceding solid (12.2 g, 66.8 mmol) in methanol (130 ml). The solution was then heated at 80aC for 20 hours. The solution was cooled to temperature and the volatiles were removed in vacuo. The residue was taken in ethyl acetate (200 ml). The mixture was washed (3 x 100 mL with saturated sodium bicarbonate, 2 x 200 mL with water, 1 x 100 mL with saturated sodium chloride), dried (sodium sulfate) and concentrated in vacuo to provide methyl 4- chlorocinamate. A portion of the preceding product (5.0 g, 25.4 mmol) was dissolved in dichloromethane (50 ml). The solution was protected from light, palladium acetate was added and the mixture was cooled to -30 ° C. Ethereal diazomethane (prepared from 21.0 g of N-methyl-N-nitrosourea) was added dropwise to the stirred mixture. The excess diazomethane was quenched with acetic acid and the mixture was concentrated in vacuo. The residue was taken in dichloromethane. The resulting mixture was washed (2 x 60 mL with saturated sodium bicarbonate, 2 x 60 with water, 1 x 60 mL with sodium chloride), dried (sodium sulfate) and concentrated in vacuo. The residue was subjected to chromatography (silica, ethyl acetate / hexanes) to provide methyl 2- (4-chlorophenyl) cyclopropane carboxylate.

Hydrazine hydrate (1.45 g, 29 mmol) was added to a stirred solution of a portion of the preceding product (5.1 g, 24 mmol) in methanol (50 mL). After stirring overnight, the mixture of. The reaction was diluted with water and concentrated to remove methanol. The resulting mixture was extracted with ethyl acetate. The organic layers were washed with water (50 ml) and saturated sodium chloride (50 ml), dried (sodium sulfate) and concentrated in vacuo. The product was triturated with ether (4 x) and then dried to give 2- (4-chlorophenyl) cyclopropane carbohydrazide. A solution of 2- (4-chlorophenyl) cyclopropane carbohydrazide (50 mg, 0.24 mmol) in ethanol (5 mL) was stirred for 10 minutes. Acetic acid was added (4 drops to the solution) After stirring for 3 hours, the solvent was removed in vacuo.The product was purified by trituration to give 2- (4-chlorophenyl) - '- (3,4-dimethoxybenzylidene) ) cyclopropancarboxyhydrazide: CLE m / z 359/361, t R = 1.39 min.

EXAMPLES 32-66 The following examples are prepared using the method described in Example 31.

The chemical names for Examples 23 can be converted to structures using standard naming rules or ChemDraw Ultra 10.0.

EXAMPLE 67 '- (3,4-dimethoxybenzylidene) -2- (4,8-dimethylquinolin-2-ylthio) acetohydrazide Molecular Formula: C22H23N3O3 S; Molecular Weight (calculated): 409.5.

EXAMPLE 68 3- (9H-Carbazol-9-yl) -N- (3,4-dimethoxybenzylidene) propanhydrazide Molecular Formula: C24H23N3O3; Molecular Weight (calculated: 401.5.

EXAMPLE 95 The activity of human TRPM5 ion channels in live cells was measured in a fluorescent imaging plate reader (FLIPR). The bases of the assay (shown in Figure 1) is the calcium-dependent activation of the ion channel which occurs via activation of a receptor coupled to the G protein (GPCR). GPCR activation by an appropriate agonist causes a transient increase in concentrations of the intercellular Ca2 + ion which in turn causes the ion channel to open, left in Na + ions. This influx causes a change in the membrane potential of the cell which can be monitored as a change in the fluorescent signal of voltage-dependent fluorescent dyes (membrane potential). A demonstration of the assay is shown in Figures 4A and 4B, where traces of the fluorescent response (Ex 530 nm / Em 565 nm) against time are shown for cells containing the plasmid and false plasmid controls. While all the cells give a Ca2 + response to the endogenous muscarine GPCR against carbachol (upper panel), only the cells containing the plasmid shown as a sustained maximum for the membrane potential dye response (lower panel). For the screening test, human TRPM5 genes were cloned into HEK293 cells, and a high expression, stable clone was used for selection. The cells were grown in standard medium at 37 SC. The day before the selection, the cells were removed from the flasks and added to 384-well clear bottom plates (8K cells in 20 μl / well). On the day of the trial, 20 μ? of membrane potential dye (Part No. R8123, Molecular Devices Corp.) to the cells and the dye was allowed to take, say, loaded into the cells for 1 hour at 37 eC. The dye loaded cell plate was placed in the FLIPR along with a second plate of 384 cavities containing the test compounds, as well as positive (completely inhibited) and negative (non-inhibited) controls. The assay was initiated by the addition of 10 μ? of solution of the plate of the compound in the cell plate. During this process, continuous fluorescent records were made simultaneously for all the cavities. After the addition of the compound solution, the tips are. were washed automatically and a 3 μ stimulation solution was added? of ATP (an agonist for an endogenous purinurgic GPCR, to the cavities of the cell plate.) The height of the response was calculated and the percentage of inhibition values against negative control cavities was calculated for the test samples. assays of counters on separate cell plates using the same cells as described above In the calcium counter screen, cells were loaded with a calcium-sensitive dye (Calcium Dye, Patent No. 8090, Molecular Devices Corp.) and stimulated by ATP to verify the compounds that block the calcium activation stage mediated by GPCR On the KCl count screen, the cells were stimulated with 10 mM KCl instead of ATP to verify the compounds that inhibit the potential response of membrane by virtue of being non-specific ion channel blockers, unless otherwise indicated, the data in the table below were determined using all three assays described above, what does the percentage inhibition data provide at 10 μ ?.

EXAMPLE 70 Electrophysiological Results Standard complete cell records were obtained from HEK cells stably transfected with human TRPM5. The internal solution contained 135 mM of CsGlutamate, 10 mM of HEPES, 2 mM of MgATP, 5 mM of CaCl2 and 10 mM of EGTA. The external solution was HBSS (Gibco) buffered with 20 mM HEPES at pH 7.2. The currents were recorded with a Multiclamp 700B amplifier using PClamp software; filered at 1 kHz, sampled at 5 kHz. The housing potential was -80mV. The TRPM5 current was activated by intracellular calcium dialysis (170 nM free calcium) and sampled with 200 ms ramps from -80 to 80 mV at 1 Hz. The current amplitudes were measured at -80 and 80mV and plotted against time. Figure 2 shows a large current > 5 nA (+80 mV) activated by calcium. Note that no significant current was observed in the fake, non-transfected HEK cells (not shown) and also shows > 90% TRPM5 current inhibition when the TRPM5 transfected cells are pre-treated with 10 μ? of Example 3. Having now fully described this invention, it will be understood by those of ordinary skill in the art that it can be carried out within a broad and equivalent ranges of conditions, formulations and other parameters without affecting the scope of the invention or any modality of this. All patents and publications cited in this document with fully incorporated by reference in this document in their entirety.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (63)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Method for inhibiting a flavor, characterized in that it comprises administering to a subject in need of the same taste by inhibiting the taste one or more compounds of Formula I: or a physiologically acceptable salt thereof, wherein, R1 is C6-14 aryl, 5-14 elements heteroaryl, C3-C4 cycloalkyl, C3-cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and alkyl Ci_6, each of which is optionally substituted; R2 is H, Ci_6 alkyl, C6-io aryl, or arylC6-ioalkyl (Ci-6); R3 is H, Ci_6 alkyl, C6-io aryl or cyano; R4 is C1_6 alkyl, C6_4 aryl, 5-14 elements heteroaryl, C3_4 cycloalkyl, C3_4 cycloalkenyl, 3-14 elements cycloheteroalkyl or 3-14 elements cycloheteroalkenyl, each of which is optionally substituted, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted; or R3, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from aryl C6 ~ i / 5-14 elements heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted; wherein the compound is administered in an amount sufficient to inhibit the taste.

2. Method according to claim 1, characterized in that R1 is optionally substituted C6-io aryl.

3. Method according to claim 1, characterized in that R1 is optionally substituted 5-14-element heteroaryl.

4. Method according to claim 1, characterized in that R1 is optionally substituted C3-10 cycloalkyl or optionally substituted C3-10 cycloalkenyl.

5. Method according to claim 1, characterized in that R1 is optionally substituted cycloheteroalkyl of 3-10 elements or optionally substituted cycloheteroalkenyl 3-10 elements.

6. Method according to claim 1, characterized in that R1 is optionally substituted Ci-6 alkyl.

7. Method according to claim 1, characterized in that R2 is H.

8. Method according to claim 1, characterized in that R2 is Ci_5 alkyl.

9. Method according to claim 1, characterized in that R2 is aryl Ce- ?? or aryl C 1-6 alkyl Ci_6.

10. Method according to claim 1, characterized in that R3 is H.

11. Method according to claim 1, characterized in that R3 is Ci_6 alkyl.

12. Method according to claim 1, characterized in that R3 is aryl C6-i0.

13. Method according to claim 1, characterized in that R3 is cyano.

14. Method according to claim 1, characterized in that R4 is optionally substituted Ci-β alkyl.

15. Method according to claim 1, characterized in that R4 is optionally substituted C6-io.

16. Method according to claim 1, characterized in that R4 is optionally substituted 5-10-element heteroaryl.

17. Method according to claim 1, characterized in that R4 is optionally substituted C-i0 cycloalkyl or optionally substituted C3-i0 cycloalkenyl.

18. Method according to claim 1, characterized in that R4 is optionally substituted cycloheteroalkyl of 3-10 elements or optionally substituted cycloheteroalkenyl of 3-10 elements.

19. Method according to claim 1, characterized in that L1 is absent.

20. Method according to claim 1, characterized in that L1 is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted.

21. Method according to claim 1, characterized in that L1 contains a cyclopropyl group.

22. Method according to claim 1, characterized in that L2 is absent.

23. Method according to claim 1, characterized in that L2 is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted.

24. Method according to claim 1, characterized in that R1 is unsubstituted phenyl.

25. Method according to claim 1, characterized in that R1 is phenyl or naphthyl, each of which is substituted 1, 2 or 3 substituents independently selected from amino, hydroxy, nitro, halogen, cyano, thiol, Ci_6 alkyl, C2-6 alkenyl, Cx-e haloalkyl, Ci-6 alkoxy, C3-6 alkenyloxy, C1-6 alkylenedioxy / Ci-6alkoxy (C1-6alkyl), Ci_6 aminoalkyl, Ci_6 aminoalkoxy, Ci_6 hydroxyalkyl, C2 hydroxyalkoxy -6 monoalkylamino (C1-4), dialkylamino (C1-4), alkylcarbonylamino C2-6; C2-6 alkoxycarbonylamino, C2-6 alkoxycarbonyl, carboxy, (Ci-6) alkoxy (C2-6) alkoxy, C2-6 carboxyalkoxy and C2-6 carboxyalkyl.

26. Method according to claim 1, characterized in that R1 is a heteroaryl containing nitrogen.

27. Method according to claim 1, characterized in that R1 is selected from the group consisting of pyridyl, pyrimidinyl, imidazolyl, tetrazolyl, furanyl, thienyl, indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl and benthiazolyl, each of which is optionally substituted.

28. Method according to claim 1, characterized in that R4 is unsubstituted phenyl.

29. Method according to claim 1, characterized in that R4 is phenyl or naphthyl, each of which is substituted 1, 2 or 3 substituents independently selected from the group consisting of amino, hydroxy, nitro, halogen, cyano, thiol, alkyl Ci -6, C2-6 alkenyl, Ci-6 haloalkyl, Ci-6 alkoxy, C3-6 alkenyloxy, Ci-6 alkylenedioxy, Ci-6alkoxy (Ci_6), Ci-6 aminoalkyl, Ci-β aminoalkoxy, Ci_6 hydroxyalkyl, hydroxyalkoxy C2-6, monoalkylamino (C1-4), dialkylamino (C1-4), alkylcarbonylamino C2-6, alkoxycarbonylamino C2-6, alkoxycarbonyl C2-6, carboxy, alkoxy (Ci-6) alkoxy (C2-6), carboxyalkoxy C2 -6 and C2-6-30 carboxyalkyl.

Method according to claim 1, characterized in that R4 is a nitrogen-containing heteroaryl.

31. Method according to claim 1, characterized in that R4 is selected from the group consisting of pyridyl, pyrimidinyl, imidazolyl, tetrazolyl, furanyl, thienyl, indolyl, azaindolyl, quinolinyl, pyrrolyl, benzimidazolyl and benthiazolyl, each of which is optionally substituted.

32. Method according to claim 1, characterized in that R1 is optionally substituted C6-io aryl; R2 is H or Ci_6 alkyl; R3 is H or Ci-6 alkyl; and R4 is optionally substituted C6-10 aryl.

33. Method according to claim 1, characterized in that R1 is optionally substituted C6-io aryl; R2 is H or Ci-6 alkyl; R3 is H or Ci-6 alkyl; and R 4 is optionally substituted 5-10 element heteroaryl.

34. Method according to claim 1; characterized in that R1 is optionally substituted C6-io aryl; R2 is H or Ci_6 alkyl; R3 is H or Ci_6 alkyl; and R 4 is optionally substituted 5-10 element heteroaryl.

35. Method according to claim 1, characterized in that R1 is optionally substituted 5-10-element heteroaryl; R2 is H or Ci-6 alkyl; R3 is H or Ci_6 alkyl; and R 4 is optionally substituted 5-10 element heteroaryl.

36. Method according to claim 1, characterized in that R1 is optionally substituted C6-io aryl; R2 is H or Ci_6 alkyl; R3 is H or Ci-6 alkyl; and R4 is optionally substituted C3-i0 cycloalkyl.

37. Method according to claim 1, characterized in that R1 is optionally substituted 5-10 elements heteroaryl; R2 is H or Ci-6 alkyl; R3 is H or Ci-6 alkyl; and R4 and L2 together form -N = N-aryl.

38. Method according to claim 1, characterized in that R1 is optionally substituted 5-10 elements heteroaryl; R4 is optionally substituted C6-io aryl, such as phenyl and naphthyl; and L1 and L2 are absent.

3 9. Method according to claim 1, characterized in that R2 is H, Ci_6 alkyl, or C6-io alkyl (Ci-6); L1 is absent, or is a linker containing 1-6 carbons and / or heteroatoms and which is optionally substituted; R3, R4 and L2 together with the carbon atom form a selected group of aryl Ce- ?? ? heteroaryl of 5-10 elements, C3-10 cycloalkyl, C3-10 cycloalkenyl, cycloheteroalkyl of 3-10 elements, cycloheteroalkenyl of 3-10 elements, each of which is optionally substituted.

40 Method according to claim 1, characterized in that R1 is heteroaryl; R2 is H; R 4 is heteroaryl; L1 is absent; and L2 is N = N.

41 Method according to claim 1, characterized in that R1 is a bicycloalkyl; R2 is H; R3 is H; R 4 is aryl or heteroaryl; L1 is absent; and L2 is absent.

42 Method according to claim 1, characterized in that R1 is aryl; R2 is H; R3 is H; R 4 is aryl or heteroaryl; L1 is optionally substituted by a linker containing 2-4 carbons or hetero atoms; and L2 is absent.

43 Method according to claim 1, characterized in that R1 is cycloalkenyl; R2 is H, R3 is H, R4 is aryl or heteroaryl; L1 is optionally substituted by a linker containing 2-4 hetero atoms or carbons; and L2 is absent.

44. Method according to claim 1, characterized in that the compound of Formula I is selected from the group consisting of 4 - ((E) - ((Z) -l- (2- (benzo [d] thiazole-2 - il) methyl hydrazono) -2-methyl-propyl) diazenyl) benzoate; (E) -2- (4-Bromo-2- ((2- (quinolin-8-yl) hydrazono) methyl) phenoxy) -acetic acid; (E) -N '- (3,4-dimethoxybenzylidene) -2- (naphthalen-1-yl) -acetohydrazide; (E) - '- (3,4-dimethoxybenzylidene) -2-phenylcyclopropane-carbohydrazide; (E) -3-cyclohexenyl-4-hydroxy-1- (4-methoxybenzylidene) -butanhydrazide; (E) - '- (3,4-dimethoxybenzylidene) -4-hydroxyhexanhydrazide; 2- ((Z) -2- (phenyl ((E) -phenyldiazenyl) methylene) hydrazinyl) benzoic acid; (E) - '- (3,4-dimethoxybenzylidene) -2- (m-tolyloxy) acetohydrazide; (E) -N '- (4- (allyloxy) -3-methoxybenzylidene) -2- (3-bromobenzylthio) -acetohydrazide; (E) -N '- (4-isopropylbenzylidene) bicyclo [4.1.0] heptan-7-carbohydrazide; (Z) -1, 3, 3-trimethyl-2- ((E) -2- (2- (4-nitrophenyl) hydrazono) -ethylidene) indoline; (E) -N '- (4- (diethylamino) -2-hydroxybenzylidene) -2-phenylcyclopropanecarbohydrazide; (4-trifluoromethylthio) phenyl) carbonhydrazonoidicyanide; N - ((E) -3 - ((Z) -2- (1, 5-dimethyl-2-oxoindolin-3-ylidene) hydrazinyl) -3 -oxo-1-phenylprop-1-en-2-yl) benzamide; (Z) -2- (2- ((l-Butyl-lH-indol-3-yl) methylene) hydrazinyl) benzoic acid; (E) -4- ((2-benzyl-2-phenylhydrazono) methyl) pyridine; (Z) -N '- ((lH-pyrrol-2-yl) meleon) tricyclo [3.3.1.13'7] decan-3-carbohydrazide; (Z) -l- (2- (4- (ethyl (2-hydroxyethyl) amino) phenyl) hydrazono) -naphthalen-2- (1H) -one; (E) -4- ((2- (5-chloro-3- (trifluoromethyl) pyridin-2-yl) -2-2-methyl-hydrazono) methyl) benzene-1,3-diol; (?) -2- (3, 4-dimethylphenylamino) -? ' (4-morpholino-3-nitrobenzylidene) acetohydrazide; (Z) -3- (2-Nitro-5- (pyrrolidin-1-yl) phenyl) hydrazono) quinuclidine; (E) -2- ((2- (lH-benzo [d] imidazol-2-yl) hydrazono) methyl) -5- (diethylamino) phenol.

45. Method according to claim 1, characterized in that the compound of formula I is selected from the group consisting of N- (3- (2- ((6-Bromobenzo [d] [1, 3] dioxol-5-il methylene) hydrazinyl) -1- (4- (dimethylamino) phenyl) -3-oxoprop-1-en-2-yl) benzamide; N- (1- (4- (diethylamino) phenyl) -3- (2- (4-hydroxy-3-iodo-5-methoxybenzylidene) hydrazinyl) -3-oxoprop-1-en-2-yl) benzamide; N '- (4-Hydroxy-3-me oxybenzylidene) -3- (1-hydroxycyclopentyl) -propanhydrazide; 4-Nitro-N '- (3, 4, 5-trimethoxybenzylidene) benzohydrazide; N '- (4 - (diethylamino) -2-hydroxybenzidine) phenylcyclopropanecarboxyhydrazide; N '- (5-Bromo-2-oxoindolin-3-ylidene) -2- (2-bromo-4-methoxyphenoxy) acetohydrazide; 3- (lH-indol-3-yl) -N '- (3,4,5-trimethoxybenzylidene) propanhydrazide; N '- (2-oxoindolin-3-ylidene) -2- (2-methyl-4- (1,1-dimethylethyl) -phenoxy) acetohydrazide; 2- (4-Chlorophenyl) - '- (3,4-dimethoxybenzidin) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) -N '- (3,4-dimethoxybenzidine) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) -N '- (3,4-dimethoxybenzidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -1- (3,4-dimethoxybenzylidene) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -? ' - (3,4-dimethoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) -? ' - (3,4-dimethoxybenzidine) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) - '- (3-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) - '- (3-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) - '- (3-tri fluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (3-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -N '- (3-tri fluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) -N'-IS-trifluoromethylbenylidinyl) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) - '- (3-methoxy-benzylidine) -cyclopropane-carboxyhydrazide; 2- (3-chlorophenyl) -N '- (3-methoxy-benzylidine) -cyclopropane-carboxyhydrazide; 2- (4-chlorophenyl) - '- (3-methoxy-benzylidine) -cyclopropane-carboxyhydrazide; 2- (2-fluorophenyl) - '- (3-methoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) - '- (3-methoxy-benzylidine) -cyclopropane-carboxyhydrazide; 2- (4- fluorophenyl) -? ' - (3-methoxybenzylidine) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) - '- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) -N '- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) -N '- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (3-methylthiobenzylidin) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) - '- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (4- fluorophenyl) - '- (3-methylthiobenylidine) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) -N '- (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) - '- (2-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) -1- (2-tri fluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -N '- (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -? ' - (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) - '- (2-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (2-chlorophenyl) -N '- (4-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (3-chlorophenyl) -? ' - (4-trifluoroinethylbenylidene) cyclopropanecarboxyhydrazide; 2- (4-chlorophenyl) -N '- (4-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; 2- (2-fluorophenyl) -? ' - (4-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (3-fluorophenyl) -N 1 - (4-trifluoromethylbenylidin) cyclopropanecarboxyhydrazide; 2- (4-fluorophenyl) -N '- (4-trifluoromethylbenylidine) cyclopropanecarboxyhydrazide; N '- (3,4-dimethoxybenzylidene) -2- (4,8-dimethylquinolin-2-ylthio) -acetohydrazide; 3- (9H-carbazol-9-yl) -N '- (3,4-dimethoxybenzylidene) propan-hydrazide; and physiologically acceptable salts thereof.

46. Method according to claim 1, characterized in that the subject is human.

47. Method according to claim 1, characterized in that the compound is administered in an amount of about 0.01 mg to about 100 mg.

48. Method according to claim 1, characterized in that the compound is administered as a component of a pharmaceutical product.

49. Method according to claim 48, characterized in that the compound is present in the pharmaceutical product in an amount of about 0.01% up to 50% by weight.

50. Method according to claim 1, characterized in that the compound is administered as a component of a food product.

51. Method according to claim 50, characterized in that the compound is present in the food product in an amount of about 0.01% up to 10% by weight.

52. Method according to claim 1, characterized in that the compound is administered as a component of a dental hygienic product.

53. Method according to claim 52, characterized in that the compound is present in the dental hygienic product in an amount of from about 0.01% up to 20% by weight.

54. Method according to claim 1, characterized in that the flavor is produced by a biologically active agent.

55. Method according to claim 1, characterized in that the flavor is produced by one or more agents selected from the group consisting of antipyretics, analgesics, laxatives, appetite depressants, antacids, antiasthmatics, antidiuretics, agents active against flatulence, migraine, psychopharmacological agents, spasmolytics, sedatives, antihyperkinetics, tranquilizers, antihistamines, decongestants, receptor blockers, alcohol withdrawal agents, antitussives, fluorine supplements, local antibiotics, corticosteroid supplements, anti goiter agents, anti-epileptics, anti-epileptic agents dehydration, antiseptics, NSAIDs, active gastrointestinal agents, various alkaloids, supplements for trace elements, ion exchange resins, cholesterol depressants and lipid-lowering substances; antiarrhythmics, and expectorants.

56. Method according to claim 1, characterized in that the taste is bitter taste.

57. Method for inhibiting the depolarization of a taste receptor cell, characterized in that it comprises contacting the flavor receptor cell with one or more compounds of Formula I: I or a physiologically acceptable salt thereof, wherein R1 is C6-I4 aryl, 5-14-membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and Ci_6 alkyl, each of which is optionally substituted; R2 is H, C1-6 alkyl, C6-aryl, or arylC6-ioa.-alkyl (Ci-e); R3 is H, Ci-6 alkyl, C6-io aryl or cyano; R 4 is Ci_6 alkyl, C6-i4 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted; or R3, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a selected group of aryl e-14 eteroaryl of 5-14 elements, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted; wherein the compound is administered in an amount sufficient to inhibit the depolarization of a flavor receptor cell.

58 Pharmaceutical composition, characterized in that it comprises one or more of the pharmaceutically acceptable carriers and one or more compounds according to Formula I. I or a physiologically acceptable salt thereof, wherein R1 is C6-I4 aryl, 5-14-membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and Ci-6 alkyl, each of which is optionally substituted; R2 is H, Ci_6 alkyl, C6-io aryl or arylC6-ioalkyl (Ci-6); R3 is H, Ci-6 alkyl, C6-y aryl or cyano; R4 is Ci_6 alkyl, C6-1 ^ aryl, 5-14-membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl or 3-14 membered cycloheteroalkenyl, each of which is optionally substituted , or is cyano; L1 is absent, or is a linker containing 1 -10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1 -10 carbons and / or heteroatoms and which is optionally substituted; or R3,, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from C6-I4 aryl, 5-14-membered heteroaryl, C3-14 cycloalkyl, C3-3.4 cycloalkenyl, cycloheteroalkyl 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted.

59. Method for preparing an improved pharmaceutical composition, characterized in that it comprises adding to a composition one or more compounds according to Formula I: or a physiologically acceptable salt thereof, wherein, R1 is C6-C4 aryl, C5-4 heteroaryl, 14 elements, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and C1-6 alkyl, each of which is optionally substituted; R2 is H, Ci-6alkyl aryl S-IQ, or arylC6-ioalkyl (Ci-6); R3 is H, C1-6 alkyl, C6-io aryl or cyano; R4 is Ci-6 alkyl, Ce-u aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl or 3-14 membered cycloheteroalkenyl, each of which is optionally replaced, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted; or R3, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from aryl C6-J.4 / heteroaryl of 5-14 elements, C3-14 cycloalkyl, C3-14 cycloalkenyl , cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted.

60. Food product, characterized in that it comprises one or more food ingredients and one or more compounds according to Formula I: R3 I or a physiologically acceptable salt thereof, wherein R1 is aryl Ce-14, heteroaryl of 5-14 elements, cycloalkyl C3-i4, cycloalkenyl C3-i4, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and Ci-6 alkyl, each of which is optionally substituted; R2 is H, Ci_6 alkyl, C6-io aryl or arylC6-ioalkyl (Ci-6); R3 is H, Ci_6 alkyl, C6-io aryl or cyano; R4 is Ci-6 alkyl, C6-i4 aryl, 5-14 membered heteroaryl, C3-i4 cycloalkyl, C3-cycloalkenyl, cycloheteroalkyl of 3-14 elements or cycloheteroalkenyl of 3-14 elements, each of which is optionally replaced, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and or heteroatoms and which is optionally substituted; or R3, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from aryl C6-i4, heteroaryl of 5-14 elements, cycloalkyl C3-i4, cycloalkenyl C3-14, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted.

61. Cosmetic product, characterized in that it comprises one or more cosmetic ingredients and a compound according to Formula I: R3 I or a physiologically acceptable salt thereof, wherein R1 is C6-I4 aryl, 5-14-membered heteroaryl, C3-I4 cycloalkyl, C3-cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and C1-6 alkyl, each of which is optionally substituted; R2 is H, Ci_6 alkyl, C6-io aryl, or arylC6-ioalkyl (Ci-6); R3 is H, Ci-6 alkyl, C6-io aryl or cyano; R 4 is Ci_6 alkyl, C6-i4 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, C3-cycloalkenyl, cycloheteroalkyl of 3-14 elements or cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted; or R3, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from aryl C6-i4, heteroaryl from 5-14 elements, cycloalkyl C3-i4, cycloalkenyl C3-i4, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted.

62. Method for preparing an improved cosmetic product, characterized in that the improvement comprises adding to a cosmetic product a compound according to Formula I: I or a physiologically acceptable salt thereof, wherein R1 is C6-I4 aryl, 5-14-membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements and C1-6 alkyl, each of which is optionally substituted; R2 is H, C1-6 alkyl, C6-10 aryl, or arylC6-ioalkyl (Ci-e); R3 is H, C1-6 alkyl, C6-io aryl or cyano; R4 is Ci-6 alkyl, C6-i4 aryl, 5-14 membered heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, 3-14 membered cycloheteroalkyl or 3-14 membered cycloheteroalkenyl, each of which is optionally replaced, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted; or R3, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from C6-I4 aryl, 5-14 elements heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted.

63. Dental hygienic product, characterized in that it comprises one or more dental hygienic ingredients and a compound according to Formula I: I or a physiologically acceptable salt thereof, wherein, R 1 is C 6 -i aryl, 5-14 elements heteroaryl, C 3 - 4 cycloalkyl, C 3-14 cycloalkenyl, 3-14 elements cycloheteroalkyl, 3-14 elements cycloheteroalkenyl and alkyl Ci-6, each of which is optionally substituted; R2 is H, Ci-6 alkyl, C6-io aryl or arylC6-ioalkyl (C! -6); R3 is H, Ci-6 alkyl, C6-io aryl or cyano; R4 is C1_6 alkyl, C6-14 aryl, 5-14 elements heteroaryl, C3-14 cycloalkyl, C3-14 cycloalkenyl, 3-14 elements cycloheteroalkyl or 3-14 elements cycloheteroalkenyl, each of which is optionally substituted, or is cyano; L1 is absent, or is a linker containing 1-10 atoms and / or heteroatoms and which are optionally substituted; L2 is absent, or is a linker containing 1-10 carbons and / or heteroatoms and which is optionally substituted; or R, R4, and L2, together with the carbon atom to which L2 and R3 are attached, form a group selected from aryl C6-i4, heteroaryl of 5-14 elements, cycloalkyl C3-i4, cycloalkenyl C3-14, cycloheteroalkyl of 3-14 elements, cycloheteroalkenyl of 3-14 elements, each of which is optionally substituted.