AU2014202646A1 - Novel flavors, flavor modifiers, tastants, taste enhancers, umami or sweet tastants, and/or enhancers and use thereof - Google Patents

Abstract

NOVEL FLAVOURS, FLAVOUR MODIFIERS. TASTANTS, TASTE ENHANCERS, SAVOURY OR SWEET TASTANTS, AND/OR ENHANCERS AND USE THEREOF. 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 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.

Description

NOVEL FLAVORS, FLAVOR MODIFIERS. TASTANTS, TASTE ENHANCERS, UMAMI OR SWEET TASTANTS, AND/OR ENHANCERS AND USE THEREOF 5 This application claims the priority of U.S. provisional patent application serial number 60/494,071 filed on August 06, 2003, and also claims the priority of US. 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 10 The present invention relates to the discovery of flavor or taste modifiers, such as a flavoing 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, 15 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 20 taste perception was poorly understood, and most taste improving or taste modifyig agents have been discovered largely by simple trial and error processes. There has been significant recent progress in identifying usefld natural flavoring agents, such as for example sweeteners such as sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, certain known natural 25 terpenoids, flavonoids, or protein sweeteners. Seeibr example a recent article entitled "Noncariogenic intense Natural Sweeteners" by Kinghom et al, (Med Res Rev 18 (5) 347-360, 1998), which discussed recently discovered natural materials that are much more intensely sweet than common natural sweeteners such as sucrose, fictose, and the like. Similarly, there has been recent progress in identifying and commercializing 30 new artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, sucralose, and alitame, et., see a recent article by Ager, et a!.(Angew ChemnInt. Ed. 1998,37, 1802.1817). The entire disclosure of the two references identified above are hereby incorporated herein by reference, for the purpose of describing at least in part the linowledge of those of ordinary skill in the art regarding known sweetening 35 agents.

However, there remains in the art a need for new and improved flavoi ing agents, For example, one of the five known basic tastes is the "savory" or "umamin" flavor of monosodium glutamate ("MSG"). MSG is known to produce adverse reactions in some people, but very little progress has been made in identifying 5 artifcial 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 occuring nucleotide compounds inosine monophosphate (IMP) or guanosine monophosphate (GMP) are known to have a multiplier effect on the savory taste of 10 MSG, but IMP and GMP are very difficult and expensive to isolate and purify from natural sources, or synthesize, and hence 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 15 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 be required, would be afvery high utility and value. In recent years substantial progress has been made in biotechnology in 20 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 TI Rs, have been identified (See, eg., Nelsonet al , Cell 25 (2001) 106(3):381-390; Adler, et al Cell (2000) 100(6):693-702; Chandrashekar, et al, Cell (2000) 100,703711; Matsunami, et aL, Number (2000) 404:601-604; Li, et al, Proc Nat. Acad. Si USA (2002) 99:4962-4966; Montmayeur, et al, Nature Neuroscience (2001) 4(S):492498: U.S. Patent 6,462, 148; and PCT publications WO 02/06254, WO 00/63166 art, WO 02/064631, and WO 03/001876, and US. 30 Patent publication UP 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, including their disclosures of the identities and structures of T2Rs and TI Rs mammalian taste receptor proteins and methods for artificially expressing those receptors in cell 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 that are involved in bitter taste perception, the TIRs only includes three members, TIRI, Ti R2 and 5 T1R3. (see Li, etal. Proc. NatI Acad Sei UNA (2002) 99:4962-4966.) Recently it was disclosed inWO 02/064631 and/orWO 03/001876 that certain Tl R members, when co-expressed in suitable mammalian cell lines, assemble to form functional taste receptors. Particularly it was found that co-expression of TI R and Ti R3 in a suitable host cell results in a fumctional TI RI/T I R3 savory ("umami ") taste receptor 10 that responds to savory taste stimuli, including monosodium glutamate. Similarly, it was found that co-expression of TIR2 and TIR3 in a suitable host cell results in a functional TlR2/TI1R3 "sweet" taste receptor that responds to different taste stimuli including naturally occuring and artificial sweeteners. (See Li, et at (I). The references cited above also disclosed assays and/or high throughput screens that 15 measure TIRi11fR3 or TIR2/11R3 receptor activity by fluorometric 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 T1RI/TIR3 "savory" taste receptors, or T1R2/TlR3 "sweet" taste receptors, then embarked on a long, complex and iterative process of investigation, 20 evaluation, and optimization, so as to aiive at the various inventions described below. SUMMIARY OF THE INVENTION The invention has many aspects, all of which relate in some fashion to certain non-naturally occurring amide compounds and/or aide derivative compounds having the generic structure shown below in Formula (I): R 25 (I) wherein R, R 2 and R can be and are independently further defined in various ways, as is further detailed below. In all the embodiments of the aide compounds of Formula (I) the R 1 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 R 30 group, as will be further described below. In many but not all embodiments, the 3 amide compouns of Pm () are "primary" anmiesie. one o and R is an organic gro','u comprising at least three carbon atomaos, while the other of R2 and IR is h, drogen The amide compounds ofFor la () also comprise certain sub-classes of 5 amide derivatives or classes of derivatives related to arnides, such as for example ureas, urethanes, oxalamides, acrylamides, and the like, as will be further described below, Many ofthe sub.genuses and species of the "amide" compounds of Formula (I) are shown below to bind to and/or activate one or both of the TIRi/T1R3 "savory R) ("umami")or TI 1R21I R3 sweet receptors imWtro, at relatively low concentrations on the order of micromolar or lower concentrations. The aide compounds are also believed to similarly interact with savory or sweet flavor receptors of animals or humans in vivo, as has been confirmed by actual human taste tests of some of compounds of Fonnula (I). 15 Accordinglym'any of th-sbge"nses and species of the "amide" compounds ofFrmu (urher described hereinbelow can, at surpisingly vlow concentratio be used as savory or sweet flavoxing agents, or savory or sweet agent enhancers. Accordingly, in some embodiments, the inventiodnret to rethodulating the savory taste of a comestible or medicinal product comprising: 20 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 ainde 2 ompound, or a comestibly acceptable salt thereof' so as to form a modified comestible or medicinal product; wherein the amide compound has the formula: Ra

R

1 ' KN wherein R' comprises an organic or hydrocarbon residue having at 30 least three carbon atoms and optionally one or more heteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus; and wherein optionally one of R2 and R3 is H, and wherein at least one of the other of R2 and R 3 comprises an organic or hydrocarbon residue having at least three carbon atoms and optionally one or more heteroatorms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus, Additional optional limitations on the chemical and physical characteristics of the R' R, and R groups will be described below, Some of the atnide compounds of 10 Formula (I) have been synthesized by methods known in the prior art for various purposes, but to the knowledge of the inventors it has not been previously recogdzed that such aides 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 (1) disclosed herein are novel compounds that have not been 15 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 aide compounds of Formula (1), 20 which include but 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 comestibly acceptable salt there, can be used in mixtures or in combination with other known savory or sweet 25 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 (1), while having little or perhaps even no sweet or savory flavor when tasted in isolation, can be employed at very low concentrations in order to very significantly enhance the 30 effectiveness 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 flavor-modified comestible or medicinal products that contain flavor modulating amounts of one or more of the amide compounds disclosed herein. 5 Many of the amide compounds ofFormula(I) and/or its various subgenuses 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 aide compounds of the invention are 5 TlRI/TIR3 receptor agonists and accordingly can induce or enhance savory taste perception in humans. These compounds can enhance, potentiate, modulate or induce other natural and synthetic savory flavoring agents, In related embodiments, many of the aide compounds within the scope of Formula (I) are TIR2/T I R3 receptor agonists and accordingly can induce sweet taste 10 perception in humans at supisingly low concentrations, These compounds can enhance, potentate, modulate or induce other natural, semi-synthetic, or synthetic sweet flavoring agentssuch as for example sucrose, fructose, glucose, erythritol, isomalt, lactitol, niannitol, sorbitol, xylitol, certain known natural terpenoids, flavonoids, or protein sweeteners, aspartame, saccharin, acesulfame-K, cyclamate, 13 sucralose, and alitame, and the like, or a mixture thereof Unexpectedly, it has also been discovered that in many embodiments of the compounds of Fornula (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 20 relevant biological taste receptor proteins are significantly different. Even more unexpectedly, it has been discovered that at least some of the aide compounds of Formula (I) disclosed herein can induce or enhance both the sveet and savory tastes of thie comestible or medicinal products. Therefore in some aspects the invention is related to compounds of Formula () or its various subgenuses and species 25 compounds that modulate (eig, induce, enhance or potentiate) the flavor of loown natural or synthetic sweetener agents. In some embodiments, the invention relates to novel compounds, flavoring agents, flavor enhancers, flavor modifying compounds, and/or compositions containing the compounds of Formula (I), and its various subgenuses and species 30 compounds. In other embodiments, the invention is directed to compounds of Fornula (1) or its various subgenuses and species compounds that modulate (e.g., induce, enhance or potentiate) the flavor of monosodium glutamate (MSG), or synthetic savory flavoring agents. 6 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 (I). or a comestibly or pharmaceutically acceptable salt thereof These compositions will preferably include comestible 5 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 10 compounds within the scope of the compounds of Formula (I), and derivatives, flavoring agents, comestible or medicinal products or compositions, including savory or sweet flavoring agents and flavor enhancers containing the same. The foregoing discussion merely summarizes certain aspects of the inventions and is not intended, nor should it be construed, as limiting the invention in any way, 15 DETAILED DESCRIPTION OF THE INVENTION The present invention can be understood more readily by reference to the 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 the present compounds, compositions, 20 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 pharmaceuucal carriers or foirmuiations, or to particular modes of fonnulating the compounds of the invention into comestible or medicinal products or compositions intended for oral 25 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 the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, DEFINITIONS 30 As used herein, the term "medicinal product" includes both solids and liquid compositions, which are ingestible non-toxic materials which have medicinal value or comprise medicinally active agents such as cough syrups, cough drops, aspirin and chewable medicinal tablets, 7 An oral hygiene product includes solids and liquids such as toothpaste or mouthwash. A. "comestibly, biologically or medicinally acceptable cairrer or excipient" is a solid or liquid medium and/or composition that is used. to prepare a desired dosage 5 fon of the 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, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/fat emulsions such as 10 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 flours, solvents such as ethanol. solid edible diluents such as vegetable powders or flours, or other liquid vehicles; dispersion or suspension aids; 15 surface active agents; isotonic agents; thickening or emuIsifying 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, bitter, umami and others. The subject may be a human or an animal. 20 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 hunmam 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 fIlavoring agent in a animal or a human. 25 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" herein refers to the savory "umami" taste typically induced by MSG (mono sodium glutamate) in a animal or a human. "Savory flavoring agent,""savory compound" or "savory receptor activating 30 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 TI RI/TI R3 receptor in vitro. The subject may be a human or an animal. 8 "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, esg, sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as 5 saccharine, cyclamate, aspartame, and the like as is hither discussed herein, or a compound that activates a T1R2/TIR3 receptor in vitro. The subject may be 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, 10 and blocking, the savory taste of a natural or synthetic savory flavoring agents, e,, monosodium glutamate (MSG) in a animal or 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, ag. 15 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 20 synthetic savory flavoring agents, e.g., 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, eg sucrose, fructose, glucose, and other known 25 natural saccharidebased 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 "unami receptor activating compound" herein refers to a compound that activates an umand receptor, such as a T1RI/TIR3 receptor. 30 A. "sweet receptor activating compound" herein refers to a compound that activates a sweet receptor, such as a TlR2/TlR3 receptor An "umami receptor modulating compound"herein refers to a compound that modulates (activates, enhances or blocks) an umami receptor 9 A "sweet receptor modulating compound" herein refers to a compound that modulates (activates, enhances or blocks) a sweet receptor. An "urami receptor enhancing compound" herein refers to a compound that enhances or potentiates the effect of a natural r synthetic unami receptor activating 5 compound, e.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., sucrose, fructose, glucose, and other leown natural saccharidetbased sweeteners, or lE nwn artificial sweeteners such as saccharine, cyclamate, aspartame, 10 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 be from about 0.001 ppm to 100 ppm, or a narrow range from about 0:1 15 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 amount"herein refers to an amount of a compound that is sufficient to induce sweet taste in a comestible or medicinal product or 20 composition, or a precursor thereof A fairly broad range of a sweet flavoring agent 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 flavoring agent amounts can be from about 0,01 ppn 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. 25 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 30 range from about 0. 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, f&yom about 0I ppm to about 5 ppm, or from about 0-1 ppm to about 3 ppm, 10 A "sweet flavor modulating amount" herein refers to an amount of a compound of Formula () 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 subject. A fairly broadrange of a sweet 5 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. 10 A "savory 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., monosodium glutamate (MSG) in a comestible or medicinal product or composition. A fairly broad range of a savory flavor enhancing amount can be from about 0.001 ppm to 100 ppm, or a nanrow range from about 0-1 ppm to about 10 ppm. 15 Altemative 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 "sweet 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, 20 sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known arificial sweeteners such as saccharine, cyclamate, 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 narow range from about 01 ppm to about 10 ppm. Alternative 25 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 umami 30 receptor. A preferable range of an umami receptor modulating amount is 1 pM to 100 mI and most preferably 1 nM to 100 1 rM and most preferably InM to 30 sM. A fairly broad range of a umami flavor enhancing amount can be fom about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm, Altemative ranges ofumami flavor enhancing amounts can be from about 0.01 ppm to about 30

II

ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or fom about 0 1 ppm to about 3 ppm. A "T1 R/TIR3 receptor modulating or activating amount" is an amount of compound that is sufficient to modulate or activate a T1R/ITlR3 receptor. These 5 amounts are preferably the same as the umami receptor modulating amounts. An "umami receptor" is a taste receptor that can be modulated by a savory compound. Preferably an umami receptor is a G protein coupled receptor, and more preferably the umami receptor is a TIR1 /1.R3 receptor. Compounds of the invention modulate an umami receptor and preferably are 10 agonists of the TI R1/T 1Ri 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. 15 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 ISG. The nucleotides, IMP or GMP, are conventionally added to MSG, to intensify the savory flavor of MSG, so that relatively less MSG is needed to provide the same savory flavor in comparison to 20 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 MSC alone. 25 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 I pM to 100 miM and most preferably I nM to 100 piM and most preferably InM to 30 yM. A "T1R2rflR3 receptor modulating or activating amount" is an amount of 30 compound that is sufficient to modulate or activate a TiR2'TIRI 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 C protein coupled receptor, and more preferably the umami receptor is a TIR2/TIR3 receptor. 12 Many compounds of Fonnula (I) can modulate a sweet receptor and preferably are agonists of the T R2/T R3 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 sweet flavor in a taste test; It is 5 desirable, therefore, that such inventive compounds serve as a replacement for sucrose, fiuctose, 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 effect" relates to the enhanced savory and/or sweet flavor of a 10 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 (I) having an EC50 ratio (defined hereinbelow) of 2.0 or more, or preferably 15 5.0 or moreoro 10.0 or more, or 15.0 or more. An EC5.0 assay for sweet enhancement has not yet been developed, but in the 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 20 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 RS or d,D, 1,L or d, DL, Correspondingly, the aide compounds of the invention, if they can be present in optically active fom, can actually be present in the form of a racemic mixture of enantiomers, or in the form of either of the separate 25 enantiomers in substantially isolated and purified form, or as a mixture comprising any relative proportions of the enantiomers. Regarding the compounds described herein, the suffix "ene" added to any of the described terms means that the substituent is connected to two other parts in the compound. For example, "alkylene "is (1, "alkenylene" is such a moiety that 30 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 unsaturated. The hydrocarbon residue, when so stated however, may 13 contain or be substituted with heteroatoms such as 0, S or N, or the halogens (fluorine, chlorine, bromine, and iodine), or substituent groups containing heteroatoms (01-1, NH 2 , NO 2 , SO3H, and the like) over and above the carbon and hydrogen atoms of the substituent residue. Thus,' hen specifically noted as 5 containing such heteroatoms, or designated as "substituted," the hydrocarbon residue may also contain carbonyl groups, amno groups, hydroxyl groups and the like, or contain heteroatoms inserted into the "backbone" of the hydrocarbon residue. As used herein, "inorganic residue" refers to a residue that does not contain carbon, but contains at least some heteroatomsincluding 0, N: S: one or more 10 halogens, or alkali rnetal or alkaline earth metal ions. Examples include, but are not limited to H, Na+, Ca-+ and K+, halo, hydroxy, N02 or N 2 , As used herein, the tern "aikyl," "alkenyl" and "alkynyl" include straight- and branched-chain and cyclic monovalent substituents that respectively are saturated, unsaturated with at least one double bond, and unsaturated with at least one triple 15 bond, "Al ky" refers to a hydrocarbon group that can be conceptually fonned 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 substitutent group In sonic embodiments of the invention, the alkyl 20 groups are "Cl to C6 alkyl" such as methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, anyl, tert-amnyl, hexyl and the like. In some embodiments of the invention "C1 to C4 alkyl" groups (alternatively termed "lower alkyl" groups are methyl, ethyl, propyl, iso-butyl, sec-butyi t-butyl, and iso-propyl Some of the preferred alkyl groups of the invention have three or more carbon atoms 25 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-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl 5~enyenyl 2-heptenyl, 3lheptenyt 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight and branched chains. 30 Preferred alkynyl groups are "C2 to Cy alkynyl" such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyt 3-hexynyl, 4-hexynyl, 2-heptynyl, 3-heptynyl, 4- heptynyl, 5-heptynyl as well as di- and tti-ynes of straight and branched chains including ene-yues, 14 Hydrocarbon residues may be optionally substituted, Two of said optional substituents on adjacent positions can he joined to form a fised, 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 5 more heteroatons or an inorganic residue such as H, Na, CW" or K* The terms"substituted alkyl " substituted alkenyl" "substituted alkrynyi and "substituted alkylene" denote that the alkyl, alkenyl, aikynyl and alkylene groups are substituted by one or more, and preferably one or two substituents, preferably halogen, hydroxy, CI to C7 alkoxy, alkoxy-alkyl, oxo, C3 to C7 cycloalkyl, naphthyl, 10 amino, (monosubstituted)amino, (disubstituted)amino, guanidino, heterocycie, substituted heterocycle, imidazolyl, indolyl, pyrrolidinyl, Cl to C7 acyl, C1 to C7 acyloxy, nitro, carboxy, carhamoyl, carboxamide, N-(CI to C6 alkyl)carboxamide, NN-di(CI to C6 alkyl)carboxanide, cyano, methylsulfonylamino, thiol, C1 to C4 alkylthio or C 1 to C4 alkylsulfonyl groups. The substituted alkyl groups may be 15 substituted once or more, and preferably once or twice, with the same or with different substituents. In many embodiments of the invention, a preferred group of substi tuent groups include hydroxy, fluoro, chloro, Nit, NHCH, 3 N(1CH) 2 , CO 2

CH

3 , SEt, SCHs, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In many embodiments of the invention that 20 comprise the above lists of substituent groups, an even more preferred group of substituent groups include hydroxy, SEt, SCH, methyl, ethyl, isopropyl, methoxy, and etboxy groups, Examples of the above substituted alkyl groups include the 2-oxo-prop-l -yl, 3-oxo-but-I -yi, cyanomethyl,,nitromethyl, chloromethyl, hydroxymethyl, 25 tetrahydropyranyloxymethyl, trityloxymethyl, propionyloxymethyl, anminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-aminopropyl, I-chloroethyl, 2-chloroethyl, 1- bromoethyl, 2-chloroethyl, 1 fluoroethyl, 2-fluoroethyl. I 30 iodoethyl, 2-iodoethyl, 1-chloropropyl, 2-chloropropyl, 3- chloropropyl, I -bromopropyl, 2-bromopropyi, 3-bromopropyl, 1 -fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 2-aminoethyl, 1- aminoethyl, N-benzoyl-2-aminoethyl, N-acetyl-2-aminoethyl, N-benzoyl-1-aminoethyl, N-acetyl-1-aminoethyl and the like. 15 Examples of the above substituted alkenyl groups inchde styrenyl, 3-chloro-propen-1-y, 3--chloro-buten-l-yi, 3-methoxy-propen-2-y, 3-pheny' .buten-2-y, I-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, 5 Examples of the above substituted alkynyl groups include phenylacetylen-l -yl, I -phenyl-2-propynl -yl and the like, The tenn "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. 10 "Alkoxy" refers to an OR group, wherein R is an alkyl or substituted alkyl. "Alkoxy-alkyl" refers to an alkyl group containing an aikoxy. Preferred alkoxy groups are "CI to C7 alkoxy" such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups. The terin "CI to C7 substituted alkoxy" means the alkyl portion of the alkoxy can be substituted in the 15 sane manner as in relation to CI to C6 substituted alkyl. Similarly, the tern "CI to C7 phenylalkoxy" as used herein means "Cl to C7 alkoxy" bonded to a phenyl radicaL "Acyloxy" refers to an OR group where R is an acyl group, Prefeired acyloxy groups are "Cl to C7 acyloxy" such as formyloxy, acetoxy, propionyloxy, 20 butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy and the like. As used herein, "acyl" encompasses the definitions of alkyl, aikenyl, alkynyl and the related hetero-forms which are coupled to an additional residue through a carbonyl group. Prefeired acyl groups are "Ci to C7 acyl" such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl and the like 25 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, cycloalkyL naphthyl, amino, (monosubstituted)amino, (disubstituted)aniino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, CI to C7 aikoxy, 30 alkoxy-alkyl, Cl to C7 acyl, Cl to C7 acyloxy, nitro, CI to C6 alkyl ester, carboxy, alkoxycarbonyl, carbamoyl, carboxamide, N-(C I to C6 alkyl)carboxamide, N,N-di(C I to C6 alkyl)carboxamide, cyano, methylsulfonylamino, thiol, CI to C4 alkylthio or CI to C4 alkylsulfonyl groups. The substituted acyl groups may be 16 substiftuted once or more, and preferably once or twice, with the same or with different substituents, Examples of CI to 07 substituted acyl groups include 4-phenylbutyroyl, 3-phenylbutyroyl, 3 phenylpropanoyl, 2- cyclohexanylacetyl, cyclohexanecarbonyl, 5 24ranoyl and 3 dimethylarninobenzov. 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 cycialkyl residues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl rings, and saturated bicyclic or fused polycyclic cycloalkanes 10 such as decalin groups, norbomyl groups, and the like. Preferred cycloalkyl groups include "C3 to C7 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl rings. Similarly, the term "CS to C7 cycloalkyl" includes the cyclopentyl, cyclohexyl or cycloheptyl ringgs. "Substituted cycloalkyl" indicates the above cycloalkyl rings are substituted 15 preferably by one or two halogen, hydroxy, , C1 to C4 alkylthio, Cl to C4 alkylsulfoxide, CI to C4 alkyisulfonyl, Cl to C4 substituted alkylthio, CI to C4 substituted alkylsulfoxide, C I to C4 substituted alkylsulfonyl, CI to 06 alkyl, C I to C7 alkoxy, CI to C6 substituted alkyl, C I to C7 alkoxy-alkyl, oxo (monosubstituted)am.ino, (disubstituted)ainino, tdfluoromethyl, carboxy, phenyl, 20 substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, anino. In many embodiments of substituted cycloalkyl groups, the substituted cycloalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, chloro, N42, NHCHI N (CH 3

)

2 , C 2

CH

3 , SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trfluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. 25 The temi "cycloalkylene" means a cycloalkyl, as defined above, where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted cycloalkyiene" 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 30 substituent. The term "cycloalkenyl" indicates preferably a 1,2, or 3-cyclopentenyl ring, a 1,2,3 or 4-cyclohexenyl ring or a 1,2,3,4 or 5-cycloheptenyl ring, while the term "substituted cycloalkeniy" denotes the above cycloalkenyl tings substituted with a substituent, preferably by a O to C6 alkyl, halogen, hydroxy, Cl to C? alkoxy, 17 alkoxy-alkyl, trifluoromethyl, carboxy, alkoxycarbonyl oxo, (mronosubstituted)amino, (disubstituted)amino, phenyl, substituted phenyl, amino, or protected amino, The tem "cycloalkenylene" is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate 5 additional groups. Similarly, the term "substituted cycloalkenylene" means a cycloalkenylene father substituted preferably by halogen, hydroxy, C1 to C4 alkylthio, C to C4 alkylsulfoxide, C1 to C4 alkylsulfonyl, C1 to C4 substituted alkyltbio, C71 to C4 substituted alkylsulfoxide, C Ito C4 substituted alkylsulfonyl, Cl to C6 alkyl, C1 to C7 alkoxy, CI to C6 substituted alkyl, C1 to C7 alkoxy alkyl, oxo, 10 (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, aioxycarbonyl, phenyl, substituted phenyl, phenyithio, phenylsuifoxide, phenylsulfonvi, amino, or substituted amino group. The term "heterocycle" or "heterocyclic ring" denotes optionally substituted 3 to 8-membered rings having one or more carbon. atoms connected in a ring that also 15 have I to 5 heteroatoms, 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-substituted heterocyclic ring" means any one of the above-described heterocyclic rings is substituted with at least one amino group. Preferred heterocyclic rings include furanyl, thiotranyl, piperidyl, pyridyl, 20 moipholino, aziridinyl, piperidinyl, piperazinyl, tetrahydrofdrano, pyrrolo, and tetrahydrothiophen-yl. The tesm "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 diffennt which 25 substituents preferably can be halogen, hydroxy, thio, alkylthio, cyano, nitro, C1 to (6 alkyl, C1 to C7 alkoxy, C1 to C7 substituted alkoxy, alkoxy-akyl, C1 to C7 acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, alkoxy alkyl amiio. monosubstituted)anino, (disubstituted)amino carboxamide, N-(C I to C6 alkyl)carboxamide N, N-di(C1 to C6 alkyl)carboxamide, trifluoromethyl., N-((Cl 30 to C6 alkyl)sulfonyl)amino, N-phenyisulfonyl)amino groups, or substituted with a fused ring, such as benzo-ring. in many embodiments of substituted heterocyclic groups, the substituted cycloalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, chloro, NHz, NHCH, N(CH) 2 , 1.8

CO

2

CH

3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. An "aryl" groups refers to a monocyclic aromatic, liked bicyclic aromatIc or fused bicyclic aromatic moiety comprising at least one six merbered aromatic g "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 substitLutent groups, wherein the substituted aryl group and its substituents comprise between 6 and 1, or preferably 6 and 16 total carbon atoms. Prefeired optional substituent groups include 1, 2, 3, or 4 substituent 10 groups independently selected from hydroxy, fluoro, chloro, N1 2 , NHCH 3 , N(CH3), COrCHz, SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trilluoromethyl., methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups, The tenn Iheteroaryl" means a heterocyclic aryl derivative which preferably contains a five-membered or six-membered conjugated and aromatic ring system 15 having from I to 4 heteroatoms, such as oxygen, sulfir and/or nitrogen, inserted into the imsaturated and conjugated heterocyclic ring. Heteroaryl groups include monocyclic heteroaromatic, linked bicyclic heteroaromatic or fused bicyclic heteroaromatic moieies. Examples of heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolyl, ftranyl, thiofuranyl, oxazoloyl, isokazolyl, 20 phthalimido, thiazolyl, quinolinyl, isoquinolinyl, indolyl, or a fiuran or thiofuran directly bonded to a phenyl, pyuidyl, 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 25 heteroaronatic ring systems contain 3-12 ring carbon atoms and I to 5 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur atorms The term 'Ksubstituted 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, 30 hydroxy, protected hydroxy, thio, aikylthio, cyano, nitro, CI to C6 alky, Cl to C7 substituted alkyl, CI to C7 alkoxy, CI to C7 substituted alkoxy, alkoxy-aikyl, CI to C7 acyl, Cl to C7 substituted acyl, Cl to C7 acyloxy, carboxy, alkoxycarbonyl, carboxyniethyl, hydroxynethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(CI to C6 alkyl)carboxamide, N, N-di(C1 to 19 C6 alkyJ)carboxamide, trifluoromethyl, N-((C to C6 alkyl)sulfonyl)amino or N(4henylsulfonyl)amino groups, In many embodiments of substituted heteroaryl groups, the substituted cycloalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, chloro, NH, NHCH 6 , N(CHA, 5 CO 2

CH

3 , SEt, SCH 3 , methyl, ethyl, isopropy 1, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. Similarly, "arylalkyf" and "heteroarylalkyf" 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, 10 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, heteroaryl or substituted heteroaryL Preferred groups also include benzyl, 2-phenylethyl, 3-phenyl-propyl, 4-phenyl-n-butyl, 3-phenyl-namyi, 3-phenyl 15 2-butyl, 2-pyridinyhnethyl, 2-(2-pyridinylethyl, and the lIke. The tenn "substituted arylalkyl" denotes an arylaikyl group substituted on the alkyl portion with one or more, and preferably one or two, groups preferably chosen fiom halogen, hydroxy, oxo, amino, (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, C 1 to C6 alkyl, CI to C6 20 substituted alkyl, Ci to C7 aikoxy, C I to C7 substituted alkoxy, alkoxy-alkyl, Cl to C7 acyl, Ci to C7 substituted acyl, C1 to C7 acyloxy, nitro, carboxy, alkoxycarbonyl, carbamoyL, carboxamide, N-(Cl to C6 alkyl)carboxamideN, N-(Cl to C6 dialkyl)carboxamide, cyano, N-(Cl to C6 alkylsulfonyl)amino, thiol, CI to C4 alkyltbio, C1 to C4 alkylsulfonyl groups; and/or the phenyl group may be substituted 25 with one or more, and preferably one or two, substituents preferably chosen from halogei, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, CI to C6 alkyl, Cl to C6 substituted alky, CI to C7 alkoxy, C1 to C7 substituted alkoxy, alkoxy-aikyi, C1 to C7 acyl, C I to C7 substituted acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, 30 (disubstituted)amino, carboxamide, N-(Cl to C6 alkyl) carboxamide, N, N-di(C to C6 alkyl)carboxamide, trifluoromethyl, N-((Cl to C6 alkyl)sulfonyl)amino, N-(phenyisulfonyi)amno, cyclic C2 to C7 alkylene or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group, The substituted alkyl or phenyl groups 20 may be substituted with one or more, and preferably one or two, substituents which can. be the same or different Examples of the teim "substituted arylalkyl" include groups such as 2-phenylI -chloroethyl, 2-(4-methoxyphenyl)ethyl, 4-(2,6-dihydroxy pheniyl) 5 n-hexyl, 2-(5-cyano-3-methoxyphenyl)-n-pentyl, 3-(2,6-dimethylpheny)propyl, 4-chloro-3-aminobenzyi, 6-(4-methoxyphenyl)-.3carboxy-n-hexyi, 5-(4-aminomethylphenyl) 3-(aminomethyl)-npentyl, 5-phenyl-3-oxon-pent-d-yl and the like. The term "arylalkylene"' specifies an arylalkyl, as defined above, where the 10 arylalkyl radical is bonded at two positions connecting together two separate additional groups, The definition includes groups of the formula; -phenyl-alkyl and alkyl-phenyl-alkyl-. Substitutions on the phenyl ring can be 1,2, 1,3 or 1,4: The term "substituted arylalkylene" is an arVlalkylene as defined above that is further substituted preferably by halogen hydroxy, proteted hydroxv, CI to C4 alkylthio, CI 15 to C4 alkylsulfoxide, CI to C4 alkylsulfonyl, CI to C4 substituted alkylthio, C] to C4 substituted alkylsulfoxide, CI to C4 substituted alkyisulfonyl, C1 to C6 alkyl, Cl to C7 aikoxy, CI to C6 substituted alkyl, C. to C7 alkoxy-alkyl, oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, car boxy, alkoxycarbonyl, phenyl, substituted phenyi, phenylthie, phenyisulfoxide, 20 phenylsulfonyL, amino, or protected amino group on the phenyl ring or on the alkyl group. The temi "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, eyano, nitro, C1 to 25 C6 alkyl, CJ to C6 substituted alkyl, CI to C7 alkoxy, CJ to C7 substituted aikoxy, alkoxy-alkyl, C l to C? acyl, C I to C7 substituted acyl, CI to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxyimethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(C to C6 ailkyl)carboxamide, N, N-di(Cl to C6 alkyl)carboxamide, trifluoromethyl,N-((Cl to C6 alkyl)suifonyl)amino, 30 N-(phenylsulfonyl)amino or phenyl, wherein the phenyl is substituted or unsubstituted, such that, for example, a biphenyl results, In many emboduments of substituted phenyl groups, the substituted cycloalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, chloro, N1H, 21

NHCH

3 , N(CH><, C0 2

CH

3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and tifluoromethoxy groups. The term "phenoxy" denotes a phenyl bonded to an oxygen atom. The term "substituted phenoxy" species a phenoxy group substituted with one or more, and 5 preferably one or two, moieties preferably chosen from the groups consisting of halogen, hydroxy, protection hydroxy, thio, alkyithio, cyano, nitro, Cl to C6 alkyl, C to C7 alkoxy, CI to C7 substituted alkoxy, alkoxy-alkyl, C1 to C7I acyl, CI to C7I acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl,, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(Cl to C6 10 alkyl)carboxamide, N, N-di(CI to C6 alkyl)carboxamide, trifluoromethyl, N-((CI to C6 alkyl)sulfonyl)amino and N-phenylsulfonyl)amino The term "ubstituted 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, 15 (nionosubstituted)amino, (disubstituted)anino, guanidino, heterocyclic ring, substituted heterocyclic ring, Cl to C7 alkoxy, alkoxy-aikyl, CI to C'7 acyl, Cl to C7 acyloxy, nitro, carboxy, alkoxycarbonyl, carbamoyl, carboxamide, N-(Cl to C6 alkyl)carboxamide, N, N-(Cl to C6 dialkyl)carboxamide, cyano, N-(Cl to C6 alkylsulfonyl)amino, thiol, CI to C4 alkylthio, Cl to C4 alkylsuifonyl groups; and/or 20 the phenyl group can be substituted with one or more, and preferably one or two, substituents preferably chosen from halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C1 to C6 alkyl, CI to C7 al koxy, alkoxy-alkyl, CI to C7 acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl carboxymethyl, hydroxymethyl, amino, (mnonosubstitted)amino, (disubstituted)amino, carboxamide, N-(CI to C6 alkyl) 25 carboxamide, N, N-di(Cl to C6 alkyl)carboxamnide, trifluoromethyl, N ((Cl to C6 alkyi)sulfony)amino, N-(phenylsulfony)aMnio 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. 30 The term "substituted naphthyl" specifies a naphthyl group substituted with one or more, and preferably one or two, noieties either on the same ring or on different rings chosen from the groups consisting of halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, CI to C6 alkyl, CI to C7 aikoxy, alkoxy-alkyl, CI to C7 acyl, Ci to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, 22 hydroxymethyi, 1amno, (monosub'N - tncsticYted)ainnot carboxamtide, N-ACl to C6 a carboxamie N, NCto C6 tifluoromethyl, N((Cl to C6 aklsfn <ai or N( The terms "hao" and "hailoen" remer to the fiuoro, chloro, bromo or iodo 5 atoms There can be one or more halogen, which are the same or different Preferd 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 10 embodiments ofthe compounds o fFormula (1), if a halogen atom (including a fluoro or chioro 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 "(m ss mno" refers to a amino group with one sunbst ituenrt preferably chose en Twom the gouqp cons,,isting of' pheny subsztituted phen ,yl, C.1 t o C6 alkyl C . to C6 ubstl Co C7 acl, C1 to C7 substituted acyi, C2 to C7 alkeny, C2. to C7 subsiued alkeny C2 to C d7 akynyl C,2 to C7 substituteod-alkl, C C12 pheny,.lalkyl, C7 to C 12sutitdphnakyad "' '''N1 I9 9 i~al a heteocycli h (monosubstituted)aino cani a amino-pirotcting group as encomnpassed by tne term "protected 20 (monosubstituted)amino" The term "(disubstituted)amino" refers to an amino group substituted preferably with two substituents chosen from the group consisting ofphenyl, substituted phenyl C1 to C6 alkyl, C1 to C6 substituted alkyl, C1 to C7 acyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C7 to 012 phenylalkyt and C7 to C12 substituted 25 phenylalkyl The two substituents can be the same or different, The tei "amino-protecting group" as used herein refers to subs ofthf e amno gro ooly employed to boc k orproltct the', amn fuctoaloty' awhile reacting other functioa groups of the molecule.'The tern "protetd (monosubstitutediaminomens there is an amino-pNotctig rouponthe 30 monosubstituted amino nitrogen atoma In addition, the tenn "protected carboxamide" means there is an amino-protecting group on the carboxamide nitrogen, Similarly, the term "protected N-(C1 to 06 alkyl)carboxamide" means there is an amino-protecting group on the carboxamide nitrogen 23 T'hetermn ",alkylthIio" refer's to sul'fidve goups sunch a- s mehA ho ethylthmi, nprpyfthio, ispropytlhio, n thi-yh nd likea 0 grop s. The termn "alkyisulf oxide" indicates sutfoxide gr-oupssc smtysloie ethysulfxide n-roysufxie isprpysxfxhe nauy sulf oe, ipx M se-bOutylsulfoxide and the l.ke The tenn "alkylsulfonyl" encompasses groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, t-butylsulfonyl and the like The terms "substituted aikylthio," "substituted alkyisufoxide;" and 10 "substituted al kyIsulfonyl," denote the alkyl portion of these groups Mnay be substituted as described above in relation to "substituted alkyl," The trms o phenysulfxide," and"h u specify a thiol, a sufoxide,. or sulfone r e ani a phenryl group. The terms "substituted phienylthio ," "substi~tuted phenylufxdon "substituted's 15 pnsf meansthat the phenyl ofthee gups-an be substituted as des.bed above, i n rel.ation to "su'bstitunted phe'uny L The term "takoxycabn means an alkoxy" group attache to a carobonyl group. The term " substitutedkxn a sunbsttuted alkoxy b nded t 20 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"phenyiene" includes 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene. The term "substituted alkylene" means an alkyl group where the alkyl radical 25 is bonded, at tw o positions connecting to getiherk tw o sepanatze additional groups and f'lthe bearing an additional -substituen. Examples of"substituted alkylene" includes It 'd)-;2-e ty, no -ri eh VIe CDe iD C t 1, 2 d, 2 NydrNo xy- , -etl, -(amin)3-pry L The term substitutedd n means a phenyl g p whe the phentyl 30 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 ternis "cyclic aikylene," "substituted cyclic alkylene," "cyclic heteroalkylene," and "substituted cyclic heteroalkylene," defines such a cyclic group 24 bonded(si") to the phenyl radical resulting in a bi system. The cyclic ~~''ycli OtteO ring~ I' y ten the cyclijc group, miay be saturated or c-ontain o o two double bonds, Furlhermre, h cci group may have one or two metkhylene or ruethine groups replaced by onre Or two o xygen, niit ogen or slakatoms wlhitch are te cyclic ee-iyee 5 The ccli alkylene or hetera gopmybsst one or twice by the same or different substituents preferably selected from the group consisting of the following moieties: hydroxy, protected bydroxy, carboxy, protected carboxy, oxo, protected oxo, C I to C4 acyloxy, fornyl, C I to C? acyi, CI to C6 aikyl, C I to C7 alkoxy, C i to C4 alkyithio, CI to C4 alkvisulfoxide, C I to C4 alkylsulfonyl, halo, 10 amino, protected amino, (monosubstituted)amino, protected (monosubstituted)airino, (disubstituted)anino, hydroxymethyl or a protected hydroxymethyl. jhe cyclic alkylene or heteroalkylene g f to the benzene rdca cancon'ain two to ten ring members, but it pref'rably conikains three to sixmeber Examples of such saturated cyclic grous are e abicyclic ng 15 is 2,adihydr-indanyi and a tetralin ring. When the cyclic roups are unsaturated, exnples occur when the resuItant bicycliC ring system is a naphthyl ring or indolyl, Examples of fused ccli: groups which each contain one nitrogen ato, and one or more double bond, preferably one or two double bonds, are when the benzene radical issed to a pyridino pyran"O, pyron, N'Ipyridiny, dihy rorlo or dihydropyridiny' 20 iing 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 furo, pyrano, dihydrofarano, or dihydropyrano ring, Examples of fused cyclic groups which each have one sulfur atom and contain one or two double bonds are when the benzene radical is fused to a thieno, thiopyrano, dihydrothieno or dihydrotbiopyrano ring, 25 Examples of cyclic roups'hich contains twoheteroatoms selected from sun. ) and nitrog en and one or two double bo'ds'are"when the benzene radical ring is fused to, a thiazo tiazoO, dihyrothiazolo or dihydroisothiazolo ring. Examtnples fcyclic groups which contain two heteroatoms selected from oxygen and ntroage anId one or two double bonids are when the benz'-ene- ring is f"used to an,, oxazolo, isoxa-,zolo, 30 dihydrooxazolo or dihydroisoxazolo ring. Examples of cyclic groups which contain two nitrogen heteroatons and one or two double bonds occur when the benzene ring is fused to a pyrazolo, imidazolo, dihydropyrazolo or dihydroimidazolo ring or pyrazinyl. 25 The ter "carbam-noylrmeans aNCO- gou where the radical is boed at two position connectig two seOparate adtoagrus, One or more of the compounds ofthe inentin, may be present as a salt The "sa ethoe s h form withithe carboxylate anniins and amine 5 nitrogens and include salts farmed with the organic and inorganic anions and cations discussed below, Furthermore, the term includes salts that fain by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids. Such acids include hydrochloric, hyaofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fiunaric, palmitic, cholic, pamoic, mucic, 10 D-glutamic, D-camphoric, giutaric, phthalic, tartaric, lauiic, stearic, salicyclic, nethanesulfonic, benzenesuifonic, sorbic, picric, benzoic, cinnamic, and like acids. The tenn "organic oinxor ati on" refers to nfor the carboxylate anion of a carboxylate -salt. h ontrin are chosen fo the akl and alaieerhmtl,(uhas,, lithum, sm, ptasum, bariAn alumimmi and- 15 calcium1-n); ammnuonZiumR and monro-, d,-- and tri-alkyl aminies such astrmhyai, cyclohexlamine;and the orgaic c-ation.,-s, such asdiezamoum benzylammozni, 2hdoytyamnubs2hdoyty~ oim pheylehylenzlamonim, ibezylhyeneiamonimand like cations. Se,-e, forak examiple,"Panaetia Slsere et "a"', hr Si(9 77") 66:' 9. 20 herein by rrn. Other nations encompassed by the above tenn include the protonated f n of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glyc-ine, ornithine, histidine, phenylglycine, lysine and arginine, Furthennore, any zwitterionic form of the instant compounds forced by a carboxylic acid and an amino group is referred to by this 25 teim, For example, a cation for a carboxylate- anion will exist when R2 or R3 is substituted with a (qaeayamnu~ehlgroup, A, preferred cation for the carboxylate anion is the sodium cation. The comnpounds"' of the inven tion canu al so e xist as solvate s and hydats Th-us, these comnpoun-!ds mriay crystalliuze withn, ""or example, waters of hydration, or one, a 30number off, or any faction themof\* of mnolecules of there mother liquor solvent, The solvates anud hydrates of such comipounds are included withinM the scope of this inventafion. The term "amiino acid icludes anY one of the twenty naturall-y-ocomlring amino acids or the D)-form of any Qo ofthe naual-cuigamino acids. hI 26 addition, the term "amino acid" also includes other non-naturally occurring amino acids besides the D-amino acids, which are functional equivalents of the naturally-occurring anino acids. Such non-naturally-occurring amino acids include, for example, norleucine ("Nle"), norvaline ("Nva"), I, or D- naphthalanine, ornithine 5 ("Om"), homoarginine (homoArg) and others well kmown in the peptide art, such as those described in M Bodanzsky, "Principles of Peptide Synthesis," 1st and 2nd revised ed., Springer-Verlag, New York, NY, 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis" 2nd ed,, Pierce Chemical Co,, Rocklord, IL, 1984, both of which are incorporated herein by reference. Amino acids and amino acid 10 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, ug, 15 substituted alkyl orbenzyl wherein at least one element or radical, eg., hydrogen, is replaced by another, e. 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 structural frngment, or a moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical 20 product, regardless of whether the structural fragment or moiety is actually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more -- OCH 2

CH

2 O- repeat units in the polyester, regardless of whether ethylene glycol is used to prepare the polyester. Similarly. a 2,4-thiazolidinedione residue in a chemical compound refers to one or more -2,4-thiazolidinedione moieties 25 of the compound, regardless of whether the residue was obtained by reacting 2,4 thiazolidinedione to obtain the compound. The texm "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 30 contain various heteroatoins, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfin, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic resides can 27 preferably comprise I to 18 carbon atoms, I to 15, carbon atoms, 1 to 12 carbon atoms, I to 8 carbon atoms, or 1 to 4 carbon atoms. By the term "eff ective amount" of a compound as provided herein is meant a sufficient amount of the compound to provide the desired regulation of a desired 5 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 10 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, 15 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 20 embodiment. It will be ftriher 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 optionall" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where 25 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 unsubstitted lower alkyl and lower akyls where there is substitution. 30 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 Formnula (I) shown below: 28 N 7 (I) The amide compounds of Fonmula () do not include any amide compounds that are imown to naturally occur in biological systems or foods, such as peptides, proteins, nucleic acids, glycopeptides or glycoproteins, or the like. The aide 5 compounds of Formula (1) of the invention are man-made and artificial synthetic amide compounds, although the Applicants do not exclude the possibility that compounds of Formula (1) could conceivably be purposely prepared, either in their specified form 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. 10 For the various embodiments of the compounds of Formula (I)T the R, R 2 and groups can be and are independently further defined in various ways, as will now be further detailed, so as to form and/or include a substantial number of subgenuses and/or species of compounds of Formula (I). It is hereby specifically contemplated that any of subgen uses and/or species of compounds of Formula (1) described below 15 can, either in their specified form or as a comestibly acceptable salt, be combined in an effective amount with a comestible or medicinal product or prcursor 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 cmestible or medicinal products or precursor thereof, to form a savory or sweet flavor modified 20 comestible or medicinal product, or a precursor thereof. In some embodiments of the compounds ofFormula (), PW is a hydrocarbon residue that may contain one or more heteroatorns or an inorganic residue, and R] and R3 are each independently H or a hydrocarbon residue that may contain one or more heteroatoms; more preferably, R, R2 and R are independently selected from the 25 group consisting of arylaikenyl. heteroarylalkenyl, arylalkyl, heteroarylakyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl aryl, heteroaryl, -R 4 0H, -R4CN, -RCO2H, -R 4 C0 2 R', -RCOR 5 , -RCONRR 5 , -R 4 NRrRt -RNk(R-)OR -RSR,

R

4

SOR

5

~R

4 SO2RW ~R 4 SO2NR 6 and -R 4

N(R)SO

2 Rt or optionally substituted groups thereof and preferably one ofR or R. is H; wherein each R4 is independently 29 a hydrocarbon residue that may contain one or more heteroatoms, preferably independently selected frm small (CI-C6) alkylene or (Cl-C6) alkoxyalkylene; and wherein each R 5 and R are independently H or a hydrocarbon residue that may contain one or more heteroatoms, preferably independently selected from small 5 (C1-C6) alkyl or (Cl-C6) alkaxyalkyl In many embodiments of the compounds of Formula (I), R' comprises an organic or hydrocarbon-based residue having at least three carbon atoms and optionally one to 20, 15, 10, 8, 7 6, or 5 heteroatoms independently selected from oxygen, nitrogen, suifur, halogens, or phosphorus. 10 In many embodiments of the compounds ofFormula (I) one of R 2 and R 3 is optionally -I, and one or both of RI an d R3 comprises an organic or hydrocarbon based residue having at least three carbon atoms and optionally one to ten beteroatoms independently selected from oxygen, nitrogen, sulfur, halogens, or phosphorus. 15 The compounds of Formula (I) are relatively "small molecules" as compared to many biological molecules, and can often have a variety oflimitations on their overall absolute physical size, molecular weight, and physical characteristic, so that they can be at least somewhat soluble in. aqueous media, and are of appropriate size to effectively bind to the relevant heterodimeric TIRI/T1R3 or T 1R2/T11R3 taste 20 receptors, which share a common TIR3 protein subunit. While not wishing to be bound by any theory, it is believed that MSG binds to the TiR I subunit of T1R i/TIR3 "savory" taste receptors, and several known sweeteners bind to the T1R2 subunit of TlR2/TR3 sweet receptors. Accordingly, our unexpected and surprising discovery that the amide compounds of Formula (I) can 25 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 from a chemical/ biochemical/ biological point of view. As an example of the overlapping physical and chemical properties and/or physical/chemical limitations on the savory and/or sweet amides of Formula (I), in 30 most embodiments of the compounds of Formula (1) the molecular weight of the compounds of Formula (I) should be less than about 800 grams per mole, or in further 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 giams permole, 350 grams per mole, or 300 grams per mole. 30 'ila rly, the conpounds of.rmula () can nave prefered ranges of molcuarweght, such as fo~r exa-zmple fiom about 175 to about 500 grams per mole fi-om about 200 to about 450 gram per mAe, from about 225 to about 400igams per mole, from about 250 to about 350 g-msper mole. 5 h a related series of embodimnts, R has between 3a carbon ato'ns 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, sulfir fluorine, or chlorine, and/or at least one of R2 or R3 has been 3 and 16 carbon atoms and 0, 1, 2, 3, 4, or 5 heteroatoms independently selected from oxygen, nitrogen, sulfbr, fluorine, or chlorine; or 10 preferably at least one of R2 or R has between 4 and 14 carbon atoms and 0, 1, 2 3,, 4, or 5 heteroatoms independently selected forn oxygen, nitogen, sulfur, fluorine; or even more preferably, at least one of R 2 or R3 has between 5 and 12 carbon atoms and 0, 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfiu; Lo addition to lt' above described general phys"il' an'd chem a' 15 characteristics an/orurnitations, wich can be shared by the various suogenuses of the sw.e .and savory co munds of Formula (1), the copounds- of Formula (1) can also share more specifically deinaible chemical structural features or chemical groups or resiums, as s fiu'ther described below, For example, in some embodiments, R, R 2 . and R3 can be independently 20 selected frorn the group consisting of an arylailkenyl, heteroarylalk-enyl, arylalkyl, heteroarylalkyl, alkyl, aikoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -ROH, R 4 0R P7tRCN, -R.4C2H, -R4C02R R , - 4 OR, -RSR, and RSO2R 5 , and optionally substituted derivative thereof comprising 1, 2, 3, or 4 carbonyl, amino groups, hydroxyl, or halogen groups, and wherein R. and R 5 are C 25 C6 hydrocarbon residues. In faRUther related emoiets of the amanide comipo unds of Fozunula (1), R- RX and IR can be independently seletx'red from the group consisting of an arylalieny3, hetroaylakenlarylalkyl],heeoryak alkyl, alt ko)xy-'alkylq, alke~nyl, cycloalkyl, cycloallkenyi, heterocycie, aryandhtterOaryl g-,roups, anI otonall substited 30 derivatives thereofcomprising 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 substuents independently selected from hydroxy, fluoro, NH 2 , NHCH 3 , N(0H 3 )2, 31i CO2CA S~t, SC~yethyl, ethyl, sopropyl, vin-yl,tifurmhyehx, ethoxy, isopropoxy, and tiiuoromethoxy stttrops& In m "any mthe compouds of Formula ,e ofR and Ris hydrogen and the other or R group is anoa r r groit up. For exanpIe, 5 in many embodiments of the compounds ofFormula (1), at least one or R 1 and R is a branched or cyclic organic residue having a carbon atom directly bonded to both (a) the aide 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 10 optional additional carbon atoms, and optionally from 10 zero to five heteroatoms independently selected from oxygen, nitrogen, suiftu; fluorine, and chlorine Such branched R 2 and R? groups include organic radicals having the formula: (R, N a 15 wherein na and nb are independently selected frion 1, 2, and 3, and each R 2 aor R substituent residue is independently selected fnom hydrogen, a halogen, a hydroxy, or a carbon-containing residue optionally having from zero to five heteroatoms independently selected forn oxygen, nitrogen, sulfur, and a halogen. In some such embodiments, the R or R are independent substituent groups, but in other 20 embodiments one or more of the R7' or R"" radicals can be bonded together to form ring structures. In some such embodiments of the compounds of Formula (I), at least one of the RJ and R is a branched alkyl radical having S to 12 carbon atoms, or at least one of R2 and R is a cycloalkyl or cycloalkenyl ring comprising 5 to 12 fing carbon 25 atoms n such embod~1tAiments'. ot and R therhed alky radical o the cycoaly. or cycloalkenyl ring an be optionally substituted with 1, 2,, or 4 substitute" groups independently selected from roxy fluoro, chloro NH2., NHCHk,N( ss CO2Cs SEt, SCl methyl, ethyl isoropy, vinyi, triuoromethyl,inmthoxy, eh~o'xyisoNpropoxy, and uoromethoxy. 32 in other enbodinents of th' amide cm s atleast one of the Pt and Ri is a "benzyl cav ino"g thestrnucture N-." wherein Ar is an aromatic or heteraromatic ring such as phenyl, pyridyl, furanyl, S thiofuranyl, pyrrolyl, or similar aromatic ring systems, m is 0,1, 2, or 3, and each R is independently selected from hydroxy, fluoro, chioro, N.H, NHCH 3 , N(CH3)j, C0 2 CH3, SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoronethyl, aethoxy, ethoxy, isopropoxy, and trifluoromethoxy, and each R 2 ' substituent group can be independently selected from the group consisting of an alkyl, alkoxy-aIkyl, alkenyl, 10 cycloalkenyl, cycloalkyl, -R 4 0H, -R'O R -R 4 CN, -R4CO2H, -R4CO R5, -R 4 COR', -R SR- and -R 4 S0 2 R group, In many eboen the com d of F la (1), at east one of R or Sis a C ranche aky Thse CrCe branched alkyls have een founo be highly ettective: R grous for both savory and sweet anide compounds In further 15 embodiments the C -C Cbrceak may optinaiiy substituted with one or two substituents independently seected from a hydroxy, fluoro, chloro,, NHClk N(CH3)b, COC., S S, methyl, ethyL isopropyl, vinyl, tu m y netIhox xy, isopropoxy, and triluoromethoxy group. In farther embodiments of the compounds ofFomila (), at least one of R 2 or 20 W is an ca-substituted carboxylic acid or a-substituted carboxylic acid lower alkyl ester. Preferably, at least one of R 2 or W is an a-substituted carboxylic acid lower alkyl (especially methyl) ester In some such preferred. embodiments, the a substituted carboxylic acid or a-substituted carboxylic acid ester residue corresponds to that of a naturally occurring and optically active a-amino acid or an ester thereof, 25 or its opposite enantiorner. In many emodinents of te compounds o1omula (I), at least oneo ofR or .3 is a 5 or 6 membered aryl or heteroaryl ain, oprionally substituted with 1, 2,3 or4 subs % tut groups selected kom tlhe groupcnsstn oakyl aikoxyl,akxyayl OAN cN 2H, CHOc CO , wC2RS t, halogen, a3ken, a ccoaiky, cycoalkenyr, 30 aryl, and heteroaryl: and R( is CrC 5 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, NI- 2 , HNCH3, N(CH3) 2 , C0 2 C1 3 , SCH , SEt, methyl, ethyl, 33 isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In some embodiments of the compounds offFormula (I), at least one of R or RI is a phenyl, pyridyl, firanyl, thiofuranyl, or pyrrolyl ring optionally substituted $ with one or two substituents independently selected from hydroxy, fluoro, chloro, NH2, NHCH 3 , N(CH3)2, CQCH, SCH 3 , SEt, methyl, ethyl isopropyl, vinyl, influoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. In many embodiments ofthe compounds of Formula (I), at least one of R2 or

R

3 is a cycloalkyl, cycloalkenyl, or saturated heterocyclic ring having 3 to 10 ring 1.0 carbon atoms, optionally substituted with 1, 2, or 3 subsituents independently sciected from the group consisting of NHt, N-HCH,,, N(CH3)2, CCH., SEt, SCH 3 ,

CC

4 alkyl, C-C4 haloalkyl, CrC4 alkoxy, CrC4 haloalkoxy, hydroxy, and halogen. In some father embodiments, at least one of R2 or R is a cyclopentyl, cyclohexyl, cycloheptyl cyclooctyl ring, or piperidyl ring optionally substituted with 1, 2, or 3 15 substituents independently selected from the group consisting ofhydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3

)

2 , CO2C1 3 , SEt, SC1 3 , methyl, ethyL isopropyl, vinyl, trfluoromethyL, methoxy, ethoxy, isopropoxy, and tifluoromethoxy. In some preferred embodiments, at least one of R or R is a cyclohexyl, optionally substituted with 1, 2, or 3 methyl groups Examples of such methyl substituted cyclohexyl rings 20 have the formula or In many embodiments of the compounds 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 having the formula: (R2' 25 or (Rm wherein m is 0,1, 2, or 3, and each RI can be bonded to either the aromatic or non aromatic ring and is independently selected from hydroxy, fluoro, chioro, NH,

NHCH

3 ,N(C11 2 C0 2

CH

3 , SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, It is to be 34 understood that optical and/or diastereomexic isomerism can occur on the cyclohexyl or cyclopentyl 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 R2 or R? is a 1-(1,2,3,4) S tetrahydronapthalene ring with certain preferred substitution patterns. In particular, at least one of R2 or R3 may have the formula: ror RR R 2'or wherein each R are independently selected from the group consisting of hydrogen, 10 hydroxy, fuoro, chloro, NHz, NHCH, N(CH)2, C013, SCH, SEt, methyl, ethyl, isopropyl, vinyl, trifuoromethyl, methoxy, ethoxy isopropoxy, and tri uoromethoxy groups. Similarly, in some preferred embodiments, at least one of R2 or R3 may have the formula: CI or In some embodiments at least one of R? or R? is an unsubstituted 1-(1,2,3,4) tetrahydronapthalene ring in racemic or optically active form, as shown below: or or 35 n mainy prefeed embodiments ofthe aide compounds of Formula( having one or both of savory and sweet receptor agonist actiity, there is a preferred suibgenus of amide compourds ,aing tihe owingformua (i): (R)-A" N--R wherein A comprises a 5 or 6 membered ary or heteroaryl ring; ma is 0, 1, 2, 3 or 4; each R C is independently selected from alkyl, alkoxy, alkoxy-alkyl, hydroxyalkyl, OH, CN, CO2HT, CO2RtCHO, CORt SR, haloge n, alkenyl, cycloalkyl, cycloalkenyl, heterocycac, aryl, and heteroaryl; and R6 is CYCs alkyl, and R 2 can be any of the 10 embodirments contemplated herein above, or the like, in som mbodiments, the A group of Fornula (1I) comprises an ryl ring,, it contains at least one six-membered aromatic benzering- Thice alvs inc-iude at esbeed a en' x wich may not, but inany e dments a futers s with at least N, 2,or 3 R sumbtituen groups ind"eendently e 15 from the group consisting of hydroxy, fluoro, chloro, NH- 2 , NHCH , N(CH)2, COOCH SCHt, SEt, methyL ethyL, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In some preferred embodiments, one or two of the R" substituent groups are bonded together to fom a saturated a'kylenedioxy ring on an phenyl ring, as 20 exemplified by the foliowingpreferred structures (U a) and (IIb) .0 2 N)R H wherein RI and JR , are independently h ,ydroe or aower alkyl, or alterawtively Ra and Rare independently hydrogen or methy or aematively both Ra and Ra hydrogen, 25 Ln many embodiments of the amide compounds of Formula (N), A is heteroaryl ring, and typically a monocyclic or fused bicyclic heteroaryl ring. The 36 fsed bicyclic heteraryls are typified by the following benzofurans (Formula HC) and benzothiofurans (Formula (l1d): 0 0 wherein ni is 0, 1 2, or 3 and each R can be bonded to either the phenyl or heteroaryl 5 rings and each R' is independently selected from, hydroxy, fluoro, chloro, NII2,

NHCH

3 , N(CI1h); CO 2

CH

3 , SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. Additional examples of fused bicyclic heteroaryls as A groups are typified by the following benzoxazole compounds (Formula le) and (Formula (Mf): 1 0 S Ior H or wherein R, or R, is independently hydrogen or a lower akyl. In many embodiments of the amide compounds of Formula (T) A is a monocyclie heteroaryl ring, The monocyclic heteroaryls that can be used as an A group in Formula (H) are typified by the allowing sructtres: R N) or 37 3- OtO 1 01 -~~ N -'Tor tA JR - Yf IA wherein m is 0, 1 2 or 3, and each R is independently selected from, hydroxy, 5 fluoro, chloro, NI H 2 , NHCH3, N(CH 3

)

2 , C0 2 CH3, SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy. and trituoromethoxy, In some prefertred embodiments of the compounds of Formula (U), A is a substituted firan, tbiofuran, or oxazole ring, so as to foim compounds having Formulas (Hg), (I1h) and (i): 00 N", - -- 10 (H)or ONm) 011) wherein m is 0, 1, or 3 and each R is independently selected from hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 )g, C0 2 CH3,SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, orifluoromethyl, methoxy, ethoxy, isopropoxy, and rifluoromethoxy. In some of 15 these embodiments, in is I or 2. In many embodiments of the compounds of the various subgenuses of Formula (H) described immediately above, at least one of R or R 3 can be a CrCl branched aikyl; an a-substituted carboxylic acid or an ct-substituted carboxylic acid 38 lower alkyl 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, fluoro, chloro, Nit, NHCII 3 , N(C13), CO2C 3 ,: SCH 3 St, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups; a 5 cyclohexyl, optionally substituted with 1, 2, or 3 methyl groups; or a ~(I,2,3,4) tetrahydronapthalene ring or an 2,3-dihydro-H-indene ring having the formula: 1, wherein i is 0,, 2, or 3, and each R can be bonded to either the aromatic or non aromatic ring and is independently selected from hydroxy, fluoro, chloro, NI-I, 10 NHCI, N(CI-3) CO2CII 3 , SCI- 3 , SEt, 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 subgenuses of aromaic or 6eteroaromaic amide compounds of Formula(II) described immediately above contain many excellent agonists of 15 TiRi/T1R3 savory ("umami") taste receptors, and/or T1R2/TIR3 sweet taste receptors, at very low concentrations of the aide compound on the order of micrornolar concentrations or less, and can induce a noticeable sensation of a savory umami flavor in humans, and/or can serve as enhancers of the savory umami flavor of MSG, or significantly enhance the effectiveness of a variety of klown sweeteners, 20 especially saccharide based sweeteners. Accordingly, many of the aromatic or heteroaromatic amide compounds of Fonula (Ii) can be utilized as savory or sweet flavoring agents or savory or sweet flavor enhancers when contacted with a vide variety of comestible products and/or compositions, or their precursors, as is described elsewhere herein. 25 In another subgenus of the compounds ofFonnula (1), the aide compound has Formula (HI): 0 39 wherein A comprises a 5 or 6 nenbered sr, or heteroaryi ring; n is ,23or4; eac' R ideendnt\ Nssetfr alkyl, akosxy , alkoxy-akyl, hydroxyaikyl, OCN, CO2-H, CHO"C, COIR." CO2,R , SH1, S halogenl, alkenyl, cYcloalkyl, cycloalkenyl,aryA and heteroaryl andR is C -C6 alkyl; B is a 5 or 6 nemixered arl 5 or heteroaryl iing; in' is 0, 1, 2, 3 or 4; R 2 is selccted from the group consisting of alkyl, alkoxy, alkoxy-alkyl, OH, CN, C2 H, CHO, COR, CO2R.SR halogen, alkenyl, cycloalkyl, cycloalkenyi, aiyl, and heteroaryl: and R6 is Cts alkyL In the compounds ofFormula (II), the optional R and R 2 substituent groups can also be independently selected from hydroxy, Buoro, chloro, NH 2 , NHCH 3 , 10 N(CHi), CO 2 CHi,SCHi, SEt, methyl, ethyl, isopropyl, vinyl, trifluoronethyl, methoxy, ethoxy, isopropoxy, and trifluoronethoxy groups. In the compnounds of F3omula M) both the A and B rns compri se a firveor six mernbered aryl or hee ,ay rin, r te A r an of th various emodiments of the A rings recie above for the comCpound f ( nuin I e and i5th mnocyclic and bicyclic heteroayls"4 canobe suiabe. In some bicyclic eaoiments, the A ring'of theconnpournds Formula (111) ha-ve the blowiQng structures: 0 KIt or ~Or

RR

R for < 20 wherein R, and R, are independenty hydrogen or a lower aikyl In th cOmpunds5 of5 frla ()N, the BN rngs are typilNly an Itinally substitut mnoliCIve or six"' mebrdayl or hetermaryl ring, sucha hnl pyridyl, foranyi thiofuirany, rol, and like mnocycles in some emNbodiNment cma-o "N'ds~ ' A+-~r I,:,'N 'a NdNH compound of Formla() wh-ereinis ny, e whereinN the' a.mi comtpouind is 25 readily derived from an substituted aniline precursor, can in many cases be previously known chemical compounds, but we believe it has been previously unknown that such compounds can be used as very effective mnami flavorant compounds, at less than micromolar concenrations or less, see for exanpe compound A I in Table I below, 40 Urea Conrounda In another subgenus of the aide compounds of7ormula (I), the amide compound is a urea compound having the Formula (IV) C) H R" (IV) 5 wherein R R 7 R and R are each a hydrocarbon residue that may contain one or more heteroatoms or an inorganic residue, and preferably is independently selected from. arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl cycloalkyl, cycloalkenyl, aryl and heteroaryl groups, each of which may be optionally substituted, or one ofR' or can be and often is H, 10 In some embodiments of the urea compounds of Formula (IV) R? and re 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, cliloro, NH, NHCH 3 , N(CI1 3

)

2 , COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxv 15 groups. Examples of such urea compound can have the Formulas (IWa) and (Nb): (Iva) (iVb) wherein m and n are independently 0, 1, 2, or 3, and each Reand R 2 is independently selected from fluoro chloro, NH, NHCH,, N(CHJ, COCH, SEt, SCH1, methyl, 20 ethyl, isopropyl, vinyl, tdfluoromethyl, methoxy, ethoxy, isooxy, xy, and trifluoromethoxy. In such embodiments, n is preferably 0. in additional em bodiments of the urea compounds of Formula (IV), H" and one ofR7 and HW are independently selected from arylalkenyls, heteroarylalkenyls, arylaikyls, heteroarvlalkyls, alkys, alkoxy-alkyls, alkenyls, cycloalkyls, 25 cycloalkenyls, aryls and heteroaryls, each of which carbon containing groups may be optionally substituted with 1, 2, or 3 substituents independently selected from 41 hyd\rogen,huo, COOCtsyCH3, SEt, methyl, ethyl, isopropyl vinyl, r mh eh ,ethoxy, isopropoxy, and trif luorometh Oxyrus In aditinal mbodment of he uea cmpouds0 of Fornmula (IVJ)jR' and' 5 one of R! and Rs are independently selected from arylalkyl, heteroarylalkyl, alky, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which may optionally comprise one to five heteroatoms independently selected from oxygen, nitrogen, sulfr, chlorine, and fluorine. In additional embodiments of the urea compounds ofFormula (IV), R 9 and 10 one of R7 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, chloro, NFH2, NHCH 3 , N(CH3)2, CO2CH 3 , SEt, SCIh. methyl, ethyl, isopropyl, vinyl, trfluoromethyl, methoxy, ethoxy, isopropoxy, and trifuoromethoxy 5n ad"ii o naI em, bod aents I o0 f t urea co po0un ds f 'Formua ('IV a onc o fR and Rhas. one of the heteroaromkatic formulas: Rl TIN. Sr S 0 -r/O or (or N (R t-(k\ 20 42 N r N (R' x.N> In (PT wherein m is 0,1, 2, or 3, and each R" independently selected from hydrogen, hydroxy, fluoro, chioro, NH , NHCH 3 , N(CH 3 ), COOCH 3 , SCH 3 , SEt, methyl, ethyl, 5 isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy goups. In such embodimentsR'is preferably a C 3 -Ci branched alkyl, arylalkyl, or a cycloalky that can be optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy fluoro, chloro, NH,, NHCH 3 , N(CH3)2, COOCH, SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, 10 methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups In additional embodiments of the urea compounds of FoRula (IV), at least one ofR' and R is a phenyl ring optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH3, N(CH3),, COOCH3, SCH3. SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, 15 methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups, In such embodiments, R 9 is preferably a CrCiw branched alkyl, arylalkyl, or a cycloalkyl that can be optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NRh NHCH 3 , N (CHR, COOCH3, SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy 20 groups, In additional embodiments of the urea compounds of Formula (W), R9 is a C3 CID branched alkyl. In additional embodiments of the urea compounds ofFormula (IV), R 9 has the structure HC\W R N1 or R! 25 wherein B is a phenyl, pyxidyl, furanyl, thiofiranyl, pyirole, cyclopentylcyclohexyl, or piperidyl ring, in is 0,1, 2, or 3, and each R is independently selected from 43 yroge, hydroxy, fluoro, chloro,N HH, N(CHT), CO . SCH, SDt, met yl, ety Spry, viny trformeh letoxy, ethoxy, lspooy n trifloromthox grous, ad R "s aselected frolhe grou~pcnstigfanak, alkoxyalkyt alkenyl, cyokn ca ,R4 , -R4R -RCNR :) ~R C' Rr. R COR R SR ad -RSO2R) cominsing 1 to 12 carb In another subgenus of he anide compounds of Formula (1), the amide compound is an oxalamide compound having Foimula (V): o R3 RZ' N N 4 R20 (V) wherein RN-14anR are each independenty selected a hydrocarbon res iae t may eferab, R and : are i ndeny selected fromtn group oonsisting or arlkl hteroaryaki, heterocycle~a'yor optionally sub-stiitued groups thereof and 15 R and R ae each iependent ora hydrocarbon residue that may contain one or more heteroatoms; preferably R 2 , and R- are H or CC alkyl, or optionally substituted groups thereof. More preferably R 20 and R.

0 are H. Moreover, there can be 0, 1, 2, 3, or 4 optional substituent groups for R and Re independently selected fron hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 )2, C2CH 3 SCH3, SEt, 20 methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and tIfluoromethoxy groups In preferred embodiment of the oxalamide compounds of Formula (V), R10and R' are independently selected hydrocarbon residues having at least three carbon atoms and optionally one to ten heteroatoms independently selected from oxygen, 2 n gen, surhalogens or phi'losphorus., and wherein Rwand R' ar independently lecte hdrogeIn and a hydrocatbon residue havig at leastthreecarbonatoms andtioal ne to) ten heeratm i n selctdroma xygen, nitr'4ogeni, sulflu, halogens, orphsors In many preferred embodiment of the oxalamide compounds ofFomnda (V), 30 R7and R* are hydrogen In such embodiments, RIO and R3 0 can be independently 44 selected from the group consisting of arylalkyls, cycloalkyl-alkyls, and heterocycie-alkyis comprising fve to 15 carbon atoms, wherein each of R 0 and RH can optionally comprise one to one to four substituents independently selected from hydrogen, hydroxy, fluoro, choro, NHI, NHCH 3 , N(CH-y2, C0 2

CH

3 , SEt, SCH3, 5 methyl, ethyl, isopropyl, vinyl, triflnoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In many embodiments of the oxalamide compounds of Formula (V), the oxalamide compound has the Formula (Va): 0 o

R

4 (Va) 10 wherein A and B are independently an arylt heteroaryl, cycloalkyl, or a heterocycle comprising 5 to 12 ring atoms; m and n are independently 0, 1, 2, 3 or 4~8; R 20 and

R

40 are hydrogen, Ra5' is hydrogen or an alkyl or substituted alkyl residue comprising one to four carbon atoms; R is absent or a C-Cs alkylene or a CwCs substituted alkyJene; R7n and RO are independently selected from the group consisting of 15 hydrogen, alkyl, alkoxyl, alkoxy-alkyl, OH, SR 9 , halogen, CN, NO 2 , COzR COR 9 , CONRR", NR9R NR 9 COR', SOR9, SO2R', SONR 9 R, NRSO2R" alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; R9 and R' are independently selected from -I, C-C5 alkyl, C 3

-C

6 cycloalkyl, and CiCS alkeny In preferred embodiments of the oxalamide compounds of Formula (Va), R5 20 is a -CH 2

CH

2 . group, A and B are independently selected from phenyl, pyridyl, furanyl, thiofuranyl and pyrrolyl rings and R' and R8 are independently selected from hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 )2, CO 2

CH

3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. 25 In some embodiments of the oxalamide compounds of Formula (Va), A and B are independently a phenyl, pyridyl, furanyl, benzofuranyl, pyrrole, benzotbiophene, piperidyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; m and n are independently 0, 1, 2, or 3; R 2 0 and R 40 are hydrogen; R 50 is hydrogen or methyl; R5 0 is a C-Cs or preferably C 2 alkylene; R and R are independently selected from hydrogen, 30 hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 )2, CO 2

CH

3 , SEt, SC 3 , methyl, ethyl, 45 iSopropy, vinyl trif t l thoxy ethoxy, isopropoxy, and triiuoromethoxy p)Zz35. ofte- oxa lam p nds ofFornxla (V), the oxalaide conpoud ha's theFm (Vb): RO a (R )m N (R-o b (Vb) wherein A is a phenyl, pyridyl, furanyl, pyrrole, piperidyl, cyclopentyl, cyciohexyl, or cycloheptyl ring; m and n are independently 0, 1, 2, or 3; R.' is hydrogen or methyl; P is I or 2; andR 3 and R8 are independently selected fron the group consisting of hydrogen, hydroxy, fluoro, chloro, NH2, NHC1 3 , N(CH.)2, COOCE1, SCH, SEt, t0 mthiyl, ethyl, isopropy, vinyl'tilodehl methoxy, ethoxy, isprpoy adnd trifluorornethoxy , or two of R tgedher fon a meth dioxyrig. In som e embodimens of te oxalamiwde comapounds frorm ()hyy radical has the structure: tAt 4. or 15 In certain prefer-ed embodiments of the amide compounds o f Formula (V), the oxalamide compound has the Formula (Vc) R0 (Vc) herein A is a susttuedarl r etroaryl uing cmrs gfv to 12 carbon atoms; R" is hlydrogen or methyl; n,, is 0, 1, 2, or 3; each R' sidpnetyslce 20 from the group consising of hydroxy, fluoro, chloro, NH12, NHCH3,. N(CH3)2, CO2CHl , SEt, SCH3, methyl, ethiyl, isopropyl, Vinyl, tifuoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromnethoxy groups, In some emodmntif the oxalamnide compounds of Fainnula (Ve), Arl is a 2-, 3-, or 4-mono-substituted phenyl, 2,4-, 2,3, 2,5, 2,6, 3,5-, or 36dsbtuedphenyl, 3-alkyk-4-substituted phenyl, a 46 ,,ri-substituted phenyl wvherein the stubst--ituent groups aRre independently selected f',rm the groum consisting of hydrogen, hydroxy, fiuoro, chloro, NIH, NHCH, N(CH);' C2CHsSE, SCH3 mthyl, ethyA, isopro yomethy, methoxy, ethoxipoxy, and viuorot'hoxy, or two aIjacent substituents together foan 5 a methylenedioxy ring on the phenyl ring, i some embodiments of the oxalamide compounds ofFormula (Vc), Ar 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, Ni, NHCH 3 , N(CH 3

)

2 , COCH , SEt, SCH, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, nethoxy, 10 ethoxy, isopropoxy, and trifluoromethoxy. In certain preferred embodiments of the amide compounds of Fomula (V), the oxalamide compound has the Foimula (Vd): R N 0 N (Vd) (Vd) wherein A is a substituted aryn or heterary r 'ioncmpsirn. fve to 12 carbon atoms; 15 R 0 is hydrogen or methyl; n is 0, 1, 2, or 3; each R" is independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NHI, NHCH 3 , N(CH3),

COOCH

3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and iffluoromethoxy . Preferably, A is a phenyl, pyridyl, furanyl, pyrrole, piperidyl, cyclopentyl, cyclohexy, or cycloheptyl ring ring 20 optionally substituted with 1, 3, or 3 subbtituent groups independently selected from the group consisting of hydrogen, hydroxy, fluoro, chioro, Nit NHCH 3 , N(CH 2 ),

COOCH

3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, tifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. ncertain pmr dmbodents of"te amide comnpounds of Foimula(V),te 25 xaamde conpou'nd has thc Forfnua (Vel) ~H K di N,2(V ) wer ein In and n arindpndn: 0, 1,2, or 3;: R andR areidpednl selected from the group consisting ovfhydrogenaikyl, alkoxy>, alkoxy -akyk, OH, SR halogen'CNNN, 4 CiR COR, CONR4R), NR R NR. C'OR SOR, A ' ,- c -'- 'o- -o

SO

2 R> S2NRR, NRtSOYR, aikenyl, cycloalkyl, cycloalkenyl, aryl, heteroary, 5 and heterocycle; and R and R are independently selected from H, CJQ alkyl, C3

C

6 cycloalkyl, and C 1

-C

6 alkenyl groups. Preferably, RO and R are independently selected from the group consisting ofhydrogen, hydroxy, fluoro, chloro, NHL, NHCH,, N(CIH) 2 , COOCH 3 , SC 3 ,SEt, methyl, ethyl, isopropyl, vinyl, trifiuoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups, 10 Preferably, the pyridy- R radical of the oxalamide compound ofFormula (Ve) has the structure: As can be no-ted by iseto of the Exm nples attached rinblw om,~o 'd c"F oalmd copudfor ulas(V)-Ve are excellent agonis,,ts odfITIR1/I kR3 5 savory ("Aumami") 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 uiami flavor of MSG. Accordingly, oxalamide compounds ofFormulas (V), (Vd) and (Ve) can be utilized as savory flavoring agents or savory flavor enhancers when contacted with a wide 20 variety of comestible products and/or compositions, or their precursors, as is described elsewhere hereirt Acrylamide Compounds In another subgenus of the aide compounds ofFormula (1), the aide compound is an acrylamide compound having Formula (VI): (R E R2 2®')5 V4-1k", wherein A. is a 5 or 6 menbered aryl or heteroaryl ring; n is 0, 1, 2, 3 or 4, each RI is independently selected fr om alkyl alkoxyl, alkoxy-alkyl, OH, CN, CO2H, CO2R 6 , CHO, COR, SR 6 , halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl, 48 R canbe any of te various rinabove wi respect tothaidsoorua() In some of the acramide compounds of Formula (VI), A is a phenyl n anid "I-,,I U,."ad" ca 'mcn'c, ~ -be mn is 1 2, 3 or 4, or preferably n is I or . and R selected fn 5 hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 )2, C2CHa, SEt, SCI3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromnethoxy groups. some of the acrylamide compounds of Form ula (VI RE is a (~Cio alkyl, or an -substituted carboxylic acid lower alkyl ester. Sorarmcetcali...e... .. !gds 10 Many of the aide compounds ofFonnula (I) or its various enumerated subgenuses comprise acidic or basic groups, so tha. depending on the or basic clharacter-, ("pH".) of the comtrestAible or mnedicinalt comnpositions in wihthey are they may be prtas salt wic are preferably comestibly accepta (i~e designated as generanly recognized as safe, or GRAS) orharmaceutcaly IS acceptable salts (many of which have been recognized by the Federal Food and Drg Admoinistrati, 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 20 associate cornestibly 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 alli metal cations (ithium, sodium, and potassium cations), alkaline earth metal cations (magnesium, calcium, and the like), or ammonium (NH4)* or orga nically substituted ammonium cations su lxas (R-NH 25 cations. The armide compounds of Formtula (I) having basic substituent groups, such as amino or nheterocyclic groups, wil tend (at eaineu tral pnysiological pH, or at the acidic p-t conmon in nany toods) to be present n sohtion in the formu of cationic ammonium groups, and therefore will in preferred 30 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 49 carboxylic acids (acetates, citrates, tarwates, anionic salts of fatty acids, eta), halides (especially fluorides or chlorides, nitrates, and the like. The aide compounds ofFomula (),and its various subgenuses should preferably be comestibly acceptable, i.e. deemed suitable for consumption in food or S 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 Extract Manufacturers Association and declared as to be "Generally Recognized As Safe" ("GRAS"). The FEMA/GRAS evaluation process for flavorant compounds is 10 complex but well known to those of ordinary skill in the food product preparation arts, as is discussed by Smith et aL in an article entitled "GRAS Flavoring Substances 21," Food Technology, 57(5), pgs 46-59, May 2003, the entire contents of which are hereby incorporated herein by reference. When being evaluated in the FEMAIGRAS process, a new flavorant 15 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 100-fold, or 1000-fold, or even higlier 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 aide compounds of the invention might involve 20 combining the aide compound with rat chow and feeding it to laboratory rats such as Crl:CD(SD)IGS BR rats, at a concentration of about 100 milligrams/Kilogram body weight/day for 90 days, and then sacrificing and evaluating the rats by various medical testing procedures to show that the aide compound of Formula (I) causes no adverse toxic effects on the rats. 25 TheQo uhadftheInventioasg y orSweetaste Enhancers The amide compounds of Formula (I) and its various compound sub-gen uses and species, as described above are intended to be savory or sweet taste Ilavorant compounds or flavor modifiers for comestible or medicinal products. As is apparent from the teachings and Examples herein, many compounds of Fonmula (I) are 30 agonists of an hTIR/hTIR3 "savory" receptor, or an hTIR2/hTlR3 sweet receptor, at least at relatively high amide compound concentrations, and accordingly many of the amide compounds of Formula (I) can have at least some utility as savory or sweet flavorants or flavor enhancers, at least at relatively high concentrations. 50 Never rtheles it is preferable tomueas, litle of such arti'ficia l flavora nts as possible, so as to minimize both cost and any uh ide effect' o adnmtra'tio of t compounds ofFonua (1) at hig. conentration level Accordingly,, it isdesirableto test the com'ponds of Formna (I) for their 5 effectiveness as taste receptor agonists at lower concentration levels, so as to identify the best and most effective amide compounds within the compounds of Formiula (I), As was disclosed in WO 03/001876, and U.S. Patent publication US 2003--0232407 Al, and as described hereinbelow, laboratory procedures now exist for measuring the agonist activities of compounds for an hTIRl/hTiR3 "savory" and hTIR2/hT1R3 10 sweet receptors. Such measurement methods typically measure an "EC%",i&. the concentration at which the compound causes 50% activation of the relevant receptor. PrefeCraby, the aide comonds ofl: F (.) that a favr modifiers have an EC5 forthe nh lTiTR3 receptor ofless than about 10 piM. Melore preferably, such amzide comound hav an. Eta fo h TR TR eetor 05 1f'eSs th, a about 5 ptM, 3 M,2 pM, N p, -r 0.5 pM, Preferabv, the- amide compounds "Frmula (I) that are sweet flavor modifiers or sweet flavor enhancersha an E.. for the h1 R2/!T1R3 receptor of less than about 10 puM, More preferablyy, suamid compounids have an ECSgo for the hl'R"2/hT1R3 recr& feth about 5 pM, 3 pM 2 um, ;M, or 05 pM 20 In some embodinents, the amide compounds of Formula (I) are savory flavor modulators or enhances of the agonist activity of monosodium glutamate for an hTIR I /hTIR3 receptor. Hereinbelow is described an assay procedure for so-called EC5o 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 ofMSG 25 require to v 50% of the availabe hcti/hT1R 3k)% n receptors, Pref erably, the amide compouns of Formula () whe dissolved in a water solution comprising about u-pMfof the amuide compound will decrease the observed EQso of mnsdu gluaate fO. 1 an R1TR 3 'receptor expressed in an HE2,93-Go:15 cell line by at least 50%, iLe. the aide compound wil nave an EC5i ratio of at least 2.0, or 30 prefekrably3. 50or70 Although no specific ECao ratio assays for sweet enhancers have yet been developed, it is believed the amide compounds of Formula (I), and more specifically many of the aides of Formula (II) can modulate the binding of a known sweetener 51 such a fso'r example, sucro far' uts" galoseeryr lsomnalt, lactitl, mnnito', sorbitol, xylitol, a known natural terpenoid, 'lavonoido protein aspartame. sacchi, acesulfame-K, a cyclamatesn sra Ae alitame or eryt hral to an hT1R'2/h'TIR3 receptor, A ppropriateassays fr s .h st properties canbe readily developd byone fordinaryskil in the arts by using appropriate cell lines exprsing hTIR21113 receIptors. The above identified assays are useful in identifying the most potent of the amide compounds of Foninula (1) for savory and/or sweet taste modifier or enhancer properties, and the results of such assays are believed to correlate well with actual 10 savory or sweet taste perception in animals and humans, but ultimately the results of the assays can be confimed, 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 b y taing the candidate compounds in aqueous soli ons, as compared to control aqueous solution, or alternatively by tasting the aides of the 15 inventions in actual f000 compositions. Accrdngy, in order to identify the nniore potent of thve savory tas.kte mnodifiers or agna aWater solution copiiga savoryy flavor mnodifyi',,ng- amout4o the ziamide compounld sAhould have a savory taste as; judged by the majoil ty of a panel of atles e'human tste tesA A'ters, 20 Correspondingly, in order to identify the more potent of the savorly taste enhances a water solution, comprising a savory flavor modifying amount of a amide compound of Fonn ula (I) and 12 mnM monosodium glutamate, would have an increased savory taste as comparWd to a control water solution Comprising 12 mMIV monosodium glutamate, as determined by the majority of a panel of at least eight 25 imnuman taste testers.ea , nor to identify the more potent of the taste enhancers, a water so tion, comprising a savory flavor m odifying amount of (,,preferzably about 30, 140, 5, or 2 ppm) of the amide compound of Fonula () ad12 amM onOsodiumn gltaate will have an increased s glury taste as, ould v an control water motion comprising 12 conoswae giutampate an 1 2 pM 30 mnosimnoptspate, as determined by the majority of a panel of at least eight human taste testers, Similar human taste tes"ti" g procedures can be used to identify which of the compounds Of Formula (1) are the more effective sweet taste agents or sweet taste enhancing agents Preferred sweet taste modifiers of Fomnula (1) can be identified

'N-.

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; Prefeired sweet taste enhances of Formula (1) can be identified when a water 5 solution comprising a sweet tasting amount of a known sweetener selected from the group consisting of sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, a known 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 10 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/i100 15 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. 20 Usiln the Compounds of Formula (D to Prep are Comestible Conmositions 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 ruedicinal compositions wherein savory or sweet compounds are conventionally utilized. These compositions include compositions for 25 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 flavor modifiers thereof) are well aware of a large variety of classes, subclasses and species of the comestible 30 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 subgenuses and species of the compounds of Formula (I) could be used to modify or enhance the savory and/or sweet flavors of the i3 following list comestible compositions, either singly or in all reasonable combinations or mixtures thereof: One or more confectioneries, chocolate confectionery, tablets, countlines, bagged selflines/sofilinesboxed assortments, standard 5 boxed assortments, twist wrapped miniatures, seasonal chocolate, chocolate with toys, alfajores, other chocolate confectionery, mints, standard mints, power mints, boiled sweets, pastilles, gums, jellies and chews, toffees, caramels and nougat, medicated confectionery, lollipops, liquorice, other sugar confectionery, gum, 10 chewing gum, sugarised gu, sugar-free gum, functional gum, bubble gum, bread, packaged/industrial bread, unpackaged/artisanal bread, pastries, cakes, packaged/industrial cakes, unpackaged/artisanal cakes, cookies, chocolate coated biscuits, sandwich biscuits, filled biscuits, savoury biscuits and 15 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' portion dairy ice cream, single portion water ice cream, multi-pack dairy ice cream, multi-pack water ice cream, take-home ice cream; 20 take-home dairy ice cream, ice cream desserts, bulk ice cream, take-home water ice cream, frozen voghurt, artisanal ice cream, dairy products, ilk, fiesh/pasteurised milk, full 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, fictional and other condensed milk, flavoured milk drinks, dairy only flavoured milk drinks, flavoured milk drinks with fruit juice, soy milk, sour milk drinks, fermented dairy drinks, coffee whiteners, powder 30 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 54 yoghurt, drinking yoghurt, regular drinking yogurt, probiotic drinking yoghurt, chilled and shelf- stable desserts, dairy-based desserts, soy-based desserts, chilled snacks, fromage frais and quark, plain fromage frais and quark, flavoured fromage frais and quark, savoury fromage &ais and quark, sweet and savoury snacks, fruit snacks, chipsfcrisps, extruded snacks, tortilla/com chips, popcorn, pretzels, nuts, other sweet and savoury snacks, snack bars, granola bars, breakfast bars, energy bars, flit bars, other snack bars, meal replacement products, slimuning products, 0 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, uht soup, frozen soup, pasta, canned pasta, dried pasta, chilled./flesh pasta, noodles, plain noodles, 15 instant noodles, cups/bowl instant noodles, pouch instant noodles, chilled noodles, snack noodles, canned food, canned meat and meat products, canned fish/seafood, canned vegetables, canned tomatoes, canned beans, canned fmit, canned ready meals, caned soup, canned pasta, other canned foods, frozen food, frozen processed red meat, frozen processed poultry, frozen processed fish/seafood, frozen processed vegetables, frozen meat substitutes, frozen potatoes, oven baked potato chips, other oven baked potato products, non-oven frozen potatoes, frozen bakeryproducts, frozen desserts, frozen ready meals, frozen pizza, frozen soup, frozen 25 noodles, other frozen food, dried food, dessert mixes, dried ready meals, dehydrated soup, instant soup, died 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, chiHed 3-10 smoked fish, chilled lunch t child ready meals, chilled pizza, chilled soup, chilled/fresh pasta, chilled noodles, oils and fats, olive oil, vegetable and seed oil, cooking fats, butter, margarine, spreadable oils and fats, functional spreadable oils and fats, sauces, dressings and condiments, tomato pastes and purses, 55 bouillon/stock cubes, stock cubes, gravy granules, liquid stocks and fonds, herbs and spices, fenented 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 fonnula, prepared baby food, dried baby food, other baby food, spreads, jams and preserves, 10 honey, chocolate spreads, nut-based spreads, and yeast-based spreads. Preferably, the compounds of Formula (1) 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 15 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 ingestible composition will be produced that contains a sufficient amount of at least one compound within the scope of Formula (1) or its various 20 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 Foin ula (1) will be added to the 25 comestible or medicinal product, so that the savory or sweet flavor modi'ed 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 30 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 ingestible composition what savory compounds are present and the concentrations thereof, and 56 the effect, of thew partic-aar comnpoun~d on such savory compounds1, As,-, -noted, a tgn:ficant a t ofthe comp.ofor'mula i) is for m(inducing enhan-cig ozr inhibiting ,) the saoyor 'sweet zaste-s or other r taste proqprtiepozohe natural or sy savory tasta'nts. A broad but also low range o enti o of 5 the amide compounds of Formula (1) would typically be required, ie. from about 0.001 ppm to 100 ppm , or narrower alternative ranges fom about 0.1 ppm to about 10 ppm, from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 01 ppm to about 5 ppm, or from about 0,1 ppm to about 3 ppm. Examples of foods and beverages wherein compounds according to the 10 in vention may be in coporated included b y wa of example the Wet Soup Category, the Dehydrated and Culinary Food Category, the Beverage Category, the Frozen Food Category, the Snack Food Category, and seasonings or seasoning blends. "Wet Soup Category" -neaus w Sid soups regardless of concentration or container including ftoze n So 'upsF purpose of tdefinition ou ts)mens t 5 tfood prepar ed from" mneat, olr'ih eeals grain, fruit and ohrigeins cooked in a liquid whichnay include v .isb pie o or alte ingredients. It may be lear (as, a broth) or thick (as a 'Nhowder), mmoio, pu>red or chunky, readytosserve, semi-condensed or condensed andcinay be served hot or cold, as a first course or as the main course of a mealor as a between meal snack (sipped 20 like a beverage), Soup may be used as an ingredient for preparing other meal components and may range from broths (consonm) 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 25 co"ncentratedbouion, bouillon and bouiillkn like products in pressed ube, tablets or powder or granulatedfo.rm which ar sold separately as a finished product or as an VXde"' 'N' s u ce ingren whin aprodust saucs ad recipe mixessof t"(cnnology); (ii) Meal solutions products such as:' ehydratd and f'reeze dried soups, 'incluig de te Ned instant soups, dehydrated read-to-cook soups, 30 dehydrated or ambient preparations of ready-made dishes, meals and single serve entres including pasta, potato and rice dishes; and (iii) Meal embellishment products such as: condinents, marinades, salad dressings, salad toppings, dips, breading, batter mixes, shelf stable spreads, barbecue sauces, liquid recipe mixes, concentrates, sauces 57 or sauce mixes, including recipe mixes for salad, sold as a finished product or as an ingcdient 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 5 powdered beverages. Other examples of foods and beverages wherein compounds according to the invention may be incorporated included by way of example carbonated and non carbonated beverages, e.g., sodas, fruit or vegetable juices, alcoholic and non alcoholic beverages, confectionary products, e g., cakes, cookies, pies, candies, 10 chewing gums, gelatins, ice creams, sorbets, puddings, jams, jellies, salad dressings, and other condiments, cereal, and other breakfast foods, canned frints 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 15 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 20 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; 25 wherein the amide compound has the formula: 0 Ri IL (1) wherein the amide compound is an amide of Formula (1), or any of its various subgenuses or species compounds described herein, wherein R', R 2 , and R can be defined in the many ways also described hereinabove. 58 The invention also relates to the modified comestible or medicinal products 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 (I) and its various subgenuses can be 5 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 Foimiula (I) could be dissolved in or dispersed in or one one of many comestibly acceptable liquids, solids, or other carriers, such as water at neutral, acidic, or basic pH, fruit or 10 vegetable juices, vinegar, marinades, beer wine, natural water/fat 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 15 vegetable powders or flours, and the like, and then combined with precursors of the comestible or medicinal products, or applied directly to the comestfble or medicinal products. Lingh m id um udof Fomula The starting materials used in preparing the compounds of the invention, i.e. 20 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 25 for example, Sigma-Aldrich Corporation of St. Louis Missoui USA and their subsidiaries Fluka and Riedel-de Hae.n, at their various other worldwide offices, and other well lt-iow suppliers such as Fisher Scientific, TCI America of Philadelphia PA, ChemDiv of San Diego CA, Chembridge of San Diego CA, Asinex of Moscow Russia, SPECS/BIOSPECS of the Netherlands, Maybridge of Cornwall England, 30 Acros, TimTec of Russia, Comgenex of South San Francisco CA and ASDI Biosciences ofNewark Deleware. It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. The skilled artisan given the literature and this disclosure is well 59 equipped to prepare any of the necessary starting materials and/or claimed compounds hi some of the Examples cited below, starting materials were not readily available, and therefore were synthesized, and the synthesis of the starting materials is therefore exemplified. 5 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, 10 estexification, saponificationnitrations, hydrogenations, reductive amination and the like. These manipulations are discussed in standard texts such as March's Advanced Organic Chemisty (3d Edition, 1985, WileyInterscience, New York), Feiser and Feiser's Reagents jbr Organic Synthesis, Carey and Sundberg, Advanced Organic Chenisty and the like, the entire disclosures of which are hereby incorporated by 15 reference in their entirieties for their teachings regarding methods for synthesizing 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/orincreasing the yield of the reaction. Often the 20 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 car be forznd for example in T. Greene and R Wuts, Protecting Groups in Organic Syntheis, 3" Ed, John Wiley & Sons (1999) 25 The following abbreviations have the indicated meanings: CH3CN = Acetonitrile CHCla= Chloroform DIC =NNDiisopropylcarbodiimide DIPEA = Diisopropyiethylamine 30 DMAP =4-(dimethylamino)~pyridne DMF= NN-dimethylformamide EDI = 1-(3Dinethylaminopropyl)-3-ethylcarbodiimide hydrochoride DCM =Dichoromethane 60 ESEMS electron spray mass spectrometry EtN = triethylam ine EtOAc = ethyl acetate EtOH = thyl Alcohol 5 Fmoc N(9-fluorenyhnethoxycarbony> HC = Hydrochloric acid H2SO4= Sulfuric acid HORt 1 1-Hydroxybenzotriazole MeDH = Methyl Alcohol 10 MgSO4= magnesium sulfate NaHCO= sodium bicarbonate NOH =Sodium Hydroxide Na 2 S0 4 = Sodium Sulfate Ph= phenyl is rt= room temperature SPOS = solid phase organic synthesis THF = tetrahydrofuiran TLC= thin layer chromatogaphy Alkyl group abbreviations 20 M e= methyl Et = ethyl n-Pr =normal propyl i-Pr -isopropyl n-Bu =normal butyl 25 i-Bu= isobutyl t- Bu = tertiary butyl s-Bu secondary butyl n-Pen normal penty i-Pen = isopentyl 30 n-Hex = normal hexyl i-Hex = isohexyl Polymer supported reagent abbreviations PS-Trisamine = Tris42-aminoethyi)amine polystyrene PS-Chloroacetyi = 61 PS- NCO methylisocyanate polystyrene PS-benzadehvde = PS-TsN{Nhz= toluensulfonylhydrazone polystyrene 5 The following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified here. 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 10 to prepare the necessary and/or claimed compounds by those methods given the literature and this disclosure, Scheme la Method A 9'PS-Carbodimide

R

1 ' %H Method S: Carbodiimide As shown in Scheme ila, amide derivatives (I) are prepared from the coupling of 15 acid derivatives (RT) with amines (IHI) in the presence o f a coupling reagent such as 1-ethyl 343-dimethylamihopropyl)-carbodiiniide hydrchloride 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 2 +R2 Base i 2 R X R3 R 20 X = halide As shown in Scheme I b, aide derivatives (I) are alternatively prepared from the coupling of acid halides, esters, or anhydrides (IV) with amines (UI) in the presence of a base. Scheme le - Synthesis o f Amides Via Combinatorial Arrays 25 The following procedure was used and can be used to synthesize amides in combinatorial array, 62 * Use acetonitrile as system solvent, Weigh amines into mL vials Using Tecan, dissolve anines to 100 mM in DCM/CHCN (1:2, from trough), IWeigh acid into 8 mL vials, 5 * Using Tecan, dissolve acids to 110 mM in DCM/CH 3 CN (1:2, from trougl) & Preload 1.2 mL Greiner plate with 30 mg PS-carbodiimide resin using Peli 1400 Case Titer plate IL Use acetonitrile as the system solvent for synthesis, a Add 200 mL (20 mmol, I equiv.) of amine to each well of the synthesis plates. a Add 200 mL (22 mmol, 1. 1 equiv.) of acid to each well of the synthesis plates. 10 0 Add I 10 mL (22 mmol, 1 1 ecquiv,) of HOBt (0.20 M in DMF) to each well of the synthesis plates by 8-channei pipete. a Seal plates with cap mat and shake (nonnal speed) at room temperature overnight. a Load 20 mg/well PS-Trisamine resin into the synthesis plates using Titer plate loader thin-. Ajust resin amount based on its loading. 15 0 Add 200 mL of DCM/CHCN to plate a Foil seal plates and shake (fast speed) at room temperature overnight. a Use methanol as system solvent for transfer to storage plate. a Transfer 150 mL to the storage plate then wash 2 tines with 150 mL of methanol '(shake slowly for 5 min). Perform transfers from Top in each well, (Needle heigh 20 -2) a Dry plates in Genevac. a Make up analytical plates (2.5 mM theoretical) and submit for analysis, a Dilution plates made up based on analytical results. Scheme Ic. Preparation of Oxalamides R A0R 5

R

4 NH R 0 R 3 'N' JR 25R~ 0 0 As a general procedure, one amine is allowed to react with ethyl oxalyl chlomide in the presence of tertiary amine in organic solvent, such as dioxane, acetonitrile, tetrahydrofiran, tetrahydropyran, and dimethyiformamide, at room temperature for 0.5 2 hours. Then the second amine is added and the suspension is heated at 80 'C using oil bath 30 overnight or at 160 4C in a microwave reactor for 5 minutes. The reaction mixture can be 63 subject to preparative HPLC, or an aqueous work-up and the crude product can typically be readily purified by recrystalization, flash column chromatography, or other methods well Iaiown to those of ordinary skill in the art to afford the pure oxalamide. Yields reported below were not optimized. Scheme Id. Preparation ofUreas R -NCO + Ooxane NR ROa N ~ rt, C/n 5g( Sh Scheme 2 xtt 1-. x! '- x-1 -- --- --- -- -- -- -- - . .... .... .. V VaB X, Xasnd X are each idependstly PIky! or t.koxy Scheme 2 describes a method for preparation of pyrazines derivaRvs (VIII), For instance, reaction of substituted or unsubstituted 2,3-dianiinopropionic acids (V) with 2,3 diones (VI) under heating conditions in the presence of base yields, after acidification, the substtd pyrazine-2-carboxyic acid (VII), The acid is condensed with various aiines (Mi1) to produce the desired amide (XIII) using the conditions shown nm Scheme la. 15 Scheme 3 "CHC or't X4 Out N 64 b It xl11 4 skyk!. haide, aikoxy or thioalky Scheme 3 describes a method for preparation of benzofiaran derivatives (XII). For instance, reaction of 2-hydroxybenzaldehydes (IX) with 2-bromo-malonic acid diethyl este 64 (X) under heating conditions in the presence of base yields substituted benzoflran-2 carboxylic acid (XI). The acid is condensed with various amines (III) to produce the desired amide (XlI) using the conditions shown in Scheme I a. Scheme 4 xm Vvzxv R o --- - R - - - - R - -- arboin-d H D 2 X4Xcabdn e xiiixxy xx vi 0 .<a COH!OMF ) ,,,te Mi xx ){.is Halky aRyl ayialky. e a -aky x as vta i alkoyaikyt kayaikyli heterayialki 5 Xisham~ Scheme 4 describes methods of preparation of an alkoxyalkyl amide (XX). In one method phthalic anhydride (xu I) is heated with amino alcohol (YV) to give the alcohol (XV) which is then reacted with alkyl halide (XVI) in presence of a base to produce the alkoxy (XVII), Treatment of the phtalimide (XVII) with hydrazine produce the desired 10 amine (XVIII) that is father condensed with the acid (II) as described in scheme I a to provide the alkoxyalkylamide (XX). Altenatively acid (II) is condensed with the amino alcohol (XIV) using the method describe in scheme I a to provide the alcohol (XL,) that is further alkylated to give (XX). Scheme 5 H O HNx XJI C.)H Base Hcarbourrne H 5 XXH XXV Sis halide

X

7 is H, alky, alkoxyakyl, aryl, arykalkyl, heteroarykalkyl 15 Xg and X are each idependently H, alky, alkoxyakyt arylalkyl and hetera 65 Scheme 5 describes a methods for the preparation of amidoa.mide (XXIV). Akyl 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 1 a to provide the amido amide derivative (XXIV). 5 Scheme 6 R2 0 HgNON OH H VNR HO OA9\carvodimide XI R R HC o a'rb6. - -iin XXVXXV1 I1 0 VR ~ H 2 - N"'~ ___ XXVWI Scheme 6 describes a methods for the preparation ofbenzooxazoie (XX V111). AMnino phenol (XXV) can be condensed' with a variety of r-eagents to foum thle benzoxazok 10 (XV)having a wide variety of substituenat X9 using a method described in the liter-aturei (see e.g, I JMat Uhe.- 28 (1985) 1255) and/or by the method cited in Examples 39 to 47. The benzooxazole intermediate (XXVI) is then condensed with ainte (V) using the method described in scheme 1 a to give the amide XX h.Alternatively the amide (XXVII) is prepared by first condensing the amino phenol1 (XXV) with the amaine (V) to 15 gYive the ainophl0 intermediate (XXVIII1) that is- &Euther converted to the benzoxazoie (XVII) using the variou s method described above, Measuring the Biological Activity of the Compounds of The Invention CTell based technologies and assays, such as those disclosed in WO 02/064631 J, andW,;O 03/00187 6, and US. Patent Publication US 2003-0232407 Al were used both to '20 initially screen a w ide variety of classes of compounds fbr agonist or antagonist activity for TIRi/TIR3 "savory" taste rceptors, or TIR2/TIR3 "sweet" taste receptors that had been expressed ini appropti' te cell lines. Once i-nitial "hits" were obtaimed for amide compounds in such cell ies, the same assays anid also certain cell and/or receptor-based assays were used as analytical tools to measure the ability of the compounds of Formula ( 25 to e-nhnce the savory taste of MSC or the s-weet taste of kno-wn sweeteners such as sucrose, frutctose, and were used to provide empirical data to guide an interative process or 66 synthesizing and testing stmotural variants of the aide 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 ofFonnula (I) that modulate (increase or decrease) the activity of the TIR1/TIR3 (preferably hTIRI/hT.R3) savory taste receptor (umani receptor), alone or in combination with another compound that activates hT1Ri/hTiR3, eg., MSG. Particularly, in many embodiments the invention relate to the 10 amides of Fonmula (I) that modulate the activity ofhTiR1ihTIR3 (human umami receptor) in vitro and/or in vivo, Inanother aspect, the invention relates to compounds that modulate the human perception of savory (umaii) 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 15 species o f the aide compoimds of Formula (1) that modulate (increase or decrease) the activity of the TIR 2/TIR3 (preferably hTlR2/hTIR3) sweet taste receptor (alone or in combination with another compound that activates hTIR2/hTIR3, or otherwise induces a sweet taste, eg sucrose, glucose, fructose, and the like. Particularly, the invention relates to the amides of Formula (1) that modulate the activity ofhTiR2/hTIR3 (human sweet 20 receptor) in vitro and/or in vivo. In 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 25 that at least some ofthe aide 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 h TIRl/hTIR3 Umarni3Tase ecetor Acvatina In order to identify new savory flavoring agents and enhancers, including 30 compounds with savory agonist and enhancer activities (dual activity), the compounds of Formula (I) were screened in primary assays and secondary assays including compound dose response and enhancement assay. In a primary assay for potential ability to modulate umami taste, aide compounds of Formula (1) that can be either savory flavoring agents in their own right or flavor enhancers of MSG are identified and scores of their activities are 67 given as percentage of the maximum MSG intensity (%). In compound dose response, an EQ0 is calculated to reflect the potency of the compound as a savory agonist or enhancer. An HEK293 cell line derivative (See e.g,, Chandrashekar, et al Cell (2000) 100: 703711) which stably expresses GalS and hTlR1/hTlR3 under an inducible promoter 5 (see WO 03/001876 A2) was used to identify compounds with savory tasting properties Compounds covered in this document were initial selected based on their activity on the hTlRI/hT1R34IEfK293-Gal5 cell line, Activity was determined using an automated fluoromettic imaging assay on a FLIPR instiment (Fluorometric Intensity Plat Reader, Molecular Devices, Sunnyvale, CA) (designated FLIPR assay). Cells from one 10 clone (designated clone 1-47) were seeded into 384-well plates (at approximately 48,000 cells per well) in a medium containing Dulbecco's modified Eagle's medium (DMEM) supplemented with GlutaMAX (Invitrogen, Carlsbad, CA), 10% dialyzed fetal bovine serum (Invitrogen, Carlsbad, CA) 100 Units/ml Penicillin G, 100 Agfnl Streptomycin (Invitrogen, Carlsbad, CA) and 60 pM mifepristone (to induce expression of 15 hTIRI/hTlR3, (see WO 03/001876 A2) 1~17 cells were grown for 48 hours at 374C. I-1 cells were then loaded with the calcium dye Fluo-3AM (Molecular Probes, Eugene, OR), 4 yM in a phosphate buffered saline (D-PBS) (Invitrogen, Carlsbad, CA), for L5 hours at room temperature. After replacement with 25 gl D-PBS, stinulation was performed in the FLIPR instrument and at room temperature by the addition of 25 a D~PBS supplemented 20 with different stimuli at concentrations corresponding to twice the desired final level. Receptor activitywas quantified by deterining the maximal fluorescence increases (using a 480 nmn excitation and 535 nm emission) after normalization to basal fluorescence intensity measured before stimulation. For dose-responses analysis, stimuli were presented in duplicates at 10 different 25 concentrations ranging from L5 nM to 30 PM Activities were normalized to the response obtained with 60 mM monosodium glutamate, a concentration that elicits maximum receptor response, EC 5 s (concentration of compound that causes 50% activation of receptor) were determined using a non-iinear regression algorithm, where the Hill slope, bottom asymptostes and top asymptotes were allow to vary. Identical results were obtained 30 when analyzing the dose-response data using commercially available software for non linear regression analysis such as GraphPad PRISM (San Diego, Califoaia). In order to determine the dependency ofhTlRlI/hTlR3 for the cell response to different stimuli, selected compounds were subjected to a similar analysis on 1-17 cells tha had not been induced for receptor expression with mifepristone (designated as un-induced 68 1-17 cells). The un-induced .1-17 cells do not show any functional response in the FLIPR assay to monosodium glutamate or other savory-tasting substances. Compounds were presented to un-induced unami cells at 10 gM-or three times the maximum stimulation used in the dose-response analysis, Compounds covered in this document do not show any 5 functional response 'hen using un-induced umami cells in the FLIPR assay In some aspects of the present invention, an EC 5 0 oflower than about 10 mM is indicative of compounds that induce TIRI/TIR3 activity and is considered a savory agonist Preferably a savory agonist will have BC 5 values of less than about 1 mM; and more preferably will have EC. values of less than about 20 pM, 15 pM, 10 pM, 5pM, 3 10 g M, 2 pM, I M, 0.8 pM or 0.5 gM. In umami taste enhancement activity assay experiments, which produce an "EC. ratio" measurement ofhow effectively the amide compounds of the invention enhance the savory flavorant (typically MSG) already in a test solution A series of measurements of the dose response is run in solutions comprising MSG alone, then a second dose response i 15 run with MSG in combination with predetermined amounts of a candidate compound of Formula (I) at the same time. This assay, increasing concentrations of monosodium glutamate (ranging from 12 tM 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 pM, 20 1.0 pM, 3 gM, 1. gM, 03 pM, 0. UM and 0,03 iM, The relative efficacy of compounds of Fonmula (1) at enhancing the receptor was detennined by calculating the magmntude of a shift in the EC5s for monosodium glutamate. Enhancement was defined as a ratio (EC 0 oR) corresponding to the EC 5 o of monosodium glutamate, determined in the absence of the test compound, divided by the EC 5 s of monosodium glutamate, determined in the presence of 25 the test compound. Compounds exhibiting ECoP > 2.0 were considered enhancers. Stated alternatively, "EC 50 ratio" as compared to MSG is calculated based on the following definitions:

EC

5 Ratio vs. MSG EC 0 (MSG)/ECso (MSG + [Compound]) wherein "[compound]" refers to the concentration of the compound of Formula (1) 30 used to elicit (or enhance or potentate) the MSG dose response. It should be noted that the EC 0 ratio measured can depend somewhat on the concentration of the compound itself. Preferred savory enhancers would have a high ECs 5 Ratio vs. MSG at a low concentration ofthe compound used. Preferably the ECo ratio 69 experiments to measure umami enhancement are run at a concentration of a compound of Formula (1) between about 10 pM to about 0)J uM or preferably at 10 PM or 30 AM. An EC4o ratio of greater than I is indicative of a compound that modulates (potentiates) hTiRJ/hTlR3 activity and is a savory enhancer. More preferably, the savory 5 taste enhancer compounds of Formula (I) will have EC5, ratio values of at least 1.2, E5, 2.0, 3,0 40, 5.0, 80, 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 ofT1R1,T1R3 in vitro. It is anticipated that similar assays can be designed using other compounds known to activate the TIRI/TIR3 receptor 10 Specific compounds and generic classes of compounds that been shown to modulate hTIR/hTIR3 based on their ECre 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/savory compounds of 15 Formula (1) are reported hereinbelow. Comparable ECso assays for activity of the compounds of Formula (1) for sweet receptor agonism and/or sweet taste perception in human are also reported hereinbelow. n Vitro hTIR2/hT1R3 Sweet Taste Receptor ActivationAssav An HEK293 cell line derivative (Chandrashekar, T, Mueller, K.L., Hoon, M.A., 20 Adler, EFeng, L., Guo, W., Zuker, CS,, Ryba, G J el,l 2000, 100, 703- 11.) that stably expresses Gal5 and hTIR2/hTiR3 (Li, X, Staszewski, L, Xu, Durick, K, Zoller, M, Adler, E. Proc Natl Acad Sci USA 2002,99,4692-4696) see also World Patent # WO 03/001876 A2) was used to identify compounds with sweet taste enhancing properties. 25 Compounds covered in this document were initially selected based on their activity on the hTIR2AiTIR3-HEK293-Ga1 I cell line (Li, et al. vide supra), Activity was determined using an automated fluorometric imaging assay on a FLIPR instrument (Fluorometric Intensity Plate Reader, Molecular Devices, Sunnyvale, CA) (designated FLPR assay). Cells from one clone (designated S-9 cells) were seeded into 384-well plates 30 (at approximately 50,000 cells per well) in a medium containing DMEM Low Glucose (Invitogen, Carlsbad, CA), 10% dialyzed fetal bovine serum. (Invitrogen, Carlsbad, CA), 100 Units/mI Penicillin G, and 100 pig/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 70 hours at 37 'C. S-9 cells were then loaded with the calcium dye Fluo-3AM (Molecular Probes, Eugene, OR), 4 pM in a phosphate buffered saline (D-PBS) (Invitrogen, Carlsbad, CA), for 1 hour at room temperature. After replacement with 25 pl D-PBS, stimulation wa performed in the FLIPR instrument and at room temperature by the addition of 25 p1 D 5 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 arn excitation and 535 rn emission) after normalization to basal fluorescence intensity measured before stimulation. For dose-responses analysis, stimuli were presented in duplicates at 10 different 10 concentrations ranging from 60 nM to 30 pM. Activities were normalized to the response obtained with 400 muM D-fructose, a concentration that elicits maximum receptor response. EC50s were determined using a non-linear regression algorithm (using a Senomyt 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 15 available software for non-linear regrsion analysis such as GraphPad PRISM (San Diego CA). In order to determine the dependency ofhTR2!hTIR3 for the cell response to different stimuli, selected compounds were subjected to a similar analysis on HEK293 Glx5 cells (not expressing the human, sweet receptor). The HEK293-G15 cells do not 20 show any functional response in the FLIPR assay to D-Fructose or any other lmown sweeteners Similarly, compounds covered in this document do not induce any functional response when using lHEK293-Gx15 cells in the FiJPR assay. EXAMtPLES The following examples are given to illustrate a variety of exemplary embodiments 25 of the invention and are not intended to be limiting in any manner. For the purpose of this document, the compounds individually disclosed in the following Examples 1-174 and corresponding Tables A-B can be referred in shorthand by the number of the example. For example, as shown immediately bellow, Example I discloses a synthesis of a particular compound (N-(heptan-4-yl)benzo[dJ[L3]dioxoie-5 30 carboxamide), and the results of experimental assays of its biological effectiveness, which compound is and can be referred to herein in shorthand fonn as Compound 1, Similarly, the first compound illustrated in Table A can be referred to elsewhere herein as Compound Al. 71 tX1UJMIC ;1 NAhcptnu4-YDbcnzo diftI d 1dioxtik ole arbeoandde To a solution ofheptan-4-anine (8 06 muL 54 nnol) in triethylamine (15.3 mL 5 108 miiol) and dichioromethane (135 mL) was added, dropwise at 0oC, a solution of benzo[1,3]dioxole-5-carbonyl chloride (10 g, 54 mmol) dissolved in dichloromethane (135 nmL). The reaction mixtme was stirred for l h. Solvent was removed under reduced pressure and the residue was dissolved in EtOAc: The organic layer was washed successively with I N aq HC , 1 N aq. NaOH, water, brine, dried (MgSO 4 ) and 10 concentrated. The residue was recrystallized in EtOAc and Hexanes to afford 6.9 g of N (heptar-4-yl)enzo[d][1,3]dioxole5-carboxanide (48.3%) as a white solid. 'H NMR (500 MXliz, CDC 3 ): 6 0,92 (t, 611), 1.38 (in, 6H), 1.53 (in, 211), 4 11 (m, 1H), 5.63 (n, 1H), 6.01 (s, 2H), 7.98 (d, 1H), 7.27 (s, d, 2H). MS(M+T, 264). The compound had ECso for activation of a hTIRI/hTiR3 umami receptor 15 expressed in an HEK293 cell line of 0.2 siM, and when present at 0.03 pM enhanced the effectiveness of monosodium glutamate with an ECso ratio of 6.92. E.ramtle 2 N43methvihetauv1henzofdlu e 1dioxole-catrbaide 20 Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and 2-mnethylheptan-4-amine (example 2a) 'H NMR (500 MHz, CDC1t): 6 0.93 (m, 9H); 1-38 (in, 5H); 1.53 (i, 111); 1.66 (in, 1H); 4.21 (in, 1H); 5.61 (d, 1H); 6.01 (s, 2H); 6.82 (d. 1H); 7.26 (in, 2H), MS (278, M+H1) a. preparation of 2-inethylheptan-4-anine: 25 To a solution of 2-methylheptan4-one (4.24 g, 33,07 mmol), in methanol (60 mL), were added ammnionium acetate (25.50 g, 330,71 mmol) and sodium cyanoborohydride ( 2.08 g, 33.07 miol). The reaction mixture was stirred at room temperature for about 24 72 hours. The solvent was removed under reduced pressure and the residue was diluted with water and basified with 15 % NaOH aqueous and extracted with ether. The extract was washed with bine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 3.3 g of 2~methylheptan-4-amine (77%). MS (M+H, 130) 5 The compound had EC, for activation of a bT1Rl/bT1R3 unami receptor expressed in an 1EK293 cell line of 022 wp1 Exampe 3 N43-methylhexan-3v~entol 3i jdioxeled5-arboxnauide 0 10 Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and 2-methvlhexan-3-amine (example 3a) 'HNMR (500 MHz, CDCli): d 0.93 (m 9H); 1,37 (m, 3H); 1,56 (m, 1H); 1.83 (m, IH); 4.01 (m, 111); 5.67 (d, 111); 6.02 (s. 2H); 6.82 (d, 1); 7.28 (m, 2H). MS (M±H, 264), a. 2 methylhexanamine was prepared using the same procedure described in 1.5 example 2a starting fom 2-methylhexan~3-one Yield:40%. H NMR (500 MHz, CDC: L 0,86 (d, 311); 091 (m,6H); 120-1,29 (m, 2H)1.38-147 (m, 2H); h47 (s, 2H); 158 (m, 11) 2.51 (m, ]H). MS (M+H,116). The compound had ECs 0 for activation of a hTRi/h1R13 umani receptor expressed in an H1EK293 cell line of 0.61 pM 2xampe 4 NA%2-dimneth vkvclobav benzo~ dl fL3Idioxoie-5tearbxanmde 2,3-dimethycyclohexanamine (20 pmo) and benzo[d][I,3jdioxole-5-carboxylic acid (1-1 eq) were each dissolved in acetonitrile/dichioromethane (200 sLL, 2:1), PS 25 Carbodiimide resin (2 eg) was loaded into a 1.2 mL 96 well Greiner plate, followed by the addition of amine and acid solutions. Hydroxybenzotriazole (11 eq) was dissolved in DMF (100 mL) and was added into the reaction well. The reaction was shaken ovemight at room 73 temperature Once the reaction was completed, PS-Trisamine resin (1.5 eq) was added into the reaction mixture and the solution waas 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 5 dimnethylcyciohexyl)benzo[d][1,3]dioxole-5-carboxamide MS (M4H, 276.20). The compound had ECso for activation of a hTIR'TIIR3 umami receptor expressed in an HEK293 cell line of0,45 gM, and when present at I pM enhanced the effectiveness of monosodium glutamate with an EQo ratio of 8.41 ExAuLte 5 10 N45 -- Mtiea benz U diio -r boxanide Prepared in a similar manner to example I using benzo[d][1,3]dioxole-5-carbony chloride and 5-nethylhexan-3-amine (example Sa). Yield; 48 % 11 NNfR (500 Mlz, CDCQ): 6 0.94 (mn, 9H); L37 (t, 311); 1.45 (m, 111); 1.64 (m, 211); 413 (m, 1H); 5.61 (d, 15 111); 6,01 (s, 2H); 6.82 (d, 111); 7.27 (m, 2H) MS (M+H, 264), a, 2-methylihexan-3-amine was prepared using the same procedure described in example 2a starting from 5-methylhexan-3-one. Yield:54%. MS (M+H, 116). The compound had EC.

9 for activation of a hTlR1/hTR3 uimami receptor expressed in an HEK293 cell line of 0.57 AM. 20 Exniple 6 (R'kethvI 24benzoi [13 dioa6-aroxado4ethhentanuate NN Prepared in a similar manner to example 1 Asing benzojd][1,3]dioxoie-5-carbonyl chloride and D-eacine methyl ester hydrochloride. Yield: 83 %, H NMR( (500 MHz, 25 CDC 3 ): 0.98 (m, 611); 1.63-.67 (m, 1H); 1,71-L76 (m, 211); 3.76 (s, 3H);4.83 (in, 1l); 6&03 (s, 211); 6.38 (d, 111); 6,83 (d, 111); 7.32 (s, 111); 7.33 (d, 1H), MS (M+I, 294). m.pt 89-90 "C 74 The compound had EC, for activation of a hTIR1JhTIR3 umami receptor expressed in an HEK293 cell line of 034 pM, and when present at 01 tM enhanced the effectiveness of monosodimn glutamate with an EC 5 0 ratio of 4.9. Edampiet 2 Ng Aerfdonpta ~Ilbe~hnzokf d ~3hdioxote5dearboxarnide Prepared in a smiilar manner to example 4 using benzo[dJ[1,3]dioxole-5-carboxylic acid and 1,2,34-tetrahydronaphthale1n-l-amine MS (M+H4, 2966), The compound had ECs 3 for activation of a hTIRl/hTiR3 umami receptor 10 expressed in an -IEK293 cell line of 0.71 pM, and when present at 0.3 pM enhanced the effectiveness of monosodium glutamate with an ECo ratio of 728 (Rh 1-Ghyrxy4intyUetn bez 1dioxot354arhossirnide -lA 15 Prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxvlic acid and (R)-aminoleucinol. MS (M+i-1, 266.1) The compound had an ECso for activation of a hTlRI/hTlR3 umami receptor expressed in an HEK293 cell line of 9 yiM, a d when present at 3 pM enhanced the effectiveness of monosodium glutamate with an EC 5 ratio of 2. 20Examnple~9 (R)~N4I--methoxv4~mnethylpenit 2-vbenzofddi >3dioxQleO- beazod~i idioxoe~ S-carboxvle acid Prepared in a similar manner to example 4 using (R)-l-iethoxy-4-methyl and pentan-2-aimne (example 9a) Yield: 55%, -H NMR (500 MHz, CDCb1): 4 0.95 (m, 6H); 143 (m, 1H); L55 (in, 1H); 165 (i, IH); 3.36 (s, 34);3.46 (m, 2H); 4.33 (in, 1H); 6,01 (s, 2H); 6.13 (d, 1H.); 6.82 (d, 1H); 7.23 (m, 2H), MS (M+H, 230) 5 a. (R)-1-methoxy-4-methylpentan-2-amine To a solution of (R)-2-(1-methoxy-4-methylpentan-2-yl)isoindolinc-1,3-dione (example 9b) ( 3.87 g, 14.84 inmol) in methanol (30 mL.), was added hydrazine hydrate (0.866 nil, 17:81 rvmnol) and the reaction mixture was warmed up to 45 'C for about 3 hours. The mixture was acidified with 2N HCI and stirred at 45 'C for 30 min. The 10 solution was cooled to room temperature, filtered and evaporated. The residue was taken up with 2N NaOH and extracted with ether, dried over MgSO4, filtered and evaporated to give 1.51 g of (R)-1 -methoxy-4-methylpentan-2-amine. Yield 77 %. 'H NMR (500 MHz,

CDC

3 ): 6 0.91 ( m, 6H ); 1. 17 ( ni, 2H ); L58 (s, 2H ); L71 (i, 1.L ); 3.02 ( m, 1 ); 310 (im, 11); 332 (n m 1H); 3.35 ( s,3H) 15 b. (R)2(1-methoxy4-methyipentan2yi)isoindoline13-dione (R).2-(1-hydroxy4methylpentan2-y)isoindolie ,3.-dione (example 9c) (5.88 g, 23.87 mmol) was dissolved in dry THE (25 mL) and hexamethyl-phosphoramide (30 mL) and the solution cooled to 0 'C Sodiun hydride (60 % in mineral oil, 1 15 g, 28.65 mol) was added and after 10 minutes iodomethane (7.43 ml, 119.35 mminol ) was added dropwise 20 and the solution was warmed up slowly to room temperature and stirred overnight. The reaction mixture was poured into ice/water, extracted with EuOAC, washed with brine, dried over MgS04, filtered and evaporated. The residue was purified on silica gel (20 % EtOAC in hexane) to give 3.92 g of(R)-2(1-methoxy-4-methypenan-2-yl)isoindoine t3-dione (63 %). 25 c. (R})2-(1-hydroxy-4-mezhylpentan-2-yl)isoindoline-1,3-dione: Phthalic anhydride (10.30 g, 69,55 mmol ) and D-Leucinol (8.15 g, 69.55 mmol) were mixed in THF (100 mL), the reaction mixture was heated at 85 'C and refluxed for 13 hours. After cooling to room temperature, water was added and the solution was extracted with EtOAC, the extracts were washed with I N HCl, water, aq. NaHCO-, water 30 and brine, dried over MgSO 4 , filtered and evaporated to give 8.1 g of(R)-2-(1-hydroxy-4 mnethyipentan2-yl)isoindoline-1,3-dione (47 %). 1H NMR (500 MHz, CDC13): 6 0,94 (n, 6H); 1,54 (im, 2:H); 1.99 (im, 1H); 3.86 (m, 1H); 4.04 ( m, 1H); 4.47 (im, 1H); 7;72 (im, 2H); 73 (im, 2H), 76 The compound had an ECso for activation of a hT1RI/hT1R 3 umami receptor expressed in an HEK293 cell line of 3,5 pM, Example 10 (R0-methyl bhnzo~dU 5 3kdile- arboxamido)~3methvlbutatwate Prepared in a similar manner to example 4 using benzo[d][ ,3]dioxoIe-5-carboxylic acid and (R)-methyl 2-amino-3-methylbutanoate.Yieid: 50%. MS (M+H; 280.1), The compound had an ECs 5 for activation of a ITRI /bTiR3 umani receptor expressed in an HEK293 cell line of 1.16 pM 10 Examile 11I 2(benzold fl3diox -.. a.rboxamidoV4~methypentvi dihydrogenl hosphae v e N-(1-hydroxy-4-methylpentan-2-yl)benzo d][1 ,3]dioxole-5-carboxaimide (example I I a) (057 mmol, 151 ing) was dissolved in anhydrous acetonirile (2 ml) and 1 ml of 0.45 15 M solution of tetrazole in acetonitrile was added u der nitrogen and stirred for 5 min. Then 0.627 (1I eq, 207 pl) of dibenzyl diisopropyl phosphoroamidite was added drop wise under nitrogen, The mixture was stirred for 1h. 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 20 oftert.butyihydroperoxide (4 M solution in nonane) for 30min, The solvent was evaporated and the dibenzylester intermediate was purified (preparative TLC). The benizyl groups were hydrolyzed using trifluoroacetic acid (3 ml of a mixture of 95% TPA and 5% water, 1.5 h, rt). The final product was dried down providing 69 mg (35%) of pure material, H NMR (500 MHz, CDCI): 6 0.88-0.90 (1, 6H), 1.23-1.27 (in, 2H), 1.36-137 25 (n; 1H), 1.53-1.62 (rn 2H), 3,93 (s. IH), 398 (s, 1H), 4.32 (s, 1H), 5,90 (s;2H), 666-6.67 (d, 1H), 6.98-6.99 (h,2H), .14 (s, 211); P1: 6 0,51(s), MS (M4H, 346.0), 77 a. N(1-hydroxy4methypentan-2-y)benzod)[l,3]dioxoie5carboxamide was prepared in a similar manner to example 4 from piperonylic acid and 2-amino-4-methyl pentan-1-oL The compound had an EC 0 for activation of a lITIRl/I R3 umami receptor 5 expressed in an HEK293 cell line of 10.9 pM. F ~janje li .N-(hexan 3 )]4 mnethnsxv -- mthibenzainide NN Prepared in a similar manner to example 4 using 4-methoxy-3-inethylbenzoic acid 10 and hexan-3-amine (example 28a) ' 1 NM (500 MHz, CDC13): 6 0.94 (m, 6); 1.41 (m, 4H); 146 (ma, 1H); 1.64 (m, 1H); 2.24 (s, 3H); 387(s, 3H); 4.08 (m, 1H); 5.69 (d, 1H); 6.83 (d, 1H); 7.54 (s, 1H); 7.62 (d, IH). MS (M+H, 250). The compound had an ECs for activation of a hTIRi/hTIR3 umani receptor expressed in an HEK293 cell line of 0.12 pM. 15 Example1 (RVNW1 -dbmethvambia4qmethylaopentaun yD benzo dl [131 dioxole-5 carboxamide (R)-2-(benzo[d][1 ,3]di oxoie-6arboxamido) 4-methylpemanoic acid (example 20 13a) (52 rg, 0.19 mmiol) inDIF (4 mnL) and dinethyl amine (2M in Methanol, 36 pL, 2 eq) were condensed in presence of HOMt (26mg, leg) and of l-ethyl-43 dimethylaninopropvl)-carbodiimide hydrochloride (44 mg,L.2 eg) at room temperature overnight, The reaction mixture was evaporated and the residue was dissolved in ethylacetate and washed successively with saturated NaHCO 3 and water, dried over MgSO 25 filtered and evaporated to give 48.6 ng of the product (84%). The material was further purified usingRP-IPLC. 'H NMR (500 MHz, CDC): 3 0.93-0.94 (d, 3H), 1.03-L05 (d, 3H), 1.48-152 (in, iH), 1 59463 (inH), 2.93 (s, 3H), 3.14 (s, 3H), 5.17-5,21 (Im, 1H), 78 6.01 (s, 2H), 680-6.82 (d, 1H), 6.89-6,91(d, 1H), 7.29-3.30 (d,IH), 7.33-7,35 (dd, 1H), MS (M+1; 307.2), a, (R)-2-(beizo[d][1,3]dioxoie-6-carboxanido)-4-methylpentanoic acid: Prepared in a similar manner to example I using benzo[d][1,3]dioxole-5-carbony 5 chloride and D-Leucine Yield: 55% MS (M+H, 280.2). The compound had an EC 0 for activation of a hTIRI/hTIR3 umami receptor expressed in an IEK293 cell line of L06 sgM Exampkl 14 2QbenzofdUl3ldoxole aiearboxamideohentv acetate K' j' To a solution of N~(1-hydroxypentan 2)vlbenzo[d][1,3]dioxole-5-carboxamide (example 14a) (59.8mg, 0,238mmol) in dichloromethane (5 mL) was added triethylamine (166 mL, 1 19 inol), Acetyl anhydride (112.5mb IL 19mmol) was slowly added and the mixture was stirred under argon at ambient temperature overnight. The solution was 15 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-(benzo[d][1,3jdioxole-6 carboxamido)pentyl acetate (73%). !H NMR(CDCIh): S095 (t, 311, J=7.2 Hz), 1.43(m, 2H1), 157(m, 211). 2.1 (s, 3lH), 4,11(dd, 1, j= 3.5 Hz, .= 11,5 Hz), 4.27(dd, 1H,J= 3-5 20 Hz, J= I14 Hz), 4,29 (in, 1H), 6.02 (s, 2H), 6,1 (m, 1H), 6.82 (d, H, 8.4 Hz), 7.27 (m 2H). MS (M+H, 294). a. N-(1-hydroxypentan-2-yl)benzo[d][l,3]dioxoile-5-carboxamide was prepared in a similar manner to example 4 using benzo[d][1,3]dioxole-5-carboxylic acid and 2 aminopentan-1-ol. Yield: 76%, MS (M+H, 252), 25 The compound had an EC 0 for activation of a hTIRi/hTR3 umarni receptor expressed in an HBK293 cell line of 11 9 FtM, and when present at 3 pM enhanced the effectiveness ofmonosodiun glutamate with an ECs ratio of 4.1. 79 S Prepared in a similar, manner to e-xample 13 using 2-(3-pyridy )ethylamine and (R,) 2-(enz~d [1,}dixol-6-aroxaido-4-ethlpetanicacid (example 13a). (MS M+ 384.2), The compound had an EC,,c far activation of a hTlR1/hT1R3 urnami receptor expressed in an HE K293 e-ell line of 1, 7 pM. (fR)-12hydroxymethyl(pyrndin eth)uometh t yfopdly lib enztof dI iio ecarboxaide <I b A ' Prepared in a similar manner to example 13 using R/S propinea andd (R)-2 1.5 (benzo[d][13dioxoecarboxamido)4.methylpenanoic acid (example 13a). (MS M+ 363.2) The compound had an ECso for activation of a hT1Ri/hTiR3 amami receptor expressed in an HElK293 cell line of 3 FM. 1aramp 17 2h0 N1hta - 61ethylbenz[dA darboamide 0 H Prepared in a similar manner to example 4 using 6-methyibenzo[d][1,3]dioxol carboxylic acioid and heptan-4-amainei MS (M+xpH, 278a67). 80 The compound had an ECso for activation of a hTIR1/hTIR3 umami receptor expressed in an HEK293 cell line of 0.11 i±M. Example 18 N-lean-vi 2 -methlhenzo dl I ~dinxeeecarboxamkde N-(hptan-4-yl)-3,4-dihydroxybenzamide (example 1 S) (0:5 nmol was dissolved in toluene (1.6 mL). P-Toluenesulfonic acid monohydrate (0 3eq) was added to the reaction, followed by addition of acetaldehyde (2eg). The reaction was performed using microwave (180C, 300W) and ran for 10 minutes The solvent was evaporated The residut 10 was dissolved in methanol (1 ML) and purified bylHPLC, Yield 20%, MS (M+H 278 0), a. N4eptan-4-yl)-34-dihydroxybenzamide was prepared in a similar maier to example 4 using 3,4-dihy&oxybenzoic acid and heptan4-amine. Yield- 25%. MS (MH,. 252l). The compound had an ECs for activation of a hTIR1/hTIR3 umami receptor 15 expressed in an HEK293 cell line of 0.1 gM, and when present at 0U3 W.M enhanced the effectiveness of monosodium glutamate with an EC 0 ratio of 3.68. Example 19 Ethyl 2-(5-( eptan-4-ylcarbamoyl)benzo[d][1,3]dioxo-2-yl)aeetate 20 N-(heptan-4-yi)3,4-dihydroxybenzamide (example 18a) (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 pt) of propynoic acid ethyl ester was added and a mixture waas retluxed for 24 h The solvent was evaporated and a solid was dissolved in dichloromethane and extracted with 10% NaHCO and water. The crude product was purified by chromatography on silic 25 gel to give 72 mag of desired product (71%), 'H NMR (500 MHz, CDCb): 6 0,91-0.94 (t, 6H) 1.234.30 (m, 4H), 1.37-1,41 (41), 297-2.98 (d, 21), 3.70-3.74 (dd, 2H), 4.12417 81 (n, 11), 4,2-4-24 (m, 3H), 5,61-564 (d, 1H), 6.58-6.60 (t, 11), 6,79"681 (d, IH), 723 (s, 1H), 7,60-785 (b, 1H). MS (M+H, 350.1), The compound had an EC c for activation of a hTIRi/hTR3 urnami receptor expressed in an HEK293 cell line of 14 pM, and when present at 3 pM enhanced the 5 effectiveness of monosodium glutamate with an EC5j ratio of2.5. N-(heptan-4wvlV2,2-d4imetvhlenztfdl {idkieol5earboxamide Prepared in a similar manner to example 4 using sodium 2,2 40 dimethylbenzo[d][1,3]dioxoie-5-carboxylate and 4-heptylamine (example 20a). Yield 30%, 'H NMRT 0.92 (t, 6H, J= 7.2 Hz), 1,42 (m, 6H), 1.53 (in, 2H), 1,68 (s, 6H), 4,12 (m, 1H), 5,61(d, 111, J=89 Hz), 6,72 (d, 111, J-8Hz), 7.16 (d, 1H, J::-LS Hz), 7.22 (dd, 111, J= L5 Hz,J= 17 Hz). MS (MH, 292). a. Sodium 2,2-dinethyibenzo[d 1,3]dioxole-5-carboxylate and 4-heptylamine: 15 Ethyl 2,2-ditnethylbenzo[d][1,3]dioxole-5-carboxylate (example 20b)(461mg, 2.08 mmol) was stirred in dioxane (16mL) and L.ON aqueous NaOH (4.16 mL) for 20 hours at room temperatureThe solvent was removed under reduced pressure to afford the desired product (449mg). (M-H, 193). 'b. Ethyl 2,2-dimethylbenzo[d][1,3]dioxole-5-carboxylate: 20 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 trap for 20 hours. After solvent removal under reduced pressure, the crude was dissolved in ethyl acetate and washed successively with a saturated aqueous solution of sodium bicarbonate, water, and 25 brine. The organic layer was dried over anhydrous sodium sulfate. Purification by chromatography on silica gel using a gradient hexane:ethy! acetate, 90:10 to 75:25, afforded a white powder (539.1mg, 49%). 'HNMR(CDC1): 1.36 (t, 3H, J= 7.2Hz), 1.6i (s. 61),4.32 (q, 2H, J=7.1 Hz,J= 14.2Hz), 6,74 (d, i H d, =82H z), 7.38 (d, ihJ= L.7 Hz), 7.61 (ddi, lH,..f= 1.83HzJ=f83 Hz) 82 The compound had an ECs for activation of a hTlR1/hTIR3 umami receptor expressed in an HEK293 cell line of 2,7 pM - N H 5 1e Prepared in a similar manmer to exanie 4 using 2isopropylbenzodi [1,3]dioxole 5-carboxylic acid (example 21a) and 4 -hepthylamine. Yield: 34%. 3H NMR(CDCI): 6 0.92 (t 6H, J=7.2Hz.), 1,04 (d, 6H, J= 6.9 Hz), 1.40 (m, 6H), 1.43 (m, 2H), 2,15 (m, 1H), 411 (m, 1H), 5.62 (d, 1H, J= S.9Hz), 5.96 ( d, IH, J= 4,4 Hz), 6.75 (d, 1H, J= 8. Hz), 7,19 10 (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 Edi [1L3]dioxoile-5-carboxylic acid: 3,4-dihydrobenzoic acid (154.12 mg, 1Immol)and isobutyraldehyde (182 LI, 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 180 C with a power set at 275. The solution 15 was filtered and evaporated to afford 100mg ofthe desired product (48%). MS (M-H 207) The compound had an ECo for activation of a hTiRI/hTIR3 umami receptor expressed in an HEK293 cell line of 11.5 pM, and when present at 3 pM enhanced tbe effectiveness of monosodium glutamate with an ECso ratio of 2.2. 2.0 2s .dluroNqea4-ybezeidlt3dio$oleearboxamide FoN F O'k Prepared in a similar manner to example 4 using 2,2.-difluorobenzo[d] [1 ,]dioxole 5-carboxylic acid and 4-hepthylamine. (M+H, 300.2). The compound had an EC 50 for activation of a hTIRI/hTiR3 umami receptor 25 expressed in an HEK293 cell line of 1.51 pM, and when present at I pM enhanced the effectiveness of monosodium glutamate with an EC 0 ratio of2.87. 83 23jihydrodbeuzoi,4ldioxineo carborwik acid (I-nmwl-buvihamide NN H Prepared in a similar manner to example 4 using 2,3 Dihydro-benzoll,4]dioxines6 5 catboxylic acid and heptan-4-amine. MS (M+H, 27832). The compound had an EC5 3 for activation of a hTIRI/hT1R3 umami receptor expressed in an HEK293 cell line of 0.49 IM Example 24 N~(heptan -vh~3l4dihdro2WhenzohL4dxeieee~*arhoxandde 10 .. A Prepared in a similar manner to example 4 using 2.3-Dihydro-ben zo[i,4jdioxine-6 carboxylic acid and heptan-4-amine, MS (M+H, 292,2). The compound had an ECc for activation of a hTi i/hTlR3 umami receptor expressed in an HEK293 cell line of 6.4 gLM. 15 Exanne :25 benzofan 2 -arboxvylI -ropibutv))antdde Prepared in a similar manner to example I using benzofuran-2-carbonyl chloride and heptan-4-amine. Yield: 73%. 1fH NMR (500 MHz, CDCl1): 6 0,93 (t, 611, J= 7.2 Hz), 20 1.41 (in, 3H), 3,01 (s, 3H), 4.18 (in, 1H), 6.29 (d, IH,J= 9.94 Hz), 7.20 (d, IH, J= 862 Hz), 7.37 (in, 211), 7,44 (s, 1H) MS (M+H, 260) The compound had an ECsO for activation of a hTIIRII/TTR3 uiani receptor expressed in an HEK293 cell line of 0.88 pM, and when present at 0.3 tM enhanced the effectiveness of monosodium glutamate' wh an ECso ratio of 2. 84 ]Nehetang4-5Smethylhenzufuran 2arboxamide Prepared in a similar manner to example 4 using S methvlbenzofuan-2-carboxyhc 5 acid (example 26a) and. heptan-4~amine. Yield: 46%. H NMR (500 MHz, CDCI): & 0.94 (t,6H, J=::::7.2Hz), 1.41 (i, 10H),2.44 (s, 1H), 4.8 (i, 1H), 6.29 (d, 1HJ= 8.6 Hz), 7.21 (d, 111, 1 84 Hz), 7.37(m. 2H), '44 (s, 111). MS (M+11, 274) a. 5-methylbenzoflran-2-carboxyiic acid: 2A-Hydroxy-5-methvibenzaidehyde (544.2 mg, 4 mmol) was combined with diethvlbromomalonate (1 mL, 6 mnol) and 10 potassium car bonate (.1. g, 8 mmol) in methyl ethyl ketone (5 nL) and the mixture was heated to reflux overnight. The solvent was 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 under reduced pressure and the residue was then treated with a 2,0 N solution of S12S04. The flee acid was then 13 extracted with copious amounts of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, Ethyl acetate removal afforded 566mg of 5-.Methyl-2 carboxybenzofuran (80%) as of a yellowish powder. 'H NMR (500 MIlz, CD 3 OD): 32.44 (s, 3H), 7.30 (d, 1H, J= 8.7 Hz), 7.45 (d, 1H, J= 8.5 Hz), 7.51 (d, 2H, J= 7.5 Hz). The compound had an EC 5 o for activation of a hTIRl/hTIR3 unami receptor 20 expressed in an HEK293 cell line of 0.94 jiM, Enamole 27 Q(RNmethyl In4ethvl2-(5-inethyibenzofuran2 .ar boxamidq)pentannate ~ -0 Prepared in a similar manner to example 4 using 5-methyilbenzofuran-2-carboxylic 25 acid (example 26a) and D-leucinemethyl ester. 'H NMY1R (500 MHz, CDCi,): 30.98 (d, 3H, J::: 6,26 Hz), 1.00 (d, 3H, J::: 6.17 Hz), 1.56 (s, 311), 176 (m, 3H), 2.48 (s, 3H), 3.78 (s, 3H), 4.86 (in, 1H), 6.95 (in, 1H), 7,23 (dd, 1H, J= 8.54 Hz, J= 1.55 Hz ), 7.40 (m, 2H). 7.44 (dd, 1I, J= 1.72, .= 0.9 Hz) MS 304 (MiH, 304) 85 The compound had an ECo for activation of ahT1RI/hT1R3 umami receptor expressed in an HEK293 cell line of 0. 1 mM. Example 28 3hex-34 5-ethylbtenzofura, 2carboxamUide 5/ Prepared in a similar manner to example 4 using 5-methylbenzofian-2-carboxylic (example 26a) and hexan-3-amine (example 28a) Yield: 49%, 'H NMR (500 MHz, CDlI: 0,94 (m, 6H), 1.40-L68 (m, 6H), 2.36 (s, 3H), 4.07 (M, 1H), 5.74 (d,.H, J= 8.9 11z), 7 16 (d, 1H,J= 780 Hz), 7.31 (dd, 1H, J= 1.73 Hz=,J 1.73 Hz), 7 66 (d, 111, J= 10 L72Hz) MS +H, 260). a. Hexan-amine was prepared using the same procedure described in example 2, starting from hexan-3-one. Yield: 58 %. H NMR (500 MIHz, CDCI 3 ): 6 094 (m, 6H); 1.36-1,58 (m, 6H); 2.83 (m, IH); 3.12 (s, 2H). MS: (102, M+H), The compound had an EC 5 o for activation of a hT1Ri/hT1R3 umami receptor 15 expressed in aniEK293 cell line of 0.74 pM Examplie 29 Nghexanw3-yWa5methoxubenmthtranu2-earboxamiide Prepared in a similar manner to example 4 using 5-nethoxybenzofuran-2 20 carboxylic acid and hexan-3-anine (example 28a). Yield: 32%. 'H NMRIv. (500 MHz,

CDC

3 ): 5096 (ma, 6H); 1.40-167 (n, 6.H); 3.85 (s, 3H); 4 09 (in, 1H); 6,28 (d, 1H); 7.01 (dd, 1H); 7.08 (d, 11H); 7.38 (i, 2H). MS ( 276, M+H). The compound had an ECo for activation of a hTIRMtTiR3 umami receptor expressed in an HEK293 cell line of0.4 pM1. 86 E~Xample 30 (Rbnetfvl 36eveohexi ~245 methoxvbenzofaranc2crhoxamiidoi pyanoate 5 carboxyhr- acid and (R)-methyl 2~mnY-ycoeypopnae iel& 45%. MS (M+H, 260.3). The compound had an ECso for activation of a hTIRI-/hT'IR 3 um ami receptor expressed in an HEK293 cell line of 1. 14 pM, Prepared in a similar manner to example 4si carboxylic acid and 5--methylhexan-3-aminie (example Sa). Yield: 67%, 1H NNM (500 MH z, CDCh3): 6 0.96 (m, 911); 1 39-1 52 (m, 311); 1.66 (m, 211); 3 ,8 5 (s, 311); 4,17 (m, 15IH), 6124 (d, IH) 7.01 (dd, IH); 7,08 (d, 1H); 7:38 (m, 2H), MS ( 290, M+H) The compound had an ECso, for activation of a hT1R1/hTIR3 umai renCptor expressed in an HE K293 cell1 fine of 1.04 ptM Prpgaradenu Of (~ehl4clr45mteezer 20 garboxadeea Prepared in a similar manner to example 4 using 5chlorobenzofuran-2-carboxylic acid and D(eucine methyl esterx MS (M+Hr 324), The compound had an ECo for activation of a hTIRI/hTR3 unami receptor 25 expressed in an HEK293 cell line of 1.82 pM. 8-7 {tKtnethyt 4-mnethyl-2I3.ntvhenzofuran-caboaid1penltalate 0 -/ Prepared in a similar manner to example 4 using 3methylbenzofran2carbOXyhe 5 acid and D-leucine methyl ester. MS (M+H, 304). The compound had an EC 50 for activation of a hTIR1/hTIR3 umami receptor expressed in an HEK293 cell line of IS pM. Exanle 34 N4heptau4lUbenzojb thiophene-2 ctrbexamide 10 Prepared in a similar manner to example 4 usng enzob]thiophene-carboxylic acid and 4ihepthylamine. MS (M+H, 276), The compound had an ECs for activation of a hTIRI/hTLR3 uniami receptor expressed in an HEBK293 cell line of (121 pM. Prepared. in a similar manner to e <ample 4 using lH-indole-2-carboxylic acid and 4-hepthylamine MS (M+H, 259). 20 The compound had an EC.

5 for activation of a hTIRi/hT1R3 nmami receptor expressed in an HEK293 cell line of 6.8 pM 88 (R).'ethyl 4-aethb 2-$5methylj I1 indole h earboxamid&etamwate Prepared in a similar manner to example 4 using 5-Mvethyll- H-inidole-2-car boxylfic 5 acid and D-leucine methyl ester. Yield: 50%, 'H NMR (500 M*1z, CDC13): 60,98(d, 3.H, J= 6,3.H z), 1,00(d, 3H,T J= 6.1 Hz), 2,44 (s, 3H), 3,784(s, 3H), 4 87(mn, I H), 6.56 (d, 1HJ = 8,39 Hz), 6. 85 (dd, 1H, J = 194 Hz, J=- 0. 68 Hz), 7- 12 (dd, 1H, J = 18.46 Hz., J= 1. S5 H ) 7.31(d, 1H,J=8&45 Hz), 71142 (s, 1H)- MS (MIH+, 303). The compound had an E Cao for activation of a hT1R1/hTIR3 umami receptor 10 expressed in an HEK293 cell line of 6 6 gM.l N Ij~henvtan- 4-vIf. -methylI 1H-In dalse2-earb oxamide

N

Prepared in a sirnilar manner to example 4 using 1-m-iethyl-1H-inidole-2-carboxyli 1.5 acid and 4-hepthylanmine, Yield 45%.'H NMRP (500 MHz, CDC13): 6 0.95 (t, 6H, J= 7,2 Hz), 1L46 (n, 4H1), 1,57 (m, 4H), 4,05 (1, 3H), 4.15 (m, 1H), 5.85 (d, 1H), 6.80 (s, 1H), 7A (t,1HJ- -4 z),7;1 (, 1, J 7. H), .38(d,1HJ= .H ),7.62 (d, H,J=8 Hz) MS (M+-H, 2'73). The compoundhad ank ECat) for activation of a hT1R1/hTlR 3 umami receptor 20 e-xpressed ink an HFEK293 cell line of 1 79 piM, 89 beptan~bv1Ylkbenzo d liidaztie-Sarboxafnde HH Prepared in a similar manner to example 4 using IIH-benzo[d]inidazole-'5 5 carboxylic acid and 4-hepthylainine. Yield: 80% 11 NMR (500 11z, CDC 3 ): 6 0.94 (t, 611, J= 7.2 Hz) 1.42 (m, 611), 157 (m, 211) 4,21 (m, 111), 6,18 (m, 1H), 7.64 (m, 2H), 8.16 (m, 111), 8.28 (s, 111). MS (M+H, 260). The compound had an EC5 for activation of a hTJRl/TIR3 umami receptor expressed in an HEK293 cell line of 18 6 pM 10 F 'x mp gk 39 henazcazoe-e~carboxyli acid 41propy1butv4arndde Prepared in a similar manner to example 4 using benzooxazol-5-carboxylic acid (Example 39a) and 4-heptylamine. H NMR (500 Mvflz, CDC 3 ): 816 (d, J= 5.4 Hz, 1HI) 15 7.89 (d, J= 8. 6 Hz, 1H), 7.64 (d, J= 8.6 Hz, 1H) 5.82 (d, J= 8.6 Hz, 1H) 410-422 (n, 1H1), 1 58-1.62 (m, 411), 1.40449 (m, 4H), 0.95 (t, J= 7.2 Hz, 611); ESTMS: 261 (M'H. a. benzooxazol-5-carboxylic acid: A mixture of 3-am. nino-4hydroxybenzoic acid (500 mg, 3.26 mmol) and trimethyl orthoformate (5 nL) was heated at 650C for 2 h under argon. The reaction mixture was cooled to room temperature, filtered and washed with 20 hexanes. 'The filtrate was concentrated in vacuo to afford the product as a white solid (78 nag, 15%): H1NMR(500MHz, CDCb): 8.57 (d, J=1.5Hz, 1H), 820 (ad,J=8,4 1. Hz, 111), 820 (s, 111), 7,67 (d, J= 9,0 Hz, 1H). MS (M+H, 164). The compound had an EC5s for activation of a hTIR1/hTIR3 umami receptor expressed in an HEK293 cell line of 1.91 FM. 90 2 -Methvylbenooxazole- arboxe acid Pikro vl-buti)mide Prepared in a similar manner to example 4 starting from 2 -methyl benzooxazol5- 5 carboxylic acid (example 40) and 4-heptylamine H NMR (500 MHz, CDC 3 ) 3 8.00 (d, J = 1, Hz, 1H), 7,77 (d, 1= 8;5, 1A Hz, 1H), 7.50 (d, J= 8.5 Hz, 111),579 (d,T= 83.9 Hz, 1HI for NH) 4.10-4.22 (m, IH), 2,66 (s, 3H), 1.58-1 65 (m, 4H), 1.38-1.55 (m, 4H), 0.94 (t, J= 7.2 Hz, 6H); MS(APCI, M+): 275.2. a. 2.-methyl benzooxazol-5-carboxylic acid: A mixture of 3-aniino-4 10 hydroxybenzoic acid (1.5 g, 9.79 mmnol) and trimethyl orthoacetate (15 mL, large excess) was heated at 65 'C for 5 hirs 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%): III NMR (500 MHz , CD 3 oD) 3 3.26 (d, J= 17 Hz, IH), 8,07 (dd, J= .5, 1.6 Hz,1 H), 7.67 (d, J=8.2 Hz, 1H), 2.67 (s, iH); 15 MS(APCLtM+1): 17810 The compound had an ECc: for activation of a hTlRI/hTIR3 umanii receptor expressed in an HEK293 cell line of 0.33 iM. Example 41 2~Ethv~enzoaxazle~6~c'arboxylic acid (.Uroiwlt betilVa mdde A mixture of 3 amino-4-hydroxy-N-( -propylbutyl)benzamide (example 41 a) and trimethyl orthopropyrate was heated at 65 C for 5 hr under N 2 . The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified on silica gel via Preparative-TLC (3% MeOH in CH 2 CI) to afford the product as a white 25 solid (42 mg, 73%): rnp 107-108 "C; MS(APCX M+1): 28910. 91 a. 3-amino-4-hbydroxy-u(~propylbutyl)benzamide was prepared in a similar manner to example 4 using 3-Amino-4-hydroxybenzoic acid and 4-heptylanine. Yield 57 %.'H NMR (500 MHz, CDC1 3 ): 65 0.93 (t, 6H); 1.26-1 .51 (in, 8H), 4.09 (m, 1H), 6,74 (m, 1H); 7,05 (s, 1H); 7.43 (m, 2H); 7.77 (m, 2H).MS: ( 251, M+H ). 5 The compound had an EC, 0 for activation of a hT1R1/hTlR3 umami receptor expressed in an EK293 cell line of0,68 pM, Exanle42 2-Methtxy-ezooxagey~cadhoxvii acid t I-rOI)vbutI-amide io~ ~ ~ rxml~ 10 Prepared in a similar manner to example 41 using 3..amino-4~hydroxy-NX(1 propylbutyl)benzamide (example 4aa) and tetramethylorthocarbonate Yield: 60% mp 137-138 C; IS (M+H, 291 10). The compound had an EC5 for activation ofa hTlRI/hTlR3 uiami receptor expressed in an HEK293 cell line of 0.69 pM. 15 Emmrnple 43 '2-EthiAx -be nzooxazole-5yarboxyic acid (Iprapv4btvWianude Prepared in a similar manner to example 41 using 3 amino-4-hydroxy-N -(1 propylbutyi)benzamide (example 41 a) and tetraethoxymethane: nip 128129 T; MS 20 (M+H, 305 1), The compound had an EC 5 o for activation of a hTlRi/hTIR3 uani receptor expressed in an HEK293 cell line of 5 M. 92 Exampie 44 Nihetan-4vl}-2methn hiolbenzv~ doxalecsrerbxamnide t. -- P7 -1g tm To a solution of N-(Heptan-4-yl)-) (mercapto)benzo[djoxazole-5-carboxamide 5 (example 44a) (50mg, 0.17 mmol) in DMF (3 mL) at 0 *C was added K 2 00 3 (29 mg, 0.17 mmol) and Mel (29 mg, 0.20). The resulting reaction mixture was heated at 80 'C overnight. The solvent was removed under reduced pressure. The residue was diluted with dichloromethane and washed with water, dried (Na2SO 4 ), filtered, concentrated in vacuo, purified via PTLC (15% EtOAc in hexanes) to afford the product as a white solid (50 mg, 10 96%): mp 113 -114 "C; iH NMR (500 MHz, CDCI) 6 7.94 (d, J= 1,8 Hz, IH), 7.73 (dd, J = 8.5, 1. 6 Hz, 11), 7,46 (d, J= 8.4 Hz, 1H), 536 (d, J= 3 4 Hz, IH),4:15-4.25 (In, IH), 2.77 (a, 3H), 1.58-1.65 (m, 211), 1.1.38 -155 (i, 611), 0.94 (t, J=7,2 Hz, 611); MS(A.PCI, M+): 307.2. a. N-(Heptan-4-yl)-2-(xercapto)benzo[d]oxazole-5-carboxamnide: To a solution 15 3-anino-4-hydroxy-N-(i -propylbutvl)benzamide (example 41a) (250 mg, 1.0 imol) in EtOH 'as added KSCSOEt (160 ing, LO mmol), The resulting reaction mixture was heated at 80 C ovemight. The solvent was removed under reduced pressure. And the residue was taken up in water. The resulting mixture was acidified with HO.A.c to pH - 5 and then filtered, The residue was washed with water to afford the product as a white solid 20 (160 ing, 55%). MS (M+H, 293.1). The compound had an EC 50 for activation of a hTlRi/hTIR3 uman receptor expressed in an H11K293 cell line of 3.1 gM. Chil~romnethy1 benzooxaze tarboxylic acid ('Ppronvbhntvnamide 25 C 93 Prepared in a similar manner to example 41 using 3-amino-4~hydroxy-N-(1 propylbutyl)benzamide (example 41a) and trimethyl chioro-orthoacetate. Yield: 65%. mp 108.5-109 *C. MS (M+H, 309.05). The compound had an EC 5 s for activation of a hTlRI/hT1R3 umami receptor 5 expressed in an HEK293 cell line of 0.23 iM. ZAMiethyhbenzooka izole-&oarboxyie acid (1 rop t-ln amide Prepared in a similar manner to example 4 using 2 methyl benzooxazol -6 10 carboxylic acid (example 46a) and 4-heptylanine Yield 50%: 'H NMR? (500 Mz ,

CD

3 OD) 6 8.19 (d, J= 1.4 Hz, 1H), 8.05 (dd, j= 8.3, LI Hz, 1H), 7.63 (d, J- 8-2 Hz, 1H), 2.68 (s, III) MS (M+1,178.10) a. 2.methyl benzooxazol-6catboxyiic acid was prepared in a similar manner to example 40a from 4-amino-3-hydroxybenzoic acid (50%): 'H NMR (500 MHz , CD 3 OD) 15 3 8.19 (d, J=1.4 Hz, IH) 8.05 (dd, J= 83, 1.5 Hz, 1H), 7 63 (dJ- 8.2 Hz, IH), 2.68(s, 1H); MS (M-H, 178.10), The compound had an EC 5 o for activation ofa hTIR1/hTIR3 uimami receptor expressed in an HEK293 cell line of 2. 1pM. Example 47 20 2Chloromethybenzooxaole6-earbox he acid rowvbutvihandde Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1 propylbutyl)benzamide (example 47a) and trimethyl chloro-orthoacetate. The product was obtained as a white solid (45 mg, 73%): mp 137.0437-5 0 C; MS (MI+H, 309.05. 25 a. 3-amino-4-hydroxy-N-(i-propvbutyl)benzamide was prepared in a similar manner to example 41a from 4-amino-3-hydroxybenzoic acid. Yield: 50%. 1 H NMR. (500 MHz,CDC{):6 0.91 (t, 6H); 1.41 (m,6H); 1.54 (m, 2H)1;4,13 (m, 1H); 5.8i (d, 1H); 6.63 (d, 1H), 6.95 (d, 1H); 782 (s, 1H). MS: (251, M+H) 94 The compound had an EC. for activation of a hTlRIh TR3 unami receptor expressed in an HEK293 cell line of 0.45 pM 4~meth 3methy)visulfMnMN-I rj p butvibheinaide Preaparsd in a similar manner as example 4 using 4-methyh3-(methylthio)benzoic acid (example 48a) and 4-heptylamine. Yield; 50%. 'H NMRl (500 HU, CDC 3 ); 6 0,93 (t. 611, J= 7.2 Hz), 1,40-1 41 (m, 81H), 235 (s, 3H), 251 ( s, 1 H), 415 (n, 111), 5.75 (d, 1H, J 85 Hz), 7.15 (d, 111, J=78 1Hz), 7.31 (d, 1H, J= 7.8 Hz), 7.65 (d, 1H J= L5 Hz), MS 10 (M+H, 280). a. 4-inethyl-3-(methylthio)benzoic acid: 3-Amino-4-methyibenzoic acid was suspended in icexwater (55 mL), and concentrated HCl (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 stirred far another 15 minutes. Then, an aqueous 15 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 250n iL of water. The reaction vessel was placed in a preheated oil bath at 70C and the 20 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 30"C Sodium hydroxide (0.782 g) was added and stirred to dissolution Dimethylsulfate (530 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 25 H12S04 and extracted with EtOAc. The extracts were washed with water then dried over anhydrous MgSO 4 . 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 4-nethyl3-(iethylthio)benzoic acid as a pale yellow powder (2 g). 'H NMR (500 MH, CDOk): 5 2.39 (s. 3H), 2.54 (s, 3H), 7.24 30 (d, 1H, J= 7.8 Hz), 7.79 ( d, 1H, J= 78 Hz), 7,86 (d, 1H, J= S 5 Hz), 95 The compound had an EC 5 D for activation of a h TIRI/h TiR3 umami receptor expressed in an HEK293 cell line of 0,21 uM. Example 49 (R) nethvI 4methe244..nethykne3tthvi I tbenzamidohpentanoate Prepared in a similar manner to example 4 asing 3 rnethy-4(methythio)benzoic acid (example 48a) and D Leucine methyl ester. Yield: 45%. IH NMR (500 MHz, CDCi): d 097 (d, 3H, J= 6.36Hz), 0.99 (d, 3H, J= 6.1 Hz) 1.64-177 (n 2H), 2.36 (s, 3H). 251(s 3H), 3,77 (s, 3H), 4.85(m, iH) 6,50 (d, IH, J= 8,10 liz), 7.18 (d, II, J=7.83 Hz) 7.38 10 (dd, IIH, J= 7.77 Hz, J= 1.78Hz), 7,65 (d. 1I, ,J= 1.65 H1z). MS (M+H, 310). The compound had an EC5 for activation of a hTIR.1/hT1R3 umami receptor expressed in an HE1K293 cell line of 0,1 iM, txande 50 fR)-methy 4jnethy[~44nettthithibenzam id;etanate Prepared in a similar manner to example 4 using 4 (methyltbio)henzoic acid and D Leucine methyl ester. MS (M+H, 296). The compound had an ECs 0 for activation of a hTlRI/hT1R3 umami receptor expressed in an HEK293 cell line of 0U6 pM N4.heptan4vII.3methy 44ethythobanzamnide Prepared in a similar manner to example 4 using 3-methliv4-(methylthio)benzoic acid (example 51 a) and 4-hepthylamine 1H NMlR (500 Miz, CDCl9: 5 0.93 (t, 6H); 1.37 96 1.46 (in, 6H); 1 54-L56 (m, 2H); 2.35 (s, 3H); 2.49 (s, 3H); 4.17 (m, 1H); 5,73 (d, 1H); 7,14 (d, 1H); 752 (s, IH)7.58 (d, 1H). MS (280, M+H ) mp: 129-131 *C. a.3ethyl-4-(methylthio)benzoic acid was prepared using the same procedure described in example 48a starting from 3-Amino-4-methylbenzoic acid, Yield 30 % "H 5 NIR (500 Hz, CDCb): 8 2.36 (s, 311); 2.53 (s, 3H); 7,17 (dj 11); 7,85 (s, 1H); 7,93 (d iH). The compound had an EC 5 for activation of a hTIRI/hI 1 P3 umami receptor expressed in an HEK293 cell line ofO12 pM Exam21e 52 ~y Prepared in a similar manner as described in example 4 using 4-methoxy-3 methylbenzoic acid and 2-mrethyi4-heptanamine (example 2a). Yield 45%KH NfR (500 MHz, CDC): 4 0.93 (in, 9H); 139 (r, 5H); 1.53 (in, 1H); 1,67 (in H); 2.24 (s, 3H); 3.86 15 (s, 3H); 4.23 (m, 1H); 5.64 (d, 1H); 6.82 (d, 1H); 7.54 (, 1) 7.61 (d, 1H). MS ( 278, M+H), The compound had an EC 50 for activation of a hTIRi/hT1R3 umani receptor expressed in an HEK293 cell line of 0.1 pOM. 20 4;mth tetejl.N ba e Prepared in a similar manner to example 4 using 4-methoxym3-methylbenzoic acid and 5-methylhexan-3-amine (example 5a) H NMR (500 MHIz, CDC 3 ): 5 0.94 (m, 9H); 1.38 (in, 2H) 1.47 (m, 1K); 1.65 (in, 2H); 224 (s 3H); 3.86 (s, 3H); 4.16 (in, 1H); 5.65 (d, 25 1 H); 6.83 (d, 1H); 7.54 (s, 1H); 7.61 (d, 1K). MS ( 264, M+H). The compound had an ECs for activation of a hTIRM/hTR 3 umami receptor expressed in an HEK293 cell line of 0.09 pM. 97 Example 54 4..nethoxv~N~C 6(4eniethxihvhen i):3~methvlhenzamide Prepared in a similar manner to example 4 using 3-methyl-4-methoxy--benzoic acid 5 and 1(4-nethoxyphenyl)butan-lamine (example 54a).Yield 52%. 'H NMR (500 MLz, CDC): 0,94 (t, 311); L31-1.41 (m, 211); 1,82-192 (m, 211); 2.22 (s, 31); 3.79 (s, 311);3.86 (s, 311); 5-11 (m, 111); 6.14 (d, 11) 6.81 (d, 111); 6,88 (d, 211) 7.28 (d, 2M); 753 (s. 111); 7,61 (d, 111). MS (328,M+H ), a, 1-(4-methoxyphenyl)butan-1amine was prepared as described in example 2a 10 from 1-4-methoxyphenyl)butan-Pone Yield 90%. MS (M+H 180). The compound had an EQGo for activation of a hTlRi/hT1R3 iani receptor expressed in an IEK293 cell line of 3.14 pM. (R'Imtxy3-nethyEhN43/metln 14n~-ethtrv244-oxadiaz 4.5 15 vbhutybbenzamide ,N Prepared in a similar manner to example 4 using 4methoxy-3-methylbenzoic acid and 3-methyll-3-methyl-[I2,4]oxadiazol-5-yi)-butylamine (Example 55a). MS (M+H, 318), 20 a, (-3-methyl- (3-methy-,2,4-oxadiazol5Byl)butan-.amine: Boc-D-Leu-OH (0.23 g, I mmol) was treated with N-hydroxyacetamidine (74 mg, I eq) and DIC (155 pL, 1 eq) in dioxane (2 mL) at room temperature overight. Another portion of DIC (1 equiv) was added and the reaction mixture was heated at 1104C for 4 hours. After removal of the solvent, the residue was treated with 50% TFAJDCM (2 mL) for I h and then the solvent 25 was evaporated. The crude mixture was purified by preparative IPLC (C-1S column, MeOH~H20 mobile phase and formic acid as modifier) to give 75 mg of the amine (45% 98 yield). 'HNMR (500 MHz, CDCi): 6 095 (d, 3), 0.99 (d,3H). L70-1.78 (m, 1H), 1.92 1.98 (m 2H), 2,39 (s, 3H), 3.50 (b, 2H, NH 2 ), 4.65 (t, N1) MS (M+H, 170). The compound had an EQ 0 for activation of a hT1RI/hT1R3 umami receptor expressed in an H1EK293 cell line of 5A pM Exmpik56 NNH Prepared in a similar manner as example 4 using 4-ethoxy-3-methyl benzoic acid (example 56a) and 4-heptylamine. Yield: 75%. 'H NMR (500 MHz, CDCh): 5 0.93 (t, 6H) 10 [374.45 (m, 611); 153-159 (in, 211); 2.24 (s, 3 H); 4.07 (q, 2H); 4.15 (m IH); 5,67 (d, 111); 6,80 (d, I1); 7.54 (s, 1H1); 7.58 (d,1H). MS (278, M+l) a. 4-ethoxy~methyi benzoic acid: 4-hydroxy-3-methyl benzoic acid (10 g) was dissolved in DME (400 mL) followed by the addition ofsodin carbonate (3eq) Ethyl iodide (3eq) was dissolved in DMF (50 mL) was added dropwise to the reaction mixture 15 and the solution was stirred ovemight, 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 200I1 methanol/water (3:1). Lithium hydroxide (3eq) was added and allowed to stir ovemight. Upon the completion of hydrolysis., the solvent was removed and the product was crystallized using 20 ethyl acetate/hexane mixture to give 8.2 g of 4-ethoxy~3~methyl benzoic acid. Yield: 70%, MS (M1, 179,20). The compound had an EC 50 for activation o f a hT1Rl/hT1R3 umami receptor expressed in an HEK293 cell line of 0.17 pM E mpe57 25 4-thoxyN~mehoypntan Vu-3mththaza~wmide, 99 99 Prepared in a similar manner as example 4 using 4-ethoxy-3-methyl benzoic acid (example 56a) and 1--methoxypentan-2-amine (example 57a). Yield: 33%. MS (M+H, 280.1). a. i-methoxypentan-2-amine was prepared in a similar manner to example 9a fron 5 2-(1inethoxypentan-2-yl)isoindoiline- 1,3-dione (example 57b). Yield 67%, 'H NMR (500 MH, CDCl): 0,91 (t. 3H); 1,24 -1,45 (m,4H); 152 (s, 2H); 2.94 (in, 1H); 3.12 (t, 1H ); 3.33 (i, 1K); 3.35 ( s, 3H). b. 2-(1methoxypentan-2-y)isondolned,3-dione was prepared in a similar marner to example 9b from 2-(1-hydroxypentan-2-yi)isoindoline-1,3-dione (example 57c). 10 Yield: 82%, 'H NMR (500 MHz, CDCli): 6 0.91 (t, 3H); 132 (1m, 2K); L64 (in, 1K); 2,03 (im, 1H); 3.31 (s, 3H); 3.54 (i, 111); 3.98 (t, 111); 4.50 (in, 1K); 7.70 (in, 2H); 782 (m 2H). c. 2-(1-hydroxypentan-2-yl)isoindoline-1,3-dione was prepared in a similar manner to example 9c using isobenzofiran-1,3-dione and 2-aminopentan-1-ol. Yield 62%. 15 'KNMR (500 MHz, CDCI3)i 0.92(t, 31); 1,33 ( m, 2H); 176 (im, 1H); 1.95 ( m, 1 H ); 388 (in, 1H); 4.06 (m1, IH);4,39 (m, 1H); 7.72 (in 2H);783 (in, 2H). The compound had an ECs. for activation of a hTiRIhT1R3 unami receptor expressed in an HEK293 cell line of 0.69 gM. Example 58 20 4-hvdroxy-3-mthxNl -- opvlbutlbenzamide Prepared in a similar manner as described in example 4 using 4-hydroxy-3-miethyl benzoic acid and 4-heptylamine. MS (M+H1, 250.2). The compound had an ECso for activation of a hTiR/hTiR3 umami receptor 25 expressed in an HEK293 cell line of 0,92 iM Erxunupl 59 Nihean4A4(2niethxvethox4 nethlvihenamide 100 Potassium hydroxide (4 mmol) was dissolved in ethanol (5 mL) and heated at 804C 4-hydroxy-3-nithyl-N-(propyl-btyl)-benzanide (example 58) (Imnol) was added into the solution followed by chloroethanol (3 mmol) The reaction was stirred overnight at 80'C, The reaction mixture was concentrated down and dissolved in 5% citric acid, he 5 mixture was stirred for I hour. The aqueous mixture was extracted three times with 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 H.PLC to yield 39% of N4heptan-4-yl)-4-(2-methoxyethoxy)3-methylbenzamide. MS (M+1H, 30825) The compound had an EC& for activation of a hTIRI/hTI R3 unami receptor 10 expressed in an .HEK293 cell line of 0 21 p.M, ExaMtLe 60 tRumethyi 23inro-44mewthoxxbenzianudo) 4-meth~'frentanoate Prepared in a similar manner to example 4 using 3-fluoro~4-methoxybenzoic acid 15 and D-ieucine methyl ester MS (M+H, 298). The compound had an EC 5 for activation of a hTIRl/hTiR3 umami receptor expressed in an HEK293 cell line of 0.3 p.M, Example 61 3gehtoro4~metoxy-NAentani-3-vfbenzamiide 20 Prepared in a similar manner to example 4 using 3-pentylamine and 3-chioro-4~ niethoxy benzoic acid. Yield 40%. MS (M+F, 256.20). The compound had an EC for activation of a hTlRl/hTlR3 umami receptor expressed in an HEK293 cell line o f0.56 p.M, and when present at 0.3 pM enhanced the 25 effectiveness of monosodium glutamate with an EGso ratio of 6.28. 101 Example 62 fR)amehvL2{ hlo~ra-4~a ethov bcnzaido)4-methvipeentanoate Prepared in a similar manner to example 4 using 3-chloro-4-nethoxy benzoic acid 5 and D-leucine methyl ester hydrochloride, MS (M±H, 31410). The compound had an ECsO for activation of a hTIR1/hTlR3 umami receptor expressed in an HEK293 cell line ofQ08 gM, and when present at 0.01 tM enhanced the effectiveness of monosodium glutamate with an EC, 0 ratio of 13.18 Exa ple 63 10 (RV3-chluoo4~methowv N-fl -phenywlthfhenzamide Prepare in a similar manner to example 4 using (R)-i -phenylethanamine and 3 chloro-4-methoxy benzoic acid. MS (M+H, 290.0), The compound had an ECfo for activation of a hTIR1IhT1R3 umari receptor 15 expressed in an HEK293 cell line of2.5 tM, and when present at 0.3 pM enhanced the effectiveness of monosodium glutamate with an EC,5 ratio of 2,7 Example 64 4-Chloro-iethyl N41i propvkhuthbenzamiide cr 20 Prepared in a similar maimer to example 4 using 4-chloro -3-methyl benzoic acid and heptan-4-amine. MS (M+H, 268). The compound had an EC5, for activation of a hTllR1/hTlR3 urmami receptor expressed in an H1EK293 cell line of 8 M. 102 34DinethoxyN 0 reQ btlbenztaide j ~ NH'~' Prepared in a similar manner to example 4 using 3,4dimethoxv benzoic acid and 5 heptan-4-amine. MS (MH, 279.37), The compoimd had an EC 5 o far activation of a hTIRI/hTIR3 uanami receptor expressed in an HEK293 cell line of 0,36 pM. Ea le66 (R}iethvl2-44%mrno~-3 ethbenamidv)4 methyllbanD oate Prepared in a similar manner to example 4 using 4-fluoro-3-methylbenzoic acid and D-leucine methyl ester, MS (M+H 282 The compound had an ECs for activation of a hTIRI/hTIR3 inami receptor expressed in an HEK293 cell line of 0.32 'M Prepared in a similar manner to example 4 using 4-rmethoxy-3,5-dimethylbenzoic acid anid 2-methylheptan-4-amine (example 2a). MS (M+-H, 292.2). 20 The compound had an Eso for acti-vation of a hTIRIA/MTR 3 uma-mi receptor expressed in an HEK293 cell line of 0,85 IA1, 103 tAj-dieutv-[N(2Q ithyfhg 43-Itbewzaifd Prepared in a similar manner to example 4 using 34-dimethylbenzoic acid and 5 hexan-3-arine (example 3a). iH NMR (500 MHz, CDCi&): 6 0 94 (m, 9H); 1.39 (in, 3H); 1.56 (m, 111); 1.84 (m, 1H); 2-30 (s, 3$); 2.31 (s, 3H); 4.04 (m, 1$); 5.76 (d, 1); 7.1 (d, 1) 7.46 (d, 1H); 7.55 (s, 1); MS (248, M-H). The compound had an EC50 for activation of a hTIR1/hTI.R3 umami receptor expressed in an HEK293 cell line of 0.11 iM 10 Example 69 .4inethy1AN42*nieth lheptai-4abbheainkde Prepared in a similar manner to example 4 using 3,4 dimethylbenzoic acid and 2 methylheptan-4-amine (example 2a) H NMR (500 MHz, CDCb): 6 0.94 (m, 9H); L40 15 (m, 5H); 1.53 (m, PH); 1.68 (m, 1H); 2.29 (s, 3H); 2.30 (s, 3H); 4.24 (in 1H); 5.69 (d, 1H); 7.17 (d, 1H); 7.46 (d, 1H); 7.54 (s, 1H). MS (262, M+11). The compound had an EC 0 for activadon of a hTlRl/hTiR3 umami receptor expressed in an HE <K293 cell line of 0. 13 M, Example' 70 20 4-dimethyVN'f5Smethyltena henam1ide 104 Prepared mn a similar maner to example 4 using 3,4-dimethyibenzoic acid an d 5 inethyihexan-3-amine (example Sa). 'H NMR (500 MHz, CDCII) 5 0.94 (in, 9H); 1,38 (in, 2H); 1 46 (m, 1H); 1,65 (in, 2H); 2.29 (s, 3H); 2.30 (s, 3H); 4.18 (m, 1H); 5.70 (d, iH); 7 17 (d, 1H-); 7.46 (d, IH); 7, 55 (s, 1H). MS ( 248, MH ). 5 The compound had an ECso for activation of a hTIR1/hTiR3 unami receptor expressed in an HEK293 cell line of 0. 17 .M. E xa~e7 i-N41-methoxv-inethylpenta2.-vl3S4-dimetbibenzamde 10 To a solution of (R)-N-(l-hydroxy-4-methylpentan 2-yl)-34-dimethylbenzamide (1.59 g, 6,39 mmol) (example 71a) in dryDMF (20 mL) was added powdered NaOH (281 mg, 7 mmol) an the solution was stirred at 0"C for 2 hrs. lodomethane (1 eq, 6.39 nmol) was added in DMF (10 mi) drop-wise over period of 1 hr. The temperature was kept at 0C and the mi xTure was stirred for 1 hr. The reaction was quenched by adding 300 nil of 15 water. The aqueous layer was extracted with dichloromethane, dried over MgSO4 and evaporated. The residue was putified by flash chromatography on silica-gel (toluene-ethyl acetate; 5-20% gadient) to give 1.23 g (R)-N-(l imethoxy-4-methylpentan-2-yl)-3,4 dimethylbenzamide (73%), 'H NMR (500 MHz, CDCh): 6 0.94-0.97 (t, 6H1), 1.41- 1.47 (M, 111), 1.54-1,60 (m, 1H), 1.64-168 (m, 111), 2.29 (d, 6H), 336 (s, 3H), 3.45-3.50-(m, 20 2H), 4.344.39 (m, 1H), 6.23-6.25 (d, 111), 7,16-7.17 (d, 1H), 7.47-7.49 (dd, 1H, 7.56 (a, 1H). MS (M+H, 264,3) a. (R)-N-(l-hydroxy-4-iethylpentan-2-y)--3,4dimnethylbenzamide was prepared in a similar manner as described in example 4 using 3,4-dimethylbenzoic acid and with (R)-aminoleucinol . Yield: 75%, MS (M+H, 2503). 25 The compound had an ECo for activation of a hTIRi/hTlR3 umami receptor expressed in an WEK293 cell line of 0.2 p.M, 105 _____ nito yethoype lu...ty24 3,4-dimetvhenzamkde To a solution of (PQN-(1 hydroxy4methylpentar 2-yl)~3,4dmethyibenzamide 5 (Example 71a) (0.24 mmol) dissolved in dry DN (2mt) was added at CT powdered NaOH (0.36 mnol, 14.5 ing, 1.5 eq) and the mixture was stined for 1 hr at 0C Then chloro-methoxy-metbane ( 19 .3pl, I eq) was added and the reaction stored at 0'C for 1 hour. The reaction was quenched with water (30 nL) and the mixture was extracted witb dichlorometliane. The organic phase was dried over MgS04and evaporated. The crude 10 product was puified by preparative TLC (20% ethyl ac-etate/hexanes) to give 37.7 ng of (R)-N-(1-(methoxymethoxy)-4-methylpentan-2-yl)-3,4-dimethylbenzamide (53%). '.H NMIR (500 MHz, CDCh): 6 0.98-L,00 (t, 6H), 1.49-1.53 (m, 111), 158-1.64 (m, 111), 169 1.73 (n, 2H), 232-233 (d, 6H), 3.38-3.39 (t, 311), 3.64-3.72 (ddd, 2H), 4.41-4;44 (in, H), 4,65-4.69 (dd, 211). 6.37-6.39 (d, 111), 7.19-7.21 (d, 1H4), 7.50-7,52 (dd, 1H), 760 (sb. 1H), 15 MS (MI , 294.3) The compound had an BE for activation of a hT1RlIhTR3 umami receptor expressed in an HEFK293 cell line of L06 pM. Exanitlk 73 N4&I Methwxiethytb2-methyk ro vI)a3 4-.dimnehylbenzamide 20 Prepared in a similar manner to example 71 using N-(i-hydroxy-3 -Inethylbutan-2 yl)-3,4-dirnethylbenzamide (example 73a) and methyl iodide. Yield 87%. 'IH NMR (500 MHz, CDCla): 6 0,97-1.00 (dt, 6H), L96-2,00 (n, 1H), 2.29 (s 3H), 2.30 (s 311), 3.35 (s, 3H), 3.42-3.45 (dd, 1H), 3.60-3.62 (dd,1H), 4.01-4.05 (m, 1H), 6.31-6.33 (d 1H), 7.16 25 7,18 (d, 111), 7.48-7.50 (dd, 1H), 7.56-7.57 (d, 111). MS (M+H1, 250). a. N-(1-hydroxy-3-methyibutan-2-yi)-3,4-dimethylbenzaniide was prepared in a similar manner to example 71 a using 3,4-dimethoxybenzoic acid and 2-anno-3 methylbtan--ol. Yield 75% MS (Ms11, 236.2). 106 The conrnpound had an ECfo for activation of a hTIR/hT 1R3 umami receptor expressed in an HEK293 cell line of 0.37 p4M. Exain iplIe 7 4 fRVinemtyl 22-nindhoxy-4imethxytkk~ibnzamido)h4zetthaeutauoate Prepared in a similar manner to example 4 using 2 methoxy-4-(nethylthio)benzoic acid and D-leucine methyl ester. MS (M+H, 326), The compound had an EC 5 for activation of a hTIR1I/TIR3 umami receptor expressed in an IEK293 cell line of 15.8 VLM 10 xample75 N~Qjnethvlh esanu4-vIebenzoldi 13 dinon1e5 carboxamide Prepared in a similar manner to example 4 using 3-(4-Methoxy-phenyl)-acrylic acid and 5-methylhexan-3-amine (example 5a). Yield: 59% 'II NMR (500 MNHz, CDC(I): 6 15 0.93 (m, 9H); 1.33 (t,211); L43 (m, IH); 1,58-L67 (m, 2H); 3.83 (s, 3H); 4.11 (m, 1H); 5.19 (d, 1H); 6.25 (d, 1H); 688 (d, 2)7,44 (d, 2H); 7.58 (d, 1H), MS (276, M+H). The compound had an ECso for activation of a hT1R1hTiR3 umami receptor expressed in an FEK293 cell line of 0.24 y.M. 20 N4144hy ropv&34442: ydroxytethbxypienvfacilamide I\ H N-(1-Ethy.-propyl)-3-(4-hydroxy-phenyl)-acrylamide (example 76a) (0.44 mmol, 103 mg) was dissolved in absolute ethanol with KOH (0.7 mmol, 37 mg). The mixture was stirred at 80C for 1 hr. Then 2-chloro-ethanol (1.7 6 mmol, 118 ill) was added dropwise 25 and the mixture was refluxed overnight. Following evaporation the crude product was 107 dissolved ina dichioromethane and washed wth water and 5% citric acid. The organic phast was evaporated and the residue was purified by chromatography on silica gel to give 73 ni of desired product (60%), 'H NMR (500 MHz, CDClf): 3 0.920.95 (t, 6H), 1,25 (s, 1H),.404-16 (m, 2H), 1.59-1.64 (n, 211), 3.93-94 (m, 1H), 3.95-3,98 (m, 21), 4.09-4] 5 (m, 2H), 5,28 -5.30 (d, 11), 6 26-6.29 (d, 1H), 6.8-6,90 (d, 2H), 7,43-7,45 (d, 211), 7.56 759 (d, 1H). MS (M+H, 278 1). a. N-(PIEthylpropy1)~3-(4-hydroxy-pheny)-acrylamide was prepared in a similar manner as described in example 4 from 4-hydroxy-cinnamic acid and 3-pentylamine, MS (MH, 234.10). 10 The compound had an ECte for activation of a hTIR 1hTUR 3 unani receptor expressed in anHEK293 cell line of 5.8 iM Exande. 77 (E>Nqheptam-4-1>.3i thiorhen2-lacryhade 15 Prepared in a similar manner as described in example 4 frorn (E-3-(thiophen-2 yl)acrylic acid and 4-hepthyiamine. 'MS (M+H, 252) The compound had an ECo for activation of a hTlRi/hTIR3 umami receptor expressed in an HEK293 cell line of 0.44 pM. Examrple 7$ 20 (RE}nmethyi 4-neth i2-oc0etnmidpenatanoate H Prepared in a similar manner as described in example 4 from (E)-oct-2-enoic acid and 1-leucine methyl ester MS (M+H, 270). The compound had an EC50 for activation of a hT lIR/hTIR3 umami receptor 25 expressed in an HEK293 cell line of 0,92 pM. 108 .Examphe79 3-4~Methxhenv}.N'.-3-methvMl -pntplb0avrhnide Prepared in a similar manner to example 4 using 3~(4-methoxy-pheny)-acrylic ack 5 and 3-methyl-i-propyl-butylamine (example 2a) Yield: 65%. IH NMTR (500 MHz, CDCi): 6 0.90-0.95 (m, 911), 1.30-139 (m, 51), 1.49-1.50 (m, IH), 1.64-167 (m, 111), 3.82 (s, 3H), 4.17 -4.18 (m, IH), 5.18-5.20 (d, 1H), 6.22-6 26 (d, 1H), 6-86-689 (d, 2H), 7.42-7.45 (d, 2H). 756-7.59 (d, 1H). MS (M+IH, 290.1) The compound had an BC 50 for activation of a hTlRI/hT1R3 umami receptor 10 expressed in an HEK293 cell line o fl 84 ptM. Exampkl 80 N 41~Meth oxvmeth-3~melty-butv1)344et~h ~hexvi-aeyamnide Prepared in a similar manner as described in example 71 f-ho 3-(4--methoxy 15 phenyl)-acrylic acid and D-leucinol. Yield: 41%. H NMR (500 Mz-la, CDCl 3 ): 60,93-0.96 (t, 6H4), 1284A2 (mn, lH), 1.48-1.54 (mn, 1H1), 1.63-1.66 (in, 1H1), 3.36 (s, 3H1), 3.41-3.46 (n, 2H), 382-3.83 (s, 3H), 429-4.31 (n, 111), 5.694571 (d, 1H), 624-6.27 (d, 1H), 6.87 6,89 (d, 211), 743 (a, 1H), 7.44 (s, 1H), 7.56-7.59 (d, 1H). MS (M+H, 292.1). The compound had an Es for activation of a hTIR]/hT1R3 imam receptor 20 expressed in an HEK293 cell line of 0.90 PM. 109 example 81I N41Benyl~ydosyeth -47mth M_ ahen -act-lamide H 100 Prepared in a similar manner as described i example 4 from 3-(4-methoxy 5 pheny acrylic acid and D-phenylaianinoi. MS (M+H, 312.3). The compound had an EC 9 o for activation of a hT1RI/hTIR3 amami receptor expressed in an HEK293 cell line of 1.1 gM. '4~Ethoxv-nhenvW-N41<-ethycprbpy-aervamide Prepared in a similar manner to example 4 using 34-ethoxy-phenyl-acrylic acid and 3-pentyiamine-MS (M±H, 262.2) The compound had an EC5 0 for activation of a hTiRI/hTi R3 unami receptor expressed in an HEK293 cell line of 1.35 pM. 15 pxni In3 acryictcidand 2 -lecin meh ester.an MSv (M+H, 282 2),mt~hl ete e Peres ed in aK9 simlr maner as.5 deciepnMml fo -hope-i 110 4-MethVgnt-2-enoic ac'id f ~2 3,4tetrahydr~ naphthalen] -$)-amide N. H [ Prepared in a similar manner as described in example 4 from 4-methyl-pent-2-enoit 5 acid and 1,2M3,4-tetrahydro-naphzhaen jiamine. 1S (M+H. 244.2). The compound had an EC 0 for activation of a hTIRI/hTIR3 umani receptor expressed in an H1EK293, cell line of 1 5 pM. 3-(2~Fluoro-lenytx~N~tI -prpvl~batyflraervlainkde F C' ( Prepared in a similar manner as described in example 4 from 342-fluoro-phenyi) acrylic acid and 4-heptyamine. MS (M+H, 2642) The compound had an ECs for activation of a hTIRl/hTlR3 umami receptor expressed in an FEK293 cell line of 0.16 [M pee 86 Prepared in a similar manner as described in example 4 from 3-(2-nethoxy phenyl)-acrylic acid and 4-heptylamine. MS (M+H, 276.2). 20 The compound had an EC 0 for activation of a hTIRI/hTiR3 umami receptor expressed in an HEK293 cell line of 0.90 pM.

Eatupie 87 343A4dimetho hev.~N4Jpri-hv-aerva mide 0 Oy>A N H Prepared in a similar manner as described in example 4 froa 3-(3,4..dinethoxy 5 phenyi)-acrylic acid and 4-heptylamine. MS (M+H 306.2). The compound had an EC", for activation of a hTIR hTiR3 umami receptor expressed in an HEK293 cell line of 0.97 piM, and when present at 0.3 pM enhanced the effectiveness of monosodium glutamate with an ECo ratio of 2.4. xample89 10 3.42zigkxd *yQ et ghexyl..aervlamide NN Prepared in a similar manner as described in example 4 from -(2-methoxy phenyl)-acrylic acid and 2-methybcyciohexylamine. MS (M+Hi 2742). The compound had an EC, 0 for activation of a hTlRI/hTiR3 umami receptor 15 expressed in an HEK293 cell line of 3,4 ptM Exarnen 90 N-theptan.y4Mbbenzofuraie5-carbexanmde Prepared in a similar manner to example 4 using henzofuran~5carboxylic acid and 20 heptan-4-amine Yield 41% MS (M+H, 260-2 ). The compound had an EC, 0 for activation of a hTIRlIhTiR3 umami receptor expressed in an HEK293 cell line of 1.19 jiMv 112 Examrtle 91 NdeptnkiVl 5l) dirnethtyjp njin~antj4d Prepared in a similar manner to example 4 using 5,6-Dimethylpicolinic acid S (Example 9la) and 4-heptylamine. Yield: 49% H NMR (500 MHz CDCI): 8 0,9-0.4 (t, 6H), 1-38-148 (m,4H1), 14941,61 (m, 4H), 2.32 (s, 3H), 2.52 (s, 3H), 4.11-4,13 (m, 1H) 7,52 -7.53 (dH), 7.93-7.94 (d, 1H). MS (M+H, 249.1). a. 5,6-Dimethylpicolinic acid: 5,6-dimethylpicolinonitrile (example 91b) was refluxed in concentrated HCl (15 mL) overnight. The solvent was evaporated and the solid 10 residue was co-evaporated several times with EtOM. Drying provided 453 mag of 5,6 Dimethylpicolinic acid (80%) as a white solid. MS (M+H 1521). b. 5,6-dimethylpicolinonitrile: 2,3-lutidine (13.25 nnol) was refluxed overnight with 18 ml of glacial AcOH and 6 ml of hydrogen peroxide. The solvent was evaporated and the residue was co-evaporated two times with water, basified with Na2COs and 15 extracted with chloroform. The organic layer was dried over Na 2

SO

4 and evaporated to give 1.45 g of a crystalline product. The product (615 mg, 5 mmol) was reacted with trimethylsilane carbonitrile (55 mmol) in dichloromethane (10 mL) at room temperature for 5 ain followed by addition of dimethylcarbamoyl chloride (5 mnmol) and the solution was stirred at room temperature for 3 days. The reaction mixture was treated with 10% 20 potassium carbonate (10 ml,), the organic layer was separated and the aqueous layer was extracted 2 times with dichloromethane The organic phase was died over Na2SO4 and evaporated to give 495 mg of 5,6-dimethylpicalinonitrile (75%). 1H NTMR (500 MHz,

CDCI

3 ): 2.35 (s, 3H.), 2.53 (s, 3H), 7.43-7,45 (d, 1H), 7.51-7,52 d, 1iH);"C: a 1971, 22.80, 117.87, 126.36, 130,60, 136.58, 137,66, 159.84) MS (M+H, 133.1), 25 The compound had an EC5 0 for activation of a hTIRi/hTlR3 umarm receptor expressed in an HEK293 cell line of 2.8 LM, 113 Eample 92 fithamn kNdhe tan-4 ez e N Prepared in a similar manner to example 4 using 4-diethylamino benzoic acid and 5 4-heptylamine (31% %). A H NMR (500 MHz, CD)l1: S E192(t, 6H, 717 Hz), 1.18 (t 61,J= 7,04 Hz), 1,41(m, 4H), 1.55( m, 411), 3,39 (in, 4H), 415 (m, 1H), 5.62 (m, 111), 6,64(d,21H, J=: 1026Hz ), 7.64 (d, 2H, J= 10.26 H) MS (M+H, 291). The compound had an EQ 0 for activation of a hT1RIlhTIR3 uiami receptor expressed in an HEK293 cell line of 7.6 piv Prepared in a similar manner to example 4 using 2,6-Dimethoxylisonicotinc acid and D-leucine methyl ester. 'H NMR (500 MHz, CDCb3): 6 0,92 (d, 3H1-, J=7.27 Hz), 0;93 15(d, 3.H,.==7,26 Hz), 1.41-1.58 (m, 8H), 195 (s,,3H), 4.08 (s, 3H), 4,15 (m, MH), 6.43 (d, IH, J= 8.32 Hz),T747 (mn, broad, lH), 8,41 (d, 1H, J= 8.34 Hz). MS (M+4H,,3 11). The compound had an E~j ) for activation of a hT1R1/hTIR3 -- mlni rece-ptor expressed in an HBK293 cell line of 1.91 pM.s n 114 ExaxuLIle J4 Prepared in a similar manner to example 4 sing sodium 6-methoxynicotinate 5 (example 94a) and 4-hepthylamine. Yield: 44%. MS (MH, 251). a- methyl 6-methoxynicotinate (2.097g, 1256mmol) was dissolved in dioxane (30mL), An aqueous solution ofNaOH. (LON, 25mL) was added to the solution and the mixture was stirred at room temperature ovemight. The solvent was removed under reduced pressure to provide 2.2 g of sodium 6-methoxynicotinate. 10 'The compound had an ECM for activation of a hTIR11hTlIR3 umami receptor expressed in an HEK293 cell line of 2.66 pM. Eajmyle~ tSkdimiethvInytazin 22carbhevlie ac d (Iyrovlbutyh~atide 15 Prepared in a similar manner to example 4 using 5, dimethykpyrazine-2 carboxylic acid (example 95a) and 4-heptylamine. 'H NMRI (500 MH7, CDCi,: 6 0.91 .0.94 (t, 6H), '.35-142 (m, 4H), 1.48-1-51 (m, 2H), 1.55-160 (m, 2H)> 2.572,60 (d, 6H), 41334.16 (in, 1H), 7.52-7.53 (d, 1H), 9.09 (s, 1H); MS (MiH, 250). a. 56-dimethApyrazine-2-carboxylic acid: To a solution of 2,3 20 diaminopropionic acid (10 g, 9.6 mmol) inmethanol (20mL) was added butane-2,3-dione (728 pL; 115 mmol) and NaOH (14 g; 56.6 mmol) The mixture was refluxed for 2 h and 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 dichloromethane, washed with 10% citric acid, dried over 25 MgSO 4 and filtered. The solvent was removed under reduced pressure to give 5,6 dimethyipyrazine-2-carboxylic acid as a volatile solid The compound was used as is in the next step, 115 The compound had an EC 50 for activation of a h TlRI/hTR3 umami receptor expressed in an H1EK293 cell line of L.01 M. 2-cbhro.Nshentan-4.-fk6-methvlnicathnamide 2.-tN 2'. Prepared in a similar manner to example 4 using 2-chloro-6-methynicotinic acid and 4-Heptylamine. MS (M+H, 269). The compound had an ECc. for activation of a hT1R1/hT R.3 umami receptor expressed in an HEK293 cell line of 3.9 pM 10 Examiple 97 2-vaN}heNta-4h 4 methoixvbenzamwide Prepared in a similar manner to example 4 using 2-cyano-4-methoxybenzoic acidand 4-Heptylamine, Yield: 73%. H NMIR (CD 3 OD): 30 94 (t, 6H, J 7.3 Hz), 1.38 15 (m, 411), 1.53 (n, 4H), 4,02 (s, 31),4.12 (m, 1H), 7,27 (d, 1H,,J= 9A0 Hz), 8 11 (d, 2H, J = 2.21 Hz), MS (M+H, 275) The compound had an EC5o for activation of a hTlRl/hTIR3 umami receptor expressed in an HEK293 cell line of 1,39 1 iM, and when present at I sdM enhanced the effectiveness of monosodium glutamate with an EC 5 0 ratio of 4.52. 20 Exam pkie H Prepared in a similar manner to example 4 using 4,5dinethyl-fian-2-carboxylic acid and D-leucine methyl ester. Yield: 27 %. H NMR (5001MHz, CDC 3 ); 6 0.96 (t, 6H), 116 1.66 (m, 3H). 1,96 (s, 3H), 2,26 (s, 3H), 3,75 (s, 3H), 4.78 (m, IH), 6.51 (d, 111), 6.89 (s, IH). MS (M+H, 268). The compound had an ECa5 for activation of a hTIRI/hT1R3 unami receptor expressed in an HEK293 cell line of 0.59 1 iM. N.~hin-44M)V3dnecthv1Htpvazoie-S-nexar nide C 4NN K H Prepared in a similar manner to example 4 using 1,3.dimethyl-1l-pyrazole-5 carboxylic acid and 4-heptylamine. H NMR (500 MHz, CDCl): b 0.90 (t, 6H, J 7.2 Hz) 10 L 41 (n, 4H), 1.50 (i, 4H), 2.27 (s, 3H), 3.77 (s, 3H), 4,09 (m, 1H), 6.49 (d, 1H), 6.53 (s, IH) MS (M+H, 238). The compound had an EF. for activation of a hT1RIMTIR3 umami receptor expressed in an HEK293 cell line of 7.8 uM. Example 100 N Prepared in a similar manner to example 4 using 1,3-dimethyl-iH3-pyrazole-5 carboxylic acid and 4-heptylamine. MS (M+H, 241) The compound had an EC for activation of a hTiRI/hT1R3 umami receptor 20 expressed in an HEK293 cell line of 7.2 jM.

Example 101 Nth erta4 yviuoie-4roxanide 'NN H Prepared in a similar manner to example 4 using quinoine-6-carboxylic acid and 4 5 hepthylamine. 'HNMR (500 MHz, CDC13) 5 0,96 (t, J= 7.2 Hz, 6H), 1,42-L58 (in, 6H), 162-170 (m, 2H), 4.18-4.20 (m, 111), 5.95 (d, J= 9,0 Hz, 111), 7.49 (br s, 111), 8.04 (dd, i = 85, 1.5 Hz, 11), 8.17 (d, J= 8,5 Hz, 1H), 827 (d, J= 8.2 Hz, 111), 8.30 (s, 1), 8.99 (br s, 11); MS (M IH, 271.2) The compound had an ECso for activation of a hT1RI/hTIR3 umami receptor 10 expressed in an H1EK293 cell line of3.2 p.M. Example 102 Nbheptan 4 1)uinoline-3 carbexamnide N-N. Prepared in a similar manner to example 4 using quinoline-3-carboxylic acid and 15 hepthylamine: 'H NMTR (500 M1z, CDCl3) 6 0.96 (t, J= 7.3 Hz, 6H), 1,40-L58 (m, 6H), 1 ,60-1.67 (m, 2H), 4.20-430 (m, 111), 6.01 (d, j= 8.8 Hz, 111), 7.61 (t, J 75, 1H), 7.80 (t 7.6 Hz, 111), 7.90 (d, J= 8.1 Hz, 1H), 8.15 (d, Jit 8.5 Hz, 11-1), 8.57 (d, i= 12 Hz, 11), 9.26 (br s, 1H); MS (M+H, 271.2), The compound had an ECs 5 for activation of a hT1R 1/h1 R3 umami receptor 20 expressed in an HEK293 cell line of 15,8 pM. 118 N .hetan4-yI sm wihne i earboxamide Prepared in a similar manner to example 4 using isoquinoline-l -carboxylic acid an 5 heptamine: H NMR (500 MHz, CDC) 3 0.98 (t,J= 7.05 Hz, 6H), 1.42-1.56 (in, 6H), 1.58-1.66 (m, 2H), 4.20-4,32 (m, iH), 5.83 (d, J= 9.1 Hz, 1) 7,36 (d, J 4.2, 11H), 7.60 (t,J 7.7 Hz, IH), 7.75 (t,J= 7.7 Hz, 1H), 8.11 (d, J= 8.5 Hz, IH), 8.18 (dJ= 8.4 Hz, 1H 888 (d, J= 4.9, 1H), MS(APCI, M+): 2712. The compound had an ECso for activation of a hTlRi/hTiR3 umami receptor i0 expressed in an HiEK293 cell line of 14.2 pl ExaimAt 104 4~Methoxv~.NA methosvnethy1~3-methykhbuiv) ymnethyvbbenzamide Prepared in a similar manner as described in example 71 from 4-methoxy-3-methyl 15 benzoic acid and D-leucinol. Yield: 86%, H NMR (500 MHz, CDCli); 3 0,94-0.97 (t, 6H), 1.42-1.47 (m, iH), 1.54-1.60 (n, IH), 1.64-1.68 (m, 2H), 2.24 (a, 3H), 3.37 (s, 3H), 3,46-3.48 (i, 2H), 3.87 (s, 3H), 4.35-438 (in, iH), 6,14-6,16 (d, 1.H), 682-684 (d, 1H), 7.56 (d, 1H), 7.61-7.63 (dd, IH), MS (MtIH, 280.3). The compound had an EC ,o for activation of a hTlRiihTR3 unami receptor 20 expressed in an HEK293 cell line of0.24 p.M. 119 Eamiple 105 NI444trifluoroetoxbnzvhiphene~.2earboxandde CF Prepared in a similar manner as described in example 4 from thiophene-2 5 carboxylic acid and (4-(trifluoromeihoxy)phenyl)inethanainine. MS (M+H., 303). The compound had an BC( for activation of a hTlRIMTR3 umami receptor expressed in an HEK293 cell line of 2,4 iM 10 06 Prepared in a similar manner as described in example 4 from 4-methoxy-3 methylbenzoic acid and 24(furan-2-ylmethylthio)ethanamine Yield 58%, 'H NMR (500 MHz, CDCl) 223 (s, 3H), 2.76 (t, 2H, J= 6,37 Hz), 3,59 (q, 2H, J= 12.2 Hz), 3,76 (s, 2H), 3.86 (a, 3H), 6.22 (dd, 1H, J= 3.49 Hz, J: 2-67 Hz), 6.30 (dd, 111, = 3,04 Hz, J= 15 178Hz4 646 (m, 1H,broad), 6.83 (d, 1H, J &51 Hz), 734(dd, 1H, J= L97 Hz, J=1 Hz) 7.56 (d. 1H, J = 172 Hz), 7.61(dd, 1H, J= 853 Hz, J= 2.25 Hz). MS (M+H, 306). The compound had an ECo for activation of a hTIRI/hT1R3 inami receptor expressed in an HEK293 cell line of 5.6 pM. Exampe 107 20 Thiophene-I-carboxylic acid 4trihtormethnxv-benzvgamide H F F Prepared in a similar nanmer to example 4 using thiophene-3-carboxylic acid and 4 trifluoromethoxy-berzylamine MS(M+H, 302.0) The compound had an ECsO for activation of a hTIR/hTIR3 umami receptor 25 expressed in an HEK293 cell line of 2.2 ptM, and when present at 3 p.M enhanced the effectiveness of monosodium glutamate with an ECo ratio of 8.5. 120 Example 108 3~Metvhtthpioene~2~carboxe acid 2 4 imethbenzylamide Prepared in a similar manner to example 4 using 3-methyi-thiphene-2-carboxylic 5 acid and 2,4-diniethoxy-benzylanine. MS (M+H, 292,2). The compound had an ECs 0 for activation of a hTiR/hTI R3 umami receptor expressed in an HEK293 cell line of 56 pM, and when present at 3 pM enhanced the effectiveness of monosodium glutamate with an EC 3 0 ratio of 5,8. Fxaimple 109 02 5-Pyrid2-v-hhihene2-earboxv ie acid 24ydimethoxwzviade Prepared in a similar manner to example 4 using 5-pyridin-2-yl-thiophene-2 carboxylic acid and 2,4-dimetoxy-benzylamine, MS (M 355.2). The compound had an ECO fr activation of a hTiRl/hTIR3 umami receptor 15 expressed in an HEK293 cell line of 286 pM and when present at 3 pM enhanced the effectiveness of monosodium gitamate with an ECO ratio of 8. oo'V 20 Prepared in a similar manner to example 4 using 2-methy--2H-pyrazole-3 carboxylic acidand 2,4-dimethoxy-benzylatnine, MS (M+H, 276.2), The compound had an ECso for activation of a hTIRiAMT1R3 unami receptor expressed in an HEK293 cell line of 6 ptM, and when present at 3 sM enhanced the effectiveness of monosodium glutamate with an ECs5 ratio of 7.9, 121 and 1-methiyl-3-phenyl-propylamine. MS (M+H, 284.2) The compound had an ECQ for activation of a hTlR1 nTi R3 wnami receptor expressed in an HBK2193 cell Ine of 2.7 pM, and when present at.03 pM enhanced the effectiveness of monosodium glutamate with. an EC50 ratio of 7. Emxanme 112 NcN Prepared in a similar mamner to example 4 using beno[i3dioxie-5-carboxyli c acid 2(4-ethyl-phenyl)-ethylamine. MS (M+H, 2982) The compound had an EC 5 o for activation of a h T1RI/hTIR3 umami receptor 15 expressed in an HMK293 cell line of 86 pM,a effectivenessofmoomae an at benzamide N ' Prepared in a similar manner to e example 4 using 4bethoxmeybnzoic acid 20 and -phenyu-tylamine h MS (Mn+M, 298(2). The compound had an EC for activation of a hTiRI/hTiR3 manai receptor expressed in an HEK293 cell line of 26 5tM. 1:2:2 Enple 114 4-Medhoxv-3--methy 4Njy idin butvikbenzamide. H Prepared in a similar manner to example 4 using 4-inethoxy-3-methyl-benzoic acid 5 and 1-pridin-2-yl-butylamine. H NMR (500 MHz, CDCI): 5 0.91-0.92 (t, 3H), 1.25-13 (m, 2H, 185-1.9 (m, 211), 3.86 (s, 311), 525-53 (m, 111), 6.80-6.82 (d, 111), 7.2-7.3 (m, 2H), 7.42-7.44 (d, 1H),6 76-77 (m, 3H), 8,6 (d, 1H). MS (M-H, 2991). 'The compound had an EC 50 for activation of at TIR i/hTR:3 umami receptor expressed in an HEK293 cell line of 1.54 p M. 10 E XaMPe 115 l Benzos 1b3hidiox-S-carhoxvice acid 11 4.pethoxviihenvkbutvbamaide Prepared in a similar manner to example 4 using benzo[1,3]dioxole-5- carboxylic acid and 1-(4-miethoxy-pbenyl)-butyiamine H NMR (500 MHz, CDCi): 0.93-0.95 (t, 15 3H), 1 30-139 (in, 2H), 1.80-1.90 (m, 2H), 3,79 (s, 3H), 5.08-5.09 (dd, 1H) 6.00 (s, 2H), 6,10-612 (d, 1H), 6.79-6,80 (d, 1H), 6.87(s, 1H), 6,88 (s, 1), 7,25-7,28 (in, 4H), MS (M-H, 328 1). The compound had an EC 0 for activation of a hTIRI/hTIR3 umami receptor expressed in an HEK293 cell line of 4.12 pM. 4t-nk316 4-Ethexo%4'4i4-mteaphenv)hutv11-3ptbh-enzamnide 123 Prepared in a similar manner to example 4 using 4-ethoxy-3-methylbenzoic acid and 1(4-methoxy-phenyl)-butylamine 'H NMR (500 MHz2 CDCi): & 0.93-0.96 (t, 3H), 1.31-1441 (m, 211), 1.41~1.45 (t, 3H), 1.82192 (m, 2H), 2.28 (s, 3H), 3.79 (s, 3H), 4.04 4.08 (f 2H), 5,10-512 (d, 111), 6.126.14 (d, 11H, 6.78-6,80 (d, 11), 6.87 (s, 1), 6.88 (s; 11), 726-7.29 (m, 211), 7.52-7.53 (d, 111), 7.57-7,59 (d, 1H), MS (M+11, 342.1), The compound had an ECsr for activation of a hTlRihTIR3 umami receptor expressed in an HEK293 cell line of 3,9 1M ExampeU 4..Methexv-NAIRM(4-rnethx-phenvikthy~h3mhvlezamnide CH Prepared in a similar manner to example 4 using 4-miethoxy-3- methyvl,-enzoic acid and 1-(R)-(4-methoxy-pheniyl)-ethylamiine.,MS (M4H, 300 1). The compound had an. BO for activation of a h T1RI/hTR3 umami receptor expressed in an HEK293 cell line of 28 iM. 14 RenzA13d oe-croylic acidI in danj -tamid 0 Y 00 r Prepared in a similar manner to example 4 using benzo[1,3dio.xole-l-carboxylic acid and indan-yl-am n. MS (M+H, 2820) 20 The compound had an EC 5 o for activation of a hTiRlihT1R3 umami receptor expressed in an H-EK293 cell line of 1,2 .8M, ad when present at 03 M enhanced the effectiveness ofirmonosodium glutamate with an ECs5Gratio) of 5,33, Example 119 4Rmeth~i~ox~eActh y pet acin4 -lenaide 124 Prepared in a similar manner as described in example 4 from 4-methoxy-3 methylbenzoic acid and pentan3-amine. MS (MN +.H, 236) The compound had an EQ 0 o for activation of a hT.Rl/TR3 umami receptor expressed in an HEK293 cell line of 0.4 prM, Exampl~e 12$) 3~meth$NApodetvifaran2 earbxamide 12 Prepared in a similar manner as described in example 4 from 3-methylfran-2 carboxylic acid and 2-p-tolylethanamine MS (M+H, 244). 10 The compound had an EQeo for activation of a hTlRi/hTlR3 umami receptor expressed in an H.K293 cell line of 6 gxM, and when present at 1 p.M enhanced the effectiveness of monosodium glutamate with an ECo ratio of 3.3. N4244imthxvbenzv5 1)2 (111 yrr&l 1vbewamide ... ........... N H Prepared in a similar manner to example 4 using 1-2-lHpyro-1 yl)phenyl)ethanone and 2,4-drnethoxy-benjylamine. MS (M-H, 337.2) The compound had an EC.

0 for activation of a hTlRI/hTlR3 umami receptor expressed in an HEK293 cell line of 1L66 F.M, and when present at I pM enhanced the 20 effectiveness of monosodium glutamate with an EC 0 ratio of I 1 Additional amidee" compounds that were synthesized and experimentally tested and found to have a relatively high level of efflectiveness as an activator of a hTlR1/hTlR umami receptor expressed in an HEK293 cell line. The results of that testing are shown below in Table A, 125 Table A - Upnwni Amid -s COMPOUn3d Umam ECS* ratio (W5, Al 0,22 2.74 3 t6 Dich k3o~N 44exhn) A2 - 9 ' 0 A3 ~ \ ~ 6,14 0.03 amio]4 ethyl eftnor ai mdhyl ~ h-y estr ______ -'.............4 --------------- 'A 03 ---------------- ------ ------- 2..... --------------- ...... 4... (netU"orttioie acd nwh~ I .26r Table A UmpiAie:-r os No. .X......(63W A8 046

J

Q 7 AI ------------- A ~~ It .0 50 metyl 4bezofraz5 -choxamido) ............ ____ .- s t ..... ... : .... ... 127 Table A - Umami Amides Compound Uman sratm(v@ N i Comopoud 1 UT { -' s4) M%) hsA.D A13 144 6 e-3thoxy-N rpentan yl~ )benzofluran~ 2cavboxamiide A 14 1 j14 2 [(5-M'ethoxy benz ofran 2 cambony amio 4 -methvsulfanyl 3uyrc ch methl ester niethy! 2-( mnethoxjbenzofbran 2-carboxamido~. (mcethyiltno)butanoa e A15 114 (IR2R)-ethyl 2/5 methoxybe3zothran-2 c atboxa Nid~o)c2~eatpenyat N-- --------- AIS A 187L 5 mthoxy N (- me hyletan-4 128 ck)~ nm Mso M - ~I - --- ,------- P bca-2cmxa i& A24 / i-3.7 N (ncta N- 3 vmebenzoep ra -4 .. ... .... .... ... .... .... ... .... .... ... .... .... .. t. >-29 Table A - Uaami Amides compournd Tmui EC.,rti (vs. * No. ECi (t'01 MG),tM . ....... .... - A acid estt A26 1.

-- -- -- ----- ---- ----- ---- 1- --- ---- -- A274 Ivehy2[(6n1y ---------- 6----------------X IO ---------------------------------------- /v ----------- ---------------- ------------------------- 'v2v 12,. 644 '4 '4'4 130 .. . ......... .. T --- A ---- Umai i Amides CompoundUmami A31 Q62 ------------------- .... p.' 4--------- .................... 4,5 - mcMN (2 -m K 7 1 lheyl A34 -A, A35 QK. ------------------ ------ ---- ------ ------ -a1 A ------------------- Compound Ummii tc.-ao * a No. ____ CmpudELD~iMG (R methyl } -n~ A3, C2 K (It) rffiv4 mawi (qin cid ca-oadcotao A40Z el -- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - TA~~~fiC,- ra-tra&, SCom-ponnd '' un /oton W"' A41 2.l' ..... ..... Pf-I ----- N- ------- ------ A45 A43 R)-ek'y 13 Tsablt A - L t rm iAmides - -------- -------- ---------- -- --- --- --------- -------- N"m l p w i - e r { \ > tl C ) I ~ 4 A48651 ,7 N-' -ph211$n--y P>vz: -j A49 7,13 40 ni w - Lmlfac.,i.; vtl'yjC,,e N \~~ 3,N 4 Table A - TUmanbf Amides, C ompound Umnami E5C ratio (vs N ~ ~~~ /o~ud-IG ASI 1.58 I ~ A521.6 ..... A ....... N..N.. At~ 5 1.a65 AAA4 A 55 A01A2. A-- -- --- --- -- ......... ... .Y ... 1... 13 _______ _____Table A - Timi A~e Compound..................Umami 1krati kIvs. * No. _____ awmd ~ o t} ~ S) (um) A56 A \ 'j01 AAS? Af- 02 ------ -- c~v 4~.nxy ( ....................- ----- -------------------- --------- A 59 0-2 10. V 0.2 t (R-mtyl2-4 /--------I--------- ....... - 3t~cS'X- -rxtby-N36- Table A -Uniamii Amides I~ compound ...........Umam --~ -i -N---- ---- No- ~ ~ Compound E(>(&j MG A-62 'N -d ..... ... ........dietme y-ehyl- p3a- A65 J \\-in -137 Table A- IUma-,i A....... Compound .. am ......... -i ------------ A 66 02 --------------- ---- -------- -- N (24i dire 10be'y) 5( I yi2i?;oncvtn)mA -vx ________ ___________ _______ nRmti : .4mt yimdob ---- --- --- --- --- --- --- j-- ------ -- 0 3 2 -- ----- ------ ----- -- ----------- -- -- -- -- -- -- -- - Table A -Uniamni Amides Compound Umami E~ aov No. 0,34 4-etnoxy -3rnea'7yiN r(- rnadaylhextn 3'i CR) wnhl2 -mrnthoxy-, A74 N3 4.980 N fiunm N (heptan-4-14 1394 _______ _____ abke A - 1Jma -,3i Amidi ~ ---------- --- -- --- -- --- - --- -- -- --- -- --- -- -- - -- ------ .. ,,,..-- '1m - t ------- Jr ~m tovN Ah 7S4&nyhnasdJ 0.46 102 03 A 1) 0.4, 040 Table A -U mami Amides Compound mami Ecs ratio (vS No. Cououd C_____ (M ~ .MSG) (u (R)-me~thyi 4 methy 2~(4 pmpsRe AeImnSCenmo A K2.N ~ > A>wts- 4) H AS4 0..3 N heptan 4 yb 2 hydrzx-3 A85 03 fR)-meth;y12-(3,5 dimethylbeazauk) 4 A86 -- .-- 53 methyl 244met-zhoxy-3~ ethytiopbtan1te 141- Tabk, A - Umami Amides ~Comnpound tX~~E~rto(s w4 -----\ A90. 1. 4 Compound Tmamn Ec, ratio (Ys. No, A92 Q' ~ 65 4 Ne e~b edlea N OH '2 'S A93 5.7 A.94 0.7,2 R)-4 /mt N2 methxy -1 A93 74 (Re)-methyl 2-(4-.methoxy3, 3 dimethylbenzamida)-4 143 Tble A - ITmarni Amides csmpouod No - Com ound t 0,76 .. ....... .... ... ...... --- -- -- --- -- -- -- --- -- -- -- --- -- -- znetbox phe..........3 A 98 A9- 0659 4-xwthox-N ( mrhoxycow 4-4l ~CopondTable A - Umami An-ides Copun EtI ratio (vs:, c~ NoNi ANN -(I ~N- -x -> -N Nf - ----- AiN 1,6 7,6 ---------- o y ~ ( 1 A1036 (lSNR-et 2-3cfm4 ---------- -_ __- ----------- -------------- -------- ------------------------------- ------------------------------- -- - - a l r~ i rit ___ Compound uda rato (Vs AIN NN." A104 I137 i 4 phenyl c iIdexli acd 4A A105 138 2"9 N' N 3etaykya~ A106 39 4,01 0 Mt(2 4 meThvdhmnam1tiden A I06 - i 1 94 103 Numerous amide compounds of Formula (1) that fall within the subgenus of oxalamide compounds described elscwheie herein wer also synthesized and experimentally tested for effectiveness as activator of a hTiRI/hTIR3 umami receptor 5 expressed in an HEK293 cell line General procedures A for the preinradeon of an oxalamide Synthesis of 1N(241thax Nbenzv N ~42wvridin24ybethfloxaalmidet N) A H 10 2-Methoxybenzyl amine (5 mmol) was mixed with triethylamine (2 equiv) in anhvydrous Dioxane. Ethyl oxalyl chloride (1 equiv.) was added and the mixture was shake 146 at room temperature for 0.5-2 hours, Then 2-(2-pyridinyl)ethyl amine (I 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.~he organic layer was dried by sodium sulfate and solvent was evaporated to give the crude product, which was 5 purified by flash column chromatography to afford the title compound: yield 70%, np 118 119 'C; m/e=' 314 [M+1-]; 1H NMRf (CD0l): 3.02 (t, 2H), 3.76 (dt, 2H), 3.86 (s, 3H), 4.47 (d, 211), 6;80-6,90 (m, 211), 7.14-7.18 (m, 2H), 7.20 -7.30 (m, 2H), 7.55-7 62 (m, 11), 775-7.83 (mi 11),8 05-812 (m, 11), 8.55-863 (m, 1H) The compound had an EC 50 for activation of a hTIR/hT1R 3 umani receptor 10 expressed in an HEK293 cell line of034 pMN4, and when present at 0.3 gM enhanced the effectiveness ofmonosodium glutamate with an EC 50 ratio of 18.85. Example 123 N42.4-Dmethoxv-benzyU-N M-2+vrdin-2-yethyh-onandmde N.P 9 0 ~~N HNN C6 ~0 15 Prepared in a similar manner to example 122 using 2,4-dimethoxybenzyl amine ethyl oxalyl chloride and 2-(2-pyridinyl)ethyi amine. Yield 72%, nip 123-124 "C; in/e 344 [Mi1] H NMR (CDCq): 8 3.02 Ct 2H); 3.73 (dd, 211); 3.78 (s, 3H); 3 82 (s, 3H) 4.38 (d, 2H) 6.40 (dd, 111); 6.44 (d, 1H); 7.14 (n, 3H); 7.59 (m, 1H); 7,82 (t, lI); 8.11 (t 1H); 8.56 (d, 1H); '3C NiR: 6 36.9, 38.9, 39.4, 55.6, 55.6, 98.8, 104,1, 117.8, 121,9 20 123.5, 130.7, 136.8, 149,6, 158.8, 158.8, 159.6, 1601, 16L0. The compound had an EC 5 0 for activation of a hTIR/blT1R3 umanmi receptor expressed in an HEK293 cell line off0.09 gM, and when present at 0,3 gMI enhanced the effectiveness of monosodium glutamate with an ECf 0 ratio of 6.51. ExaMle 124 25 t D-oxalamide 0 H N S ~' N Prepared in a similar manner to example 122 using (3-methyl-thiophen-2-y!) methylamine, ethyl oxalyl chloride and 2-(2-pyridinyl)ethyl amine. Yield 40%; mp. 122 147 124 'C; m/e 304 [M I]; H NMR (DMSO-): 5 2,19 (s, 3H), 2.92-2.95 (t, 2H), 3.48. 3,52 (dd 2H), 437-438 (d, 2H), 6.79-680 (d, 1,H), 7,20-7.27 (in, 3H), 7,67-7.71 (dt, 1K) The compound had an EC50c, for activation of a hT1R/hTIR3 umani receptor 5 expressed in an HEK293 cell line of 0.37 pfvt Exapile 125 General Procedure B for the Snthesis of an Oxalanide N44-u.thlhbenyi DN. 2~yridt4ethvaalamide oH r N N N H 10 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)ethyl amine (1 equiv.) was added and the suspension wa: 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%; mp. 152~154 'C; m/e = 29, 15 [M+1]H 1 K NMR (CDCI,): 3 2 33 (s, 3H), 3.10 (t, 2H), 3.75 (di, 2H), 4A3 (d, 2H), 7,10 7015 (m, 4H), 7.18-7.22 (mr, 2H), 7.65-773 (m, 2K), 812 (h, 1H), 8,60 (d, 1H) The compound had an BC 50 for activation of a hTIRi/hTR3 umami receptor expressed in anHEK293 cell line of 0.41 piM Exanle 126 20 7 NM eth y 4: mietih px y b enz-Av4 -N'2~ yr i in-2 -vI-e th V -Oxxa IImidtIe 03 0 Prepared in a similar manner to example 122 using 2-methyl-4-iethoxybenzy amine, ethyl oxalyl chloride and 2-(2-pyridinyl)ethyl amine. Yield 51%; m.p. 133-134 *C m/e = 328 [M+l]; 'H NMR (CDClb) 6 2.29 (s, 3H); 3,04 (t, 2H); 374-3,77 (m, 2H); 3.7 25 (s, 3K); 4.40 (d, 2H); 6.69-6.73 (m, 2K); 7.13-718 (n, 3H); 7,51 (t, 1H); 7.60-7.63 (Ir 1K); 8.17 (t, 1K); 8,58 (d, 1H). The compound hadanECfor activation of a hT1Ri/hTIR3 umami receptor expressed in an HEK293 cell line of 011 p.M 148 Exank 127 H Prepared in a similar manner to example 125 using 2,4-dimethoxybenzyl amine 5 ethyl oxalyl chloride and 3-(2-pyridinyl)propyl amine. Yield 60%; m/e = 358 [M+1]; F NMR (CDCI4): 8 199-2,04 (in, 2H); 2.84 (t, 2H); 3.36 (dd, 211); 3,79 (s, 3); 182 (s, 3H 460 (d, 2H); 6,41-6.45 (m, 2H); 7,i0 7.17 (m, 311); 7.57-7,60 (m, 1H); 7.81 (t, 111); 7.8 (t, 1H); 8,54 (d, IH) The compound had an EQm for activation of a hTIRI/hTlR3 unami receptor 10 expressed in an HEK293 cell line of 1.84 iM. EhinniLe 128 N-(4-ethOxvhenzy -N-2-ridin-2-v-jethyDnoxalamIde H Ns, Prepared in a similar manner to example 125 using 4-methoxybenzyl amine, ethy 15 oxalyl chloride and 2-(2-pyridinyi)ethyl amine, Yield 50%; m.p, 156-158 -C; 'H NMR 3.05 (t 3H), 3,72-3.77 (m, 2H), 3.79 (s, 3H), 4.40 (d, 211), 6.86 (d, 2H), 7,16-7.22 (m, 4H) 7,65-769 (in, 3H), 8 15 (b, 1H), 8.62 (d, 111). The compound had an ECSO for activation of a hTiRl/h TVR3 umani receptor expressed in an HEK293 cell line of 035 M, Exam le 129 N~42,4flhnethnxv~benzv1i'' 2(3 methpiyri n2)Lhvexalamide N N H 0~0 Prepared in a similar manner to example 125 using 2,4 dimethoxybenzyl nine, ethyl oxaiyi chloride and 2-(3-methylpyridin-2-y1)ethyl amine (example 129a). Yield 10%; 25 m/e = 358 [M+11}; 1H NMR (CDCI,: 5 2.28 (s, 31), 3.01 (t, 2H), 3.75-3.82 (m, 2H), 3,79 149 (s, 3H), 3;82 (s, 3.H), 4.39 (d, 2H), 6.41 (dd, 1H), 6-44 (d, 1.H) 7,10 (t, 1H), 7.15 (d, II), 7.45 (d, 111), 7.81 (bs, 1H), 8.28 (bs, 1H), 8.40 (d, 1H). a. 2-(3-Methyipyridin-2-yl)ethyl amine: To a solution of 2-(3-methylpyridine-2 yflacetonitrile (example 129b) (95 mg, 0,72 mmol) in THF (05 mL) was added 1 M 5 BHryTHF (2,2 mL, 2.2 mmol) dropwise at room temperature. The resulting mixture was heated in a microwave reactor at 130 'C for 7 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 'C for 4 min, The reaction mixture was washed with Et 2 O (3x3 mL), then cooled to 0 "C and 10 N aqueous NaOH (0.8 m) was added. The aqueous solution was 10 saturated with K 2 CO . The product was extracted with CHCI 3 (6x5 mL. The organic extracts were dried (1:1 K 2 COJNa 2 SO4), filtered. concentrated in vacuo to afford an oil (8: ng, 86%), which was used directly in Example 8. mle= 137 fM+1]. b. 2-(3~Methylpyridne2~y1)auetonitrile: To a solution ofn-BuLi (2.5 N in hexanes, 7.92 mL, 19.8 mmol) at -78 *C under N 2 was added dry THF (75 mL), followed 15 immediately by a solution ofdryMeCN (1 .15 mL, 21.78 mmol) in anhydrous THE (30 mL) over a 3unin period. The resulting reaction mixture was stirred continuously at -78 for 1 h. Then 2-bromo-3-methylpyridine (516 mg, 3 mmol) was added. The resulting reaction mixture was stirred at -78 'C for I h, then warmed to room temperature, and quenched with water. The organic solvent was evaporated in vacuo, dissolved in CH2C12 20 The organic layer was washed with brine, dried (MgSO4 )concentrated, purified via column chromatography (20% EtOAc in hexanes) to afford the product quantitatively: m/e 133 [-M+1]. The compound had an ECQ for activation of a hTIRi/hT1R3 umami receptor expressed in an HEK293 cell line of 1.64 pM 25 Example 130 N4234fDnethylduran lniethyN (42-pvridi-2~vi-eth-oxalamide 0 Prepared in a simihr manner to example 122 using 2,5 dirnethyi-furan-3 yimethylamine, ethyl oxalyl chloride and 2-(2-pyridinyl)ethyl amine. Yield 51%; m~p. 112 30 115 *C; m/e= 302 [M4+1; 11H NMIR(DMSO-dd.: 5 2.14 (s, 3H), 2.18 (s, 3H), 2.91-2.94 (t, 150 21) 3.47-3,51 (dd, 2H), 3.98-3,99 (d, 2H), 5-89 (s, 11), 7.20-7.25 (n, 2H), 7.68-771 (dt, 1H), 8,48-849 (d, 1H), 881-8.84 (t, 1H), 8.97-9,00 (t 1). The compound had an EC 50 for activation of a hTIRI/hTIR3 unlamni receptor expressed in an HEK293 cell line of 101 gM. Ni 3Dim thyld-Wvre4-2-v1methvI )N t 2~pyridi-vethyfboxalanmke Prepared in a similar manner to example 122 using i,5~dimethyliKHpxoi-2 ylmethyl amine, ethyl oxalyl chloride and 2-(2-pyridinyl)ethyl amine. Yield 25%; mp. 10 147-149 'C; n/e = 301 [M+1}; H NMR (DMS t 6 ): 6 2.11 (s, 3H), 292-295 (t, 2H) 3.3 (s, 3H), 3.48-3.52 (q, 2H), 4s24-4.25 (d, 2H), 5.64-5.65 (d, 1H), 5.79-5.65 (d, 1H), 7.20 725 (in, 2H), 7.68-771 (dt, il), 8.48-8949 (d, 1H), 8 82-886 (in, 2H). The compound had an ECs fcr activation of a hTiRI/hTIR3 umami receptor expressed in an HEK293 cell line of 2.3 pM. 5 0 N N' H Prepared in a similar manner to example 125 using (2-methoxy-4 methylphenyl)methanamine (example 132a), ethyl oxalyl chloride, and 2-(2-pyridinyl)eth) 20 amine, yield 20%. m.p: 128-131 C; mie = 328 [M-+1; IH NMR( CDC): 2.33 (s, 3H); 3,02 (t, 2H); 3.73 (m, 2); 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, IH); 8.56 (d, 1H). a. (2-methoxy-4-methylpheny)inmethanamine: To a solution of2-methoxy-4 methylbenzamide (example 132b) (200 mg, 1.21 inmol ) in THF (0.5 mL) was added I M 25 BHrT HF(2.4 ml, 2.42 mmol) slowly at room temperature. The resulting mixture was heated in a microwave reactor at 130 4C for 7 min. Then 6 N aqueous HKU (1 nL) was added dropwise at room temperature. The resulting mixture was heated in a microwave reactor at 120 *C for 4 min. The reaction mixture was washed with EtO (3x3 mL), then cooled to 0 *C and 10 N aqueous NaOH (0.8 mL) was added. The aqueous solution was 151 saturated with K 2 CO. The product was extracted with CHC3 (6x5 rL), The organic extracts were dried (1:1 K 2 CO39NaSO), filtered, concentrated in vacuo to afthrd 180 mg of (2-methoxy-4- methylphenyl)methanamine which was used directly in Example 1H. b, 2-methoxy4-methylbenzanide: 2-methoxv-4~methylbenzoic acid (500 mg, 5 3.01 mol) was mixed with 1-ethyl-3-(3-dimethlainopropyl)carbodiimide hydrochloride (577 mg, 101 mmol) and 1 -hydroxybenzotriazole (407 mg, 3.01 mmol ) in 25 ml of dichlioromethane at rt. and stirred for 5 min. 2M ammonia solution in methanol (4,5 ml, 9.03 mmol ) was added, the reaction mixture was stirred at rt for about 5 in. then it was diluted with dichloromethane, washed with IN HC, sat. NaHCO 3 , water and brine, 10 dried over MgSO 4 . filtered and evaporated to give 440 mg of 2-methoxy-4 methylbenzamide, yield 88%. The compound had an ECO for activation of a hTlRUh.TlR3 umami receptor expressed in an HEK293 cell line of 0.4 uM 15 NA4-dim thrben N 2( yridin-,vnethy)x-olamide Prepared in a similar manner to example 125 using (2,4 dimethylphenyl)methanamine (example 133a), ethyl oxalyl chloride, and 2-(2 pyridinyl)ethyl amine, yield 60%; m.p, 148449 "C; m/c= 312 [MU1);H MR (CDCls): 20 2,28 (s, 311); 2.30 (s, 311); 3.05 (t, 2H); 3,76 (dd, 211); 4.43 (d, 211); 6.99 (in, 2H); 7,11 (d, 111); 7.17 (m,211); 7.54 (s, 1H); 7-.62 (in, 11); 8.17 (s, 111); 8.58 (d, 11). a. (2,4-Dimethylphenyl)methanamine: Lithium aluminum hydride lM 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-dimethylbenzonitrile (LO g, 7.6 mimol ) in 15 ml of anhydrous ether was 25 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 *C, anhydrous sodium sulfate was added, and imul 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 MgSO 4 , filtered and evaporated to give 1.03 g of pure (2,4-dimethylphenyl)methanamine 30 in quantitative yield without purification. The compound had an EC 0 for activation of a hTiRl/hTiR3 umami receptor expressed in an HEK293 cell line of 0.07 uM, 152 Example 134 N44toxv2emethxybenzylU N'2 f'(ptidh2-v thynxaamide N) C Prepared in a similar manner to example 125 using (4-ethoxy-2 5 inethoxyphenyl)mnethanaiine (example 134a), ethyl oxalyl chloride, and 2-(2 pyridinyl)ethyl amine; yield 10% mp, 117-418 C; n/e = 358 [M+l]; 'HNIR (CDCI3); L 40 (t, 3H); 3.03 (t, 211); 3.74 (dd, 2H); 332 (s, 3H); 4.01 (dd, 2H); 4.39 (d, 2H); 6.39 (d, 1H); 6.44 (s, MH); 7.15 (m, 3H), 7.61 (m, 1N); 7,81 (s, 1H); 8310 (s, 1H); 8.56 (d, 1H). a. (4-ethoxy2methoxypheny)methanamine: To a solution of 4-ethoxy-2 10 methoxybenzaldehyde (example 134b) (330 mg, 4.88 mmol) in 50 mi of anhydrous methanol, were added ammonium acetate (75 g, 97.60 mmol) and sodium cyanoborohydride (613 mg, 9.76 mmol). The reaction mixture was stirred at r.t for about hr. then it was concentrated on a rotary evaporator, the residue was diluted with water and basined with 15 % aqueous NaOH, extracted with ethyl acetate, washed with water and 15 brine, dried over MgSO 4 , filtered and the solvent was evaporated, the residue was column chromiatographed on silica gel (DCVTeOH 9:1) to afford 150 ing of product; yield 17 % (The method was not optmized). b. 4-Ethoxv-.2-mnethoxybenzaldehyde: To a solution of 4-hydroxy-2 methoxvbenzaldehyde (1 0 g, 6.57 mmol ) in 10 ml of acetone, was added potassium 20 carbonate (0.91 g, 6.57 minol ) and iodoethane (1.6 nil, 19.71 mnol ), ihe reaction mixture was stirred at rt over night Acetone was removed on a rotary evaporator; the residue was diluted with water and ethyl acetate; extracted with ethyl acetate, washed with brine, dried over MgSO 4 , filtered and evaporated to give crude product, which was column chromatographed on silica gel (ethyl acetate/hexane = 1:4) to give 943 mg of product; yiel 25 80%. The compound had an EC 3 for activation of a h 11R1/hTIKR3 unami receptor expressed in an HEK293 cell line of 0. 1 uM 153 ExaiMde 135 N44hexv.3-methiv h. 2 pidh4 etbhi Wxalandde N Prepared in a similar manner to example 125 using (4-methoxly-3methylphenyl) 5 methanamine (example 135a), ethyl oxalyl chloride, and 2(2-pyridinvethyl amine yield 12%; m p. 145-147 'C; m/e= 328 [M+1]; 'H NMR (CDC'4) 2.19 (s, 3H); 3-04 (t, 2H); 336 (dd,2H); 3.81 (s, 3H); 4.37 (d, 2H); 676 (d, 1H); 7,06 (m, 2H); 7.16 (m, 21H); 7 61 (m, 1H); 7.66 (s, 1H); 3 18 (s, 11H); 8.58 (d, 1H), a. 4-Methoxy3-methylphenyl)methanamine: Prepared in a similar manner to 70 example 134a using 4-methoxy-3-methylbenzaldehyde, arinnonium acetate, and sodium cyanoborohydride in MeOH; yield 22% (110 mg) The compound had an ECsc for activation o f a hTlR1/hT11R3 umani receptor, expressed in an HEK293 cell line of 1,04 uM. Elmunple 136 u N~(ehloabenv&NM~(pidia 2 yhethlUonaide: N Prepared in a similar manner to example 125 using (2-chlorophenyl)methanmnine ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 45%; m/e= 31.8 [M+1] The compound had an EQCs for activation of a hTIRI hTIR3 umami receptor 20 expressed in an HEK293 cell line of 0.01 uM 1'Lx.pun 137 N4(2J dibydrobenscdbi tl',4ldioxin.'v hv1b)DNb24pvrin~2-yniethv1) oxalamids o 0 H 0" ~ ~ kI _ " 'I C MA -" 'N.' ) Prepared in a similar manner to example 122 using (2,3-dihydrobenzo[hjl[,4j 25 dioxin-5-yl)methanamine, ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 50%; m/e = 342 [M+ 1] The compound had an EC 0 for activation o f1a hT1R1/hT1R3 umann receptor expressed in an IHiEK293 cell lIe of 03 ul. 154 Example 138 Neenjdl a3dioxoV-vflei N (2-fwyriin2:lethvjoajhd H r N N~~'' N, Prepared in a similar manner to example 125 using benzo[d}[l,3jdioxol-5 5 ymethanamine, ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyi amine; yield 35%; n/e 322 [M+1-. The compound had an EC 5 o fr activation of a hi TIP] JhTlR 3 umami receptor expressed in an HEK293 cell line of 0 5 uM. Example 139 10 N44-EthylmbewvN2{vridin-2vlDehvoxalanade N N H r Prepared in a similar manner to example 125 using 4-ethylbenzylamine, ethy oxalyl chloride, and 2-(2-pyridinyi)ethyi amine; yield 38%; r/e= 312 [M+11. The compound had an E;o for activation of a hTIRI/hT1R3 innami receptor 15 expressed in an .HEK293 cell line of 0."9 uM Prepared in a similar manner to example 125 using bnoaa--hehlmn 20 ethyl oxalyl chloride, and 2-(2-pyxidinyl)ethy1 amine; yield 64%; n/e= 324 [M+1]. The compound had an ECIso for activation of a hTlR1/hT1R3 umami receptor expressed ina an HEK293 cell line of 1 78 uM, Examiple 141 N-4ehov abnyltnetvievN ~24pvvrid-2-~~iu-2tthvfloxhanaide ,C o C 25, 15 Prepared in a similar manner to example 122 using 4~methoxycarbonyipheny methylamine, ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 52%; Ve = 34: [M+11. The compound had anECso for activation of a h TlRl/hTl R3 umami receptor 5 expressed in an HEK293 cell line of 3,63 uM. ~ N .Y N -N N Prepared in a similar manner to example 122 using 2-carbamoylphen 10 methylamine, ethyl oxalyl chloride, and 2-(2-pyridinyl)ethyl amine; yield 48%; rn/e = 34. The compound had an ECV for activation of a hT1RI/hTIR3 umami receptor expressed in an HEK293 cell line of 8.5 uM. Euanple 143 15 da24 mjeQpr g j~r2g&fjgage Prepared in a similar manner to example 125 using 2,4-dimethoxybenzylamine, ethyl oxalyl chloride, and 1-(pyridin-2-yl)propan-2-yi amine (example 143a); yield 34%; a/e = 357 [M+1]. 20 a. 1-(Pyridin-2-ylpropan2-yi amine: Prepared in a similar manner to example 129a using 2-(pyridine-2-yl)propanenitrile (example 143b); crude product was used directly in example 143; yield 53%; dVe = 137 [M+I]. b. 2-(pyridine-2-yi)propanenittile: 5 mmol of 2-(pyridine-2-yl)acetonitile was dissolved in 8 ml anhydrous THF and placed in an ice bath, Potassium t-butoxide (1 equiv 25 was added and reaction was stired for 30 minutes Methyl iodide (1 equiv) was dissolved in 5 mL anhydrous TIF and added slowly over 30 minutes Reaction was stirred overnight at room temperature. Solvent was evaporated and crude rnixture was dissolved in ethyl 156 acetate and washed with water. Ethyl acetate layer was evaporated and product was purified by preparative TLC (30% Ethyl acetate/Hexane); yield 71%; de = 133 [M+i1]. The compound had an EC for activation of a h T1R1/hT1R3 umami receptor expressed in an HEK293 cell Ine of 0.4 uMf 5 Examtple 144 N 4~,4Di meth(xsbezvyfN L(2 ridi-.2-y~jropv ax aIatndde o o N N 0 Prepared in a similar manner to example 125 using 2,4-dimethoxybenzylamine, ethyl oxalyl chloride, and 2-(pyridin-2-yl)propylamine (example 144a); yield 35%; W/e = 10 357 [M+1, a. 2~(pyridin-2yl)propylamine 10 mmoi of 2-methylpyridine was dissolved ir anhydrous THF and kept under inert condition at 0 *C. Butyl lithium (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 15 was cooled again to 0 C and acetonitrile (2 equiv) was added dropwise-Reaction was stirred ovemight at room temperature After cooling the reaction to 0 'C, 30 mL of methanol was added into the reactionmixture. 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 20 wth ethyl acetate. The combined extracts were washed with water, brine and died down over sodium sulfate. Solution was concentrated down and dissolved in ether. Product was extracted with 3 N aqueous HCL and the acidic extract was washed with ether and made basic with NaO- Product was extracted exhaustively with ether. The combined ether extracts was washed with water and dried down over sodium sulfate. Solvent was 25 evaporated down to yield sufficiently pure product; yield 47%; n/e = 137 [M+i]. The compound had an EC5 0 for activation of a hTIRI/hTiR3 umami receptor expressed in an HEK293 cell line of LO7 uMI N'42-MethoaxbenzvlV.N 424vrdin-2K1ethydOxalamide NN 157 Prepared in a similar manner to example 125 using 2-methylbenzylarine, ethy oxalyl chloride, and 2-pyridin-2-yi)ethylamine; at/e 298 [M-+13; 'H NMR (CDCI) 2,32 (s, 3H), 3.11. (t, 21), 338 (dt, 2H), 4s46 (d, 2H), 7.15-7.26 (m, 6111), 7.50-7.55 (rn 1H), 7.62-7.67 (m, 1), 8.12-8-15 (m, 1H), 8.60 (d, 1H), 5 The compound had an EC 0 for activation of a hTIRI/hTIR3 umami receptor expressed in an HEK293 cell line of 0.59 uN1. Example 146 N42J~DimnetxhoybenzvD)NM2P ridi,2-v~Lethyoxalande A H5 10 Prepared in a similar manner to example 125 using 2,3-dimethoxybenzylamine ethyl oxalyl chloride, and 2-(pyridin-2-yl)ethylamiine; / = 343 [M+11. The compound had an EQ 0 for activation of a hTIRi/hTIR3 unmami receptor expressed in an HEK293 cell line of 0.69 uM. Example 147 15 Nh2MethyltlbenzvIh)N (2-(yrtfin-2~ethy Doxsamide *H ~ %N N Prepared in a similar manner to example 125 using 2-methylthiohenzylamine, ethy oxalyl chloride, and 2-(pyridin-2-yl)ethylamine; /e 330 [M+1]; 'H NMR (CDCl,) i 2,49 (s, 3H), 3,08 (t. 2H), 3.77 (dt. 2H), 4.55 (d, 2H), 7,11-7.14 (m, I H), 7.15-7.20 (1n 20 2H), 7,22-7.27 (m, 3W), 762 (t, 1W), 7.78-7.83 (in, 1H), 8.08-& 11 (im, 1H), 8.56 (d, 1H). The compound had an EC5 for activation of a h TlRl/hTiR3 umami receptor expressed in an HEPK293 cell line of 0.96 uM. Example 148 N~42eHdrxvhenzv-NW424yridin-2-yAethyvixalamide OH C N~< NN 25 Prepared in a similar manner to example 125 using 2-hydroxybenzylamine, ethy oxalyl chloride, and 2-(pyridin-2-yl)ethylamine; m/e = 300 [4+1 1 158 The compound had an ECso for activation of a hTl/hTlR3 umami receptor expressed in an HEK293 cell line of :11 uN Exan ie 149 .N~.Rernznjd~it3idioxa4-4 haethvl 2yridin2vethvloxalamide H 5 Prepared in a siilar manner to example 125 using henz'o[d][1,3]dioxol-4-vimethvi amIne (example 149a), ethyl oxalyl chloride, and 2-(pyidin-2-yl)ethyl amine; yield 12%; a/eI= 328 [M+1]; 'H NMR (CDCl): & 3.12 (in, 2H), 3.77-3-80 (in, 2H), 4.46-4.47 (d, 2H), 5.98 (s211). 6,74-6.79 (in, 3H), 7.24 (i, 1H), 7,7-7.8 (in, 3H), 8.10-8.15 (in, 1H), 8.58 10 8.59 (in, 11). a. Benzo[dLl,3]dioxol-4-yhnethyl amine: Prepared in a similar manner to example 134a from benzo[d] [l,3]dioxole-4-carbaldehyde and airnoniumn acetate. The crude material contained app, 20 % of the product (m/e - 152 2 [M+l]) and was used directly in example 149. 15 The compound had an EQ 5 for activation of a hTIRl/hTIR3 umaini receptor expressed in an HEK293 cell line of 0.17 uM. 20 Prepaed in a imila xannerlt exm125uigbez50h~ohn2 ylehnaine, ethyloxalyl c lorie n 2(Zpridin2-yl)etl aiine; i 2% k 0 240 [M+1; 'H NIM (DMSO-d6): 6 292-295 (t, 2H), 3.48-3,53 (rm, 2H), 4 55-4.56 (d 2H1), 7.20-7,25 (m, '2H), 738-7.41 (m, 211), 7,50 (s , 1H1), 7,66-7,70 (m, 1i1i), 7.95-7.99 (m 2H1), 8.47-8,49{(d, MH), 8,88-8,90 (t, 1H-), 9,29-9.31 (t, 1H1), 25 The compound had an EC-r, for activation of a hT1R1/hTIR3 wnai receptor expressed in an aEK293 cela limn of 034 uM2o 159 Exitmpte 151 NMenoi~hzo[2-yhnethylrN '42-{yri4im2IheItn hoxalatnide pC Prepared in a similar manner to example 125 using benzo[d]thiazol-2 5 yimethanamine, ethyl oxalyl chloride, and 2-(pyridin2-yi)ethyl amine; yield 33%; m/e 341 [M+1]; 'H NMR (DMSO-ds): 6 2.95-2,98 (t, 2H), 3,52-3,57 (m, 2H), 4,72-4,73 (d 2H), 7.22-.24 (m, 1H), 7:25-7,27 (d, 1H), 7.40-7.44 (t 1H), 7.48-51 (t, 1H), 7,69-7.7 (dt, iH), 7,95-7.96 (d, 1H), 8.05A07 (d, 1), 8:49-8.50 (d, 1H), 896-8,98 (t, il) 9.67 9.70 (t, 1H). 10 The compound had an EQ 0 for activation of a hT1RI/hTIR3 umami receptor expressed in an EEK293 cell line of 4.4 uM. Example 152. N4(5aMothyvfaran-'yvhmethyljN2-(2-(nvidin-2vlnethv~jgxaluide oH ' i Ns N,, 15 Prepared in a similar manner to example 125 using (5-methylftiran-2 yI)methanamine, ethyl oxalyl chloride, and 2-(pyridin-2-yl)ethy amine; yield 38%; p/e' 288 [M1]; IH NIR (DMSO-ds): 6 2.20 (s, 3H), 2.92-2.95 (t, 2H), 348-3.52 (m, 2H) 4.23-4.24 (d, 2H),596-5.97 (d, iH), 6-06-6.07 (d, iH) 7.20-7.25 (m, 21H), 7,68-7.71 (t ilH) 8,48-8.49 (d, 1H), l 85-8.87 (t, 1.H), 9,04-9.07 (t, 1H) 20 The compound had an ECso for activation of a hTIRl/hT1R3 umami receptor expressed in an HEK293 cell line of 4,9 uM Exaiple 153 25 Prepared in a similar -manner to exam-pie 125 using (2~methylfuran-3~ yl)methanamaine (example 1 53a), ethyl oxalyl chloride, and 2-(pyridin-2-y1)ethyl amie; yield 50%; im/e 288 [M+];IHNMR (DMSO-d):. 65 2,23 (s, 3H), 2.91-2194 (1, 2H),3,48 160 3.52 (q, 2H), 405-4 06 (d, 2H), 6.30-631 (d, 1F), 7.20-7.25 (in, 2H), 7,38-7.39 (d, 1H), 767-7.71 (dt, 1H)8 S48-8.49 (d, 1H), 8.83-8,86 (t, 1H), 9.04-9 .07 (t, 1H). a. (2-Methylfuran-3-yl)methanamine: A solution of 10 mmol (1,256 mi) of methyl 2-methylfiwan-3-carboxylate and 38.9 mmol (2:1 g) ofNaOMe in 20 ml of 5 formamide was stinred 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 MgSO4 and concentrated to give 1.05 g (83%) of 2-inethyifuran-3-carboxamide as oil (Me 126.2 [M+ 1]). The amide was dissolved in dry T IF (10 ml) and drop-wise added to 15 ml of 1M LiAlH4 with 15 ml THF at 0 'C under argon Then the mixture was stirred for 5 irs at 60 10 _C, Following cooling, 50% aqueous THF (30 mil) was added to the mixture at S-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 EC50 for activation of a hTiRifhT1R3 umaini receptor expressed in an HEK293 celI line of 182 uM Prepared in a similar manner to Example 122 using 2,4-dinmethoxybenzylamnine, ethyl oxalyl chloride, and 2-(4-methylpyridin-2-yl)ethyi amine (example 154a); yield 11%; 20 d/e = 358 [M+1; m~p. 144145 "C; 'H NMR (CDCb): 6 2,31 (s, 3H), 2.97 (t, 2H), 3.71 (q, 2H), 3.79 (s, 3H), 3.83 (s, 3B), 4.39 (d, 2H), 6.40 (dd, 1H), 6.44 (d, 1H), 6,97 (s, 1H), 6,98 (d, 1H), 7,15 (d, 1H), 781 (br s, 1H), 8.08 (br s, 1H), 8.41 (d, 1H). a. 2-(4.Methyipyridin~2-yi)ethyi amine: Prepared in a similar manner to example 129 using 2-(4-niethylpyridin-2-yl)acetonitrile (example 154b); yield 83%; We= 25 137 [Mi1), b, 2.(4-Methylpyridin-2-yi)acetonitile: Prepared in a similar manner to example 129b using 2-bromo-4-methylpyridine, acetonitrile and n-BuLi; yield 88%; mle 133 [Mil]. The compound had an ECso for activation of a hTIRI/hTiR3 umami receptor 30 expressed in an HEK293 cell line o f 1.64 uM 161

N

0 0 H Prepared in a similar manner to Example 122 using 2,4-dimethoxybenzylamine, 5 ethyl oxalyl chloride, and 24(5-methyipyridin--yl)ethyi amine (example 155a); yield 9%; me = 358 [M+1J; mp. 124 125 0c; 'H NMR (CDCl) 6 2.30 (s, 3H), .97 (t, 2H), 3,0 (q, 2"H), 3.79 (s, 3H), 3,82 (s, 3H), 4,38 (d, 2H), 6.40 (dd, 1H) 6.44 (d, 1H), 703 (d, 1H), 7.14 (d, 111), 7,40 (dd, 111), 7.81 (br s, 1H), 8.08 (bra, 111), 8.38 (d, 111), a. 2(5-Methyipyridin-2-yl)ethyl amine: Prepared in a similar manner to 129a 10 using 2(5methyipyridin2-yl)acetonitriie (155b); yield 40%; m/e = 137 [M+1]. b. 2-54iethylpyridin42vl)acetonitile: Prepared in a similar manner to 129b using 2-bromo-5~methylpyridine., acetonitile and nBuLi; yield 68%; m/e = 133 [M+1]. The compound had an ECs 0 for activation of a hTIRl/hT1R3 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-dimethoxybenzylamine ethyl oxalyl chloride and 2-(thiophen-2-yi)ethyl amine; yield 72%; rn/s = 349 [M+1]; mp 20 146-447 "C; H NMR(CDCI 3 3.06 (t, 211, 3.58 (q, 2H), 380 (s, 31), 3.83 (a. 31), 444 (d, 2H), 6.41 (dd, 111), 6.45 (d, 1H), 6.84 (dd, 1H), 6.93 (dd, 1H), 7A5 (d, 1H), 7.16 (d: 1H). 7 61 (br s, 1H), 7,81 (br a, 1H). The compound had an ECQ for activation of a hT1R/hT1R3 umami receptor expressed in an H1E1K293 cell line of 4.87 uM 162 Exampleg157 Nh nh e I N (245 eth iYdin 2 yvW etvoxaianide O O' HN Prepared in a similar manner to Example 125 using 2-nethoxy-4 5 iethylbenaylamine (example 132a), ethyl oxalyl chloride and 2-(4-methylpyridin-2 yl)ethylamine (example 155a). Yield 20%; mp. 116: 117 *C; '11 NMR (CDCI 3 .): 3 2.31 (s, 311), 2,34 (s, 3H), 3,00 (t 211), 3.71 (q, 2H), 3.84 (s, 3H), 442 (d. 2H), 6,69 (s, 1), 6.71 (d, 14 7 05 (d, 1H), 7.11 (d, 114), 743 (d, 111), 2.84 (br s, 1H), 8.04 (br s, 11) 839 (s, 1K); MS(M+H, 342), 10 The compound had an EC; 0 for activation of a hTiRlliTlR3 unami 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 hT1RI/hT1R umami receptor expressed in an -EK293 cell line. The results of that testing are shown 15 below in Table B Commu ompound UmanmiECse Ec 5 e rat w (Vs Compound

N

Bi NJ-(2,4-dimethaoxyben yi)N2-(2~(furan~2 O4 HN' B2H 0K N .4-oxy2-methoxybenzy')-N2-(21 163 UompiECs Ec ratio (vs No Compound /1 \\ - - - - -- - - -- - - -- - - - -- - - . .. . B311 N ( t oprop-o en yl)- N2~ y-n 13 / C NH' HN- 1 / N Numerous amide compounds ofFonmula (1) that fall within the subgenus of "urea" compounds described elsewhere herein were also synthesized and experimentally tested fo effectiveness as activator of a hTIRI/hT1R3 umamir receptor expressed hi an HEK293 cell t-C-chorpftti1)3 he ptu-4-vfLtren 5 lin To a solution of heptan-4-ami-ne (0 18 Il 1 mmol) in CH 2 C12 (5 mL) was added I 10 chloro-2-isocyanatobenzene (0.12 mL, 1 mmol) at room temperature. The reaction mixture was stirredfor2 li A white solid was precipitated out The reaction mixture was filtered. The solid was washed with C.H2Cl2 to afford 1-(4-chlorophenyl)-3-(heptan-4-yl)urea (180 mag, 67%) as a white solid, np: 135-136 0 C .1 NMR (500 MHz, ODCIf): 30.93 (1 61), 145 (m, 6H) 153 (n 2H), 380 (br a, 1H), 4.33 (d, 1H), 6.00 (s, 1H), 6.95 (td, 11), 7.23 15 (dt, 1H), 7,33 (dd, 1H), 8.13 (dd, 1H). MS(M+1H, 269), 164 'The compound had an EC 0 for activation of a hTlRiihTR3 unami receptor expressed in an HEK293 cell line of 37 gM and when present at a M enhanced the effectiveness of monosodium glutamate with an Ps ratio of 4.95. Example 159 IL t42-nneth&% yhen 34heptan4l)urea Prepared in a similar manner to example 158 using heptan-4-amine and 1 isocyanato2,4-dimethoxybenzene. Yield: 88%. mp 1.72.173 C 1H NMR (500 Mlfl-z, CDCla): 6 0.93 (t, 6H), 1.45 (m, 811), 3.82 (s, 3H), 3,83 (m, 11), 3.84 (s, 1H), 4.32 (br s, 10 1H), 6 34 (br s, lH)E649 (d, IH), 6.50 (s, 1H), 7.71 (d, 1H). MS (M+H, 295) The compound had an EC 5 0 far activation of a hTlR1/hTIR3 uimami receptor expressed in an f-1EK293 cell line off l98 FM, and when present at 0.3 pM enhanced the effectiveness of monosodium glutamate with an ECIU ratio of 7.61. Example 160 15 144-etimoyphenl)~3-2-pyridine-2-v}etlvurea H H 'C) N. N N" Prepared in a similar manner to example 158 using 2-(pyrdine.2-vlethananine am 1-ethoxy-4-isocyanatobenzene Yield: 95%. mp: 163464 C. 'H NMR (500 MHz, CDCi): 3 1,43 (t, 3H), 3.03 (t, 2H), 3,68 (t, 2H), 4.03 (q, 211), 5.69 (br s, 1H), 6.45 (br s, 20 1H), 6.84 (m,2H), 7.14 (m, 3H), 7.20 (dlH), 7.64 (dtH), 8,43 (dd, 111) MS (4+11,286). The compound had an ECs 0 for activation of a hTIRL/hTR3 umami receptor expressed in an HEK293 cell line of 4.1 pM, and when present at I pM enhanced the effectiveness of monosodium glutamate with an ECIo ratio of 4.2. 165 EXanitk 161 1-(isoproyv1AIein 2 idine- e uea H H Prepared in a similar manner to example 158 using 2(pyridine-2-yi)ethanamine an 5 1-isocyanato-4-isoproplbenzene, Purified via column chromatography (1% MeOll in

CH

2 C to 3% MeOH in CH 2 CU) to afford 1(4-isopropylphenyi)4(2pyridine-2 yl~ethyi)urea (130 mg, 50%) as a white solid, mp: 72-73 C .H NMR (500 MHz, CDC1): 1 L25 (d, 611), 289 (mn, 1H), 3.06 (t, 2H), 3.70 (t, 21H), 5.80 (br s, 11H), 6.55 (br s, 1H), 7.19 (m. 5H), 7.24 (d, 1H). 7.68 (dt, 1H), 8.46 (d, 1H). MS (M+H, 284), 10 The compound had an EC 0 for activation of a hT1Ri/h.TR3 umami receptor expressed in an H1EK293 cell Tne of 098 ptM Additional "urea" compounds were synthesized and experimentally tested and found to have a relaively high level of effectiveness as an activator of a hTRllhT1R3 umami receptor expressed in an HEK293 cell line, The results ofthat testing are shown i 5 below in Table C ____________ Table C - Unmaali 1Jrpa5 omffpound Con Comprnrnd iC1PACName raniCD HN C1 HN C1 C1 HN- K 4 . -------- H- -. . -- Q -4-- ------------- - --- --- - -- C! F16N Table C -Urnamn 11rcaN MSl MAC Nam ra 0 N, C4 0.79 12.15 FHN N 0 I= H HN HN, C) 0 ri H 430 C7 H H b(,t-ietsyHex,41I,62 0 C9_____ 4r 2hiv~h~x~ 167 Table C Umani Ureas mnami Ec50 Compound corn RNPACName EC ratio (vs. UM -MSG, 00 NH.51 11 3 O N N H H 1,5 4.49 Npoy N3-r 1,244 F N 1 (2-fluorophenylk3~(1 2 3,4-tetahydmoaaphthalen = ea C12 1,67 -o Fi CB O.72 1 7 H N N ( dit hVxyp .en...p.nt.....urea....... Numerous amide compounds of Formula (T) that fall within the subgenus of "acrylanide" compounds desetibed elsewhere herein were also synthesized and experimentally tested for effectiveness as activator of a hTiR1/hT1R3 umami receptor 5 expressed in an TEK293 cell line. The results of that testing are shown below in Table D. Table D UmanniAervnmides CoudCompound Unmani ECs Fes ratio Compound 4 6 26 (....N(2,4-dimethylpe.n.n 3 .) . 168 TalD - UnriAnq~k V500wound CompourndTrnrVC Eerai to -- ----- ys- kI No. tt L\ 0t (WE nwyl2- 3 -(4-methoxyphinyi) (B) srnthyI 2-(3-(4-mefhoxvzhenuyl) N D5 Mahy 3. p0ny oyi3 (B N-Or-'ptan 4 l 3-(4 D6 0.7 6.3

------"----------------

DS 0,9496 16 Table D - Umami Acrytanides Compunda EC Et radtF Compound No SN 39 D 10 L----9- 19 I --------- _/ R me-thy- 4 nethyb, 2 (3 il tp N D, 2L2 )-4-me-h-N-(2~m-thy- ye--he-y £3D 23 7 03 he~tU~imtheyl 2.rVtbdin D14 43 MAg N 4 hxvsni yexd....... 1710 Compound Urami EC Ec.O raio @ No ... ....... ~fl 03A-h NK. SG nAl D15 154 E)N(h e P YA 4 1 (EY~(hphe-&yl)-1444 D16Ax N 136 3-3 EF 3 (3 4 dimethxyphe ayfl4(N Ihmiw "vozv lavo Vpeni trmisng.fgpanelists General Panelist Selection: Basic screening of sensory taste testers: Potential panelists were tested for their abilities to rank and rate intensities of solutions representing 5 the five basic tastes. Panelists ranked and rated intensity of five different concentrations of each of the five following compounds: sucrose (sweet), sodium chloride (salty), citric acid (sour), caffeine (bitter), and monosodium glutainate (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. t 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 ofbasic tastes and off-tastes A small goup of panelists (n=5) taste approximately 5 concentrations of the compound (range typically between 1-100 pM, in half-log cycles, ag., 1, 3, 10, 30, and 100 pM) in 15 water and in a solution of 12 mM MSG to evaluate enhancement. Panelists rate the five basic tastes (sweet. salty, sour, bitter, and savory) 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 20 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) in a larger study. 171 Trained Panelist Selection: A trained exprt panel was used to finther evaluate compounds that had been tested with the preliminary taste test. Panelists for the trained panel were selected from the larger group of qualifying taste panelists. Panelists were fiirthertrained on savory taste by ranking and rating 5 experiments using MSG and IMP combinations. Panelists completed a series of ranking, rating and difference from reference tests with savory solutions. In ranking and rating experiments, panelists evaluated easy MSG concentrations (0, 6, 18, 36 nmt) and more difficult MSG concentrations (3, 6, 12, 18 mM MSG) in water. Compound testing with Trained Panel: Compounds tested by the trained panel wer 10 evaluated in difference from reference experiments. Panelists were given a reference sample (12 mM MSG + 100 pM IMP) and asked to rate samples on a scale of -5 to --5 in terms of difference in savory taste flom the reference (score: -S = much less savory taste than the reference; 0 = same savory taste as the reference; +5= much more savory taste than the reference). Test samples were solutions with varying amounts of MSG, TI, and 15 the compound. Typically, each session compares the reference sample to numerous test samples .Tests typically included various samples with varying concentrations of MSG ant IMP, as well as one blind sample of the reference itself, to evaluate panel accuracy. Results of the taste tests are deserbe 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 AM + 20 MSO when compared to 100 pM IMP + MSG. 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 be done similarly as described above, 2:5 Table 3, Savory Taste Test Results Compound Chemical Name Taste Data No. E N (heptan-4 12 mM MSG + 3 pM cpd as strong as Example 1 yl)benzo[d}[1,3]dioxol&-5 12mM MSG + 100 1rM vIP carboxamide Exape 6 (R)-methyl 2-(benzo[d][l. 3] 12 mM MSG + 10 tM cpd as strong as dioxole-6-carboxamido)-4- 12mM MSG + 100 pM IMP (R)-N-(1-methoxy-4- 12 nMMSG + 3 ILM cpd as strong as Example 71 L rmethylpentan-2-yl)3,4- 12mM MSG + 100 p.M IMP duethyibenzamide17 172 Compound Chemical Name Taste Data Exape98etvl a23 ~ 12 mM MSG 10 eM cpd as strong a, ExNample 98 crmethyhuta-5- O+ 0 . l carboxamido)-4 4Methoxy-N-(1 12 mM MSG + 3 pM cpd as strong as Example 104 methoxymethyl-3-methyl- 12mM MS G+ 100 giM IMP (, 4 Dimethoxy-benzyl) 12 mM MSG+ 1 N cpd as strong as (2-pyridin-2-yl-ethyl)- 12mM MSG- 100 pM IMP oxalamide ExNl 1h12 mM MSG + 03 pM cpd as strong Example 157 methylbenzyl)-N-(2(5- as 12mM MSG+ 100 pM IMP methylpyridin-2 S t d de Numerous amide compounds of Formula (I) were synthesized and experimentally tested for effectiveness as activator of a hT1R2b/hTR3 "sweet" receptor expressed in an 5 HEK293 cell line. Examples of the synthesis and biological effectiveness testing in terms of Sweet EC 50 measurements for such sweet compounds are listed below. Moreover, man of the "sweet" amides of Formula (I) were also screened for activity in the umami ECs am

EC

5 5 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 10 enhancers for use in comestible and medicinal products and compositions, Exanmle 162 23 536-tetrafinor-4~methy N (2 mnethvlyevohxv)benzamide H 2,3,5,6 -- tetrafluoro-p-toluic acid acid (4.00 g, 19.22 nmol) , HOBt (5 19 g, 38.44 15 mmol) and EDCI (4.42 g 23.06 mnol) were mixed in 200 nil of anhydrous DCM and 30 ml of anhydrous DMEW The mixture was cooled to 04C and allowed to stir under Ar for 15 minutes. To the mixture was added 2-methylcyclohexanamine (3,05 mL 2306 mmol) and the reaction mixture was allowed to slowly warm to ambient temperature and stored overnight The reaction mixture was diluted with DCM, washed with IN 11C1, water, 173~~ aqueous NaHCO, water and brine, drying over MgSO 4 , filtration and removal of solvent is vacuQ, afforded the crude product as a pale yellow solid Recrystallization (EtOI/1H 2 0) amn drying in vacuo gave 5.23 g of the title compound as a white solid (mixture of 2 diasteromers, 90%), '1 NMR (CDCL) 3 0,95, 101 (d, J=' TO, 6,6 Hz, 311) L1-2.1 (m, 5 911), 2.29 (m, 311), 370, 4.29 (m, 111), 5,65, 5.92 (n, 111). MS ( 304.1, MAH )n p. 202 204 C. The compound had an EC> for activation of a hT1R2hTIR3. sweet receptor expressed in an HEK293 cell line of 0.39 tiM. Example 163 10 fSM54etr11oro~4ethv[ (3 mthylbum~2-viihenzamnide NF Prepared in a sihilar manner to Example 162 using (S)-3-methyibutan-2-amine and 2,3,5,6 -tetraluoro-putoluic acid acid (93%), 'H NMR (CDC 3 ) 5 0.98 (d, J:::: 6.9 Hz, 611) 1. 18 (d, J 6.8 Hz. 3H), 229 (in, 3H), 4,09 (in, 1H), 5.72 (bs, 1H).MS ( 3041, M+H) in. p 15 146447 *C. The compound had an ECso for activation of a bTlR2/hTIR3 sweet receptor expressed in an HEK293 cell line of 0 6 pM. Example 164 Nedoheptvh2g35 6&tetrauaaro~-4-methvIhenzamnide F H N 20 Prepared in a similar manner to Example 162 using cycloheptylamine and 2,3,5,6 tetrafluoro-p-toluic acid (94%). H NMAR (CDC13) 8 1.53 (r, 611), 1.57 (in, 411), 2.03 (m, 2H) 2.28 (m, 3H), 417 (in, 1H), 5.85 (bs, 1H)MS (304.1, M+H) in. p. 164-165 'C, The compound had an EC 5 0 for activation of a hTIR2/hT1R3 sweet receptor 25 expressed in an HEK293 cell line of 1.85 IM, 174 Examipie 165 KLf ineiigna~3vtt36 talore etyhgesd

F

t F Prepared in a similar manner to Example 162 ing 2,4-dimethylpentan-amine 5 and 2,3,5,6 .-tetrafluoroup-ohuic acid (90%) 'H NMR (CDC13) b 0.91 (d, J= 6.7 H z, 6K), L OU (d, J = 6.8 Hz, 6H), 185 (m, 2H), 2,29 (in 3H), 382 (m, 1H), 5.52 (bd, iH)MS (306.1, M+H) n. p. 184-187 "C. The compound had an ECo for activation of a hT1R2/T1IR3 sweet receptor expressed in anHEK293 cell line of 0.81s.M. 10 Exasmple 166 Ntf( 7~dimneth 41L2,3,44etrahydronachthalendVvW-31ethviisaazoe-4arbxamnidt N-0 HN To a solution of 3-methylisoxazole4-carboxyiic acid (83 mg, 0.0.67 mmol), HOBt (100 mg, 0.74 mnol) and EDCHCl (142 mg, 0.74 mmol) in DMF (4 mL), was added 5,7 15 dimethyl-1,2,3,4-tetrahydronaphthyl--amine (example 166a) (130 mg, 0.74 mmol). The reaction mixture was stirred for 24h at t, at which time the solvent was removed under reduced pressure and the residue was purified by flash-column chromatography (10 1 Hex:EtOAc) to afford 134mg of N-(5,7-dimethyl-1,2,3,4-tetrahydronaphtbalen--.yl).3 methylisoxazole4-carboxamide (70 %) as a white foamy solid. !H NIM (500 MHs 20 DMSO-d 6 ): L i174 (n, 2H), 1,86 (m, 2H), 2.16 (s, 3H), 2.19 (s, 3H), 2.43 (s, 3H), 2.55 (m, 2H), 5,10 (in, 1H), 6.86 (s, 1H), 6.89 (-, 1H), 8.60 (d, 1H, J:= 8.40 Hz), 9.27 (s, 1H). "C NMR (125 MHz, DMSO-d): 3 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,2,3,4-tetrahydronaphthalen-bamine: A catalytic amount of 25 Raney nickel (slurry in water) was washed with dry MeOH under argon in a round bottom flask. To a solution of the washed Raney Ni in methanolic ammonia (25 mL, 7N), was 175 added 5,7-diiethyl3,4-dihydronaphthalen..1(2H)-one oxime (example 166b) (420 ng, 222 mmol), and the mixture was stined under a balloon of 112 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 MgSC;, filtered and the solvent was 5 removed under reduced pressure to afford 360 mg of 5,7-dinethybt,2,3,4 tetrahydronaphthalen-4-amine (93 %). 'H1 NMR (500 VHz, CDC 6): 5 166-1.83 (m, 4H-), 196 (n, 2H), 2.19 (s, 311), 2.28 (s, 3H), 255 (im, 11H), 2.66 (m, 1H ) 3,97 (in, IH), 6.88 ( s, 111 ), 7.09 ( s, 1H ). b. Preparation of 57-.diimethyi3,4-dihydronaphthalend(2H)-one oxime: To a 1.0 mixture of5,7-dimethyl-3A+dihydronaphthalend(2Hone (20 g, 11.48 mmol) and hydroxylamine hydrochloride ( 1.6 g, 19,73 mmol ) in 10 ml of water at 70 'C, were added MeOH (14 mL), THF (3 mL) and a solution of sodium acetate ( 2.53 g, 30.83 Immol, in 7 mL of HO). Stirring was continued for 85 min at 70 'C, at which time a precipitate was fonned and 1.0 ml of water were added. The resulting mixture was stirred at room 15 temperature for 2 hr. Upon completion, the product was collected by filtration to afford 2.12 g of 5,7-dimethyb3,4-dihydronaphthalen4 (211)-one oxime (98 %), MS (M+11, 190). The compound had an ECso for activation of a hTR2/hT1R3 sweet receptor expressed in an HEK293 cell line of 0,76 pM. 20 3-hk2ro~2irtyAy-16 metho13Aetrahydron hen~1-vt benzamide HN Prepared in similar manner to Example 166using 5-methoxy-1,2,3,4 tetrahydronaphthalen,1-amine (Example 167a), Yield 40 %. -H NMR (500 MHz, DMSO d 6 ): & 1,73 (in, 1H), 1.83 (m, 1H) 1.96 (n, 2H), 2.61 (m, 211), 3.78 (s, 311) 5.27 (m, 1IH), 25 6.78 (d, 1H, J= 782 Hz), 6.86 (m, 2H), 7.14 (t, 1H, = 7.98 Hz), 7.60 (dd, 1H, J= 188, 1.30 Hz), 7.94 (dd, 1H,I =8 03, 139 Hz), 9.30 (d, IH, J 8.06 Hz), 13,80 (s, 1H) "C MIR (125 MHz, DMSOd): 6 19.5, 22.7, 289,47.4, 55.3, 108.6, 115.8, 1187, 1198, 176 121.1, 125.9, 126,2, 126.4, 1338, 137,3, 156.7,156, 168 7. MS(M+H, 332).Mp 175-17 "C. a. 5-methoxy-,2,34-tetrahydronaphthaien-1i-amine: Prepared in a similar manner to example 166a using 5-methoxy-14-dihydronaphthalen-1(2H)-oneYield 94 %. 5 1-H NMR (500 MHz, CDCI); 1631 :79 (m, 4H), 194 (m;2H), 2.60 (m, MH ), 271 ( m, IH ),3 82 ( s, 3H ) 3.97 (m, I H), 631 (d, IH ), 7.02 ( d, I H ), 7 (t, IH ), The compound had an ECs for activation of a hTiR2/hTlR3 sweet receptor expressed in an HEK293 cell line of021 pM IR a_'168 Prepared in a similar manner to Example 162 using 2,6-dimethylbenzoic acid and 2-methylcyclohexylamiine.Yield: 59%, 'H NM.R (500 MHz, CDC1 3 ): S 0.88-0.94 (3W, dd), 1,14489 (9H, m), 2.21-2,22 (6H, d), 3,39-3,45 (IH, nm), 7.02-7,03 (2Hd), 712-7.15 (IH, 15 t), 8.11-8,13 (IH, d). MS(M+H, 246.2) The compound had an EC 0 for activation of a hTiR2/hTiR3 sweet receptor expressed in an HEK293 cell line of 1.88 pM, Example 169 4-ethox2,dhnet N4 methev dhexmthbenza mide 20 Prepared in a similar manner to Example 166 using 4-methoxy2'-,6-dimethylbenzoi acid (example 169a) and 2-methylcyclohexflamine NMR (500 MHz, CDCl): S 0.86 0.92 (3H, dd), 1.00-1.85 (n, 9H), 2;18-2.19 (6H, d), 3 33-3-45 (1H, m), 3.71-372 (3H, d), 6.59 (2H, s), 7,98-8.05 (1HF, in), MS (276.2, M+H1) 25 a. 4-methoxy-2,6-diimethylbenzoic acid: 2-Bromo-5-methoxy-1,3 dimethyzbenzene (example 169b) (3.38 g, 15.79 mmol) was without further pumifncation dissolved in 100 ml of dry '11 The mixture was cooled to -.78"C and under argon n butyllithium (1.6 M solution in hexanes, 9.9 ml, 15,8 rumol) was added drop wise over 15 177 min and the mixture was stirred for 15 more min at -78"C. 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 'as stirred as long as evolution of carbon dioxide continued. Then the mixture was poured over ice (100 ml) and acidified using 6N HCi, The organic layer was S separated and water phase was extracted with EtOAc. Organic extracts were combined, washed' wth brine, water, dried over MgSO4 and concentrated under vacuum. The product 4-methoxy-2,6-dimethylbenzoic acid was obtained as a white solid (217 g, 95%), (M+H, 181). b, 2.4Bromo-5-methoxy-1i,3-dimethylbezenes:W2 mmoi a f 1 muethoxy-3,5 10 dimethylbenzene (2.82 ml) was dissolved in 100 ml of dry acetonitrile followed by 22 mnol (3.56 g) ofN-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-bromo-5~methoxy-1,3-dimethylbenzene (3.9 g, 92%) as white solid . 'H NMR (500 MHz, CDCO): & 2.41 (6H, s), 3.78 (3H, s), 6.67 (2H, 15 s)} The compound had an EC 0 for activation of a hTlR2/hT 1R3 sweet receptor expressed in an HEK293 cell line of2Ai M (RYNNL2 234etrahdronphthalenAl vtfaranvcarboxamide 200 To a solution of furan-3-carboxylic acid (100 mg, 0.68 mmol), HOBt (240 mg, 1.7i mmol) and EDCIHCI (196 mg, 1.03 mmol) in CH 2 C1 2 (8 iL) and DMF (1.5 mL) at 0 *C, was added (R)-1,23,4-tetrahydronaphthalen-I -amine (160 RL, 1.06 mmol). The reaction was stirred at rt for 24h, after which CH2CL was added. The resulting solution was washed 25 with saturated NaHCO3, H20, brine, died over MgSO 4 and concentrated in vacua, Recrystallization from EtOH/H2O afforded (R)N.(12,3,4tetrahydronaphthalen-1-yl)25 dihydrofnranu-3-carboxamide. IH NPMR (500 MHz, CDC): 6 1.89 (n, 3H), 2.12 (in, 1H), 2.84 (m, 2H), 5,35 (m, 1H), 5.96 (br d, IH, -1.75 Hz), 6.59 (dd, 1H, J = 1.90, 0.86 Hz), 178 713 (m, 1H), 7.19 (i, 211), 7.32 (m; 111), 7.43 (t, III, J=" 173 Hz), 7.93 (m, 111), MS(M+H, 242). The compound had an EC5 0 for activation of a hT1R2/hTIR3 sweet receptor expressed in an HEK293 cell line of 6.6 pM, Examle 171 (Rl=~wmetviYNO244tetrahvdronbhthaniestI.vzwsoAearbxandde NJo <! IN 0" Prepared in a similar manner to Example 170 using 5 -methylisoxazole-4-carboxylic acid. Purified by preparative TLC (5:1 Hex'EtOAc). 'H NMR (500 MHz, CDCl): & 1.80 10 (m, 311), 2,12 (m, 1H), 2.74 (s, 3H), 2.85 (m, 2H), 5.35 (m, 1H), 5,89 (br d, 1H, J= 7,75 Hz), 7,10 (m 11H), 7.18 (m, 211), 7.32 (m, 111), 8.26 (s, IH) MS(M+H, 257). fhe compound had an BC 50 fr activation of a hT1R2/hTIR3 sweet receptor expressed in an HEK293 cell line ofS. pM Example 172 addd -cloo--thylp~zhenyoyaat en (335tmg i,0cmmo)udr argost. ro _pig L'.5" Me, T-o a solution ofisoindoline (233my, 2.0 rmol) in dry 14-dioxane (10mL,) was adde-d 4.clr*2nehlhniaiscyanate (335 mng, 2.0 mnmol) under argon at room temperature. The reaction mixture was then stirred at RT overnight, The solvent was 20 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. ;H NMR (500 MHz, DMSO-d 6 ): 6 224 (s, 2H), 4,76 (s, 411), 7.20 (dd, J = 2.5. 8.5 Hz 1H), 7,27 (d, J= 2.5 Hz, 1H), 7,304.32 (n, 211), 7.34~7,37 (m, 211), 7.42 (d, J 83.5 Hz 1H), 7.84 (s, 1HI); '3C NMR (DMSO-d) 4 17.7, 51.9, 122.8, 1256, 126.8, 127.3 1281, 129.5, 134.7,136.8, 25 154,2; MS(vf'F, 287); EA calc'd for C 1 X1 5 CLN20: C, 67.02; fl, 5.27; N, 9.77; Found C, 66.82; H, 5.41; N, 9.92. 179 The compound had an Eso for activation of a hTIR2/hTIR3 sweet receptor expressed in an HEK293 cell line of 0.89 pM Fxampe 1 73 E(4-mdehoxyK2 methy lpihent dlne2caroxanwsde To a solution of isoindoline (576 mg 4.0 umol) in dry 1,4-doxanue (20 aL) was added 4-methoxy-2-methyiphenyl 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 chiomatography on 10 silica gel (EtOAc/hexanes: 1:1) to-give the title compound (1 18 g, 84 %) as a white solid. I NMR (500 MHz, DMSO-d) 6 219 (s, 3H), 372 (s, 3H), 473 (s, 4H), 6.72 (dd, J = 2.5 Hz, 8.5 FsH 111), 6.78 (d., J= 2.5 Hz, 1H), 7.17 (d, . = 8.5 H z7 ), 7;30-7.32 (m 2H), 7.34-7.36 (m, 2H), 7.74 (s, 1H), C NMR(DMSO-d): 5 18.2, 5L95 55.1, 110.9, 115, 1 122.8, 12.2, 127.8, 1306,1351 1370, 154,9, 1565; MS(MH*, 283); EA calcd for 15 CrHSgN20:: C, 72.32; H 6.43; N, 9.92; Found C, 72.16; H, 6.82; N, 9:98. The compound had an EC 50 for activation of a hTiR2/hTI1R3 sweet receptor expressed in an HEK293 cell line of 4.5 M Exanwie 174 Nie~yedaxvpjena tei~nosie-2..arbduxane 20 To a solution of 3,4~(methylenedioxy)niline (150 mg, 1.09 mmol) in dry DCM (4 mL) was added dropwise phenyl chloroformate (0.138 ml, 1.09 mmol) and triethylamme (0.153 ml, 1.09 mmol), After the reaction mixture was stired at r't for 8 hr., isoindoline 25 (0.123 ml, 1.09 mniol) and triethylamine (0.153 mnl, 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:165166 C 'H NMR 180 (CDCLh 500 MHz): 4.82 ( s,4H); 5.93 ( s, 2H); 620 ( s, 1H);6:73 (s, 21); 717 (a, ll ); 7.30 ( m, 4H ) MS (M . 283). The compound had an ECW fir activation of a hT1R2/hTW3 sweet receptor expressed in an HEK293 cell line of 1.05 uM. 5 Example 175 3-ethl-sxazoe-4-.carbxylic acid 0, 234etrahvdro-nmaphth alen4~-yk.amide. N-O H N To a solution of 3-Methy-isoxazole-4-carboxylic acid (0.52 g, 406 mmol) in DC/ (15 mL) and DMTF (2 mL), was added HOBt (1 1 g, 814 mmol) and EDC1 (0.896 g 4.67 10 minol) The clear yellow solution was cooled to 0 C and allowed to stir under Ar for 15 minutes. To the solution was added (R-Amino-2,3,4-teahydronaphthaene (073 mL. 5.04 nmoland the reaction mixture was allowed to slowly warm to ambient temperature and was stired for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCOs water, brine (50 mL, drying over MgSO 4 , filtration and removal of 15 solvent in vacuo. Silica gel chromatography (0- 25% Hexane;EtOAc) afforded the title compound (650 mg; 62.5 %) as a sticky solid. 4H NMR (CDC) 6 188 (m, 31), 2.12 (m, IH), 2.51 (s, 31), 2.81 (in, 211), 5.32 (in, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (in, 2H) 7.20 (i. 2H); 'C NMR (CD0h) 6 11.22, 20,15, 294 30.35, 47,93, 116.3, 126.2, 127.88, 128 88, 129.65, 136.25, 133.00, 158,45, 160,28. ESIMS: 257 (4H) EA calc'd fo 20 C 5 HirN 2 0 2 : C, 70,29; 1, 6,29; N, 10.93; found C, 70.61; H, 6.11; N, 11.09. The compound had an EC, for activation of a hTIR2/hTiR3 sweet receptor expressed in an HEK293 cell line of 58 M, Numerous ande compounds of~ormula(1) were also synthesized and experimentally tested for effectiveness as activator of a hT1R2/hTiR3 "sweet" receptor 25 expressed in an HE1K293 cell line. The results of that testing are shovn below in Table B, 181 Table E Sweet EnhancgrAmides Sweet Umami ummi Componud No Compound ECsr ECs EC _________________ ~uM uM rt NoN H cl 34hloro 2~hydroxy-N24 methyl 2 3.4 N OH (R>3-chlor 2-hydroxyN1(2 4 tetrahv I-a I baeny BbenauamEi dc 1.6 OH H E43 C OH H N C1 3-chloro-2-hydoxy-N~(6~methox y~1 b2 34 Mraiy&amathaV'ybeand 182 Table E -Sweet EnlianccjAm ides CopudSweet Umatn!.... UMami No Com~pound IC IM. 13N! ratio 3~~tnethyLN - (2 nkthyl IN 2 1$:tayoohhk 4 ' OH' hir----------x~ - - -1----A I,. As OF OOH .2.........h.t.... .3.. .i.3......

Tabie Ewet EnhanmerAm des Coenpound Sweet imami Umami NomdEC E EC No.Compound Brio NoN uM u ratio E 1 N2A6 3methy1 N-t4 methyJ L2,3 4 edhydnsnphhalen l-Vsexazolez4 Arbxmd E12 28 N-45-methoey 1 2,3 4 tetrahydronaphthalen- yl)- 3 H El3 2L9 u)' clor 2 ety N(2 E 4 H 2.9b1 S)-2,6-die :yN2-73 4 Y N E15 H 302 P16 1304 CI 3)6d:hloro2-mehyWN-(L2,34 1 84----------------------------- a8 CpoundCopudMX No. uiM. uM ao E? 17cl.O 3.13 OH E1139 -OH ------------------------ o- N------------- -~ -4... ............-------- E19o~-t~.et1-y{oz~de____ o 150 t~raydnapht ~n I -flirnnxpthidc - Table E - Sweet EnhancerAnidui Compound topm t~e jam mm Nomma I Cs b% ____ uMI um ratio .... ch or ......... 2.. F-,24H 6,4 'OHH 0 E25 N .79 yfl& - - ------------------ 0 NN F F 0 ------- nfio-4--- 3- ehybuan2 Table E -Sweet EnbancerAniides sweet lUmami Ulmami Compound Cmon C C C NO, ii o NN 0,2] F y F 0 N-(3$Aim F NH }529 F 0 / Q 42 H c IN 4A~om-N-2~ T 2,y yci eir1)4 o-4 H N/ 0,6 187 ---- - --- - Table E- f En ane3 .. Amides. ... - --- ------------- Sweet Vmsamni Umami CompoundCopudEe 1 EC UM 0 ratio 0 >0 0 . 1336 0.9 0 ________~~ Tah £-Seet £nhsancerAmides Copond. Comxpound1 EC.Q nECo C

N'

t 0 HN F 0 BAA 102,

--------

N-(2R-.ycu[ 21 e~n--yV189 ,6 - Tale E - Sw~t EnhancerAnudes Compound opudIIlIl No.-E~~-E% E 5 I - -------- tt um ... uM ratio F F > HN-' -' - -- - -- -- -- (R)-'23,5,6-txtafuoo- 4- e thyP4-ebyttn ---------- ........... ------ --- * ~ a R 49 ,2 0 0 - --- --- N----3- iehlyihxl-,, tr49thyIeezmid H? -cioro N (23 dhydr~ohIlel-yi4,tirx thd$ O en z amru de -------- ----- ----- ---- Table E - Swet -nhan--rA i des Compound Swpnu ~eet Umatm Umaim No. CC __________ __________ !M uM rti 9hl HN E2 1.52 ............... .. ------ - ------- --- ------ 1-- *T N EA NM ES4 L130.66 C N NH E55 L89 5 bmmeozoM.3(4N2 3(-md hvnh .1ohxtzaid c t Ct tt NH E55 19 Br N r & 2-Ainm -riehtyck ny1) - 2aamide 'NN 58 N2 23 N F9 191 Table E - Sweet Ehne~de CopondCopondSweet Umami ttumami Coooun ECsG c E(, -------- 31 ratio F H I', s9 F2 4~N 2.07 E6O 2 .4 F F:o -f41iozo-N44N2me hi oexD3 F NH H 132 9, 21 H N FRI. fl.(N 278 ------------------- ----..... .... ... ..... ...........

Table E -Sweet EnhaacerAniAdc Sweet Umdnu Umam compound Cipud-E Nos- aM 'M Eaflo ~E66 <-> ---- ---- ---- ---- --- -- -- ---- ---- ---d -- --- - ------- E69 H FIN et cclo .xyftea....a....id... E'72 3 35 (2 F F ------............--- -------------- 11)7 Table E - Sw eet EnhancerAmides Compound SetTmm N.Compound EcM uM~ ratio 2, 1 -7 62H.4 / N - d 336 hlcco xy) H E77 N N t ~ c acid~ hykydohtxy1)-2 1pO............. PS N NN~194 ______ Table IC-Sweet EnbancerAmides Compound Compound

I',C

5 EC5& ECs No. u m ratio 1 ~. OH OH H 4A --- --- -- --- - £31 F < 43 6-N E 93 4J5 N-4e~o ZhetbvyI!-m hyl- tiI H t mc tN Nybn 7 a £83 ................ ................................ 4......................... O9 _______Tab le F. -SWeet EnhanWCerA mides Compound Ionntn Compond rcs~rERce, No. E85 N '- 4 N tz..tc..j..di

.................

3 *cl HN 3,-dChoro-424dmylmy)-4 ------------- ----------..... ........ .................... N'. N N> . ----- --- ----- -- -- ( i o -- fk r --- -fuo o ----- -- l-l -- -- -- -- - -89 \ / \ 2,71 -- --- --- --- --- - --. .. ... - -- - --- -- --- -- --- Cl9 Table E - Sweet EnhancerAmides ____ Comeeun Urnari Umami CopudCompound EC5t EC~a Ecu No, N ai £,91 2 i4 .* -N .......... n....tnssxti~ £92 2.N 74 I-2 nkll £-94 ~ 3d 3-chlorctN - 4 1-dfrethoe evnyl>4 fhooenzamide ----- ----- ----- ----- ---- - -- - -- - - -- - -- - Pi44-teir'svtsao Pststoard 197 ------ - ------ -- "Fble E-Sweet Enhamces'Affl Le Sweet Umams Umaml Compound COMPOUnd ECso ECse EC 3 uam u ratio E7 425 3,6 Dichioro N (2,4 dimethyhpheny4) 2 methoxy t Y E99 - j N- N' -N / 0 ~ 0 £100 3N t NI N (2 methyi-4-nittophenyl)soindoiine-2 carboxamide F HN -F E101 L3 ar3httLt bw;amid~ b~rid ____ H C)20 NN N Nt 0 N-(2-methyl-3-nitrophenyi)isoindoline-2 carb.xamide F F NH ______________N#-2,3,-riuoheny)iondoline-2-_boxanxk -de ___ 198 Table E -- S EnhznerAmdes e Compound EC NN /

HN

4 ±ihftoph t d2in a ood P10704 C)C 2 ci I,-e El11 4.NN~ 15,4 093 Nc%4 dio eophn l44itdonro soquir

N-

NN ---------- N n - ----------------------------- -------- /i 9 TableE Sveet nhancerAmides CopudSweet Umami Umam Compound EC EC C copondtatdos o eictnuesrabl caatrsiorffatecs No. ar i ndi E0. N43 0 c d s sed wen diss--i-- akeastatsu H / 0/ 4 1 wee Praodr an apprlorenquantiyoft epementl compoUnnd isaissldint watr tpall alo oinsigt th% ethns whic vais utilizesad o -aidntalo diprno the mon teaeousstc solutions .otinn Wh_,1,an 0Mcentroate othe experimental compound;ma alobeisonalve i aquous solutons mto ar"e atnt" (forex apte, 4% t5 a Fie human Subjects are usted for reiminfseary taste arbtets . The bjectrhave demonrtd abiy o tasted the dsired iast attribues, andare soraints aee Mwagtude S.cale ls fromh 0.1 (Brleth ble csweetnlied to 100 (Sitrongeistosno i magibe Sweeness Subjects resfr prolmaingr drinetedng (e ets ate)eo a es demonstrate abiit totsetedsre4at tiuc n r riedt< s aee I hour prior to the test. Subjects eat a cracker and rinse with water four times to clean the 20 mouth before taste tests, 200 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 comp found dissolved in an appropriate key tastant (e g., 4% sucrose, 6% fructose, or 6% fructose/glucose, typically at p- 1 7 1) at various concentrations of the experimental 5 compound may also be served to the Subjects. Subjects also receive a reference sample of the key tastant (eg., sucrose, fructose, or fructose/glucose typically at pH 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 (LIS) for sweetness, 10 saltiness, soumess, bitterness, savory (umami), and other (off-taste), Subjects rinse three times with water between tasting. 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% Bfuctose, or 6% fructose/glucose, typically at pH 7.1) without the experimental compound. Then 15 solutions o f the key tastant plus experimental compound are tasted in increasing order of concentration. The key tastant solution can be retasted for comparison with key tastant + experimental compound solutions ifnecessary. 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 20 compound will be tested at in subsequent sensory experiments. To confuim preliminary test results, the test may be repeated with another small group of panelists. The preliminary profiling test is always the first test perbrmed on a new experimental compound. Depending on the results of the preliminary profiling test, additional more quantitative tests may be performed to further characterize the 25 experimental compound. "Difference from Reference" Human Taste Test Procedures Ptupose: 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 typicaly 1 5-20 Subjects) in order to obtain statistically significant 30 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, i.e., a sweetener) and one sample is the "Test" (which may or may not include an experimental 201 compound). Subjects rate the difference in intensity of the test sample compared tothe reference sample for the key attribute on a scale of-5 (much less sweet than the reference) to -4-5 (much more sweet than the reference). A score of 0 indicates the test sample is equally as sweet as the reference. 5 Procedure: Ten or more Subjects are used for the "Difference fiom 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 didng (except water) for at least I hour prior to the test. Subjects eat a cracker and rinse with water four times to clean the mouth, 1.0 Test solutions can include the experimental compound in water, the expeimental compound plus a key tastant (e g, 4% sucrose, 6% sucrose, 6% frictose, 6% fructose/glucose, or 7% fructose/glucose, at pH 7.1 or 2.8), and a range of key tastant only solutons as references, Samples of the key tastant without the experimental compound are used to 5 determine if the panel is rating accurately; i.e., the reference is tested against itself (blind) to detemine how accurate the panel is rating on a given test day. The solutions are dispensed in 10 ml volumes into 1 oz, sample cups and served to the Subjects at room temperature. Subjects first taste the reference sample then immediately taste the test sample and 20 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, 25 The scores for each test are averaged across Subiects 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 Tukey'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 30 test (paired, wo-tailed; alph a =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 tor the measurement of sweet taste enhancement For example, for testing (R)-3-methylN-(I,2,3,4 tetrahydronaphthalen-1-yl)isoxazole-4-carboxamidea reference sample consisting of 4% 202 sucrose was used, w hich 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 2,3,5,6-tetrafluoro-4 methyl-N-methylcyclohexyl)benzamide, a 50:50 mix offrictose:glucose was used to 5 better model high fructose com syrup solutions commonly utilized 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. After initial studies in 6% fructose/glucose at pH 7.1, studies shift to evaluating the performance of the compound in 10 a product prototype more similar to a cola beverage, i.e. higher concentrations ofsweetene 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 15 Table F. Sweet Taste Test Results Compound Contents of Solution pH Perceived Equivalent No. Sweet Solution 174 50uM Compound 174 6% sucrose - 4% sucrose 171 30 aM Compound 171 Greater than 6% but less than + 6% uctfructose/uose 170 p H 71 Greater than 6% but less than 30 uM Compound 170 8% fructose/glucose + 6% frLctose/glucose 162 10 uM Compound 162 pHinI Greater than or equal to + 6% fructosughucose 8% fractosegluco se 162 10 uM Compound 162 pH2.8 Greater than or equal to + 7% fructose/glucose 9% frcoegucose 168 30 uM Compound 168 p 7 1 Equal to 8% huctose/glucose + 6% futs/lcs 163 10 uM Compound 163 p1H 7.1 Greater than 6% but less than * + 6% tctose/glucose 8% fructose/glucose The pH of these aqeous solutions was not measured or controlled. 203 Sap PrearatIon Ui An Ethanol Stock Solution A compound of the invention is diluted using 200 proof ethanol to 1000x the desired concentration in soup, The compound can be sonicated and heated (if stable) to 5 ensure complete solubility in ethanol. The soup from bouillon base is made by adding 6 g of vegetable bouillon base in 500 mL of 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 IP 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 I 000x ethanol stock is added for a 10 final ethanol concentration of 0.1 %, If the ethanol interferes with the taste of the soup, a higher concentration of ethanol stock solution can be prepared provided the compound is soluble. EanLe 7 Chin Preparation 15 A salt mixture of a compound ofthe invention is made by mixing with salt such tha a 1.4% of the salt mixture added w/w to chips would result in the desired concentration of the compound, For I ppm final of the compound on chips, 7 mg of the compound is mixec with 10 g of salt. The compound is ground using a mortar and pestle with the salt and the compound and salt are mixed' weli. The chips are broken into unifonn small pieces by 20 using a blender. For each 9&6 g of chips, 1.4 g of the salt mixture is weighed out. The chip pieces are first heated in a microwave for 50 seconds 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 making 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 25 evenly over the chips, Example 178 Cookie g anfo A compound ofthe invention is diluted using 200 proof ethanol to 1000x the desired concentration in the final product The compound can be sonicated and heated (if 30 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 vith dry 204 components (i.e., flour, sugar, salt, cocoa) which have been well mixed. Dough is portioned out onto a baking sheet, and baked at desired temperature until done. Juce Eyeaio 5 A compound of the invention is diluted using 200 proof ethanol to lON0 the desired concentration in juice. The compound is further blended with the alcohol component of natural and/or artificial flavors to make a "key". The flavor key is blended with a portion ofjuice concentrate to assure homogeneity. The remainder of the juice concentrate is diluted with water and mixed. Sweeteners, such as HFGS (High Fructose 10 Com Syrp), aspartame, or sucralose, are mixed in and blended. The favor/compound portion is added as a final step, and blended. ExamPLe18) Spicy Tomato Juice or Blodv Mary Mix A compound of the invention is added as a dry ingredient to the spice blend and 15 blended thoroughly. Spice blend is dispersed into a portion of th e tomato paste, blended, and that blended paste is futter blended into the remaining paste. The paste is then dilute< 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 20 variations can be made in the present invention without departing from the 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. It 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. 205

Claims (156)

1. 2. The method of clafm I wherein the amide compound has a molecular weight from 175 to 500 grams per mole.
2. 3. The method of clann I wherein the aide compound has a molecular weight from 200 to 450 grais per mole.
3. 4. The method of claim 1 wherein the amide compound has a molecular weight from 225 to 400 grams per mole.
4. 5. The method of claim i wherein the amide compound has a molecular weight from 250 to 350 grams permole.
5. 6. The method of claim I wherein R'i and one of R 2 and R have between 3 and 14 carbon atoms,
6. 7. The method of claim 2 wherein R I and one of R7 and R h between 4 and 12 carbon atoms. 206
7. 8. The method of claim I wherein Ri and one of R and R have between 4 and 10 carbon atoms.
8. 9. The method of claim I wherein R has between 3 and 16 carbon atoms and 0, 1. 2, 3, 4, or 5 heteroatoms selected f om oxygen, nitrogen, sulfur, fluorine, or chlorine.
9. 10- The method of claim I wherein one of R2 or R 3 has between 3 and 16 carbon atoms and 0, 1, 2 3 4, or 5 heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine, or chlorine. 11, The method of claim I wherein one of R2 or R 3 has between 4 and 14 carbon atoms and 0, 1, 2, 3, 4, or 5 heteroatoms independently selected from oxygen, nitrogen, sulfur.
10. 12. The method of claim 1. wherein one of R 2 or R 3 has between 5 and 12 carbon atoms and 0, 1, 2, or 3 heteroatoms independentfy selected fiom oxygen, nitrogen, and sulfur.
11. 13. 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, sulfr9 fluorine, or chlorine, and one ofR or R 3 has between 5 and 12 carbon atoms and 0, 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur.
12. 14. The method of claim 1 wherein R' and one of R 2 and R are independently selected from the group consisting of an arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -ROH, -R'O R 5 -R 4 CN, -R 4 CO2H, -R00R 5 , -RCOR, -R 4 SR', and -R 4 SOR, and optionally substituted derivative thereof comprising 1, 2, 3, or 4 carbonyl, amino groups, hydroxy, or halogen groups: and wherein R and R- are CC6 hydrocarbon residues.
13. 15. The method of claim 7 wherein R and one of R 2 and R 3 are independently selected from the group consisting of an arylalkenyl, heteroarylalkenyl, arylalkyl, heteroarylalkyl, alkyl, alkoxy-alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl groups, and optionally substituted derivatives thereof comprising 1, 2, 3, or 4 sustituent groups, independently selected from hydrogen, hydroxy, fluoro, chloro, Ni NHCH 3 , N(CH 3 ) 2 , COCH 3 , SEt, SCH 3 , methyl, ethyl isopropyl, vinyl, trifluoromethyL methoxy, ethoxy, isopropoxy, and trifhioromethoxy groups.
14. 16. The method of claim 1 wherein one of R 2 and R is a branched or cyclic organic residue having a carbon atom directly bonded to (a) the aide nitrogen atom and 207 (b) two additional carbon atoms, and wherein the branched or cyclic organic residue comprises hydrogen atoms, up to 10 optional additional carbon atoms, and ft &om zero to tnve heteroatoms independently selected from oxygen, nitrogen, sulfur, fluorine, and chlorine.
15. 17. The method of claim I wherein one of R 2 and RI has the formula -C-H C wherein na and nb are independently selected from 1, 2, and 3, and each Ra or R 2 substituent residue is independently selected from hydrogen, a halogen, a hydroxy, or an carbon-containing residue optionally having from zero to five heteroatoms independently selected from oxygen, nitrogen, sulfa, an a halogen. 18 The method of claim I wherein one of R2 and R is a branched aikyl radical having five to 12 carbon atoms,
16. 19. The method of claim I wherein one of R2 and R' is a cycloalkyl or cycloalkenyl ring comprising 5 to 12 ring carbon atoms that can be optionally substituted with 1, 2, 3, or 4 independently selected from hydrogen, hydroxy, fluoro, chloro, N112, NHCH3, N(CH 3 ) 2 , CO 2 Cs1 3 , SEt, SCM 3 , methyl, ethyl, isopropyl, vinyl, trifinoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups, 20, The method of claim I wherein one of R and R3 has the structure gfAr--(R ) H 2 orRA wherein Ar is a phenyl, pyridyl, firanyl, thiofuranyl, or pyrrole ring, in is 0,, 2, or 3, each R is independently selected from hydrogen, hydroxy, fluoro, chloro, NH-2, NHCH 3 , N(CH3)2, CtCH, SMt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy and R' is selected from the group consisting of an alkyl, alkoxy-alkyl, alkenyl, cycloalkenyl, cycloalkyl, -R 4 OH, -RO R' -R'CN, -IttO, -1, -RCO2t , -RCOR', -RSR, and -R 4 ,0 2 It2 comprising I to 12 carbon atoms.
17. 21. The method of claim I wherein the amide compound has the formula: 208 0 ( A2 H wherein A comprises a 5 or 6 maembered aryl or heteroaryl ring; m is 0, 1, 2, 3 or 4; each R is independently selected from alkyl, alkoxy, alkoxy-alkyl, hydroxyalkyl, OH, CN, CO2H, CO 2 R%,CHO, COR 6 , SR', halogen, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl; and R is ClC(, alkyl 22 The method of claim 21 wherein A is a phenyl ring or a pyridyl ring
18. 23. The method of claim 22 wherein in is 1., 2, or 3,
19. 24. The method of claim 23 wherein each R is independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH3) 2 , COOCH 3 , SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, or a monocyclic aryl or heteroaryl group
20. 25. The method of claim 21 wherein A is a phenyl ring and each R' is independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH3) 2 , COOCH 3 , SCH3, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. 26, The method of claim 25 wherein R2 is a Cto branched alkyl
21. 27. The method of claim 21 wherein R is a CrCw branched alkyl substituted with one or two substituents independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH3) 0 2 CCH3, CO2CH3, SCH, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. 28 The method of claim 2$ wherein R2 is a I,2A4) tetrahydronapthalene ring or an 2,3-dihydro-IH-indene ring having the formula wherein in is 0,1, 2, or 3, and each R 2 can be bonded to either the aromatic or non aromatic xing and is independently selected from hydroxy, fluoro, chloro, NH2, 209 NHCH 3 , N(CH 3 %, CO 2 CH3, SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
22. 29. The method of claim 25 wherein R 2 is a phenyl ring optionally substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, NH 2 , NHCH3, N(CH) 2 , CO 2 CH 3 , SCH, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. 30, The method of claim 21 wherein R is an substituted carboxylic acid or x substituted carboxylic acid lower alkyl ester.
23. 31. The method of claim 25 wherein R- is an c-substituted carboxylic acid methyl ester
24. 32. The method of claim 31 wherein the a-substituted carboxylic acid or a-substituted carboxylic acid ester residue corresponds to that of a naturally occurring c-amino acid or an ester thereof, or its opposite enantiomer
25. 33. The method of claim 21 wherein A is a monocyclic heteroaryl wherein each R" is independently selected from. hydrogen, hydroxy, fluoro, chloro, NIt, NHCH 3 , N(CHj 2 , C00CH 3 , SCH, SEt, methyl, ethyl, isopropyl, vinyl, trifhioromethyl, mnethoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
26. 34. The method of claim 21 wherein A has one of the following formulas R N Ni (R 210 (R Rr (RM NNR AN (R h "Y R4 ~ or N e- n W1 01 wherein m is 0, 1, 2, or 3, and each Ris independently selected from ydroxy, fluoro, chloro, NH2 NHCH3, N(CH-A)2, CO2CH3, SCHa, SEt, methYl, ethY, 'V c isopropyl, vinfyl. trifluoromethyl, methioxy, ethoxy, isopropoxy, trifluoromethoxy, or a monocyclic aryl or heteroaryl group,
27. 35. The method of claim 34 wherein R2 has the formula ()IM r wherein mi is 0,j, 2, or 3, and each P 'can be bonded to either the aromatic or non aromatic ring and is independently selected f hydroxy, fluoro, chloro, NH2, Noro, cN(C), CO2CH,SCH3, SEt, methy, eth, sp , viyl, ethyl, tif luoromethyl, methoxy, ehoxy, isopropoxy, and trifloromethoxy rou
28. 36. The method, of clain 21 wherein. A is a monecyclic, fuised bicyclic or linkled bicyclic aromatic heteroaryl, optionally substituted with 0, 2-, 3or 4 substituents independently selected from hydro-xy, fluoro, cioro, NH2, NH1CH3, N(CH,)2, CO2CI .SCH3 , SEt, methyl, ethyl, isopropyl, vinyl, t-rifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy groups
29. 37. The method of claim I wherein the amide compound has the formula 211 0 0 O2 N--R >N^RR H H V/ b2 or wherein in is 0 1, 2, or 3 and each R. can be bonded to either the phenyl or heteroaryl rings and each Ri is independently selected frorn, hydroxy, fluoro, chloro, NH, NHCH 3 , N(CH 3 ) 2 , CO2C-1 3 , SCH 3 SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, rnethoxy, ethoxy, isopropoxy, and trifluoromethoxy,
30. 38. The method of claim 37 wherein n is I or 2,
31. 39. The method of claim I. wherein the aide compound has the fonnula o 0 N-R ( -R (R (R or R wherein m is 0, 1, 2, or 3 and each R" is independently selected fiom, hydroxy, flaoro, chloro, NH 2 , NHCH3, N(CH 3 ) 2 , CO 2 CH 3 ,SCH, SEt, methyl, ethyl. isopropyl, vinyl, triftluoromethyl, methoxy, ethoxy, isopropoxy, and in luoromethoxy. 40, The method of claim 39 wherein in is I or 2.
32. 41. The method of claim I wherein the aide compound has the formula RH wherein Ria and Ri are independently hydrogen or a lower alkyl.
33. 42. The method of claim 41 wherein REa and Rib are independently hydrogen or methyl.
34. 43. The method of claim 41 wherein Ris a CrCj branched alkyl
35. 44. The method of claim 41 wherein R has the formula 212 wherein m is 0,1, 2. or 3, and each R 2 can. be bonded to either the aromatic or non aromatic ring and each R' is independently selected from hydroxy, fluoro, chloro, NH2, NHCH, N(CH)2, CO 2 CH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, tifluoromethyl, methoxy, ethoxy, isopropoxy, and ftuioromethoxy groups.
36. 45. The method of claim 1 wherein the amide compound has the formula R$R R H R~ wherein RI or R, is independently hydrogen or a lower alkyl. 46 The method of claim 45 wherein R- is a lower alkyl and R 2 is a C-Ci branched alkyl 47, The method of claim I wherein the amide compound has the fotmula: 0 (R N-B-(R ) H wherein A comprises a 5 or 6 membered aryl or heteroaryl ring; mn is 0, 1, 2, 3 or 4; each R" is independently selected from alkyl, alkoxyl, aikoxy-alkyl, hydroxyalkyl, OH, CN, CO 2 H, CHO, COR, CO SH, SR', halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl and R is C 1 -s alkyl; B is a 5 or 6 membered aryl or heteroaryl ring; m' is 0, 2,3 or 4; R is selected from the group consisting of alkyl, alkoxyl, alkoxy-alkyl, OH, CN, CO 2 H, CHO, Cot, C0 2 R 6 SR, halogen, alkenyl, cycloalky, cycloalkenyl, aryl, and heteroaryl: and R 6 is CrC 6 aikyl. 48, The method of claim 47 wherein A is a monocyclic or fused bicyclic heteroaryl ring wherein each R and each R"is independently selected from hydrogen, hydroxy, 213 fluoro, chloro, NH 2 , NHCH,3 N(CH-2, COOCH 3 , SCH * SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, inethoxy, ethoxy, isopropoxy, and trifluoromethoxy group'.
37. 49. The method of claim 47 wherein A is a monocyclic heteroaryl ring.
38. 50. The method of claim 47 wherein A has one of the formulas z , (R G(N (4- orr R NN NrOr or (N (R' '\nc N wherein. m is 01 2, or 3, and each RO can be bonded to either the aromatic ornon aromatic rfig and each R is independently selected fro-n independently selected from hydrogen, hydroxy, fluoro, chloro, NH2, NHCH,, N(CH3)2, CO2CH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy., ethoxy, isopropoxy, and trifluoromethoxy goups, 51 The method of claim 47 wherein the (R )-A radical has the formNula 214 0 or Rb Ria Or R wherein RI, and R uare independently hydrogen or a lower alkyl
39. 52. The method of claim 48 wherein B is a phenyl ring and each R is independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ) 2 , CO 2 CH 3 , SEt, SCH , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxV, ethoxy, isopropoxy, and trifuoromethoxy groups. 53 The method o f claim 47 wherein A is a substituted phenyl ring and B is a substituted cyclohexyl ring.
40. 54. The method of claim I wherein the anide compound has the formula 0 H wherein A is a 5 or 6 membered aryl or heteroaryl ring; m is 0, ,2, 3 or 4; each R" is independently selected from alkyl, alkoxyl, alkoxy-alkyl, OH, CN, CO 2 H, CO2R6, CHO, CORt, SR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl
41. 55. The method of claim 54 wherein A is a phenyl, pyridyl, furanyl, or thiofianyl ring and each RCis independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ) 2 , CO 2 CH, SEt, SCH, methyl, ethyl, isopropyl, vinyl, tifioromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, goups. 56 The method of claim 55 wherein A is a phenyl fing and m is 1, 2, 3 or 4. 57, The method of claim 56 wherein m is I or 2, 58, The method of claim 55 wherein R is a CrCo branched alkyl. 59, The method of claim 55 wherein R" is an ct-substituted carboxylic acid lower alkyl ester,
42. 60. The method of claim I wherein the amide compound is a urea compound having the formula: 215 RAk 9 Ra wherein R 9 and one or two of R' and R 8 comprise a hydrocarbon residue having at least three carbon atoms and optionally one to ten heteroatoms selected from oxygen, nitrogen, sflfur, halogens, or phosphorus; and wherein optionally one ofR 7 and R? is hydrogen. 61 The method of clain 60 wherein R7 and R? together form a heterocyclic or heteroaryl ring having 5, 6, or 7 ring atoms that maybe optionally substituted with 1, 2, or 3 substituents independently selected from hydroxy, iluoro, chloro, NH. 2 , NHCH 3 , N(CHQ 2 , COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy isopropoxy, and trifluoromethoxy
43. 62. The method of ciaim 61 wherein the urea conmound has the structure N or -NH -R-) 63 The method of claim 60 wherein one ofR 7 and R 8 is hydrogen, 64, The method of claim 63 wherein R9 and one of R 7 and R. are independently selected from arylalkenyls, heteroarylalkenyls, arylalkyls, heteroarylalkyls, alkyls, alkoxy-alkyls, alkenyls, cycloalkyls, cycloalkenyls, atyls and heteroaryls, each of which carbon containing groups may be optionally substituted with 1, 2, or 3 substituents independently selected from hydrogen, hydroxy, fluoro, chioro, NH 2 , NHCH-, N(CH 3 ) 2 , COOCH3, SCH 3 , S"Et, methyl, ethyl, isopropyl, vinyl, trifluoromethy, methoxy, ethoxy isopropoxy, and trifiluoromethoxy.
44. 65. The method of claim 63 wherein R and one of R 7 and R 8 are independently selected from alkyl, phenyl, cyclohexyl or pyridyl, each of which may optionally comprise one to four substituents independently selected from hydroxy, fluoro, chlioro, NH 2 , NHCH 3 , N(CH 3 ) 2 O2CHIt, SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. 66 The method of claim 63 wherein one ofR 7 and R has one of the formulas 216 i or 0 ' ~ / 0p N{ /N< JA NN (R 1 (R R1 N Rl in P VIT or or Rr N ( R1 RRR RR y f , hor N N C z, tu mr substiue waith 01, 2, or 3 n sbtents Windependently selected &fon hydrogen, hydroxy, fluoro, chloro, NH2, NHCH3,N(CH3),,, COOCH3, SCH3, SEt, methyll, ethyl, isopropyl, vinyl, tiffluoromethyl, methoxy, ethoxy, isopro-poxy, and trifluorornethoxy .
45. 68. The method of claim 63 wherein Rne isR an s achenlyl -igotoal n or L:rmethjxyj w8 hermeno o cis 63, 2, eei or 3s. an eaC)bachR'idenntysled frol hdroen
46. 69. The method of claim 63 wherein R has the structure 217 HCO HO ~ R or wherein B is a phenyl, pyridyl, furanyl, thiofuranyl, pyrrole, cyclopentylcyclohexyl, or piperidyl ing, m is 0,1, 2, or 3, and each R is independently selected from hydrogen, hydroxy, fluoro, chloro, NH, N CH. N(OH)2, COOCH SCIt, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy ethoxy, isopropoxy, and trifluoromethoxy and R 9 is a selected From the group consisting of an alkyl, alkoxy-alkyl, alkenyl, cycloalkenyl, cycloalkyl, -R 4 0H4 -R0 R5 -R4CN, -R CH, -R 4 C0 2 R, -R4CORt -RtR, and -R 4 S0 2 Ri comprising I to 12 carbon atoms. 70, The method of claim 63 wherein the urea compound has the fornula: 1-(2-cliorophenyl)~3 -(heptan-yl)urea, 1-(2,4-dichlorophenyl)-3-(1 -phenylpropyl)urea, l-(2,4-dimethoxy'phenyi)-3(heptan4-y)urea, 1-(2-iluoropheny)-3-(heptan4-y)urea, or 1~(4-sopropylpenyl)>3-2-pyridin-2-y)ethy)urea.
47. 71. The method of claim 1 wherein the amide compound is an oxalamide compound having the formula RR 0 wherein R" 0 and R 30 are independently selected hydrocarbon residues having at least three carbon atoms and optionally one to ten heteroatoms independently selected from oxygen, nitrogen, sulftr, halogens, or phosphorus, and wherein R 2 and R 4 ' are independently selected from 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
48. 72. The method of claim 71 wherein Raand R 4 are hydrogen.
49. 73. The method of claim 71 wherein R and R"' are independently selected from the goup consisting of arylalkyis, heteroarylalkyls, cycloalkyl-alkyls, and heterocycle alkyls comprising five to 15 carbon atoms, and wherein each of RI and R"J can optionally comprise one to one to four substituents independently selected from 218 hydrogen, hydroxy, fluoro, chloro, NHR, NHCH 3 , N(C1 3 )., Co 2 C1 3 , SE, SC13, methyl, ethyl, isopropyl, vinyL trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy 74, The method of claim 1 wherein the aide compound is an oxalamide compound having the formula R 5 0 0j RE (RDmA NR*P, (Raog), R 2 0 0 wherein A and B are independently an aryl, heteroaryl, cycloalkyl, or a heterocycle comprising 5 to 12 ring atoms; m and n are independently 01 1, 2, 3 or 4-8 R 20 and R 4 0 are hydrogen, R Yis hydrogen or an alkyl or substituted alkyl residue comprising one to four carbon atoms; R6 is absent or a CpCs alkylene or a CC 5 substituted alkylene; R and RO are independently selected from the group consisting of hydrogen, alkyl, alkoxyl, alkoxy-aikyl, OH, SRt halogen, CN, NO 2 , COR 9 , COR, CONR 9 R' 0 , NRR 1 , NR 9 COR , SOR 9 , SO 2 R SONR R , NR 9 SO 2 R , aikenyl, cycloalkyl, cycloalkenyL, aryl, heteroaryl, and heterocycle; R" and R1 0 are independently selected from H, Q -C 6 alkyl, C 3 -C 6 cycloalkyl, and CvC6 alkenyi; 75, The method of claim 74 wherein A and B are independently a phenyl, pyridyl, furanyl, benzofuaranyl, pyrrole, benzothiophene, pipexidyl, cyclopentyl, cyclohexyl, or cycloheptyl ring; in and n are independently 0, 1, 2, or 3; R 2 ('and R 4 ) are hydrogen; R is hydrogen or methyl; Rt is a C 2 alkylene; R7 and R are independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ) 2 . CO2CH 3 , SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
50. 76. The method of claim I wherein the aide compound is an oxalamide compound having the formula 219 (RE~a R5 I A , wherein A is a phenylpyridyl, furanyi, pyrnole, piperidyl, cyclopentyl, cyciohexyl or cycloheptyl ring; m and n are independently 0, 1, 2, or 3; RIO ishydrogen or methyl; P is 1 or 2; and RA and R are independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NH1t NH1CH 3 , N(CH1 3 2 , COOCIL, SCR 3 , St, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two-of R 73 together foam a methyenedioxy ring.
51. 77. The method of claim 76 wherein the pyridyl-RS 0 radical has the structure or 78 The method of claim 1 wherein the amide compound is an oxalamide compound having the fotnula ArO N JA 0 wherein Ar is a substituted aryl or heteroaryl ring comprising five to 12 carbon atoms R 0 is hydrogen or methyl; 11 is 0, 1, 2, or 3; each R'3 is independently selected from the group consisting of hydroxy, fluoro, chloro, NH, NHCH 3 , N(CH 3 )2, CO 2 CH, SEt, SCH. methyl, ethyl, isopropyl, vinyl, tiifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
52. 79. The method of claim 78 wherein Ar is a 2-, 3-, or 4-mono-substituted phenyl, 2,4-, 2,3-, 2,5, 2,6, 3,5-, or 3,6-disubstituted phenyl, 3-alkyl-4-substituted phenyl, a tri substituted phenyl wherein the substituent groups are independently selected from the group consisting of hydroxy, fluoro, chiloro, NH 2 , NHCH 3 , N(CH) 2 , C02CH, 220 SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifiuoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two of the substituents together form a methylenedioxy ring on the phenyl rirg. 8& The method of claim 78 wherein Ar is a substituted heteroaryl ring comprising 5 to 1.2 carbon atoms and wherein the substituent groups are independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(C.H 3 ) 2 , CO 2 CH, SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, metboxy, ethoxy, isopropoxy, and trifluoromethoxy
53. 81. The method o f clain I wherein the amide compound is an oxalamide compound having the formula o ~ N wherein A is a substituted aryl or heteroaryl ring comprising five to 12 carbon atoms: R. 0 is hydrogen or methyl; m and n are independently 0, 1, 2, or 3; each R7e or Rg is independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NH , NHCH 3 , N(CH 3 ) 2 , COOCH 3 , SCH 3 , SEt methyl, ethli, isopropyl, vinyl, trifluoromethyl methoxy, ethoxy, isopropoxy, and trifluoromethoxy
54. 82. The method of claim I wherein the amide compound is an oxalamide compound having the formula wherein m and n are independently 0, 1, 2, or 3; and R '"and R' are independenty selected ftom the group consisting of hydrogen, alkyl alkoxyl, alkoxy-alkyl, OH, SR, halogen, CN, NO, CO 2 R9, COR, CONR 9 R', NR 9 Rt NRCOR , SOR , SO 2 R, SO 2 NRYR', NR 9 SO 2 R't alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocycle; 221 R and R' 0 are independently selected from H, C+Cc alkyl, CrICs cycloalkyl, and Cs alkenyl 83, The method of claim 82 wherein R' and R, are independently selected from the group consisting ofhydrogen, hydroxy, fluoro, chloro, NI-b, NHCH 3 . N(CH 3 L, O2CCH, SH, SC1, methyl, ethyl, isopropyl, vinyl, tifluoromethyl, methoxy, ethoxy, isopropoxy, and tdfluoromethoxy.
55. 84. The method of claim 82 wherein the pyridyl-R radical has the structure 7' NN or
56. 85. The method of any of claims 1-84 wherein the log" of the partition coefficient of the amide compound between n-octanol and water is less than 5.5
57. 86. The method of claim I wherein the modified comestible or medicinal product is a food fc animal consumption, 8-1 The method of claim 1 wherein the modified comestible or medicinal product is a food for human consumption. 88 The method of any of claims 1-,4 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 fIods, dried foods, chilled foods, oils and fats, baby foods, and spreads.
58. 89- The method of any of claims -84 wherein the modified comestible or medicinal product comprises one or more meats, poultry, fish, vegetables, grains, or fruits.
59. 90. The method of claim I wherein the modified comestible or medicinal product is a frozen food, an uncooked food, or a fully or partially cooked food.
60. 91. The method o f claim 1 wherein the modified comestible or medicinal product is a soup, a dehydrated or concentrated soup, or a dry soup.
61. 92. The method of claim I. wherein the modified comestible or medicinal product is a snack food.
62. 93. The method of claim I 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. 222
63. 94. The method of claim 1 wherein the modified comestible or medicinal product is a cake, cookie, pie, candy, chewing gan, gelatin, ice cream, sorbet, pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or fruit sauce.
64. 95. The method of any of claims l-14 wherein the modified comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate.
65. 96. The method of clam I wherein the modified comestible or medicinal product is a soda, or juice.
66. 97. The method of claim 1 wherein the modified comestible or medicinal product is an alcoholic beverage. 98 The method of any of claims 184 wherein the modified comestible or medicinal product is a pharmaceutical composition for oral administration
67. 99. The method of clan I wherein the modified comestible or medicinal product is an oral hygiene product.
68. 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.
69. 101. The method of clan I wherein the aide compound is present in the modified comestible or medicinal product in a concentration from about 0.05 ppm to about 15 ppm. 102 'Ihe method of claim I wherein the amide compound is present in the modified comestib'e or medicinal product in a concentration from about 0.1 ppm to about 5 ppm.
70. 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.
71. 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.
72. 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 1.2 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 223
73. 106. The method of clainn I wherein a water solution comprising the savory flavor modifying amount of the amide compound and 12 mM monosodiun glutamate has an increased savory taste as compared to a control water solution comprising 12 mM monosodium glutamate and 100 pM inosine monophosphate, as determined by the majority of a panel of at least eight human taste testers.
74. 107. The method of claim 1 wherein a water solution comprising about 10 ppm of the awnide 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. 108, The method of claim wherein the amide compound is a savory agonist for an hTiR1/hTIR3 receptor.
75. 109. The method of any of claims 1-84 wherein the aide compound has an ECr for the hTlR1/hTlR3 receptor of less than about 2 pM
76. 110. The method of claim 1 wherein the amide compound, when dissolved in a water solution comprising about I pM of the amide compound decreases the observed EC 5 of monosodium glutamate for an hTIRl/hTIR3 receptor expressed in an HEK2193-Ga15 cell line by at least 50%. 111, The method of claim I 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.
77. 112. The method of claim I wherein the aide compound is comestibly acceptable,
78. 113. The method of claim I wherein the amide compound is or can be shown to be generally recognized as safe, 114, The method of claim I wherein the amide compound, when combed with rat chow and fed to Cril:CD(SD)iGS BR rats at a concentration of about 100 miliigrams/Kilogram Body weight/day for 90 days causes no adverse toxic effects on the rats. 115, The modified comestible or medicinal product produced by any of claims 1-84.
79. 116. A method for increasing the sweet taste o fa comestible or medicinal product comprising: a) providing at least one comestible or medicinal product, or a precursor thereof, and 224 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 aide compound, or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product; wherein the amide compound has the structure 0 (R) N-R2 UIL H wherein A is an aryi or heteroaryl ring having from 3 to 12 ring atoms; in is 01,2,3 or 4; each R" is independently selected from the group consisting of Cr-C4 alkyl, CrC 4 haloalkyl, Cr-C 4 haloalkoxy, Cr-C4 alkoxyl, CE-C 4 alkoxy-alkyl, Cr-C 4 hydroxy alkyl, 01H, NI 2 NHR NR 2 , CN, CO2H, CQRt CI, CORt SH, Rk 6 , and halogen, wherein R 6 is CErC 4 alkyl; R comprises a branched alkyl or cycloalkyl optionally substituted with one to four substituents independently selected from alkyl, alkoxyl, alkoxy-alkyl, hydroxyalkyl OH, Ni, MR 6 , NR%,CN, CO 2 H, COIRt CHO, CORt SH, SR 6 , halogen, alkenyl, cycloalkyL cycloalkenyl, aryl, and heteroaryl and R is CrC 6 alkyl; and wherein the aide compound has a molecular weight of 500 grams per mole or less
80. 117. The method of claim 116 wherein each R" and each optional substituent for R2is independently selected from the group consisting ofhydrogen, hydroxy, fluoro, chloro, NH?, NHCHI-, N(CH 3 ), COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, Vinyl, tiifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
81. 118. The method of claim 117 wherein A is an aryl ring comprising 6 to 12 ring carbons.
82. 119- The method of claim 117 wherein A is a napthiyl ring.
83. 120. The method of claim 117 wherein A is a phenyl ring.
84. 121. The method of claim 120 wherein in is 1, 2, 3, or 4. 122 The method of claim 121 wherein R 2 is a branched CrClo alkyl.
85. 123. The method of claim 121 wherein R? is a branched C 3 -GC alkyl, substituted with 1, 2, or 3 substituent groups independently selected from hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH3) 2 , CO 2 CH 3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, 225 trifluoromethyl, inethoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, and pyridyt 124 The method of claim 121 wherein R' is a cycloalkyl or cycloalkenyl ring having 3 to 10 ring carbon atoms optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting ofhydroxy, fluoro, chloro, NH 2 , NHCH NCH 3 ) , CO 2 CH 3 ,SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups
86. 125. The method of claim 121 wherein R 2 is a cycloalkyl or cycloalkenyl ring having 5 to 8 ring carbon atoms, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting ofhydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH13) 2 , CO 2 CH-N, SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, tifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups,
87. 126. The method of claim 121 wherein R. is a cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl ring, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ), CO 2 CH 3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and tri fluoromethoxy groups.
88. 127. The method of claim 121 wherein R is a cyclohexyl, optionally substituted with 1, 2 or 3m ethlw groups
89. 128. The method of claim 121 wherein R 2 has the for rula )
90. 129. The method of claim 121 wherein R is a 1-indane having the formula wherein in is 0,1, 2, or 3, and each R 2 can be bonded to either the aromatic or non aromatic ring and is independently selected from hydroxy, fluoro, chloro, NH 2 , NHCH 3 . N(CH 3 )z, COzCHI, SEt, SCH, rmethyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and txifluoromethoxv
91. 130. The method of claim 121 wherein R 2 is a 1-1,2,3,4) tetrahydronapthalene having the formula 226 wherein m is 0,1, 2, or 3., and each RI cane bonded to either the aromatic or non aromatic ring and is independently selected from hydroxy, fluoro, chloro, NH2, NHCH 3 , N(CLIbs, COOCIL, SCH 3 , SEt, methyL ethyl, isopropyt viny], trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. 131, The method of claim 121 wherein R 2 has the formula RRr wherei each R are independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NH2, NHCHi, N(CH3)2, COOCH13 SCH.1 SM, methyl, ethyl isopropyl, vinyl trifluoromethyl, meotho-xy, ethoxy, isopropo-xy, and trifluoromethoxy A
92. 132. The method of claim 121 wherein RW has the formula or
93. 133. The method of claim 121 wherein R 2 has the formula CCHgo -OV 134 The method of claim 121 wherein R is a 1(12,3,4) tetrahydronapthalene ring having the foimula 227
94. 135. The method of claun 121 wherein Rt is an 1V(12,3,4) tetrahydronapthaiene ring having the formula 136, The method of claim 121 wherein R is an 1-(1;2,3,4) tetrahydronapthalene ring having the formula
95. 137. The method of claim 117 wherein A is a monocyclic heteroaryl,
96. 138. The method of claim 117 wherein A has one of the formulas (R, (R' L (R (R'R R (R(Rt0 22R m
97. 228- N ( 1 17 N wherein M is 0, 1 '2 or 3, and each R" is independently selected friom, hydroxy, fluoro, chloro, NH2, NHCH3 N(CH 3 ) 2 , C0 2 CH3, SEt, SCH3- methyl, ethyl, isopropyl vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, or trifluoromethoxy, 139. The method of claim 117 wherein A has the formula R N i whereinR is hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH3, N(CH3)2, O 2 CCH 3 , SH, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, or trifluoromethoxy. 140. The method of claim 138 wherein R 2 is a branched CrCjo alkyl 141, The method of claim 138 wherein R2 is a branched C3-Gm alkyl, substituted with 1, 2, or 3 substituent groups independently selected fTorn hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ) 2 , CO2CH,, SEt, SCH, methyL ethyl isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenyl, and pyridyl. 142. The method of claim 138 wherein R is a cycloalkyl having 3 to 10 ring carbon atoms, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, fluoro, chloro, NH 2 , NHCHI, N(CH 3 ) 2 , CO2CH 3 , SEt, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups, 143. The method of claim 138 wherein R2 is a cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NICH 3 , N(CH3) 2 , 229 CO2CH 3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. 144. The method of claim 138 wherein R 2 is a cyclohexyl, optionally substituted with 1, 2, or 3 methyl groups. 145. The method of claim 138 wherein R 2 has the fonnula 146. The method of claim 138 wherein R.2 is a 1-indane having the formula kt wherein m is 0,1, 2, or 3, and each R can be bonded to either the aromatic or non~ aromatic ring and is independently selected from hydroxy, fluoro, chloro, NH 2 , NHCH 3 N(CH), CO 2 CHa, SEt, SCH, methyl, ethyl, isopropyl, vinyl, trifluorornethyl, methoxy, ethoxy, isopropoxy, and bifluoromethoxv. 147, The method of claim 138 wherein R is a 1-(1,2,3,4) tetrahydronapthalene having the fonnula wherein m is 0,1, 2, or 3, and each R can be bonded to either the aromatic or non aromatic ring and is independently selected fioin hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH), CO 2 CH 3 , SEt, SCH, methyl, ethyl, isopropyl, vinyl, trifluoromethyl methoxy, ethoxy, isopropoxy, and trifluoromethoxy. 143. The method of claim 18 wherein R2 has the formula or or 230 RR p 2 Ci oror wherein each R' are independently selected from the group consisting of hydrogen, hydroxy, fluoro, chloro, NH, NHCH, N(CHO2, 02CCH 3 , SH, SCH , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, or triflu oromethoxy. 149. The method of claim 138 wherein R has the formula or 150. The method of claim 138 wherein R has the formula CHOr 0U 3 NsN> or N 151. The method ofclan 138 wherein R is a 1 -(1,2,3,4) tetrahydronapthalene ring having the formula 152. The method of claim 116 wherein the modified comestible or medicinal product is a food for animal consumption. 153. The method of claim. 116 wherein the modified comestible or medicinal product is a food for human consumption, 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 products, ice creams, dairy products, sweet and savory snacks, snack bars, meal 231 replacement products, ready meals, soups, pastas, noodles, cared foods, fozen foods, dried foods, chilled foods, oils and fats, baby foods; and spreads. 155. The method of any of claims 1164151 whereni the modified comestible or medicinal product comprises one or more meats, poultry, fish, vegetables, grains, or fruits. 156. The method of claim 116 wherein the modified comestible or medicinal product is a frozen food, an uncooked food, or a filly or partially cooked food. 157. The method of claim 116 wherein the modified comestible or medicinal product is a soup, a dehydrated or concentrated soup, or a dry soup, 158 The method of claim 116 wherein the modified comestible or medicinal product is a snack food. 159, The method of elaim 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. 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. 161 The method of any of claims 116-151 wherein the modified comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate. 162, The method of any of claims 116151 wherein the modified comestible or medicinal product is a soda, or juice, 161 The method of any of claims 116-151 wherein the modified comestible or medicinal product is an ak oholi beverage. 164. The method of any of claims 116-151 wherein the modified comestible or medicinal product is a pharmaceutical composition intended for oral administration 165. The method of claim 116 wherein the modified comestible or medicinal product is an oral hygiene product. 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 0.001 ppm to about 100 ppm. 167. The method of claim I l7wherein the amide compound is present in the modified comestible or medicinal product in a concentration from about 0.1 ppm to about 30 ppm. 232 168. 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. 169. The method of any of claims 116-151 wherein the aide compound is present in the modified comestible or medicinal product in a concentration from about 0.1 ppm to about 5 ppm. 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. 171. The method o f any of claims 116151 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 judg&d by the majority of a panel of at least eight human taste testers. 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, fructose, glucose, erythritol, isomalt, lactito, mannitol, sorbitol, xylitol, a known natural teipenoid, flavonoid, or protein sweetener, aspartame, saccharin, acesulfame-K, cyclamate, 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 lmown sweetener, as judged by the majority of a panel of at least eight human taste testers. 173. The method of claim 116 wherein a water solution comprising the sweet flavor modif dying 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 majority of a panel of at least eight human taste testers. 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 ililiters of a 50:50 mixture of sucrose and fructose, as judged by the majority of a panel of at least eight human taste testers, 175. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amide compound and about 16 mM of aspartame has a 233 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 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 at least eight human taste testers. 177. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amid compound and about 10 inMl of cyclamate has a sweeter taste than a control water solution comprising about 10 mA of cyclamate, as judged by the majority of a panel of at least eight human taste testers. 173. 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 sucralose has a sweeter taste than a control water solution comprising about 0.4 mMi of sucralose, as judged by the majority of a panel of at least eight human taste testers. 179. The method of claim 116 wherein a water solution comprising the sweet flavor modifying amount of the amide compound and about 0,2 mM of alitame has a sweeter taste than a control water solution comprising about 0.2 nM of alitame, as judged by the majority of a panel of at least eight human taste testers 180. The method of clan 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. 181. The method of claim 116 wherein the amide compound modulates the binding of a sweetener selected from the group consisting of sucmose, fructose, glucose, erAhritol, isomalt, lactitol, mannitol, sorbitol, xylitol, a kmown natural terpenoid, flavinoid, or protein sweetener, aspartame, saccharin, acesufame-K, a cyclamate, sucralose, alitame or erythritol to an hTIR2/hTLR3 receptor expressed in an HEK293-Gc 5 cell line. 182. The method of claim 116 wherein the amide compound has an EC 50 for binding an hTIR2hTR3 receptor expressed in an HEK293-Gd5 cell line of less than about 10 sM. 234 183, The method o f any of claims 116-151 wherein the amide compound has ain EC for binding an hTIR2/hTiR3 receptor expressed in an HEK293-God5 cell line ofless than about 5 p. 184, The method of claim 116 wherein the amide compound h as an ECso for binding an hTlR2/hTIR3 receptor expressed in an HEK293-Ga15 cell line of less than about 2 PM 185. The method of claim 116 wherein the amide compound has an EC.,. for binding an hT1R2/hTIR3 receptor expressed in anRBK293-Ga15 cell line of less than about I pMC 186. The method of claim 116 wherein the aide compound is not a peptide compound. 187. The method of claim 116 wherein the amide compound is comestibly acceptable. 188. The 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 concentation in the fiished product. 189. The method of claim 116 wherein the amide compound, when combined with rat chow and fed to CrhCD(SD)1GS BR rats at a concentration of about 100 I milligrams/kilogram body weight/day for 90 days causes n o adverse toxic effcts on the rats. 190, A comestible or medicinal product produced by the process of one of any of claims 116-189. 191. A method for increasing the 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 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 forna a modified comestible or medicinal product; wherein the amide compound has the structure 0 (RI;)Mg-- N-R2 wherein A is a n aryl or heteroaryl ring having from 3 to 12 uing atoms; 235 m is 0, ,2, 3 or4; each R" is independently selected from the group consisting of hydroxy, fluoro, chloro, NH 2 , NHCH, N(CH1 5 ) 2 , C0 2 CH, SEt, SCH3, methyl, ethyL isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy; P 1 is a phenyl ring, optionally substituted with 1, 2, or 3 substituents independently selected fRom the group consisting of, hydroxy, fhioro, chloro, NH 2 , NHCH 3 , N(C1 3 ) 2 , CO CH 3 , SEt, SCI,,, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy; and wherein the amide compound has a molecular weight of 500 grams per mole or less. 1.92, 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 193. The method of claim 191wherein 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. 194. The method of claim 191wherein the modified comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate 195. The method of claim 191 wherein the modified comestible or medicinal product is a soda, or juice, 196. The method of claim 191 wherein the modified comestible or medicinal product is an alcoholic beverage. 19,7 The method of claim 191 wherein the modified comestible or medicinal product is a pharmaceutical composition intended for oral administration. 198, The method of claim 191 wherein the modified comestible or medicinal product is an oral hygiene product. 199. The method of claim 19iwherein the aide compound is present in the modified comestible or medicinal product in a concentration from about 0.001 ppm to about 100 ppm. 236 200. The method of claim 191 wherein the amide compound is present in the modified comestible or medicinal product in a conceontration from about 0.1 ppm to about 10 ppm. 201. The modified comestible ormedicinal product produced by the method of claims 191-200. 202. A method for modulating the 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 about 0.001 ppm to about 100 ppm of at least one non-naturally occurring urea compound, or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product; wherein the urea compound has the formula: wherein m and n are independently 0, 1, 2, or 3, and each Rand R is independently selected from fluoro, chloro, NH 2 , NHCH, N(CH 3 ) 2 C 0 2 CH. 3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. 203. The method of claim 202 wherein n is 0. 204, A comestible or medicinal product produced by the method of claim 202. 205. A comestible or nidicinal product, or a precursor thereof comprising about 0.001 ppm to about 100 ppm of at least one non-naturally occurring aide compound, or a comestibly acceptable salt thereof, wherein the amnide compound has the formula: (R")N H wherein A comprises a 5 or 6 membered aryl or heteroaryl ring; m is 0, 1, 2, 3 or 4; 237 each R' is independently selected from hydrox , fluoro, chloro, NIL, 3HCHi N(CLH) 2 , CCH3, SEt, SCH3, methyl, ethyl, isopropyl, vinyl, triftuoromethyl, methoxy, ethoxy, isopiopoxy, and trifluoromethoxy; and R comprises between 4 and 14 carbon atoms and 0, 1, 2, 3, 4, or 5 heteroatoms independently selected from oxygen, nitrogen, sulfaiT. 206. The comestible or medicinal product, or a precursor thereof of claim 205 wherein A is a phenyl ing. 207, The comestible or medicinal product, or a precursor thereof of claim 206 wherein in is 1, 2, or 3. 208. The comestible or medicinal. product, or a precursor thereof of claim 206 wherein R2 is a Cs-C!- branched alkyl 209. The comestible or medicinal product, or a precursor thereof of claim 206 wherein Ris an substituted carboxylic acid or a-substituted carboxylic acid methyl ester. 210. The comestible or medicinal product, or a precursor thereof of claim 205 wherein the amide compound has the formula 0 2 R wherein R and R, hare independently hydrogen or methyl 211. The comestible or medicinal product, or a precursor thereof o f claim 210 wherein R 2 is a Cr-m branched alkyl 212. The comestible or medicinal product, or a precursor thereof of claim 210 wherein R 2 is an a-substituted carboxylic acid or a-substituted carboxylic acid methyl ester 213, The comestible or medicinal product, or a precursor thereof of claim 205 wherein A is a monocyclic heteroaryl having one of the formulas oor RY 4k H N N A (K 1 y__~~~ or Q NY ( C b (R (R 238 'Y '' p 1 N N~ N or ~OF or (R Ror S IN (R or or (Ri N (RI (R wherein mn is 0, 1, 2, or 3, and each Rl is independently selected from hydrogen, hydroxy, fluoro, chloro, NH12, NHCH , N(CH,)2, CO2.CH3, SEt, SCHI, methyl, ethyl, isopropyl, vinyl, trifluoromecthyl, mnethoxy, ethoxy; isopropoxy, and trifluoroJethoxy. 214. T'he comestible or medicinal product, or a precursor thereof of claim 213 wherein R is a CiCs0 branched alkyl 215. The comestible or medicinal product, or a precursor thereof of claim 213 wherein 1 2 is an Qosubsituted carboxylic acid or a-substituted carboxylic acid methyl ester. 216, The comestible or medicinal product, or a precursor thereof of claim 205 wherein the miaied comestible or medicinal product is a food fco human consumptin. 217 The comestible or medicinal product, or a precursor thereof of ai claim 205 215 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 fbods, dried foods, chilled foods, oils and fats, baby foods, and spreads. 213. A comestible product, or a precursor thereofofulaim 205 comprising one or more meats, poultry, fish, vegetables, grains, or fiits. 239 219. A comestible product, or a precursor thereof of claim 205 that is a frozen food, an uncooked food, or a fuliy or partially cooked food. 220. A comestible product, or a precursor thereof of claim 205 that is a soup, a dehydrated or concentrated soup, or a dry soup. 221. A comestible product, or a precursor thereof of claim 205wherein the modified comestible or medicinal product is a snack food. 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. 223. A comestible product, or a precursor thereof of claim 205wherein the modified comestible ortmedicinal 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. 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. 225, A comestible product, or a precursor thereof of claim 205 wherein the modified comestible or medicinal product is a soda, or juice. 226 A comestible product, or a precursor thereof of claim 205 wherein the modified comestible or medicinal product is an alcoholic beverage. 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 coniposition for oral administration. 228. A comestible product, or a precursor thereof of claim 205 wherein the modified comestible or medicinal product is an oral hygiene product.
98. 229. A comestible ormedicinal 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 H 0 240 wherein A and B are independently an aryl heteroaryl, cycloalkyl, or a heterocycle comprising 5 to 12 ring atoms; rn and n are independently 0, 1, 2, 3 or 4-8, R is hydrogen or an alkyl comprising one to four carbon atoms; R is absent or a C 5 Cs aikylene; R 0 and RE are independently selected from the group consisting ofhydrogen, hydroxy, fiuoro, chloro, NI NHCH 3 , N(C1 3 2, CO 2 CH 3 , SEt, SCHI, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two ofR together forn a methylenedioxy ring.
99. 230. A comestible product, or a precursor thereof of claim 229 wherein A and B are independently a phenyl, pyridyl, ftiranyl, beuzofuranyI, pyrrole, benzothiophene, piperidyl, cyclopentyl, cyciohexyl, or cycloheptyl ring; i and n are independently 0, 1, 2, or 3; R5 is hydrogen or methyl; R: is ~CH or -CH 2 CH2 231, A comestible product, or a precursor thereof o f claim 230 wherein B is an optionally substituted pyridine ring.
100. 232. A comestible product, or a precursor thereof of claim 231 wherein the pyridyl-R radical has the structure j% 4 1 015
101. 233. A comestible product, or a precursor thereof of claim 229 wherein the aide compound is an oxalamide compound having the formula (R~hN ~WN V ,N P(R%~ wherein A is a substituted ary, or heteroaryl ring comprising five to 12 carbon atoms; m and n are 0, 1. 2, or 3: each R' and R is independently selected from the group consisting o fhydrogen, hydroxy, fluoro, chloro, NH, NHCH 3 , N(CH) CO 2 CH3t.SEt, SCH 3 , methyl, 241 ethyl, isopropyl, vinyl, rifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two of R 0 together form a methylenedioxy ring. 234, A comestible product, or a precursor thereof of claim 233 wherein A is a 2-, 3-, or 4-mono-substituted phenyl, 2,4-, 2,3-, 2,5, 26 3,5-, or 3,6-disubstituted phenyl, 3 alkyl~4-substituted phenyl, a tii-substitated phenyl, wherein the R 72 groups are independently selected from the group consisting of, hydroxy, fluoro, chloro, NH2, NHCH 3 , N(CH4) 2 , COCH 3 , SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two of R together form a methylenedioxy ring
102. 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, fluoro, chioro, NHt, NHCH 3 , N(CH) 2 , CO 2 CH 3 , SPt, SCHI-, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy group.
103. 236. A comestible product, or a precursor thereof of claim 233 wherein A has one of the formulas T or or R(R Rn Az' Ii G' or 01' (R(RI(R (R VY 'Y _R~ I ( R R2 242 (RTN N wherein m is 0 1 2, or 3, and each R is independently sewcted from independently selected from hydroxy, fluoro, chloro, NIH2, NHCHU I. N(CH 2)2, COOCH 3 , SCH;, SEt, methyl, ethyl, isopropyl, vinyl, tif!uoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy 237 An oxalanide compound having the formula 0 ) H 8 " A-- N aR 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 R? 0 P. is independently selected from the group consisting of, hydroxy, fluoro, chloro, N1 2 . NHC1 3 , N(CH3). COOCH3, SC 3 , SEt, methyl, ethyl, isopropyl, vinyl, tiifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, or two of RS 3 together foni a methylenedioxy ring; or a comestibly acceptable salt thereof
104. 238. The oxalamide compound of claim 237' herein B is a pyridyl ring,
105. 239. The oxalamide compound of claim 237 wherein the pyridyl-R radical has the structure or
106. 240. The oxalamide compound of claim 238 wherein A is a phenyl ring.
107. 241. The oxalamide compound of claim 240 wherein B is a pyridyl ring.
108. 242. The oxalamide compound of claim 240 wherein the pyridyl-R radical has the structure 243 241 The oxalanide compound of claim 237 wherein A has one of the formulas (R RR -RR (R (R (Rx if o (R N r < I ps (R(RyR wherein m is 01, 2, or 3, and each R 'is independently selected from, hydroxy, fluoro, chloro, NH2,3NHCH3, N(CH3)2 COOCH3, SCH3,SEt, meth, etyI isopropyL, vinyl, trifluoromiethyl, methoaxy, ethoxy, isopropoxy, and trifluoromethoxy
109. 244. The oxalamide compound of claim. 243vwherein B is a pyridyl ring, 24i. The oxalamide compound of claim 244 wherein the pyridyl~-R"radical has the s;tmeture di244 or N
110. 246. An oxalamide compound of claim 237 having the fonnula NI1-(2-methoxy-4-methylbenzyl)-N(2-(pyridinl-yi)ethyl)oxalamide, NI-(2,4-dimethoxybenzyl)-N2-(245methylpyridin-2-vl)ethyl)oxalamide, N14t2,4-dimethylbenzy)-N2(2yidin-2-yl)ethyi)oxalamide, N1-(24-dimethoxybenzy)-N2-(24pyridin-2-ylethyl~oxalamnide, N-(2,4-Dimethoxy-benzyl)-N(2-pyridin-2-yl-ethy)oxaiamide; or a comestibly acceptable salt thereof
111. 247. A comestible or medicinal product, or a precursor thereof comprising at least a sweet flavor modulating amount of at least one non-naturally occuning amide compound, or a comestibly acceptable salt thereof, wherein the amide compound has the frmula 0 (R.) -A N R wherein A is an optionally substituted phenyl ring or is a hetroaryl ring having one of the formulas 0 ~ ~ ror (R C J( 1 r( R' TIN Or 4 ' or ~ 1 (R (R (R-- E N. - nor 245 Oor or (R ('R N( i I or N or (Rh ~ R' (R' wherein ma is 0 1 2, or 3, and each R. is independently selected from, hydroxy, fluoro, chloro, NH 2 , NHCHa, N(CH) 2 , COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, and wherein R 2 is a branthed C-C 0 aikyl, or a cyclohexyL tetrahydronapthalene, or indanyl group, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting ofhydroxy, fluoro, chioro, NH., NHCH 3 , N(CH3) 2 , COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifuoromethoxy 248, The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R 2 is a branched CyCi alkyl 249, The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R 2 is an optionally substituted cyclohexyl ring.
112. 250. The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R 2 is a cyclohexyl, optionally substituted with 1, or 3 methyl groups.
113. 251. The comestible product or medicinal product, or a precursor thereof of claim 247 whereinR 2 has the formula 24 246
114. 252. The cornestible product or me dicinal product, or a precursor thereof of claim 247 wherein R2 is a I ndanyl having the formula wherein in is 0,, 2, or 3, and each R2 is independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 ), COOCH;, SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and tiffluoromethoxy, 251 The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene having the formula wherein in is 0,1, 2, or 3, and each R 2 can be bonded to either the aromatic or non aromatic ring and is independently selected fron hydroxy fluoro. chloro, NH, NHCH 3 , N(CH ), COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, 254, The comestible product or medicinal product, or a precursor thereof of claim. 247 wherein RA has the formula or or RR oor r R wherein R is hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CHb) 2 , COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoiomethoxy. 247 255, The comestible product or medicinal product or a precursor thereof of claim 247 wherein R has the formula or >~ 256, The comestible product or medicinal product or a precursor thereof of claim 247 wherein R] has the formula C-. ~ or 257 The comestible product or medicinal product, or a precursor thereof of claim 247 wherein P? is a 1-(1,2,3,4) tetrahydronapthalene ring having the formula 258& The comestible product or medicinal product, or a precursor thereof of claim 247 whereiR2 is an (R)~1-(1,2,3,4) tetrah~ydroniapthalene ring having, the formula
115. 259. The comestible product or medicinal product, or a precursor thereof of claim 247 wherein R2 is an (R)-/L,2,3,4) tetrahydronapthalene ring having the formula 26.1 The comestible orxmedicinal product, or a precursor thereof of claim 247wherein the modified comestible or medicinal product is, a food for hurnan consumption.
116. 261. The comestible or medicinal product, or a precursor thereof of claer7in the modified comestible or medicinal product is selected from the group consisting 248 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
117. 262. A comestible product, or a precursorthereof of claim 247 comprising one or more meats, poultry, fish, vegetables, grains, or ufiits. 261 A comestible product, or a precursor thereof of claim 247 that is a frozen food, an uicooked food, or a flly or panially cooked food, 264, A comestible product, or a precursor thereof of claim 247 that is a soup, a dehydrated or concentrated soup, or a dry soup
118. 265- A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is a snack food. 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. 267, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is a cake, cookie, pie, candy, chewing gom, gelatin, ice cream, sorbet, pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or f&it sauce.
119. 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.
120. 269. A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is a soda, or juice.
121. 270. A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is an alcoholic beverage.
122. 271. A comestible product, or a precursor therof of claim 247 wherein the modified comestible or medicinal product is a pharmaceutical composition for oral admnistratior. 272, A comestible product, or a precursor thereof of claim 247 wherein the modified comestible or medicinal product is an oral hygiene product
123. 273. An aide compound having the formula 249 A NR 2 H wherein A is a phenyl ring or is a heteroaryl ring having one of the formulas P P Or or (R In H T (ICR Q or mR1 In ( I S 'A m n i N ~ N N.; (!. or s y 'r N" 2 wherein m is 0, 1, 2, or"3, and each R" is independently selected from, hydroxy, fluoro, chloro, NH12, NHCH3,N(CH )2, COOCT-1, SCH,3, SEt, meth-yL ethyl iso pro pyl, vinyl tiffluoromiethyl, methoxy, ethoxy, isopropoxy, and triffloromecthloxy , and wherein Rs (a)a abran(hedC C alkl or (b)Oacyclohexyl, tetrahydronapthalene, or indany group, optionally substitutedwth 1, 2 or 3 substituents independently selected from the goup consisting of hvydroxy, fluoro, t ~t-:250 chloro, NH 2 , NHCH3, N (C113)2, COOCH 3 , SCH SEt, methyl, ethyl, isopropyl, Vinyl, trifluoromethyl, methoxy, etboxy,isopropoxy, and trifluoromethoxy; or a comestibly acceptable salt thereof
124. 274. The amide compound of claim 273 wherein R2 is a branched CCi alkyl 275 The amide compound of claim 274 wherein A is an optionally substituted phenyl ring. 276, The amide compound of claim 274 wherein A is an optionally substituted pyridyl ring.
125. 277. The amid compound of claim 274 wherein A is a heteroaryl ring having the formula N'j 0-: wherein R is hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CH 3 )2, COOOH, SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxv, and trifluoromethoxy.
126. 278. The aniide compound of claim 275 wherein R2 is an optionally substituted cyclohexyl ring.
127. 279. The anide compound of claim 275 wherein the cyclohexyl ring is substituted with 1, 2, or 3 methyl groups.
128. 280. The aide compound of claim 275 wherein PA has the formula 281 The aide compound of claim 275 wherein R is a 1-indanyl having the formula wherein n is 0,1, 2, or 3, and each R is independently selected from, hydroxy, fluoro, chloro, NH 2 , NHCH, N(CH 3 ) 2 , COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. 251
129. 282. The amide compound of claim 275 wherein R2 is a -(,2,34) tetrahydronapthalene having the formula wherein m is 0,1, 2, or 3, and each R can be bonded to either the aromatic or non aromatic ring and is independently selected from, hydroxy, fluoro, chloro, NH 2 , NHCH 3 , N(CHt)2, COOCH3, SCH , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. 283 The amaide compound ofclahn 275 wherein R2 has the formula e -9 R oor R whereina each R 2'is indepenldenatly selected from the group corasisting of hydrogen, hydroxy, fluoro, chloro, N.H2, NHCH3, N(CH3)2, COOCH3, SCH3, SEt, methyl, ethyl isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy
130. 284. The amide compound of clahn 275 wherein R2 has the forma Or
131. 285. The amide compound of claim 275 wherein R2 has the formula
132. 286. The amide compound of claim275 wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene ring having the fonnula 287, The aide compound of claim 275 wherein .R is an (R)-1-(,23,4) tetxahydronapthalene ring having the formula
133. 288. The amide compound of claim 277 wherein R 2 is an optionally substituted cyclohexyl ring.
134. 289. The aide compound of claim 277 wherein the cyclohexyl ring is substituted with 1, 2., or 3 methyl groups.
135. 290. The amide compound of claim 277 wherein R 2 has the fornula ?~~ or$ 291, The amide compound of claim 277 wherein R 2 is a 1-indanyl having the formula wherein m is 0,1., 2, or 3, and each R 2 can be bonded to either the aromatic or non aromatic ring and is independently selected from hydrogen, hydroxy, fluoro, chloro NH2, NHCH 3 , N(CH3) 2 , COOC H, SCH, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
136. 292. The aide compound of claim 277 wherein R2 is a 1-(1,2,3,4) tetrahydronapthalene having the formula 253 (R wherein m is 0,2, or 3, and each R" can be bonded to either the aromatic or non aromatic ring and is independently selected from hydroxy, fluoro, chloro, NH7, NHCH 3 , N(CH) 2 , COOCH, SCH, SEt, methyl, ethyl. isopropyl, vinyL trifluorometbyl, methoxy, ethoxy, isopropoxy, and tifluoromethoxy.
137. 293. The amide compound of claim 277 wherein R 2 has the fomxla N: R2 A Aor or r 2 wherein each R 2 is independently selected from the group consisting of is hydrogen, hydroxy, fluoro, chloro, NH 2 . NHCH 3 , N(CH 3 )2, COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy., ethoxy, isopropoxy, and trifluoromethoxv
138. 294. The amide compound of claim 277 wherein R2 has the formula 295, The aide compound of claim 277 wherein R 2 has the fonrula 2? CYor 254
139. 296. The amide compound of claim 277 wherein R is a 1-(1,2,3,4) tetrahydronapthalene ring having the formula
140. 297. The amide compound of claim 277 wherein R is an (R)-1-(1,2,3,4) tetrahydronapthalene ring having the formula 298 An aide compound having the formula: 3-chioro-2-hydroxy-N-(2-methyl- 1,2,3,4-tetrahydronaphzhaien- I -yl)benzamide, 3- chloro-2-hydroxy-N -(5nethoxy- 1,2,3,4-tetrahydronaphthalin- 1-yl)benzamidc, (R)-3-chloro-2-hydroxy-N-(1,2,3,4-tetrahydronaphthalen-1. -yl)benzamide, 3,-chloro-2-hydroxy-N-(5-hydroxy- 1,2,3,4-tetrahydronaphthalen I -yl)benzamide, 3-chloro-2-hydroxy-N-(4-nethyl- 1,23,44-tetrahydronaphthalen-i1-Iy)benzamide, 3-chloro-2-hydroxy-N-(6&methoxy-1,2,3,4-tetrahvdronaphthalen -I -yl)benzamide, 3-chioro-2-hydroxy-N-(,2,3,4-tetrahydronaphthaien-I -yl)benzamide, 2,3-dihydroxy-N-(2-methyl-I,2,3,4-tetrahydronaph thalen- yl)benzamide, 2-hydroxy-N-(2-methyl 1,2,3,4-tetrahvdronaphthalen- 1 -yi)benzamide, 2,3-dihydroxy-N-(5-methoxy-1,2,34-tetrahydronaphthalen-1-yl)benzamide, (S)-2,6-dinethyl-N-(1,2,3,4-terthydronaphthalen- yl)benzamide, N-(5,7-dimethyl- ,2,3,4-tetrahydronaphthalen-i-yl)~3-methylisoxazole-4 carboxamide, 3-methyl-N-(2-methyl-1;2,3,4-tetrahydronaphthalen I yl)isoxazoie-'4-carhboxamide, 3-methyl-N-(4-methyl I1,2,3,44etrahydronaphthalen- 1-yl)isoxazole-4-carboxamide, N-(5~methoxy-,2,3,4-tetrahydronaphthalenlryl)-3-methylisoxazole-4~ carboxamnide, (R)-5-bromo-N-(1,23 3,44etmahydronaphthalen-1-ywi)nicotinarni do, (R)-3-methyl-N-(1,23,44etrahydronaphthailen-1-yl)isoxazole-.4-carboxamide, (S)-5bromo-N-(L2,3,4-tetrahydronaphthalen- 1-yi)nicotinamide, (R)-N.(1,2,3,4-tetrahvdronaphthalcn- -yl)furan-3-carboxamide, 25.5 (R)-..5-methylN-( 1,2,3,4-tetrahydronaphthaien1-yl)isoxazoie-4-carboxamide (R4-Nj(1,2,3,4-tetrahydronaphthaien-1-yl)fitran-3-.carboxamide, 3-methyi-N-(1,2,3,4 -tetrahydronaphthalen- 1 yflisoxazole-4carboxamide, N-3,3-dunethyibutan-2-yl)-2,3,56-tetrafluoro-4methylbenzamide, 2,3,5,6-erafuoro4-methy-N(3nethylbutan-2-yl)benzamide, 2,3,5,6-tetrafluoro-4-methyl-N-(2-methylcycohexyl)benzamide, N-(2-methylcyciohexyi>3jtrifluoromethoxy)benzamide, 3-chioro-5-fluoro4N (2-methyicyciohexyl)benzamide, (R)-N-(3,3adietyibutan-2yl)-2,3,5tetrathoro-4-methylbenzamide, 4-fluoro-N-2-methyicyciohexyl)-3-trifluoromethy)benzamide, (S)~2,3,5,6-tetrafluoro-4-methyl~N~(3-methylbutan-2-yl)benzamide, 2,5-dichoroN42-methylcyciohexyi)benzamide, 3,5dichloro2,6-dimxethoxyN-(2-methyicyciohexyibenzamide, or 2,6-dimethy-N-2-methydyiohexy)benzamide; or a comestibly acceptable sal thereof
141. 299. A urea compound having the formula: N' N H H wherein R 7 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, NH2, NHJCHL N(CH3)t, C0 2 CH3, SEt, SCH 3 , methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, ispropoxy, and trifluoromethoxy, and R? is a branched Cr~Cm alkyl, or a cyclohexyl, tetrahydronapthlalene, or indanyl group, optionally substituted with 1, 2, or 3 substituents independent selected from the group consisting of hydroxy, fluoro, chioro, Nil 2 NHCE, N(CHla), COOC~t, SCHE, SEt, methyl ethyl, isopropyl, vinyt tiifluoromethyt methoxy, ethoxy, isopropoxy, and trifluoromethoxy ; or a comrestibly acceptable salt thereof.
142. 300. The compound of claim 299 wherein R 7 is an optionally substituted phenyl ring
143. 301. The compound of claim 300 wherein R 9 is a branched CrCo aikyl 256
144. 302. The compound of claim 300 wherein Re is is an optionally substituted cycohexyl ring. 303, The compound of claim 302 wherein the cyclohexyl ring is substituted with 1, 2, or 3 methyl groups 304, The compound of claim 302 wherein R9 has the formula 30-5 The compound of claim 299 wherein R9 is a 1-indanyi having the formula wherein mn is 0, 1, 2, or 3, and each R9 is independently selected fr'oml hydrogen, hydroxy, fluoro, corNH2, NHCH3, N(CH3)2 COOCH , SCH3,, SM, methyl, ethyl, isopropyl, vinyl, tiifluoromethyl, methoxy, ethoxv, isopropoxy, anld trifluoromethoxy.
145. 306. The amaide compound of claima 299 wherein R9 is a 1-(l,2,.3,4) tetrahydronapthalene having the formula wherein m is 0,a2, or 3, and each-R9 can be bonded to either the aromatic or non aromatic ring and is independently selected fuom, hydroxy, fluoro, chloro, NH NHCH 3 , N(CH 3 ) 2 , COOCH 3 , SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy
146. 307. The amide compound of claim 299 wherein R9 is a 1-(1,2,3,4) tetrahydronapthalene ring having the formula 308 The amide compound of claim 299 wherein R7 is a heteroaryl ring having one of the formulas 257 (R(Rt z(R'Y N RR N Ns (RrX (RIVxs (R) R S kk (R" or 5 -1 " ; hydroxy, fluoro, chloro, NHz NHCH3a N(CH3),, COOCH3, SQH3, SEt, mnethy], ethyl, isopropyl, vinyl, t-lrcifiromthyl, methoxy, ethoxy, isopropoxy, id trifluoromethoxy.,
147. 309. The compound of claim 308 wherein R9 a branched C,,Cto alkyl. 310 The compound of claim 308 wherein R? is an optionally substituted cyclohexyl ring&
148. 311. The compound of claims 308 wherein the cyclohexyl ring is substitued with) 1, 2, or 3 methyl groups,
149. 312. The compoundRof claim 308 whereinR? has the foNmula 258
150. 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 2991-312.
151. 314. A urea compound having the formula: Rs R K R . N N HH wherein R? 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, chloto, NH 2 , NHCH. N(CH 3 )7 COOCH 3 SCH, SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyL methoxy. ethoxy, isopropoxy, and trifluoromethoxy, and R? has the structure j B-#(Rlm st HC G~ B~(iRm RC or R wherein R'is hydrogen, a 0 :-Cio alkyl, B is a phenyl, pyridyl, furanyl, thiofuranyl, pyrrole, cyclopentylcyclohexyl, or piperidyl ring, m is 0,1, 2, or 3, and each R is independently selected from hydrogen, hydroxy, fluoro, chloro, NH 2 , NHCH 2 , N(CH 3 ) 2 , COOCH, SCH 3 , SEt, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy. or a comestibly acceptable salt thereof 315 The compound of claim 314 wherein R7 is an optionally substituted phenyl ring and B is phenyl or pyidyl.
152. 316. The compound of claim 314 wherein R7 is an optionally substituted phenyl ring and B is and optionally substituted cyclohexyl
153. 317. A comestible or medicinal product, or a precursor thereof comprising at least a savory flavor modulating amount-ofat least one compound of claim 314, 318, An am ide compound having the formula (R)-methyl 2-3-chioro4methoxybenzamido)-4-methypentanoate, 4-methoxy3methyl-N-(5-methyhexan-3-y)benzaide, 259 N-(heptan-4~yl)-2-methylbenzo[df l 3]dioxole-5-carboxamide, (S)-methyi 4-methyl-2-(4-methyl3(methlthio)benzamido)pentanoate 4-methoxy-rmethy-N-(2amethylheptan-4-yi)benzamide, N-(heptan-4-il)-6-methylbenzo[di)[hi,3]dioxole-5-carboxamide, 3,4--dimethyl-N (2-methylhexan-3-yl)benzamide. (R)-methyl 4-methyb2(methylbenzofran-2carboxmido)pentanoate, N-(hexan-3-yl)-4-methoxy>-methylbenzamide, N-heptan-4/yl)3-methy4-methylthi&)benzamide, N-(hexanm3-y)-3-methyl4-(methylthio)benzamide methyl 2-(-chloro~-methoxybenzamnido)hexanoate, 334Adimethy1~N42(methylheptan-4-yl)benzamide, N-hea y .4-dimnethyibenzamiide, N-(heptan-4-yl)-3,4-dimethylbenzanide, (R)-methyl 4-methyl-2-(4-(methylthio)benzamido)pentanoate, 4-ethoxy-N-(heptan-4-yl)3-nmethylbenzamide, 3,4-dimethylN-(5-Nmethylhexan-3-yl)benzamide, (R)-nethyl 4-,iethyb2-(4-vinylbenzarmido)pentanoate, 4&methoxy/3-methybN-(2-miethylhexan-3-yl)benzamide, N-(heptan-4-yl)benzo[d][1,3]dioxle-5-carboxamide, (R)-methyl 2-(benzo[d][1,3]dioxole.6&carboxanido)-44tnetiylpentanoate, (R)-N-(1-methoxy-4-methypentan-2-yl)-3,4-dimethyl benzamide, (R)-methyl-2-(2,3-dimethylfann-5~carboxamido)-4-methyipentanoate, or 4-M.ethoxy-Na(1 -methoxymethyi3-methyl-butyl)-3~nethy-benzamide; or a comestibly acceptable salt thereof 319 An arnide compound having the foirula: N-(heptan-4~yl)benzo[d][1,3]dioxole-5-carboxamide or N-(24-Dimethoxy-enzyl-N'2-pyridin-2-ythy)-oxaamide; or a comestibly acceptable salt thereof.
154. 320. A comestible or medicinal product comprising the compounds of claim 319 at a concentration between about 0:01 to about 10 ppn.
155. 321. The comestible or medicinal product of claim 320 wherein the comestible or medicinal product is a a food for human consumption.
156. 322. An urea compound having the formula: 1-(2-chloropheny)-3 -(heptan-4-yl)urea, 260 i-(214-dilchiorophenyi)-341l -phenylpropyi)urea, 1U2 ,4-dimiethoxypshny>-3-(heptan-4-yi'urea. 144-isopropyiphenyi -3(--(pyridihm2 -y1}ehyi )urea; or a coxneszibly acceptable safz therwof. 261