AU2016206281A1 - Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof - Google Patents

Abstract

The present invention relates to the discovery of flavour or taste modifiers, such as flavouring or flavouring agents and flavour or taste enhancers. In particularly, savoury 5 or sweet taste modifiers, savoury or sweet flavouring agents and savoury or sweet flavour enhancers, for foods, beverages, and other comestible or orally administered medicinal products or compositions. 7984845_1 (GHMatters) P59273.AU.3

Description

NOVEL FLAVORS, FLAVOR MODIFIERS, TASl'ANTS, TASTE ENHANCERS, UMAMI OR SWEET TASTANTS, AND/OR ENHANCERS

AND USE THEREOF

This application claims the priority of LIS. provisional patent application serial number 60/494,071 filed on August 0.6,2003, and also claims the priority of U.S. provisional patent application serial number 60/552,064, filed March 09, 2004, the entire disclosures of which are hereby incorporated herein by this reference.

FIELD OF THE INVENTION

The present invention relates to the discover}' of flavor or taste modifiers, such as a flavoring or flavoring agents and flavor or taste enhancers, more particularly, savory (“umami”) or sweet taste modifiers, - savory or sweet flavoring agents and savory or sweet flavor enhancers, for foods, beverages, and other comestible or orally administered medicinal products or compositions.

BACKGROUND OF THE INVENTION

For centuries, various natural and unnatural compositions and/or compounds have been added to comestible (edible) foods, beverages, and/or orally administered medicinal compositions to improve their taste. Although it has long been known that there are only a few basic types of “tastes,” the biological and biochemical basis of taste perception was poorly understood, and most taste improving or taste modifying agents have been discovered largely by simple trial and error processes.

There has been significant recent progress in identifying useful natural flavoring agents, such as for example sweeteners such as sucrose, fructose, glucose, erythritoi, isomalt, laetitol, mannitol, sorbitol, xylitol, certain Mown natural terpenoids, fiavonosds, or protein sweeteners. See for exam pie a recent article entitled “Nbncariogenic Intense Natural Sweeteners” by Kinghom ei aL (Med Res Rev IS (5) 347-360,1998), which discussed recently discovered natural materials that are much more intensely sweet than common natural sweeteners such as sucrose, fructose, and the like. Similarly, there has been recent progress in identifying and commercializing new artificial sweeteners, such as aspartame, saccharin, acesnlfame-K, cyciamate, sueralose, and alitame, etc., see a recent article by Ager, et ;ri,(Angew Chem inf Ed. 1998, 37, 1802-1817). The entire disclosure of the two references identified above are hereby incorporated herein by reference, for fire purpose of describing at least in part the knowledge of those of ordinal}' skill in the art regarding known sweetening agents.

However, there remains in the art a need for new and improved flavoring agents. For example, one of the five known basic tastes is the “savory” or “umaxm” flavor of monosodium glutamate (“MSG”)· MSG is known to produce adverse reactions in some people, but very little progress has been made in identifying artificial substitutes for MSG. It is known that a few naturally occurring materials can increase or enhance the effectiveness of MSG as a savory flavoring agent, so that less MSG would be needed for a given flavoring application- For example the naturally occurring nucleotide compounds inosine monophosphate (IMP) or guauosine monophosphate (GMP) are known to have a multiplier effect on the savory taste of MSG, but IMP and GMP are very difficult and expensi ve to isolate and purify from natural sources, or synthesize, and bonce have only limited practical application to most commercial needs in food or medicinal compositions. Less expensive compounds that would provide the flavor of MSG itself, or enhance the effectiveness of any MSG that is present could be of very high value. Similarly, discovery of compounds that are either new “High Intensity” sweetners (Le. they are many times sweeter than sucrose) would be of value, or any compounds that significantly increase the sweetness of known natural or artificial sweeteners, so that less of those caloric or non-caloric sweeteners would he required, would be of very high utility and value.

In recent years substantial progress has been made in biotechnology in general, and in better understanding the underlying biological and biochemical phenomena of taste perception. .For example, taste receptor proteins have been recently identified in mammals which are involved in taste perception. Particularly, two different families of G protein coupled receptors believed to be involved in taste perception, T2Rs and T1 Rs, have been identified. (See, e.g., Nelson, et ah, Cell (2001) 106(3):381-390; Adler, etal., Cell (2000) 100(6):693-702; Chandrashekar, e£ al., Cell(2000) 100:703-711; Matsunams, etal., Number (2000) 404:601-604; Li, et al, Proa Nod. Acad. Sci USA (2002) 99:4962-4966; Montmayeur, et el., Nature Neuroscience (2001) 4(8):492-498: U-S. Patent 6,462,148; and PCX publications WO 02/06254* WO 00/63166 ait, WO 02/064631, and WO 03/001876, and U.S. Patent publication US 2003-0232407 Al) . The entire disclosures of the articles, patent applications, and issued patents cited immediately above are hereby incorporated herein by reference, for all purposes, incl uding their disclosures of the identities and structures of T2Rs and TIKs mammalian taste receptor proteins and methods for artificially expressing those receptors in ceil lines and using the resulting cell lines for screening compounds as potential “savory” or “sweet” flavoring agents.

Whereas the T2R family includes a family of over 25 genes drat are involved in bitter taste perception, the TIRs only includes.three members, T1R1, T1R2 and T1R3. (see Li, etaL.Proc. Ntitil. Acad. Set. IMA (2002) 99:4962-4966;) Recently it was disclosed in WO 02/064631 and/or WO 03/001876 that certain T1R members, when eo-expressed in suitable mammalian sell lines, assemble to form functional taste receptors. Particularly it was found that co-expression of T1R1 and T1R3 in a suitable host cell results in a functional T1R1/T1R3 savory' (“umami”) taste receptor that responds to savory taste stimuli, including monosodium glutamate. Similarly, it was found that co-expression of T1R2 and T1K3 in a suitable host cell results in a functional T1R2/T1R3 “sweet” taste receptor that responds to different taste stimuli including naturally occurring and artificial sweeteners. (See Li, et al (Id.). The references cited above also disclosed assays and/or high throughput screens that measure T1R1/T1.R3 or 71R2/T1R3 receptor activity by fiuorometnc imaging in the presence of the target compounds. We employed the above-described assays and/or high throughput screening methods to identify initial “lead” compounds that modulate the activity of T1K1/T1R3 “savory” taste receptors, or T1R2/T1R3 “sweet” taste receptors, then embarked on a long, complex and iterative process of investigation, evaluation, and optimization, so as to arrive at the various inventions described below.

SUMMARY OF THE INVENTION

The invention has many aspects, all of which relate in some fashion to certain tton-naturally occurring amide compounds and/or amide derivative compounds having the generic structure shown below in Formula (Ϊ):

wherein R5, Rz and R3 can be and are independently further defined in various ways, as is hxrther detailed below. In ail the embodiments of the amide compounds of Formula (I) the R:: group is an organic residue comprising at least three carbon atoms, with a variety of alternative limits on the size and/or chemical characteristics of the R1 group, as will he further described below. In many hut not all embodiments, the amide compounds ofFormula (I) are “primary” amides, i.e. one ofFT and RJ is as organic group comprising ai least three carbon atoms, while the other of R* and RJ is hydrogen.

The amide compounds ofFormula (I) also comprise certain sub-classes of amide derivatives or classes of derivatives related to amides, such as for example ureas, urethanes, oxalamides, acrylamides, surd the like, as will be further described below.

Many ofthe subgenuses and species of the “amide” compounds ofFormula (I) are shown below to bind to and/or activate one or both of the T1R1/T1R3 “savor/’ (“umamr)or T1K2/T1R3 sweet receptors in-vitro, at relatively low concentrations on fee order of micromolar or lower concentrations. The amide compounds are also believed to similarly interact wife savory or sweet flavor receptors of animals or humans in vivo, as has been confirmed by actual human taste tests of some of compounds ofFormula (I).

Accordingly, marry ofthe subgenuses and species ofthe “amide” compounds ofFormula (I) further described hereinbelow can, at surprisingly low concentrations be used as savory or sweet flavoring agents, or savory or sweet agent enhancers. Accordingly, in some embodiments, the invention relates to methods for modulating the savory taste of a comestible or medicinal product comprising: a) providing at least one comestible or medicinal product, or a precursor thereof, and b) combining the comestible or medicinal product or precursor thereof with at least a savory flavor modulating amount, or a sweet flavor modulating amount, of at least one non-naturally occurring amide compound, or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product; wherein the amide compound has fee formula:

wherein R1 comprises an organic or hydrocarbon residue having at least three carbon atoms and optionally one or more heteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus; and wherein optionally one ofR* and R3 is H, and wherein at least one of the other of and R3 comprises an organic or hydrocarbon residue having at least three carbon atoms and optionally one or more heteroatoms independently selected bom oxygen, nitrogen, sulbu\ halogens, or phosphorus.

Additional optional limitations on the chemical and physical characteristics of the Rl. R2, and R3 groups will be described below. Some of the amide compounds of Formula (1) have been synthesised by methods known in the prior art for various purposes, but ίο the knowledge of the inventors it has not been previously recognized that such amides can be utilized at very low concentrations as savory or sweet flavoring agents, or savory or sweet taste enhancers. Moreover many of the amide compounds of Formula (I) disclosed herein are novel compounds that have not been previously synthesized at all, and are effective savory or sweet taste flavoring agents or taste enhancers ,

The invention also relates to the comestible or medicinal products produced by the processes mentioned above, and to comestible or medicinal products or compositions, or their precursors that contain the amide compounds of Formula (I), which include hut are not necessarily limited to food, drink, medicinal products and ; compositions intended for oral administration, and the precursors thereof.

In many embodiments, one or more of the amide compounds of Formula (I) further identified, described, and/or claimed herein, or a eomestibiy acceptable salt thereof, can be used in mixtures or in combination with other known savory or sweet compounds, or used as flavor enhancers in comestible food, beverage and medicinal compositions, for human or animal consumption.

In some embodiments, the amide compounds of Formula (I), while having little or perhaps even no sweet or savory' Savor when tasted in isolation, can be employed at very low concentrations in order to very significantly enhance the effecti veness of other savory or sweet flavor agents in a comestible or medicinal composition, or a precursor thereof. The inventions described herein also relate to the Favor-modified comestible or medicinal products that contain flavor modulating amounts of one or more of the amide compounds disclosed herein.

Many of the amide compounds of Formula (I) and/or its various stibgenuses of amide compounds, when used together with MSG or alone, increase or modulate a response in vitro, and savory taste perception in humans at surprisingly low concentrations. In some embodiments, the amide compounds of the invention are T1R1/T1R3 receptor agonists and accordingly can induce or enhance savory taste · perception in humans. These compounds C3n enhance, potentiate, modulate or induce other natural and synthetic savory flavoring agents.

In related embodiments, many of the amide compounds within the scope of Formula (I) are T1R2/T1R3 receptor agonists and accordingly can induce sweet taste perception in humans at surprisingly low concentrations. These compounds can enhance, potentiate, modulate or induce other natural, semi-synthetic, or synthetic sweet flavoring agents, such as for example sucrose, fructose, glucose, erythritol, , isomalt, lactitol, mannitol, sorbitol, xylitol, certain known natural terpenoids, flavonoids, or protein sweeteners, aspartame, saccharin, acesulfame-K, eyclamate, sucralose, and alitame, and the like, or a mixture thereof.

Unexpectedly, it has also been discovered that in many embodiments of the compounds of Foimula (I) there are significant structural similarities and/or overlaps between the amide compounds that can produce or enhance the sweet and savory tastes of comestible or medicinal compositions, even though it is believed that the relevant biological taste receptor proteins are sigmtksntly different. Bven more unexpectedly, it has been discovered that at least some of the amide compounds of Formula (I) disclosed herein can indace or enhance both the sweet and savory tastes of foe comestible or medicinal products. Therefore in some aspects the invention is related to compounds of .Formula (F) or its various subgenuses and species compounds that modulate (e.g,, induce, enhance or potentiate) the flavor of known natural or synthetic sweetener agents,

In some embodiments, the invention relates to novel componnds, flavoring agents, flavor enhancers, flavor modifying compounds, and/or compositions containing the compounds of Formula (I), and its various subgenuses and species compounds.

In other embodiments, the invention is directed to compounds of Formula (1) or its various subgenuses and species compounds that modulate (e.g., induee, enhance or potentiate) the flavor of monosodium glutamate (MSG), or synthetic savory flavoring agents.

In some embodiments, the invention relates to comestible or medicinal compositions suitable for human or animal consumption, or precursors thereof, containing at least one compound of Formula (1), or a comestibly or pharmaceutically acceptable salt thereof. These compositions will preferably include comestible products such as foods or beverages, medicinal products or compositions intended for oral administration, and oral hygiene products, and additives which when added to these products modulate the flavor or taste thereof, particularly by enhancing (increasing) the savory and/or sweet taste thereof.

The present invention also relates to novel genuses and species of amide compounds within the scope of the compounds of Formula (I), and derivatives, flavoring agents, comestible or medicinal produets or compositions, including savory or swfeet flavoring agents and flavor enhancers containing the same.

The foregoing discussion merely summarises certain aspects of the inventions and is not intended, nor should it he construed, as limiting the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

The present invention can be understood more readily by reference to die following detailed description of various embodiments of the invention and the Examples included therein and to the chemical drawings and Tables and their previous and following description. Before tbe present compounds, compositions, and/or methods are disclosed and described, it is to be understood that unless otherwise specifically indicated by the claims, the invention is not limited to specific foods or food preparation methods, specific comestibles or pharmaceutical carriers or formulations, or to particular modes of formulating the compounds of fee invention into comestible or medicinal products or compositions intended for oral administration, because as one of ordinary skill in relevant arts is well aware, such things can of course, vary. It is also to be understood that fee terminology used herein is for the purpose of describing particular embodiments only and is not intended to he limiting.

DEFINITIONS

As used herein, the term “medicinal product” includes both solids and liquid compositions which are ingesdhie non-toxic materials which have medicinal value or comprise medicinally active agents such as cough syrups, cough drops, aspirin and chewable medicinal tablets.

An. oral hygiene product Includes solids end liquids such as toothpaste or mouthwash. A. “comestibly, biologically or medicinally acceptable catrier or excipient” is a solid or liquid, medium and/or composition that is used, to prepare a desired dosage form of die inventive compound, in order to administer the inventive compound in a dispersed/diluted form, so that the biological effectiveness of the inventive compound is maximized. A comestibly. biologically or medicinally acceptable carrier includes many common food ingredients, such as water at neutral, acidic, or basic pH, Sint or vegetable juices, vinegar, marinades, beer, wine, natural water/fat emulsions such as milk or condensed milk, edible oils and shortenings, fatty acids, low molecular weight oligomers of propylene glycol, glyceryl esters of fatty acids, and dispersions or emulsions of such hydrophobic substances in aqueous media, salts such as sodium chloride, wheat Hours, solvents such as ethanol, solid edible diluents such as vegetable powders or flours, or other liquid vehicles; dispersion or suspension aids; surface active agents: isotonic agents; thickening or emulsifying agents, preservatives; solid binders; lubricants and the like. . A “flavor” herein refers to the perception of taste and/or smell in a subject, which include sweet, sour, salty, hitter, umami, and others. The subject may fee a human or an animal. A “flavoring agent” herein refers to a compound or a biologically acceptable salt thereof that induces a flavor or taste in a animal or a human, A “flavor modifier” herein refers to a compound or biologically acceptable salt thereof that modulates, including enhancing or potentiating, and inducing, the tastes and/or smell of a natural or synthetic flavoring agent in a animal or a human, A “flavor enhancer” herein refers to a compound or biologically acceptable salt thereof that enhances the tastes or smell of a natural or synthetic flavoring agent, “Savory flavor*1 herein refers to the savors'· “umami” taste typically induced fey MSG (mono sodium, glutamate) in a animal or a human, “Savory' flavoring agent,” “savory compound” or “savory receptor activating compound” herein refers to a compound or biologically acceptable salt thereof that elicits a detectable savory flavor in a subject, e.g., MSG (mono sodium glutamate) or a compound that activates a T1R1/T1R3 receptor in vitro. The subject may be a human or an animal. “Sweet flavoring agent,” “sweet compound” or “sweet receptor activating compound” herein refers to a compound or biologically acceptable salt thereof that elicits a detectable sweet flavor in a subject, e.g, sucrose, fructose, glucose, arid other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like as is farther discussed herein, or a compound that activates a T1S2/T1R3 receptor in vitro. The subject may he a human or an animal, A “savory flavor modifier” herein refers to a compound or biologically acceptable salt thereof that modulates, including enhancing or potentiating, inducing, and blocking, the savory taste of a natural or synthetic savory flavoring agents, e.g., monosodium glutamate (MSG) in a animal of a human, A “sweet flavor modifier” herein.refers to a compound or biologically acceptable salt thereof that modulates, including enhancing or potentiating, inducing, and blocking, the sweet taste of a natural or synthetic sweet flavoring agents, e.g,, sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like, in a animal or a human. A “savory' flavor enhancer” herein refers to a compound or biologically acceptable salt thereof that enhances or potentiates the savory taste of a natural or synthetic savory flavoring agents, eg., monosodium, glutamate (MSG) in a animal or a human. A “sweet flavor enhancer” herein refers to a compound or biologically acceptable salt thereof that enhances or potentiates the sweet taste of a natural or synthetic sweet flavoring agents, e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like as is further discussed herein in an animal or a human.

An Armani receptor activating compound” herein refers to a compound that activates an umami receptor, such as a T1R1/T1R3 receptor. A. “sweet receptor activating compound” herein refers te a compound that activates a sweet receptor, such as a T1R2/T1R3 receptor.

An "umami receptor modulating compound” herein refers to a compound that modulates (activates, enhances or blocks) an umami receptor. A “sweet receptor modulating compound” herd» refers to a compound that modulates (activates, enhances or blocks) a sweet receptor.

An “umami receptor enhancing compound” herein refers to a compound that enhances or potentiates the effect of a natural or synthetic umami receptor activating compound, &g., monosodium glutamate (MSG). A “sweet receptor enhancing compound” herein refers to a compound that enhances or potentiates the effect of a natural or synthetic sweet receptor activating compound, e.g.t sucrose, fructose, glucose, and other Mown natural saccharide-based sweeteners* or known artificial sweeteners such as saccharine, eyclamate, aspartame, and the like as is further discussed herein. A “savory flavoring agent amount” herein refers to an amount of a compound that is sufficient to induce savory taste in a comestible or medicinal product or composition, or a precursor thereof. A fairly broad range of a savory flavoring agent amount can he from about 0.001 ppm to 100 ppm, or a narrow range from about 0,1 ppm to about 10 ppm. Alternative ranges of savory flavoring agent amounts can be from about 0,01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm. to about 5 ppm, or from about 0.1 ppm to about 3 ppm. A “sweet flavoring agent amount51 herein refers to an amount of a compound that is sufficient to induce sweet taste in a comestible or medicinal product or composition, or a precursor thereof. A fairly broad range of a sweet flavoring agent amount can be from about 0.0Q1 ppm to 100 ppm, or a narrow' range from about 0.1 ppm to about 10 ppm. Alternative ranges of sweet flavoring agent amounts can be from about 0,01 ppm to about 30 ppm, from, about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0. 1 ppm to about 3 ppm. A “savory flavor modulating amount” herein refers to an amount of a compound of Formula (I) that is sufficient to alter (either increase or decrease) savory taste in a comestible or medicinal product or composition, or a precursor thereof, sufficiently to be perceived by a human subject. A fairly broad range of a savory flavor modulating amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of savory flavor modulating amounts can. be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm. A “sweet flavor modulating amount” herein refers to an amount of a compound of Formula (I) that is sufficient to alter (either increase or decrease} sweet taste in a comestible or medicinal product or composition, or a precursor thereof} sufficiently to be perceived by a human suhj ect. A fairly broad range of a sweet flavor modulating amount can be from about 0.001 ppm to 100 ppm,, or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of sweet flavor modulating amounts can be from about 0.01 ppm to about 30 ppm. from about 0.05 ppm to about 15 ppm, from about 0,1 ppm to about 5 ppm, or from about 0,1 ppm to about 3 ppm. A “savory flavor enhancing amount’’ herein refers to an amount of a compound Slat is sufficient to enhance the taste of a natural or synthetic fl avoring agents, e.g.„ xnonosodiunr glutamate (MSG) in a comestible or medicinal product or composition. A fairly broad range of a savory fl avor enhancing amount can be from about 0,001 ppm to 100 ppm . or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of savory flavor enhancing amounts can, be from about 0,01 ppm to about 30 ppm, from about 0,05 ppm to about 15 ppm. from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm. A “srveet flavor enhancing amount” herein refers to an amount of a compound that is sufficient to enhance the taste of a natural or synthetic flavoring agents, e,g·., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cydamate, aspertame, and the like as is further discussed herein) in a comestible or medicinal product or composition. A fairly broad range of a sweet flavor enhancing amount can be from about 0.001 ppm to 100 ppm , or a narrow range from about Θ.1 ppm to about 10 ppm. Alternative ranges of sweet flavor enhancing amounts can be from about 0.01 ppm to about 30 ppm, from about 0,05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.

An “umami receptor modulating amount” herein refers to an amount of a compound that is sufficient to modulate (activate, enhance or block) an xtxnaxni receptor. A preferable range of an umami receptor modulating amount is 1 pM to 100 mM and most preferably 1 nMto 100 μ,Μ and most preferably InM to 30 pM. A fairly broad range of a umami flavor enhancing amount can be from about 0 001 ppm to 100 ppm , or a narrow' range from about 0.1 ppm to about 10 ppm. Alternative ranges of umami flavor enhancing amounts can be from about 0,01 ppm to about 30 ppm, from about· 0,05 ppm to about 15 ppm, from about 0,1 ppm to about 5 ppm, or from about QJ ppm to about 3 ppm· A “TlR1/T1R3 receptor modulating or activating amount” is an amount of compound that is sufficient to modulate or activate a T1R1/T1R3 receptor. These amounts are preferably the same as the umami receptor modulating amounts.

Ah ‘‘umami receptor* is a taste receptor that can be modulated by a savory compound. Preferably an umami rseeptor is a G protein coupled receptor, and more preferably the umami receptor is aT!Rl/TlK3 receptor.

Compounds of the invention modulate an umami receptor and preferably ate agonists of the. T1R1/T1R3 receptor. An agonist of this receptor has the effect of activating the G protein signaling cascade. In many cases, this agonist effect of the compound on the receptor also produces.a perceived savory flavor in a taste test, it is desirable, therefore, that such inventive compounds serve as a replacement for MSG, which is not tolerated by some in, for example, comestible products.

In addition, this agonist effect also is responsible for the synergistic savory taste effect, which occurs when a compound of the invention is combined with another savory flavoring agent such as MSG. The nucleotides, IMP or GMP, are conventionally addpd to MSG, to intensify the savory favor of MSG, so that relatively less MSG is needed to provide the same savory Savor in comparison to MSG alone. Therefore, it is desirable that combining compounds of the invention with another savory flavoring agent such as MSG advantageously eliminates the need to add expensive nucleotides, such as IMP, as a flavor enhancer, while concomitantly reducing or eliminating the amount of a savory compound such as MSG needed to provide the same savory flavor in comparison to the savory compound or MSG alone. A “sweet receptor modulating amount” herein refers to an amount of a compound that is sufficient to modulate (activate, enhance or block) a sweet receptor. A preferable range of an sweet receptor modulating amount is 1 pM to 100 mM and. most preferably 1 nM to 100 μΜ and most preferably InM to 30 μΜ. A “T1R2/T1R3 receptor modulating or activating amount” is an amount of compound that is sufficient to modulate or activate a T1R2/T1R3 receptor. These amounts are preferably the same as the sweet receptor modulating amounts. A “sweet receptor” is a taste receptor that can be modulated by a sweet compound. Preferably an sweet receptor is a G protein coupled receptor, and more preferably the umami receptor is a T1R2/TJR3 receptor.

Many compounds of Formula (I) can modulate a sweet receptor and preferably are agonists of the T1R2/T1R3 receptor. An agonist of this receptor has the effect of activating the G protein signaling cascade. In many cases, this agonist effect of the compound on tire receptor also produces a perceived sweet flavor in a taste test, It is desirable, therefore, that such inventive compounds serve as a replacement for sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like, or mixtures thereof as is further discussed herein. A “synergistic effect71 relates to the enhanced savory and/or sweet flavor of a combination of savory and/or or sweet compounds or receptor activating compounds, in comparison to the sum of the taste effects or flavor associated effects associated with, each individual compound. In the case of savory enhancer compounds, a synergistic effect on the effectiveness of MSG may be indicated for a compound of Formula (!) having an BC50 ratio (defined hereinbelow) of 2.0 or more, or preferably 5.0©rmore, or 10.0 or more, or 15.0 or more. An EC 50 assay for sweet enhancement has not yet been developed, but in die case of both savory and sweet enhancer compounds, a synergistic effect can be confirmed by human taste tests, as described elsewhere herein,

When the compounds described here include one or more chiral centers, the stereochemistry of such, chiral centers can independently be in the R or S configuration, or a mixture of the two The chiral centers can be further designated as R or S or R,S or d,D, 1,L or d.L D,L, Correspondingly, die amide compounds of the invention, if they can be present in optically active form, can actually fee present In the form of a racemic mixture of enantiomers, or in the form of either of the separate enantiomers in substantially isolated and purified form, or as a mixture comprising any relative proportions of the enantiomers.

Regarding the compounds described herein, die suffix Mene” added to any of the described terms means that the substituent is connected to two other parts in the compound. For example, “alkylene ” is “alkenylene” is such a moiety that contains a double bond and “alkynylene” is such a moiety that contains a triple bond.

As used herein, hydrocarbon residue” refers to a chemical sub-group within a larger chemical compound which has only carbon and hydrogen atoms. The hydrocarbon residue may be aliphatic or aromatic, straight-chain, cyclic, branched, saturated or misatiirated. The hydrocarbon residue, when so stated however, may contain or be substituted wife heteroatoms such as O, S or N, or the halogens (fluorine, chlorine, bromine, and iodine), or substituent groups containing heteroatoms (OH, N%, NCfe, SO3H, and the like) over and above the carbon and hydrogen atoms of the substituent residue. Thus, when specifically noted as containing such heieroaioms. or designated as “substituted,” the hydrocarbon residue may also contain carbonyl groups, amino groups, hydroxyl groups and the like, or contain heteroatoms inserted into the “backbone” of the hydrocarbon residue.

As used herein, Anorganic residue” refers to a residue that does not contain carbon, but contains at least some heteroatoms, including Ο, N, S, one or more halogens, or alkali metal or alkaline earth metal ions. Examples include, but are not limited to H, Ma+, Ca-H- and K+, halo, hydroxy, NO2 or 14¾.

As used herein, the term “alkyl,” “alkenyl” and “alkynyl” include straight- and branehed-chain and cyclic monovalent substituents that respectively are saturated, unsaferated with at least one double bond, and unsaturated with at least one triple bond, “Alkyl” refers to a hydrocarbon group feat can be conceptually formed from an alkane by removing hydrogen from the structure of a hydrocarbon compound having straight or branched carbon chains, and replacing the hydrogen atom with another atom or substituted: group. In some embodiments of the invention, the alkyl groups are “Cl to C6 alkyl” such as methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-buiyl, amyl, tert-amyl, hexyl and the like. In some embodiments of the invention “Cl to C4 alkyl” groups (alternatively termed “lower alkyl” groups are methyl, ethyl, propyl, iso-butyl, see-butyl t-hutyl, and iso-propyl. Some of the preferred alky] groups of the invention have three or more carbon atoms preferably 3 to 16 carbon atoms, 4 to 14 carbon atoms, or 6 to 12 carbon atoms.

Preferred alkenyl groups are “C2 to C7 alkenyl” such as vinyl, allyl, 2- butenyl, 3-butenyl, 2-pentenyl, 3-pentenyI, 4-pentenyk 2-hexenyi, 3-hexenyl, 4~hexenyl, 5~hexenyl, 2-heptenyl, 3-hepteny], 4-heptenyl. 5-heptenyl, 6-heptenyi, as well as dienes and trienes of straight and branched chains,

Preferred alkynyl groups are “C2 to C7 alkynyl” such as ethynyl, propynyl, 2~butynyl, 2-pentyuyl, 3-pentynyl, 2- hexynyl, 3-hexyny], 4~hexynyl, 2-heptynyl, 3- heptynyl, 4- heptynyl, 5-heptynyl as well as di- and tri-ynes of straight and branched chains including ene-ynes.

Hydrocarbon residues may be optionally substituted. Two of said optional substituents on adjacent positions can be joined to forni a fused, optionally substituted aromatic or nonaromatic, saturated or unsaturated ring which contains 3-8 members. Optional substituents are generally hydrocarbon residues that may contain one or more heteroatoms or an inorganic residue such as H, Na1', Ca'~ or K+.

The terms “substituted alkyl,” “substituted alkenyl ” “substituted alkynyl,” and “substituted alkylene” denote that the alkyl, alkenyl, alkynyl and alkylene groups are substituted by one or more, and preferably one or two substituents, preferably halogen, hydroxy, C 3 to C7 alkoxy, alkoxy-alkyl, oxo, C3 to C7 cycloalkyl, naphthyl, amino, (monosuhsiituted)anuno, (disubstituted)amino. guanidine, heterocycle, substituted heterocyele, imidazolyi, indolyl, pyrroiidinyi, Cl to C7 acyl, Cl to C7 acyloxy, nitre, carboxy, carbamoyl, carboxamide, N-(C1 to C6 alkyljcarhoxamide, N,N~di{C1 to C6 alkyljcarboxsmide, eyano, methylsulfonylamino, thiol, C1 to C4 alkylthio or C1 to C4 alkylsulfonyl groups. The substituted alkyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents. In many embodiments of the invention, aprefetred group of substituent groups include hydroxy, iluoro, chloro, NH?., NHCH3, N(CHj)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, hifinorom.ethy!, methoxy, ethoxy, isopropoxy, and irihuoromethoxy groups. In many embodiments of the invention that comprise the above lists of substituent groups, an even more preferred group of substituent groups include hydroxy, SEt, SCH3, methyl, ethyl, isopropyl, methoxy, and ethoxy groups.

Examples of the above substituted alkyl groups include the 2-oxo-prop-l-yl, 3*oxO“but-l-yl, cyaaomethyl, aitromethyl, chloromethyl, hydroxymethyl, tetrahydropyranyloxyinethyl, trityloxymethyl, propionyloxymetbyl, aminomethyl, carboxymetbyl, aliyloxycarbonylmetbyl, allyloxycarbonyiaminomeihyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, triiluoromethyi, 6-hydroxybexyl, 2,4-diehloro{n-butyI), 2-aminopropyI, 1-ehloroethyl, 2- chloroetbyl, 1~ bromoethyl, 2-chloroethyl, Tfluoroethyl, 2-fluoroethyl, 1-iodoethyl, 2-iodoethyi, l~chloropropyl, 2~ehloropropy], 3- chloropropyl, 1-bromopropyl, 2-bromopropyi, 3-bromopropyl, l-fluoropropyl, 2-rluoropropyl, 3- fluoropropyl, 2-aminoethyl, 1- aminoethyl, N-benzoyl-2»aminoethyl, N-acetyI-2-ammoethyi, N-benzoyl-1 -aminoethyl, N-acelyM-aminoethyl and the like.

Examples of the above substituted alkenyl groups include styrenyl, 3-chloro-propert-l-yl, 3-ehloro-buten-l-yl, 3~melhoxy-propen-2~yl, 3-phenyl .-huten-2-yl, 1 -cyano-buten-3-yl and the like. The geometrical isomerism is not critical, and all geometrical isomers for a given substituted alkenyl can be used.

Examples of the above substituted alkynyl groups include phenylacetylen-1 -yl, l-phenyl-2~propyn-l-yl and the like.

The term “oxo” denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone moiety, , “Alkoxy” refers to an OR group, wherein R is an alkyl or substituted alkyl. “Alkoxy-alkyl” refers to an alkyl group containing an alkoxy.

Preferred alkoxy groups are “C1 to C? alkoxy” such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. The term “C1 to C? substituted alkoxy” means the alkyl portion of the alkoxy can be substituted in the same maimer as in relation to Cl to C6 substituted alkyl. Similarly, the term “Cl to C? phenylalkoxy” as used herein means “Cl to C7 alkoxy” bonded to a phenyl radical. “Acyioxy” refers to an OR group where R is an acyl group.. Preferred acyl ox y groups are “Cl to C7 acyioxy” such as formyloxy, acetoxy, proplonyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like.

As used herein, “acyl” encompasses the definitions of alkyl, alkenyl, alkynyl and the related hetero-forms winch are coupled to an additional residue through a carbonyl group. Prefesred acyl groups are “Cl to C7 acyl” such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like. More preferred acyl groups are acetyl and benzoyl.

The term “substituted acyl” denotes the acyl group substituted by one or more, and preferably one or two, halogen, hydroxy, oxo, alkyl, eycloalkyl, naphthyl, amino, (monosubstituted)amino, (disubstituied)ammo, guanidine, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, Cl to C7 alkoxy, alkoxy-alkyl, Cl to C7 acyl, Cl to C7 acyioxy, nitre, C'l to C6 alkyl ester, carboxy, alkoxyearbonyl, carbamoyl, carboxamide, N-(C! to 06 alkyl}earbcxamide, M,N-di(C 1 to C6 alkyl)earboxamide, oyano, methylsulfonylamino, thiol, C1 to C4 alkyltlrio or C1 to C4 alkylsuifonyl groups. The substituted acyl groups may be substituted once or more, and preferably once or twice, with the same or wife different substituents,

Examples of Cl to C7 substituted acyl groups include 4-pbenylbutvroyl, 3-pbenylbutyroyl, 3 pbenylpropanoyl, 2- cyclohexanylaeetyl, eyelohexaneearbonyl, 2-furanoyl and 3 dimethylaminobenzoyl.

Cycloalkyl residues are hydrocarbon groups within a molecule that comprise at least one ring having 3 to 8 carbon atoms linked into a ring. Examples of such cyeklky! residues include eyciopropyl, cyclobutyl, eyclopentyl, cyelohexyl, cycloheptyl, cyclooctyl rings, and saturated hieyclic or .feed polycyclic cycloalkanes such as decalin groups, norbomyl groups, and the like.

Preferred cycloalkyl groups include “€3 to C7 .cycloalkyl” such as eyciopropyl, cyclobutyl, eyclopentyl, cyelohexyl or cycloheptyl rings, Similarly, the term “C5 to C7 cycloalkyl” includes the eyclopentyl, cyelohexyl or cycloheptyl rings. “Substituted cycloalkyl” indicates fee above cycloalkyl rings are substituted preferably by one or two halogen, hydroxy,, Cl to C4 alkylthio, Cl to C4 alkyisulfoxide, Cl to C4 alkylsulfonyl, Cl to C4 substituted alkylthio, Cl to C4 substituted alkyisulfoxide, Cl to C4 substituted alkylsulfonyl, Cl to 06 alkyl, Cl to C7 alkoxy, Cl to C6 substituted alkyl, C l to C7 alkoxy-alkyl, oxo {monosubstituted)amino, {disnbsiituted)ainino, tdfluoromethyl, carboxy, phenyl, substituted phenyl, phenylihio, phenylsulf oxide, phenylsulfonyl, amino. In many embodiments of substituted cycloalkyl groups, the substituted cycloalkyl group will have 1,2, 3, or 4 substituent groups independently selected from hydroxy, fluo.ro, chforo, NHz, NHCHj, N(CHj)2, CO2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, trill uoromethyl, metboxy, ethoxy, isopropoxy, and trilluoromethoxy groups.

The tenn “cycloalkylene” means a cycloalkyl, as denned above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups. Similarly..,the term “substituted cycloalkylene” means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substituent.

The term “eycloalkenyl” indicates preferably a 1,2, or 3-eyelopen.tenyl ring, a 1,2,3 or 4-cyelohexenyl ring or a 1,2,3,4 or 5-eycloheptenyi ring, while the term “substituted cycloaikenyl” denotes the above cycloalkenyl tings substituted with a substituent, preferably by a Cl to C6 alkyl, halogen, hydroxy, Cl to C7 alkoxy, alkoxy-aikyl, trifluoromethyl, carboxy, aikoxycarbonyl oxo. (monosubstitute^ammo, (disubstituted)amino, phenyl, substituted phenyl, amino, or protected amino.

The term “eyeloalkenyiene” is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups, Similarly, the term “substituted cycloalkenyiene” means a cycloalkenylene further substituted preferably by halogen, hydroxy. Cl to €4 alkylthio, Cl to C4 aikylsulfoxide, Cl to C4 alkylsuifonyl, Cl to €4 substituted alkylthio, Cl to C4 substituted alkylsulfoxide, C1 to C4 substituted alkylsuifonyl, C1 to C6 alkyl, Cl to C7 alkoxy, Cl to C6 substituted alkyl, Cl to C7 alkoxy-alkyl, oxo, (monosubstituted)amino, (disubstituted3amino, trifluoromethyl, carboxy, . aikoxycarbonyl, phenyl, substituted phenyl, phenylibio, phenylsulfoxide, phej'sylsuifonyl, amino, or substituted amino group.

The term “heterocycle*1 or “heterocyclic ring*’ denotes optionally substituted 3 to 8~membered rings having one or more carbon atoms connected in a ring that also have 1 to 5 heteroaioms, such as oxygen, sulfur and/or nitrogen inserted into the ring. These 3 to 8-membered rings may be saturated, unsaturated or partially unsaturated, but are preferably saturated. An “amino-subsiimted heterocyclic ring*’ means any one of the above-described heterocyclic rings is substituted with at least one amino group. Preferred heterocyclic rings include feranyl, thiofhranyl, piperidyl, pyridyl, moipholino, axiridinyl, piperidinyl, piperazinyl, tetrahydrofurano, pyrrolo, and tetrahydrothiophen - yl.

The term “substituted heterocycle” or “substituted heterocyclic ring” means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents preferably can be halogen, hydroxy, thio, alkylthio, cyano, nitre, Cl to C6 alkyl, Cl to C7 alkoxy, Cl to C7 substituted alkoxy, alkoxy-aikyl, Cl to C7 acyl, Cl to C7 acyloxy, carboxy. aikoxycarbonyl. carboxymethyl, hydroxymethyl, alkoxy-aikyl amino, monosubstitutedfamino, (disubstituted)amino carboxandde, N-(C1 to C6 aikyi)carboxamide, N, N-di(CI to C 6 alkyl)carboxamide, trifluoromethyl, N-({C1 to C6 a1kyi)suif0nyl)amin.o, N-(phenyisulfony])ammo groups, or substituted with a fused ring, such as benxo-ring. In many embodiments of substituted heterocyclic groups, the substituted cycloaikyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, ehloro, MHs, MHCH 14(0¾)¾ COjCHj, SEt, SCH3, methyl, ethyl, isopropyl, 'vinyl, iriilgoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromeihoxy groups.

An “aryl” groups refers to a monocyclic aromatic, linked bicyclic aromatic or fused bicyclio aromatic moiety comprising at least one six membered aromatic “benzene” ring, preferably comprising between 6 and 12 ring carbon atoms, such as phenyl, biphenyl or naphthyl groups, which may be optionally substituted with various organic and/or inorganic suhsiituteni groups, wherein the substituted aryl group and its substituents comprise between 6 and IS, or preferably 6 and 16 total carbon atoms. Freferred optional substituent groups include 1, 2, 3, or 4 substituent groups independently selected h orn hydroxy, fiuoro, chloro, £3¾ NHCH3,1^((¾)¼ CO7CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

The tenn ThetcroaryF means a heterocyclic aryl derivative which preferably contains a five-membered or six-membered conjugated and aromatic ring system having from 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen, inserted into the unsaturated and conjugated heterocyclic ring. Heteroaryl groups include monocyclic heteroaromatic, linked bicyclic heteroaromatic or based bicyclic heteroaromatic moieties. Examples of heteroaryls include pyrldinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolyl, fkrarryl, thioibranyl, oxazoloyl, isoxazolyl, phthalimido, thiazolyl, quinolinyl, isoquinolinyl, indolyl, or a fiiran or thioferan directly bonded to a phenyl, pyndyl, or pyrrolyl ring and like unsaturated and conjugated heteroaromatic rings. Any monocyclic, linked bicyclic, or fused bicyclic heteroaryl ring system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. Typically, the heteroaromatic ring systems contain 3-12 ring carbon atoms and 1 to 5 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur atoms.

The term “substituted heteroaryl” means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents preferably can be halogen, hydroxy,protected hydroxy, thio, alkylthio,cyano,nitro, Cl to C6 alkyl, Cl to C7 substituted alkyl, Cl to C7 alkoxy, Cl to C7 substituted alkoxy, alkoxy-alkyi, Cl to C7 acyl, Cl to C? substituted acyl, Cl to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, {monosubstitutedjammo, (disubslituted)amino, carboxamide, N-(C1 to C6 alkyljcaxboxamide, N, M-di(Cl to C6 alkyJ)carboxamide, triiluorotnethyi, N-((C1 to C6 aikyl)sulfoxiyl)amino or N-(|(lienyls«]foiiyl)aiumo groups. In many embodiments of substituted heteroary! groups, the substituted cydoalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, ehloro, NHs, NHCEb, 14((¾)¾ COjCHj, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, trifluorometliyl, methoxy, ethoxy, isopropoxy, and mfluoromethoxy groups.

Similarly, “arylaikyl” and ‘''heteroaryiaikyf5 refer to aromatic and heteroaromatic systems which are coupled to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated, carbon chains, typically of 1-6C. These carbon chains may also include a carbonyl group, thus making them able to provide substituents as an acyl moiety. Preferably, arylalkyl or heteroarylalkyl is an alkyl group substituted at any position by an aryl group, substituted aryl, heteroary] or substituted heteroary! Preferred groups also include benzyl, 2-phenylethyl, 3-phenyl-propyl, 4-phenyi-n-butyi, 3-phenyl-n-amyL 3~phenyb 2-butyl, 2-pyridmyhnethyl, 2'(2-pyridinyl)ethyl, and the like.

The tetm “substituted arylalkyl” denotes an arylalkyl group substituted on the alkyl portion with one or more, and preferably one. or two, groups preferably chosen horn halogen, hydroxy, oxo, amino, (monosnbslitated)amino, (disubstitufed)ammo, guanidine, heterocyclic ring, substituted heterocyclic ring, CI to C6 alkyl, C1 to C6 substituted alkyl, Cl to Cl alkoxy, C l to C7 substituted alkoxy, aikoxy-alkyl. Cl to C7 acyl, Cl to C7 substituted acyl, Cl to €7 acyloxy, niiro, car boxy, alkoxyearbonyi, carbamoyl, carboxamide, N-(C1 to C6 alkyl)earboxamide, N, N~(C1 to C.6 dialkyl)carboxamide, cyano, N-(C1 to C6 alkjdsnlibnyllamino, thiol, Cl to C4 alicydtbio, C1 to C4 alkylsnlfonyl groups; and/or the phenyl group may be substituted with one or more., and preferably one or two, substituents preferably chosen from halogen, hydroxy, protected hydroxy, thio, aikylthio, cyano, nitro, CI to C6 alkyl, C1 to C6 substituted alkyl, Cl to C7 alkoxy, Ci to C7 substituted alkoxy, alkoxy-alkyi,

Cl to C7 acyl, CI to Cl substituted acyl, C1 to C7 acyloxy, car boxy, alkoxyearbonyi, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstitnted)amino, carboxamide, N-(CI to C6 alkyl) carboxamide, N, N-di(Cl to C6 aIkyl)earboxamide, trifluoromethyi, N-((C1 to C6 alkyl)suIfonyi)amino, N-(plienylsulfonyl)ammo, cyclic C2 to C7 alkylene or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group, The substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can. be the same or different

Examples of the term ‘‘substituted arylalkyl” include groups such as 2-phenyl-l~cMoroethyL 2-(4-xnetlmxyphenyl)e.thyl, 4-(2,6-dihydroxy phenyl)- . n-hexyl, 2-(5~cyano-3“methoxyphenyl)-n“pentyI, 3-{2,6-dimethylphenyl)prQpy], 4- chloro-3-amin.oherjzyh 6-(4-methoxypheny])-3-carboxy-n.-hexyl5 5- {4-ammomethylphenyl)~ 3'(aminomethyl)m-pentyl, 5-phenyl-3-oxo-n-pent-l-yl and the like.

The term “arylalkylene” specifies an arylalkyl, as defined abo ve, where tire arylalkyl radical is bonded at two positions connecting together two separate additional groups. The definition includes groups of the formula: -phenyl-alkyl- and alkyS-phenyl-alkyk Substitutions on the phenyl ring can be 1,2,1,3 or 1,4. The term “substituted arylalkylene” is an arylalkylene as defined above that is farther substituted preferably by halogen, hydroxy, protected hydroxy, Cl to C4 alkylthio, Cl to C4 alkylsnlfoxide. Cl to C4 alkylsulfonyl, Cl to C4 substituted alkylthio. Cl to C4 substituted alkylsulfoxide, Cl to C4 substituted alkylsulfonyl, Cl to C.6 alkyl, Cl to C? alkoxy, Cl to C6 substituted alkyl. Cl to C7 alkoxy-alkyl, oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, ear boxy, alkoxycarbonyl, phenyl, substituted phenyl, phenyithio, phenylsulfoxide, phenylsulfonyk amino, or protected amino group on the phenyl ring or on the alkyl group.

The term “substituted phenyl” specifies a phenyl group substituted with one or more, and preferably one or two, moieties preferably chosen from the groups consisting of halogen, hydroxy, protected hydroxy, thio, alkylthio, cyan©, nitro, Cl to C6 alkyl, Cl to C6 substituted alky], Cl to C7 alkoxy, Cl to C7 substituted alkoxy, alkoxy-alkyl. Cl to C7 acyl, C1 to C7 substituted acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(C1 to C6 alkyl)carboxamide, N, N~di(€l to C6 alkyl)carhoxamide, triiluorom.ethyl, 14-((01 to C6 alkyl)suifony3)amin.o, N'(phenylsulf03iyl)amino or phenyl, wherein the phenyl is substituted or nnsubstituted, such that, for example, a biphenyl results. In many embodiments of substituted phenyl groups, the substituted cycloalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, chloro, NH ;, NHCHj, N(CH3)i5 CO2CH3, SEt,SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

The term “phenoxy" denotes a phenyl bonded to an oxygen atom. The term “substituted phenoxy” specifies a phenoxy group substituted with one or more, and preferably one or two, moieties preferably chosen from the groups consisting of halogen, hydroxy, protected hydroxy, thio, alkyltbio, cyano, nitro, Cl to C6 alkyl, Cl to C7 alkoxy, C3 to C7 substituted aikoxy, alkoxy-alcyl, Cl to C7 aeyl, Cl to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstitut®d)ammo, (disubstituted)amino, carboxamide, N-(C1 to C6 alkyl)carboxamide, N, N~di(Ci to C6 aikyl)carhoxamide, trifluoromethyl, N-((C1 to C6 alkyI)sulfonyl)amino andN-phenylsu!fonyl)amino.

The term “substituted phenylalkoxy” denotes a phenylalkoxy group wherein the alkyl portion is substituted with one or more, and preferably one or two, groups preferably selected from halogen, hydroxy, protected hydroxy, oxo, amino, (monosubstituted)amino, (disubstituted)amino, guanidine, heterocyclic ring, substituted heterocyclic ring. Cl to C7 alkoxy, alkoxv-aikyl. Cl to C7 acyl, Cl to C? acyloxy, nitro, carboxy, alkoxycarbonyl, carbamoyl, carboxamide, N~(C1 to 05 alkyl)earboxamide, N, N-(C1 to C6 dialkyl)carboxamide, cyano, N-(C1 to C6 alkylsulfonyl)amino, thiol, Cl to C4 alkyltbio, Cl to C4 alkylsulfonvl groups; and/or the phenyl group can be substituted with one or more, and preferably one or two, substituents preferably chosen from halogen, hydroxy, protected hydroxy, thio, alkyltbio, cyano, nitro, Cl to C6 alkyl, Cl to C7 alkoxy, alkoxy «alkyl. Cl to C7 acyl, Cl to C7 acyloxy, carboxy, alkoxycarbonyl carboxymethyl, hydroxymethyl, amino, (monGsubstituied)animo, (disubstitmed)aminG, carboxamide, N~(C1 to C6 alkyl) carboxamide, N, N-di(CJ. to C6 alkyl)carboxamide, trifluoromethyl, N ((Cl to C6 alkyl)sulibnyl)amino, N~(phenylsulfonyi)amino or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl or phenyl groups may he substituted with one or more, and preferably one or two, substituenis which can be the same or different.

The term “substituted naphthyl” specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, thio, alkyltbio, cyano, nitro, C J to Co alkyl, Cl to C7 alkoxy, alkoxy-^lkyl, C1 to C7 acyl, C l to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstitnted)aminG, (disubstituted)ammo, carboxamide, N-(C! to C6 alkyl)carbGxamide, N, N-di(Cl to C6 a!kyl)carboxamide, trifluoromethyl, N-((C1 to C6 alkyl)sulfonyl)amino or N (phenylsuifonyl)amino.

The terms "halo” and “halogen” refer to She fluoro, chloro, bromo or iodo atoms. There can be one or more halogen, which are the same or different. Prefer red halogens are chloro and fluoro. Although many of the compounds of the invention having halogen atoms as substituents are very effective in binding to the relevant taste receptors, such halogenated organic compounds can often have undesirable toxicological properties when administered to an animal in vivo. Therefore, in many embodiments of the compounds of Formula (I), if a halogen atom (including a fluoro or chloro atom) is listed as a possible substitutent atom, an alternative preferred group of substitutents would NOT include the halogen, fluorine, or chlorine groups.

The term "(monosubstituted)ammo” refers to an amino group with one . substituent preferably chosen from the group consisting of phenyl, substituted phenyl. Cl toC6 alkyl. Cl toC6 substituted alkyl, Cl to C? acyl, Cl to C? substituted acyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C2 to C? alkynyi, C2 to C7 substituted alkynyi, C7 to C12phenylalkyl, C7 to C12 substituted phenylalkyl and heterocyclic ring. The (monosubstituted)anjino can additionally have an amino-protecting group as encompassed by the term "protected (monosubsti tuted)amino”

The term M{disubstituied)arnino” refers to an amino group substituted preferably with two substituents chosen from the group consisting of phenyl, substituted phenyl, C1 to C6 alkyl, C ί to C6 substituted alkyl, C1 to C7 acyl, C2 to C7 alkenyl, C2 to C7 alkynyi, €7 to C12 phenylalkyl, and C7 to Cl2 substituted phenylalkyl The two substituents can be the same or different

The ten» “amino-protecting group” as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule. The term “protected (monosubstituted)amino” means there is an amino-protecting group on the monosubstituted amino nitrogen atom, in addition, the term “protected carboxamide” means there is an amino-protecting group on the carboxamide nitrogen. Similarly, the term “protected N-(C1 to €6 alky|)carboxamide” means there is an amino-protecting group on the carboxamide nitrogen.

The term “alkylthio” refers to sulfide groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butyltMo, t-butyltMo and like groups.

The term “alkylsulfoxide” indicates sulfoxide groups such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropyisulfoxide, n-butylsulfoxide, sec-butylsulf oxide and the like.

The term “alkylsui&nyl” encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsul&nyl, isopropylsulfonyl, n-butylsulfonyl, t-butyisulfonyl and the like. .

The terms “substituted alkylthio.” “substituted alkylsulf oxide,” and “substituted alkylsulf onyl,” denote the alkyl portion of these groups maybe substituted as described above i n relation to “substituted alkyl”

The terms ‘^shenylthio,” “phenylsuiioxide” and “phenylsulfonyl” specify a thiol, a sulfoxide, or sulfone, respectively, containing a phenyl group. The terms . “substituted phenylthio,” “substituted phenylsulfoxide,” and “substituted phenylsulfonyl” means that the phenyl of these groups can he substituted as described above in relation to “substituted phenyl.”

The term “aJkoxycarbonyt” means an “alkoxy” group attached to a carobony! group. The term “substituted alkoxycarbonyl” denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to substituted alkyl.

The term “phenylene” means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups.

Examples of“phenylene” includes 1,2-phenyiene, 1,3-phenylene, and 1,4-phenyiene.

The term “substituted alkylene” means an alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional substituent Examples of “substituted alkylene” includes aminomethylene, l-(amino)4,2-ethyl, 2-{ammo)4,2~ethyl, l*(acetamido)-l ,2-ethyl, 2-{aeetamido)-I,2-ethyl, 243ydroxy·· 1,1-ethyl, l-(amino)-!,3-propyl.

The term “substituted phenylene·” means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups, wherein the phenyl is substituted as described above in relation to “substituted phenyl.”

The terms “cyclic alkylene,” “substituted cyclic alkylene,” “cyclic heterodlkylene,” and “substituted cyclic heteroalkyiene,” defines such a cyclic group bonded (“fused”) to the phenyl radical resulting in a blcydic ring system. The cyclic group may be saturated or contain one or two double bonds. Furthermore, the cyclic group may have one or two methylene or rnetbine groups replaced by one or two oxygen, nitrogen or sulfur atoms which are the cyclic heteroalkylene.

The cyclic aikyleue or heteroalkylene group may be substituted once or twice by the same or different substituents preferably selected from the group consisting of the following moieties; hydroxy, protected hydroxy, carboxy, protected car boxy, oxo, protected oxo, C l to C4 acyloxy, formyl, C i to 07 acyl, Cl to €6 alkyl, C1 to €7 aikoxy, C i to €4 alkyitbio, Cl to G4 alkylsulfoxide, € I to C4 alkylsulfonyl, halo, amino, protected amino, (niormsubstituted)amino, protected (mouosubstituted)auduo, (disubstituted)amino, hydroxymethyl or a protected hydroxymethyl.

The cyclic aikyleue or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members. Examples of such saturated cyclic groups are when the resultant bicyclic ring system is 2,3-dihydro-indanyl and a tetralin dug. Wheu the cyclic groups are unsaturated, examples occur when the resultant bicyclic ring system is a naphthyl ring or iadolyl. Examples of fesed cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to apyridino, pyra-no, pyrrole, pyridiisyi, dihydropyixolo, or dihydropyridirtyl bug. Examples of fused cyclic groups which each contain one oxygen atom and one or two double bonds are when the benzene radical ring is fused to a fk'o, pyrano, dihydroferano, or dihydropyrano ring. Examples of fused cyclic groups which each have one suitin' atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrotbiopyrano ring. Examples of cyclic groups which contain two heteroatoms selected horn sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolo, isotbiazolo, dihydrothiazolo or dihydroisothiazolo ring. Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazoio, isoxazolo, dihydrooxazolo or dihydroisoxazolo ring. Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyi

The term “carbamoyl” means a -NCO- group where the radical is bonded at two positions connecting two separate additional groups. !

One or more of the compounds of the invention, may be present as a salt The term “salt” encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic snions snd cations discussed below. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fhmaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutarie, phthalic, tartaric, iauric, stearic, salicyclic, methanesulfonic, beuzenesulfonie, sorbic, picric, benzoic, cinnamic, and like acids.

The terns “organic or inorganic cation” -refers to counter-ions far the carboxylate anion of a carboxylate salt. The counter-ions are chosen from the alkali and alkaline earth metals, (such as lithium, sodium, potassium, barium, aluminum and calcium); ammonium and mono-, di- and tri-alkyl amines such as trimethylamine, cyelohexylamine; and the organic cations, such as dibenzylammonium, benzylamruonium, 2~hydroxyethylammonium, bis(2-hydroxyethjd)ammonium, phenytethylbenzylammonium, dibenzylethylenediammosium, and like cations. See> for example, “Pharmaceutical Salts,” Berge, et al, J. Pharm. ScL (197?) 66:1-19, which is incorporated herein by reference. Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine. Furthermore, any zwitierionic form of the instant compounds formed by a carboxylic add and an amino group is referred to by this term. For example, a cation for a carboxylate anion will exist when R2 or R3 is substituted with a (quaternary ammonium)methyl group. A preferred cation for the carboxylate anion is the sodium cadon.

The compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallise with, for example, waters of hydration, or one, a number of, or any & action thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention.

The term “amino acid” Includes any one of the twenty naturally-occurring amino acids or the D-form of any one of the naturally-occurring amino acids. In addition, the term “airdho acid’5 also includes other non-naturally occurring amino adds besides the D-amino adds, which are functional equivalents of the naturally-occurring amino acids. Such non-naturally-occurring amino acids include, for example, nor! engine (“Nle”), norvaline (“Nva”), L- or D- naphthalanine, ornithine (“Orn”), homoarginine (homoArg) and others well known in the peptide art, such as those described in M Bodanz&ky, “Principles of Peptide Synthesis,” 1st and 2nd revised ed., Spitisger-Yerlag, New York, NY, 1984 and 1993, and Stewart and Young, “Solid Phase Peptide Synthesis,” 2nd ecL Pierce Chemical Co., Rockford, If., 1984, both of which are incorporated herein hy reference. Amino acids and amino acid analogs can be purchased commercially (Sigma Chemical Co.; Advanced Chemtech) or synthesized using methods known in the art “Amino acid side chain” refers to any side chain from the above-described “amino acids.” “Substituted” herein refers to a substituted moiety, such as a hydrocarbon, u.g.,. substituted alkyl or benzyl wherein at least one element or radical, e.g,, hydrogen, is replaced by another, e,g.f a hydrogen is replaced by a halogen as in chlorobenzyl. A residue of a chemical species, as used in the specification and concluding claims, refers to a struc tural fragment or a moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the structural fragment or moiety is actually obtained from the- chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCHjCHjQ- repeat units in the polyester, regardless of whether ethylene glycol is used to prepare the polyester. Similarly, a 2,4-thia'SOlidinedione residue in a chemical compound refers to one or more -2,4-thiazolidinedione moieties of the compound, regardless of whether the residue was obtained by reacting 2,4-thiazolidinedione to obtain the compound.

The term “organic residue” defines a carbon containing residue, i.e. a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or fee like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-snbstituted amino, amide groups, etc. Organic resides can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to S carbon atoms, or 1 to 4 carbon atoms.

By the term "effective amount” of a compound as provided herein i§-meant a sufficient amount of the compound to provide the desired regulation of a desired function, such as gene expression, protein function, or a disease condition. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the species* age, general condition of the subject, specific identity and formulation of the drug, etc. Thus, it is not possible to specify an exact “effective amount," However, an appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," “an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an aromatic compound" includes mixtures of aromatic compounds.

Often, ranges are expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other , endpoint “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, andthatthe description includes instances where said event or circumstance occurs and instances where it does not For example, the phrase “optionally substituted lower alkyl” means that the lower alkyl group may or may not be substituted and that the description includes both unsuhstituted lower alkyl and lower alkyls where there is substitution.

The Amide Compounds of The invention

The compounds of the invention are all organic (carbon containing) compounds that all have at least one “amide” group therein, have the following general structure, which will be hereinafter referred to as the amide compounds having Formula (I) shown below:

The amide compounds of Formula (I) do not include any amide compounds that are known to naturally occur in biological systems or foods, such as peptides, proteins, nucleic acids, glycopeptides or glycoproteins, or the like. The amide compounds of Formula (I) of the invention are man-made and artificial synthetic amide compounds, although the Applicants do not exclude the possibility that compounds of Formula (I) could conceivably be purposely prepared, either in then specified ion:;! or In the form of a peptide or protein-modified “prodrug” form by human beings utilizing one or more of the methods of modem biotechnology.

For the various embodiments of the compounds of Formula (I), the R1, R: and R3 groups can he and are independently further defined in various ways, as will now be farther detailed, so as to form and/or include a substantial number of subgenuses and/or species of compounds of Forxnula (I). It is hereby specifically contemplated that any of subgenuses and/or species of compounds of Formula (I) described below can, either in their specified form or as a eomestibly acceptable salt, be combined in an effective amount w itb a. comestible or medicinal product or precursor thereof by the processes and/or methods described elsewhere herein, or by any such other processes as would be apparent to those of ordinary skill in preparing comestible or medicinal products or precursor thereof, to form a savory or sweet flavor modified comestible or medicinal product, or a precursor thereof.

In some embodiments of the compounds of Formula (I), R* is a hydrocarbon residue that may coatain one or more heteroatoms or an inorganic residue, and R2 and R3 are each independently H or a hydrocarbon residue that may contain one or more heteroatoms; more preferably, R.*, RJ and Rl are independently selected from the group consisting of arylalkenyi, beteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl. alkenyl, cycloaikyl, cycloalkenyl, aryl, heteroaryl, -R4GH, -R4CN, -R4C02H, ~R4CQ2R5, -R4CGR5, -R4CQNR'Rs, -R4N(R')C0R6, -r4se5, -R4SOK5, -R4S02R5, -R4SOiNR5R6 and -R4N(R5)S02R<!, or optionally substituted groups thereof and preferably one ofR2 or R3 isH; wherein each R4 is independently a hydrocarbon residue that may contain one or more heteroatoms, preferably independently: selected from small (C1-C6) alkylenc or (C1-C6) alkoxyalkylene; and wherein each R5 and Rc' are independently H or a hydrocarbon residue that may contain one or more heteroatoms, preferably independently selected from small (C1-C6) alkyl or (C1-C6) alkoxyalkyl.

In many embodiments of die compounds of Formula (I), R: comprises an organic or hydrocarbon-based residue having at least three carton atoms and optionally one to 20,15, 10, 8, 7, 6, or 5 heteroatoms independently selected from oxygen, nitrogen, snlfbr, halogens, or phosphorus.

In many embodiments of the compounds of Formula (I), one of.R3 and R3 is optionally H, and one or both ofR3 andR3 comprises an organic or hydroear bon~ based residue, having at least three carbon atoms and optionally one to ten heteroatoms independently selected from oxygen, nitrogen, sulfnr, halogens, or phosphorus, ,

The compounds of Formula (I) are relatively “small molecules” as compared to many biological molecules, arid can often have a variety of limitations on their overall absolute physical size, molecular weight, and physical characteristics, so that they can be at least somewhat soluble in aqueous media, and are of appropriate size to effectively bind to die relevant heterodimeric T1R1/T1R3 orT!R2/TlR3 taste receptors, which share a common T1R3 protein subunit

While not wishing to be bound by any theory, it is believed that MSG binds to theTIR] subunit ofT!R1/TlR3 “savory” taste receptors, and several known sweeteners bind to the T1R2 subunit of7IR2/TiR3 sweet receptors. Accordingly, our unexpected and surprising discovery that the amide compounds of Formula (I) can share many overlapping physical and chemical features, and can sometimes bind to either one or'both of the savory and sweet receptors, is perhaps in retrospect reasonable and/or rational horn a chemical/ biochemical/ biological point of view.

As an example of the overlapping physical and chemical properties and/or physical/chemical limitations on die savory and/or sweet amides of Formula (I), in most embodiments of the compounds of Formula (I), the molecular weight of the compounds of Formula (I) should be less than about 800 grams per mole, or in tether related embodiments less than or equal to about 700 grams per mole, 600 grams per mole, 500 grams per ole, 450 grams per mole, 400 grams per mole, 350 grams per mole, or 300 grams per mole.

Similarly, the compounds of'Foimula (I) can have preferred ranges of molecular weight, such as for example from about 175 to about 500 grams per mole, from about 200 to about 450 grams per mole, from about 225 to about 400 grams per mole, from about 250 to about 350 grams per mole.

In a related series of embodiments, R* has between 3 and 16 carbon atoms or 4 and 14 carbon atoms or 5 and 12 carbon atoms, and 0, 1, 2,3,4, or 5 heteroatoms selected from oxygen, nitrogen, sulfur, fluorine, or chlorine, and/or at least one of R2 or R3 has been 3 and 1.6 carbon atoms and 0,1,2, 3, 4, or 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine, or chlorine; or preferably at least one ofR* orR* has between 4 and 14 carbon atoms and 0, 1,2,3, 4, or 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine; or even more preferably, at least one ofR2 or R3 has between 5 and 12 carbon atoms and 0,1,2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.

In addition to the above described general physical and chemical characteristics and/or limitations, which can be shared by the various subgenuses of the sweet and savory compounds of Formula (I), the compounds of Formula (I) can also share more specifically definable chemical structural features or chemical groups or residues, as is further described below.

For example, in some embodiments, R1, R4, and R3 can be independently selected from the group consisting of an arylalkenyl, heieroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -R4OH, ~R4OR5,-R4CN, -R4CQ2H, -R4CG2R5S ~R4CORs, ~R4SR.5, and -R4$OrR5.. and optionally substituted derivative thereof comprising 1,2, 3, or 4 carbonyl, amino groups, hydroxyl, or halogen groups, and wherein R4 and Rs are Ct-Cg hydrocarbon residues.

In further related embodiments of the amide compounds of Fonnnla (I), R’, R* and R" can be independently selected from the group consisting of an arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalky!, cycloalkenyl, heterocycle, aryl and heteroaryl groups, and optionally substituted derivatives thereof comprising 1, 2» 3 or 4 carbonyl, amino groups, hydroxyl, or chlorine, or fluorine groups. In both of the embodiments just mentioned, an alternative and preferred set of optional substituent groups would be substituents independently selected from hydroxy, fluoro, chloro, NH&amp; MHCBj, N(CH3)2, COaCHj* SEt, SCRs, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, metfaoxy, ethoxy, isopropoxy, and trifluoromethoxy substituent groups.

In many embodiments of the compounds of Formula (1), one ofR** and R3 is hydrogen and the other R2 or R5 group is an organic residue or group, For example, in many embodiments of the compounds of Formula (I), at least one or R^ and RJ is a branched or cyclic organic residue having a carbon atom directly bonded to both (a) the amide nitrogen atom and (b) two additional carbon atoms from other organic residues, which are branched or cyclic, organic residues comprising additional hydrogen atoms and up to 1 δ optional additional carbon atoms, and optionally from aero to five heteroatoms independently selected from oxygen, nitrogen, sulfur, ' fluorine, and chlorine. Such branched R2 and R3 groups include organic radicals having the formula:

wherein na and nb are independently selected from i, 2, and 3, and each R2* or Ra substituent residue is independently selected Rom hydrogen, a halogen, a hydroxy, or a carbon-containing residue optionally having from zero to five heteroatoms independently selected from oxygen, nitrogen, sulfur, and a halogen. In some such embodiments, the R‘&amp; or R&amp; are independent substituent groups, but in other embodiments one or more of the R2* or Ra radicals can be bonded together to form ring structures.

In some such embodiments of the compounds of Formula (I), at least one of the R2 and R3 is a branched alkyl radical having 5 to 12 carbon atoms, or at least one of R2 and R3 Is a cycloalkyl or cycloalkenyl ring comprising 5 to 12 ting carbon atoms. In such embodiments of R 2 and R* the branched alkyl radical or the cycloalky] or cycioaikenyl ring can be optionally substituted with 1,2,3, or 4 substituent groups independently selected from hydroxy, iluoro, chloro, NHb, NHCl-fr, N(CH;i)2, CQ2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, niethoxy, ethoxy, isopropoxy, and trifluoromethoxy. 1¾ other embodiments of the amide compounds of Formula (I)s at least one of the R2 and R.'5 is a “benzylic” radical having the structure

wherein Ar is an aromatic or heteraromatic ring such as phenyl, pyridyl, furanyl, thiofkranyi, pyrrolyl, or similar aromatic ring systems, m is 0,1,2, or 3, and each R2 is independently selected from hydroxy, fluoro, chloro, NHj, NHCH3, NfCHs)?., CQ2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and triiluGromethoxy, and each R2* substituent group can be independently selected, from the group consisting of an alkyl, aikoxy-alkyh alkenyl cydoaikenyl, cycloalkyl, ~R4OH, -R40 R5, -R*CN, -R4C02H, -R4C02Rs, -R4COR5, -R4SRs, and -R^SOaR* group.

In many embodiments of the compounds of Formula (I), at least one ofR* or R* is a CVCjo branched alkyl. These C3-Q0 branched alkyls have bees found to be highly effective R4 groups for both savory and sweet amide compounds In farther embodiments the C.3-C10 branched alkyl may optionally substituted with one or two substituents independently selected from a hydroxy, fluoro, chloro, Mi* NHCHj, NCCHjfr, CO2CH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy group.

In further embodiments of the compounds ofFomiuIa (I), at least one of R2 or R* is an α-substituted carboxylic acid or «-substituted carboxylic acid lower alkyl ester. Preferably, at least one ofR2 or Rs is an «-substituted carboxylic acid lower alkyl (especially methyl) ester, hr some such preferred, embodiments, the «* substituted carboxylic add or «-substituted carboxylic acid ester residue corresponds to feat of a naturally occurring and optically active «-amino acid or an ester thereof, or its opposite enantiomer..

Is many embodiments of the compounds of Formula (I), at least one ofR“ or R* is a 5 or 6 membered aryl or heteroaryl slug, optionally substituted with I, 2, 3 or 4 substituent groups selected from the group consistingof alkyl, alkoxyl, alkoxy-alkyi, OH, CN, C02H, CHO, COR6, C02R6sSR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl: and R6 is CvC* alkyl Preferably the aryl or heteroaryl ring is substituted with 1,2,3 or 4 substituent groups selected from the group consisting of hydroxy, fluoro, chloro, NH&amp; MHCH3, N(CH3}2, C02CH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromeihyl, methoxy, ethoxy, isopropoxy, and irifluorometboxy groups.

In some embodiments of the compounds of Formula (I), at least one of R:? or R3 is a phenyl, pyridyi, fnranyl, thiofriranyi, or pyrrolyl ring optionally substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, KHr, NHCH3, 14((31¾)¾ CCkCHs, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trif luorometfryl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy.

In many embodiments of the compounds of Formula (I), at least one of Rz or R3 is a cycloalkyl, cycloalkenyl, or saturated heterocyclic ring having 3 to 10 ring carbon atoms, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NH2, NHCHj, 14((¾)¾ COjCHj, SEt, SCH3, Ci-Q. alkyl, Ci-Cfr haloalkyl, C1-C4 alkoxy, Q-C4 haloalkoxy, hydroxy, and halogen. In some Farther embodiments, at least one ofR~ or RJ is a cyclopentyl, cyclohexyl, eycloheptyl, eyclooctyl ring, or piperidyl ring optionally substituted with 1, 2, or 3 substituents independently selected from the gronp consisting of hydroxy, fluoro, chloro, NH2, MICH* N(CH3)2, CQ2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, tniluoFomethyl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy. In some preferred embodiments, at least one of R2 or R3 is a eyclohexyl, optionally substituted with 1, 2, or 3 methyl groups. Examples of such methyl substituted eyclohexyl rings have the formula

In many embodiments of the com pounds of Formula (1), especially compounds having activity for sweet receptors, at least one of R2 or R3 is a 1 -(1,2,3,4) tetrahydronapthalene ring or an 2,3-dihydro-IH-indene ring haying the formnla:

wherein m is 0,1, 2, or 3, and each R2 can be bonded to either the aromatic or non-aromatie ring and is independently selected fr om hydroxy, fluoro, chloro, INSHj, MHCH3, N(CH3)2, CO2CH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, hifluoromethyl, meihoxy, ethoxy, isopropoxy, and frifluoromethoxy, It is to be understood that optical and/or diastereomede isomerism can occur on the cyclohexyi or cyclopeniyi rings of these substituent, and differing optical and/or diastereomers can often have at least somewhat differing biological activities.

In some embodiments at least one of ΪΓ or R3 is a 1-(1,2,3,4) tetrahydronapthaiene ring with certain preferred substitution patterns. In particular, at least one of R2 or R3 may have the formula:

wherein each R2' are independently selected than the group consisting of hydrogen, hydroxy, fmoro, chioro, MHz, MICH* N(CIR)z, COOCH3, SCII3, 8Bt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, meihoxy, ethoxy, isopropoxy, aod triiiuoromethoxy groups. Similarly, in some preferred embodiments, at least one of R2 or R3 may have the formula:

In some embodiments at least one of R2 or R3 is an ««substituted 1-(1,2,3,4) tetrahydronapthaiene ring in racemic, or optically active form, as shown below:

In many preferred embodiments of the amide compounds of Formula (I) having one or both of savory and sweet receptor agonist activity, there is a preferred subgenus of amide compounds having the following formula (II):

wherein A comprises a 5 or 6 membered ary! or heteroaryl ring; m is 0, 1, 2, 3 or 4; each Re is independently selected from alkyl, alkoxy, alkoxy-alkyl, hydioxyalkyl, OH, CN, C02H, COzR^CHO, COR6, SR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl; and R6 is Ci-Gg alkyl, and R2 can be. any of the embodiments contemplated herein above, or the like.

In some embodiments, the A grasp of Formula (II) comprises as aryl ring, i.e. it contains at least one six-membered aromatic benzene ring: The aryls include at least benzene and naptbalene rings, which may not, but in many embodiments me further sustituted with at least 1,2, or 3 R* subtituent groups independently selected from the group consisting of hydroxy, fluoro, chloro, Ml2s MHCHj, 1^(0¾)¾ COOCH3, SCHj, SEt, methyl ethyl isopropyl, vinyl, trifluororaethyl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy groups.

In some preferred embodiments, one or two of the R5 substituent groups are bonded together to form a saturated alkylenedioxy ring on an phenyl ring, as exemplified by the following preferred structures (II a) and (Ills);

wherein Rj* arid Rti>are independently hydrogen or a lower alkyl, or alternatively Ru and Rt{>are independently hydrogen or methyl, or alternatively both RJS and Rib are hydrogen.

In many embodiments of the amide compounds of Formula (II), A is heteroaryl ring, and typically a monocyclic or fused bicyclic heteroaryl ring. The fused bicycHc heteraryls are typified by the following henzofurans (Formula He) and benzothiofnrans (Formula (lid);

wherein m is 0,1, 2, or 3 and each R5 can be bonded to either the phenyl or heteroaryl rings and each R5 is independently selected from, hydroxy, Huoro, chloro, Mij, NHCH3,N(CH3)i5 CCfrCTL·, SCHj, SBt, methyl, ethyl, isopropyl, vinyl, irifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

Additional examples of fused bicyclie heteroaryls as A groups are typified by the following benzoxazole compounds'(Formula lie) and (Formula (Hi):

wherein Ria or Rm is independently hydrogen or a lower alkyl.

In many embodiments of the amide compounds of Formula (Π), A is a monocyclic heteroaryl ring. The monocyclic hetemaryls that can be used as an A group in Poxmula (H) are typified by the following structures:

wherein ra is G, ls 2, or 3, and each Rr is independently selected from, hydroxy, fluoro, chloro, NH?, NHCH3, NCCHs)?, CO2CH3, SCH* SEt, methyl, ethyl, isopropyl, vinyl, triilnoromethyl, methoxy, ethoxy, Isopropoxy, and triiluoromethoxy,

In some preferred embodiments of the compounds of Formula (Π), A is a substituted furan, tbichiran, or oxazole ring, so as to form compounds having Formulas (X!g), (Eh) and (Hi):

wherein m is 0,1,¾ or 3 and each R is independently selected from hydroxy, riuoro, chloro, NH2, hffilCHj, >h(Cii-i):;. CGaCHsjSCHs, SEt, methyl, ethyl, isopropyl, vinyl iriiluoromethyl methoxy, ethoxy, isopropoxy, and trifluoroniethoxy. la some of these embodiments, m is 1 or 2.

In many embodiments of the compounds of the various subgenuses of Formula (II) described immediately above, at least one of R2 or R3 can be a C3-C40 branched alkyl, an «-substituted carboxylic acid or an «-substituted carboxylic acid lower alley! ester; a 5 or 6 membered aryl or heteroaryl ring, optionally substituted with 1 , 2, 3 or 4 substituent groups selected from the group consisting of hydroxy, fluoxo, chloro, Mis, NHCHj, N(CH3)&amp; COiCHS;t SCH3, SBt, methyl, ethyl isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups; a cyclohexyl optionally substituted with 1,2, or 3 methyl groups; ora 1-( 1,2,3,4) tetrahydronapthalene ring or an 2,3-dihydro-lH-iadene ring having the formula:

wherein m is 0,1, 2, or 3, and each R2 canhe bonded to either the aromatic or nonaromatic ring and is independently selected from hydroxy, iluoro, chloro, hdh, MICIR, if(CHs)2, CO2CH3, SCII3, SBt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy; as were described hereinabove with respect to the general amide compounds of Formula (I).

The snbgenuses of aromatic or heteroaromatic amide compounds of Formula(II} described immediately above contain many excellent agonists of T1R1/T1R3 savory (“mnamT) taste receptors, and/or TIR2/T1R3 sweet taste receptors, at very low concentrations of the amide compound on the order of micromolar concentrations or less, and can induce a noticeable sensation of a savory rnnami flavor in humans, and/or ean serve as enhancers of the savory umami flavor of MSG, or significantly enhance the effectiveness of a variety of known sweeteners, especially saccharide based sweeteners.

Accordingly, many of the aromatic or heteroaromaiic amide compounds of Formula (11) can be utilized as savory or sweet flavoring agents or savory or sweet flavor enhancers when contacted with a wide variety of comestible products and/or compositions, or their precursors, as is described elsewhere herein.

In another subgenus of the compounds of Formula (I), the amide compound has Formula (III):

wherein A comprises a 5 or 6 membered aryl or heteroaryl ring; m is 0, 1, 2, 3 or 4; each E! is independently selected from alkyl, alkoxyl, alkoxy-alkyi, hydroxyalkyl, OH, CN, C02H, CKO, COR6, COjR6 , SH, SR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroary! and R6 is Ci-Ce alkyl; B is a 5 or 6 membered aryl or heteroaryl ling; mf is 0, 1, 2, 3 or 4; R2 is selected from the group consisting of alkyl, alkoxyl, alkoxy-alkyl, OH, CN,CG2H, CEO, COR6, COzR6iSRs, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl: and R° is Cj-Ce alkyl

In the compounds of Formula (EG), tire optional R1 and R2 substituent groups can also be independently selected from hydroxy, fluoro, chloro, NH2; ISiHCHj, N{CH3)2, COjCHjjSCHs, SBt, methyl, ethyl, isopropyl, vinyl, triflnoromethyl methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

In the compounds of Formula (Ell), both the A and B rings comprise a five or six membered aryl or heteroary! ring. For the A ting, any of the various embodiments of the A. rings recited above for the compounds of Formula (II), including phenyl and the monocyclic and bicyclic heteroaryls can be suitable. In some bieyclic embodiments. She A ring of the compounds of Formula (III) have the following structures:

wherein and R}j, are independently hydrogen or a lower alkyl

In the compounds of Formula (III), the B rings are typically an optionally substituted monocyclic five or six membered aryl or heteroaryl ring, such as a phenyl, pyridyi, foranyl, ihiofriranyi, pyrrolyf, and like monocycles. In some embodiments compounds of Formula (ΕΠ) wherein B is phenyl, he, wherein the amide compound is readily derived from an substituted aniline precursor, can in many eases be previously known chemical compounds, but we believe it has been previously unknown that such compounds can be used as very effective umami flavorant compounds, at less than mseromolar concentrations or less, see for example compound AI in Table 1 below.

Urea Compounds

Ixi another subgenus of the amide compounds ofFormula (I), the amide compound is a urea compound having the Formula (.TV):

wherein R7, R8 and R9 are each a hydrocarbon residue that may contain one or more heteroatoms or an inorganic residue, and preferably is independently selected tom. arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl and heteroaryl groups, each of which may be optionally substituted, or one ofR7 or Rs can be and often is 1L hi so;ne embodiments of the urea compounds of Formula (IV), R7 and Rs together form a heterocyclic or heteroaryl ring having 5, 6, or 7 ring atoms that may be optionally substituted with 1, 2, or 3 substituents independently selected from hydroxy, fluoro, ehloro, NHb, NHCHj, NtCH^, COOCHj, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. Examples of such urea compound can have the Formulas (IV a) and (JVb):

wherein m and n are independently 0, 1, 2, or 3, and each R1 and R? is independently selected from fluoro, ehloro, NH2, NHCH3, NfCFRjj, COjCffc, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. In such embodiments, ix is preferably 0.

In additional embodiments of the urea compounds of Formula (IV), R9 and one of R' and Rs are independently selected from arylalkenyls, heteroarylalkeuyls, arylalkyls, heteroarylalkyls, alkyls, alkoxy-alkyls, alkenyls, eycloalkyls, cycloalkenyls, aryls and heteroaryls, each of which carbon containing groups maybe optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy., fluoro, cbloro, NHj, MIC.R3, N(CHs)j.s COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, raethoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

In additional embodiments of the urea compounds ofFormula (IV), R* and one of R7 and R8 are independently selected from arylalkyl, heteroarylalkyl, alkyl, cydoalkyl, aryl, heterocycle, and heteroaryl, each of which may optionally comprise one to five heteroatoms independently selected from oxygen, nitrogen, sulfur, chlorine, and fluorine.

In additional embodiments of the urea compounds ofFormula (IV), R9 and one of R' and R8 are independently selected from alkyl, phenyl, cyclohexyl, or pyridyl, each of which may optionally comprise one to four substituents independently selected from hydroxy, fluoro, ehloro, NH2, NHCH3, N(CH3>2, CO2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In additional embodiments 0 f the urea compounds ofFormula (IV), at least one of R' and R* has one of the heteroaromatic formulas:

1 t wherein m is 0,1, 2, or 3, and each R independently selected fr om hydrogen, hydroxy, fluoro, chloro, frlHr, NHCH3, NfCife)?, COQCH3, SCH3. SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy groups. In such embodiments. R7 is preferably a C3-C; Q branched alkyl, arylalkyl or a cycloalkyl that can be optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, INHs, NHCH3, NCCHj^, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl,, trifluoromethyl, methoxy, ethoxy, isopropoxy, and irifluoromethoxy groups.

In additional embodiments of the urea compounds of Formula (IV), at least one of R' and R8 is a phenyl ring optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH2, NHCH3, Ν(ί%)ί, COOCH3, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy groups. In such embodiments, R9 is preferably a CR-iR) branched alkyl, arylalkyl, or a cycloaikyi that can be optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, Mk MHCHj, N(CH3)i, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy groups.

In additional embodiments of the urea compounds of Formula (IV), R3 is a C3-Cio branched alkyl In additional embodiments of the urea compounds ofFormula (IV), R9 has the structure

wherein B is a phenyl,, pyridyl, fruanyl, thioforanyl, pyxrole, eyclopentyfrcyclohexyl, or plperidyl ring, m is 0,1, 2, or 3, and each R* is independently selected from hydrogen, hydroxy, fluoro, chloro, NHa, NHCH3, N(CHj)a3 COOCH3, 5011¾ SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, sthoxy, asopropoxy, and trifluoromethoxy groups, and R:'a is a selected from the group consisting of an alkyl, , alkoxy-alkyl, alkenyl, eydoalkenyfrcyeloaikyl, ~R4GH, -R40 R* -R*CK -R^COzH, -R^COaR^, -R^GOR*, ~R4SRJ, and dl^SChR3 comprising 1 to 12 carbon atoms, or preferably

In another subgenus of the amide compounds of Formula (I), the amide compound is an oxalamide compound having Formula (V):

wherein E^and R·*’ are each independently selected a hydrocarbon residue that may contain one or more heteroatoms, or preferably, Ri0 and R;ai are independently selected from the group consisting of aryiaikyt, heteroarylaikyi, heterocyde-alkyl, or optionally substituted groups thereof and R20 and R40 are each independently H ora hydrocarbon residue that may contain one or more heteroatoms; preferably R20, and R40 are H or C1-C3 alkyl, or optionally substituted groups thereof More preferably R20 and R40 are H, Moreover, there can be Ο, I, 2, 3, or 4 optional substituent groups for R® and R30 independently selected from hydroxy, fluoro, chloro, NH&amp; NHCH3, N(CHi)2s COrCHajSCHs, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

In preferred embodiment of the oxalamide compounds of Formula (¥), Ri0and R30 are independently selected hydrocarbon residues having at least three carbon atoms and optionally one to ten heteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus, and wherein R2oand R40 are Independently selected fr om hydrogen and a hydrocarbon residue having at least three carbon atoms and optionally one to ten heteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus.

In many pretested embodiment of the oxalamide compounds ofFoimula (V), R20and R** are hydrogen. In such embodiments, R® and R*0 can be independently selected, from the group consisting of arylalkyls, heteroarylalkyls, eycloalkyl-alkyls, and heterocycle-alkyls comprising five to 15 carbon atoms, wherein each of R10 and R3C can optionally comprise one to one to four substituents independently selected from hydrogen, hydroxy, fluoro, chloro, Miz, NHCH3, N{CHj)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, irifiuoramethyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy groups.

In many embodiments of the oxalamide compounds of Formula (V), the oxalamide eompo?md has the Formula (Va):

wherein A andB are independently an aryl, heteroaryl, cyefoalkyl, or a heterocycle comprising 5 to 12 ring atoms; m andn are independently 0, 1, 2, 3 or 4-8; R'Asnd R40 are hydrogen, RXl is hydrogen or an alkyl or substituted alkyl residue comprising one to four carbon atoms; R60 is absent or a C<-G* alkyletie or a Ci-Cs substituted alkylene; R70 and Rg0 are Independently selected from the group consisting of hydrogen, alkyl, alkoxyl, alkoxy-alkyl, OH, SR9, halogen, CN, NGz, COzR9, COR9, COI\R9Ri0, HR9R,0: KR9CORi0, SGR9, S02R9, 50?MR9R10,14R9SO2Ri0, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; R9 and R10 are independently selected from II, CR&amp;, alkyl, Cs-Cs cyeloalkyl, and CsAR alkenyl.

In preferred embodiments of the oxalamide compounds of Formula (Va), R60 is a -CH2CR2. group, A and B are independently selected from phenyl, pyridyl, foranyl, thiofuranyl and pyrrolyl rings and R'9 and R80 are independently selected fr om hydroxy, fluoro, chloro, ASH.?, NHCK3, N{CHj)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy groups.

In some embodiments of the oxalamide compounds of Formula (Va), A and B are independently a phenyl, pyridyl, furanyl, henzofuranyl, pyrrole, benzotbiophene, piperidyl, cyclopentyl, cyelohexyl, or cycloheptyl ring m and n are independently 0, 1,2, or 3; R20and R40 are hydrogen; R50 is hydrogen or methyl; R60 is a Cj-Cs or preferably G? alkylene; R7!) and RS9 are independently selected from hydrogen, hydroxy, fluoro, chloro, MIj, MIQ-L·, K(CIl3)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyi, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.·

In many embodiments of the oxaiamide compounds ofFormula (V), the oxaiamide compound has the Formula (Vb):

wherein A is a phenyl, pyridyl, furanyl, pyrrole, piperidyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; m and n are independently 0,1, 2, or 3; R50 is hydrogen or methyl; P is 1 or 2; andR70 and R*° are independently selected from the group consisting of hydrogen, hydroxy, flaorp, chloro, NH&amp; NHCH3, N(CHs)2s COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyi, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two of R,0 together form a methylenedioxy ring.. In some embodiments of the oxaiamide compounds ofFormula (Vb), the pyridyl-R*0 radical has the structure:

In certain preferred embodiments of the amide compounds 0 f Formula (V), the oxaiamide compound has the Formula (Vc):

wherein ArJ is a substituted aryl or heteroaryl ring comprising five to 12 carbon atoms; Rw is hydrogen or methyl; n is 0,1,2, or 3; each is independently selected from the group consisting ofhydroxy, fluoro, chloro, NHj, NHCH3, N(CHs)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, hifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In some embodiments of the oxaiamide compounds ofFormula (Vc), Ar3 is a 2-, 3-, or4-mono-substituted phenyl, 2,4-, 2,3-, 2,5, 2,6, 3,5-, or 3,6-disuhstituted phenyl, 3-alkyi-4~substituted phenyl, a tri-substituted phenyl wherein the substituent groups are independently selected irons the group consisting of hydrogen, hydroxy, fluoro, ebloro, NH2, NHCHs, NfCHjJa, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyi, methoxy, ethoxy, isopropoxy, and tsriiluoromeihoxy, or two adjacent substituents together form a methylenedioxy ring on the phenyl ring, hr some embodiments of the oxaiamide compounds of Formula (Vo), Ar3 is a substituted heteroaryl ring comprising 5 to 12 carbon atoms and wherein the substituent groups are independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NH&amp; NHCH&amp; Nf'CHj'hs CQ3CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyi, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.

In certain preferred embodiments of the amide compounds of Formula (V), the oxaiamide compound has the Formula (Vd):

wherein A is a substituted srvl or heteroaryl ring comprising live to 12 carbon atoms; R50 is hydrogen or methyl; n is 0, 1,2, or 3; each R80 is independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NHj, MICH3, NCCHs)?, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyi, methoxy, ethoxy, isopropoxy, and trifluoromethoxy . Preferably, A is a phenyl, pyridyl, furanyl, pyrrole, piperidyl, cyclopentyi, cyclohexyl, or cycloheptyl ring ring optionally substituted with 1, 3, or 3 substituent groups independently selected from dm group consisting of hydrogen, hydroxy, fluoro, chloro, NHj, NHCH3, N(CHj);{, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyi, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. fc certain preferred embodiments of the amide compounds of Formula (V), the oxaiamide compound has the Formula (Ve);

wherein m and n are independently 0, 1, 2, or 3; R50 and R80 are independently ' selected from the group consisting of hydrogen, alkyl, alkoxyl, alfcoxy-alkyl, OH, SR9, halogen, CN, N02> CCh.R9, COR9, CONR9Rs0, NR9R10, NR9CORi0, SOR9, SCARP SChNR^R*0, NR^OaR*0, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heteroeyele; and R9 and Rl° are independently selected firomH, Cj-Q alkyl, C3-Cg cycloalkyl, and Cj-Q alkenyl groups. Preferably, R70 artdR80 are independently selected from the group consisting ofkydrogen, hydroxy, fluoro, chioro, NH2, NHCH3, N(CBh)2, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, Iriikoromefhyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups, Preferably, the pyridyl-R83 radical of the oxalamide compound ofFormula (Ve) has fee structure:

As can be noted by inspection of the Examples attached hereinbelow, oxalamide compounds ofFormulas (Va)-(Ve) are excellent agonists of T1R1/T3R3 savory ("umami”) taste receptors at very low concentrations on the order of micromolar concentrations or less, induce a noticeable sensation of a savory umami flavor in humans, and/or can serve as enhancers of the savory umami flavor of MSG. Accordingly, oxalamide compounds ofFormulas (Ve), (Vd) and (Ve) cats be utilized as savory flavoring agents or savory flavor enhancers when contacted with a wide variety of comestible products and/or compositions, of their precursors, as is described elsewhere herein.

Acrylamide Compounds M another subgenus of the amide compounds ofFormula (I), the amide < compound is an acrylamide compound having Formula (VI):

wheretn A is a 5 or 6 membered aryl or heteroaryl ring; m is 0,1, 2,3 or 4; each R is independently selected from alkyl, alkoxyl, alkoxy-alkyi, OH, CN, COjH, CCfrR6, CHO, COR6, SR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroasyl, and R* can be any of the various embodiments ofR* described hereinabove with respect to the amides ofFormula (1).

In some of the acrylamide compounds ofFormula (VI), A is a phenyl ring and m is 1,2,3 or 4, or preferably m is 1 or 2, and R' can be independently selected from hydrogen, hydroxy, ftuoro, chloro, NHz, NHCHs, 14((3¾)¾ CO2CH3, SEf, SCK3, methyl, ethyl, isopropyl, vinyl trifluoromethyl, methoxy, ethoxy, isopropoxy, and. trifluoromethoxy groups, hi some of the acrylamide compounds ofFormula (VI), R2 is a Ca-Cio alkyl, or an «-substituted carboxylic acid lower alkyl ester.

Many of the amide compounds of Formula (I) or its various enumerated subgenuses comprise acidic or basic groups, so that depending on the acidic or basic character (“pH”) of the comestible or medicinal compositions in which they are formulated, they may be present as salts, which are preferably coraestibiy acceptable (he. designated as generally recognized as safe, or GRAS) or pharmaceutically acceptable salts (many of which have been recognized by the Federal Food and Brag Administration),

The amide compounds of Formula (I) having acidic groups, such as carboxylic acids, will tend (at near neutral physiological pH) to be present in solution in the form of anionic carboxylates, and therefore will in preferred embodiments have an associate ccmestibly and/or pharmaceutically acceptable cation, many of which are known to those of ordinary skill in the art, Such comestibly and/or pharmaceutically acceptable cations include alkali metal cations (lithium, sodium, and potassium cations), alkaline earth metal cations (magnesium, calcium, and the like), or ammonium (NH<)+ or organically substituted ammonium cations such as (Κ-ΜΗ^Γ cations.

The amide compounds ofFormula (I) having basic substituent groups, such as amino or ni trogen containing heterocyclic groups, will tend (at neat neutral : physiological pH, or at the acidic pH common in many foods) to be present in solution in the form of cationic ammonium groups, and therefore will in preferred embodiments have an associate comestibly and/or pharmaceutically acceptable anion, many of which are known to those of ordinary skill in the art. Such comestibly and/or pharmaceutically acceptable anionic groups include the anionic form of a variety of carboxylic acids (acetates, citrates, tartrates, anionic salts of fatty acids, ei c,). halides (especially fluorides or chlorides), nitrates, and the· like.

The amide compounds ofFormuia (I).and its various subgenuses should preferably be comestibly acceptable, i.e. deemed suitable for consumption in food or drink, and should also be pharmaceutically acceptable. The typical method of demonstrating that a flavorant compound is comestibly acceptable is to have the compound tested and/or evaluated by an Expert Panel of the Flavor and Extra ct Manufacturers Association and declared as to be “Generally Recognised As Safe” (“GRAS”). The FEMA/GRAS evaluation process for flavorant compounds is complex but well known to those of ordinary skill in the food product preparation arts, as is discussed by Smith et at. in an article entitled “GRAS Flavoring Substances 21,” Food Technology, 57(5), pgs 46-S9, May 2003, the entire contents of which are hereby incorporated herein by reference.

When being evaluated in the FEMA/GRAS process, a new flavorant compound is typically tested for any adverse toxic effects on laboratory rats when fed to such rats for at least about 90 days at a concentration i0O-fold, or 1000-fold, or even higher concentrations than the proposed maximum allowable concentration of the compound in a particular category of food products being considered for approval For example, such testing of the amide compounds of the invention might involve combining the amide compound with rat chow and feeding it to laboratory rats such as Crl:CD(SD)IGS BR rats, at a concentration of about 100 railligrams/Xilogram body weighl/day for 90 days, and then sacrificing and evaluating the rats by various medical testing procedures t© show that the amide compound ofFormuia (I) causes no adverse toxic effects on the rats.

The Compounds of the Invention as Savory or Sweet Taste Enhancers

The amide compounds of Formula (I) and its various compound sub-genuses and species, as described above are intended to be savory or sweet taste flavorant compounds or flavor modifiers for comestible or medicinal products. As is apparent from the teachings and Examples herein, many compounds of Formula (I) are agonists of an hTlRi/hTlR3 “savory” receptor, or anhTlR2/hTlR3 sweet receptor, at least at relatively high amide compound concentrations, and accordingly many of the amide compounds ofFormuia (I) can have at least some utility as savory or sweet flavorants or flavor enhancers, at least at relatively high concentrations.

Nevertheless, it is preferable to use as little of such artificial flavorants as possible, so as to minimise both cost and say undesirable health side effects of administration of the compounds of Formula (I) at high concentration levels. Accordingly, it is desirable to test the compounds of Formula (1) for their effectiveness as taste receptor agonists at lower concentration levels, so as to identify the best and most effective amide compounds within the compounds of Formula (I). As was disclosed in WO 03/001876, and U.8. Patent publication US 2003-0232407 A I, and as described hereinbelow, laboratory procedures now exist for measuring the agonist activities of compounds for an hTlRi/h'TlR3 “savory” and hT!R2/bTlR3 sweet receptors. Such measurement methods typically measure an “ECso", the concentration at which the compound causes 50% activation, of the relevant receptor.

Preferably, the amide compounds of Formula (I) that are savory flavor modifiers have an EC5.3 for the hTlRl/hTlR3 receptor ofless than about 10 μΜ. More preferably, such amide compounds have an EC50 for the hTlRl/hTl R.3 receptor ofless than-about 5 μΜ, 3 μΜ, 2 μΜ, 1 μΜ, or 0.5 μΜ.

Preferably, the amide compounds of Formula (I) that are sweet flavor modifiers or sweet flavor enhancers have an ECjo for the hT!R2/hTlR3 receptor of less than about 10 μΜ. More preferably, such amide compounds have an EC50 for the hI'1R2/hTlR3 receptor ofless than about 5 μΜ, 3 μΜ, 2 μΜ, 1 μΜ, or 0.5 μΜ,

In some embodiments, the amide compounds of Formula (I) are savory flavor modulators or enhancers of the agonist activity of monosodium glutamate for an hTlKl/hTlR3 receptor. Hereinbelow is described an assay procedure for so-called ECjy ratios, i.e. for dissolving a compound of Formula (I) in water containing MSG, and measuring the degree to which the amide compound lowers the amount of MSG required to activate 50% of the available hT!R3/hTlR3 receptors. Preferably, the amide compounds of Formula (I), when dissolved in a water solution comprising about I ,«M of the amide compound will decrease the observed ECsq of monosodium glutamate for an hTIRl/hTIRS receptor expressed in an HEK293-G«15 cell line by at least 50%, i.e the amide compound will have an EC50 ratio of at least 2.0, or preferably 3.0,5.0, or 7.0.

Although no specific EC50 ratio assays for sweet enhancers have yet been developed, it is believed the amide compounds of Formula (I), and more specifically many of the amides of Formula (Π) can modulate the binding of a known sweetener such as for example sucrose, fructose, glucose, erythritol, isomalt, iactitoi, mannitol., sorbitol, xylitei, a known natural terpenoid, flavonoid, or protein sweetener, aspartame, saccharin, acesulfame-K, a cyclamate, sucralose, alitame or erythritol to an h'TlE2/hTiR3 receptor. Appropriate assays for such sweet enhancement properties can be readily developed by one of ordinary skill in the arts by using appropriate ceil lines expressing hTXR2/hT 1R3 receptors.

The above identified assays are useful in identifying the most potent of the amide, compounds of Formula (I) for savory and/or sweet taste modifier or enhancer properties, and the results of such assays are believed to correlate well with actual savory or sweet taste perception in animals and humans, but ultimately the results of the assays can be confirmed, at least for the most potent of the compounds of Formula (I), by human taste testing. Such human taste testing experiments can be well quantified and controlled by taxing the candidate compounds in aqueous solutions, as compared to control aqueous solution, or alternatively by tasting the amides of the. inventions i n actual food compost lions.

Accordingly, in order to identify the more potent of the savory taste modifiers or agents, a water solution comprising a savory flavor modifying amount of the amide compound should have a sa vory taste as judged by the majority of a panel of at least eight human taste testers.

Correspondingly, in order to identify the more potent of the savory taste enhancers, a water solution, comprising a savory .fla vor modifying amount of an amide compound of Formula (I) and 12 mM monosodium glutamate, would have, an increased savory taste as compared to a control water solution comprising 12 mM monosodium glutamate, as determined by the majority of a panel of at least eight human taste testers. Preferably, in order to identify the more potent of the savory taste enhancers, a water solution comprising a savory flavor modifying amount (preferably about 30, 10, S, or 2 ppm) of the amide compound of Formula (I) and 12 mM monosodium glutamate will have an increased savory taste as compared to a control water solution comprising 12 mM monosodium glutamate and 100 μ,Μ inosine monophosphate, as determined by the majority of a panel of at least eight human taste testers.

Similar human taste, testing procedures can be used to identify which of she compounds of Formula (I) are the more effective sweet taste agents or sweet taste enhancing agents. Preferred sweet taste modifiers of Formula (I) can be Identified when a modified comestible or medicinal product has a sweeter taste than a control comestible or medicinal product that does not comprise the amide compound, as judged by the majority of a panel of at least eight human taste testers.

Prefesred sweet taste enhancers of Formula (I.) can be identified when a water solution comprising a sweet tasting amount of a known sweetener selected from fee group consisting of sucrose, fructose, glucose, erythritol, isomalt, laetilol, mannitol, sorbitol, xylitol, a knowm natural terpenoid, flavonoid, or protein sweetener, aspartame, saccharin, acesulfame-K. cyclamate, sucralose, and alitame, and a sweet flavor modifying amount of the amide compound (preferably about 30, 10, 5, or 2 ppm) has a sweeter taste than a control water solution comprising the sweet tasting amount of the known sweetener, as judged by the majority of a panel of at least eight human taste testers. In such taste test experiments, sucrose would preferably be present at a concentration of about 6 grams/100 milliliters, a 50:50 mixture of glucose and fructose would preferably be present at a concentration of about 6 grams/100 milliliters, aspartame would preferably be present at a concentration of about 1,6 mM, acesulfame-K would preferably be present at a concentration of about 1.5 mM, cyclamate would preferably be present at a concentration of about 10 mM, sucralose would preferably be present at a concentration of about 0.4 mM, or alitame would preferably be present at a concentration of about 0.2 mM.

Flavors, flavor modifiers, flavoring agents, flavor enhancers, savory (“umami”) flavoring agents and/or flavor enhancers, according to the invention have application in foods, beverages and medicinal compositions wherein savory or sweet compounds are conventionally obliged. These compositions include compositions for human and animal consumption. This includes foods for consumption by agricultural animals, pets and zoo animals.

Those of ordinary skill in the art of preparing and selling comestible compositions (i.e edible foods or beverages, or precursors or Savor modifiers thereof) are well aware of a large variety of classes, subclasses and species of the comestible compositions, and utilize well-known and recognized terms of art to refer to those comestible compositions while endeavoring to prepare and sell various of those compositions. Such a list of terms of art is enumerated below, and it is specifically contemplated hereby that the various snbgenuses and species of the compounds of Formula (I) could be used to modify or enhance the savory and/or sweet flavors of the following list comestible compositions, either singly or in all reasonable combinations or mixtures thereof:

One or more confectioneries, chocolate confectionery, tablets, countlines, bagged selilines/sofrhnes, boxed assortments, standard boxed assortments, twist wrapped miniatures, seasonal chocolate, chocolate with toys, alfajores, other chocolate confectionery, mints, standard mints, pov/er mints, boiled sweets, pastilles, gums, jellies and chews, toffees, caramels and nougat, medicated confectionery, lollipops, liquorice, other sugar confectionery, gum, chewing gum, sugarised gang sugar-free gum, functional gum, bubble gum, bread, packaged/industriai bread, unpackaged/artisanai bread, pastries, cakes, packaged/industriai cakes, unpaekaged/artisanal cakes, cookies, chocolate coated biscnits, sandwich biscuits, filled biscuits, savoury biscuits and crackers, bread substitutes, breakfast cereals, rte cereals, family breakfast cereals, flakes, muesli, other rte cereals, children’s breakfast cereals, hot cereals, ice cream, impulse ice cream, single c portion dairy ice cream, single portion water Ice cream, multi-pack dairy ice cream, multi-pack water ice cream, take-home ice creamy take-home dairy ice cream, ice cream desserts, bulk ice cream, take-home water ice cream, frozen yoghurt, artisanal ice cream, dairy products, milk, fresh/pasteurised milk, hill fat fresh/pasteurised milk, semi skimmed fresh/pasteurised milk, long-life/uht milk, full fat long life/uht milk, semi skimmed long life/uht milk, fat-free long life/uht milk, goat milk, condensed/evaporated milk, plain condensed/evaporated milk, flavoured, functional and other condensed milk, flavoured milk drinks, dairy only flavoured milk drinks, flavoured milk drinks with Suit juice, soy milk, sour milk drinks, fermented dairy drinks, coffee v/hiteners, powder milk, flavoured powder milk drinks, cream, cheese, processed cheese, spreadable processed cheese, unspreadable processed cheese, unprocessed cheese, spreadable unprocessed cheese, hard cheese, packaged hard cheese, unpackaged hard cheese, yoghurt, plain/natural yoghurt, flavoured yoghurt, fruited yoghurt, probiotic yoghurt, drinking yoghurt, regular drinking yoghurt, probiotic chinking yoghurt, chilled and shelf- stable desserts, dairy-based desserts, soy-based desserts, chilled snacks, fromagefrais and. quark, plain frontage frais and quark, Savoured h omage frais and quark, savoury fromage frais and quark, sweet and savoury snacks, fruit snacks, chips&amp;risps, extruded snacks, tortilla/com chips, popcorn, pretzels, nuts, other sweet and savoury snacks, snack bars, granola bars, breakfast bars, energy bars, Suit bars, other snack bars, meal replacement products, shunning products, convalescence drinks, ready meals, canned ready meals, frozen ready meals, dried ready meals, chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup, canned soup, dehydrated, soup, instant soup, chilled soup, uiit soup, frozen soup, pasta, canned pasta, dried pasta, chilled/ffesh pasta, noodles, plain noodles, instant noodles, cups/bowl instant noodles, pouch instant noodles, chilled noodles, snack noodles, canned food, canned meat and meat products, canned fisb/seafood, canned vegetables, canned tomatoes, canned beaus, canned intit, canned ready meals, canned soup, canned pasta, other canned foods, d ozen food, dozen processed red meat, frozen processed poultry, frozen processed frsfr'seaiood, dozen processed vegetables, frozen meat substitutes, frozen potatoes, oven baked potato chips, other oven baked potato products, non-oven frozen potatoes, frozen bakery products, frozen desserts, d ozen ready meals, frozen pizza, frozen soup, frozen noodles, other frozen food, dried food, dessert mixes, dried ready meals, dehydrated soup, instant soup, dried pasta, plain noodles, instant noodles, cups/bowl instant noodles, pouch instant noodles, chilled food, chilled processed meats, chilled fish/seafood products, chilled processed fish, chilled coated fish, chilled smoked fish, chilled lunch, kit, chilled ready meals, chilled pizza, chilled soup, chilled/iresh pasta, chilled noodles, oils and tats, olive oil, vegetable and seed oil, cooking fats, butter, margarine, spreadable oils and fats, functional spreadable oils and fats, sauces, dressings and condiments, tonus to pastes and purees, bouillon/stoek cubes, stock cubes, gravy granules, liquid stocks and fends, herbs and spices, fejmented sauces, soy based sauces, pasta sauces, wet sauces, dry sauces/powder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low fat salad dressings, vinaigrettes, dips, pickled products, other sauces, dressings and condiments, baby food, milk formula, standard milk formula, follow-on milk formula, toddler milk formula, hypoallergenic milk formula, prepared baby food, dried baby food, other baby food, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads.

Preferably, the compounds of Formula (I) can be used to modify or enhance the savory or sweet flavor of one or more of the following sub-genuses of comestible compositions: confectioneries, bakery products, ice creams, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, or spreads, or a mixture thereof.

In general an mgestible composition will be produced that contains a sufficient amount of at least one compound within the scope of Formula (I) or its various subgenuses described hereinabove to produce a composition having the desired flavor or taste characteristics such as “savory” or “sweet” taste characteristics.

Typically at least a savory flavor modulating amount, a sweet flavor modulating amount, a savory flavoring agent amount, or a sweet flavoring agent amount, of one or more of the compounds of Formula (I) will be added to the comestible or medicinal product so that the savory or sweet flavor modined comestible or medicinal product has an increased savory and/or sweet taste as compared to the comestible or medicinal product prepared without the amide compound, as judged by human beings or animals in general, or in the case of formulations testing, as judged by a majority of a panel of at least eight human taste testers, via procedures described elsewhere herein.

The concentration of savory or sweet flavoring agent needed to modulate or improve the flavor of the comestible or medicinal product or composition will of course vary dependent on many variables, including the specific type of iagestible composition, what savory compounds are present and the concentrations thereof, and the effect of tbs particular compound on such savory compounds. As noted, a significant application of the compounds ofFormula (I) is for modulating (inducing, enhancing or inhibiting) the savory or sweet tastes or other taste properties of other natural or synthetic savory tastsnts. A broad but also low range of concentrations of the amide compounds ofFormula (I) would typically be required, Le. horn about 0.001 ppm to 100 ppm , or narrower alternative ranges from about 0.1 ppm to about 10 ppm, from about 0.01 ppm to about 30 ppm, from about 0,05 ppm to about IS ppm, from about 0.1 ppm to about S ppm, or from about 0,1 ppm to about 3 ppm.

Examples of foods and beverages wherein compounds according to the invention may be incorporated included by way of example the Wet Soup Category, the Dehydrated and Culinary Food Category, the Beverage Category, the Frozen Food Category, the Snack Food Category, and seasoning* or seasoning blends. “Wet Soup Category” means wet/liqnid soups regardless of concentration or container, including frozen Soups. For the purpose of this definition soup(s) means a food prepared from meat, poultry, fish, vegetables, grains, fruit and other ingredients, cooked in a liquid which may include visible pieces of some or all of these ingredients. It maybe clear (as a broth) or thick (as a chowder), smooth, pursed or chunky, ready-to-serve, semi-condensed or condensed and may be served hot or cold, as a first course or as the main course of a meal or as a between meal snack (sipped like a beverage). Soup may be used as an Ingredient for preparing other meal components and may range from broths (consommb) to sauces (cream or cheese-based soups), “Dehydrated and Culinary Food Category” means: (i) Cooking aid products such as: powders, granules, pastes, concentrated liquid products, including concentrated bouillon, bouillon and bouillon like products in pressed cubes, tablets or powder or granulated form, which are sold separately as a finished product or as an ingredient within a product, sauces and recipe mixes (regardless of technology); : (ii) Meal solutions products such as: dehydrated and freeze dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated ready-to-cook soups, dehydrated or ambient preparations of ready-made dishes, meals asd single serve entrees including pasta, potato and rice dishes; and (iii) Meal embellishment products such as: condiments, marinades, salad dressings, salad toppings, dips, breading, hatter mixes, shelf stable spreads, barbecue sauces, liquid recipe mixes, concentrates, sauces ox sauce mixes, including recipe mixes for salad, sold as a finished product or as an ingredient within a product, whether dehydrated, liquid or frozen. “Beverage Category* means beverages, beverage mixes and concentrates, including but not limited to, alcoholic and non-alcoholic ready to drink' and dry powdered beverages.

Other examples of foods and beverages wherein compounds according to the invention may be incorporated included by way of example carbonated and noncarbonated beverages, e,g., sodas, fruit or vegetable juices, alcoholic and nonalcoholic beverages, confectionary products, a.g.., cakes, cookies, pies, candies, chewing gums, gelatins, ice creams, sorbets, puddings, jams, jellies, salad dressings, and other condiments, cereal, and other breakfast foods, canned fruits and fruit sauces and the like.

Additionally, the subject compounds can be used in flavor preparations to be added to foods and beverages. In preferred instances the composition will comprise another flavor or taste-modifier such as a savory tastant Accordingly, in some embodiments, the inventions relate to methods for modulating the savory or sweet taste of a comestible or medicinal product comprising: a) providing at least one comestible or medicinal product, or a precursor thereof, and . b) combining the comestible or medicinal product or precursor thereof with at least a savory flavor modulating amount or a sweet flavor modulating amount of at least one non-naturaliy occurring amide compound, or a comcstxbly acceptable salt thereof, so as to form a modified comestible or medicinal product; , wherein the amide compound has the formula:

wherein the amide compound is an amide of Formula (I), or any of its various subgenuses or species compounds described herein, wherein R1, R2, and RJ can be defined in the many ways also described hereinabove.

The invention also relates to the modified comesti ble or medicinal produets produced by such processes, and similar processes for producing comestible or medicinal products well known to those of ordinary skill in. the art.

The amide compounds of Formula (!) and its various subgenuses can be combined with or applied to the comestible or medicinal products or precursor thereof in any of innumerable ways known to cooks the world over, or producers of comestible or medicinal products. For example, the amide compounds of Formula (I) could be dissolved in or dispersed in or one one of many eomestibly acceptable liquids, solids, or other carriers, such as water at neutral, acidic, or basic pH, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/f at emulsions such as milk or condensed milk, edible oils and shortenings, fatty acids, certain low molecular weight oligomers of propylene glycol, glyceryl esters of fatty acids, and dispersions or emulsions of such hydrophobic substances in aqueous media, salts such as sodium chloride, vegetable flours, solvents such as ethanol, solid edible diluents such as vegetable powders or flours, and the like, and then combined with precursors of the comestible or medicinal products, or applied directly to the comestible or medicinal products. .

Making The Amide Compounds of Formula ffj

The starting materials used in preparing the compounds of the invention, Le, the various structural subclasses and species of the amide compounds ofFormula (1) and their synthetic precursors, especially the organic carboxylic acids and benzoic acids, isocyanates, and the various amines, anilines, amino acids, etc, were often known compounds, or made by known methods of the literature, or are commercially available from various sources well known to those of ordinary skill in the art, such as for example, Sigma-Aldrich Corporation of St. Louis Missouri USA and their subsidiaries Fluka and Riedel-de Haen, at their various other worldwide offices, and other well 3mow suppliers such as Fisher Scientific, TCI America of Philadelphia PA, CheruDiv of San Diego CA, Chembridge of San Diego CA, Asinex of Moscow Russia, SPECS/BIOSPECS -of the Netherlands, Maybridge of Cornwall England, Acros, TimTec of Russia, Comgenex of South San Francisco CA and ASDI Biosciences of Newark Beleware. ,

It will be apparent to the skilled artisan that methods for preparing precursors and fimctiouaiity related to the compounds claimed hereto are generally described in the literature. The skilled artisan given the literature and this disclosure is well equipped ίο prepare any of the necessary starting materials and/or claimed compounds. In some of the Examples cited below, starting materials were not readily available, and therefore were synthesised, and the synthesis of the starting materials is therefore exemplified.

It is recognized that the skilled artisan in the art of organic chemistry can. readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification, saponIfication,nitraiions, hydrogenations, reducti ve animation and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry (3d Edition, 1.985, Wifey-Interseience, New' York], Feiser and Feiser’s Reagents for Organic Synthesis, Carey and Sundherg .Advanced Organic Chemstty and the like, the entire disclosures of which are hereby incorporated by reference in their entirieties for their teachings regarding methods for synthesising organic compounds.

The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts, Protecting Groups in Organic , Synthesis, 3ίή Ed., Mm Wiley &amp; Sons (1999),

The following abbreviations have the indicated meanings:, CH jCN — Acetonitrile CHCls = Chloroform PIC = Ν,Ν'-Piisoprepylcarbodiimide DIPEA = Diisopropylethylamine DMAP ~ 4-(dimethy!amino)-pyridine DMF” N,N -d imethylformamide EDO. = l-(3»DxmeihylaminoprGpyl}-3-ethyiearbodiimide hydrcehoride DCMDichlorOmethane ESIMS “ electron spray mass spectrometry Et3N = trieihylamine EtOAc = ethyl acetate EtOH = Ethyl Alcohol

Fmoc Nd9-fluorenyhnethoxyearbonyi·-HC1 = Hydrochloric acid H2SO4 = Sulfuric acid HOBt::: 1 -Hydroxybenzci triazole MeOH ™ Methyl Alcohol MgS04“ magnesium sulfate NaHCOj - sodium bicarbonate NaOH = Sodium Hydroxide NajSOi = Sodium Sulfate Ph = phenyl ri ~ room temperature SPOS — solid phase organic synthesis THF = tetrahydroforan TLC = thin layer chromatography

Alkyl group abbreviations Me= methyl Et™ ethyl mPr = normal propyl i-Pr = isopropyl n-Bu = normal butyl i-Bu = isobotyl i.-Bu = tertiary butyl s-Bu — secondary butyl n-Pen = normal pentyl i-Feri = isopentyl n-Hex = normal hexyl i-Hex = isohexyl

Polymer supported reagent abbreviations PS-Trisamine = Tris-(2--amrnoethy1)amine polystyrene PS 'ChloroaeetyS::: PS'NCO ~ methylisocyanate polystyrene PS-henzadehyde = PS-TsNHNHz::: tolnensuJfonyihydrazone polystyrene

Tire following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase based chemistries, including combinatorial chemistry. The skilled artisan, is thoroughly equipped to prepare the necessary and/or claimed compounds by those methods given the literature and this disclosure.

Scheme la

As shown in Scheme la, amide derivatives (1) are prepared from the coupling of acid derivatives (II) with amines (III) in the presence o fa coupling reagent such as 1-ethyl-3“(3-diinethylaminopropyl)-carbodiimide hydrochloride and a base. In Method A, a polymer supported (PS) carbodiimide is used. Method B uses a non-polymer supported carbodiimide.

Scheme lb - Alternative Method for Preparing Amides

As shown in Scheme lb, amide derivatives (I) are alternatively prepared from the coupling of add halides, esters, or anhydrides (IV) with amines (III) in the presence of a. base.

Scheme le - Synthesis of Amides Via Combinatorial Arrays

The following procedure was used and can be used to synthesize amides in combinatorial array. ® Use acetonitrile as system solvent * Weigh amines into S mL vials. * Using Tecan, dissolve amines to 100 mM in DCM/CH jCN (1:2, fiom trough). * Weigh acid into 8 mL vials, * Using Tecan, dissolve acids to 110 mM in DCM/CHsCM (1:2, from trough). * Preload 1.2 mL Greiner plate with 30 mg PSmarbodiimide resin using Peii 1400 Case Titer plate II. Use acetonitrile as the system solvent for synthesis. ® Add 200 mL (20 mmol, 1 equiv.) of amine to each well of the synthesis plates. ® Add 200 mL (22 mmol, 1,1 equ iv,) of acid to each well of the synthesis plates. * Add 110 mL (22 mmol, 1,1 equiv,) ofHQBt (0.20 M in DMF) to each well of the synthesis plates by 8-channei pipette. ® Seal plates with cap mat and shake (normal speed) at room temperature, overnight ® Load 20 mg/well PS-Trisamine resin into the synthesis plates using Titer plate loader thin-I. Adjust resin amount based on its loading, ® Add 200 mL of DCM/CHjCN to plate. ® Foil seal plates and shake (fast speed) at room temperature overnight ® Use methanol as system solvent for transfer to storage plate. ® Transfer 150 mL to the storage plate then wash 2 times with 150 mL of methanol ‘(shake slowly for 5 min.). Perform transfers horn Top in each well, (Needle heigh -2) ' ® Dry plates in Genevac. ® Make up analytical plates (2.5 mM theoretical) and submit fix analysis. ® Dilution plates made up baaed on analytical results.

Scheme 1c. Preparation of Oxalamldes

As a general procedure, one amine is allowed to react with ethyl oxalyl chloride in the presence of tertiary amine in organic solvent, such as dioxane, acetonitrile, tetrahydrofirran, tetrahydropyran. and .dimethylfermamide, at room temperature fix 0.5 -- 2 hours. Then the second amine is add»d and the suspension is heated at 80 °C using oil bath overnight or at 160 °C in a microwave reactor for 5 minutes. The reaction mixture can be subject to preparative. HFLC, or an aqueous work-up and the crude product can typically b« readily purified by reerystalization, flash coharm ebromatography, or other methods well known to those of ordinary skill in the art to afford the pure oxalamide. Y ields reported below were not optimized.

Scheme Id. Preparation oftlreas

Scheme 2 describes a method for preparation of pyrazines derivatives (VH1). For instance, reaction of substituted or unsubstituted 2,3-diaminopropiomc acids (V) with 2,3-diones (VI) under heating conditions in the presence of base yields, after acidification, the S3ibstitutgdpyraz!ne~2-carboxylic add (VII). The acid is condensed with various amines (Hi) to produce the desired amide (XIII) using the conditions shown m Scheme la.

Scheme 3

Scheme 3 describes a method for preparation of benzofuran derivatives (ΧΠ). For instance, reaction o f 2-hydroxybenzaldehydes (IX) with 2-hromo-malonic add diethyl este. (X) under heating conditions in the presence of base yields substituted henaofuran-2-carboxylic acid (XI). The acid is condensed with various amines {ITT} to produce the desired amide (Xll) using the conditions shown in Scheme la.

Scheme 4

Scheme 4 describes methods of preparation of an alkoxyalkyl amide (XX). In one method phthalic anhydride (XTTT) is heated with amino alcohol (XiV) to give the alcohol (XV) -which is then reacted with alkyl halide (XVI) in presence of a base to produce the alkoxy (XVTi). Treatment of the phtalimide (XVII} with hydrazine produce the desired amine (XV1E) that is further condensed with the add (Π) as described in scheme 1 a to provide the alkoxyalkylamide (XX). Alternatively acid (Π) is condensed with the amino alcohol (XIV) using the method describe in scheme 1 a to provide the alcohol (XEX) that is farther alkylated to give (XX).

Scheme S

X ss halide X7rs Ht alky!, alkoxyalkyl, aryl, aryl-alkyl, heieroaryl-aiky!

Xg and X::, are each independently th alkyl, alkoxyalkyl, aryialkyt and hetera

Scheme 5 describes a methods for the preparation of amide-amide (XXIV). Alkyl halide (IV) is treated with amino acid (XXI) as described in scheme lb to give the corresponding acid (XXII) that is further condensed with amine (XXIII) as described in scheme la to provide the amido amide derivative (XXTv).

Scheme 6

Scheme 6 describes a methods for the preparation ofbenzooxazole (XXVIII). Amino phenol ( XXV) can be condensed wife a variety of reagents to form the benzoxazok (XXVI) having a wide variety of substituent Xs using a method described in the literature (see e.g, J, Μσΐ Chem. 28 (1985) 1255) and/or by the method cited in Examples 39 to 4/. The benzooxazole intermediate (XXVI) is then condensed with amine (V) using the method described in scheme 1 a to give the amide (X7\VI1). Alternatively the amide (XXVII) is prepared by first condensing the amino phenol (XX V) with the amine (V) to give the aminophenol intermediate (XXViΓΠ that is further converted to the benzoxazoie (XXVH) using the various method described above.

Measuring the Biological Activity of the Compounds of The Invention

Cell based technologies and assays, such as those disclosed in WO 02/064631, andWO 03/001876, and U S, Patent Publication US 2003-0232407 A.! were used both to initially screen a wide variety of classes of compounds for agonist or antagonist activity for T1R3/T1R3 “savory” taste receptors, or T1R2/T1R3 “sweet” taste receptors feat bad been expressed in appropriate cell lines. Once initial “hits” were obtained for amide compounds in such cell lines, the same assays and also amain cell and/or receptor-based assays were used as analytical tools to measure the ability of the compounds of Formula (I' to enhance the savory taste of MSG or the sweet taste, of known sweeteners such as sucrose, fructose, and were, used to provide empirical data to guide an alterative process of synthesizing and testing structural variants of the amide compounds, in combination with occasional human taste testing of high interest compounds, so as to design, test, and identify species and genuses of compounds with increased and optimized levels of desirable biological activities.

Many embodiments of the inventions .relate to the identification of specific compounds and classes of the amide compounds of Formula (I) that modulate (increase or decrease) the activity of the T1R1/T1R3 (preferably hTlRl/hT1.R3) savory taste receptor (nmami receptor), alone or in combination with another compound that activates liTlRl/hTlR3, e.g.y MSG. Particularly, in many embodiments the invention relate to the amides of Formula (I) that modulate the activity of hTlRl/hTlR.3 (human umami receptor) in vitro and/or hi vivo. In another aspect, the invention relates to compounds drat modulate the human perception of savory (umami) taste, alone or in combination with another compound or flavorant, when added to a comestible or medicinal product or composition.

Many embodiments of the inventions relate to the identification of classes and/or species of the amide compounds of Formula (I) that modulate (increase or decrease) the activity of the T1R2/T1R3 (preferably hTlR2/hTlR3) sweet taste receptor (alone or in combination with another compound that activates IRilR2/hTIR3, or otherwise induces a sweet taste, e.g„, sucrose, glucose, fructose, and the like. Particularly, the invention relates to the amides of Formula (I) that modulate the activity 0.fhTlR2/hTlR3 (human sweet receptor) in vitro and/or in vivo, hr another aspect, the invention relates to compounds that modulate the human perception of sweet taste, alone or in combination with another compound or flavorant composition, when added to a comestible or medicinal product or composition. '

In some embodiments of the invention, it has been very unexpectedly discovered that at least some ofthe amide compounds of Formula (I) can modulate the human perception of both umami and sweet taste, alone or in combination with another compound or flavorant composition, when added to a comestible or medicinal product or composition. In Vitro hTI.Rl/hTl.FJ Umami Taste Recemor Activation. Assay hr order to identify new savory flavoring agents and enhancers, including compounds with savory agonist and enhancer activities (dual activity), the compounds of Formula (I) were screened in primary assays arid secondary assays including compound dose response and enhancement assay. In a primary assay for potential ability to modulate umami taste, amide compounds of Formula (!) that can he either savory flavoring agents in their own right or flavor enhancers of MSG are identified and scores of their activities are gives as percentage of the maximum MSG intensity (%). In compound dose response, an EQso is calculated to reflect the potency of the compound as a sa vor/ agonist or enhancer,

AnHE.K293 cell line derivative (See e.g., Chandrashekar, sted., Cell (2000) 100: 703-711) which stably expresses GcrfS and hTlRi/aTIR3 under an inducible promoter (see WO 03/001876 A2) was used to identify compounds with savory tasting properties.

Compounds covered in this document were initially selected based on their activity on the hTlRl/hTlR3rH.BK293-Gal5 cell line, Activity was determined using an automated iluorometxie. imaging assay on a FLIPR instrument (Fluorometric Intensity Platt Reader, Molecular Devices, Sunnyvale, CA) (designated FLIPR assay). Cells from one clone (designated clone T-17) were seeded into 384-well plates (at approximately 48,000 cells per well) in a medium containing Dulbecco's modified Eagle’s medium. (BMEM) supplemented with GlutaMAX (Invitrogen, Carlsbad, CA), 10% dialyzed fetal bovine serum (Invitrogen, Carlsbad, CA), 100 Units/ml Penicillin G, 100 /tg/inl Streptomycin (Invitrogen, Carlsbad, CA) and 60 pM mifepristone (to induce expression of hTlRl/hTlE.3, (see WO 03/001876 A2). 1-17 cells were grown for 48 hours at 37°€. T-17 cells were then loaded with the calcium dye F!uo-3AM (Molecular Probes, Eugene, OR), 4 μΜ in a phosphate buffered saline (D-PBS) (Invitrogen, Carlsbad, CA), for 1,5 hours at room temperature. After replacement with 25 gl D-PBS, stimulation was performed in the FLIPR instrument and at room temperature by the addition of 25 al D-PBS supplemented with different stimuli at concentrations corresponding to twice the desired final level. Receptor activity was quantised by determining the maximal fluorescence increases (using a 480 mn excitation and 535 nm emission) after normalization to basal fluorescence intensity measured before stimulation.

For dose-respouses analysis, stimuli were presented in duplicates at 10 different concentrations ranging from 1,5 nM to 30 μΜ. Activities ’were normalized to the response obtained with 60 mM monosodium glutamate, a concentration that elicits maximum receptor response. EQ&amp;s (concentration of compound that causes 50% activation of receptor) were determined using a non-linear regression algorithm, where the Hill slope, bottom asymptotes and top asymptotes were allow to vary, identical results were obtained when analyzing the dose-response data using commercially available software for nonlinear regression analysis such as GraphPad PRISM (San Diego, California).

In order to determine the dependency ofhTlR!/hT!R3 for the cell response to different stimuli, selected compounds were subjected to a similar analysis on 1-17 cells that had not been induced for receptor expression with mifepristone (designated as un-induced 1-17 cells). The un~indueed .1-17 cells d© not show any functional response in the FLIPK assay to monosodium glutamate or other savory-tasting substances. Compounds were presented to ua-induced nrnarni cells at 10 μΜ-or three times the maximum stimulation used in the dose-response analysis. Compounds covered in this document do not show any functional response when using un-indueedurnami cells in the FLFPR assay.

In some aspects of the present invention, an EQ® of lower than about 10 mM is indicative of compounds that induce T1R1/T1R3 activity and is considered a savory agonist. Preferably a savory agonist will have EC» values of less than about 1 mM; and more preferably will have EC» values -of less than about 20 μΜ, 15 μΜ, 10 μΜ, 5μΜ, 3 μΜ, 2 μΜ, 1 μΜ, 0,8 μΜ or 0.5 μΜ. Τη umami taste enhancement activity assay experiments, which produce an “EC» rado” measurement of how effectively the amide compounds of the invention enhance the savory ilavorant (typically MSG) already in a test solution.. A series of measurements of ; the dose response is ran in solutions comprising MSG alone, then a second dose response i, run with MSG in combination with predetermined amounts of a candidate compound of Formula (1) at the same time,

In this assay, increasing concentrations of monosodium glutamate (ranging from 12 μΜ to 81 mM) were presented, in duplicates, in the presence or absence of a fixed concentration of the test compound. Typical compound concentrations tested were 30 μΜ, 10 μΜ, 3 μΜ, 1 μΜ, 0.3 μΜ, 0.1, μΜ and 0,03 μΜ. The relative efficacy of compounds of Formula (I) at enhancing the receptor was determined by calculating the magnitude of a shift in the ECso for monosodium glutamate. Enhancement was defined as a ratio (ECgoR) corresponding to the EC» of monosodium glutamate, determined in the absence of the test compound, divided by the ECso of monosodium glutamate, determined in the presence of the test compound. Compounds exhibiting ECjqR > 2.Q were considered enhancers.

Stated alternatively, “EC» ratio” as compared to MSG is calculated based on the following definitions: EG» Ratio vs. MSG ~ EC.» (MSG),''EC® (MSG + [Compound)) wherein “[compound]5’ refers to the concentration of the compound of Formula (I) used to elicit (or enhance or potentiate) the MSG dose response.

It should be noted that the EC» ratio measured can depend somewhat on the concentration of the compound itself. Preferred savory enhancers would have a high ECso Ratio v&amp; MSG at a low concentration of the compound used. Preferably the EC» ratio experiments to measure umami enhancement are ran at a concentration of a compound of Formula (I) between about 10 μΜ to about §,1 μΜ, or preferably at 1.0 μΜ or 3.0 μΜ.

An EC;o ratio of greater than 1 is indicative of a compound that modulates (potentiates) hTIRl/hTIRS activity and is a savory enhancer. More preferably, the savory taste enhancer compounds of Formula (I) will have ECjo ratio values of at least 1.2, 1.5, 2,0, 3.0, 4.0, 5.0, 8,0, or 10.0, or even higher.

In one aspect, the extent of savory modulation of a particular compound is assessed based on its effect on MSG activation ©f T1R1/T1R3 in vitro. It is anticipated that similar assays can be designed using other compounds known to activate the T1RI/T1R3 receptor.

Specific compounds and generic classes of compounds that been shown to modulate hT!Rl/"nT!R.3 based on their BC«o ratios evaluated according to the above formula are identified in the detailed description of the invention, the examples, and the claims.

The procedures used for human taste testing of the umami/savery compounds of Formula (I) are reported hereinbelow. Comparable EC50 assays for activity of the compounds of Formula (I) for sweet receptor agonism and/or sweet taste perception in humans are also reported hereinbelow.

In Vitro hTlR2/hTlF3 Sweet Taste Receptor Activation Assay;

An HEK293 cell line derivative.(Chandrashekar, 1, Mueller, K.L., Boon, M.A., Adler, K., Feng, L., Gno, W, Zuker, (IS., Ryha, NJ.,. Cell 2000, 109, 703-711,) that stably expresses Gal 5 and hTiR2/hTlR3 (Li, X., Staszewski, L„ Xu, H., Burick, K„ Zoller, M.a Adler, E. Proc Nad Acad Sd US A 2002,99,4692-4696.) see also World Patent # WO 03/001876 A2) was used to identify compounds with sweet taste enhancing properties.

Compounds covered in this document were initially selected based on their activity on the hTlR2/hTlR3-HEK293-Gal 5 cell line (li, et al. vide supra). Activity was determined using an automated fluorometric imaging assay on a FLIPS, instrument (Fluorometric Intensity Plate Reader, Molecular Devices, Sunnyvale, CA) (designated FLIPR assay). Cells from one clone (designated S-9 cells) were seeded into 384-well plates (at approximately 50,000 cells per well) in a medium, containing DMEM Low Glucose (Invitrogen, Carlsbad, CA), 10% dialyzed fetal bovine serum. (Invitrogen, Carlsbad, CA), 100 Units/ml Penicillin G, and 100 pg/ml Streptomycin (Invitrogen, Carlsbad, CA) (Li, et al. vide supra) see also World Patent #WO 03/001876 A2). S-9 cells were grown for 24 hours at 37 nC. S-S1 cells were then loaded with the calcium dye Fluo-3AM (Molecular Probes, Eugene, OR), 4 μΜ in a phosphate buffered saline (D-PBS) (Invitrogen, Carlsbad, CA), for 1 hour at room temperature. After replacement with 25 μΐ D-PBS, stimulation wa; performed in the FLIPR inshuinent and at room temperature by the addition of 25 ul D~ PBS supplemented with different stimuli at concentrations corresponding to twice the desired final level. Receptor activity was quantified by determining the maximal fluorescence increases (using a 480 am excitation and 535 ran emission) after normalization to basal fluorescence intensity measured before stimulation.

For dose-responses analysis, stimuli were presented in duplicates at 10 different concentrations ranging from. 60 hM to 30 μΜ. Activities were normalised to the response obtained with 400 mM D fructose, a concentration that elicits maximum receptor response. ECSOs were determined using a non-linear regression algorithm (using a Senomyx', Inc. software), where the Hill slope, bottom asymptotes and top asymptotes were allow to vary. Identical results were obtained when analyzing the dose-response data using commercially available software for non-linear regression analysis such as GraphFad PRISM (San Diego CA).

In order to determine the dependency of hTiR2/hTlR3 for the cell response to different stimuli, selected compounds were subjected to a similar analysis on HEK293-Gaf 5 cells (not expressing the human sweet receptor). The HEK293-Gcd5 cells do not show any functional response in the FLIPR assay to D-Fructose or any other knowm sweeteners. Similarly, compounds covered in this document do not induce any functional response when using HEK293-Gad5 cells in the FLIPR assay.

EXAMPLES

The following examples are given to illustrate a variety of exemplary embodiments of the invention and are not Mended to be limiting in any manner.

For the purpose of tins document, the compounds individually disclosed in the following Examples 1-174 and corresponding Tables A-E can he ref eared in shorthand by the number of the example. For example, as shown immediately bellow, Example 1 discloses a synthesis of a particular compound (N~(heptan~4-yl)feenzo[dJ[l ,3]dioxole-5-earboxamide), and the results of experimental assays of its biological effectiveness, which compound is and can be referred to herein in shorthand form as Compound 1, Similarly, the first compound illustrated in Table A can be referred to elsewhere herein as Compound AL

To a solution of heptane-amine (8.06 ml., 54 mmol) in iriethylamine (15.3 ml·, 108 mmol) and dichloromethane (135 mL), was added, dropwise at 0°Ό, a solution of benzo[i,3]dioxole-5-carboayl chloride (10 g, 54 mmol) dissolved in dichloromethane (135 mL). The reaction mixture was stirred for 1 h. Solvent was removed under reduced pressure and the residue was dissolved, in EtOAc. The organic layer was washed successively with 1 N aq, HQ, 1 N aq, NaOH, water, brine, dried (MgSCL) and concentrated. The residue was recrystallised in EtOAc and Hexanes to afford 6.9 g of N-(heptan-4~yl)benzo[d][l,3]dioxole--5~carboxamide (48.3%) as a white solid. 5H NMR (500 MHz, CDCh) a 0.92 (t, 6H), 1.38 (m, 6H), 1.53 (m, 21¾ 4,11 (m, 1H), 5.63 (m, IM), 6.01 (s, 2H), 7.98 (d, 1H), 7.27 (s, d, 2H). MS(M+H, 264).

The compound had ECso for activation of a hTlRl/hTlR3 umami receptor expressed in an HEK293 cell line, of 0.2 μΜ5 and when present at 0.03 p.M enhanced the. effectiveness of mouosodium glutamate with an ECso ratio of 6.92,

Prepared in a similar manner to example 1 using hengo[d][l,3]dioxole“5--carbonyl chloride and 2-methylheptan-4-amine (example 2a). ‘H KMR. (500 MHz, CDCh): i> 0.93 (m, 9H); i:38(m, 5H); 1.53 (m, Hi); 1.66 (m, 1H); 4.21 (m, 1H); 5.61 (<!;. IK); 6.01 (s, 2H); 6.82 (d, 1H); 7.26 (m, 2H). MS (278, MAH) a. preparation of 2-me?hylheptam4--amine: '

To a solution of 2“methyrneptan-4-one (4,24 g, 33.07 mmol), Inmethanol (60 mL), were added ammonium acetate (25.50 g, 330,71 mmol) and sodium cyanoborohydride ( 2.08 g, 33.07 mmol), The reaction mixture was. stirred at room temperature for about 24 hours. The solvent was removed tinder reduced pressure and the residue was diluted with water and basified with 15 % NaOH aqueous and extracted with ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give S3 g of 2~methylheptan-4-amind (77%). MS (Mt-H, 130).

The compound had EC5r> for activation of a hTlRJ/hTlR3 run ami receptor expressed in an I iKK'293 cell line of 0.22 μΜ.

Prepared in a similar manner to example 1 using benzo[d][ls3]dioxGle-5-carbonyl chloride and 2-roethyihexan-3-amine (example 3a). *HMMR (500 MHz, CDC1V): δ 0.93 (m, 9H% 1.37 (m, 3H); 1.56 (xn. 1H); 1.83 (m, 1H): 4.01 (m, 1H); 5.67 (d, 1H): 6.02 (s, 211); 6.82 (d, 1H); 7.28 (m, 2H). MS (M+H, 264). a, 2-methvlhexan-3-amlne w'as prepared using the same procedure described in example 2 a starting from 2-methylhexan~3-one. Yield:40%. lH NMR. (500 MHz, COCK): i 0.86 (d, 3H); 0.91 (m, 6H); 1.20-1.29 (m,2H);1.38-l,47 (m,2H); 1.47 (s,2H); 1.58 (m, 1H); 2.51 (m, 1H). MS (M+H, 116).

The compound had ECjc for activation of a hTlRl/liTlR3 umami receptor expressed in an 1 IRK793 eel! line of 0.61 μΜ. N"(23KlimethvIcyedohexyr)himoldlil,31dioxol^5-'esit'boxamMei

2,3-dimethylcyclohexanamine (20 pmol) and benzo[d][l 53]dioxole-5-carboxylic acid (LI eg) were each dissolved in acetonitrile/dicblororoethane (200 μΐ., 2:1). PS-Carhodiimide resin (2 eg) was loaded into a 1.2 mL 96 well Greiner plate, followed hv the addition of amine and acid solutions, Hydroxybexizotriazole (l.leq) was dissolved iuDMF (100 ml.) and was added into the reaction well. The reaction was shaken overnight at room temperature. Once the reaction was completed, PS-Tiisarnine resin (1.5 eq) was added into the reaction mixture and the solution was allowed to shake overnight at room temperature. Acetonitrile (200 mL) was added into the reaction well, and the top clear solution was transferred into anewplate, The solution was evaporated to give N-(2,3-dimethylcyclohexyi)benzo[d][l ,3]dioxole-5-carboxamide, MS (Μ+Ή, 276.20).

The compound had ECso for activation of a hTIRl/kTISB umami receptor expressed in an Ι-ΙΈΚ293 cell line of 0..45 μΜ, and when present at 1 μΜ enhanced the effectiveness of monosodium glutamate with an ECso ratio of 8.4.

Prepared in a similar manner to example 1 using heua:o[d][lJ3]dioxole-5~carhouyl chloride and 5-rnethylhexan-3-amine (example 5a). Yield: 48 %. 'll N1V1R (500 MHz, CDCls): S 0.94 (m, 9H); 1.37 (t, 311); 1.45 (m,1H); 1.64 (m, 2H); 4.13 (m, 1J-I); 5.61 (d, IK); 6.01 (s, 2H); 6.82 (d, 1H); 7.27 (m, 2H). MS (M+H, 264). a. 2-methylhexail·-3-amine was prepared using the same procedure described in example 2a starting from S-meiliylhexan-P-one. Yield:54%. MS (M+H, 116).

The compound had ECso for activation of a hTlR!/hTlR3 umami receptor expressed in an KBK'293 cell line of 0.57 μΜ.

Prepared in a similar manner to example 1 using benzo[d][ls3]dioxole-5-earhouyl chloride and E>-!euciae methyl ester hydrochloride. Yield: 83 % JH NMR (500 MHz, C.DCI3): a 0.98 (m, 6H); 1.63-1.67 (m, 1H); 1.71-1,76 (m, 2H); 3.76 (s, 3H);4.83 (m5 1H), 6.03 (s, 2H); 6.38 (d, 1H); 6.83 (d, 1H); 7.32 (s, IH); 7.33 (d5 1H). MS (M+H, 294). m.p: 89-90 yC.

The compound had EC® for activation of a liTlRl/hT!R3 umami receptor expressed in an HBK293 cell line of 0,34 μΜ, and when present at 0.1 μΜ enhanced the effectiveness of monosodium glutamate with an EC® ratio of 4.9.

Prepared in a similar manner to example 4 using hengo[d][13]dioxoIe-5-carhoxylic acid and i^^Sjd-tetrahydronaphthalen-i “amine. MS (M4TI, 296.6).

The compound had EC.® for activation of a b,T!Rl,fe,TiR3 nmami receptor expressed in an HEK293 cell line of 0.71 μΜ, and when present at 0.3 μΜ enhanced the effectiveness of monosodinm glutamate with an EC® ratio of 7.S.

Prepared in a similar manner to example 4 using benxo[dj[l,3]dioxole-5“Carboxylie acid and (RJ-ammoleucinoL MS (M-s-H, 266.1)

The compound had tin ECso for acti vation of a hTlRl/hTlR3 umami receptor expressed in an HEK293 cell line of 9 μΜ, a d when present at 3 μΜ enhanced the effectiveness of monosodinm glutamate with an EC50 ratio of 2,

Example 9 IΪ feMkm.de-5~ be»3a»idl jl JMioxole-5»cari>oxvile acid

Prepared in a similar manner ίο example 4 using (R)-l~methoxy-4-methy] and peatan-2-aixnlne (example 9a). Yield: 55%. Ή NMR (500 MHz, CDClj): θ 0.95 (m, 6H); 1.43 (m, IH); 1.55 (m, IH); 1.65 (m, 1H); 3.36 (¾ 3H);3.46 (m, 2H); 4,33 (m, 1H); 6.01 (¾ 2H); 6.13 (d, IH): 6.82 (d, IH); 7.28 (m, 2H). MS (M+H.280). a. (R)-l-metlxixy-4-meth>lpent£n-2-amine

To a solution of (R)-2-(l-mellioxy-4-meihylpentari~2-yl)isoirIdoline-l:,3-dione (example 9b) ( 3.87 g, 14.84 mmol) in methanol (30 mL), was added hydrazine hydrate (0.866 ml, 17.81 nanol) and the reaction mixture was warmed up to 45 °€ for about 3 hours. The mixture was acidified with 2M HO and stirred at 45 "C for 30 min. The solution was cooled to room temperature, filtered and evaporated. The residue was taken up with 2N NaOH and extracted with ether, dried over MgS04, filtered and evaporated to give 1.51 g of (R)4~methoxy-4-meihylpentan-2~amme, Yield 77 %. 5H bSMR (500 MHz, CDClj): 3 0.91 (m, 6H ); 1.17 (m, 2H ); 1.58 (s, 2H ); 1.71 ( m, 1H ); 3,02 ( m, 1H ); 3.10 (m, 1H); 3.32 (m, 1H ); 3.35 ( s, 3H). b. iR)"2'(]."metlioxy4™methylpentan"2"y1)isoindoline'l,3'dione (R)”2“(l“hydroxy"4-methylpentan”2-yl)isoindoline"l,3 -dione (example 9c) (5,88 g, 23.87 mmol) was dissolved in dry THF (25 mL) and hexamethyl-phosphoramide (30 mL) and the solution cooled to 0 cC. Sodium hydride (60 % in mineral oil, 1.15 g, 28.65 mmol) was added and after 10 minutes iodomefhane (7.43 ml, 119.35 mmol) was added dropwise and the solution was warmed np slowly to room temperature and stirred over night. The reaction mixture was poured into ice/water, extracted with EtOAC, washed with brine, dried over MgS04, filtered and evaporated. The residue w'as purified on silica gel (20 % EtOAC in hexane) to give 3,92 g of (R)-2-(l~methaxy-4-methylpentan-2-yl)isoifldoine“ IR-diorte (63 %). e. (R)-2-(I-hydroxy-4-methylpeutan-2-yl)isomdoline-l,3-dione:

Phthalic anhydride (10.30 g, 69,55 mmol) and D-Leucinol (8,15 g, 69.55 mmol) were mixed in TKF (100 mL), the reaction mixture was heated at 85 °C and refluxed for 18 hours. After cooling to room temperature, water was added and the solution was extracted with EtOAC, the extracts were washed with 1 N HC1, water, ac. NaHCOa, water and brine, dried over MgSC.L, filtered and evaporated to give 8.1 g of(R)-2-(l-hydroxy~4-mefhylpentan-2"yl)isoindo!ise"I,3~dione (47 %). lH NMR (500 MHz, CDCL): d 0.94 ( m, 6H); 1,54 (m, 2H); 1.99 (m, IH); 3.86 (m, IH); 4.04 ( m, IH); 4.47 (m, IH); 7.72 (m, 2H); 7.83 (m, 2H).

The compound had an ECso for activation of a hT1Rl/hTlR3 umami receptor expressed in an HEK293 ceil line of 3.5 μΜ,

Prepared in a similar manner to example 4 using henzo[d][l ,31dioxole-5-carboxylic acid and (R)-methyl 2-ammo-3micthy3buianoa.te.Yieid: 50%. MS (M+H; 280.1),

The compound had an £Csc> for activation of ahTlRb'b:TlR3 uinaini receptor expressed in an HEK293 cell line of 1.16 μΜ.

N~( 1 -hyriroxy-4~methylpentan-2-yl)benzo Fd] [ 1,3]dioxole-5~carboxamide (example Ϊ la) (0.57mmol, 151 mg) was dissolved in anhydrous acetonitrile (2 mi) and 1 ml of0,45 M solution of tetrazole in acetonitrile was added u der nitrogen and stirred far 5 min. Then 0.627 (1.1 eq, 207 μ!) of dibenzyl diisopropyl phosphoroamidite was added drop wise under nitrogen. The mixture was stirred for lh. The solvent was evaporated and a crude intermediate was dissolved in DCM and washed twice with 2% potassium carbonate and brine and dried with sodium sulphate. The material was dried down and oxidized with 5 ml oftert.butylhydroperoxide (4 M solution in nonane) for 30min, Tire solvent was evaporated and the dibenzylester intermediate was purified (preparative TLC). The bertzyl groups were hydrolyzed using tdfluoroacetic acid (3 ml of a mixture of 95% TFA and 5% water, 1.5 h, rt). The final pmduct was dried down providing 69 mg (35%) of pure material, *H NMR (500 MHz, CDCR): δ 0.88-0.90 ({, 6H), 1.23-1.27 (ms 2H), 1.36-1,37 (m, IH), 1.53-1.62 (m; 2H), 3.93 (s, 1H), 3.98 (s, 1H), 4.32 (s, 1H), 5.90 (s5 2K), 6.66-6.67 (d, Hi), 6,98-6.99 (b, 2H), 7.14 (s, 2H); sJP: 5 0,51 (s). MS (M+H, 346.0). a. N-(l-hydroxy-4-methylpentmi-2-yl)benzo[dj[l,3]diQXole-5-carboxamide was prepared in a similar manner to example 4 from piperonylic add and 2-ammo-4~methyl-pentan-I-oi.

The compound had an ECse fsr activation of a hlTRl/hTVR3 umami receptor expressed in an HEK293 cell line of 10.9 μΜ.

Prepared in a similar manner to example 4 using 4-meihaxy-3~methylbenzpic add and hexan-3-amine (example 28a). ]H NMR (500 MHz, CDCI3): δ 0.94 (rn, 6H); 1.4i (rn, 4H): 1.46 (m, IH); 1,64 (m, IH); 2.24 (s, 3H); 3.87{s, 3H); 4.08 (rn, 1H); 5.69 (d, 1H); 6.83 (d, IH): 7.54 (s, 1H); 7.62 (d, IH). MS ( M+H, 250).

The compound had an EC.sq for activation of a hTlRl/hTlR3 umami receptor expressed in an HEK293 ceil line of 0.12 μΜ. carboxamide

(R)-2-(haizo[d][l:3]dioxole~6-earboxamido)-4~meihyipentanoic add (example 13a) (52 mg, 0.19 mmol) in.DMP (4 mL) and dimethyl amine (2M in Methanol, 36 pL, 2 eq) were condensed in presence of HOBt (26mg, 1 eq) and of 1 -ethyl-3-(3-dimethylammopropyl)-carbodiimide hydrochloride (44 mg, 1.2 eq) at room temperature overnight The reaction mixture was evaporated and the residue was dissolved in ethylaeetate and washed successively with saturated NaHCOj and water, dried over MgSQ filtered and evaporated to give 48.6 mg of the product (84%). The material was further purified usingRPHPLC. 5H Ή MR (500 MHz, CDCI3): δ 0.93-0.94 (d, 3H), 1.034.05 (d, 3H), 1.484.52 (m, IH), 1.59-1.63 (χη,ΙΗ), 2.98 (s, 3H), 3.14 (¾ 3M), 5.17-5.21 (m, 1H), 6.01 (s, 2H), 6.80-6.82 (d. 1H), 6.89-6,91(d, 1H)S 7,29-3.30 (d,lH), 7.33-7.35 (dd, 1H). MS (M+H; 307.2), a. (R)“2-(benzc[d][l,3]diGxole-6-carboxamido)-4-methyipentanoic add:

Prepared in a similar manner to example 1 using benzo[d][1.3]dioxole-5-carhonyl chloride and D-Leucine. Yield: 55% MS (M+H, 280.2).

The compound had an ECjo for activation of a hT!Rl/hTl.R3 umami receptor expressed in an ΙΓΒΚ293 cell line of 1.06 μΜ,

To a solution ofM-(d-hydrox>pemam2-yl)benzo[d][ly3]dioxole-5-carboxamide (example 14a) (59.8-mg, 0.23.8mm ol) in dichloromefhane (5 m:L) was added triethylamine (166 mL, 1.19 mmol). Acetyl anhydride (112.§m.L, 1.19mmol) was slowly added and the mixture was stirred under argon at ambient temperature overnight Tire solution was washed successively with a saturated solution of sodium, bicarbonate., water and brine. The organic layer was dried over anhydrous sodium, sulfate. Filtration followed by solvent removal under reduced pressure afforded 50.8 mg of 2-(benx.ojd } [ 1,3jdioxok 6-carboxainido)penty] acetate (73%). Ή NMR(CDC13): §0.95 (t 3Η» J~ 7.2 Hz), 1.43(m, 2H), 1.57(m, 2H){ 2.1 (s, 3H), 4.11(dd, 1H, /-3.5 Hz,/- 11.5 Hz), 4.27(dd, 1H,/= 3.5 Hz, J~ 11.4 Hz), 4,29 (m, 1H), 6.02 (¾ 2H), 6.1 (m, 1H), 6.82 (d, 1¾ 3 = 8.4 Hz), 7.27 (m 2H). MS (M+H, 294). a. N-(l~hydroxypentan~2-yl)benso[d][l,3]dioxole-5~carboxamide w'as prepared in a similar manner to example 4 using benzo[d][l>3]dioxole-5-carboxylic add and 2-aminopentan-l-oi, Yield: 76%. MS (M+H, 252),

The compound had an ECjo for activation of a hTlRl/hTl.R3 umami receptor expressed in an H.EK.293 eeli line of 11,9 μΜ, and when present at 3 μΜ enhanced the effectiveness of monosodium glutamate with an ECjo ratio of 4.1.

Example IS

Prepared in a similar manner to example 13 using 2~(3-pyridy'1)ethykmine and (R.)-2-(be.nzo[d][lJ3]diQxole'6"Carboxamido)-4-methylpentanoic acid (example 13a). (MSM+ 384.2) .

The compound had an ECso fcr activation of a hTlRl/hTlR3 umami receptor expressed In an HEK293 cell line of 1.7 μΜ.

yBhpn:goidiiI31dtoiotP-S“garbomtaldP

Prepared in a similar manner to example 13 using R/S propinoi and (R>2-(benzo[d][li3]dioxole“6”Carboxamido)-4-rnethylpentanoic acid (example 13a). (MS Μ-ί- 363.2) .

The compound had an ECsq for activation of a hTlRl/hTlR3 nmarni receptor expressed in an HEK293 ceil line of 3 μΜ.

Prepared in a similar manner to example 4 using 6-methylbenzo[d][R3]dioxoie~5-carboxylic acid and hepian-4-arnine.. MS (M+H, 278.67).

The compound had an ECLs for activation of a hTlRL'hT13l3 umami receptor expressedin an HEKi*?3 ceil lineof 0.11 μΜ,

N~(heptan~4~yl)-3.4~dihydroxybenzamide (example IS a) (0,5 mmol) was dissolved in toluene (1.6 mL). P-Toluenesu Ironic acidmonohydrate (0.3eq) was added to the reaction, followed by addition of acetaldehyde (2et0. The reaction was perfoimed using microwave (ISOC, 3G0W) and ran for 10 minutes. The solvent was evaporated The residue was dissolved in methanol (1 ML) and pusifiedby HPLC, Yield 20%,MS (M-f-Ii 278.10). a. N-tlieptan-4-y!)-•3,4-diliydroxyfeenzamide was prepared in a similar maimer to example 4 using 3,4-dihydroxybenzoie add and heptan-4-amine. Yield: 25%. MS (M+H. 25 2,1).

The compound had an ECL.:, for activation of a hTlRl/hTiR.3 umsmi receptor expressed in an HEK293 cell line of 0.1 μΜ, and v/hm present at 0,03 μΜ enhanced the effectiveness of monosodium glutamate with an ECjg ratio of 3.68,

Example 19

Ethyl 2-(5-( epian-4-ykarbamoyS)benzo [d] [l,3jdioxoli~2~yl)aeeiate

M-(heptan-4-yl)-3j4-dihydroxybenzam.ide (example 1 Sa) (0.29 mmol, 75 mg) was dissolved in dry acetone with 6 eq excess (242 mg) of potassium carbonate then 1.2 eq excess (36 pi) ofpropynoie acid ethyl ester was added and a.mixture was refluxed for 24 h Tlie solvent was evaporated and a solid was dissolved in dlchlorometliane and extracted with. 10% NaHCQj and water. The crude product was purified by chromatography on silici gel to give 72 mg of desired product (71 %). NMR (500 MHz, CDCh): d 0.91-0.94 (t, 6H), 1.23-1.30 (m,4H), 1.37-1.41 (4Ϊ1), 2.97-2.98 (d, 211), 3.70-3.74 (dd, 2H), 4.12-4.17 .(hi, IH), 4.2-4.24 (m, 3H), 5.61-5.64 (d, IH), 6.58-6.60 (t, 1H)S 6.79-45.81 (d. IH), 7.23 (s5 111), 7.60-7,85 (h, 1H). MS (M+H, 350.1).

Tlie compound had an EC )50 for activation of a hTlRl/hTlR3 umami receptor expressed in an HEK293 cell line of 14 μΜ. and when present at 3 pM enhanced the effectiveness of monosodium glutamate with an ECso ratio of2.5 .

Example 39

Prepared in a similar manner to example 4 using sodium. 2,2-dimethylhfmzo[dl[l,3]dioxole-5-earboxylate and 4~heptylamihe (example 20a). Yield 30%. lH NMR:6 0.92 (t, 6H, J= 7.2 Hz), 1.42 (m, 6H), 1.53 (in, 2H), 1.68 (¾ 6H), 4,12 (m, IH), 5.61(4 IH, J - 8.9 Hz), 6.72 (4 IH, J-8Hz), 7.16 (d, IH,./- 1.5 Hz), 7.22 (dd, IH, /- 1.5 Hz,/= 17 Hz). MS (M.-i-H, 292). a. Sodium 2,2-dimethylbenz.o[d][1,3]dioxole-5-earboxylate and 4-heptylamme: Ethyl 2,2-dimethylbenzo[d][l,33dioxole~ o-carboxylale (example 20b)(461mg: 2.08 mmol) was stirred in dioxane (16mL) and 1 .ON aqueous NaOH (4.16 mL) for 20 hours at room temperature. The solvent was removed under reduced pressure to afford the desired product (449mg). (M-H, 193). 'b. Ethyl 2,2~dimethylbenzo[d][L3]dioxo3e-5-carboxylate:

Ethyl 3,4-dihydroxybenzoate (910.9 mg, 5mmol) was combined with 2,2-dimethoxypropane (1.23 ml, 10 mmol) and a catalytic amount of p-toluene sulfonic acid in toluene, The mixture was heated to reflux using a Dean-Stark hap for 20 hours. After solvent removal under reduced pressure, die crude was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium bicarbonate, water, and brine. The organic layer was dried over anhydrous sodium sulfate. Purification by chromatography on silica gel using a gradient hexaneiethyl acetate, 90:10 to 75:25, afforded a white powder (539.Img, 49%). lHNMR(CDCl3): δ 1.36 (1, 3H, J~ 7.2Hz), 1.65 (s, 6H), 432 (q, 2H, J= 7.1 Hz, J” 14.2Hz), 6.74 (d, IH,d, J= 8.2Hz), 7.38 (d, Ih,ΤΙ .7 Hz), 7.61 (dd, IH, /-1.8 Hz, /- 8.3 Hz),

The compound had an ECjo for activation of a hTIRl/hTIRS umami receptor expressed in an HEK293 eeii line of 2.7 μΜ.

Prepared in a similar maimer to example 4 using 2-isopropylbenzo[d][l,3]dioxole~ S-carboxylic acid (example 21a) and 4-hepthylamine. Yield: 34%, ]H NMR(CDCh): δ 0.91 (t, 6H, J~7,2Hz), 1,04 (d, 6H, J~ 6.9 Hz), 1.40 (m, 6H), 1.43 (in,2H), 2.15 (m, 1H), 4.11 (m, 1H), 5.62 (d, 1H, /« 8.9Hz), 5.96 ( d, 1H, /= 4,4 Hz), 6.75 (d, IH, J= 8.0 Hz), 7.19 (d, 1H, J = 1.8 Hz), 7.22 (d, IH, J= 1.9 Hz), 7.23 (d, IH, J = 1.6 Hz). MS (M+H, 291). a. 2'isopropylbenzo[dj[l,33dioxole"5-carhoxylic acid: 3,4'dihydrobenzoic acid (154.12 mg, lmmol)and isobutyraldehyde (182 μΐ., 2 mmoles) were combined in toluene (3mL) and a catalytic amounts ofp-toluene sulfonic acid was added. The mixture was subjected to the microwave for 10 minutes at ISO °C with a power set at 275. The solution was filtered and evaporated to afford lOOmg ofthe desired product (48%). MS (M-H, 207)

The compound had an EC® for activation of a hHRI/hTlR3 umami receptor expressed in an HEK293 cell line of 11.5 μΜ, and when present at 3 μΜ enhanced the effectiveness of monosodium glutamate with an EC50 ratio of 2.2 . ^2-dlll«oro»N>fher>ia«~4-yi)'bea%0f.dlfl

Prepared in a similar manner to example 4 using 2,2-difluorobenzo[d][l,3]dioxole~ 5-carboxyltc acid and 4-hepthylamine. (M+H, 300.2).

The compound had an ECso for activation of a hTlRl/hTlB3 umami receptor expressed in an HEK293 cell line of 1.51 μΜ, and when present at 1 μΜ enhanced the effectiveness of monosodium glutamate with an ECso ratio of 2.87.

Prepared in a similar manner to example 4 using 2,3-DiliydrO"benzo[l,4]dioxine-6-carboxylic acid and heptan-4-amine. MS (M+H, 278,2),

The compound had an EC50 for activation of a hTlRl/hTlR3 umami receptor expressed in an HEX293 cell line of 0.49 μΜ.

Exauude 24

Prepared in a similar manner to example 4 using 2,3-Dihvdro-benzo[i djdmxme-o· carboxylic add and lieptan-4-amine. MS (M+H, 292,2),

The compound had an ECso for activation of a hTl'Rl/hT 1R3 umami receptor expressed in an HEK293 cell line of 6.4 μΜ. l:auriridura.nrr..curlKiXvHciRnronvlisutvi)anniic

Prepared in a similar manner to example 1 using henzof«ran-2~carbonyl chloride and heptan-4-amine. Yield: 73%. Ή NMR (500 MOz, CDCI3); δ 0,93 (t, 6H, /= 7.2 Hz), 1.41 (m, 8H), 3.01 (s, 3H), 4.18 (m, 1H), 6.29 (ds 1 H,J = 9.94 Hz), 7,20 (d, 1H, J= 8,62 Hz), 7,37 (m, 2H>, 7.44 (s, 1H). MS (M+H, 260)

The compound had an ECso for activation of a hTlRl/liTlR3 umami receptor expressed in an HEK293 cell line of 0,88 μΜ, and when present at 0.3 μΜ enhanced the effectiveness of monosodium, glutamate with an EC50 ratio of 2.6,

Example 26

Prepared in a similar manner to example 4 using S-methylbenzofiir'an-d-carboxylic acid (example 26a) and heptan-4-amiiie. Yield: 46%. Ή NMR (500 MHz, CDClj): δ 0.94 7.2 Hz), 1.41 (m, 10H), 2.44 (s, 1H), 4.18 (m, 1H), 6.29 (d51H,./- 8.6 Hz), 7.21 (d, 1H, /- 8.4 Hz), 7.37(m, 2H), 7.44 (s, 1H), MS (M+H, 274) a. 5-metfeylbenzoftiran-2-carboxylie acid: 2-Hydroxy-5-methylbenzaldehyde (544,2 mg, 4 mmol) was combined with diethylbromomaSonale (1 mL, 6 mmol) and potassium carbonate (1,1 g, 8 mmol) in methyl ethyl ketone (5 ml.) and the mixture was heated to reflux overnight The solvent waa removed by rotary evaporation to afford a crude oil. The oil was then taken in a 10% solution of potassium hydroxide in ethanol (10 mL) and heated to reflux for 45 minutes. The solvent was removed tinder reduced pressure and the residue was then treated with a 2.0 N solution ofEhSCH. The flee acid was then extracted with copious amounts of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Ethyl acetate removal afforded S66mg of S-Methyl-2-carboxybenzofhran (80%) as of a yellowish powder. Ή NMR (500 MHz, CD3OD): 52.44 (s, 3H), 7.30 (d, 1H, J= 8,7 Hz), 7.45 (d, 1H, /- 8.5 Hz), 7.51 (d, 2H, /- 7.5 Hz).

The compound had an BCse for activation of a liTlRl/hTlRB umami receptor expressed in an HEK293 cell line of 0,94 μΜ.

Example 27

Prepared in a similar manner to example 4 using Sunethylbenzoinran/Lcarboxylie acid (example 26a) and D -leucinemethyl ester. lH NMR (500 MHz, CDCI3): ¢0.98 (d, 3H, /- 6.26 Hz), LOO (d, 3H, /- 6.17 Hz), 1.56 (s, 3H), 1.76 (m, 3H), 2.48 (s, 3H), 3.78 (s, 3H), 4,86 (m, 1H), 6.95 (m, 1H), 7.23 (dd, 1H, /= 8.54 Hz, /= 1.55 Hz), 7,40 (m, 2H). 7.44 (dd, 1H, /= 1.72, /= 0.9 Kz). MS 304 (M-fH, 304)

The compound had an EC<o for activation of a hlTRl/hllRS nmami receptor expressed in an HEK293 cell line of 0.11 μΜ.

Prepared in a similar manner to example 4 using '5-methylben20&amp;ran-2-carboxylic (example 26a) and hexan-3~amine (example 28a) .Yield: 49%. '5H HMR (500 MHz, CDCb): §0.94 (m, 6H), 1.40-1.68 (m, 6¾ 2.36 (¾ 3H), 4.07 (m, 1H), 5.74 (d, IK, J - 8.9' Hz). 7.16 (d, 1H,J— 7.80Hz), 7.31 (dd, 1H,/ = 1.73 Hz,/ - 1.73 Hz),7.66 (d, 1H,J= 1.72 Hz). MS (M+H, 260). a. Hexan~3~amine was prepared using the same procedure described in example 2i starting bom hexan- 3-one. Yield: 58 %. Ή NMR (500 IvIHz, CDCk): 5 0.94 (m, 6H); 1.36-1,58 (m, 6H); 2.83 (m, 1H); 3.12 (¾ 2H). MS: (102, M+H).

The compound had an ECso for activation of a hTlR]/hTlR3 umami receptor expressed in anHBK293 cell line of 0.74 μΜ.

‘Prepared in a similar manner to example 4 using 5-methoxybenzob.iran~2-cafboxylic acid and hexan-3-annne (example 28a). Yield: 32%. Ή NMR (500 MHz, CDCb): δ 0.96 (m, 6H); 1.40-1.67 (m, 6.H); 3.S5 (s, 3H); 4.09 (in, 1H); 6,28 (d, 1H); 7.01 (dd, Hi); 7.08 (d, 1H); 7.38 (rn, 2H). MS (276, M+H).

The compound had an EC*g for activation of a h'TI RUh I IR3 nmami receptor expressed in an HBK293 ceil line of 0.4 μΜ.

Prepared in a similar manner to example 4 using 5-metlioxybenzofiiran-2-carboxyKc acid and (R)~methyl 2-amino-3-cyciohexy1propanoate, Yield: 45%. MS (M+H, 260.3).

The compound had an ECso for activation of a liTlRi/hTlRB uni ami receptor expressed in an HEK293 cell line of 1.14 μΜ.

Prepared in a similar manner to example 4 using 5-niethoxybenzoferan-2--carboxylic add and 5-methylhexan-3-amme (example 5a). Yield: 67% lH NMR (500 MHz, CDCls): 6 0.96 (m, 9H); i .39-1.52 (m, 3H); 1.66 (m, 2H); 3.85 (s, 3H); 4.17 (m, 1H); 6.24 (d, 1H); 7.01 (dd, 1H), 7.0S (d, 1H); 7.38 (ms 2H). MS ( 290, M+H).

The compound had an ECst> for activation of a hTIRl/hTlE.3 nmami receptor expressed in an ΗΈΚ293 cell line of 1.04 μΜ. carboxanndehxmtamnde

Prepared in a similar manner to example 4 using 5-chlorohenzofuran-2-carboxylie acid and Ddeucine methyl ester. MS (M+H, 324),

The compound had an EC50 for activation of a hTXRl/hTIR3 utnanii receptor expressed in an HEK293 cell line of0.82 μΜ.

Rxamnk; 3¾

Prepared in a similar manner to example 4 using 3-methylbeniroftran-2-carboxylic acid and D-leucine methyl ester, MS CM · FT, 304),

The compound had an EC'sq for activation o f a hTlRl/hTlR3 umami receptor expressed in an HEK293 cell line of L18 μΜ.

Prepared in a similar manner to example 4 using beneo[bjthiophene~2~carboxylic acid and 4~hepthylamine. MS (M+H, 276),

The compound had air EC50 for activation of a ETlRl/hTlRS umami receptor expressed in an HEK293 cell line of 0,21 μΜ. teaamla 35 N-fheritau-4-v1)-lH-indole-2-earhoxamide

Prepared in a similar maimer to example 4 using lH-indole-2-carboxyhc acid and 4-hepthylamine. MS (M+H, 25S>),

The compound had an ECso for activation of a hT!Rl/h.TlR3 rnnsmi receptor expressed in an HEK293 cell line of 6.8 μΜ,

Prepared in a similar manner to example 4 using 5-Methyl· lH-indoIe-2-carboxylic acid and D-leueine methyl ester. Yield: 50%. 5ΗΝΜΚ (500 MHz, CDClj): S098(d, 3H, J~ 6.3'Hs), 1,0'0(d, 3H, /= 6.1 Hz.), 2,44 (s, 3H), 3.784(s, 3H), 4.8?(m, 1H), 6.56 (d, 1H, / = 8.39 Hz), 6.85 (dd, 1H, /=1.94 Hz, /= 0.68 Hz), 7.12 (dd, 1H, /= 8.46 Hz, /- 1.55 Hz), 7.31(d, 1H, J= 8.45 Hz), 7,42 (s, 1H).. MS (MH+, 303).

Tire compound had an ECjo for activation of a hTlRl/hTlR3 uroami receptor expressed in an HEK293 cell line of 6.6 pM.

Prepared in a similar manner to example 4 using l-metliyhlH-indole-^-earboxylic acid and 4-hepthylamine. Yield 45%. lHNMR (500 MHz, CDClj): δ 0.95 (t, 6H. /= 7,2 Hz), 1.46 (m, 4H), 1.57 (m, 4H), 4,05 (s, 3H), 4.15 (m, 1H), 5.85 (d, 1H), 6.80 (s, 1H), 7.H (t, 1H,/ = 7.4Hz),7,31 (t, 1H,/= 7.5Hz),7,38(d, 1H,/=8.4Hz), 7.62 (d, IB,/ = 8 Hz). MS (Μ+H, 273).

The compouadhad an ECso for activation of a hTlRl/hTlK3 umami receptor expressed in anHEK293 cell line of 1,79 uM.

Prepared in a similar manner to example 4 using lH-bsB2o[d]iirfMazQle»5 -carboxylic acid and 4-hepthylamine. Yield: 80%. Ή NMR (500 MHz, CDCh): δ 0.94 (t, 6H, J- 72 Hz), 1.42 (m, 6H), 1,57 (m, 211), 4,21 (m, 1H). 6.18 (m, 1H), 7.64 (m, 2H)S 8.16 (m, 1H). 8,28 (s, 1H). MS (M+H, 260).

The compound had an ECso for activation of a hTIRl/hTlR3 umami receptor expressed in an HEK'293 cell line of 18.6 μΜ.

ExuBmfeM

Prepared in a similar manner to example 4 using benzooxazoI-5-ear boxy lie add (Example 39a) and 4~hepiylamme. lHNMR (500 MHz. CDClj): P 8.16 (d, J~ 5.4 Hz, 1H) 7.89 (d, J= 8.6 Hz, 1H), 7-04 (d, J = 8.6 Hz, 1H),5.82 (d, ,/= 8.6 Hz, 1H) 4.10-4.22 (m, 1H), 1,58-1.62 (m, 4H), 1.40-1,49 (m, 4H), 0.95 (t, J = 7.2 Hz, 6H); ESTMS: 261 (Μ*!!), a. benzooxazol--5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (500 mg, 3.26 mmol) and trimethyl orthoformate (5 inL) was heated at 65°C for 2 h under argon. The reaction mixture was cooled to room temperature, filtered and washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a white solid (78 mg, 15%): :HNMR (500 MHz, CDCI3): 5 8.57 (d, J= 1.5 Hz, :111., 8,20 (dd5J= 8,4, 1.8 Hz, 1H), 8.20 (s, 1H), 7.67 (6,./=9.0¾ 1H).MS (M+H, 164).

The compound had an ECjy for activation of a hTIRl/hTIRS umami receptor expressed in an HEK.293 cell line of 1.91 μΜ. 2-MetlxvI-»l>efeo^a^ole"S~eayt>Qm'lfe add Cl -om-Wj-bti tylVainMe

Prepared in a similar manner to example 4 starling from 2 -methyl henzooxazol-5-earboxyhc add (example 40) and 4-heptylamine. :H NMR (500 MHz, CDClj) δ 8.00 (d, J = 1.6 Hz, 1H), 7.77 (d, /= 8,5, 1.6 Hz, IH), 7.50 (d, J- 8.5 Hz, 111),5.79 (d, /= 8.9 Hz, lHforNH) 4.10-4.22 (m, M), 2.66 (s, 3H), 1.58-1.65 (m, 4H), 1.38-1.55 (m,4H), 0.94 (t, /= 7.2 Hz, 6E); MS(APCI, M+l): 275.2. a, 2-methyl henzooxazoI-S-carhoxylic add: A. mixture of 3-amino-4-hydroxybenzoic add (1.5 g, 9.79 mmol) and irimethyl orthoacefate (15 mL, large excess) was heated at 65 qC for 5 hrs under argon. The reaction mixture was cooled to room temperature, filtered, washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a yellow solid (1.4 g, 80%); Ή NMR (500 MHz , CD3QD) δ 8.26 (d, J- 1.7 Hz, IH), 8.07 (dd, /= 8,5,1.6 Hz., IH), 7.67 (d, /=8..2 Hz, IH), 2.67 <s, IH); MS(APC1, M+l); 178.1.0.

The compound had an EC so for activation of a hTlKf/hTlR3 umami raeeptor expressed in anHEK293 cell line of 0.33 μΜ. .

A mixture of 3 -mrmo-4-hydfoxy-N-(l -propylbutyl)benzamide (example 41 a) and trimethyl orthopropyrate was heated at 65 °C for 5 hr under Nj. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified on. silica gel via Preparati.ve-TLC (3% MeOH in CHjClj) to afford the product as a white solid (42 mg, 73%); mp 107-108 °C; MS(APCI, M+l): 289.10. a. 3~3nhne-4-hydroxy~N~( l~propylbutyl)benzamide was prepared in a similar manner to example 4 using 3-Amino-4~hydroxybenzoic acid and 4-heptylamine. Yield 57 %,iH NMR (500 MHz, CDC13): δ 0.93 (t, 6H); 1.26-1.51 (m, 8H); 4.05) (m, IK); 6.74 (m, ffi); 7.05 (s, ill); 7.43 (m, 2H); 7.77 (m, 2HJ.MS: ( 251, M+H)-

The compound had an ECjo f«r activation of a hTlRl/hTlR3 umami receptor expressed m anHEEK293 cell line of 0,68 μΜ.

, Prepared in a similar manner to example 41 using 3-amiuo-4-hydroxy-N-( 1-propy1butyl)benzamide (example 4aa) and tetrametliylortliocarbonate. Yield; 60%. mp 137-138 °C; MS (M+H, 291.10). . The compound had an EC50 for activation of a liTIRI/liTIRS umami receptor expressed in an ΗΈΗ293 cell line of 0.69 μΜ.

Example 43

Prepared in a similar manner to example 41 using 3-anrino-4~hydroxy~N-(1-propylbatyBhenzamide (example 41a) and tetraeihoxymetliane: mp 128-129 °C; MS (M+H, 305.1).

The compound had an ECjo for activation of a hTl Rl/hTlR3 umami receptor expressed in anHEK293 cell line of 5 μΜ.

To a solution ofN-(HeptaQ-4-yl>2-(inercapt©)feenzo[rf3oxazole"5-carfeoxajnide (example 44a) (50m g, 0.17 mmol) in DMF (3mL) at 0 °C was added K2OO.3 (29 mg. 0.17 mmol) and Mel (29 mg, 0.20). The resulting reaction mixture was heated at 80 f;C overnight The solvent was removed under reduced pressure. The residue was diluted with diehloromethane and washed with water, dried (NajSOO, filtered, concentrated in vacuo, purified via FTLC (15% EtOAc in hexanes) to afibrd the product as a white solid (50 mg, 96%)·. mp 113-114 “C: ’H NMR (500 MHz, CDCI3) 8 7.94 (d, /= 1,8 Hz, IH), 7.73 (dd, J = 8.5, 1.6 Hz, 1H), 7.46 (d, /= 8.4 Hz, 1H), 5.76 ¢6,/= 8.4 Hz, 1H), 4.15-4.25 (m, 1H), 2.77 (s, BIT), 1.58-1.65 (m,2H), 1.1.38-1.55 (m, 6H), 0.94 (t,/=7,2 Hz, 6H); MS(APCI, M-l·): 307.2. a, N-(Hepian-4-yl)-2-(mercapto)benzo[/]oxazole-5-carboxamide: To a solution 3-amino-4-hydroxy-N--(l-propylbutyl)henzamide (example 41a) (250 mg, 1.0 mmol) in EtOH was added KSCSOEt (160 mg, LG mmol). The resulting reaction mixture was heated at 80 °C overnight The solvent 'was removed under reduced pressure. And the residue was taken up in water. The resulting mixture was acidified with HOAc to pH - 5 and then filtered. The residue was washed with ’water to afford the product as a white solid (160 mg, 55%). MS (M+H, 293.1).

The compound had an EC50 for activation of a hTlRI/hTlR3 umami receptor expressed in an HBK293 cell line of 3.1 pM. CMPramethvI benzooxazoTS-carboxvlig acid (1 -sm>s>vi-b u tvfiamide

Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-{'l-propy!buiyl)benzamtde (example 41a) and dimethyl cMaro-orthoacetate. Yield: 65%. mp 108.5-109 °C. MS (M+H, 309.05).

The compound had an ECso for activation of a hTlRl/hTiR3 umami receptor expressed in an HBK293 cell line of 0,23 μΜ.

Example 46 IPMetlsyi-feimooxagok-thgarhoadic acid il-orouvl-batyIVamsde

Prepared in a similar maimer to example 4 using 2-methyl benzooxazol-6-carboxylic acid (example 46a) and 4-heptylamme Yield 50%: !H NMR (500 Mils , . CDjOD) δ 8.19 (d,J- i.4 Hz, 1H), 8.05 (dd, J- 8.3, 1.5 Hz, 1H), 7.63 (d, /= 8.2 Hz, TH), 2.68 (s, 1H); MS (M+l. 178.10). a. 2-methyl benzooxazol~6-carboxyltc acid was prepared in a similar manner to example 40a from 4-amino-3-'hydroxybenzoic acid (S0%): NMR (500 MHz , CD3OD) 5 8.19 (d, / = 1.4Hz, 1H), 8.05 (dd,/= 8.3,1.5 Hz, 1H),7.63 (d,/= 8.2 Hz, 1¾ 2.68(s, 1H); MS (M+H, 178.10).

The compound had an ECso tor activation of a hTlRl/bTIK3 umami receptor expressed in an HEK293 cell line of 2.1 μΜ. , ^-Clirtornmefei-feenzQo.xa'znk'-d-earhPXYiie add j'1-nroovl-hn tvlbamide

Prepared in a similar manner to example 41 using 3"amino-4-hydroxy-N-(l-propylhutyl)be,nzarrude (example 47a) and dimethyl chloro-orthoacetate. The product was obtained as awhile solid (45 mg, 73%): mp 137.0-137.5 °C; MS (M+H, 309,05. a. 3-amino-4-hydroxy-N-(l-propyIhutyl)henzamide was prepared in a similar maimer to example 41a from 4-ammo-3-hydroxybenzoic acid. Yield: 50%, 5ΗΗΜΕ_ (500 MHz, CDCI3): δ 0.91 (t, 6H); 1.41 (m, 6H); 1.54 (m, 2H); 4.13 (m, 1H); 5.81 (d, 1H); 6.63 (A im mv 7 eo η, rm x/fc-rocs

The. compound had an ECjo fcr activation of a hTlRl/h'f'l R3 umatni receptor expressed in an HEK293 cell line of 0.45 μΜ. ..___—____* *.. n.........-.

Preaparsd in a similar manner as example 4 using 4-methyd-3“(meihylibio)beiizoic acid (example 48a) and 4-heptylamine. Yield; 50%. *H NMR (500 MHz, CDCh): δ 0.93 (t 6H, /= 7.2 Hz), 1.40-1.41 (m, 8H), 2.35 (¾ 3H), 2.51 ( s, 1H), 4.15 (m, Hi), 5.75 (d, 1H,/ === 8.5 Hz). 7.15 (ds 1H, J= 7.8 Hz), 7.31 (d, 1H, /= 7.8 Hz), 7.65 (d, 1H, J= 1.5 Hz). MS (MAH, 280). a. 4-meth3d-3-(inefhyltli3o)beiizoic acid; 3-Anj3no-4-meihylbeozoic acid was suspended in ice- water (55 itiL), and concentrated HCi (8.56 mL) was slowly added. An aqueous solution of sodium nitrite (2.4 g in 5.5 mL) was added to the suspension over a period of 15 minutes and the mixture was stined fcr another 15 minutes. Then, an aqueous solution of sodium acetate (9.31 g in 18 ml.) was added dropwise, The reaction was allowed to proceed for 45 min. A heavy orange precipitate was obtained. The precipitate was filtered off and washed with small portions of ice-cold water. The solid was combined with a solution of potassium xanthogenate (11.93 g) and potassium carbonate (8.22 g) in 250 mL of water. The reaction vessel was placed in a preheated oil hath at 70°C and the mixture was stirred for 25 minutes. The reddish solution was taken out of the bath and stirred for 15 minutes or until the temperature reached 30υ€, Sodium hydroxide (0.782 g) was added and stirred to dissolution. Dimethylsulfate (5.70 mL) was added. The mixture was stirred for 1 hour at room temperature then briefly refluxed. Solvent removal under reduced pressure yielded an orange solid. The solid was treated with a 2.0 N solution of H2SO4 and extracted with EtOAc. The extracts were washed with water then dried over anhydrous MgSCL· The solvent was removed under reduced pressure to give a reddish crude solid. The solid was adsorbed on silica gel and purified by column chromatography (gradient 5 to 50% ethyl acetate in hexane) to give 4mieiiiyl-3-(methyltbIo)hen?.oic acid as a pale yellow powder (2 g). SHNMR (500 MHz, CDG3): 3 2.39 (s. 3H), 2.54 (s, 3H), 7.24 (d. 1.Η» J= 7.8 Hz), 7.79 (d, 1H, /= 7.8 Hz), 7,86 (d, 1H, J= 1.5 Hz).

The compound had an ECjy for activation of a hTlRI/ihXTRd umami receptor expressed in an HEK293 cel! line of 0,21 μΜ.

Prepared in a similar maimer to example 4 using 3--methy1-4-(methylthio)feenzoie acid (example 48a) and D Leucine methyl ester. Yield: 4S%. 5H NMR (500 MHz, CDCls): d 0.97 (d, 3H, J= 6.36Hz), 0.99 (d, 3H, 6.1 Hz), 1.644.77 (m, 2H),2.36 (s, 3H), 2.51(s 3H), 3,77 (s, 3H), 4.85(m, 1H), 6.50 (d, 1H, /- 8.10 Hz), 7.18 (d, 1H, /-7.83 Hz), 7.38 (dd, 1H, /- 7.77 Hz, /- 1.78Hz), 7.65 (d, 1H, /= 1.65 Hz). MS (M+H, 310).

The compound had an ECso for activation of a hTlRl/hTlR3 umami receptor expressed in an HEK293 cell line of 0.1 μΜ.

Prepared in a similar manner to example 4 using 4-(methylthio)benzoie acid and D Leucine methyl ester. MS (M+H, 296). .

The compound had an KC50 fix activation of a hTIRI/hTIRS urnami receptor expressed in an HEK293 cell line of 0,16 μΜ.

ExumpIeSl

Prepared in a similar manner to example 4 using 3-me&amp;yI~4-(methyltMo)benzoic acid (example 51a) and 4-hepthykrnine. NMR (.500 MHz, CDCL): 6 0.93 (t, 6H); 1.37- 1.46 (in, 6H); 1.54-1.56 (m5 2H); 2.35 (s, 3H); 2.49 (s, 3H); 4.17 (m, 1H); 5.73 (d, 1H); 7,14 (d, 1H); 7.52 (¾ }H);7.58 (d,1H). MS (280, M+H) m.p: 129-131 !>C. a. 3-met3iyl--4-{nieihyltMo)benzoic acid was prepared using the same procedure described in example. 48a starting from B-Amino-d-methylfeenzmc acid. Yield 30 %. Ή NMR (500 MHz, CDCb): δ 2.36 (s, 3R); 2.53 (3,3H); 7.17 (d, 1H); 7.85 (s, ill); 7.93 (d, 1H).

The compound .had an ECjq Bar activation of a hTIRl/hTIRS umami receptor expressed in an HEK293 cell line of 0.12 μΜ.

Prepared in a similar manner as described in example 4 using 4-methoxy-3-methy!benzoic acid and 2-methyS-4-heptanamine (example 2a), Yield; 45%.¾ NMR (500 MHz, CdCR): o 0.93 (m, 9H); L39 (m, 5H); 1,53 (rn. 1H); 1.67 (nvlH); 2.24 (¾ 3H); 3.86 (s, 3H); 4.23 (m, 1H); 5.64 (d, 1H); 6.82 (d, 1H); 7.54 (s, 1H): 7.61 (d, 1H). MS (2785 M+H).

The compound had an EC50 for activation of a hTIRl/hTIRS umami receptor expressed in an HEK293 cell line of 0.1 μΜ. ,

Prepared in a similar manner to example 4 using 4-meihoxy-3-methylbenzoic acid and 5-metbyibexan-3-amine (example 5a). lH NMR (500 MHz, CDCb); δ 0.94 (m, 9H); 1.38 (m, 2H); 1.47 (m, 1H); 1.65 (ms 2H); 2.24 (s, 3H); 3.86 (s, 3H); 4.16 (m, 1H); 5.65 (d, 1H); 6.83 (d, 1H); 7.54 (s, 1H); 7.61 (d, 1H). MS ( 264, M+H).

The compound had an EG® for activation of a hTIRl/hTIRS umami receptor expressed in an HEK293 cell line of 0.09 μΜ,

Prepared in a similar manner to example 4 using B-methyl-4-methoxy-benzoic acid and i-(4-methoxyphenyl)butan-l-amine (example 54a).Yield 52%, Ή NMR(5GG MHz, CDCij): δ 0.94 (t: 3H); 1.31-1.41 (m, 2H); 1.82-1.92 (m, 2Hi; 2.22 (s,3H); 3.79 (s, 3H);3.86 (s, 31% 5.11 (m, 1H); 6.14 (d, 1H); 6.81 (d, 1H); 6,88 (d, 2H). 7.28 (d, 2H); 7,53 (¾ IH); 7,61 (4 1H). MS (328, M+H). a, 1 -(4-methoxyphenyl)butan-l-amine was prepared as described m example 2a from l-(4-methoxyphenyl)butan-l-one, Yield 90%. MS (M+H, 180).

The compound had an EC;o fa· activation of a hTlRI/hTlR3 nmami receptor expressed in an HEK293 cell line of 3.14 μΜ·

Example 55 yihmfvhbenxamkle

Prepared in a similar manner to example 4 using 4-meihoxy-3~methylbenzoie acid and 3-methyl4~(3-rnethyl~[i,2,4]oxadiazol-5~yI)“butySamine (Example 55a), MS (M+H, 318). a, (R)-3-methyi-l-(3-meihyl~l32,4-oxadiazo!-5-yl)butan~!-amme: Boc-D-Leu-OH (0.23 g, 1 mmol) was treated with N-hydroxyaceiamidine (74 mg, 1 eq) and DIG (155 uL, 1 ep) in dioxane (2 mL) at room temperature overnight. Another portion of DIC (1 equiv) was added and the reaction mixture was heated at 110°C for 4 hours. After removal of the solvent, the residue was treated with 50% TFA/DCM (2 mL) for 1 b and then the solvent was evaporated. The crude mixture was purified by preparative HPLC (018 column, MeOH-HzO mobile phase and formic acid as modifier) to give 75 mg of the amine (4584 yield). ‘HNMR (500 MHz, CDCI3): δ 0.95 (d, 3H), 0.99 (4 3H), 1.70-1.78 (1¾ 1H), 1.921.98 (m. 2H), 2,39 (s, 3H), 3,50 (b, 2H, NH2), 4.65 (1, 1H). MS (M+H, 170).

The compound had an EC.® for activation of a hTlRl/hTlR3 umami receptor expressed in an HEK2.93 cell line of 5.4 μΜ.

Example S6

Prepared in a similar manner as example 4 using 4-ethoxy-3-methyl benzoic acid (example 56a) and 4-heptyIamme. Yield: 75%. *H NMR (500 MHz, CDCK): δ 0.93 (t, 6H) 1.37-1.45 (m, 6H); 1.53-1.59 (m, 2H); 2.24 (s, 3H); 4.07 (q, 2H); 4.15 (m, lH)j 5.67 (d, 1H); 6,80 (d, 1H); 7.54 (¾ 1H); 7.58 (d, 1H). MS (278, Mill) a, 4-ethoxy-3-methyl benzoic acid: 4-hydroxy-3-methyl benzoic add (10 g) was dissolved in DMF (400 mL) followed by the addition of sodium carbonate (3eq). Ethyl iodide (3eq) was dissolved in DM'F (50 mL) was added drop-wise to die reaction mixture and the solution was stirred overnight. After the reaction was completed, the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was isolated and evaporated. The residue was dissolved in 200mL methauol/water (3:1). Lithium hydroxide (3eq) was added and allowed to stir overnight Upon the completion of hydrolysis, the solvent was removed and the product was crystallized using ethyl acetale/hexane mixture to give 8.2 g of 4-ethoxy~3~meihyi benzoic acid. Yield: 70%, MS (M-H, 179.20).

The compound bad anECso for activation of a IiTlRl/liTlRe umaroi receptor expressed in an HEK293 cell line of 0.17 μΜ.

Prepared m a similar maimer as example 4 using 4-ethoxy-3-methyl benzoic acid (example 56a) and l-metboxypentan-2-amiue (example 57a), Yield: 33%. MS (M+Hs 280,1). a. l-methoxypenian-2-amitie was prepared in a similar manner to example 9a iron 2--(1-ιη6ΐ1ιοχ)φ6ηί^ΐ'2-γ1)ί3θίηάοϋβ6453“άίοη6 (example 57b), Yield 67%. £H NMR (500 MHz, OXla): § 0 91 (t, 3H); 1.24 -1.45 (m, 4H); 1.52 (s, 2H); 2.94 (m, 1H); 3,12 (t, 1H ): 3.33 ( m, 1H ); 3.35 ( s, 3H ). b. 2-(1 -metlioxyper:taiv2-yl)isoindoline-l,3~dione was prepared in a similar manner to example 9b from 2-(l-liydroxypentan"2-yl)isoindoliiie-lJ3-dione (example 5?c)„ Yield: 82%. lH NMR (500 MHa, CDCb): δ 0,91 (t, 3H ); 1.32 (m, 2H): 1.64 (m, 1H); 2,03 (m, 1H); 3.31 (s, 3H); 3.54 ( m. HI); 3.98 (t, 1H); 4.50 (m, 1H ); 7.70 (m, 2H); 7.82 (m, 2H). " c. 2-il-hydroxypentan-2-yl)isoiniIoline-I,3~diane was prepared in a similar manner to example 9c using isobenzoim'an~!,3~dione and 2-aminopentan-l-ol. Yield 62%. 5H NME. (500 MKa, CDCh) o 0.92(ί,3H); 1.33 (in,2H); 1.76 (m, 1H); 1.95 (si, 1H ); 3.88 (m, 1H); 4.06 (m, 1H >; 4.39 (m, 1H ); 7.72 (m, 2H); 7.83 (m, 2H).

The compound bad an EC5.3 for activation of a hTlRl/hT'lR3 urn ami receptor expressed in an HEK293 cell line of 0.69 μΜ.

Prepared in a similar manner as described in example 4 using d-hydroxy-S-metbvl benxoie acid and 4~hepiylamine. MS (M-fH, 250.2).

The compound had an EC53 for activation of a hTIRI/hXlJG nmami receptor expressed in an HEK293 cell line of 0,92 μΜ.

Potassium hydroxide (4 mmol) was dissolved in ethanol (5 xnL) and healed at 80¾. 4-bydroxy~3~meihyl-N-(l-propyl--hutyl)~benz,amide (example 58) (Immol) was added into the solution followed by cliloroetlianol (3 mmol). The reaction was stirred overnight at 80°C. The reaction mixture was concentrated down and dissolved in 5% citric acid, he mixture was stirred for 1 hour. The aqueous mixture was extracted three times wife ethyl acetate. The combined ethyl acetate was washed with water and dried down over sodium sulfate. The organic layer was concentrated down and purified by HPLC to yield 39% of N“(heplan-4"yl)-4“(2-methoxyethoxy)'3“methylbenxamide. MS (M-hH, 308.25).

The compound had an EG» for activation ofahTlRI/h'TlR3 tananii receptor expressed i n an HEK293 cell line of 0.21 μΜ,

Prepared in a similar manner ίο example 4 using 3--iluoiO~4-methoxybenzoic acid and B-leucine methyl ester, MS (M+H, 298).

Tire compound had an EC·.* for activation of a hTLRl/hTl.R3 nmami receptor expressed in an HEK293 cell line of 0-3 μΜ.

Prepared in a similar maimer to example 4 using 3-pentylamine and 3-chloro-4~ methoxy benzoic acid. Yield 40%. MS (Md-H, 256.20).

The compound had an EC$o for activation of a hTIRI/hT!R3 nmami receptor expressed in an HEK293 cell line of 0.56 μΜ. and when presentat 0.3 pM enhanced the effectiveness of monosodium glutamate with an ECsa ratio of 6.28.

Prepared in a similar manner to example 4 using 3~cMoro-4-methoxv benzoic acid andD-leucine methyl ester hydrochloride, MS (M+H, 314.10).

The compound had an EC® for activation of a hTIRl/hTIRS umami receptor expressed in an HEK293 cell line of 0.08 p.M, and when presen t at 0.01 μΜ enhanced the effectiveness of monosodium glutamate with an EC® ratio of 13.18.

Prepare in a similar manner to example 4 using (R)-l -phenylethanamine and 3 cfeioro-4-methoxy benzoic acid. MS (M+H, 290.0).

The compound had an EC® for activation of a h'TlRl/hTlSB umami receptor expressed in an HBK293 cell line of 2.S μΜ, and when present at 0.3 μΜ enhanced the effectiveness of monosodium glutamate with an ECjo ratio of 27 , 4-€htere4l''MethvRN"(i^propyl%uty!Phepzantlde

Prepared in a similar maimer to example 4 using d-chloro-B-methyl benzoic acid and heptaa-4-amine. MS (M+H, 268).

The compound had an EC® for activation of a hTlRl/hTlRB umami receptor expressed in an HEK293 cell line of 0.3 μΜ.

Prepared in a similar manner to example 4 using 3,4dimethoxy benzole acid and heptan-4-amme, MS (M s H, 279.37).

The compound had an EC50 fee activation of a hTlRl/hTlRB umami receptor expressed in an HEK293 cell line of 0,3.6 μΜ.

Prepared in a similar manner to example 4 using 4~finoro~3~methylbensoic acid and I)~leucine methyl ester. MS (Μ H, 232).

The compound had an EC50 for activation of a liT!R!/hTlR3 omarni receptor expressed in an HKK293 cell line of 0.32 μΜ.

Prepared in a similar manner to example 4 using 4~meth.oxy-3>5-dimeihy!benxoic acid and 2-methylheptan-4~amine (example 2a), MS (M+H, 292.2).

The compound had an E.C50 for activation of a hT1Rt/hTlR3 umami receptor ’ expressed in an HER293 cell, line of 0.85 μΜ.

Prepared in a similar manner to example 4 using 3:,4-dimethylbensoic add and hexan-3-aisirie (example 3a). jH "4Mi? (500 MHz, CDCH): 8 0.94 (m3 9H); 1.39 (m, 3H); 1.56 (m, 1H); 1.84 (m, 1H); 2.30 (s, 3H); 2.31 (a, 3H); 4.04 (m, Hi); 5.76 (d, ill); 7.18 (d, 1H); 7.46 (d, 1H); 7.55 (s,1H); MS ( 248, M+H).

The compound had anECso tor activation of a liTlRl/hTl.R3 umami receptor expressed in an HEK293 cell line of 0.11 μΜ.

Prepared in a similar maimer to example 4 using 3,4-dimeth.ylbenroic add and 2-methylheptan~4-amine (example 2a). !H NMR (500 MHz, CDCR): 8 0.94 (m, 9H); 1.40 (m, 5H); 1.53 (m, lH); 1.68 (m, IK); 2.29 (¾ 3H); 2.30 (s, 3H); 4.24 (m, 1H); 5.69 (dsIK); 7.17 (d, 1H); 7.46 (d, IK); 7.54 (¾ 1H). MS (262, M+H).

The compound had an EGso for activation of a hTIRl/hTIRS umami receptor expressed in an HBK293 cell line of 0,13 μΜ 3,4"dimothvI~N~f5-rnetlniltcxars“3-yI)h&amp;nzaMde

Prepared m a similar manner to example 4 using 3,4-dimethylhenzoic acid and 5--methyihexan-3-amine (example 5a), *H NMR (500 MHz, CDClj): δ 0.94 (m, 9H); 1.38 (is, 2H); 1.46 (m, IH); 1.65 (m, 2H); 2.29 (s, 3H); 2.30 (s, 3H); 4.18 (m, 1H>. 5.70 (d, IH), 7.17 (d, IH); 7.46 (d, IH); 7,55 (s, IH). MS ( 248, M-:~H).

The compound had an ECsq for activation of a hT!Rl/hTIR3 umami receptor expressed in an HEK293 ceil line of 0,17 μΜ.

To a solution of (R)“N-(l»hydr0xy“4-methy]pentan-2“y])“3s4-dimethy]ben;zamide (1,59 g, 6,39 mmol) (example 71a) in dryDMF (20 niL) was added powdered NaOH (281 mg, 7 mmol) an the solution was stirred at 0°C for 2 hrs. lodomethane (1 eq, 6.39 mmol) was added in DMF (10 ml) drop-wise over period of 1 hr. The temperature was kept at 0”C and the mixture was stirred for l hr. The reaction was quenched by adding 300 ml of water. The aqueous layer was extracted with dichloromethane, dried over MgSCH and evaporated. The residue was purified by flash chromatography on silica-gel (toluene-ethyl acetate; 5-2034 gradient) to give 1,23 g (R>N-(lrmethoxy-4~melhylpentan-2-yI)-3,4-dimethylbenzamide (73%), JHNMR (500 MHz·, CDGfe): 6 0.94-0.97 (ί, 6H), 1.41-1.47 (Μ, 1H), 1.54-1.60 (m, IH), 1.64-1.68 (m, IH), 2.29 (d, 6H), 3,36 (s, 3H), 3.45-3.50-(m, 2H), 4,34-4.39 (m, IH), 6.23-6,25 (d, IH), 7.16-7.17 (d, IH), 7.47-7.49 (dd, IH), 7.56 (s, IH). MS (M+H, 264.3) a. (R)~N~(l~hydroxy“4-methylpen:tar:-2-yl)-3,4~dimethylbeszamide was prepared in a similar manner as described in example 4 using 3,4-dimethyibenzoic acid and with (R)-amino]eucinoI. Yield: 75%. MS (M+H, 250.3),

The compound had an EC® for activation of a hTlR!/hTlR3 umami receptor expressed in anHBK293 cell line of 0.2 μΜ.

To a solution of (R)-N-(l-hydroxyM-methylpentan-2-yl)~3^dimethylbenzamide (Example 71a) (0.24 mmol) dissolved in dry DM? (2mL) was added at 0°C powdered NaOH (0,36 mmol, 14,5 mg, 1,5 eq) and the mixture was stirred for 1 hr at 0°G Then cMoro-methoxy-metbane (19.3μ1,1 eq) was added and the reaction stirred at Q°C for 1 hour. The reaction was quenched with water (30 mL) and the mixture ’was extracted with dichloromethane. The organic phase was dried over MgSCR and evaporated. The crude product was purified by preparative TLC (20% ethyl aeetate/hexanes) to give 37.7 mg of (R)-N-(l-(methoxytnethoxy)-4~meihyipentan-2-yl)-3,4~diroethyIbenzamide (53%). ,lH MMR (500 MHz, CDClj): δ 0.98-1.00 (t, 6H), 1.49-1.53 (m, 1H), 1.58-1.64 (m: 1H), 1.69 1.73 (m, 2H). 2.32-2.33 (d, 6H), 3.38-3.39 (t, 3H), 3.64-3.72 (ddd, 2H)S 4.41-4.44 (ms 1H), 4,65-4.69 (dd, 2H), 6 3? 6.39 (d, 1H), 7.19-7.21 (d, 1H), 7.50-7.52 (dd, 1H), 7.60 (sb, 1H). MS (M-rH , 2.94.3). ,, The compound had an EC® for activation of a hTlRI/hT1R3 umami receptor expressed in an HEK293 cell hue of 1.06 μΜ. N"(l-Mfethnxvmpfhyil-2-triefityI“propyl%3,4~(lgmefeyi-bfctt4gmi£l^

Prepared in a similar manner to example 71 using N-(l-hydroxy-3-methylbutan-2-yl)-3,4-dimethylbenzamide (example 73a) and methyl iodide. Yield 87%, Ή NMR (500 MHz, CDClj): δ 0.97-1.00 (dt,6H), 1.96-2.00 (m, 1¾ 2.29 (s, 3¾ 2.30 (s, 3PI), 3.35 (s, 3H), 3.42-3.45 (dd, 1¾ 3.60-3.62(66,1¾ 4.01-4.05 (m, 1H), 6.31-6.33 (d, 1H), 7.16 7.18 (d, 1H), 7,48-7.50 (dd, 1¾ 7.56-7.57 (ds 1H). MS (M+H, 250). a. N-(!-hydroxy-3-methylbutan~2-y])~3,4-<iimethylbenaamide was prepared in a similar manner to example 71a using 3,4-dimeifooxybenzoic acid and 2-anbno~3-methylbutan-l-oL Yield 75%, MS (M-fH, 236.2).

The compound had an BCsg far activation of ahTiRhhTIRB umami receptor expressed in an HEK293 ceil line of 0.87 μΜ,

Prepared in a similar manner to example 4 using 2-ineihoxy-4-(methyiihio)benzoic acid and Ώ-leucine methyl ester. MS (M+H, 326).

The compound had an EChr, for activation of a hTlRi/'iff :R3 umami receptor expressed in an ITSK293 cell line of 15,8 μΜ,

Prepared in a similar manner to example 4 using 3-(4-Methoxy~phenyl)-acrySic acid and 5-methylhexan-3-amine (example 5a), Yield: 59%, fH NMR (500 MHz, CDCK): δ 0.93 (m, 9H); 1,33 (ts2H); 1.43 (ms :H); 1.584.67 (m, 2H); 3.83 (s, 3H); 4.11 (m, 1H); 5.19 (d, 1H); 6,25 (d, :H): 6.88 (d, 2H>;7,44 (d, 2H); 7.58 (d, IH). MS (276, M+H).

The compound had an EC50 for activation of a hT!Rl/hT!R3 umami receptor expressed in an HE.K293 cell line of 0.24 μΜ.

Bxamnk 76

N-(I-Ethyl-propyl)-3-(4-hydrQxy~phenyl)~aerylaTnide (example 76a) (0.44 mmol, 103 mg) was dissolved in absolute ethanol with KQH (0.7 mmol, 37 mg). The mixture was stirred at 80°C for 1 hr. Then 2-chloro-ethanol (1,76 mmol, 118 uL) was added dropwtse and the mixture was relluxed overnight. Following evaporation the crude product was dissolved in dichioromethan.e and washed with water and 5% citric acid. The organic phase was evaporated and the residue was pnriiied by chromatography on silica gel to give 73 m£ of desired product (60%). SH KMR (500 MHz, CDOs): δ 0.92-0.95 (t, 6H), 1.25 (s, 1H).L40-1.46 (np 2H), 1.594.64(in, 2H), 3.93-3.94(¾ IE), 3.95-3.98 (in, 2H), 4.09-4.11 (m, 2H), 5.28-5.30 (d, 1H), 6.26-6.29 (d, 1H), 6.88-6.90 (d, 2H), 7.43-7.45 (d, 2H), 7.56 7.59 (d. 1H). MS (M-f H, 278.1). a. N-(i-Ethyl-propyl)~3-(4-hydroxy~phenyl)~acrylamide was prepared in a similar manner as described in example 4 from, d-hydroxy-dnnaoiic acid and 3-pen iylamine. MS (M-S-H, 234.10).

The compound had an EC;ii for activation of a hTl.Rl/hTl.R3 umami receptor expressed in anHEK293 cell line of 5.S μΜ.

Prepared in a similar manner as described in example 4 from (E)“3-(ihiophen-2“ y!)aery!ie acid and 4-hepthylamine. MS (M+H, 252).

The compound liad an EC30 for activation of a liTlRl/hTl.R3 umam.i receptor expressed in an HE-K293 ceil line of 0.44 μΜ.

Exomnle ?S

Prepared in a similar manner as described in example 4 from (E)-oct~2-enoic add and D-leucine methyl ester. MS (M+H, 270).

The compound had an ECso for activation of a hTlRl/hTlB.3 uroami receptor expressed in an HEK293 cell line of 0,92 μΜ.

Example 79

Prepared in a similar manner to example 4 using 3~(4-metiK3xy-pheriyl)-aerylie acic and 3-methyl-1 -propyl-butylamine (example 2a). Yield: 65%. Ή NMR (500 MHz, CDGV): δ 0.90-0.95 (m, 9H), 1.30-1.39 (m, 5H), 1.49-1.50 (m, 1H), 1.64-1.6? (m, 1H); 3.82 (s, 3H), 4.17-4.18 (m, 1H), 5.18-5.20 (d, lift 6.22-6.26 (d, ΓΗ), 6.86-6.89 (d, 2H), 7.42-7.45 (d, 2H). 7.56-7.59 (d, 1H). MS (M+H, 290.1).

The compound had an EC*o fcr activation, of a liTIRl/hTIRB omami receptor expressed in an HEIC293 cell line of 1.84 μΜ.

Prepared in a similar manner as described in example 71 fan 3-(4--rneihoxy-phenyl)'acrylic acid and D-leucinoL Yield: 41%. Ή NMR (500 MEfe, CDCI3): 60.93-0.96 (t, 6.H), 1.38-1.42 (m, 1H), 1.48-1.54 (m, 1H), 1.63-1.66(m, 1H), 3.36 (s,3H), 3,41-3.46 (m, 2H), 3.82-3.83 (s, 3R), 4.29-4.31 (m, 1H), 5.69-5.71 (d, 1H)S 6.24-6.27 (d, 1H), 6.87 6.89 (d, 2H), 7.43 (s, 1H), 7.44 (s, 1H), 7.56-7.59 (d, 1H). MS (M+H, 292.1).

The compound liad an ECso for activation of ahTlK.l/hTlK.3 umami receptor expressed in an HEK293 cell line of 0-90 μΜ.

Prepared in a similar manner as described in example 4 from 3-(4-methoxy-phenyl)-acrylic acid and. D-phenylaianirtol MS (M+H, 312.3).

The compound had an ECso for activation of a liTlRl/hTlJ<3 umami receptor expressed in an HEK293 cell line of LI μΜ.

Prepared in a similar manner to example 4 using 3-(4-eiboxy-phenyl)-acrylie acid and 3-pen tylamine.MS (M+H, 262.2).

Tire compound had an ECjo for activation of a hTlRl/bTU?3 urnami receptor expressed in an HEK293 cell line of 1.35 μΜ.

Prepared in a similar manner as described in example 4 from 3-tfriopfren~2-yl-acrylic acid and D-Ieucin.e methyl ester. MS (M-tHs 282.2).

The compound had an ECsq for activation of a liTlRl/hTLR3 umami receptor expressed in anMEIC293 cell line of 0.59 μΜ.

Prepared in a similar manner as described in. example 4 from 4-methyi-pent-2~enoic acid and l,2s3s4-tetrahydro-naphlhalen4-ylamine. MS (M+H, 244.2).

The compound had an EC so for activation of a hTlRI/hTlR3 umsmi receptor expressed in an HEK293 eel! line of 1.5 μΜ. 3R2~Fhm.rn-phfe«vIV.NMl-pytmYl~bntyl)-aeryItm«de

Prepared in a similar manner as described in example 4 from M2~tiuoro--phenyl)· acrylic acid and 4-heptyiamine. MS (M+H, 264.2).

The compound had an ECso for activation of a hTlRl/hTl.R'3 umami receptor expressed in an PIEK293 cell line of 0.16 μΜ.

Prepared in a similar manner as described in example 4 from 3-(2-methoxy~ phenyl)-acrylle acid and 4-heptylamine. MS (M+H, 276.2).

The compound had an ECjo for activation of a hT!El/hTiR3 umami receptor expressed in anHEK293 cell tine of 0.90 μΜ.

Kaatmmjje 87

Prepared in a similar manner as described in example 4 from 3-(3,4-dimeihoxy-phenyl)~acrylic add and 4-heptylamine. MS (M+H, 306.2).

The compound had an ECjo for activation of a hTIRl/’ltTlRS umami receptor expressed inanHBK293 cell line of 0.97 μΜ, and when present at 0.3 μΜ enhanced the effectiveness of monosodium glutamate with an ECjo ratio of 2.4.

Prepared in a similar manner as described in example 4 from 3-(2-methoxy-phenyl)-acrylic acid and 2-methyhcyclohexylamine. MS (M+H, 274,2).

The compound had an ECjo for activation of a liT!Rl/hTlR3 umami receptor expressed in an HEK293 cell line of 3,4 μΜ

Prepared in a similar manner to example 4 using bermofuran-S-earboxylie acid and heptan-4-amine. Yield 41%. MS (M+H, 260.2 ).

The compound had an ECsq for activation of a hTIRl/hTIR3 umami receptor expressed in an HEK293 cell line of 1.19 μΜ,

Prepared in a similar manner to example 4 using 5,6-Dimethyipicolinie acid (Example 91a) and 4dieptylamina Yield: 49%. 5K NMR (500 MHz, C.DCI3): δ 0,91-0.94 (1,6H), 1-384.48 (m,4H), L49 -L61 (m,4H), 2.32 (s, 31¾ 2.52 (s, 3H), 4.11- 4.13 (m, 1H] 7.52 -7.53 (dslH), 7,93-7.94 (d, 1H). MS (M+H, 2491). a. 5.6-Dimethylpicolinic acid: 5,6-dimethylpieolinomitrile (example 91b) was refluxed in concentrated HC1 (15 mL) overnight. The solvent was evaporated and the solid residue was co-evaporated several times with EtOH. Drying provided 453 mg of 5,6-Dimethylpicolinic acid (80%) as a white solid. MS (M+H, 152.1). b. 5,6-dimelhylpicoIinonitrile: 2,3-1 ulidhie (13.25 mmol) was refluxed overnight with 18 ml of glacial AcGH and 6 ml of hydrogen peroxide. The solvent was evaporated and the residue was co-evaporated two times with water, hasifed with.Na2.CO3 and extracted with chloroform. The organic layer was dried over NagsCL and evaporated to give 1.45 g of a crystalline product The product (615 mg, 5 mmol) was reacted with trimethylsiSaue carbonitrile (5.5 mmol) in dichiorome thane (10 mL) at room temperature for 5 min followed by addition of dimethylcarbamoyl chloride (5 mmol) and the solution was stirred at room temperature for 3 days. The reaction mixture was treated with 10% potassium carbonate (10 mL), the organic layer was separated and the aqueous layer was extracted 2 times with dichloromethane, The organic phase was dried over NasSCL and evaporated to give 495 mg of 5,6-dimethyipioolinonitrile (75%). ' B NMR (500 MHz, CDCh): δ 2.35 (s, 3H), 2,53 (s, 3H), 7.43-7.45 (d, 1H), 7,51-7.52 (d, 1H): 13C: δ 19.71, 22.80, 117.87,126.36,130.60,136.58,137.66, 159.84), MS (M+&amp; 133.1).

The compound had an ECjq for activation of a hTlRl/hTlR3 rnnami receptor expressed in an HEK293 cell line of 2.8 uM.

Prepared in a similar manner to example 4 using 4-diethylamino benzoic add and 4-heptylamine. (31% %). Ή NMR (500 MHz, CDCI3): δ 0.92(1,6H,/= 7.17 Hz), 1.18 (t, 6H, /= 7.04 Hz), L41(m, 4H); 1.55( m, 4H), 3.39 (m, 4H), 4.15 (m, 1H), 5.62 (m, 1H), 6.54 (d,2H, /- 10.26Hz ), 7.64 (d,2H,/= 10.26 Hz). MS (M+H, 291).

The compound had an EC50 for activation of a liTlRl/hTlR3 umami receptor expressed in an HEK293 cell line of 7.6 μΜ.

Prepared in a similar manner to example 4 using 2,6-Bimeihoxy-isonicotinic acid and D-leucine methyl ester. 5H NMR (500 MHz, CBCI3): δ 0.92 (d, 311,/-7.27 Hz), 0.93 (d, 3H,./= 7,26 Hz), 1.41-1.58 (m, 8H), 3.95 (s, 3H), 4.08 (s, 3H), 4.15 (m, IHj, 6.43 (d, 1H, /= 8.32 Hz), 7.47 (m, broad, 1H), 8.41 (d, 1H, /= 8.34 Hz). MS (M+H; 311).

The compound had an EC53 for activation of a hT!Rl/hTIR3 umami receptor expressed in an HEK293 cell line of 1.91 μΜ,

Prepared in a similar manner to example 4 using sodium 6-methoxynieotixiate (example 94a) and 4-lieptliyIamixie, Yield: 44%. MS (M+H, 251). a. methyl 6-methoxyiscotmate (2.097g, 12.56mxnol) was dissolved in dioxane (30mL), An aqueous solution ofNaOH (1 .ON, 25mL) was added to the solution and the mixture was stirred at room temperature overnight The solvent was removed under reduced pressure to provide 2.2 g of sodium 6~methoxynieotmate,

The compound had anEC*o for activation of a liTlRl/hTIRS umami receptor expressed in an HEK293 cell line of 2.66 μΜ, :

Example 9S »^-dlPtethvIpw^xtot^2~carfeo:sTMe add (l-prapvl>ujx'.OajpMe

Prepared in a similar manner to example 4 using 5?d-dimethyl-pyrazine-2-carboxylic acid (example 95a) and 4~heptylamme. Έ NMR (500 MHz, CDCI3): δ 0.91.0.94 (t, 6Ή), 1,35-1.42 (m, 4H)51.48-1.51 (m, 2H), 1.55-1.60 (m, 2¾ 2.57-2.60 (d, 6H), 4.13-4.16 (m, 1H)S 7.52-7.53 (d, 1H)S 9.09 (s, 1H); MS (M+H, 250). a, SjO-dinxethyi-pyrazine-l-carboxylic add: To a solution of 2..3-diaminopropiouic acid (:1.0 g, 9.6 mmol) in methanol (20 ml.) was added hutane-23-dione (728 pL; 11,5 mmol) audNaOH (1.4 g; 56.6 mmol). The mixture was refluxed for 2 hand then cooled to room temperature while air ’was bubbled through for 1 hour. The white precipitate was filtered and the gelatinous product was concentrated under vacuum. The crude product was taken up in diehloromethane, washed with 10% citric add, dried over MgSC>4 and filtered. The solvent was removed under reduced pressure to give 5,6-dimethyl-pyraaiue^-carboxylic acid as a volatile solid. The compound was used as is in the next step.

The compound had an EC50 for activation of a iiTlR3/bTl.R3 umami receptor expressed in an HBK293 cell line of 1,01 μΜ.

Prepared in a similar manner to example 4 using 2-chloro-6-methylmcotinic add and 4-Heptylamine. MS (M~H, 269).

The compound had an ECso for acti vation of a hTlEi/hlTR3 umami receptor expressed in an HEK293 cell line of 3.9 μΜ.

Prepared in a similar manner to example 4 using 2-cyano-4-methoxybenzoic aeidand 4-Heptyiannne. Yield: 73%. Ή NMR (CD3OD): §0-94 (g 6H, J = 7.3 Hz), 1.38 (m, 4HX 1.53 (ms 4H), 4,02 (s, 311),4.12 (m, 111), 7,27 (d, 111,/= 9.40 H4 8.11 (d, 2H, J = 2.21 Hz). MS (M+H, 275).

The compound had an ECs> for acti vation of a hTlRl/hTlR3 nmand receptor expressed in an RFK293 cell line of 1,39 μΜ, and when present at 1 μΜ enhanced the effectiveness of monosodium glutamate with an ECse ratio of 4,52. ,

Prepared in a similar manner to example 4 using 4,5-dimethyl-fnran-2-carboxylie acid and D-leucine methyl ester. Yield: 27 %. :H NMR (500 MHz, CDClj): δ 0.96 (t 6H), 1.66 (m, 3H). 1.96 (s, 3H), 2.26 (s, 3H), 3.75 (s, 3H), 4.78 (m, 1H), 6.51 (d, 1.H), 6.89 (¾ 1H). MS (M+H, 268).

The compound had an EC-so for activation of a hlTRl/hTIRS umami receptor expressed in an HEK293 cell line of 0.59 μΜ.

Example 99

Prepared in a similar manner to example 4 using 1,3-dimethyl--IH-pyrazole-S-carboxylic acid and 4-heptylamine. Ή NMR (500 MHz, CDCb): 6 0.90 (t, 611,/=17.2 Hz) 1.41 (m, 4H), 1.50 (m, 4¾ 2.27 (s, 3H), 3.77 (¾ 3H), 4.09 (m, 1H), 6.49 (d, 1H), 6.53 (s, !M). MS (M+Hj 238).

The compound had an EC50 fesr activation of a hTIRl/hTlR3 umami receptor expressed in an HEK293 cell line of 7.8 μΜ.

Prepared in a similar manner to example 4 using 1,3-dimethyl·lH-pyrazole-5-carboxylic acid and 4-heptylamine. MS (M+H, 241).

The compound had an ECjs for activation of a hTiRl/hTljR.3 umami receptor expressed in an KEK.293 cell line of 7.2 μΜ.

Prepared in a similar manner to example 4 using qtiiiiolme-6-carboxylic acid and 4-hepthylamine, lU NMR {500 Mlz, CDCb) δ 0.96 (t, /= 7.2 Hz, 6H\ 1.424,58 (m, 6H), 1.624.70 (m, 21-3), 4.18-4.20 (m, 1H), 5.95 id, J- 9.0 Hz, 1H), 7.49 (brs, 1H), 8.04 (dd, J = 8.5,1.5 Ms, 1H), 8.17 (d, /= 8.5 Hz, 1H), 8,27 (d, /= 8.2 Hz, III), 8.30 (s, 1PI), 8.99 (br S; 1H); MS (M+H, 271.2).

The compound had an EC50 for activation of a hT!Rl/hTlR3 umami receptor expressed in an HEK293 cell line of 3,2 p.M,

Prepared in a similar manner to example 4 using qninoline-3-carboxylie acid and hepihylamine: !H NMR (500 MHz, CDCk) 0 0.96 (t, /= 7.3 Hz, 6H), 1,40-1.58 (m, 6H), 1.604.67 (m, 2H), 4,20-4.30 (1¾ 1H), 6,01 (d, /- 8.8 Hz, 1H), 7.61 (1,/-7.5, 1H), 7.80 (t /= 7.6 Hz, 1H), 7.90 (d,J- 8.1 Hz, 1H), 8,15 (d, J- 8.5 Hz, 1H), 8.57 (d, J= 1.2 Hz, 1H), 9.26 (brs, IH); MS (M+H, 271.2).

The compound had an EC5o for activation of a hTlRl/hTlR3 nmami receptor expressed k an HBK293 cell line of 15,8 pM.

Examiik· 103

Prepared in a similar manner to example 4 using isoqumoline-1-carboxylic acid anc heptamine 'Ή KMR (500 MHz, CDCh) δ 0.9¾ (.1,,/=7.05 Hz, 5H), 1.42-1.56 (m, 6H): 1.584,66 (m, 2H), 4.20-4.32 (m, Hi), 5.83 (d, J- 9.1 H% 1H); 7.36 (d, J- 4.2, 1H), 7.60 (t,/= 7.7 Hz, 1H), 7.75 (t5,/= 7.7 Hz, 1H), 8.11 (d,J = 8.5 Hz, !H), 8.18 (d,/- 8,4 Hz, 1H), 8.88 (d,/-4.9, Hi); MS(APC1, M+) 271,2.

The compound had an EC50 for activation of a hTlRI/hTIR3 umami receptor expressed in anREK293 cell line of 14.2 pM,

Prepared in a similar manner as described in example 71 from i-methoxy-S-mefhyl benzoic acid and D4eueinoL Yield: 86%.1H NM3R. (500 MHz, CDClj): δ 0.94—0.97 (t, 6H), 1.424.47 (m, 1H), 1.544.60 (m, 2H), 1.64-1.68 (m, 2H), 2.24 (s, 3H), 3.37 (s, 3H), 3,46-3.48 (m, 2H), 3.87 (s, 3H), 4.35-4.38 (m, 1H), 6,14-6.16 (d, 1H), 6.82-6.84 (d, ίH), 7.56 (d, 1H), 7.61-7.63 (del, 1H). MS (Μ H, 280.3).

The compound had an IC30 fcf activation of a hTlRl/hTl,R3 umami receptor expressed in an HEK293 cell line of 0.24 pM,

Example IQS

Prepared in a similar manner as described in example 4 from thiophene ·/.-carboxylic add and (4-(triilnoromeihoxy)phenyl)methanamine. MS (M+H, 303).

The compound had an EC50 for activation of a hTlRl/hTl R3 umaroi receptor expressed in an HB&amp;293 cell line of 2,4 μΜ.

Example 106

' Prepared in a similar manner as described in example 4 from 4~methoxy-3- methylbenzoic acid and 2-(hiran~2-ylmethylthio)sthanamine. Yield 58%, 3H NMR (500 MHz, CDCk) 2.23 (s, 3H), 2,76 (t, 2H, /— 6,37 Hz), 3,59 (q, 2¾ /= 12.2 Hg), 3.76 (s, 2H), 3.86 (a, 3H), 6.22 (dd, lH,/= 3.491-3¾ J 2 671¾ 6.30 (dd, 1H, ./= 3.04 Hz, J= 1 1.78 Hz), 6,46 (ro, Hi, broad), 6,83 (d, III, J-- 8.51 Hz), ?.34(dd, IH, ./1.97 Hz,/= 1 Hz), 7.56 (d, 1H, 3 = 1.72 Hz), 7.61(dd, 1H, J= 8.53 Hz,/= 2.25 Hz). MS (M+H, 306 ).

The compound had anECso for activation of a hTlRl/hTIR3 nmami receptor expressed in an HEK293 eel! line of 5.6 μΜ.

Thiophme-$~eaHK>^ilc add 4-triflimromctfeozv-hen.gvlamirie

Prepared in a similar xnarmer to example 4 using thiophene-3-carboxylic acid and 4 trifiuoromethoxy-benz.yiamins. MS (M+H, 302,0). .

The compound had an EC® for activation of a hTIRl/hTlR3 umami receptor expressed in an HEK293 ceil line of 2.2 μΜ, and when present at 3 μΜ entranced the effectiveness of monosodium glutamate with an ECjo ratio of 8.5.

K'SmagfelQS

Prepared in a similar manner to example 4 using 3-methy3-tiiiophene“2-carb©xylic acid and 2,4-dimethcxy-benzylamine, MS (M+H, 292.2).

The compound had an EC50 for activation of a hTI Rl/hTl R3 umami receptor expressed in an HBK293 ceil line of 5.6 μΜ» and when present at 3 μΜ enhanced the effectiveness of monosodium glutamate with an EC50 ratio of 5.8. acid a^dlmetltoxy-bea^kmMe

Prepared in a similar manner to example 4 using 5-pyfidin-2-yl-thiophene-2-carboxylic acid and 2,4~dimethoxy-henzylamine, MS (M+H, 355.2), lire compound had an ECjq for activation of a hT!Rl/hTl.K3 umami receptor expressed in an HEK293 cell litre of 2.86 μΜ» and when present at 3 uM enhanced the effectiveness of monosodium glutamate with an ECjq ratio of 8.

Example 110

Prepared in a similar manner to example 4 using 2~methy]-2H-pyraaoIe-3-earboxylic acidand 2,4-dmrefeoxy-benzylatnine, MS (M+H, 276.2).

The compound had an BCjo for acti vation of a hTiRLhT!R3 umami receptor expressed in an HEK293 cell line of 6 μΜ, and when present at 3 μΜ enhanced the effectiveness of monosodium glutamate with an ECsa ratio of 7.9.

Prepared, in a similar manner to example 4 using 4-bydroxy~3-methy!-benzoic acid and l-methyl-S-phenyl-propykmine. MS (M+H, 284.2)

The compound had an HQ» for activation of a hTIRbnTI R3 «.mami receptor expressed in an BBK293 cel! fine of 2.7 μΜ, and when present at 03 μΜ enhanced the effectiveness of monosodium glutamate with an EC50 ratio of 7.

Prepared in a similar manner to example 4 using benxo[l,3]dioxole-5-earboxylie acid and 2"(4-ethyl'phenyr)-eihylamine. MS (M+H„ 298.2),

The compound had an ECTo for activation of a hT'lRl/hTlR3 umami receptor expressed in an HEK293 cel! line of 3.S6 μΜ.

Example 1.13

Prepared in a similar manner to example 4 using 4~meihoxy^3-methyl-ben2:oic acid and l-phenybbutyiamme. MS (M+H, 298.2).

The compound had an ECjq for activation of a hTIRi/hT'i R3 nmami receptor expressed in an HEK293 cell line of 2,5 μΜ.

Prepared in a similar manner to example 4 using 4-methoxy-3-methy l-henzole aeid and l-pyridin-2-yl~butylarnine. H Nfvl'R (500 MBz. CDClj): δ 0.91-0.92 (l, 3H), 1.25-1.3 (m, 2111.85-1.9 (m, 21¾ 3.86 (s, 3H), 5.25-5.3 (m, 1H), 6.80-6.82 (d, IK), 7.2-7.3 (m, 2HX 7.42-7.44 (d, 1H), 7.6-7,7 (1¾ 3H), 8..6 (4 1H). MS (M+H, 299.1).

The compound had an ECso for activation of a .bTlRl/hT1R3 umami receptor expressed in an HE K293 cell line of 1.54 μΜ.

Example 115

Benxofl Jldloxoie-S-earboxyllc add 13 -f4-meih oxv~ nhen y IV butv 1 i -amide

Prepared in a similar manner to example 4 using benzo[l,3]dioxole-5-carboxylic acid and l~(4-msthQxy-phenyl)-butyiamin:e ‘ H NMR (500 MHz, CDQ3): δ 0.93-0.95 (t, 3H)S 1.30-1.39 (m, 2H), 1.80-1.90 (m, 2H), 3.79 (s, 3H), 5.08-5.09 (dd, 1H), 6.00 (s, 2H), 6,10-6.12 (d, 1H), 6.79-6,80 (d, 1H), 6.87(¾ 1H), 6,88 (s5 111), 7.25-7,28 (m, 4H). MS (M+H, 32.8.1).

The compound bad an ECsa fix activation of a bTlRl/bTlR3 umami receptor expressed in an HEK293 cell line of 4.12 p.M. '

Example 116

Prepared in a similar manner to example 4 using 4-ethoxy-3-methyl-benzQie acid, and l-(4-methoxy-ph«snyl)-buty3amine. Ή NMR (500 MHz, CDCi-j): δ 0.93-0.96 (t5 3H), 1.31-1.41 (m, 2H)S 1.414.45 (t, 3H); 1.824.92 (m; 2H), 2.28 (s, 3H), 3.79 (s, 3H), 4.04 4.08 (q, 2H), 5,10-5.12 (d, 1H), 6.12-6.14 (d 1H), 6.78-6.80 (d5 1H), 6.87 (s, 1H); 6.88 (s, 1H), 7.26-7.29 (m3 2H), 7.52-7.53 (d, 1H), 7.57-7.59 (d, 1H). MS (M+H, 342.1).

The compound had an ECse lor activation of a hTIRl/hTIRS umami receptor expressed in an HEK2.93 cell line of 3.9 μΜ.

Prepared in a similar manner to example 4 using d-meihoxy-S-methyl··benzole acid and l-(R)-(4~methoxy-phenyI)-ethyiamine. MS (M+H, 300.1).

The compound hadanECsg for activation of ahTlR.l/hXlR3 umami receptor expressed in anHEK293 cell line of 2.8 μΜ. .Example i 18

Prepared in a similar manner to example 4 using benzo[ 1,3]dioxole-5-carb©xylic acid and indan 1-ylamine. MS (M+H, 282.2).

The compound had an EC;o for activation of a hTIRl/hTIRS umami receptor expressed in an HEK293 cell line of 1.2 μΜ, and when present at 0.3 μΜ enhanced the effectiveness of monosodium glutamate with an EC50 ratio of 5,33.

Prepared in a similar maimer as described in example 4 from 4-methoxy~3-methylberszoic acid and pentan-3-amine. MS (M+H, 236)

The compound had an BC50 for activation, of a h.Tl RVhTIR3 umami receptor expressed in an HEK293 cell line of 0.4 μΜ.

Prepared in a similar manner as described in example 4 from 3-methylfhran-2-carboxylic acid and 2-p-tolyletbanamine. MS (M+H, 244).

The compound had an EC30 for activation of a liTlRl/hTlR3 umami receptor expressed in an HBK293 cell line of 6 pM., and when present at 1 p.M enhanced the ^ effectiveness of monosodium glutamate with an EC*q ratio of 3.3.

Prepared in a similar maimer to example 4 using l-(2-(iH- pyno!· 1 · yl)phenyl)ethauone and 2,4-dimethoxy-bensylamine.MS (M-hH, 337.2).

The compound had an EC50 for activation of a hT!Rl/hTlR3 umami receptor expressed in an REK293 cell line of 1.66 μΜ, and when present at 1 μΜ enhanced the effectiveness of monosodhim glutamate with an ECjq ratio of 11 .

Additional “amide” compounds that were synthesized and experimentally tested and found to have a relatively high level of effectiveness as au activator of a hTlRl/hlTR' umami receptor expressed hi an KEK293 cell line. The results of that testing are shown below' in Table A

Numerous amide compounds of Formula (I.) that fail within the subgenus of “oxalamide4t compounds described elsewhere herein were also synthesized and experimentally tested for effectiveness as activator of a hTlRl/hTlR3 umami receptor expressed in an HBE293 cell line

Synthesis of N-^~Met&amp;ettv4>ea3svlll~NM2-‘t)YtldI»~2~yl~etfaylVojgalat»iide;

/FMethoxyber-xyl amine (5 mmol) was mixed with triethylamme (2 equiv.) in anhydrous Dioxane. Ethyl oxalyl chloride (1 equiv.) was added and the mixture was shaker at room temperature for 0.5-2 hours. Then 2-(2-pyridinyl)ethyl amine (1 equiv.) was added and the suspension was heated at 80 °C overnight. The solution was concentrated and the residue was dissolved in ethyl acetate and washed with water. The organic layer was dried by sodium sulfate and solvent was evaporated to give the crude product., which was purified by Hash column chromatography to afford the title compound: yield 70%, m.p. 118-119 °C; rn/e™ 314 [M+l]; 1H NMR (CDOh): δ 3.Q2 (ί, 2H), 3.76 (df 2H), 3.86 (s, 3H), 4.47 (d, 2H). 6.80-6.90 (m, 2H), 7.14-7.18 (m, 2H), 7.20-7.30 {m, 2H), 7.55-7.62 (m, 1H), 7.75-7.83 (m. Hi), 8.05-8.12 (m, IB), 8.55-8.63 (ms Hi).

The compound had an ECjo for activation of ahTlRl/liTlRS umami receptor expressed in anHEK293 cell line efO.,34 μΜ, and when present at 0.3 μΜ enhanced the effectiveness of monosodium glutamate with an ICso ratio of 18.85.

Prepared in a similar manner to example 122 using 2,4-dmiethoxybenayl amine ethyl oxalyl chloride and 2-{2-pyridinyl)ethyl amine. Yield 72%. m.p. 123-124 °C; m/e = 344 [M-f l]t Ή NMR (€DC13): δ 3.02 (t, 2H); 3.73 (dd, 21¾ 3.78 (s, 3ff); 3.82 (s, 3H) 4.38 (d, 2H) 6.40 (dd, 1H); 6.44 (d, 1H); 7.14 (m, 3H); 7.59 (m, 1H); 7.82 ft, 1H); 8.11 (t 1H); 8.56 (d, 1.H); 13C NMR: 5 36.9, 38.9, 39.4, 55.6, 55.6, 98.8, 104.1, 117.8, 121.9 123.5, 130.7, 136.8, 149.6, 158.8, 158.8, 159.6, 160.1,161.0.

The compound had anECjo f® activation of a hTlRl/hTI R3 umami receptor expressed in an HE K 293 cell line of 0.,09 μΜ, and when present at 0,3 μΜ enhanced the effectiveness of monosodinm glutamate with an EQ® ratio of6.51.

Prepared in a similar manner to example 122 using (3-methyl-thiophen~2-yl)-methylamine, ethyl oxalyl chloride and 2-(2-pyridinyl)ethyl amine. Yield 40%; m.p. 122- 124 cc; m/e - 304 [H NMR (MiS(M6): δ 2.19 (s, 3H), 2-92-2.95 (t, 2H), 3.48· 3.52 (dd, 2H), 4.37-4.38 (d, 2H), 6.79-6.S0 (d, 1H), 7.20-7.27 (ιυ, 3H), 7.67-7.71 (dt, 1H) 8.48-8.49 (d, 1H), 8.87-8.89 (t, 1H)> 9.25-9.28 (t, 1H).

The compound had an BCjo for activation of a hTlRl/hTlR3 mnami receptor expressed in an HEK293 cell line of 0-37 μΜ.

General Procedure B for the Sathesis of an Oxalanside

4-Methylbenzyl amine (1 mmol) was allowed to react with ethyl oxalyl chloride (3 equiv.) in the presence of tiiethyl amine (2 equiv.) in acetonitrile at room temperature fo· 0.5 - 1 hour, Then 2-(2-pyridinyl)ethy3 amine (1 equiv,) was added arid the suspension was heated-at 160 °C in a microwave reactor for 5 minutes. The reaction mixture was subject t< preparative HPLC to give the pure title oxalamide: yield 60%; m,p. 152-154 °Q m/e = 291 [M+lj; !H NMR (CDCT,): S 2.33 (s, 3H), 3.10 (t, 2H), 3.75 (dl, 2H), 4-43 (d, 2H), 7.10 7015 (m, 4H), 7.18-7.22 (ns, 2H), 7.65-7.73 (m, 2H), 8.12 (h, 1H), 8.60 (d, 1H).

The compound had an EC50 for activation of a hT!Rl/hTlR3 umami receptor expressed inanHEK293 cell line of 0.41 μΜ,

Prepared in a similar manner to example 122 using 2-methy3-4-rnethoxyhenzy amine, ethyl oxalyl chloride and 2-(2-pyridmy])ethyI amine. Yield 51%; m.p. 133-134 °C m/e = 328 [M+l]; SH NMR (CDCI3): δ 2.29 (s, 3H); 3,04 (t, 2H); 3,74-3.77 (m, 2H); 3.?: (s, 3H); 4.40 (d, 2H); 6.69-6.73 (rn, 2H); 7.13-7,18 (rn, 3H); 7,51 (t, 1H); 7.60-7.63 (m 1H); 8.17 (t, 1H); 8.58 (d, 1H).

The compound had an EC50 for activation of a hTlRl/hTlR3 umami receptor expressed inan HEK293 cell line of 0.,11 μΜ.

Prepared in a similar manner to example 125 using 2,4-dimethoxybenzyl amine ethyl oxalyl chloride and 3-(2~pyridinyi)propyl amine. Yield 60%; m/e = 358 [M+1J; lK NMR (CDCi3): § 1-99-2.04 (m, 2H): 2.84 (t, 2H); 3.36 (dd, 2H); 3.79 (s, 3H); 3.82 (s5 3H 4.60 (d, 2H); 6.41-6.45 (m, 2H); 7.10-7.17 (m, 3H); 7.57-7.60 (m: 1H); 7.81 (t, 1H); 7.8i (0 1H); 8,54 (d, 1H).

The compound had so ECsr for activation of a hTlRl/hTlR3 umami receptor expressed in an HEK293 cell line of 1.84 μΜ. .

Prepared in a similar manner to example 125 using 4-methoxybenzyl amine, ethy oxalyl chloride and 2-(2-pyridmyi)ethyl amine. Yield 50%; m.p. 156-158 °C; 1H NMR 3.05 it, 3H), 3.72-3.7? (m, 2H), 3.79 (s, 3H), 4.40 (d,2H), 6.86 (d, 2H), 7.16-7.22 (m, 4H) 7,65-7.69 (m, 3H)S 8,15 (b, 1H), 8.62 (d, 1H).

The compound had an ECjo for activation of a hTlRi/hTlR3 nmami receptor expressed in anHEK293 cell line of 0.75 μΜ.

Prepared in a similar manner to example 125 using 2,4-dimethoxybenxyI amine, ethyl oxalyl chloride and 2~(3-methylpyridin-2~yl)etliyl amine (example 129a). Yield 10%; m/e = 358 [M+ij; NMR (CDCh): § 2.28 (s, 3Ή), 3.01 (ΐ, 2H), 3.75-3.82 (m, 2H), 3.79 (s, 3H), 3.82 (s, 3.H). 4.39 (d, 2H), 6.41 (dd, 1H), 6-44 (d, 1H), 7.10 (t, 1H), 7.15 (d, 1H), 7.45 (d, III), 7.81 (bs, 1H), 8.28 (bs, 11¾ 8.40 (d, 1H). a. 2-(3-Methylpyridin-2-yl)eihyl amine: To a solution of 2-(3-methylpyridiue~2~ yi)acetonitrile (example 129b) (95 mg, 0.72 mmol) in THF (0.5 ml.) was added 1 M BHj-THF (2.2 mL, 2.2 mmol) drcpwise at room temperature. The resulting mixture was heated in a microwave reactor at 130 aC for? min. Then, 6 N aqueous HCI (1 mL) was added dropwise at room, temperature. The resulting mixture was heated in a microwave reactor at 120 'JC for 4 mm. The reaction mixture was washed with (3x3 mL), then cooled to 0 °C and 10N aqueous XaOH (0.8 mL) was added. The aqueous solution was saturated with K2COa. The product was extracted with CHCIj (6x5 mL). The organic extracts were dried (1:1 K^OTs/Na^SO*), filtered, concentrated in vacuo to afford an oil (81 mgs 86%), which was used directly in Example 8. m/e= 137 [M+l]. ' b. 2-(3-Methylpyiidme-2~yl)acetonitrile: To a solution ofn-BuLi (2.5 N in hexanes, 7.92 mL. 19.8 mmol) at -78 °C under Nawas added dry THF (75 mL), followed immediately by a solution ofdry'MeCN (1.15 mL, 21.78 mmol) in anhydrous THF (30 ml) over a 5-min period. The resulting reaction mixture was stirred continuously at -78 °( for 1 h. Then 2“bromo-3-methy!pyridine (516 mg, 3 mmol) was added. The resulting reaction mixture was stirred at -78 °C for 1 h, then warmed to room temperature, and quenched with water. The organic solvent was evaporated in vacuo, dissolved in CH^Cb-The organic layer was washed with brine, dried (MgSCL), concentrated, purified via column chromatography (20% EtOAc in hexanes) to afford the pr oduct quantitatively: m/e =-133 [M+l].

The compound had an EC$o for activation of a hXlRl/LTlR3 umami receptor expressed in an HEK293 cell line of 1.64 pM.

Example 130

Prepared in. a similar manner to example 122 using 2,5“dimethyi-furan-3-ylmethylamine, ethyl oxalyl chloride and 2-(2-pyridinyl)ethy1 amine. Yield 51%; m.p. 112115 °C; m/e= 302 [M+l]; lH NMR(DMSO-dg): 3 2.14 (s, 3Ή), 2.18 (s, 3H), 2.91-2,94 (t, 2H), 3.47-3.51 (dd, 2H), 3.98-3.99 (d, 2H), 5.89 (s, 1H), 7.20-7.25 (m, 2H)S 7.68-7.71 (dt, 1H), 8,48-8.49 (d, 1H), 8.81-8.84 (t, 1H)., 8.97-9.00 (t, 1H).

Tne compound had an EC50 for activation of a hTIRl/hTIRS urnami receptor expressed In an HEK293 cell line of 1.01 μΜ.

Prepared in a similar manner to example 122 using 1,5-dimethyl-lH~pyrrol--2·' ylmethyl amine, ethyl oxalyl chloride and 2-(2-pyridinyi)ethyl amine. Yield 2530; m.p. 147-149 °C; m/e - 301 [Μ+ϊ]; 'Ή NMR lpMSO-d6): δ 2.11 (s, 3H), 2,92-2.95 (t, 2H), 3.31 (¾ 3H), 3.48-3.52 (q, 2H), 4.24-4.25 (d, 2H), 5.64-5.65 (d51H), 5.79-5.65 (d, 1H), 7.20 7.25 (m, 2H), 7.68-7.71 (dt, 1H), 8.48-8.49 (d„ 1H), 8,82-8.86 (in, 2H).

The compound had an EC so fcr activation of a hTlRl/hTlB.3 ism ami receptor expressed in an 53HR293 ceil line of 2.3 μΜ.

Prepared in a similar manner to example 125 using (2-rnethoxy-4-methylphenyi)methanarnine (example 132a), ethyl oxalyl chloride, and 2~(2-pyridinyl)eth\ amine, yield 20%. m.p; 128-131 °C; nye~ 328 [M-H]; Ή NMR( CDCI3): 2.33 (s, 3H); 3,02 (t, 2H); 3.73 (m, 2H); 3.84 (s, 3H); 4.42(d,2H); 6.70 (m, 2H);7,14 (m, 3H); 7.60 (m, 1H); 7.86 (s, 1H); 8.09 (s, 1H); 8.56 (d, 1H). a. (2-methoxy-4-methylphenyl)methanamine: To a solution of 2-me8ioxy-4-methylbenzamide (example 132b) (200 mg, 1.21 mmol) in THF (0.5 mL) was added 1 M BH oTRF (2.4 ml, 2.42 mmol) slowly at room temperature. The resulting mixture was heated in a microwave reactor at 1.30 °C for 7 min. Then 6 M aqueous HCi (1 mL) was added dropwise at room temperature. The resulting mixture was heated in a microwave reactor at 12.0 °C for 4 min. The reaction mixture was washed with EtsO (3x3 mL), then cooled to 0 °C and 10 N aqueous NaOH (0.8 mL) was added. The aqueous solution was saturated with K.2CO3. The product was extracted with CHG3 (6x5 niL). The organic extracts were dried (1:1 K^COyNarSOiO, filtered, concentrated in vacuo to afford 180 mg of (2-methoxy-4- methylphenyl)methanamme which was used directly in Example 11. b, 2-methoxy~4-mefhylbenzarnide: 2~methoxy-4-melhylbenzoic acid (500 mg, 3.01 mmol) was mixed with 1-ethyl··3-(3-dimeihylaminopropyl}carbodiimide hydrochloride (577 mg, 3.01 mmol) and 1 -hydroxybenzotriazole (407 mg, 3..01 mmol) in 25 ml of dicMoromcthane at r.t. and stirred for 5 min. 2M ammonia solution in methanol (4,5 ml, 9.03 mmol) was added, the reaction mixture was stirred at r.t for about 5 1m then it was diluted with dichloromethane, washed with IN HC1, sat. NaHCGs, water and brine, dried over MgSCfo filtered and evaporated to give 440 mg of 2-melhoxy-4-methylbenzamide, yield 88%.

The compound had an EC.® for activation of a hTlRI/b.TlR3 trmarni receptor expressed in an HEK293 ceil line of 0.04 uM

Prepared in a similar maimer to example 125 using (2,4-dimethylphenyl)methanamine (example 133a), ethyl oxalyl chloride, and 2--(2-pyridinyl)ethyl amine, yield 60%, m,p, 148-149 °C; m3e~312 [Μ·Η]; Ή NMR (CDCI3): 2.28 (s, 3H); 2.30 (s, 3H); 3.05 (t, 2H); 3,76 (dd, 211); 4.43 (d, 2H); 6.99 (m, 2H); 7,11 (d, III); 7.17 (m,2H); 7.54 (s, 1H); 7.62 (rn, 1H); 8.17 (s, 1H); 8.58 (d, 1H). a. (2,4-Dimethylphenyl)methanamme; Lithium aluminum hydride 1M solution in THF (15.2 ml, 15.2 mmol) was placed in a pre-dried flask under argon at 0 °C a solution of 2,4-dimethylbenzonihiIe (1,0 g, 7.6 mmol) in 15 ml of anhydrous ether was added drop wisely. After the addition, the reaction mixture was warmed up slowly to r.t. and stirred for 3 hr, then it was cooled to 0 °G, anhydrous sodium sulfate was added, and 1ml of water was added drop wisely. The mixture was diluted with ethyl acetate, the insoluble matter was filtered out, the filtrate was washed with water and brine, dried over MgSCR, filtered and evaporated to give 1.03 gofpure(2,4-dimethylphenyl)methanamine in quantitative yield without purification.

The compound had an ECso for activation of a hTIRl/hTIR J urnami receptor expressed in an HBK293 cell line of 0.07 uM.

Prepared in a similar manner to example 125 using (4-eihoxy-2-methoxyphenyl)methanamine (example 134a), ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 10%, m.p. 117-118 °C, m/e = 358 [MM], {HNMR (CDCij): 1.40 (t, 3H); 3.03 (t,2H); 3.74 (dd, 2H); 3.82 (s, 3H); 4.01 (dd, 2H); 4.39 (d,2H); 6.39 (d, 1H); 6,44 (s, 1H): 7.15 (m, 3H), 7.61 (m, IE); 7.81 (s, 1H); 8.10 (s, 1H); 8.56 (d, 1H). a. (4~eihox.yM-methoxyphenyl)methanamine: To a solution ef 4-ethoxy~2-methoxybenzaldehyde (example 134b.) (880 mg, 4,88 mmol) in 50 ml of anhydrous methanol, were added ammonium aeetate (7.5 g, 97.60 mmol) and sodium cyanoborohydtade ¢613 mg, 9.76 mmol). The reaction mixture was stirred at r.t. for about A hr. then it was concentrated on a rotary evaporator, the residue was diluted with water and basified with 15 % aqueous MaOH, extracted with ethyl acetate, washed with water and brine, dried over MgSOi, filtered and the solvent was evaporated, the residue was column chromatographed on silica gel (DCMtMeOH 9:1) to afford 150 mg of product; yield 17 % (The method was not optimized). b. 4-Ethoxy"2-methoxybensaldehyde: To a solution of 4-hydroxy-2-methoxybenzaldehyde (1.0 g, 5.57 mmol) in 10 ml of acetone, w'as added potassium carbonate (0.91 g. 6.57 mmol) and iodoethane (1.6 ml, 19.71 mmol), the reaction mixture was stirred at r.t, overnight. Acetone was removed on a rotary evaporator; the residue was diluted with water and ethyl aeetate; extracted with ethyl acetate, washed with brine, dried over MgSOi, filtered and evaporated to give crude product, which was column chromatographed on silica gel (ethyl acetate/hexane = 1:4) to give 943 mg of produet; yieli 80%. '

lire compound had an BCja for activation of a .hTl.Rl/hTlE3 umami receptor expressed in an HEK293 cell line of 0.1 uM

Prepared in a similar manner ίο example 125 using (4-methoxy-3~meihylphenyiy methanamine (example 135a), ethyl oxaiyl chloride, and 2-^2-pyridinyi)ethyl amine, yield 12%; m.p, 145447 °C; xn/e* 328 [M+l]; lH NM.R (CDC13): 2.19 (s, 3H); 3.04 (t, 2H); 3.76 (dd, 2H); 3.81 (s, 3H); 4.37 (d, 2H); 6.76 (d, 1H); 7.06 (m, 2H); 7.16 (m, 2H); 7.61 (m, 1H): 7.66 (s, 1H); 8.18 (s, IH); 8.58 (d, 1H). a. 4~Methoxy-3-meihyIphenyl)methanamine: Prepared in a similar manner to example 134a using 4-methoxy-3-methylhens;aldehyde; ammonium acetate, and sodium cyanohorohydride in MeOH; yield 22% (110 mg), ·

The compound had an ECso for activation of aliTlRl/liTTR3 umami receptor expressed in an HEK293 eel! line of 1.04 uM.

Prepared in a similar manner to example 1.25 using i2mhlorophenyi)methanamini ethyl oxaiyl chloride, and 2-{2-pyrtd5nyi)ethyl amine; yield 45%; m/a™ 31.8 [M-H],

The compound had an ECso for activation o f a hTIR!/hTl R3 umami receptor expressed in an HEK293 cell line of 0,01 uM

Example 13?

Prepared in a similar manner to example 122 using (2,3"d'drydrGbenzo[bj[l,4} dioxin-5~yi)methanamine, ethyl oxaiyl chloride, and 2-(2~pyridinyl)ethyl amine; yield 50%; rate- 342 i'Mi !].

The compound had an ECso for activation of a hTIRl/ftTIRS umami receptor expressed in an HEK293 cell line of 0,3 uM,

Prepared in a similar manner to example 125 using benzo[d][l,3]dioxol-5 ylmethanamiae, ethyl oxaiyl chloride, and 2-(2-pyridinyi)ethyl amine; yield 35%; m/e -328 [M+l].

The compound had an EC50 for activation of a h T.1 Rl/hTl R3 umami receptor expressed in m HBK293 cell line of 0.5 uM. .

Prepared in a similar manner to example 125 using 4-ethylbenzylamine, ethy oxaiyl chloride, and 2-(2-pyridmy0eihyl amine; yield38%;m/e- 312 [M+l],

The compound had an EC$e ft* activation of a hT!Rl/hTlR3 umami receptor expressed in an HEK293 cell line of 0.29 uM.

Prepared in a similar manner to example 125 using benzofuran-S-ylmethylamine ethyl oxaiyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 64%; m/e ** 324 [M+l].

The compound had an ECjo for activation of a hTlRI/hTlRB umami receptor expressed in an HEK293 eel! line of 1.78 uM.

Prepared in a similar manner to example 122 using 4mrethoxyearbonyipben> methylamine, ethyl oxaiyl chloride, and 2-(2myddinyl)eihyi amine; yield 52%; ??vfe ™ 34: [M+l]. iFire compound had anECso for activation of a hTiR!/hTlR3 umami receptor expressed in an HEK293 ceil line of 3,63 nM.

Examnfe 142

Prepared in a similar manner to example 122 using 2-carbamoyipheny methylamine, ethyl oxaiyl chloride, and 2~(2-pyiidmyl)ethy! amine; yield 48%; m/e ~ 34. [M+ll,

The compound had an ECso for activation of ahTlRl/hTlR3 umami receptor expressed in an EEK293 cell line of 8.5 uM.

Prepared in a similar manner to example 125 using 2,4-dimethoxybenzylamme. ethyl oxaiyl chloride, and l-(.pyridin-2-yl)propan-2-yl amine (example 143a); yield 34%; m/e ~ 35? [M+l]. a, I~(Pyridin+2yyl)propan~2-y] amine: Prepared in a similar manner to example 129a using 2-{pyrMme-2-yl)propaneniirile (example 143b); crude product was used directly in example 143; yield 53%; m/e:::: 137 [M+l]. h. 2-(pyiidine“2~y!)propaneni:iiile: 5 mmol of2-(pyridine-2~yl)acetouitrilewai dissolved in 8 ml anhydrous THE and placed in an ice bath. Potassium t-butoxjde (1 equiv was added and reaction was stirred for 30 minutes. Methyl iodide (1 equiv) was dissolved in 5 mL anhydrous THF and added slowly over 30 minutes. Reaction was stirred overnight at room temperature. Solvent was evaporated and crude mixture was dissolved in ethyl acetate and washed with water, Ethyl acetate layer was evaporated and product was purified by preparative TLC (30% Ethyl acetate/Hexane^ yield 71%; in/e = 133 [M+1J.

The compound had an BCss for activation of a hTlRl/hTlR3 umarai receptor expressed in an HEK293 cell line of 0,4 uM

Prepared in a similar manner to example 125 using 2,4-dimethoxybenry'larnMe., ethyl oxalyl chloride, and 2-(pyridin-2-yi)propylamine (example 144a); yield 35%, m/e = 357 jMH]. a. 2-(pyridin-2-yl)propylamine; 10 mmol of 2-methylpyridine was dissolved ir anhydrous THF and kept under inert condition at 0 °C. Butyl lithinm (1.2 equiv) was added dropwise and stirred for additional 15 minutes at 0 °C while letting temperature to go back to room temperature. After stirring at room temperature for 1 hour, the reaction mixture was cooled again to 0 °C and acetonitrile (2 equiv) was added dropwise. Reaction was stirred overnight at room temperature, After cooling the reaction to 0 °CS 30 ml, of methanol was added into the reaction mixture. Sodium borohydride (3 equiv) was added in portion slowly at 0 °C, Reaction was stirred for another hour letting temperature to rise to room temperature. The reaction mixture was diluted with water and extracted exhaustively with ethyl acetate. The combined extracts were washed with water, brine and dried down over sodium sulfate. Solution was concentrated down and dissolved in ether. Product was extracted with 3 N aqueous HQ, and the acidic extract was washed with ether and made basic with NaOIT Product was extracted exhaustively with ether. The combined ether extracts was washed with water and dried down over sodium sulfate. Solvent was evaporated down to yield sufficiently pure product; yield 47%; m/e** 137 [M-fl],

The compound had an ECso for activation of a liTlRl/hTl'RS umami receptor expressed in an HEK293 cell line of 1.07 uM

Example 145

Prepared in a similar manner to example 125 using 2-methylbenzylamine, ethy oxalyl chloride, and '2-(pyridin-2-y3)ethylainine5 m/e - 298 [M+l]: EH MMR (CDCI3} « 2.32 (s, 3H), 3.11 (t, 2H), 3.78 (dt, 2H), 4,46 (d, 2H), 7.15-7.24 (m, 611). 7.50-7.55 (m 1H), 7.62-7.67 (m, 1H), 8.12-8.15 (m, 1H), 8.60 (d, 1H),

The compound had an BC$o for activation of a hTlRl/hTlR3 mnami receptor expressed in an HEK293 cell line of 0.59 nM.

Prepared in a similar manner to example 125 using 2,3-dimethoxybenzylamme ethyl oxalyl chloride, and 2-(pyridin-2-yl)ethylamine; m/e~ 343 [M+l],

The compound had an ECjo for acti vation of a hTl.Rl/hTlR3 umami receptor expressed in an REK293 cell line of 0-69 uM.

Prepared in a similar manner to example 125 using 2-methyIthhobenzylamine, ethy oxalyl chloride, and 2-(pyndin-2-yl)ethylaminej m/e ** 330 [M+l]; 5H NMR (CDCI3) \ 2.49 (s, 3H), 3.08 (t, 2H), 3.77 (dt, 2H), 4.55 (d,2H), 7.11-7.14 (m, 1H); 7.15-7.20 (m 2H), 7.,22-7.27 (m, 3H), 7,62 (t, 1H), 7.78-7.83 (m, IH), 8.08-8.11 (m, 1H), 8.56 (d, 1H).

The compound had an EC50 fear activation of a hTIRl/hTIRB umami receptor expressed in an ΗΈΚ293 cell line of 0.96 uM.

HxaTOle 148

Prepared in a similar manner to example 125 using 2-hydroxybenzyIamine, ethy oxalyl chloride, and2-(pyridin"2-yl)ethy3amine; m/e = 300 [M+l],

The compound had an EC*© for activation of a liT!Rl/hTlK3 umami receptor expressed in an HEK293 cell line of 3.11 uM.

Prepared in a similar manner to example 125 using benzo[d][l,3]diox0l-4-yimethyl amine (example 149a), ethyl oxalyl chloride, and 2-(pyridin-2-yI)ethyl amine; yield 12%; m/e = 328 [M+lj; lE NMR (CDC13): δ 3.12 (m, 2H), 3.77-3.80 (π, 2H), 4.46-4.4? (d, 2H), 5.98 (s, 2H). 6,74-6.79 (m, 3H), 7.24 (m, IH), 7.7-7,8 (m, 3H), 8.10-8.15 (m, IH), 8.588,59 (m, IH). ., a. Benzo[d)[lJ3]dioxol“4-ylmethyl amine: Prepared in a similar manner to example. 13 4a from benzo; dj[ 1,3]dioxole-4-carbald£hyd.e and ammonium acetate. The crude material contained app, 20 % of the product {m/e ~ 152,2 [M+i]) and was used directly in example 149.

The compound had an EC*g for activation of a hTlR3/hTlR3 umami receptor expressed in anHEK293 cell line of 0.17 nM.

Prepared in a similar manner to example 125 using benzo[b]thiophen-2-ylmethanamine, ethyl oxalyl chloride, and 2-(pyndin-2-yl)ethyl amine; yield 32%; m/e = 240 [M-H]; 'H NMR (BMSO-ds): δ 2.92-2.95 (t, 2H), 3.48-3.53 (m, 2H), 4,55-4.56 (d 2H), 7,20-7.25 (m, 2H), 7.38-7.41 (m, 2H), 7.50 (s, Hi), 7.66-7.70 (m, IH), 7.95-7.99 (m 2H), 8.47-8.49 (d, IH), 8..S8-S.9G (t, IH), 9.29-9.31 (t, IH).

The compound had anECjo for activation of a hTlRl/hTlR3 umami receptor expressed in an HBK293 cell line of0.74 uM,

Prepared m a similar manner to example 125 using benro[d]thiazol-2 yhnethanamine, ethyl oxalyl chloride, and 2-{pyridin-2-yl)ethyl amine; yield 33%; m/e : 341 [M+lj; Ή NMR (BMSO-ds): δ 2.95-2.98 (t, 2H)> 3.52-3.57 (my 2H)S 4.72-4.73 (d 2K), 7.22-7.24 (m, 1H), 7.25-7.2? (d, 1H), 7.40-7.44 (t, 1H), 7.48-7.51 (t, IH), 7.69-7.7: (dt, 1H), 7.95-7.96 (d, 1H), 8.05-8.07 (d, 1H), 8.49-8.50 (d, 1H), 8.96-8.98 (t, IH), 9.67 9.70 ft 1H).

The compound had an ECsa fcr activation of a hTlRi.TTlRS umami receptor expressed in an HEK293 cell line of 4.4 uM.

Prepared in a similar manner to example 125 using (5-methylfi.iran-2 yi)methanarmne. ethyl oxalyl chloride, and 2-(pyridin-2-yl)ethyl amine; yield 38%; m/e ! 288 [MM]; :'H NMR (DMSG-ds): δ 2.20 (s, 3H), 2.92-2.95 (t, 2H); 3.48-3.52 (m, 2H) 4.23-4.24 (d, 2H),5.96-5.97 (d, 1H), 6.06-6.07 (d3 IH), 7.20-7.25 (¾ 2H), 7.68-7.71 (f 1.H), 8.48 -8.49 (d, IH), 8.85-8.87 (t, 1H), 9.04-9.07 (t, 1H).

The compound had an ECso for activation of a hT!Rl/hTlR3 umami receptor expressed in an HEK293 cell line of 4,9 uM

Prepared in a similar manner to example 125 using (2-methylfuran-3-yl)methanamine (example 153a), ethyl oxalyl chloride, and 2-(pyridm-2-yl)ethyl amine; yield 50%; m/e - 288 [MM]; !HNMR (DMSOdg): δ 2.23 (s, 3H), 2.91-2.94 (t, 2H), 3.48- 3.52 (q, 2H), 4-05-4.06 (d, 21¾ 6.30-6.31 (d, 1H), 7.20-7.25 (m, 2H), 7.38-7.39 (d, 1H), 7.67-7.71 (dt, 1H), 8.48-8.49 (d, 1H), 8.83-8.86 (t, 1H>, 9.04-9.07 (t, 1H). a. (2-Methylfman-3~yl)methanarmne: A solution of 10 mmol (1,256 ml) of methyl 2~meihylfe‘an-3-carboxylate and 38,9 mmol (2.1 g) of NaOMe in 20 ml of foxmamide was stirred at 100 °C for 30 min. The reaction mixture was poured into ice-water (20 ml) and extracted with ethyl acetate (3x). The extract was dried over MgSQ4 and concentrated to give 1.05 g (83%) of 2-methylferan-3-carboxamide as oil (m/e ·™ 126,2 [M+i]), The amide was dissolved in dry THF (10 ml) and drop-wise added to 15 ml of 1M LiAIH* with 15 ml THF at 0 °C under argon. Then the mixture was stirred for 5 hrs at 60 c€, Following cooling, 50% aqueous THF (30 ml) was added to the mixture at 5-10 °C. The resulting precipitate was removed by filtration and the filtered solution was dried and concentrated to give an oily product (0.93 g, 84%).

The compound had an ECso for activation of a hTIRl/hTlB3 omami receptor expressed in an HEK293 eel! line of 1.82 uM

Prepared in a similar manner to Example 122 using 2s4-dirnethoxybenzylamines ethyl oxalyl chloride, and 2-(4-methylpyridiu-2-yl)ethyl amine (example 154a); yield 11%; is/e = 358 [M.+11; m.p. 144-145 °C; lH NMR (CDCfe): 6 2,31 (ss 3H), 2.97 (t, 2H), 3.71 (q, 2H)S 3.79 (¾ 3H), 3.83 (s, 3H)S 4.39 (d, 2H), 6.40 (dd, 1H), 6.44 (d, 1M), 6.97 (s5 1H), 6.98 (d, HI), 7,15 (d, Hi), 7.81 (br s5 JH), 8,08 (br s, 1H), 8.41 (d, 1H). a. 2-(4-Methylpyridin~2-yl)ethyl amine: Prepared in a similar manner to example 129 using 2-(4-methylpyridin-2-yl)acetonitrile (example 154b); yield 83%; nt/e -137 [M4l], b, 2-(4-Methylpyridin-2-yl)acetonittile: Prepared in a similar manner to example 129b using 2-bromo-4-methyIpyridine, acetonitrile andn-Buli; yield 88%; m/e -133 [Μ: I]

The compound had an ECso for activation of a hTlRl/hT!R3 nmami receptor expressed in an HEK293 cell Hue of 1.64 uM

Example 155

Prepared in a similar manner to Example 122 using 2,4-dimeiboxybenzylamine, ethyl oxalyl chloride, and 2-(5-methylpyridin-2“yl)e.thyI amine (example 155a): yield 9%; m/e - 358 [M+1J; m.p. 124-125 °C; Ή HMR (CDCls): δ 2.30 (s, 3H), 2.97 (t, 2H), 3.70 (q, 2H), 3.79 (s, 3H), 3.82 (¾ 3H), 4.38 (d, 2H), 6.40 (dd, 1H), 6.44 (d, 1H), 7.03 (d, 1H), 7.14 (d, 1H), 7.40 (dd, Hi), 7.81 (br s, 111), 8.08 (brs, 1H), 8.38 (d, 1H). a. 2~(5-Methylpyridin-2-yl)ethyl amine: Prepared in a similar manner to 129a using 2-(5~nmthy1pyridin~2~yl)aeeiomtrile (155b); yield 40%; m/e = 137 [M+l j. b. 2-(5-Mefeylpyridin-2~yl)aeetoni&amp;ile: Prepared in a similar manner to 129¾ using 2-bramo-5~methylpyridines acetonitrile and n-BuLl; yield 68%; m/e = 133 [M+l].

The compound had an ECso for activation of a hTIRl/hTlR3 umami receptor expressed in an HEK293 cell line of 0,07 uM

Example 156

Prepared in a similar manner to Example 122 using 2,4--dixnethoxybenzylamine; ethyl oxalyl chloride and 2-*ithiophen--2-yl)ethyI amine; yield 72%; m/e - 349 [M+l]; m-p 146-147 °G; !H NMR(CDC13): δ 3.06 (t, 2H), 3.58 (q, 2H), 3.80 (s, 3Ή), 3.83 (s, 3H), 4.4C (ds 2H), 6.41 (dd, 1H), 6.45 (d, 1H), 6.84 (dd, 1H), 6.93 (dd, 1H), 7.15 (d, 1H), 7.16 (d: 1H), 7.61 (br s, 1H), 7.81 (br 3, 1H).

The compound had an EC® for activation of a hTlRi/hTlR3 umami receptor expressed in an HEX293 cell line of 4.87 uM

Prepared in a similar manner to Example 125 using 2*methoxy-4-methylbenzylamine (example 132a), ethyl oxalyl chloride and 2“(4<methylpyridin-2-yl)ethylaxnixie (example 155a). Yield 20%; m.p. 116.- i 17 °C; ΈΗ NMR. (CDCls): δ 2.31 (s, 3H), 2.34 (Sj 3H)} 3,00 (t, 2H), 3.71 (qs 2H), 3.84 (s, 3H), 4,42 (df 2H), 6.69 (s, 1H), 6.71 (d, 1H). 7.0'S (d3 1H), 7.11 (d, 1H), 7.43 (d, 1H), 7.84 (brs,1H), 8.04 (br s, 1H), 8,39 (s, 1H); Μ8(Μ+Η, 342), . The compound had an ECso for activation o.fahTlRl/hTlRS umami receptor

expressed in an HEK293 cell line of 0.03 uM

Additional “oxalamide” compounds were synthesized and experimentally tested and found to have a relatively high level of effectiveness as an activator of a hT!Rl/hTlR3 umami receptor expressed in an H.HK293 cell line. The results of that testing are shown below in Table B.

Numerous amide compounds of Formula (I) that fall within the suhgenus of “urea“ compounds described elsewhere herein were also synthesized and experimentally tested 1½ effectiveness as activator of ahT!Rl/hTlR3 umami receptor expressed in an BBK293 cell

Example» 158

To a solution ofheptan«4~amme (0,18 ml,, 1 mmol) in CH2CI2 (5 ml.,) was added 1-cMoro-2~isocyanatobenzene (0.12 mL; 1 mmol) at room temperature. The reaction mixture was stirred for 2 h, A white solid was precipitated out The reaction mixture was filtered. The solid was washed with CH2CI2 to afford l-(4.chlor©phexiyl}-3--(heptan“4-yl)urea (188 mg, 67%) as a white solid, mp: 135-136 °C. NMR (500 MHz, CDG13): δ 0,93 (f 6H), 1.45 (m,6H), 1.53 (m5 2H)S 3.80 (hr s, 1H), 4.33 (d, IH), 6.00 (s, 1H), 6.95 (td, IH), 7.23 (dt, IH), 7,33 (dd, IH), 8.13 (dds IH). MS(M+H, 269).

The compound had an ΕΟ50 for activation of a hT!Rl/hTlR3 umami receptor expressed in an KEK293 cell line of 0,37 μΜ, arid when present at 1 μΜ enhanced the effectiveness of monosodium glutamate with an EC* ratio of 4 „95.

Prepared in a similar manner to example 158 using heptan-4-amine and 1-isocyanato-2;>4-dimethoxyheneene. Yield: 88%. mp: 1.72473 °C. *H NMR (500 MHz, GDCla): δ 0.93 (t, 6H), 1.45 (ms 8H), 3.82 (s„ 3H), 3.83 (m, IH), 3.84 (s„ IH), 4,32 (hr s, 1H), 6.34 (hr s, IH), 6.49 (d, 1H), 6.50 (s, IH), 7.71 (d, 1H). MS (M+H, 295).

The compound had an EC® for activation of a h'flRl/hTlR3 umami receptor expressed in an HEK293 cell line of 0.9S μΜ, and when present at 0.3 μΜ .enhanced the effectiveness of monosodium glutamate with an EC® ratio of 7,:61,

Prepared in. a similar manner to example 158 using 2~(p)qidine-2~yl)efhanamme ant l-ethoxy-4-isoeyanatobeimene. Yield: 95%. mp: 163464 “C. 5H NMR (500 MHz, CDCI3): δ 1,43 α 3H), 3.03 (,t? 2H), 3.68 (t, 2H), 4.03 (¾ 2H), 5.69 (br s, iH), 6.45 (br s, IH), 6.84 (m, 2H), 7,14 (m, 3H), 7.20 (d, IH), 7.64 (dt; IH), S.43 (dd, IH), MS (M+H,2S6).

The compound had an EC50 for activation of a IiT1R1/1iT1R3 umami receptor expressed in an HEK293 cell line of 4,1 μΜ, and when present at 1 μΜ enhanced the effectiveness of monosodium glutamate with an EG» ratio of 4.2 .

Prepared in a similar maimer to example 158 using 2-(pyridine-2~yl)ethanamme am I-isoeyaisato~4-isopropylbenzene. Purified via column chromatography (1% MeOH in CH2CI2 to 3% MeOH in CH2CW) to afford l~(4-isopropylphenyl)“3-{2~(pyridine-2-yl)ethyl)urea (130 mg, 50%) as a white solid, mp: 72-73 SG. lH NMR (500 MHz, CDCIj): δ 1.25 (d, 6H), 2,89 (m5 1H\ 3.06 (t, 2H), 3.70 (t, 2H), 5.80 (hr s, 1H), 6.55 (br s, 1H), 7.19 (m, SH), 7.24 (d, 1H), 7.68 (dt, 1H), 8.46 (d, 1H). MS (M+H, 284). ; The compound had an EC50 for activation of a hTlRl/h:TIR3 uisarai receptor expressed in an HEK293 cell Ime of 0 98 μΜ.

Additional “urea” compounds were synthesized and experimentally tested and found to have a relatively high level of effectiveness as an activator of a hTlRl/hTlR3 umaffii receptor expressed in an HEK293 cell line. The results of that testing are shown below in Table €.

Numerous amide compounds of Formula (I) that fall within the suhgenus of "acrylamide” compounds descuhed elsewhere herein were also synthesized and experimentally tested for effectiveness as activator of a hTlRl/hTlR3 .umami receptor expressed in an HEK293 cell line. The results of that testing are shown below in Table D.

Ilmamj/Sav'Qry Flavor Bspedmeate Using Human Panelists:

General Panelist Selection: Basic screening of sensory taste testers: Potential panelists were tested for their abilities to rank and rate intensities of solutions representing the five basic tastes. Panelists ranked and rated intensity of five, different concentrations oi each of the five following compounds: sucrose (sweet), sodium chloride (salty), citric add (soar), caffeine (bitter), and monosodium glutamate (savory). In order to be selected for participation in testing, panelists needed to correctly rank and rate samples for intensity, with a reasonable number of errors.

Preliminary Taste Tests: The panelists selected in the above procedure were deemed qualified for perfonning Preliminary Taste Testing procedures. The preliminary taste tests are used to evaluate new compounds for intensity of basic tastes and off-tastes. A small group of panelists (n~5) taste approximately 5 concentrations of the compound (range typically between MOO μΜ, in half-log cycles, e.g., 1, 3. 10, 30, and 100 μΜ) in water and in a solution of 12 mM MSG to evaluate enhancement. Panelists rate the five basic tastes (sweet, salty, sour, hitter, and sa vory) as well as off-tastes (such as chemical, metallic, sulfur) on a labeled magnitude scale. Samples are served in 10 mL portions at room temperature. The purpose of the test is to determine the highest concentration at which there is no objectionable off-taste, and determine if obvious savory taste or enhancement of savory taste exists at any of the concentrations tested. if the compound is effective and does not have objectionable off-tastes, it is tested with a trained (expert panel) ih a larger study.

Trained Panelist Selection: A trained expert panel was used to further evaluate compounds that had been tested with the preliminary taste test.

Panelists for the trained panel were- selected Tom the larger group of qualifying taste panelists. Panelists were further trained on savory taste by ranking and rating experiments using MSG and IMP cosnhinations. Panelists completed a series of ranking, rating, and difference Horn reference tests with savory solutions. In ranking and rating experiments, panelists evaluated easy MSG concentrations (0, 6, 18. 36 mM) and more difficult MSG concentrations (3, 6, 12,18 inMMSG) in water.

Compound testing with Trained Panel: Compounds tested by the trained panel wok evaluated in difference from reference experiments. Panelists were given a reference sample (12 mM MSG + 1.00 μΜ IMP) and asked to rate samples on a scale of-5 to +5 in terms of difference in savory taste horn the reference (score: -5 = much less savory' taste than the reference; 0 ~ same savory taste as the reference; -H> ~ much more savory taste than the reference). Test samples were solutions with varying amounts of MSG, IMP, and the compound. Typically, each session compares the reference sample to numerous test samples .Tests typically included various samples with varying concentrations of MSG ane IMP, as well as one blind sample of the reference Itself, to evaluate panel accuracy.

Results of the taste tests are describe in table 3 and shows that compounds of the invention have been found to provide savory taste or enhancement of the savory taste at 3 μΜ + MSG when compared to 100 gM IMP TMSG. Compounds were tested against the reference in samples with and ’without 12 mM MSG. All samples were presented in 10 ml volumes at room temperature. Two sessions ’were completed for each compound tested to evaluate panel reproducibility.

Taste Test in Product Prototype: could he done similarly as described above.

Table 3. Savory Taste Test Results

Numerous amide compounds of Formula (I) were synthesized and experimentally tested for effectiveness as activator of a hTlR2/hTlR3 “sweet” receptor expressed in an HEK293 cell line. Examples of the synthesis and biological effectiveness testing in terms of Sweet EC50 measurements for such sweet compounds are listed below. Moreover, mail] of the ‘‘sweet” amides of Formula (I) were also screened for activity in the umaini EC50 ant ECso ratio assays, and as illustrated below, some of the amide compounds of Formula (I) have significant activity and potential to simultaneously serve as savory and sweet taste enhancers for use in comestible and medicinal products and compositions.

2,3,5,6 -ietrafiuoro-jMolmc acid add (4.00 g, 19.22 mmol), KGBt (5.19 g, 38.44 mmol) and EDCI (4.42 g 23.06 mmol) were mixed in 200 ml of anhydrous DCM and 30 ml of anhydrous DMF. The mixture was cooled to 0°C and allowed to stir under Ar for 15 minutes. To the mixture was added 2-methyicydlohexanamine (3..05 ml. 23.06 mmol) and the reaction mixture was allowed to slowly warm to ambient temperature and stirred overnight The reaction mixture was diluted with DCM, washed with IN HCS, water. aqueous NaHCCh, water and brine, drying over MgSCE, filtration and removal of solvent ή vacua, afforded the crude product as a pale yellow solid Recrystallization (EtOIMEQ) ant drying in vacuo gave 5.23 g of the title compound as a white solid (mixture of 2 diasteromers, 90%). *H NM'R (CDCR) δ 0,95,1.01 (d3 J+ 7.0, 6,6 Hz, 3H) U-2.1 (an, 9H). 2.29 (m, 3H), 3.70,4.29 (m, 1H), 5.65, 5.92 (m, 1H). MS ( 304.1, M+H). m. p. 202204 °C.

The compound had an F-C-,,λ for activation of a IiTlE2/hTlR3 sweet receptor expressed in axiHEK293 cell line of 0.39 μΜ.

Prepared in a similar manner to Example 162 using (S)-3-methylbutan<2-amine and 2,3,5,6 -tetrafluoro-p-toluic acid acid (93%), !K NMR (CDCI3) δ 0,98 (d, T::: 6,9 Hz, 6H) 1.18 (d, 1=== 6.8 Hz, 3H), 2,29 (m, 3H), 4,09 (m, 1H), 5.72 (bs, 1H).MS ( 304.1, M+H ) m. p 146-147 °C.

The compound had an E.C50 for activation of a h.TlR2/hTlR3 sweet receptor expressed m an HEK293 cell line of 0.6 μΜ.

Prepared in a similar manner to Example 162 using cycloheptylamine and 2,3,5,6 -tetraOuoro-p-toluic acid (94%). Ή NMR (CDCI3) δ 1.53 (m, 61i), 1.57 (an, 411), 2.03 (an, 2H) 2.28 (m, 3H), 4.17 (an, 1H), 5.85 (bs, 1H).MS (3041, M+H) an. p. 164465 nC.

The compound had an EC53 fcr activation of a hT!R2/hTlR3 sweet receptor expressed in an HEK293 cell line of 1.85 μΜ.

Prepared in a similar manner to Example 162 using 2,4-difneihylpesitan-3-amine and 2,3,5,6 -tetrafluoro-p~tolnic acid (90%). Ή NMR (CDCI3) δ 0,91 (d, J ~ 6.7 Hz, 6H), LOO (d, J = 6.8 Hz, 6K), 1.85 (m, 2H), 2,29 (m, 3H), 3,82 fm, 1H), 5.52 (bd, 1H).M3 (.306.1, M4-H) m. p. 184487 °C.

The compound had an EC50 for activation of a hT!R2/hTlR3 sweet receptor expressed in anHBK293 cell line of 0.81 [rM.

Example 166

To a solution of 3-methyhsoxazole~4-carboxylic acid (83 mg, 0.0.67 mmol), HOBt (100 mg, 0.74 mmol) and EDCTHC1 (142 mg, 0,74 mmol) in DMT (4 mL), was added 5,7-dimeihyl-l,2,3,44etrahydronaphthyl4--amine (example 166a) (130 mg, 0,74 mmol). The reaction mixture was stirred for 24h at rt, at which time the solvent was removed under reduced pressure and the residue was purified by flash-column chromatography (10:1 Hex:EOAc) ίο afford 134 mg of /7-(5,7-dimeihyI4J2,3J4-lehahydronaphtbalen4-y 1)-3-methylisoxazole-AearboxamMe. (70 %) as a white foamy solid, Ή NMR (500 MHss, DMSO-de): δ 1.74 (m, 2H), 1.86 (m, 2H), 2.16 (s, 3H), 249 (s, 3H), 2.43 (s, 3H), 2.55 (m, 2H), 540 (m, 1H), 6.86 (s, 1H), 6.89 (a, 11¾ 8.60 (d, 1H, 7- 8.40 Hz), 9.27 (s, 1H). 1iC NM.R (125 MHz, DMSO-dg) δ 10.6, 19,1, 19.6, 20.6, 25.8,29.4,46.9, 115.4, 126.4,129.1, 132.6, 134.1,135.8, 136.6, 158.5, 159.6, 159.9. MS(M+H, 285). Mp 57-58 °C. a. 5,7-dimethyl-1,2,3,4-tetrahydronaphthalen-l-aminb: A catalytic amount of

Raney nickel (slurry in water) was wfash«d with dry MeOH under argon in a round bottom flask. To a solution ofThe washed Raney Ki in methanolie ammonia (25 mL, 7N), was added 5,7Mi:methyI-3:!4-dihydronaphthalen4(2H)-one oxime (example 166b) (420 mg, 2.22 mmol), and the mixture was stirred under a balloon of 1¾ for 20 hr. Upon completion the reaction was filtered through celite, the filtrate was concentrated in vacuo, diluted with EtOAC, washed with water and brine, dried over MgSCU, filtered and the solvent was removed under reduced pressure to afford 360 mg of 5:?-dimethyl4,2,3,4-tetrahydronapfithalen-l-amine (93 %). NMR (500 MHz, CDCI3): δ 1,66-1.S3 (m, 411), 1.96 (m, 2H), 2.19 (s, 3H), 2.28 ( s, 3H), 2.5S (m, 1H), 2.66 (m, 1H), 3,97 (in, 1H), 6,88 (s, ill), 7.09 (s, III). b. Preparation of 5,7-dimethy!-3,4-dihydronaphthalen-l(2H)-one oxime: To a mixture of5,7-dimethyl-3,4~dihydronapbthalen-l(2H)-one (2.0 g, 11.48 mmol) and hydroxylamine hydrochloride (1.6 g, 19.73 mmol) in 10 ml ofivater at 70 °C, were added MeOH (14 mL), THE (3 mL) and a solution of sodium acetate ( 2.53 g, 30.83 mmol, in 7 mL oi'HvQ). Stirring was continued fa- 85 min at 70 °€, at which time a precipitate was formed and 10 ml of w'ater were added. The resulting mixture W'as stirred at room temperature for 2 hr. Upon completion, the product was collected by filtration to afford 2.12 g of 5.7-dimethyl-3,4-dihydronaphthalen4(2H)-one oxime (98 %). MS (M+H, 190),

The compound had an EC® for activation of a hlTR2/hTl.R3 sweet receptor expressed in an HEK293 cell line of0.76 μΜ.

Prepared in similar manner to Example 166uaing 5-methoxy-l,2,3,4-tetrahydronaphthalen-1-amine (Example 167a). Yield 40 %. Ή NMR (500 MHz, DMSO-ds): 5 L73 (m, 1H), 1.83 (m, 1H), 1.96 (m, 2H), 2.61 (m, 2H): 3.78 (s, 3H), 5.27 (m, 1H), 6.78 (d, 1H, /- 7.82 Hz), 6.86 (m, 2H), 7.14 (t, 1H,./- 7.98 Hz), 7.60 (dd, 1H, /- 7.88, 1.30 Hz), 7.94 (dd, lH,/~ 8.03, 1.39 Hz), 9.30 (d, IB,./- 8.06 Hr), 13.80 (s, 1H). BC NMR (125 MHz, DMSO-de): δ 19.5,22.7,28.9,47.4, 55.3, 108.6, 115.8,118.7,119.8, 121.1, 125.9,126.2, 126.4,133.8, 07,3, 156.7,156.8,168 7. MS(M+H, 332). Mp 175-176 °C. a. 5-methoxy-l,2.,3,44etrahydt^naphthalen-1-amine: Prepared in a similar maimer to example 166a using 5-meihoxy-3s4-dihydronaplithalen--l(2H)-one. Yield 94 %. ΉMMR (500 MHz, CDCK): δ 1,63-1.79 (m, 4H), 1.94 (a, 2H), 2.60 (m, 1H), 2.71 ( m, 1H ), 3.82 ( s, 3H ), 3.97 ( m, 1H), 6.71 ( d, 1H ), 7.02 ( d, 1H ), 7.17 (t, 1H ).

The compound had an BCs&amp; for activation of a hTl.E2/hTl.R3 sweet receptor expressed in. an HEK293 cell line of 0,21 μ,Μ.

Prepared in a similar manner to Example 162 using 2,6-dimethylbenzoie acid and 2-methyleyelohexylamine. Yield: 59%. NMR (500 MHz, CDCIj): δ 0.88-0.94 (3H, dd), 1.14-1.89 (9H, m), 2.21-2.22 (6H. d), 3.39-3,45 (1H, m), 7.02-7,03 (2H,d), 7.12-7.15 (l.H, t), 8.11-8.13 (1H, d). MS(M+H, 246.2).

The compound had an EC50 for activation of a hT!E2/hTlR.3 sweet receptor expressed in an HEK293 cell line of 1.88 μ,Μ,

Prepared in a similar manner to Example 166 using 4~meihoxy~2,6-dimethylbensoi acid (example 169a) and 2~meth.ylGyclohex.ylam.ine, Έ NMR (500 MHz, CDCI3): δ 0.860.92 (3H, dd), 1.00-1.85 (m,9H), 2.18- 2.19 (6H, d), 3.33-3.45 (1H, m), 3.71-3 72 (3H, d), 6.59 (2H, s), 7.98-8.05 (1H, m). MS (276.2, M+H ) a. 4-methoxy-2,6-dimethylbenzoic acid: 2-Bromo-5-meilioxy-l,3-dimethyl benzene (example 169b) (3.38 g, 15.79 mmol) was without further purification dissolved in 100 ml of dry THF. The mix ture was cooled to -78e€ and under argon n-butylliihinm (1.6 M solution in hexanes, 9.9 ml, 15,8 mmol) was added drop wise over 15 min and the mixture was stirred for 15 more min at -78¾. Than small pieces of dry ice were added and the mixture was stirred 20 min at ~78°C. Then the cooling was removed and the mixture 'was stirred as long as evolution of carbon dioxide continued. Then the mixture was poured over ice (100 ml) and acidified using 6N HCL The organic layer was separated and water phase was extracted with EtOAe. Organic extracts were combined, washed with brine, water, dried over MgSCb and concentrated under vacuum. The product 4miethoxy~2,6~dimethyTbenzoic add was obtained as a white solid (2.7 g, 95%). (MAH, 181). b, 2~Bromo-5-inethoxy-ls3'dimethylbeiizene : 20 mmol ofl-msthoxy-3,5" dimethylbenzene (2.82 ml) was dissolved in 1QG ml of dry acetonitrile followed by 22 mmol (3.56 g) of N-bromosuccinimide. The mixture was stirred at room temperature overnight. Then the solvent vas evaporated under reduced pressure and a solid was filtered off and washed with hexanes providing 2~hromo~5-methoxy~l,3-dimethylbensene (3.9 gs 92%) as white solid. {HNMR (500 MHz, CDCh,): δ 2.41 (6¾ s), 3.78 (3H, s), 6.67 (2¾ s).'

The compound had an ECjq for activation of a hTlR2/hTlE3 sweet receptor expressed in an HEK293 cell Sine of 2,1 μΜ.

To a solution of furan~3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.7S mmol) and EDCTHCI (196 mg, 1.03 mmol) in CH2C12 (8 rnL) and DMF (1.5 mL) at 0 °C, was added (i?)-l,2s3,4-tetralsydronaphtlialen-l-amine (160 μΕ, 1.06 mmol). The reaction \yas stirred at rt for 24h, after which CHjC% was added. The resulting solution was washed with saturated NaHCOa, H2O, brine, dried over MgSCE and concentrated in vacuo, Recrystallization from EtOH/HzO afforded (i?)“M“(l,2,3,4-tetrahydronaphthalen-l“yl)-2,5-dihydroforan-3-carboxamide. fHNMR (500 MHz, CBCI3): 0 1.89 (m, 3H), 2.12 (m, 1H), 2.84 (m, 2H), 5.35 (m, 1H), 5.96 (br d, 1H, J = 7.75 Hz), 6.59 (dd, 1H, J = 1.90, 0.86 Hz), 7.23 (m, 2Η), 7.19 (m, 2H), 7.32 (m, IH), 7.43 (t, ill, J- 1-73 Hz), 7.93 (τη, IK). MS(M+H, 242).

The compound had an ECso for activation of a hTlE27hTlR3 sweet receptor expressed in an ΗΈΚ293 cell line of 6.6 μΜ.

Prepared in a similar manner to Example 170 using 5~methylisoxazole-4~carhoxylk acid. Purified by preparative TEC (5:1 Hex:EtGAc). *H NMR (500 MHz, CDCI3): S' 1.80 {m, 3H), 2.12 (rn, IH), 2.74 (¾ 3H), 2.85 (rn, 2H}, 5.35 (m, 1H), 5.89 (br d, lH,/= 7.75 Hz), 7.10 (m, 1H), 7.18 (m, 2U), 7.32 {m, 1H), 8.26 (s, Hi). MS(M+H, 257).

The compound had an EC50 for activation of a hTl.R2/hT!R3 sweet receptor expressed in an HBK293 cell line of 8.1 pM-

To a solution ofisoindoiine (238 mg, 2,0 mmol) in dry 1,4-dioxane (10 ml .) was added 4-ehloro-2-mstliylplienyI isocyanate (335 mg, 2,0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight The solvent was evaporated under reduced pressure, and the residue was purified by recrystallization from ethanol to give the title compound (540 mg, 94 %) as a white solid. Ή NMR (500 MHz, DMSO-ds): δ 2,24 (s, 2H), 4.76 (s, 4H), 7.20 (dd, 1 - 2.5, 8.5 Hz, IH), 7.27 (d, J - 2.5 Hz, Hi), 7.30-7.32 (m, 2H), 7.34-7,37 (m, 2H), 7.42 (d, J - 8.5 Hz, HI), 7.84 (s, 111); nC NMR (DMSO-dft): 5 17.7, 51.9, 122.8, 125.6, 126,8, 127.3,128.1, 129.5,134.7,136.8, 154.2; MS(MH\ 287); EA calc’d for CifJJisClNsO: C, 67.02; H, 5,27; N, 9.77; Found C, 66.82; H, 5.41; N, 9.92.

The compound had an ECsq for activation of a hTlR2/hT!R3 sweet receptor expressed in an HEK293 cell line of 0.89 μ-Μ.

To a solution ofisoindoline (576 mg, 4.0 mmol) in dry 1,4-dioxane (20 ml.) was added 4-xnethoxy-2-methylphenyl isocyanate (815 mg, 5.0 mmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight The solvent was evaporated under reduced pressure, and the residue was purified by cinematography on silica gel (EtOAc/hexanes: 1:1) to give the title compound (1.18 g„ 84 %) as a white solid, JH NMR. (500 MHz, DMSOdg); δ 2.19 (s, 3H), 3.72 (s, 3H), 4.73 (s, 4.H), 6.72 (dd, 3 - 2.5 Hz, 8.5 Hz, 1H), 6.78 (d, J - 2.5 Hz, 1H), 7.17 (d, 3 - 8.5 Hz, 1H), 7.30-7.32 (ηι, 2H), 7.34-7.36 (m, 2H), 7.74 (s, 1.H), i3C NMR £DMSO~de): δ 18.2, 51.9, 55.1,110.9, 115.1, 122.8,127.2, 127.8,130.6,135.1,137.0, 154.9, 156.5; MS£MH*, 283); EAcale’d for C}7Hi8N.2Q2: C, 72.32; TL 6.43; N, 9.92; Found C, 72.16; H, 6.82; N, 9.98.

The compound had an EC$q for activation of a hTiR2/h’HR3 sweet receptor expressed in an HBK293 cell line of 4.5 μΜ.

Ernmnle 174

To a solution of 3,4-(melhytenedioxy)amlme (150 mg, 1.09 mmol) in dry PCM (4 mL) was added dropwise phenyl chloroformate (0.138 ml, 1.09 mmol) and ihethylaroine (0,153 ml, 1.09 mmol). After the reaction mixture was sthred at r.t for 8 hr,, isoindoline (0.123 ml, 1.09 mmol) and triethylamine (0.153 ml, 1.09 mmo) were added, and the reaction mixture was stirred overnight The solvent was then removed under reduced pressure, and the residue was purified by chromatographed on silica gel (EtOAC/Hexane: 1:3) to give the title compound (185 mg, 60%) as a white solid: m.p:165-166 CC, ! IT NMR (CDCIs, 500 MHz): 4.82 ( s, 4H); 5.93 (s, 2H); 6.20 (s, 1H), 6.73 (s, 2H); 7.17 (s, 1H ); 7.30 (a, 4H). MS {MH7,283),

The compound had an EC*o ior activation, of a hTLR2/hTlK.3 sweet receptor expressed in anH£K293 cell line of 1.05 μΜ.

Example 175

To a solution of 3-Methyl"isoxazo3e-4~carboxyIic acid (0.52 g, 4.06 mmol) inDCM (.15 ru'Lj and DMF (2 mL), was addedHOBi (LI g, 8,14 mmol) and EDO (0.896 g 4.67 mmol). The clear yellow solution was cooled to 0 C and allowed to stir under /hr for 15 minutes. To the solution was added (R)-l-Amino-L2,3,4-tetrahydronaphthalene (0.73 mL. 5,04 mmoland the reaction mixture was allowed to slowly warm to ambient temperature and was stared for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCOj water, brine (50 mL), drying over MgSGa, filtration and removal of solvent Pi vacuo. Silica gel chromatography (0- 25% HexaneiEtOAe) afforded the title compound (650 mg; 62,5 %) as a sticky solid. H NMR (CDCL,) 6 1,88 (m, 3H), 2.12 (m, l.H), 2.51 (s, 3H), 2.81 (m, 2H), 5.32 (m, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (m, 2H) 7.20 (m, 2H); l3C NMR (CDCI3) δ 11.22, 20.15,29.41, 30.35, 47.93, 116.73, 126.72, 127.88,128.88, 129.65, 136.25, 138.00, 158.45, 160.28. ESMS: 257 (M*H) FA cak’d fa GTLs'XjCL: C, 70.29; H, 6.29; N, 10.93; found C, 70.61; H, 6.11; N, 11.09. >

The compound had an ECiC, for activation of a hTIR2/.hTlR3 sweet receptor expressed in an HEK293 cell line of 5.8μΜ.

Numerous amide compounds of Formula(I) were also synthesized and experimentally tested for effectiveness as activator of a hTlK2;hTlR3 “sweet” receptor expressed in an HEK293 ceil line.

The results of that testing are shown below in Table E,

Sweet Flavor and Sweet Flavor Enhancement Measurement IMng Human Panelists Purpose: To investigate the intensity of various· tastes and off-tastes of an experimental compound T o determine the maximum concentration of the experimental compound that does not elicit an undesirable characteristic or off-taste.

Overview: Various concentrations of the experimental compound (normally aqueous solutions containing 1, 3,10, and 30uM concentrations of the experimental compound; and optionally 50uM and/or lOOuM concentrations) are individually tasted by trained human subjects and rated for intensity of several taste attributes. The experimen tal compound may also be tasted when dissolved in a “key tastant” solution.

Procedure: An appropriate quantity' of the experimental compound is dissolved in water typically also containhg 0,1% ethanol, which is utilised to aid initial dispersion of the compound in the aqenous stock solution . When appropriate, the experimental compound may also be dissolved in aqueous solutions of a “key tastant” (for example, 4% sucrose, 6% sucrose, 6% ffuetose/glucose, or 7% fiructose/glucose, at pH 7.1 or 2.8).

Five human Subjects are used for preliminary taste tests. The Subjects have a demonstrated ability to taste the desired taste attributes, and are trained to use a Labeled Magnitude Seale (LMS) from 0 (Barely Detectable Sweetness) to 100 (Strongest Imaginable Sweetness). Subjects retrain from eating or drinking (except water) for at least 1 hour prior to the test. Subjects eat a cracker andrinse with water four times to dean the month before taste tests.

The aqueous solutions are dispensed in 10 nil volumes into 1 oz. sample cups and served to the Subjects at room temperature. Samples of the experimental compound dissolved in an appropriate key tastant (e.g., 4% sucrose, 6% fructose, or 6% fruetose/glucose, typically at pH 71) at var ious concentrations of the experimental compound may also be served to the Subjects. Subjects also receive a reference sample of the key tastant (e.g., sucrose, fructose, or fruetose/glucose, typically atpH 7.1) at different concentrations for comparison.

Subjects taste the solutions, starting with the lowest concentration, and rate intensity of the following attributes on the Labeled Magnitude Scale (LMS) for sweetness, saltiness, sourness, bitterness, savory (umanti), and other (off-taste). Subjects rinse three times with water between tastings. If a particular concentration, elicits an undesirable characteristic or off-taste, subsequent tastings of higher concentrations are eliminated. After a break, Subjects taste a solution of the key tastant (e.g., 4% sucrose, 6% fhsetose, or 6% fruetose/glucose, typically at pH 7,1) without the experimental compound. Then solutions o f the key tastant plus experimental compound are tasted i n increasing order of concentration. The key tastant sol ution can be retasted for comparison with key tastant + experimental compound solutions if necessary. Discussion among panelists is permitted.

The maximum concentration of an experimental compound that does not elicit an objectionable characteristic or off-taste is the highest concentration that a particular compound will be tested at in subsequent sensory experiments. To confirm preliminary test results, the test may be repeated with another small group of panelists.

The preliminary profiling test is always the first test performed on a new experimental compound. Depending on the results of the preliminary profiling test, additional more quantitative tests may be performed to further characterize tire experimental compound. “Difference from Reference55 Homan Taste Test Procedures

Purpose: To determine how the intensity of a test sample of an experimental compound differs from that of a reference sample in terms of sweetness. This type of stud; requires a larger panel (typically 15-20 Subjects) in order to obtain statistically significant data.

Overview; A group of 10 or more panelists taste pairs of solutions ’where one sample is the “’Reference” (which typically does not include an experimental compound and is an approved substance or Generally Recognized As Safe (GRAS) substance, he., a sweetener) and one sample is the “Test15 (which may or may not include an experimental compound). Subjects rate the difference in. intensity of the test sample compared tofhe reference sample for the key attribute on a scale of---5 (much less sweet than the reference) to ~i-5 (much more sweet than the reference). A score of 0 indicates the test sample is equally as sweet as the reference.

Procedure:

Ten or more Subjects are nsed for the ‘"Difference from Reference” tests. Subjects have been previously familiarized with the key attribute taste and. are trained to use the -5 to +5 scale. Subjects refrain from eating or drinking (except water) for at least 1 hour prior to the test. Subjects eat a cracker and rinse with water four times to clean the mouth.

Test solutions can include the experimental compound in water, fee experimental compound plus a key tastant (e.g., 4% sucrose, 6% sucrose, 6% fructose, 6% fmctose/glucese, or ?% fructose/glucose, at pH 7.1 or 2.S), and a range of key tastant only solutions as references. > Samples of the key tastant without the experimental compound are used to determine if the panel is rating accurately; he., the reference is tested against itself (blind) to determine how accurate the panel is rating on a given test day. The solutions are dispensed in 10 ml volumes into 1 ox, sample cups and served to the Subjects at room temperature.

Subjects first taste the reference sample then immediately taste the test sample and rate the difference in intensity of the key attribute on the Difference from Reference scale (-5 to +5). All samples are expectorated. Subjects may retaste the samples but can only use the volume of sample given. Subjects must rinse at least twice with water between pairs of samples. Eating a cracker between sample pairs may be required depending on the samples tasted. :

The scores for each test are averaged across Subjects and standard error is calculated. Panel accuracy can be determined using the score from the blind reference test. ANOVA and multiple comparison tests (such as Tulcey’s Honestly Significant Difference test) can be used to determine differences among pairs, provided the reference sample is the same among all tests. If the identical test pair is tested in another session, a Student’s t* test (paired, two-tailed; alpha - 0.05) can be used to determine if there is any difference in the ratings between sessions, A number of different reference sweeteners have been, utilized for the measurement of sweet taste enhancement For example, for testing (R)-3-meihyl~N-(l ,2,3,4-tefi‘ahydronaphihalen-i-yl}isoxaxole~4~carboxamide, a reference sample consisting of 4% sucrose was used, which has a greater than the threshold level sweetness (i.e., 2% sucrose) and a sweetness in the region of sweet taste perception where human subjects are most sensitive to small changes in sweet taste perception, For the testing of 2,3>S,6-teirafliioro-4 inethyl-N-(2-inethylcyciohexyi}benKamide, a 50:50 mix ofnnctose:glucose was used to better model high fructose com syrup solutions commonly utilised in the beverage industry, A 6% fructose/glucose mixture was demonstrated to be approximately equal in sweet taste perception as 6% sucrose, which is within the range where panelists are sensitive to small changes in sweet taste perception. Alter initial studies in 6% fructose/glucose at pH 7.1, studies shift to eval uating the performance of the compound in a product prototype more similar to a cola beverage, i.e. higher concentrations of sweetens and lower pH.

The results of some human taste tests o f the sweet amide compounds of the invention in aqueous compositions intended to model the composition of a carbonated beverage are shown below in Table F

Table F. Sweet T aste T est Results

Hmxv Fremmnio» IMPg an Ethanol Slock Solution A compound of the in ven tion is diluted using 200 proof ethanol to 1000¾ the desired concentration in soup. The compound can be sonicated and heated (if stable) to ensure complete solubility in ethanol. The soup from bouillon base is made by adding 6 g of vegetable bouillon base in 500 mLof hot water in a glass or stoneware bowl. The wate is heated to 80°C. The concentration of MSG in the dissolved bouillon is 2.2 g/L and there is no IMF added. After the bouillon base is dissolved, the ethanol stock solution is added to the soup base. For 500 mL of soup, 0,5 mL of the 1QOQx ethanol stock is added for a final ethanol concentration of 0.1 %. If the ethanol interferes with the taste ofthe soup, a higher concentration of ethanol stock solution can be prepared provided, the compound is soluble. A salt mixture of a compound ofthe invention is made by mixing with salt such tha a 1,4% ofthe salt mixture added w/w to chips would result in the desired concentration of the compound For 1 ppm final ofthe compound on chips, 7 mg ofthe compound Is mixer with 10 g of salt The compound is ground using a mortar and pestle with the salt and the compound and salt are mixed 'well. The chips are broken into uniform small pieces by using a blender. For each 98.6 g of chips, 1,4 g of the salt mixture is weighed ©ut. The chip pieces are first heated in a microwave for 50 seeonds or until warm. The pieces are spread out on a large piece of aluminum foil. The salt mixture is spread evenly over the chips. The chips are then placed in a plastic bag makng sure that all the salt is place in the bag as well. The salt mixture and chips are then shaken to ensure that the salt is spread evenly over the chips.

Cookie Fyenayaffo-n A compound ofthe invention is diluted nsing 200 proof ethanol to IQOQx the desired concentration in the final product The compound can he sonicated and heated (if stable) to ensure complete solubility in ethanol, The solution containing the compound of the invention is then mixed with other liquid ingredients (i.e., water, liquid egg, and flavorings) until well blended. The mixture is blended with a dry emulsifier such as lecithin and further blended with shortening. The shortening is blended with dry components (ie„ flour, sugar, salt, cocoa) which have beers well mixed. Dough is portioned out onto a baking sheet, and baked at desired temperature until done.

Example 179 Juice Preparation A compound of the in vention is diluted using 200 proof ethanol to lOOOx the desired concentration in juice. The compound is further blended with the alcohol component of natural and/or artificial flavors to make a “key55. The flavor key is blended with a portion of juice concentrate to assure homogeneity. The remainder of the juice concentrate is diluted with water and mixed. Sweeteners, such as H.FCS (High Fructose Com Syrup), aspartame, or sucralose, are mixed in and blended. The ilavor/compound portion is added as a final step, and blended. A compound of the invention is added as a dry ingredient to the spice blend and blended thoroughly. Spice blend is dispersed into a portion of th e tomato paste, blended, and that blended paste is further blended into the remaining paste. The paste is then dilutee with water. It may be processed at high temperature for a short time.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from tire scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein, fi is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims (295)

1. WE CLAIM: L A method for modulating the taste of a comestible or medicinal product comprising a) providing at least one comestible or medicinal product·, or a precursor thereof, and b) .combining the comestible or medicinal product or precursor thereof with at least a savory flavor modulating amount of at least one non-naturahy occurring amide compound, or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product; wherein the amide compound has the formula: O jl, .,E2 R ΊΤ R:i wherein R1 comprises a hydrocarbon residue having at least three carbon atoms and optionally one to ten heteroatoms independently selected horn oxygen, nitrogen, sulfur, halogens, or phosphorus; and wherein one of R2 and R3 is H the other of R2 and RJ comprises a hydrocarbon residue having at least three carbon atoms and optionally one to ten heteroatoms independently selected, from oxygen, nitrogen, sulfur, halogens, or phosphorus: and wherein the amide compound has a molecular weight of 500 grams per mole or less.
2. 2. The method of claim 1 wherein the amide compound has a molecular weight from 175 to 500 grams per mole.
3. 3. The method of claim 1 wherein the amide compound has a molecular weight from 200 to 450 grams per mole.
4. 4. The method of claim 1 wherein the amide compound has a molecular weight from 225 to 400 grams per mole,
5. 5. The method of claim 1 wherein the amide compound has a molecular weight from 250 to 350 grams per mole,
6. 6. The method of claim 1 wherein Rs and one of R2 and RJ have between 3 and 14 carbon atoms.
7. 7. The method of claim 2 wherein R1 and one ofR* and R.J have between 4 and 12 carbon atoms.
8. 8. The method of claim 1 wherein R1 and one of Ed and RJ have between 4 and 10 carbon atoms.
9. 9. The method of claim 1 wherein R: has between 3 and 16 carbon atoms and 0, 1. 2, 3,4, or 5 heteroatoms selected from oxygen, nitrogen, sulfur, fluorine, or chlorine.
10. 10. The method of claim 1 wherein one of R2 or R3 has between 3 and 16 carbon atoms and 0, 1., 2, 3.4, or 5 heteroatoms independently selected h orn oxygen, nitrogen, sulfur, fluorine, or chlorine.
11. 11. The method of claim 1 wherein one of R* or R3 has between 4 and 14 carbon atoms and 0, 1, 2, 3,4, or 5 heteroatoms independently selected Rom oxygen, nitrogen, sulfur.
12. 12. The method of claim 1 wherein one of R" or R3 lias between 5 and 12 carbon atoms and 0, 1, 2, or 3 heieroatoms independently selected from oxygen, nitrogen, and sulfur.
13. 13. The method of claim 1 wherein R; has between 3 and 16 carbon atoms and G , 1, 2, 3, 4, or 5 heteroatoms selected from oxygen, nitrogen, sulfur, fluorine, or chlorine, and one ofR' or R3 has between 5 and 12 carbon atoms and 0, 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
14. 14. The method of claim 1 wherein R1 and one ofR2 and R3 are independently selected from the group consisting of an arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl, cycloaikyl, cycloalkenyl, aryl, heteroaryl, ~R4OH, -R'O E5 -R4CN, -R'tXbfl, ~Ε4ί%:Ε5, -R4COR5, -R4SR5, and -R4SQ2Rs, and optionally substituted derivative thereof comprising 1, 2, 3, or 4 carbonyl, amino groups, hydroxyl, or halogen groups: and wherein R4 and R5 are ¢3-Cg hydrocarbon residues.
15. 15. The method of claim 7 wherein R: and one ofR'1 and R3 are independently selected from the group consisting of an arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl alkoxy-alkyl, alkenyl, cycloaikyl, cycloalkenyl, heterocycle, aryl, and lieteroaryl groups, and optionally substituted derivatives thereof comprising 1, 2, 3, or 4 sustituent groups, independently selected from hydrogen, hydroxy, fluoro, chioro, NIR, MICH3, NiCfRR, CO2CH3, 5Et, SCH3, methyl, ethyl, isopropyl, vinyl, trifhioromethyl, methoxy, ethoxy, isopropoxy, and tdfluoromethoxy groups.
16. 16. The method of claim 1 wherein one ofR2 andR3 is a branched or cyclic organic-residue having a carbon atom directly bonded to (a) the amide nitrogen atom and (¾) two additional carbon atoms, and wherein die branched or cyclic organic residue comprises hydrogen atoms, up to 10 optional additional carbon atoms, and from zero to five heieroatoms independently selected from oxygen, nitrogen, sulfur, fluorine, and chlorine,
17. 17. The method of claim 1 wherein one of R2 and R3 has the formula (R2ak3 C c / <3—C-~H , ? \ C\ V.20U wherein na and nb axe independently selected from 1,2, and 3, and each. E2* or R2u substituent residue is independently selected from hydrogen, a halogen, a hydroxy, or an carbon-containing residue optionally having from zero to five heieroatoms independently selected from oxygen, nitrogen, snlfirr, an a halogen.
18. 18. The method of claim 1 wherein one of R2 and R3 is a branched alkyl radical having ' five to 12 carbon atoms,
19. 19. The method of claim 1 wherein one of R2 and R’ is a cycloalkyl or eycloalkenyi ring comprising 5 to 12 ring carbon atoms that can be optionally substituted with 1, 2,3, or 4 independently selected from hydrogen, hydroxy, iluoro, chloro, 19¾ M-ICH3, NfCHih, CCbCI-L·,. SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, meihoxy, ethoxy, isopropoxy, and triSuoromethoxy groups, 20. lire method of claim 1 wherein one of R2 and R3 has the structure > ,. .Ar (R?')m £ V V H? or wherein Ar is a phenjd, pyridyl. furanyl, thio&amp;ranyl, or pyrrole ring, m is 0,1, 2, or 3, each R2 is independently selected h orn hydrogen, hydroxy, Iluoro. chloro, 19¾ NHCH<, N(CH3)2, COjCHj, SEt, SCK3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, meihoxy, ethoxy, isopropoxy, and trifluoromethoxy and R2* is selected from the group consisting of an alkyl, alkoxy-alkyl, alkenyl, eycloalkenyi, cycloalkyl, -R4GH, -R40 Rs -R4CN, -K'tCkH, ~R4CQ2RS, -R4CORs, -R4SR5s and R4SO?R5 comprising 1 to 12 carbon atoms.
20. 21. The method of claim 1 wherein the amide compound has the formula:

    wherein A comprises a 5 or 6 membored aryl or hoteroaxyl ring; m is 0,1, 2,3 or 4; each R1 is independently selected from alkyl, alkoxy, alkoxy-alkyl, hydroxyalkyl, OH, CN, CGaH, CQaR^CHO, COR6, SR6, halogen, alkenyl, cycloalkyl, cyeloalkenyl, heterocyele, aryl, and heteroaryl; and R6 is CrC&amp; alkyl.
21. 22. The method of claim 21 wherein A is a phenyl ring or a pyridyl ring.
22. 23. The method of claim 22 wherein m is 1, 2, or 3. 24» The method of claim 23 wherein each Ri is independently selected from hydrogen, hydroxy, iluoro, chloro, 14¾. IxHCfL·, h-TCHj);·;, COOCHj, 80¾ SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromeihoxy, or a monocyclic aryl or heteroaryl group.
23. 25. The method of claim 21 wherein A is a phenyl ring and each RJ i s independently selected from hydrogen, hydroxy, iluoro, chloro, NfR, NHCfL·, NlCHs);?, COOCfh, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
24. 26. The method of claim 25 wherein R2 is a €2-(¾ branched alkyl
25. 27. The method of claim 21 wherein R5 is a Cs-Cja branched alkyl substituted -with one or two substituents independently selected from hydrogen, hydroxy, fiuoro, chloro, M-I2, NHCH3, N(CH3)3j O2CCH3, CO2CH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl. methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
26. 28. The method of claim 25 wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene ring or an 2,3-dihydro-lH-indene ring having the formula

    wherein m is 0,1,2, or 3, and each R2 can be bonded to either the aromatic or nonaromatic ling and is independently selected from hydroxy, fiuoro, chloro, 14¾ NHCHj, N(CH3)2j CO2CH3, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromeihoxy groups.
27. 29. The method of claim 25 wherein R?' is a phenyl ring optionally substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, NH-;, NHCH3, N(CH3)2, CO2CH3, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
28. 30. The method of claim. 21 wherein R2 is an «-substituted carboxylic acid or a-substituted carboxylic acid lower alkyl ester.
29. 31. The method of claim 25 wherein K3 is an «-substituted carboxylic add methyl ester.
30. 32. The method of claim 31 wherein the «-substituted carboxylic acid or «-substituted carboxylic acid ester residue, corresponds to that of a naturally occurring tr-amin© acid or an ester thereof, or its opposite enantiomer.
31. 33. The method of claim 21 wherein A is a monocyclic heteroaryi wherein each Rr is independently selected from, hydrogen, hydroxy, fluoro, chloro, 191¾½ NHCH3, N(CHj)2, CQQCH&amp; SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
32. 34. The method of claim 21 wherein A has one of the following form ulas

    wherein m is Os 1,2. or 3, and each R! is independently selected from hydroxy, .tluoro, chloro, NEb, NHCH.3, N(CHj}2, CO2CH3, SCH3, SEt, methyl* ethyl, isopropyl, vinyl, tiihuoromethyi methoxy, ethoxy, isopropoxy, hifluoromethoxy, or a monocyclic aryl or heteroaryl group.
33. 35. The method of claim 34 wherein R2 has the formula

    wherein m is 0,1,2, or 3, and each Rl can be bonded to either the .aromatic or nonaromatic ring and is independently selected from hydroxy, fluoro, chloro, 14¾ MHCH3, NiCHjb, C02CH3,SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and bifluoromethoxy groups.
34. 36. The method of claim 21 wherein A is a moncyclic, fused bicyclic or linked bicyclic aromatic heteroaryl, optionally substituted with 0,1,2, 3. or 4 substituents independently selected from hydroxy, fluoro, chloro, M-I2, NHCH3, N(CH3)2» CQ2CH j,SCH}, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
35. 37. The method of claim 1 wherein die amide compound has the formula

    wherein m is 0, 1, 2. or 3 and each R1 can be bonded to either the phenyl or heteroaryl rings and each PJ is independently seleeted from, hydroxy, flnoro, chloro, MR, MiCXR, N(CH3)2, CO1CH3, SCHj, SBt, methyl, ethyl, isopropyl, vinyl, triftaororaethyl, methoxy, ethoxy, isopropoxy, and trifhioromethoxy,
36. 38. The method of claim 37 wherein m is 1 or 2.
37. 39. The method of claim 1 wherein the amide compound has the formula

    wherein m is 0,1,2, or 3 and each R1 is independently selected from, hydroxy, fluoro, chloro, MR, NHC.H3, N(CH-3)2, COrCHjjSCHj, SEt, methyl, ethyl, isopropyl, vinyl, triflnoromethyl, methoxy, ethoxy, isopropoxy, and miuoromethoxy.
38. 40. The method of claim 39 wherein in is 1 or 2.
39. 41. The method of claim 1 wherein the amide compound has the formula

    wherein Ria and Rjb axe independently hydrogen or a lower alkyl.
40. 42. The method of claim 41 wherein R;a and Rn are independently hydrogen or methyl
41. 43. The method of claim 41 wherein R2 is a C3-C10 branched alky!
42. 44. The method of claim 41 wherein R~ lias the formula

    wherein m is 9,1, 2, or 3, and each R2 can. be bonded to either the aromatic or nonaromatic ring and each R' is independently selected tom hydroxy, fluoro, chloro, MM?: NHCHs, NiCH3)2, GQ2CH* SCH3, SBt, methyl, ethyl, isopropyl, vinyl ttifluoromethyl, methoxy, ethoxy, isopropoxy, and hiflnoromethoxy groups.
43. 45.. The method of claim 1 wherein the amide compound has the formula

    wherein Ria or R^is independently hydrogen or a lower alkyl 44 The method of claim 45 wherein R;a is a lower alkyl and R2 is a C3-Q0 branched alkyl
44. 47. The method of claim 1 wherein the amide compound has the formula:

    wherein A comprises a 5 or 6 memhered aryl or heteroaryl ring m is 0, I, 2, 3 or 4; each R1 is independently selected horn alkyl, aikoxyl, alkoxy-alkyl, hydroxyalkyi, OH, CN, C02H, CHO, COR6, COP?6 , SH, SR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl and R6 is Cj-Cg alkyl; B is a 5 or 6 memhered aryl or heteroaryl ring; uf is 0, 1, 2, 3 or 4; R2 is selected torn the group consisting of alkyl, aikoxyl, aikoxy-alkyl, OH, CN, CO?.H, CHO, COR6, CO2R0· SR6 halogen, alkenyl, cycloalkyl, cyeloalkenyl, aryl, and heteroaryk and R6 is Cj-Ce alkyl
45. 48. The method of claim 47 wherein A is a monocyclic or fused hicyclic heteroaryl ring : P ^ n fir: — :: ,p ο-.-. .,.-...-¾ ; ·:'οίΐΐ,--: ·. ] :: C.. .· fluoro, chloro, Mis, iNHCH.}, N(CHj)23 COOCHs, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifl.noromethyl, meihoxy, ethoxy, isopropoxy, and tritlnoromethoxy groups.
46. 49. The method of claim 4? wherein A is a monocyclic heteroaryi ring.
47. 50. The method of claim 47 wherein A has one of the formulas

    wherein m is 0,1,2, or 3, and each R: can be bonded to either the aromatic or nonaromatic ring and each YC is independently selected horn independently selected jfrom hydrogen, hydroxy, flaoro, chloro, NH2, NHCHj, 14(0¾)^ COjCHs, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trffluoromethyl, meihoxy, ethoxy, isopropoxy, and trifluoromethoxy groups,
48. 51. The method of claim 47 wherein the fR F)m-A radical has the formula

    wherein Rjs and Ri&amp; are independently hydrogen or a lower alkyl,
49. 52, The method of claim 48 wherein Bis a phenyl ring and each R2 is independently selected from hydrogen, hydroxy, iiuoro, chloro, Ntfc, NHCH3, N(C.H3)2, CO2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

    3, The method 0 f claim 47 wherein A is a substituted phenyl ring and Bisa substituted eyelohexyl ring.
50. 54, The method of claim 1 wherein the amide compound has the formula

    wherein A is a 5 or 6 membered aryl or heteroaryl ring; m is 0, 1,2, 3 or 4; ( i each R is independently selected from alkyl, alkoxyl, alkoxy-alkyl, OH, CM, CO2H, COjR6, CHQ, COR6, SR®, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl.
51. 55. The method of claim 54 wherein A is a phenyl, pyridyl, fmanyl, or thioforanyi ring and each R is independently selected from hydrogen, hydroxy, iiuoro, chloro, NHj, NHCH3, N(CH3>2, CO2CH3, SBt, SCH3, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, groups.
52. 56. The method of claim 55 wherein A is a phenyl ring and m is 1, 2, 3 or 4,
53. 57, The method of claim. 56 wherein nr is 1 or 2, ' 5S, The method of claim 55 wherein R2 is a €3-¾ branched alkyl.
54. 59.. The method of claim 55 wherein R'! is an oi-suhstituted carboxylic acid lower alkyl ester,
55. 60, The method of claim 1 wherein the amide compound is a urea compound having the formula:

    wherein R9 and one or two of R' and R8 comprise a hydrocarbon residue having at least three carbon atoms and optionally one to ten heteroatoms selected from oxygen, nitrogen, sulfur, halogens, or phosphorus; and wherein optionally one ofR7 and RK is hydrogen. 6.1, The method of claim 60 wherein R7 and E* together fonn a heterocyclic or heteroaryl ring having 5, 6, or 7 ring atoms that maybe optionally substituted with 1, 2, or 3 substituents independently selected Rom hydroxy, fluoro, chloro, NH.2, NHCH3, NfCHsJj, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and txifluoromeihoxy
56. 62. The method of claim 61 wherein the urea compound has the structure
57. 63. The method of claim 60 wherein one of R7 and R8 is hydrogen,
58. 64. The method of claim 63 wherein Rs and one of R7 and Rs are independently selected Rom arylalkenyls, heteroarylalkenyls, arylalkyls, heteroarylaliyls, alkyls, alkoxy-alkyls, alkenyls, cycloalkyls, cycloalkenyls, aryls and lietercaryls, each of which carbon containing groups may be optionally substituted with 1,2, or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NHj, NHCHj, N(CH3)2:, COQCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy,’ isopropoxy, and triiluoromethoxy,
59. 65. The method of claim 63 wherein Rs and one of R7 and Rs are independently selected from alkyl, phenyl cydohexyl, or pyridyl, each of which may optionally comprise one to four substituents independently selected from hydroxy, fluoro, chloro, NH.2, NHC.H3, N(CHa)2, CO.:CHx SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy,
60. 66. The method of claim 63 wherein one of R' and R8 has one of the formulas

    wherein m is 0,1, 2, or 3, and each Rs independently selected from hydrogen, hydroxy, fluoro, chloro, ΜΉ2, NHCHj, N(€H3)2, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, tiiiluoromethyl, methoxy, ethoxy, isopropoxy, and tdiluoromethoxy.
61. 67. The method of claim 63 wherein one of R and R is a phenyl ring optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy, flnoro, chloro, NH2, NHCH ?. N{CH3}3, COOCH3j SCH;., SEt, methyl, ethyl, isopropyl, vinyl, trilluoromethyi, methoxy, ethoxy, isopropoxy, and trifluoromethoxy .
62. 68. The method of claim 63 wherein K3 is a €3-(¾ branched alkyl
63. 69. The method of claim 63 wherein R9 has the structure

    wherein B is a phenyl, pyridyl, furanyl, thiofhranyl, pyrrole, cyclopentylpyctohexyl, or piperidyl ring, m is 0,1, 2, or 3, and each R2 is independently selected from hydrogen, hydroxy, fluoro, chloro, 14¾ NHCH^. N(CH3)2, COOCH3, SCH3, SBt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy. ethoxy, isopropoxy, and trifluoromethoxy, and RSa is a selected from the group consisting of an alky], alkoxy-alkyl, alkenyl, eyeloalkenyl, cycloalkyl, -R4QH, -R4G Rs -R4CN, -R4COaH, -R4CQ2K5, -R4COR5, -R4SRs, and -R4S02RJ comprising 1 to 12 carbon atoms.
64. 70. The method of claim 63 wherein the urea compound has the formula; l-(2-chioropheny3)-3-(heptan-4-yl)ureaa I-(2,4~dichlorophenyl)“3-(1 -phenyipropyl)area, l-(2,4-dimethoxyphenyl)~3-(heptan-4-y])urea, l"{2-fluorophenyl)-3-{heptan"4-yl)tirea3 or l-(4-isopropylphenyl)-3"(2-(p}aidin-2-y])ethy3)urea.
65. 71. Tire method 0 f claim 1 wherein the amide compound i s an oxalamide compound having the formula

    wherein R!0and R30 are independently selected hydrocarbon residues having at least three carbon atoms and optionally one to ten heteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus, and wherein R^and R'1:1 are independently selected horn hydrogen and a hydrocarbon residue having at least three carbon atoms and optionally one to ten heteroatoms independently selected b om oxygen, nitrogen, sulfur, halogens, or phosphorus.
66. 72. The method of claim 71 wherein Ra;and R40 are hydrogen.
67. 73. The method of claim 71 wherein RSo and R30 are independently selected from the group consisting of aryialkyls, heteroarylalkyls, oycloalkyl-alkyls, andheteroeycle-alkyls comprising five to 15 carbon atoms, and wherein each of Ri0 and R'5° can optionally comprise one to one to four substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH:>, NHCH3, 14(0¾}¾ CO2CH3, SEt, SCIR. methyl, ethyl, isopropyl, vinyl, mfiuoromehhyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
68. 74. The method of claim 1 wherein the amide compound is an oxalamide compound having the formula

    wherein A and B are independently an aryl, heteroaryl, cycloalkyl, or a heterecyde comprising 5 to 12 ring atoms; m and n are independently 0, 1, 2, 3 or 4-8; R20and R4® are hydrogen, R50 is hydrogen or an alkyl or substituted alkyl residue comprising one to four ear bon atoms; R60 is absent or a Cj-Cj alkylene or a C-;-Cs substituted alkylene; R70 andRe0 are independently selected from the group consisting of hydrogen, alkyl, aikoxyl, alkoxy-alkyl, OH, SR5, halogen, CN, NCR, COjR9, COR3, CONR3Rt0, NK9K!(i, NR9CC)R50, SOR9, S02R9, SO^R*Rl°, NSW" alkenyl, oydoalkyl, cycloaikenyl, aryl, heteroaryl, and heterocycle; R.3 and R10 are independently selected from H, Cj-Cg alkyl, Cj-Cg cycloalkyl, and C;-Cg alkenyl;
69. 75. Tire method of claim 74 wherein A and B are independently a phenyl, pyridyl, furanyl, benzofhranyl, pyrrole, bemiolhiophene, pxpexidyi, cyclopentyl» eyclohexyl, or cydoheptyl ring; m and n are independently 0, 1, 2, or 3; R20and R40 are hydrogen; Ri0 is hydrogen or methyl; R60 is a C2 alkylene; R70 and R80 are independently selected from hydrogen, hydroxy, fluoro, chloro, NHj, NHCHj, N(CHj)2, CO2CH3, SEt, SCfR, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
70. 76. Tire method of claim 1 wherein the amide compound is an oxalamide compound having the formula

    wherein A is a phenyl pyridyl, furanyi, pyrrole, piperidyl, cyclopeniyl, cyclohexyl, or eycloheptyl ring; m and n are independently 0.1, 2, or 3; R"c is hydrogen or methyl; F is 1 or 2: and ΥΛ ΟΛ _ R' and R are independently selected from the group consisting of hydrogen, hydroxy, fruoro, ehloro, 19¾ MiCH3, NiCKsk, COOCFI3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifhroromeihyl, methoxy, ethoxy, isopropoxy, and trifluoromefboxy, or twoof R75 together form a methylenedioxy ring.
71. 77. The method of claim 76 wherein the pyridyl-R80 radical has the structure
72. 78. The method of claim 1 wherem the amide compound is an oxalamide compound ha ving the fonnula

    wherein Ar5 is a substituted aryl or heteroaryl ring comprising E ve to 12 carbon atoms; Rso is hydrogen or methyl; n is 0,1,2, or 3; each R80 is independently selected from the group consisting of hydroxy, fluoro, ehloro, NH&amp; NHCH* N(CH,)2s CG2CH3, SEt, SCH3s methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. '79. The method of claim 78 wherein Ar1 is a 2-, 3-, or 4~mono~substit«ted phenyl, 2,4-, 2,3-, 2,5, 2,6,3,5-, or 3,6-disubstituied phenyl, 3~a3kyl-4-substitutedphenyl, a tri-snbstiiuted phenyl wherein the substituent groups are independently selected from the group consisting of hydroxy, fluoro, ehloro, NHRlNHCHs, N(CH3)2, CO2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, irifluorcmethyl, methoxy, ethoxy, isopropoxy. and hifruoromelhoxy, or two of the substituents together forma methyienedioxy ring on the phenyl ring.
73. 80. The method of claim 78 wherein Ar! is a substituted heteroaryi ring comprising 5 to 12 carbon atoms and wperein the substituent groups axe independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, ME?, NHCHj, N(CHj)2, COzGHj, SEt, SCH.3, methyl, ethyl, isopropyl, vinyl, tnfluoromethyl, methoxy, ethoxy, isopropoxy, and trSluoromefboxy.
74. 81. The method o f claim 1 wherein the amide compound is an oxalamide compound having the formula

    wherein A is a substituted aryl or heteroaryi ring comprising fi ve to 12 carbon atoms: R'° is hydrogen or methyl; m and n are independently 0, L 2, or 3; each R70 or Rso is Independently selected h orn the group consisting of hydrogen, hydroxy, fluoro, chloro, MER, NHCHs, NCCHa)?., CGOCHs, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and hirluoromethoxy ,
75. 82. The method of claim 1 wherein the amide compound is an oxalamide compound having the formula

    wherein m andn are independently 0,1, 2, or 3; and R70 and R811 are independently selected from the group consisting of hydrogen, alkyl, alkoxyl, alkoxy-alkyl, OH, SRV, halogen, CM, NO?, CO;jR9, COR9, CONR9R50,MR9Rk,5 MR9COR10, SOR9, SOjR9, SO2MR9Ri0, NR5SOjR!0, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryi, and heteroeycle; Is and R!fi are independently selected from H, Ci-C&amp; alkyl, Cj-Cs cveloalkyl, and CrCs alkenyl
76. 83. The method of claim 82 wherein Rm and Rao are independently selected from the group consisting ofhvdrogen, hydroxy, fluoro, chloro, 141¾. MICR3, 19(0¾}¾ O2CCH3, SH, SCII3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropcxy, and tdfluoromethoxy.
77. 84. The method of claim 82 wherein the pyridyl-R83 radical has the structure
78. 85. The method of any of claims 1-84 wherein the log10 of the partition coefficient of the amide compound between n-oetanol and water is less than 5.5,
79. 86. The method of claim 1 wherein the modified comestible or medicinal product is a food for animal consumption,
80. 87. The method of claim 1 wherein the modified comestible or medicinal product is a food for human consumption.
81. 88. The method of any of claims 1 - 84 wherein the modified comestible or medicinal product is selected from the group consisting confectioneries, bakery products, ice creams, dairy products, sweet or savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, and spreads.
82. 89. The method of any of claims 1-84 wherein the modified comestible or medicinal product comprises one or more meats, poultry, fish, vegetables, grains, or fruits.
83. 90. The method of claim 1 wherein the modified comestible or medicinal product is a frozen food, an uncooked food, or a fully or partially cooked food.
84. 91. The method 0 f claim 1 wherein the modified comestible or medicinal product i s a soup, a dehydrated or concentrated soup, or a dry soup.
85. 92. The method of claim 1 wherein the modified comestible or medicinal product is a snack food.
86. 93. The method of claim 1 wherein the modified comestible or medicinal product is a cooking aid product, a meal solution product, a meal enhancement product, a seasoning, or a seasoning blend.
87. 94. The method of claim 1 wherein the modified comestible or medicinal product is a cake, cookie, pie, candy, chewing gum, gelatin, ice cream, sorbet, pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or fruit sauce.
88. 95. T he method of any of claims 1-8:4 wherein the modified comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate.
89. 96. The method of claim 1 wherein the mod ified comestible or medicinal product is a . soda, or juice.
90. 97. The method of claim 1 wherein the modified comestible or medicinal product is an alcoholic beverage.
91. 98. The method of any of claims 1-84 wherein £h e modified comesti ble or medicinal product is a pharmaceutical composition for oral administration.
92. 99. The method of claim 1 wherein the modified comestible or medicinal product is an oral hygiene product.
93. 100. The method of any of claims 1-84 wherein the amide compound is present in the modified comestible or medicinal product at a concentration from about 0.01 ppm to about 30 ppm,
94. 101. The method of claim 1 wherein the amide compound is present in the modified comestible or medicinal product m a concentration from about 0.05 ppm to about 15 ppm.
95. 102. T he method of claim 1 wherein the amide compound is present in the modified comestible or medicinal product in a concentration from about 0.1 ppm to about 5 ppm.
96. 103. The method of claim 1 wherein the amide compound is present in the modified comestible or medicinal product in a concentration from about 0.1 ppm to about 3 ppm,
97. 104. The method of any of claims 1-84 wherein a water solution comprising the savory flavor modifying amount of the amide compound has a savory taste as judged by the majority of a panel of at least eight human taste testers.
98. 105. The method of any of claims 1 -84 wherein a water solution comprising the savory flavor mod ifying amount of the amide compound and 12 mM monosodium glutamate has an increased savory taste as compared to a control water solution comprising 12 mM monosodium glutamate, as determined by the majority of a panel of at least eight human taste testers.
99. 106. The method of claim 1 wherein a water solution comprising the savory flavor modifying amount of the amide compound and 12 mM monosodium glutamate has an increased savory taste as compared to a control water solution comprising 12 mM monosodinm glutamate and 100 μΜ inosine monophosphate, as determined by the majority of a panel of at least eight human taste testers.
100. 107. The method of claim 1 wherein a water solution comprising about 10 ppm of· he amide compound and about 12 mM monosodium glutamate has an increased savory flavor as compared to a control water solution comprising only the monosodium glutamate, as judged by a majority of a panel of eight human panelists.
101. 108. The method of claim I wherein the amide compound is a savory agonist for an hTIRl/hTIRS receptor.
102. 109. The method of any of claims 1-84 wherein the amide compound has an EC jc for the hTl.R]/hT!R3 receptor of less than about 2 μΜ.
103. 110. The method of claim 1 wherein the amide compound, when dissolved in a water solution comprising about 1 («M of the amide compound decreases the observed ECso of monosodium glutamate for an hTlRl/hTlR'3 receptor expressed in an HBK293-G«15 cell line by at least 50%.
104. 111. The method of claim. 1 wherein the modified comestible or medicinal product has an increased savory taste as compared to the comestible or medicinal product prepared without the amide compound, as judged by a majority of a panel of at least eight human taste, testers.
105. 112. The method o f claim 1 wherein the amide compound i s comestibly acceptable,
106. 113. The method of claim. 1 wherein the amide compound is or can he shown t o be generally recognized as safe.
107. 114. The method of claim 1 wherein the amide compound, when combined with rat chow and fed to Crl:CD(SD)lGS BE rats at a concentration of about 100 milligrams,''Kilogram Body weight/day for 90 days causes no adverse toxic effects on the rats.
108. 115. The modified comestible or medicinal product produced b y any o f claims 1-84.
109. 116. A method for increasing the sweet taste o f a comestible or medicinal product comprising: a) providing at least one comestible or medicinal product, or a precursor thereof, and b) combining the comestible or medicinal product or precursor thereof with at least a sweet flavor modulating amount of at least one non-naturally occurring amide compound, or a comestibly acceptable salt thereof! so as to form a modified comestible or medicinal product; wherein the amide compound has the structure

     wherein A is an aryl or heteroaryl ring having from 3 to 12 ring atoms; m is 0, 1, 2, 3 or 4; each R! is independently selected, from the group consisting of CrCt alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxyi, Ce-C} aikoxy-alkyl, C1-C4 hydroxy-alkyl, OH, NHZ, biHR6, NR62, CN, C02iL CChR6, CKO, COR6, SH, SR6, and halogen, wherein R6 is Cj-C4 alkyl; Rf comprises a branched alkyl or cycloalkyl optionally substituted with one to four substituents independently selected from alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl OH, M-fc, NHR6 NRSz,CN, CG2H, CG2R6, CKO, COR6, SH, SR6, halogen, alkenyl, cycloaikyl, cycloalkenyl, aryl, and heteroaryl and R6 is CrCg alkyl; and wherein the amide compound has a molecular weight of 500 grams per mole or less.
110. 117. The method of claim 116 wherein each K! and each optional substituent for Rf' is independently selected from the group consisting ofhydrogen, hydroxy, fluoro, chloro, NHz, MiCHs, N(CH3)2s COGCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl mfluoromethyl, methoxy, ethoxy, isopropoxy, and hiiluoromethoxy groups, f 18 .. The method of claim 117 wherein A is an aryl ring comprising 6 to 12 ring carbons.
111. 119. The method of claim 117 wherein A i s a napthyl rin g,
112. 120. The method of claim 117 wherein A is a phenyl ring. 121» The method of claim 120 wherein m is 1,2,3, or 4.
113. 122. The method of claim 121 wherein R2 is a branched C.rCfg alkyl
114. 123. The method of claim 121 wherein K2 is a branched €3-(¾ alkyl, substituted with 1. 2, or 3 substituent groups independently selected from, hydroxy, fluoro, chloro, NH2, NHCH3, N{CH3)2, CG2CH3, SEt, SCH3, methyl ethyl, isopropyl vinyl, trifruoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, and pvxidyl.
115. 124. The method of claim 121 wherein R2 is a cyefoalkyl or eydoalkenyi ring having 3 to 10 ring carbon atoms optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, Sucre, chloro, NHj, NHCH3,14((2¾}¾ CO2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and ixifluoromethoxy groups,,
116. 125. The method of claim 121 wherein R2 is a eycloalkyl or eydoalkenyi ring having 5 to 8 ring carbon atoms, optionally substituted with 1,2, or 3 substituents independently selected from the group consisting of hydroxy, iluoro, chloro, NH2, NHCH3, N(CH3)?, COaCHi, SEt, SCH3, methyl ethyl isopropyl, vinyl tnfluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
117. 126. The method of claim 121 wherein R2 is a cyclopentyl, eydobexyl, cycloheptyl, or eyclooctyl ring, optionally stibstituted with 1,2, or 3 substituents independently selected from the group consisting of hydroxy, Snoro, chloro, NSfr, NHCHj, N(CH3)2, CO2CH3, SEt, SCHj. methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
118. 127. The method of claim 121 wherein R2 is a cyelohexyl, optionally substituted with I, 2, or 3 methyl groups.
119. 128. The method of daim 121 wherein R2 has the fomrnla
120. 129. The method of daim 121 wherein R2 is a 1-mdane having the formula

     w'herein m is 0,1,2, or 3, and each R2 canbe bonded to either the aromatic or nonaromatic ring and is independently selected from hydroxy, fluoro, chloro, NHz> NHCHj, N(CH3)2, CQ2CH3, SEt, SCH3, methyl, ethyl, isopropyl vinyl, frifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
121. 130. The method of daim 121 wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene having 3 ·« 1 rt

     wherein m is 0,1, 2, ©r 3, and each R2 canhe bonded to either the aromatic or nonaromatic ring and is independently selected from hydroxy, fluoro, cMoro, NHs, NHCHj, NCCHn’jj, COOCTR, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, triflnoromethyl, meihoxy, ethoxy, isopropoxy, and trifluoromethoxy,
122. 131, The method of claim 121 wherein R2h.as the formula

     wherein each RJ are independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NHj, NHCH3, 14((¾¼ COOCIT3, SCHg, SEt, methyl, ethyl, isopropyl, vinyl, triflnoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy ,
123. 132, The method of claim 121 wherein R? has the formula
124. 133, The method of claim 121 wherein R4 has the formula
125. 134, The method of claim 121 wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene ring having the formula
126. 135. The method of claim 121 whereia R2 is an 1-(1,2,3.4) tetrahydronapthalene ring having the formula
127. 136. The method of claim 121 wherein R2 is an 1-(1,2,3,4) tetrahydronapthalene ring having the formula
128. 137. The method of claim 117 wherein A is a monocyclic heteroaryl,
129. 138. The method of claim 117 wherein A has one o f the formulas

     wherein m is 0,1, 2, or 3, and each R! is independently selected from, hydroxy, fluoro, chioro, NH2, NHCH&amp; Ν(ΟΗ3)2, CG2CH3, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, trifluoromeiliyl, methoxy, ethoxy, isopropoxy, or triiluoromethoxy.
130. 139 .. The method of claim 117 wherein A has the formula ,

     whereinR* is hydrogen, hydroxy, fluoro, chioro, NH* NHCHs, N(CH3)2, Q2CCH3, SH, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, or triiluoromethoxy.
131. 140, The method of claim 13 8 wherein A2 is a branched €3-(¾) alkyl.
132. 141, The method of claim 138 wherein R2 is a branched CVCht, alkyl, substituted with 1, 2, or 3 substituent groups independently selected from hydroxy, fluoro, chioro, Mia, NHCffi. N(CH3)2, COaCEE, SEt, SCH3, methyl, ethyl isopropyl, vinyl trifluoromethyl methoxy, ethoxy, isopropoxy, triiluoromethoxy, phenyl, and pyridyl
133. 142, The method of claim 138 wherein R2 is a cycloalky] having 3 to 10 ring carbon atoms, optionally substituted with 1,2, or 3 substituents independently selected from the group consisting of hydroxy, fluoro, chioro, ΜΙ?., M-ICTL·, N(CH3)23 CO2CTI3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl trifluoromethyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy giOups.

     3. The method of claim 138 wherein R~ is a cyclopentyl, cyclohexyl, eycloheptyl, or cyclooctyl, optionally substituted with 1,2, or 3 substituents independently selected from the group consisting of hydroxy, fluoro, chioro, NH?., MICTI3, N(CH3)2, COaCife, SEt, SQ-R, methyl, ethyl, Isopropyl, vinyl triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. 144. 'The method of claim 08 wherein R2 is a. cyolohexyl, optionally substituted with 1, 2, or 3 methyl groups,
134. 145. The method of claim 138 wherein K3 has the formula
135. 146. The method of claim 138 wherein R2 is a hindane having the formula

     wherein m is 0,1, 2, or 3, and each R2 can be bonded to either the aromatic or nonaromatic ring and is independently selected firqsij hydroxy, fluoro, chloro, NER, NHCHj, N(¢1¾)¾ CO2CH3, SEt, SCI-R, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and ijifluoromethoxy.
136. 147. The method of claim 138 wherein R2 is a 1-(1,2,3^4) tetrahydronapthalene having the formula

     wherein m is Q,l. 2, or 3, and each R2 can he bonded to either the aromatic or nonaromatic ring and is independently selected from hydroxy, fluoro, chloro, NHa, NHCHj, N(CHj)2, COjCEU, SEt, SCH5, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
137. 148. The method of claim 138 wherein has the formula

     or

     wherein each are independently selected, from the group consisting of hydrogen, hydroxy, fluoro, chloro, HH2, MiCHj, N(CH;5j2, O2CCH&amp; SH, 80¾ methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropox y. or trill uoromethoxy.
138. 149. The method of claim 138 wherein R*’ has the formula
139. 150. The method of claim 138 wherein R/' has the formula ”
140. 151. The method 0 f claim 138 wherein R2 is a 1-( 1,2,3,4) tetrahydronapthalene ring having the formula

     1.52. The method of claim 116 wherein the modified comestible or medicinal product is a food for animal consumption.
141. 153. The method of claim. 116 wherein the modified comestible or medicinal product is a food for human consumption,
142. 154. The method of any of claims 116-151 wherein the modified comestible or medicinal product is selected from the group consisting of confectioneries, bakery rsrnducts. ice creams, dairy nroduets. sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, dozen foods, dried foods, chilled foods, oils and fats, baby foods, and spreads.
143. 155. Ihe method of any of claims 116-151 wherein the modified comestible or medicinal product comprises one or more meats, poultry, fish, vegetables, grains, or fruits.
144. 156. The method of claim 116 wherein the modified comestible or medicinal product is a frozen food, an uncooked food, or a frilly or partially cooked food. 1.57- The method of claim 116 wherein the modified comestible or medicinal product is a soup, a dehydrated or concentrated soup, or a dry soup.
145. 158. The method of claim 116 «'herein the modified comestible or medicinal product is a snack food.
146. 159. The method of claim 116 wherein the modified comestible or medicinal product is a cooking aid product, a meal solution product, a meal enhancement product, a seasoning, or a seasoning blend
147. 160. The method of claim 116 wherein the modified comestible or medicinal product is a cake, cookie, pie, candy, chewing gum, gelatin, ice cream, sorbet, pudding, jam, jelly, salad dressing, condiment cereal, canned fruit, or fruit sauces.
148. 161. The method of any of claims 116-151 wherein the modifi ed comestible or medicinal produet is a beverage, a beverage mix, or a beverage concentrate.
149. 162. The method of any of claims 116-151 wherein the modified comestible or medicinal product is a soda, or juice,
150. 163. The method of any of claims 116-151 wherein the modified comestible or medicinal product is an alcoholic beverage,
151. 164. The method of any of claims 116-151 wherein the modified comestible or medicinal product is a pharmaceutical composition intended for oral administration.
152. 165. The method of claim 1.16 wherein the modified comestible or medicinal product is an oral hygiene product.
153. 166. The method of any of claims 116-151 wherein the amide compound is present in the modified comestible or medicinal product in a concentration from about 0.00] ppm to about 100 ppm.

     7. The method of claim 1 l?wherein the amide compound is presets in the modified comestible or medicinal product in a concentration from about 0.1 pptn to about 30 ppm. -
154. 168. The method of claim 116 wherein the amide compound is present in the modified comestible or medicinal product in a concentration from about 0.05 ppm to about 15 ppm.
155. 169. The method of any of claims 116-151 wherein the amide compound is present in the modified comestible or medicinal product iu a concentration from about 0.1 ppm to about 5 ppm.
156. 170. The method of claim 116 wherein the amide compound is present in the modified comestible or medicinal product in a concentration from about 0.1 ppm to about 3 ppm. ’
157. 171. The method o f any of claims 116-151 wherein the modified comestible or medicinal product has a sweeter taste than a control comestible or medicinal product that does not comprise the amide compound, as judged by the majority of a panel of at least eight human taste testers. x
158. 172. The method of claim 116 wherein a water solution comprising a sweet tasting amount of a known sweetener selected from the group consisting of sucrose, fhictose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, a known natural teipenoid, flavonoid, or protein sweetener, aspartame, saccharin, acesulfame-K, cyelamafe, sucralose, and alitame, or a mixture thereof and a sweet flavor modifying amount of the amide compound has a sweeter taste than a control water solution comprising the sweet tasting amount of the known sweetener, as judged by the majority of a panel of at least eight human taste testers.
159. 173. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amide compound and about 6 grams/100 milliliters of sucrose has a sweeter taste than a control water solution comprising 6 % grams/100 milliliters of sucrose, as judged by the maj ority of a panel of at least eight human taste testers.
160. 174. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amide compound and 6 % grams/100 milliliters of a 50:50 mixture of sucrose and fructose has a sweeter taste than a control water solution comprising about 6 % grams/100 milliliters of a 50:50 mixture of sucrose and fructose, as judged by the majority of a panel of at least eight human taste testers.
161. 175. The method of claim 116 w'herein a water solution comprising the sweet flavor modifying amount of the amide compound and about 1.6 mM of aspartame has a sweeter taste than a control water solution comprising about 1.6 mM aspartame, as judged by the majority of a panel of at least eight human taste testers.
162. 176. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amide compound and about 1.5 mM of acesulfame-K has a sweeter taste than a control water solution comprising about 1.5 mM of acesulfame-K, as judged by the majority of a panel of a t least eight human taste testers.
163. 177. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amide compound and about 10 mM of cyclamate has a sweeter taste than a control water solution comprising about 10 mM of cyclamate, as judged by the majority of a panel of at least eight human taste testers.
164. 178. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amide compound and about 0.4 mM of sncralose has a sweeter taste than a control water solution comprising about 0.4 mM of sncralose, as judged by the majority of a panel of at least eight human taste testers.
165. 179. The method of claim 116 wherein a water solution comprising the sweet fl avor modifying amount of the amide compound and about 0,2 mM of alitame has a sw'eefer taste than a control %'ater solution comprising about 0.2 mM of alitame. as judged by the majority of a panel of at least eight human taste testers,
166. 180. The: method of clai m 116 wherein the modified comestible or medicinal product has a sweeter taste as compared to the comestible or medicinal product prepared - without the amide compound, as judged by a majority of a panel of at least eight human panelists,
167. 181. The method o f claim 116 w'herein the amide compound modulates the binding o f a sweetener selected from the group consisting of sucrose, fructose, glucose, erythritol. isomalt, lactitol, mannitol, sorbitol, xylitol, a known natural terpenoid, fkvinoid, or protein sweetener, aspartame, saccharin, acesufarne-K. a cyclamate, sueralose, alitame or erythritol to an hTfR2/hTHR3 receptor expressed in an HP K. 293 Gal5 ceil line.
168. 182. The method of claim 116 wherein the amide compound has an ECw for binding an hTlR2 hTiR3 receptor expressed in an HBK293-Gal5 cell line ofless than about 10 μΜ,
169. 183. The method of any of claims 116-151 wherein the amide compound has an ECsu for binding an hT!R2/hTlR3 receptor expressed in an HEK293~Gcd5 eel] line ofless than about 5 μΜ. .
170. 184. The method of claim 116 wherein the amide compound has an BCso for binding an hTlR2/hTlR3 receptor expressed in an HEK293-Gal5 cell line of less than about 2 μΜ.
171. 185. The method of claim 116 wherein the amide compound has an BQ&amp; for binding an hTiR2/hTl.R3 receptor expressed in anHBK293-Gal.5 cell line ofless than about 1 μΜ.
172. 186. The method of claim 116 wherein the amide compound is not a peptide compound.
173. 187. The method of claim 116 wherein the amide compound is comestibly acceptable. 188. lire method of claim 116 wherein the amide compound is or can be determined to ' be generally recognized as safe for use in specific food products at a specified concentration in the finished product.
174. 189. The method of claim 116 wherein: the amide compound; when combined with rat chow and fed to CrhCD(SD)IGS BR rats at a concentration of about 100 ’ milligrams/kilogram body weight/day for 90 days causes η o adverse toxic effects on tire rats.
175. 190. A comestible or medicinal product produced by the process of one of any of claims 116-189.
176. 191. A method for increasing the sweet taste o f a comestible or medicinal product comprising: a) providing at least one comestible or medicinal product; or a precursor thereof, and b) combining the comestible or medicinal product or precursor thereof with about 0,001 ppm to about 100 ppm of at least one non-naturally occurring amide compound, or a comestibly acceptable salt thereof, so as to foim a modified comestible or medicinal product; wherein the amide compound has the structure

     wherein A is an aryl or heteroary! ring having from 3 to 12. jing atoms; m is 0, 1, 2, 3 or 4; each R1 is independently selected from the group consisting of hydroxy, fluoro, chloroj M-izs M-ICI-fr, CO2CH3, SEt, SCO;:, methyl, ethyl, isopropyl vinyl, tiifluoromethyl, metkoxy, ethoxy, isopropoxy, and trifluoromethoxy; R"5 is a phenyl ring, optionally substituted with 1,2, or 3 substituents independently selected from the group consisting of, hydroxy, fluoro, chloro, 14¾ NHC.H3. ]N{CH3)?., COzCIIj, SEt, SCHj, methyl, ethyl, isopropyl, vinyl, trifluoromethyi, metboxy. ethoxy, isopropoxy, and trifluoromethoxy; and wherein the amide compound lias a molecular weight of 500 grams per mole or less.
177. 192, The method of claim 191 wherein the modified comestible or medicinal product is selected from the group consisting of confectioneries, bakery products, ice creams, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, and spreads
178. 193, The method of claim 191 wherein the modified comestible, or medicinal product is a cake, cookie, pie, candy, chewing gum, gelatin, ice cream, sorbet pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or Suit sauces.
179. 194, The method of claim 191wherem the modified comestible or medicinal product is a beverage, a beverage, mix, or a beverage concentrate!
180. 195, The method of claim 191 wherein the modified comestible or medicinal product is a soda, or juice,
181. 196, The method of claim 191 wherein the modified comestible or medicinal product is an alcoholic beverage.

     7. The method of claim 191 wherein the modified comestible or medicinal product is a pharmaceutical composition intended fix: oral administration.
182. 198. The method of claim 191 wherein the modified comestible ormedieinal product is an oral hygiene product.
183. 199. The method of claim 191 wherein the amide compound is present in the modifi ed comestible or medicinal product in a concentration from about 0.001 ppm to about 100 ppm. 2QG. The metliod of claim 191 wherein the amide compound is present in the modified comestible, or medicinal product in a concentration from about 0.1 ppxn to about 10 ppm 2.01. The modified comestible or medicinal product produced by the method of claims 191-200.
184. 202. A method for modulating the sweet taste of a comestible or medicinal product comprising: a) providing at least one comestible csr medicinal product, or a precursor thereof, and b) combining the. comestible or medicinal product or precursor thereof rvith about 0.001 ppm to about 100 ppm of at least one non-natural!y occurring urea compound, or a eomestibly acceptable salt thereof, so as to form a modified comestible or medicinal product; wherein the urea compound has the formula:

     wherein m andn are. independently 0, 1, 2, or 3, and each B. and R is independently selected from fluoro, chloro, NH&amp; NHCH&amp; N(CH.j)j, C O2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
185. 203. The method of claim 202 wherein n is 0.
186. 204. A comestible or medicinal product produced by the method of claim 202.
187. 205. A comestible or medicinal product, or a precursor thereof comprising about 0.001 ppm to about 100 ppm of at least one non-naturally occurring amide compound, or a eomestibly acceptable salt thereof,, wherein the. amide compound has the. formula:

     wherein A comprises a 5 or 6 membered aryl or heteroaryl ring; xn Is 0,1, 2, 3 or 4; each R; is independently selected Ssm hydroxy, fluoro, chtero, NH?, NHCHj, N(CH5)2, CChCHj, SEt, SCHs, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and triihioromethoxy; and R2 comprises between 4 and 14 carbon atoms and 0, 1,2, 3, 4, or 5 heteroatoms Independently selected from oxygen, nitrogen, sulfer.
188. 206. The comestible or medicinal product, or a precursor thereof of claim 205 wherein A is a phenyl ring „
189. 207. The comestible or medicinal product, or a precursor thereof of claim 206 wherein m is 1, 2, or 3.
190. 208. The comestible or medicinal product, or a precursor thereof of claim 206 wherein R* is a Cj-Cjo branched alkyl
191. 209. The comestible or medicinal product, or a precursor thereof of claim 206 wherein R2 is an «-substituted carboxylic acid or «-substituted carboxylic acid methyl ester.
192. 210. The comestible o r medicinal product, or a precursor thereof of claim 205 wherein the amide compound has the formula

     wherein Rla and Rtt, are independently hydrogen or methyl
193. 211. The comestible or medicinal product, or a precursor thereof o f claim 210 wherein R2 is a Cs-Cvo branched alkyl
194. 212. The comestible or medicinal product, or a precursor thereof of claim 210 wherein R2 is an «-substituted carboxylic add or «-substituted carboxylic acid methyl ester.
195. 213. The comesti ble o r medicinal product, o r a precursor thereof of claim 205 wherein A is a monocyclic heteroarvl having one of the formulas

     wherein m is 0, 1, 2. or 3, and each R1 is independently selected from hydrogen, hydroxy, fluoro, chloro, NHj, MiCITj, 14(0¾)¾ COjCH'i, SEt, SCEfo, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
196. 214. The comestible or medicinal product, or a precursor thereof of claim 213 wherein R2 is a Cj-Cic branched alkyl
197. 215. The comestible or med icinal product o r a precursor thereof o f claim 213 wherein R* is an ^-substituted ca&amp;oxylic acid or a-substituted carboxylic acid methyl ester,
198. 216. The comestible or medicinal product, ora precursor thereof o f claim 205 wherein the modified comestible or medicinal product is a food for human consumption.
199. 217. The comestible or medicinal product, or a precursor thereof of any of claims 205215 wherein the modified comestible or medicinal product is selected from the group consisting of confectioneries, bakery products, ice creams, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen mods, dried foods, chilled foods, oils and fats, baby foods, and spreads.
200. 218. A comestible product, or a precursor thereof o f claim 205 comprising one or more meats, poultry, fish, vegetables, grains, or fruits.
201. 219. A comestible product, or a precursor thereof of claim 205 that i s a frozen food, an uncooked food, or a fully or partially cooked food.
202. 220. A comestible product, or a precursor thereof of claim. 205 that is a soup, a dehydrated or concentrated soup, or a dry soup.
203. 221. A comestible product, ora precursor thereof of claim 205wherem the modified comestible or medicinal product is a snack food.
204. 222. A comestible product or a precursor thereof of any of claims 205-215 wherein the modified comestible or medicinal product is a cooking aid product, a meal solution product, a meal enhancement product, a seasoning, or a seasoning blend.
205. 223. A comestible product, or a precursor thereof of claim 205%'herem the modified comestible onmedicinal product is a cake, cookie, pie, candy, chewing gum, gelatin, tee cream, sorbet, pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or fruit sauce,
206. 224. A comestible product, or a precursor thereof of any of claims 205-215 wherein the modified comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate.
207. 225. A comestible product, or a precursor thereof of claim 205 wherein the modified comestible or medicinal product is a soda, or juice.
208. 226. A comestible product, or a precursor thereof of claim 205 wherein the modified ' comestible or medicinal product is au alcoholic beverage.
209. 227. A comestible product, or a precursor thereof of claims any of claims 205-215 wherein the modified comestible or medicinal product is a pharmaceutical composition for oral administration.
210. 228. A comestible product, ora pree ursor thereof o f claim 205 wherein the modified comestible or medicinal product is au oral hygiene product.
211. 229. A comestible ormMicinal product, or a precursor thereof comprising at least a savory flavor modulating amount of at least one oxalamide compound, or a comestibly acceptable salt thereof, wherein the oxalamide compound has the formula

     wherein A and B are independently an aryl, heteroaryl, eyeloalkyl, or a heterocycie comprising 5 to 12 ring atoms; m and tt are independently 0, 1,2,3 or 4-8, R3° is hydrogen or an alkyl comprising one to four carbon atoms; R65 is absent or a Ci-Cs alkylene; R'° and Rs0 are independently selected from the group consisting of hydrogen, hydroxy, fiuoro, chloro, NHj, NHCH3, NtCHjlj, CO2CH3, SEt, SCIR, methyl, ethyl, isopropyl, vinyl, iriiluoromethyi, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two ofR70 together form a methylenedioxy ring.
212. 230. A comestible product, or a precursor thereof of claim 229 wherein A and B are independently a phenyl, pyridyl, feranyl, beozarinany!, pyrrole, benzothiophene, piperidyl, cyciopentyl, cyclohexyl, or cyclobeptyl ring: m and n are independently 0, 1,2, or 3; R50 is hydrogen or methyl; R*° is -CH2- of -CHzCBr. 2 31, A comestible product, or a precursor thereof 0 f claim 230 wherein B is an optionally substituted pyridine ring.
213. 232. A comestible prodnet, or a precursor thereof of claim 231 wherein the pyridyl-R^ radical has Ore structure
214. 233, A comestible product, or a precursor thereof of claim 229 wherein the amide compound is an oxalamide compound having the formula

     wherein A is a substituted and or heteroaryl ring comprising five to 12 carbon atoms: m and 11 are 0,1,2, or 3: each Ri0 and R*° is independently selected Rom the group consisting of hydrogen, hydroxy, fiuoro, chloro. Mi?, NHCH3, N(CH3)j, CO?€H3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, bifluoromethyl, methoxy, ethoxy, isopropoxy, and trifhioromethoxy, or two of R/0 together form a methylenedioxy ring.
215. 234. A comestible product, or a precursor thereof of claim 233 wherein A is a 2-, 3-, or 4-mono-substitu.ted phenyl, 2,4-, 2,3-, 2,5, 2,6,3,5-, or 3,6-disubstituted phenyl, 3-alkyl-4-substituted phenyl, a in-substituted phenyl, wherein the R70 groups are independently selected from the group consisting of, hydroxy, iluoro, ehloro, MHj, MICHj, N(CHa)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy, or two of v together form a methylenedioxy ring.
216. 235. A comestible product, or a precursor thereof of claim 233 wherein A is substituted . heteroaryl ring comprising 5 to 12 carbon atoms and wherein the substituent groups are independently selected from, the group consisting of hydrogen, hydroxy, iluoro, ehloro, NHa NHCH3, N(CH3)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy group.
217. 236. A comestible product, or a precursor thereof of claim 233 wherein A has one of the formulas

     wherein m is 0, 1,2, or 3, and each Rl is independently selected from independently selected from hydroxy, fluoro, chloro, NB* NiiCLU, N(CIii)2, COOCIT, SCII3J SEt, methyl, ethyl, isopropyl, vinyl, triiiuoroineihyl, methoxy, ethoxy, isopropoxy, and triiluoromethoxy .
218. 237. An oxatarmde compound having the formula

     wherein A and B are a substituted aryl or heteroaryl ring comprising three to twelve ring carbon atoms; m and n are independently 0, 1, 2, or 3; each B-7l)Bi5dSsii is independently selected from the group consisting of, hydroxy, iluoro, chloro, NIB, NHCH3, N(CJ COOCH3, SCIB, SEt, methyl, ethyl, isopropyl, vinyl, triflnoromethyl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy, or two ofR'9 together form a methylened’ioxy ring: or a cornestlfely acceptable salt thereof.
219. 238. The oxalamide compound of claim 237 wherein B is a pyridyl ring,
220. 239. The oxalamide compound of claim 237 wherein the pyridyl-R80 radical has the structure
221. 240. The oxalamide compound of claim 238 wherein A is a phenyl ring,
222. 241. The oxalamide compound of claim 240 wherein B is a pyridyl ring.
223. 242. The oxalamide eomponnd of claim 240 wherein the pyridyl-Rsc' radical has the structure
224. 243. The oxakmide compound of claim 237 wherein A has one of the formulas

     wherein m is 0,1, 2, or 3, and each RE is independently selected horn, hydroxy, fiuoro, chlero, 14¾ NHCH3, N(CH3)2, COOCH3, SCH3.. SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifiuoromeihoxy.
225. 244. The oxalamide compound of claim. 243 wherein B is a pyridyl ring.
226. 245. The oxalamide compound of claim 244 wherein the pyridyl ~RS0 radical has the structure
227. 246. An oxalamide compound of claim 237 having the formula. Nl-(2-niethoxy-4-methylben2yl)-N2-(2-{5-methylpyridin-2-yl)ethyl}oxalamide} Nl-(2-methoxy-4-methylbenzyl)-N2-(2-(pyridin-2-yl)eihyl)oxalamide, Nl-(2,4-dimeihoxyhenzyl)~M2~(2-{5-meth>'lpyxjdm-2~yi)ethyl)oxalainideJ Nl-(2,4-dixnethylbenzyl)-N2-(2-(pyridin-2-yl)€ihyl)oxakm.ideJ N!-(2,4"dimeihoxybeH.zyl)"N2"(2-(pyridm-2-yl)ethyl)oxa!ainidej N-(2J4-Dinjethoxy-benzyl)-N’-(2-pyridin-2-yl-ethyl)-oxalamide; or a comes tibly acceptable salt thereof
228. 247. A comestible or medicinal product, or a precursor -thereof comprising at least a sweet flavor modulating amount of at least one non-naturally occurring amide compound, or a eomestibly acceptable salt thereof, wherein the amide compound has the formula

     wherein A is an optionally substituted phenyl ring or is a heteroaryl ring having one of the formulas

     wherein m is 0, 1, 2, or 3, and each R1 is independently selected from, hydroxy, iluoro, chloro, NH2, NHCH3, MCH3)2, COOCH3s SCHs, SEt, methyl, ethyl, isopropyl, vinyl, Irifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, and wherein R2 is a branfched Cj-Ciq alkyl, or a eyclobexyl, tetrahydronapthalene, or indanyl group, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, fiuoro, chloro·, N%, NHCHj, N(CH3)2, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, triilnoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy . 24S, The comestible product or medicinal product, or a precursor thereof of claim 247 w'herein R‘ is a branched Cj-Cia alkyl
229. 249. The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R2 is an optionally substituted cyclohexyl ring.
230. 250. Tire comestible product or medicinal product, or a pr®eursor thereof of claim 247 wlierein R2 is a cyclohexyl, optionally substituted with l, 2, or 3 methyl groups.

     51. The comestible product 0 r medicinal product, or a precursor thereof of claim 247 wherein R? has the formula
231. 252, Tbs comestible product or medicinal product, or a precursor thereof of claim 24? wherein R2 is a 1-indanyl having the

     formula wherein m is 0,1,2, or 3., and each R2 is independently selected from hydrogen, hydroxy, fluoro, chloro, MHa, MICI-R, 151(0¾)¾ COOCH3, SCI-R, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, '
232. 253- The comestible product or medicinal product, or a prsetrrsor thereof of claim 247 wherein R2 is a 1--(1,2,3,4) tetrahydronapthalene having the formula

     wherein m is 0,1, 2, or 3, and each R2 can be bonded to either the aromatic or nonaromatic ring and is independently selected from hydroxy, fluoro. chloro, NHa, NHCHs, N(CHs)?.. COQChh, SCH3, SEt, methyl ethyl isopropyl, vinyl, trifluoromethyl. methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
233. 254. The comestible product or medicinal product, or a precursor thereof of claim 24? wherein R2 has the formula

     wherein R2 is hydrogen, hydroxy, fluoro, chloro, NH2, NHCH3, N(CHj)2, CGGCH3, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. ;
234. 255. The comestible product or medicinal product, or a precursor thereof of claim 247 wherein E2 has the formula
235. 256. The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R2 has the formula
236. 257. The comestible product or medicinal product, or a precursor thereof of claim 247 * wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene ring having the formula
237. 258. The comestible product or medicinal product, ora precursor thereof of claim 247 wherein R2 is an (R)~]-{1,2,3,4) tetrahydronapthalene ring having the formula
238. 259. The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R2 is an (R)-l-(l,2,3,4) tetrahydronapthalene ring having the formula
239. 260. The comestible or medicinal product, or a precursor thereof of claim 24?wherein the modified comestible or medicinal product is a food for human consumption.

     61. The comestible or medicinal product, or a precursor thereof of claim 247wberein the modified comestible or medicinal product is selected from the group consisting of confectioneries, bakery products, ice creams, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, and spreads.
240. 262, A comestible product, or a precursor thereof of claim 247 comprising one or more meats, poultry, fish, vegetables, grains, or fonts.
241. 263, A comestible product, or a precursor thereof of claim. 247 that is a frozen food, an uncooked food, or a rally or partially cooked food,
242. 264, A comestible product, or a precursor thereof of claim 247 that is a soup, a dehydrated or concentrated soup, or a dry soup.
243. 265, A comestible product, or a precursor thereof of claim 247 wherein tire modified comestible or medicinal product is a snack food.
244. 266, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is a cooking aid product, a meal solution product, a meal enhancement product, a seasoning, or a seasoning blend.
245. 267, A comestible product, or a precursor thereof of claim 247 wherein tire modified comestible or medicinal product is a cake, cookie, pie, candy, chewing gum, gelatin, ice cream, sorbet, pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or fruit sauce,
246. 268, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate.
247. 269, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is a soda, or juice,
248. 270, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is an alcoholic beverage.
249. 271, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is a pharmaceutical composition for oral administration.
250. 272, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is an oral hygiene product.
251. 273, An amide compound having the formula

     wherein A is a phenyl ring or is a heieroaryl ring having one of the formulas

     wherein m is 0, 1, 2, or 3, and each R1 is independently selected from, hydroxy, iluoro, chloro, NBh, ISlHCH-j, N(CH3)2, COOCH3, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, biiluorornefhyl, methoxy, ethoxy, isopropoxy, and tiifluoromethoxy, and wherein R2 is (a) a branched C 5-C c alkyl, or (b) a eyclohexyl, tetrahydronapthalene, or indanyl. group, optionally substituted with 1., 2, or 3 substituents independently selected horn the group consisting of hydroxy, fluoro, chloro, MI2, NHCHj, NiCX-R)?, COOCH3, 80¾ SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethaxy ; or a comestibly acceptable salt thereof.
252. 274. The. amide compound of claim 273 wherein R2 is a branched 0?··0:.;: alkyl.
253. 275. The amide compound of claim 274 wherein A is an optionally substituted phenyl ring.
254. 276. The amide compound of claim 274 wherein A is an optionally substituted pyridyl ring.
255. 277. The amide compound of claim 274 wherein A is a heteroaryl ring having the formula

     wherein R1 is hydrogen, hydroxy, iluoro. chloro, NfR, NHCH3, N(CH3)2, GOOCH?, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and triflnoromethoxy . 27§. The amide compound of claim 275 wherein R2 is an optionally substituted cyclohexyl ring.
256. 279. The amide compound of claim 275 wherein the cyciohexyl ring is substituted with 1, 2, or 3 methyl groups. 280 The amide compound of claim 275 wherein R2 has th e formula
257. 281. The amide compound ofelaim 275 wherein R2 is a ί-indanyl having the formula

     wherein m is 0,1, 2. or 3, and each R2 is independently selected from, hydroxy, iluoro, chloro, NR.?, NHCH3, N(CH3)?.3 COOCH3, SCHh SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and h'ifluoromethoxy.
258. 282. The amide compound of claim 275 wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene having the formula

     wherein m is 0,1,2, or 3, and each R? can be tended to either the aromatic or nonaromatic ring and is independently selected from, hydroxy, fluoro, chloro, M-l?, NHCHj, N(CH'3)2, COOCH-j, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, iseptopoxy, and trifluoromethoxy .
259. 283. The amide compound of claim 275 wherein R2 has the formula

     wherein each Rz is independently selected from, the group consisting of hydrogen, hydroxy, fluoro, chloro, Nife, NHCHs, N(CH-3)2, COOCH-j, SCH$> SEt, methyl, ethyl, isopropyl, vinyl, tnfluorometbyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy .
260. 284. The amide compound of claim 275 wherein R2 has the foimxda
261. 285. The amide compound of claim 275 wherein R2 has the formula
262. 286. The amide compound of claim 275 wherein R3 is a 1-(1,2,3,4) teirahydronapthaiene ring ha ving the formula
263. 287. The amide compound of claim 275 wherein R2 is an (R)-1-(1,2,3,4) teirahydronapthaiene ring having the formula
264. 288. The amide compound of claim 277 wherein R2 is an optionally substituted cyclohexyl ring.
265. 289. The amide compound of claim 277 wherein the cyclohexyl ring is substituted with 1.2, or 3 methyl groups.
266. 290. The amide compound of claim 277 wherein. R3 has the formula
267. 291. The amide compound of claim 277 wherein R2 is a i-indanyl having the formula

     wherein m is 0,1, 2, or 3, and each R2 can be bonded to either the aromatic or nonaromatic ring and is independently sel ected from hydrogen, hydroxy, fluoro, eh loro. KHj, .NKCIR, N(CH3)2, COOCK.2, SCH2, SEt, methyl, ethyl, isopropyl, vinyl, hiflnoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
268. 292. The amide compound of claim 277 wherein R2 is a 1-(1,2,3,4) teirahydronapthaiene having the formula

     wherein m is 0,1., 2, or 3, and each R2 can be bonded to either the aromatic or nonaromatic ring and is independently selected from hydroxy, iluoro, cirloro, hl.H?., NHCH3, NfCHjJa, COOCHj, S€H3, SEt, methyl, ethyl, isopropyl, vinyl, hiiluoromeihyl, meihoxy, ethoxy, isopropoxy, and mfluoromefhoxy.
269. 293. The amide compound of claim 277 wherein R2 has the formula

     wherein each R2 is independently selected from the group consisting of is hydrogen, hydroxy, fhioro, ehloro, NHa, NHCH3, N(CH3)2, COOCHj, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, triflnorcmethyl, meihoxy, ethoxy, isopropoxy, and txiiluoromethoxy, 294. 'The amide compound of claim 277 wherein R* has the formula
270. 295. The amide compound of claim 277 wherein R? has tire formula
271. 296. The amide compound of claim 27? wherein is a 1-(1,2,3,4} tetrahydronapthaiene ring having the formula
272. 297. Tire amide compound of claim 277 wherein R* is an (R)-1-(1,2,3,4) tetrahydronapthalene ring having the formula
273. 298. An amide compound having the formula: 3~chIoro-2~hydroxy~N-(2~methyl~ 1,2,3,44etrahydronaphthalen-1 ~yi)henzamide, 3-chloro-2-hydroxy'N'(5-methoxy-l,2J3.4-tetraliydronaphthaleml"yI)benzamid.e, (R) “3-chlorO“24tydroxy-N”(l ,2,3,4-tetrahydronaphihalen-1 -yl)henzamide, 3-chloro-2-hydroxy-N-(5-hydroxy-l ,2,3,4-tetrahydronaphthalen-1 -yljbenzamide, 3-chloro-2-hydroxy-N-(4"methyl-ls2,3,4-tetrahydronaphthalen~l-yl)beiizamid.e, 3-chloro-2-hydroxy-N-(6-metho.xy-l ,2,3,4-tetrahydronaphtha Isn -1 -yl)benzamide, 3~chloro~2-hydroxy-N-( 1,2,3,4-tetrahydronaphthalen-1 ~yl)benzamide, 2,3-dihydroxy-N~(2~methyl~ 1,2,3,4-iehahydxonapb thalen-1 -yljbenzamide, 2- hydroxy-N-(2~methyl~l>2J3,4~tetrahydronaphthalen-l-yl)henzan3ide, 2,3“dihydroxy-N“(5-niethoxy“l.,2,3,4-tetrahydronaphihalen“l-yi)benzaniide, (S) -2s6“dimethyl”N-(f,2i3J4-tehTshydronaphthalen-l-yl)benzamide3 N-(5,7~dimethy 1-1,2,3,4-ieirahydronaphthalen -1 -y l)-3~me thy li soxazole-4-carboxamide, 3- methyl-N-(2-methyl-l ,2,3,4-tetrahydronaphthalen ~1-yl)isoxa7x>le-4-carboxamide, 3-methyl-N-(4-methyl-1,2,3,4-tetrahydronaphthalen-1 -yl)isoxazole-4-carboxamide, N~(5~methoxy-l,2,3;4-tetrahydronaphthalen-l -y])-3-methy!iaoxazole-4~ carboxamide, (R)-5-bromo~N -(1,2,3,4-tefcahydrcnaphthalen- 1 -vljmcotinarni de, (R) “3-methyl“N“(l,2,3,4“tetrahydroriaphthalen-l-yl)isoxazole-4-carboxamide, (S) -5-bromo-N-(1s2,3,4-tetrahydronaphthalen-1-yl)mcotinamide, (R)-N-(1,2,3,4-tetrahydronaphthaleti-l-yl)iuran-3“Carboxanijde, (R}.5-raethy]-N-(l52J3,4-t€irahydrojiaphthate'-l-yl)isoxazo]e-4-caj;boxaraideJ (R.>N- (1,2,3,4 -tetrahydronaph thaten- l-yl)iuraii-3-carboxaraide, 3-methyi-N-( 1,2,3,4-tetrahydronq>hflialen-1 -yl)isoxazol©-4-carboxamide, N-{3,3 -d'imethylbuian-2 -yI)-2,3,5,6detrailuoiO-4-methy]henzamide, 2,3,5,6AetraiIu©ro~4miethyi-N43mrethylhutan--2-yl)benzannde, 2;3,5,6-tetraili;oro-4-methy3-N'(2-methylcydohexyl)benzamide, N-(2-methyloycfohexyi)-3"itrifluori>methoxy)benzanude, 3- ch3oro-5-fluoro-N-(2--methyIcyc3ohexyl)benzamide. (R) -N-(3,3-dimethy3butan-2”yl)-2,3,5,6-teirafluoro4-methylber3zaniide, 4- fliioro-N-(2-iBethy3cyclohexyl)-3-(iriiluoroinethyl)benzamide, (S) -2,3,5,6-tetrafluoro-4-methyl-N-(3-methyIbutan-2-yl)bexi2amide, 2,5~diehloro~N42mieihyleyeIohexyi)benzanude, , 3,S-dich1oro-2,6-diinetboxy-N-(2-inetbylcycl6bexy])bei3zaiTiide, or 2,0-dimetbybM42miethyleyclobexyi)be«zamide; or a comestibly acceptable salt thereof.
274. 299. A area compound having the formula:

     wherein R7 is an aryl or heteroaryl comprising three to ten ring carbon atoms which is optionally substituted with 1, 2, or 3 substituents independently selected from, hydroxy, ftuoro, ehloro. Ni%, NHCHj, N{CH3};t, CO2CII3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluorometbyl, methoxy, ethoxy, ispropoxy, and trifluoroinethoxy, and R9 is a branched C3-Q0 alkyl, or a cyclohexyl, tefrahydronapthalene, or indanyl group, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, lluoro, ehloro, NHn NHCH3, N(Cii,)::, COGCH3, SCHj, SEt, methyl, ethyl, isopropyl, vinyl, tnfluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy : or a comestibly acceptable salt thereof. .
275. 300. The compound o f claim 299 wherein R' is an optionally substituted phenyl ring.
276. 301. The compound of claim 300 wherein R9 is a branched Cs-Cjo alkyl.
277. 302. The compound of claim 300 wherein R' is is an optionally substituted cyclohexyl ring.
278. 303. The compound of claim 302 wherein the cyclohexyl ring is substituted with 1, 2. or 3 methyl groups'
279. 304. The compound of claim 302 wherein R* has the formula
280. 305. The compound of claim 299 wherein R9 is a l-indanyl having the formula

     wherein m is 0,1,2, or 3, and each R9 is independently selected from hydrogen, hydroxy, lluoro, chioro, NH&amp; NHCH3, N(CH3)2, CGGCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, uifluoromethyl, methoxy, ethoxy, isopropoxy, and hifluoromethoxy .
281. 306. The amide compound of claim 299 wherein R9 is a 1-( 1,2,3,4) tetrahydronapthalene having the formula

     wherein m is 0,1,2, or 3, and eachR9 can be bonded to either the aromatic or nonaromatic ring and is independently selected horn, hydroxy, fluoro, chioro, NHa, NHCH3, N(CH3)2, COOCH3, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, friiluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy .
282. 307. The amide compound of claim 299 wherein R9 is a 1-(1,2,3,4) tetrahydronapthalene ring having the formula

     303, The amide compound of claim 299 wherein R7 is a heteroaryl ring having one of the fotmulas

     wherein m is Gs 1, 2, or 3, and each R1 is independently selected fromhydrogen, hydroxy, fluoro, chloro, NH&amp; NHCHg, N(CH3)2, COOCHs, 80¾ SEt, methyl, ethyl, isopropyl, vinyl, triiluoromethyl, methoxy, ethoxy, isopropoxy, and trifi nor ornethoxy ,
283. 309. The compound of claim 308 wherein Rs i s a branched C j-Cfo alkyl.
284. 310. The compound of claim 308 wherein R"' is an optionally substituted eyclehexyl ring.
285. 311. The compound of claim 30S wherein the cyelohexyl ting is substituted with 1, 2, or 3 methyl groups.
286. 312. The compound o f claim 308 wherein R9 has the form ofe
287. 313. A comestible or medicinal product, or a precursor thereof comprising at least a savory flavor modulating amount of at least one compound of claims 299-312.
288. 314. A urea compound having the formula:

     wherein R7 is an aryl or heteroaryl comprising three to ten ring carbon atoms which is optionally substituted with 1, 2, or 3 substituents independently selected from, hydroxy, fluoro, chloro, NH^NHCHa- N(CHj)&amp; COOCI-R, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and triilueromethoxy, and Rs has the structure

     wherein R9 is hydrogen, a Cl-Cto alkyl, B is a phenyl, pyxidyl, foranyl, thioferanyl, pyrrole, cyelopentylcyclohexyl, or piperidyl ring, m is 0,1, 2, or 3, and eachR2 is independently selected from hydrogen, hydroxy, iluoro, chloro, NHj, NHCH3. NCCIR)?, GOOCH·;, SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. or a comestihiy acceptable salt thereof.
289. 315. The compound of claim 314 wherein R7 is an optionally substituted phenyl ring and B is phenyl or pyndyl.
290. 316. The compound of claim 314 w'herein R7 is an optionally substituted phenyl ring and B is and option ally substituted cyclohexyl
291. 317. A comestible or medicinal product, or a precursor thereof comprising at least a savory flavor modulating amountof at least one compound of claim 314. BIB. An amide compound having the formula: (R)-methyl 2-(3-chloro-4-methoxybenxamido)-4“methylpentanoate, 4-methoxy"3-methyhN-(5-methyHiexan-3-yl}benzamide, N-(heptan~4~yl)-2-'raeihylbenzo[dJI>3]dioxole--5--carhoxamide3 (S)-meihyl 4mieihyl~2--(4miethyl~3“(methylihio)benzamido)pentanGate3 4unethoxy“3miethyl-N-(2-methylheptan-4~yl)benzamide,, N-(heptan-4'y])“6-meihyIbenzo[d][l,3]dioxoSe-5-c2rboxamide; 3j4-dimeihyi-N-(2''msihylhexan-3-yl)beiizamide3 (R)-methyl 4mieihyl-2-(5miethylbeuzofuran-2-carboxamido)pentaiiQatea N-(hexan-3-y3)-4-meihoxy-3-'metIiylbeiizamide, N~(beptan-4-y3)-3-n'iethyl-4"(methy1thio)benzamide, N-(hexan~3~yl)-3-methyM-(methy1thia)benzamide, methyl 243mhloro~4-meihoxybenz3nudG)hex8naate3 3!4-diinethyl~N~(2-xnethylheptaH"4-yl)beiizamidq, N-(hexan-3“yl)'-3:4-dimethylbenzaimdeJ N-iheptan-d-ylJ-S^-dimeihyibenzarnide, (R)~methyi4-methy]-2~(4~(methyithio)ben2:amido)pe.ntanoate, 4-etboxy"N-(heptan-4~yl}-3-methy3benz;amide, 3.4-dimethyl~N~(5~methy]hexan~3-yl)benzamide, (R)-xnethyl 4miethyb2-{4--vmylbenzamidQ)pex)tanoate, 4-methoxy-3-xnetbyl-N-(2-methylhexan*3-yl)benzamMe, N-(faeptan-4-y!)benz0[d] [ l ,3]dioxole-5-carboxamides (R)-rnethyl 2"(benz.o[d][l,3jdiQXole-6<arboxamidG)--4-metliiylpenianoate, (R)-N-(I-metboxy-4~methylpenian-2-y3)-3J4-dimethy1benzan'i!de, (R.)-methy3-2-(2,3-dimetbyl&amp;isn-5~carboxamido)-4-meihyipentanoate!, or 4-M.ethox.y-N-(l-methox>,methyl-3-Tn.eiby3«bui>,l)~3-methy!-benzarmde; or a comestibly acceptable salt thereof. .
292. 319 . An amide compound having the formula: N-(hepiam4~y])baizo[d][lj3]dioxoIe-5-6arboxamidie or N-(2,443imeihoxy~ben:zyl)~N'^2-pyndin-2~yl~ethyI)mxakmide; or a comestibly acceptable salt thereof.
293. 320. A comestible or medicinal product comprising the compounds of claim 319 at a ; concentration between about 0.01 to about 10 ppm.
294. 321. The comesti hie o r medicinal product o f claim 320 wherein the comestible or medicinal product is a a food for human consumption.
295. 322. An urea compound having die formula: l-(2-chJorophenyi)-3 -(heptan~4-yl)urea, l"(2,4"dic]ilorophenyl}-3-(l-plieiiylpropyl)urea3 l“(2,4-dimeiIioxyphenyl)'3“(hepian-4-yl)ureai l-('2-fluoropheny])“3-(hepiari-4"y1)urea, l-(4-isopropyIpheEiyl)-3-(2-(pyrid3rs.r2^i)e,thyl}urea; or a comestibly acceptable salt thereof.