CA2612314C - Bis-aromatic amides and their uses as sweet flavor modifiers, tastants, and taste enhancers - Google Patents

Abstract

The inventions disclosed herein relate to man-made bi-aromatic amide compounds that, when contacted with comestible food or drinks or pharmaceutical compositions at concentrations preferably on the order of about 100 ppm or lower, serve as sweet taste modifiers, sweet flavoring agents, or sweet flavor enhancers, for use in foods, beverages, and other comestible products, or orally administered medicinal products or compositions, optionally in the presence of or in mixtures with conventional flavoring agents such as known natural saccharide sweeteners and previously known artificial sweeteners.

Description

BIS-AROMATIC AMIDES AND THEIR USES AS SWEET FLAVOR
MODIFIERS, 'TASTANTS, AND TASTE ENHANCERS
FIELD OF THE INVENTION
The present invention relates to the discovery of flavor or taste modifiers, such as a flavoring agents and flavor or taste enhancers, more particularly, sweet taste modifiers, sweet flavoring agents, and sweet flavor enhancers, for foods, beverages, and other comestible or orally administered medicinal produets or compositions.
BACKGROUND 01? TIIE INVENTION
For cennuies, various natural and unnatural compositions and/or compounds have been added to comestible (edible) foods, beverages, and/or orally administered medicinal composition.s to improve their taste. Although it has long been known that there are only a few basic types of "tastes," the biological and biochemical basis of taste perception was poorly understood, and most taste improving or taste modifying agents have been discovered largely by simple trial and error processes.
There has been significant recent progress in identifying useful derivatives of natural flavoring agents, such as for example sweeteners that are derivatives of natural saccharide sweeteners, such as for example erythritol, isomalt, Iactitol, mannitol, sorbitol, xylitol.
= There has also bee recent progress in identifying natural terpenoids, flavonoids, or proteins as potential sweeteners. See, for example, a recent article entitled "Noncariogenic Intense Natural Sweeteners" by ICinghorn et at (Med Res Rev (1998)18(5):347-360), which discussed recently discovered natural materials that are much more intensely sweet than common natural sweeteners such as sucrose, fructose, glucose, and the like.
Similarly, there has been recent progress in identifying ............................ exid conmiereializing new artificial sweeteners, such as aspartame, saccharin, acesulfame-K, cyclamate, Sucralose, and alitame, etc., see an article by Ager eta!. (Anger', Cheat fnt Ed (1998) 37:102-1817). The entire disclosures of the references identified above are hereby incorporated herein by reference, for the purpose of describing at least in part the knowledge of those of ordinary skill in the art regarding known sweetening agents.
Nevertheless, there remains in the art a need for new and .......... unproved flavoring agents and/or sweeteners. Discovery of new "High Intensity" sweeten= (i.e., many times sweeter Fir CT/ US GS fe.34-01.0 than sucrose) would be of considerable value, especially if the new compounds induce the perception of sweetness when used at extremely low concentrations. Similarly any compounds that, when used at very low concentrations significantly multiply (enhance) the sweetness of known natural or artificial sweeteners, so that less of the known caloric sweeteners would be required, while maintaining or amplifying the perceived taste of the natural sweeteners, could be of very high utility and value in view of the rapidly increasing incidence of undesirable human weight gain and/or associated diseases such as diabetes, atherosclerosis, etc.
In recent years substantial progress has been made in bioteolmology in general and in better understanding the underlying biological and biochemical phenomena of taste perception. For example, taste receptor proteins have been recently identified in mammals that are involved in taste perception. Particularly, two different families of 0 protein coupled receptors believed to be involved in taste perception, T2Rs and Ms, have been Identified. (See, e.g., Nelson at aL, Cell (2001) 106(3):381-390; Adler at at., Cell (2000) 100(6):693-702; Chandrashelcar at at, Cell (2000) 100g03-711; Mataunami ei al., Number (2000) 404:601-604; Li et 4, Free Nati Acad Sci USA (2002) 99:4962-4966;
Montmayeur et at, Nature Neuroscience (2001) 4(S):492-498; US. Patent 6,462,148; and PCT
publications WO 02/06254, WO 00/63166 art, WO 021064631, and WO 03/001876, and Patent Publication US 2003-0232407 Al), 25 ' Whereas the T2R family includes over 25 genes that are involved in bitter taste percephon, the T1R family only includes three members, T1R1, T1R2 and T1R.3.
(See Li at al., Proc Natl Acad Act USA (2002) 99:49614966.) Recently, it was disclosed in WO 02/064631 and/or WO 03/001876 that certain T1R members, when co-expressed in suitable mammalian cell lines, assemble to form functional taste receptors. It was found that co-expression of T1R2 and T1R3 in a suitable host cell results in a functional T1R2/T1R3 "sweet" taste receptor that responds to different taste stimuli including naturally occurring and artificial sweeteners. (See Li et at, Pro' Nad Acad Sci USA (2002) 99:4962-4966.) The references cited above also disclosed assays and/or high throughput =

P Cir/USLIS,Sla3111=011:31 screens that measure T1R1/T1R3 or T1R2/T1R3 receptor activity by fluorometric imaging in the presence of the target c,ompounds.
It was recently reported in U.S. Patent Publication No. US 2005/0084506 Al, and in PCT Publication No. WO 2005041684, that various amide compounds can, at very low concentrations of a few micromolar or less, serve as savory and/or sweet flavoring agents, and/or savory and/or sweat flavor enhancers.
Disclosed herein are a new class of bis-aromatic amide compounds, which because of their particular structures, serve at unexpectedly low concentrations as unexpectedly superior and/or high intensity sweet flavorant or sweet enhancing compounds in comestible compositions. These compounds are particularly valuable when used as high intensity sweeteners in combination with other known but less potent sweeteners, such as frr The inventions disclosed and/or claimed herein have many aspects, many of which relate to methods of making or using comestible compositions containing certain non-(R2)rty R3 I
I

(I) wherein Arl, Ai?, L, le, R2, le, le, R5, m and m', some of which are optional, can be and are independently further defined in various ways, as is further detailed below in the that R5 is an organic group.

11; T 11õ11 S /- 311+0 In some aspects of the compounds of Formula (I):
i) Arl and Ar2 are independently selected from monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl rings;
ii) m is selected from the integers 0, 1, 2, 3, 4, or 5;
iii) m' is selected from the integers 0, 1, 2, 3, or 4;
iv) each RI and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
v) L is a carbon or nitrogen atom;
vi) R3 is hydrogen, oxygen, hydroxy, halogen, or a C1-C6 organic radical;
vii) R4 is absent, or hydrogen, oxygen, hydroxy, halogen, or a C1-C6 organic radical;
R5 is a C1-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.
In many embodiments of the compounds of Formula (I), L is a carbon atom. For example, in many aspects of the inventions disclosed herein relate to an amide compound having the structure:

(R2)m, R3 I /
(R1)m¨Ar1¨Ar2¨ N/R5 C

wherein i) Arl and Ar2 are independently selected from a phenyl, or monocyclic heteroaryl rings;
ii) m and m' are independently selected from the integers 0, 1, or 2;
iii) each RI and R2 is independently selected from the group consisting of OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a CI-CI organic radical;
iv) R3 and R4 are independently selected from hydrogen and a C1-C4 alkyl, C Tit S B õ,'" 253 *0 0 v) R is a C3-Cp3 branched alkyl optionally comprising one, two, or three substituents independently selected from OH, NH2, a halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.
Alternatively, in some related aspects of the compounds of Formula (I):
i) Ari and Ar2 are independently selected from monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl rings;
ii) m is selected from the integers 0, 1, 2, 3, 4, or 5;
iii) m' is selected from the integers 0, 1, 2, 3, or 4;
iv) each and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
v) L is a carbon atom;
vi) R3 is hydrogen, oxygen, hydroxy, halogen, or a Cl-C6 organic radical;
vii) R4 is hydrogen, oxygen, hydroxy, halogen, or a Cl-C6 organic radical; and viii) R5 is a Cl-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
In yet other aspects of the amide compounds of Formula (I):
a) Arl and Ar2 are independently selected phenyl or 5 or 6 membered monocyclic heteroaryl rings, b} each R1 and R2 is independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NHCH3, N(CH3)2, CN, OC(0)CH3, SCH3, S(0)CH3, S(0)2CH3, S(0)2NHCH3, SC2H6, methyl, ethyl, propyl, isopropyl, vinyl, ally!, CN, CH2OH, CH2OCH3, CH2OCH2CH3, C(0)H, C(0)CH3, methoxy, ethoxy, and isopropoxy groups, c) R3 and R4 are methyl, and d) R5 is a C3-C10 branched alkyl.
Many of the amide compounds of Formula (I) disclosed herein are novel compounds that have not been previously reported in the prior art. Many of the "amide"
compounds of Formula (I) and its subgenera are shown below to bind to and/or activate T1R2/T1R3 sweet receptors in-vitro, at unexpectedly low concentrations on the order of micromolar or lower.
The amide compounds of Formula (I) are also believed to similarly interact with sweet flavor receptors of animals or humans in vivo as has been confirmed in some cases by actual human taste tests of some of compounds of Formula (1), as described herein.
Accordingly, most or all of the subgenuses and species of the "amide"
compounds of Formula (1) further described hereinbelow can, at useful and often surprisingly low concentrations, preferably on the order of a few micromolar or less or a few ppm or less, be used in comestible compositions as sweet flavoring agents or sweet flavoring agent enhancers, so as to induce or enhance the sweet flavor of the comestible compositions.
Accordingly, in some embodiments, the invention relates to methods for modulating the sweet taste of a comestible or medicinal product comprising:
a) providing at least one comestible or medicinal product, or at least one precursor thereof, and b) combining the at least one comestible or medicinal product or at least one precursor thereof with at least a sweet flavor modulating amount of at Imst one non-naturally occurring amide compound, or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product;
wherein the amide compound is within the scope of any of the compounds of Formula (I) as disclosed or shown below, or any of its various genera or subgenera of compounds or species compounds, or their comestibly acceptable salts, as are further described below:

(R2)m, R3 (R1)m¨Ar1¨Ar2¨L

(I) In accordance with an aspect of the present invention there is provided, a method for increasing the sweet taste of a comestible or medicinal product comprising:
a. providing at least one comestible or medicinal product, or at least one precursor thereof, and b. combining the at least one comestible or medicinal product or at least one precursor thereof with at least a sweet flavor modulating amount of at least one bi-aromatic amide compound, or one or more comestibly acceptable salts thereof, so as to form a modified comestible or medicinal product;
wherein the amide compound has the structure:

(R2)m. R3 (R1)m¨Ari¨Ar2¨L

wherein i) Arl and Ar2 are independently selected from monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl rings;
m is selected from the integers 0, 1,2, 3, 4, or 5;
m' is selected from the integers-0, 1,2, 3, or 4;
iv) each RI and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
v) L is a carbon atom;
vi) R3 is hydrogen, oxygen, hydroxy, halogen, or a CI-C6 organic radical;
vii) R4 is hydrogen, oxygen, hydroxy, halogen, or a CI-C6 organic radical;
viii) R5 is a C1-C14 organic radical comprising a normal or branched alkyl or cycloallcyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof 6a In accordance with another aspect of the present invention there is provided, a method for increasing the sweet taste of a comestible or medicinal product comprising:
a. providing at least one comestible or medicinal product, or at least one precursor thereof; and b. combining the at least one comestible or medicinal product or at least one precursor thereof with from about 0.01 to about 100 ppm of at least one bi-aromatic amide compound, or a comestibly acceptable salt thereof, and a sweet flavoring agent amount of sucrose, fructose, glucose, or a mixture thereof, so as to form a modified comestible or medicinal product;
wherein the amide compound has the structure:

(R2) R3 (R1)m¨Arl¨Ar2¨C

wherein i) Arl and Ar2 are independently selected from phenyl, napthyl, indolyL
pyridyl, pyrimidyl, pyrrolyl, furanyl, thiofuranyl, quinolinyl, benzofuranyl, triazolyl, and benzothiofuranyl rings;
ii) m is selected from the integers 0, 1, 2, or 3;
iii) m' is selected from the integers 0, 1, or 2;
iv) each R1 and 112 is independently selected from the group consisting of a hydroxy, fluor , chloro, NH2, NO2, NHCH3, N(C113)2, COOCH3, SCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, ally!, S(0)CH3,.
S(0)2CH3, CN, CH2OH, C(0)H, C(0)CH3, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy radical;
v) R3 is a Ci-C4 alkyl;
vi) R4 is hydrogen, or a Ci-C4 alkyl;
vii) R5 is' a C1-C10 normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to or two substituents independently selected from hydroxy, fluor , chloro, NH2, NO2, NHCH3, N(CH3)2, COOCH3, SCH3, SC2115, methyl, ethyl, propyl, isopropyl, vinyl, allyl, S(0)CH3, S(0)2CH3, CN, CH2OH, C(0)H, C(0)CH3, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy radical;
or a comestibly acceptable salt thereof.
6b In accordance with another aspect of the present invention there is provided, a method for increasing the sweet taste of a comestible or medicinal product comprising:
a. providing at least one comestible or medicinal product, or at least one precursor thereof, and b. combining the at least one comestible or medicinal product or at least one precursor thereof with at least a sweet flavor modulating amount of at least one bi-aromatic amide compound, or one or more comestibly acceptable salts thereof, so as to form a modified comestible or medicinal product;
wherein the amide compound has the structure:

(R2)m, R3 (R1)m¨Ar1¨Ar2¨L

wherein Arl and Arz are independently selected from monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl rings;
ii) m is selected from the integers 0, 1,2, 3, 4, or 5;
iii) m' is selected from the integers 0, 1,2, 3, or 4;
iv) each RI and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
v) L is a carbon or nitrogen atom;
vi) R3 is hydrogen, oxygen, hydroxy, halogen, or a C1-C6 organic radical;
vii) R4 is absent, or hydrogen, oxygen, hydroxy, halogen, or a C1-C6 organic radical;
viii) R5 is a C1-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyi optionally comprises one to four substituents independently selected from OH, NH2, NO2, SIT, 803H, P0311, halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.
6c The invention also relates to the comestible or medicinal products produced by the methods and/or processes mentioned above, and to comestible or medicinal products or compositions, or one or more of their precursors, that contain the amide compounds of Formula (I), even if those products or compositions are not made by the processes recited herein.
In many embodiments, one or more of the amide compounds of Formula (I) further identified, described, and/or claimed herein, or one or more comestibly acceptable salts thereof, can be used singly, or in mixtures or in combination with other known sweet compounds or known sweeteners, or used as flavor enhancers in comestible food, beverage and medicinal compositions, for human or animal consumption.
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 compounds.
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 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 sweet taste thereof.
The present invention also relates to novel genuses and species of amide compounds within the scope of the compounds of Formula (I) and derivatives, flavoring agents, comestible or medicinal products or compositions, including sweet flavoring agents and flavor enhancers containing the same.
6d In accordance with another aspect of the present invention there is provided, a sweet comestible or medicinal product comprising from about 0.01 to about ppm of at least one hi-aromatic amide compound, or a comestdbly acceptable salt thereof, and at least a sweet flavoring agent amount of one or more natural, semi-synthetic, or synthetic sweet flavoring agents, or a mixture thereof, wherein the amide compound has the structure:

(R2)m. R3 (R1)m¨Arl¨Ar2¨C

wherein i) Art and Ar2 are independently selected from a phenyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl, furanyl, thiofuranyl, triazolyl, isoxazolyl, oxadiazolyl, or indolyl ring;
ii) m and Ile are independently selected from the integers 0, 1, or 2;
iii) each RI. and R2 is independently selected from the group consisting of OH, NH2, NO2, SH, SO3H, P0311, halogen, and a Ci-C4 organic radical;
iv) R3 and R4 are independently selected from hydrogen and methyl, v) R5 is a C3-C10 branched alkyl optionally comprising one, two, or three substituents independently selected from OH, NH2, a halogen, and a Ci-C6 organic radical;
or a comestibly acceptable salt thereof.
In accordance with another aspect of the present invention there is provided, a compound having the formula:
2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-isobutyl-2-methylpropanamide ;
2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methyl-N-(pentan-3-yl)propanaraide ;
(R)-N-sec-buty1-2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methylpropanamide ;
6e 2-(445-cyanopyridin-3-yl)pheny1)-N-isobutyl-2-methylpropanamide;
2-methyl-N-(2-methylbuty1)-2-(4-(pyrimidin-5-yl)phenyl)propanamide;
2-(4-(5-(ethoxymethyl)pyridin-3-yl)pheny1)-N-isobutyl-2-methylpropanamide;
N-isobuty1-2-(2-methoxy-31-(methoxymethyl)bipheny1-4-y1)-2-methylpropanamide;
N-isobuty1-2-(4-(6-(methoxymethyl)pyrazin-2-yl)pheny1)-2-methylProparramide;
N-isobuty1-2-(3'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanamide;
N-isobuty1-2-(4-(5-(methoxymethyl)pyridin-3-yl)pheny1)-2-methylpropanamide;
N-isobuty1-2-methy1-2-(4-(1-methyl-1H-pyrrol-2-yl)phenyl)proPanamide;
2-(2'-(hydroxymethyl)bipheny1-4-y1)-N-isobuty1-2-methylprop anamide;
(S)-N-(1-hydroxybutan-2-y1)-2-(3'-(methoxymethyl)bipheny1-4-y1)-2-methylprop anamide;
N-isobuty1-2-methy1-2-(4-(pyrimidin-5-yl)pheny1)propanamide;
2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(2-methoxypropy1)-2-methylpropanamide;
(R)-N-sec-buty1-2-(4-(6-cyanopyrnin-2-yl)pheny1)-2-methylpropanamide;
or a comestibly acceptable salt thereof.
The foregoing summary discussion merely summarizes certain aspects of the inventions and is not intended, nor should it be construed, as limiting the invention in any way.

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, and/or methods are disclosed 25 and described, it is to be understood that unless otherwise specifically indicated by the claims, the invention is not limited to specific foods or food preparation methods, specific comestibles or pharmaceutical carriers or formulations, or to particular modes of formulating the compounds of the invention into comestible or medicinal products or compositions intended for oral odministration, because as one of ordinary skill in relevant 30 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.

P / S Elt 17,1 Definitions 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.
An oral hygiene product includes solids and liquids such as toothpaste or mouthwash.
A "comestibly, biologically or medicinally acceptable carrier or excipient" is a solid or liquid medium and/or composition that is used to prepare a desired dosage form 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 milk or condensed milk, sugars such as sucrose, fructose, glucose, and the like, sugar alcohols such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, and the like,edible oils and shortenings, fatty acids, low molecular weight oligomers of propylene glycol, glyceryl esters of fatty acids, 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, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, or a mixture of any of the above.
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.
A "flavoring agent" herein refers to a compound or a biologically acceptable salt thereof that induces a flavor or taste in an animal or a human.
A "flavor modifier" herein refers to a compound or biologically acceptable salt thereof that modulates, including enhancing, potentiating, inducing, decreasing and/or blocking, the tastes and/or smell of a natural or synthetic flavoring agent in an animal or a human.
"Sweet flavoring agent," or "sweet compound" herein refers to any compound or biologically acceptable salt thereof that elicits a perception of detectable sweet flavor in a P C: T 11.11Si Eli S -3114-11,1 human subject, e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, Sucralose, and the like as is further discussed herein. While not wishing to be bound by theory, sweet flavoring agents are believed to be agonists of T1R2/T1R3 sweet taste receptor proteins in vitro and in vivo. Many of the amide compounds described herein are sweet flavoring agents, whose sweet taste is perceptible by a human.
A "sweet flavor enhancer" herein refers to a compound or biologically acceptable salt thereof that enhances, potentiates, or multiplies the sweet taste of another natural or synthetic flavoring agent in a comestible composition. For example, a sweet flavor enhancer can increase or multiply the sweet flavor of a comestible composition, when used in combination with another sweet flavoring agent (e.g., a sweetener, such as sucrose, fructose, glucose, saccharine, aspartame, Sucralose, etc.). While the sweet flavor enhancer may also have a sweet flavor at some concentrations when used in the absence of other sweeteners, sweet flavor enhancement occurs when the sweet flavor enhancer is used in combination with another sweet favoring agent with the result that the resulting sweetness perceived in a subject is greater than the additive effects attributable to the sweet flavor enhancer's own sweet flavor (if any), plus the sweetness attributable to presence of the other sweet flavoring agent. While not wishing to be bound by theory, in at least some cases sweet flavor enhancement may occur if the sweet flavor enhancer (such as one of the amide compounds of Formula (I)) functions as an allosteric modifier of the activity of T1R2/T1R3 sweet taste receptor proteins in vitro or in vivo.
A "sweet flavor modifier" herein refers to a compound or biologically acceptable salt thereof that modulates, including enhancing or potentiating, inducing, and blocking, the sweet taste of a natural or synthetic sweet flavoring agents, e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like, in an animal or a human.
A "sweet receptor activating compound" herein refers to a compound that activates a sweet receptor, such as a T1R2/T1R3 receptor.
A "sweet receptor modulating compound" herein refers to a compound that modulates (activates, enhances, or blocks) a sweet receptor.
A "sweet flavor modulating amount" herein refers to an amount of a compound of Formula (I) that is sufficient to alter (either increase or decrease) sweet taste in a comestible or medicinal product or composition, or a precursor thereof, sufficiently to be perceived by P C il.õ11 S 0 lEiE .7 2 3 14'11"..:11 a human subject. A fairly broad range of a sweet flavor modulating amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm, to about 10 ppm.
Alternative ranges of sweet flavor modulating amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.
A "sweet flavoring agent amount" herein refers to an amount of a compound (including the compounds of Formula (I), as well as known sweeteners) that is sufficient to induce a sweet taste in a comestible or medicinal product or composition, or a precursor thereof, as perceived by a human subject. A fairly broad range of a sweet flavoring agent amount for the compounds of Formula (I) 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 ppm to about 30 ppm, from about 0.05 ppm to about 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 of 15 Formula (I) that is sufficient to enhance, potentiate, or multiply the sweet taste of one or more natural or synthetic flavoring agents, or mixtures thereof (e.g., sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspertame, Sucralose, and the like as is further discussed herein) in a comestible or medicinal product or composition. A
fairly broad range of a sweet flavor enhancing amount can be from about 0.001 ppm to 100 ppm, or a narrow range from about 0.1 ppm to about 10 ppm. Alternative ranges of sweet flavor enhancing amounts can be from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 15 ppm, from about 0.1 ppm to about 5 ppm, or from about 0.1 ppm to about 3 ppm.
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 a sweet receptor modulating amount is 1 pM to 100 mM and most preferably 1 nM
to 100 ILL114 and most preferably 1 nM to 30 tt114.
A "T1R2/T1R3 receptor modulating or activating amount" is an amount of compound that is sufficient to modulate or activate a T1R2/T1R3 receptor.
These amounts are preferably the same as the sweet receptor modulating amounts.
A "sweet receptor" is a taste receptor that can be modulated by a sweet compound.
Preferably a sweet receptor is a G protein coupled receptor, and more preferably the sweet receptor is a T1R2/T1R3 receptor.

p E.:: T./ 11,3 Ot IEJ 3 11-11-P
Many coniPounciMS" 1 Formula (I) can modulate a sweet receptor and preferably are agonists of the T1R2/T1R3 receptor. An agonist of this receptor has the effect of activating the G protein signaling cascade. In many cases, this against effect of the compound on the receptor also produces a perceived sweet flavor in a taste test. It is desirable, therefore, that such inventive compounds serve as a replacement for sucrose, fructose, glucose, and other known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like, or mixtures thereof as is further discussed herein.
A "synergistic effect" relates to the increased sweet flavor of a combination of 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 sweet enhancer compounds, a synergistic effect on the effectiveness of a sweetener may be indicated for a compound of Formula (I) having an EC50 ratio (defined hereinbelow) of 2.0 or more, or preferably 5.0 or more, or 10.0 or more, or 15.0 or more. A
synergistic effect can be confirmed by human taste tests, as described elsewhere herein.
As used herein, "Degrees Brix" or "brix" (symbol Bx) refers to a measurement of the mass ratio of dissolved sucrose to water in a liquid. It is measured with a saccharimeter that measures specific gravity of a liquid, or more easily with a refractometer. A 25 Bx solution has 25 grams of sucrose sugar per 100 grams of liquid. Or, to put it another way, there are 25 grams of sucrose sugar and 75 grams of water in the 100 grams of solution.
When the compounds described here include one or more chiral centers, the stereochemistry of such chiral centers can independently be in the R or S
configuration, or a mixture of the two. The chiral centers can be further designated as R or S or R,S or d,D, 1,L
or d,l, D,L. Correspondingly, the amide compounds of the invention, if they can be present in optically active form, can actually be present in the form of a racemic mixture of enantiomers, or in the form of either of the separate enantiomers in substantially isolated and purified form, or as a mixture comprising any relative proportions of the enantiomers.
Regarding the compounds described herein, 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 (CH2)n; "alkenylene" is such a moiety that contains a double bond; and "alkynylene" is such a moiety that contains a triple bond.
As used herein, "hydrocarbon residue" refers to a chemical sub-group or radical within a larger chemical compound which contains only carbon and hydrogen atoms. The P C T11 10.136 2 311011-113 Int 'nydr6bar on residue may be aliphatic or aromatic, straight-chain, cyclic, branched, saturated or unsaturated. In many embodiments the hydrocarbon residues are of limited dimensional size and molecular weight, and may comprise 1 to 18 carbon atoms, 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, I to 6 carbon atoms, or 1 to 4 carbon atoms.
The hydrocarbon residue, when described as "substituted," contains or is substituted with one or more independently selected heteroatoms such as 0, S, N, P, or the halogens (fluorine, chlorine, bromine, and iodine), or one or more sub stituent groups containing heteroatoms (OH, NH2, NO2, SO3H, and the like) over and above the carbon and hydrogen atoms of the sub stituent residue. Substituted hydrocarbon residues can also contain carbonyl groups, amino groups, hydroxyl groups and the like, or contain heteroatoms inserted into the "backbone" of the hydrocarbon residue.
As used herein, "inorganic" group or residue refers to a neutral, cationic, or anionic radical substituents on the organic molecules disclosed or claimed herein that have from one to 16 atoms that do not include carbon, but do contain other heteroatoms from the periodic table that preferably include one or more atoms independently selected from the group consisting of H, 0, N, S, one or more halogens, or alkali metal or alkaline earth metal ions.
Examples of inorganic radicals include, but are not limited to, H, Li, Na, K+, Zn++, Mg, Ca, halogens, which include fluorine, chlorine, bromine, and iodine, OH, SH, SO3H, S03-, PO3H, P03-, NO, NO2, NH2, and the like.
As used herein, the term "alkyl," "alkenyl," and "alkynyl" include straight-and branched-chain and cyclic monovalent sub stituents that respectively are saturated, unsaturated with at least one double bond, and unsaturated with at least one triple bond.
"Alkyl" refers to a hydrocarbon group that can be conceptually formed from an alkane by removing hydrogen from the structure of a non-cyclic hydrocarbon compound having straight or branched carbon chains and replacing the hydrogen atom with another atom or organic or inorganic substitutent group. In some embodiments of the invention, the alkyl groups are "Ci to Cg alkyl" such as methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, and the like. Many embodiments of the invention comprise "C1 to C4 alkyl" groups (alternatively termed "lower alkyl"
groups) that include methyl, ethyl, propyl, iso-propyl n-butyl, iso-butyl, sec-butyl, and t-butyl groups.
Some of the preferred alkyl groups of the invention have three or more carbon atoms preferably 3 to 16 carbon atoms, 4 to 14 carbon atoms, or 6 to 12 carbon atoms.

Pc TS USREPISrm.'12µ4hilctiiMifoleriotes a hydrocarbon group or residue that comprises at least one carbon-carbon double bond. In some embodiments, alkenyl groups are "C2 to alkenyls" which are exemplified by vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, as well as dienes and trienes of straight and branched chains. In other embodiments, alkenyls are limited to two to four carbon atoms.
The term "alkynyl" denotes a hydrocarbon residue that comprises at least one carbon-carbon triple bond. Preferred alkynyl groups are "C2 to C7 alkynyl"
such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 2- hexynyl, 3-hexynyl, 4-hexynyl, 2-heptynyl, 3-heptynyl, 4- heptynyl, 5-heptynyl as well as di- and tri-ynes of straight and branched chains including ene-ynes.
The terms "substituted alkyl," "substituted alkenyl," "substituted alkynyl,"
and "substituted alkylene" denote that the alkyl, alkenyl, alkynyl and alkylene groups or radicals as described above have had one or more hydrogen atoms substituted by one or more, and preferably one or two organic or inorganic substituent groups or radicals, that can include halogen, hydroxy, C1 to C7 alkoxy, alkoxy-alkyl, nitrite, amide, and substituted amide, oxo, Ca to C7 cycloalkyl, naphthyl, amino, (monosubstituted)amino, (disubstituted)amino, guanidino, heterocycle, substituted heterocycle, imidazolyl, indolyl, pyrrolidinyl, C1 to C7 acyl, C1 to C7 acyloxy, nitro, carboxy, carbamoyl, carboxarnide, N-(C1 to C6 alkyl)carboxamide, N,N-di(C1 to C6 alkyl)carboxamide, cyano, C1 to C4 alkylsulfonamide, thiol, C1 to C4 alkylthio or Ci to C4 alkylsulfonyl groups. The substituted alkyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents. In many embodiments of the invention a preferred group of substituent groups include hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, CO2CH3, SH, SC2H5, S(0)CH3, S(0)2CH3, SCH3, SO3H, PO3H, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups. In many embodiments of the invention that comprise the above lists of substituent groups an even more preferred group of substituent groups include hydroxy, SC2H5, SCH3, methyl, ethyl, isopropyl, trifluromethyl, methoxy, ethoxy, and trifluoromethoxy groups.
Examples of the above substituted alkyl groups include the 2-oxo-prop-1-yl, 3-oxo-but-1-yl, cyanomethyl, nitromethyl, chloromethyl, trifluoromethyl, hydroxymethyl, tetrahydropyranyloxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, allyloxycarbonylmethyl, allyloxycarbonylaminomethyl, methoxymethyl, jçzC T/ S u-11- Ell 0 ethoxymethyl, t-butoxyrnethyl, acetoxymethyl, chloromethyl, trifluoromethyl, 6-hydroxyhexyl, 2,4-dichloro(n-butyl), 2-aminopropyl, 1-chloroethyl, 2-chloroethyl, 1-bromoethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 1- iodoethyl, 2-iodoethyl, 1-chloropropyl, 2-chloropropyl, 3- chloropropyl, 1-bromopropyl, 2-bromopropyI, 3-bromopropyl, 1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 2-amino ethyl, aminoethyl, N-benzoy1-2-aminoethyl, N-acetyl-2-aminoethyl, N-benzoy1-1 -amino ethyl, N-acetyl-l-aminoethyl, and the like.
Examples of substituted alkenyl groups include styrenyl, 3-chloro-propen-l-yl, 3-chloro-buten-l-yl, 3-methoxy-propen-2-yl, 3-phenyl-buten-2-yl, 1-cyano-buten-3-yl, and the like. The geometrical isomerism is not critical and all geometrical isomers for a given substituted double bond can be included.
Examples of substituted alkynyl groups include phenylacetylen-l-yl, 1-phenyl-2-propyn-1-y1 and the like.
Haloalkyls are substituted alkyl groups or residues wherein one or more hydrogens of the corresponding alkyl group have been replaced with a halogen atom (fluorine, chlorine, bromine, and iodine). Preferred haloalkyls can have one to four carbon atoms.
Examples of preferred haloalkyl groups include trifluoromethyl and pentafluoroethyl groups.
Haloalkoxy groups alkoxy groups or residues wherein one or more hydrogens from the R group of the alkoxy group are a halogen atom (fluorine, chlorine, bromine, and iodine). Preferred haloalkoxy groups can have one to four carbon atoms.
Examples of preferred halo alkoxy groups include trifluoromethyoxy and pentafluoroethoxy groups.
The term "oxo" denotes a carbon atom bonded to two additional carbon atoms substituted with an oxygen atom doubly bonded to the carbon atom, thereby forming a ketone radical or residue.
"Alkoxy" or "alkoxyl" refers to an -OR radical or group, wherein R is an alkyl radical. In some embodiments the alkoxy groups can be C1 to C5, and in other embodiments can be C1 to C4 alkoxy groups, wherein R is a lower alkyl, such as a methoxy, ethoxY, n-propoxy, isopropoxy, n-butoxy, t-butoxy, and like alkoxy groups. The term "substituted alkoxy" means that the R group is a substituted alkyl group or residue.
Examples of substituted alkoxy groups include trifluoromethoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, and alkoxyalkyl groups such as methoxymethyl, methoxyethyl, polyoxoethylene, polyoxopropylene, and similar groups.

P E: it / Si Ell 31+0 Fit "Alkoxyalkyl" refers to an ¨R-O-R' group or radical, wherein R and R' are alkyl groups. In some embodiments the alkoxyalkyl groups can be Ci to C8 and in other embodiments can be C1 to C4. In many embodiments both R and R' are a lower alkyl, such as a rnethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like alkoxy groups.
Examples of alkoxyalkyl groups include methoxymethyl, ethoxyethyl, methoxypropyl, and methoxybutyl and similar groups.
"Hydroxyalkyl" refers to an ¨R-OH group or radical, wherein R is an alkyl group.
In some embodiments the hydoxyalkyl groups can be C1 to C8 and in other embodiments can be C1 to C4. In many embodiments R is a lower alkyl. Examples of alkoxyalkyl groups include hydroxyrnethyl, 1-hydroxyethyl, 2-hydroxyethyl 3-hydroxypropyl, and similar groups.
"Acyloxy" refers to an RCO2- ester group where R is an alkyl, cycloalkyl, aryl, heteroaryl, substituted alkyl, substituted cycloalkyl, substituted aryl, or substituted heteroaryl group or radical wherein the R radical comprises one to seven or one to four carbon atoms. In many embodiments, R is an alkyl radical, and such acyloxy radicals are exemplified by formyloxy, acetoxy, propionyloxy, butyryloxy, pivaloyloxy, pentanoyloxy, hexanoyloxy, heptanoyloxy, and the like. In other embodiments the R groups are alkyls.
As used herein, "acyl" encompasses the definitions of alkyl, alkenyl, alkynyl and the related hetero-forms which are coupled to an additional organic residue through a carbonyl group to form a ketone radical or group. Preferred acyl groups are "C1 to C7 acyl" such as formyl, acetyl, propionyl, butyryl, pentanoyl, pivaloyl, hexanoyl, heptanoyl, benzoyl, and the like. More preferred acyl groups are acetyl and benzoyl.
The term "substituted acyl" denotes an acyl group wherein the R group substituted by one or more, and preferably one or two, halogen, hydroxy, oxo, alkyl, cycloalkyl, naphthyl, amino, (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, imidazolyl, indolyl, pyrrolidinyl, C1 to C7 alkoxY, alkoxy-alkyl, C1 to C7 acyl, C1 to C7 acyloxy, nitro, C1 to Cg alkyl ester, carboxY, alkoxycarbonyl, carbamoyl, carboxamide, N-(C1 to C6 alkyl)carboxamide, N,N-di(Ci to C6 alkyl)carboxamide, cyano, C1 to C4 alkylsulfonamide, thiol, C1 to C4 alkylthio or C1 to C4 alkylsulfonyl groups. The substituted acyl groups may be substituted once or more, and preferably once or twice, with the same or with different substituents.

PICT,/ Ili Si Eli 114,1Di Examples of Ci to 07 substituted acyl groups include 4-phenylbutyroyl, 3-phenylbutyroyl, 3 phenylpropanoyl, 2- cyclohexanylacetyl, cyclohexanecarbonyl, 2-furanoyl and 3 dimethylaminobenzoyl.
Cycloalkyl residues or groups are structurally related to cyclic monocylic or bicyclic hydrocarbon compounds wherein one or more hydrogen atoms have been replaced with an organic or inorganic substituent group. The cycloalkyls of the current inventions comprise 3 to 12, or more preferably 3 to 8, or more preferably 4 to 6 ring carbon atoms. Examples of such cycloalkyl residues include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl rings, and saturated bicyclic or fused polycyclic cycloalkanes such as decalin groups, polycyclic norbomyl or adamantly groups, and the like.
Preferred cycloalkyl groups include "C3 to C7 cycloalkyl" such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl rings. Similarly, the term "C5 to C7 cycloalkyl" includes cyclopentyl, cyclohexyl, and cycloheptyl rings.
"Substituted cycloalkyl" denote a cycloalkyl rings as defined above substituted by 1 to 4, or preferably 1 or 2, sub stituents independently selected from a halogen, hydroxy, CI
to 04 alkylthio, C1 to C4 alkylsulfoxide, C1 to C4 alkylsulfonyl, C1 to 04 substituted alkylthio, C1 to C4 substituted alkylsulfoxide, C1 to C4 substituted alkylsulfonyl, CI to 04 alkyl, C1 to C4 alkoxy, C1 to C6 substituted alkyl, C1 to C4 alkoxy-alkyl, oxo (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, or amino. In many embodiments of substituted cycloalkyl groups the substituted cycloalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, chloro, NH2, NHCH3, N(CH3)2, CO2CH3, SC2115, SCH3, S(0)CH3, S(0)2CH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
The term "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 cycloalkylene" means a cycloalkylene where the cycloalkyl radical is bonded at two positions connecting together two separate additional groups and further bearing at least one additional substituent.
The term "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 cycloalkenyl" denotes the above cycloalkenyl rings substituted with a substituent, preferably by a C1 to Cg alkyl, halogen, hydroxy, C1 to C7 alkoxy, alkoxy-alkyl, P C: T / 113 (13 Eit / 3 11.11- C1 113 trifluoromethyl, carboxy, alkoxycarbonyl oxo, (monosubstituted)amino, (disubstituted)amino, phenyl, substituted phenyl, amino, or protected amino.
The term "cycloalkenylene" is a cycloalkenyl ring, as defined above, where the cycloalkenyl radical is bonded at two positions connecting together two separate additional groups. Similarly, the term "substituted cycloalkenylene" means a cycloalkenylene further substituted preferably by halogen, hydroxy, C1 to C4 alkylthio, C1 to C4 alky1SUlf0Xide, Cl to C4 alkylsulfonyl, C1 to C4 substituted alkylthio, C1 to C4 substituted alkylsulfoxide, C1 to C4 substituted alkylsulfonyl, C1 to Cg alkyl, C1 to C7 alkoxy, Ci to Cg substituted alkyl, Ci to C7 alkoxy-alkyl, oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, alkoxycarbonyl, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, 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 comprise 1 to 5 ring heteroatoms, such as oxygen, sulfur, and/or nitrogen inserted into the ring. These heterocyclic rings can 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 unsaturated heterocyclic rings include furanyl, thiofuranyl, pyrrolyl, pyridyl, pyrimidyl, pyrazinyl, benzoxazole, benzthiazole, quinolinlyl, triazolyl, and like heteroaromatic rings. Preferred saturated heterocyclic rings include piperidyl, aziridinyl, pip eridinyl, pip erazinyl, tetrahydrofurano, tetrahydropyrrolyl, and tetrahydrothiophenyl rings.
The term "substituted heterocycle" or "substituted heterocyclic ring" means the above-described heterocyclic ring is substituted with, for example, one or more, and preferably one or two, sub stituents which are the same or different which substituents preferably can be halogen, hydroxy, thio, alkylthio, cyano, nitro, C1 to C4 alkyl, C1 to C4 alkoxy, C1 to C4 substituted alkoxy, alkoxy-alkyl, C1 to C4 acyl, C1 to C4 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, alkoxy-alkyl amino, monosubstituted)amino, (disubstituted)amino carboxamide, N-(C1 to C6 alkyl)carboxamide, N,N-di(Ci to C6 alkyl)carboxamide, trifluoromethyl, N-((C1 to C6 alkyl)sulfonyl)amino, N-(phenylsulfonyl)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, fluor , chloro, NH2, NHCH3, NO2, CN, amide, mono or disubstituted amide, P ET/ urcrs SC

cr,tx fry\ rill P03"ri, n3)2, k-,x-72%--1-1.3, i3, okv)2k.,113, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
An "aryl" groups refers to a monocyclic, linked bicyclic, or fused bicyclic radical or group comprising at least one six membered aromatic "benzene" ring. Aryl groups preferably comprise between 6 and 12 ring carbon atoms and are exemplified by phenyl, biphenyl, naphthyl indanyl, and tetrahydronapthyl groups. Aryl groups can be optionally substituted with various organic and/or inorganic sub stitutent groups, wherein the substituted aryl group in combination with all its substituents comprises between 6 and 18, or preferably 6 and 16 total carbon atoms. Preferred optional substituent groups include 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluor , chloro, NH2, NHCH3, NO2, SO3H, PO3H, N(CH3)2, CO2CH3, SC2H5, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy groups.
The term "heteroaryl" means a heterocyclic aryl derivative that preferably contains a five-membered or six-membered conjugated and aromatic ring system having from 1 to 4 heteroatoms independently selected from oxygen, sulfur, and/or nitrogen, inserted into the unsaturated and conjugated heterocyclic ring. Heteroaryl groups include monocyclic heteroaromatic, linked bicyclic heteroaromatic, or fused bicyclic heteroaromatic moieties.
Examples of heteroaryls include pyridinyl, pyrimidinyl, and pyrazinyl, pyridazinyl, pyrrolyl, furanyl, thiofuranyl, oxazoloyl, isoxazolyl, phthalimido, thiazolyl, quinolinyl, isoquinolinyl, indolyl, triazolyl, or a furan or thiofuran directly bonded to a phenyl, pyridyl, or pyrrolyl ring and like unsaturated and conjugated heteroaromatic rings. Any monocyclic, linked bicyclic, or fused bicyclic heteroaryl ring system that has the characteristics of aromaticity in terms of electron distribution throughout the ring system is included in this definition. Typically, the heteroaromatic ring systems contain 3 to 12 ring carbon atoms and 1 to 5 ring heteroatoms independently selected from oxygen, nitrogen, and sulfur atoms.
The term "substituted heteroaryl" means the above-described heteroaryl is substituted with, for example, one or more, and preferably one or two, substituents which are the same or different which substituents preferably can be halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C1 to Cg alkyl, C1 to C7 substituted alkyl, C1 to C7 alkoxy, CI to C7 substituted alkoxy, alkoxy-alkyl, C1 to C7 acyl, Ci to C7 substituted acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(C1 to C6 P r-11II /. Si Eli ,311. Ell alkyl)carboxamide, N,N-di(Ci to C6 alkyl)carboxamide, trifluoromethyl, N-((C1 to C6 alkyl)sulfonyl)amino or N-(phenylsulfonyl)amino groups. In many embodiments of substituted heteroaryl groups, the substituted cycloalkyl group will have 1, 2, 3, or 4 sub stituent groups independently selected from hydroxy, fluoro, chloro, NH2, NHCH3, N(CH3)2, NO2, S0311, PO3H, CO2C113, SC2H5, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
Similarly, "arylalkyl" and "heteroarylalkyl" refer to aromatic and hetero aromatic systems which are coupled to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated, carbon chains, typically of 1 to 6 carbon atoms.
These carbon chains may also include a carbonyl group, thus making them able to provide sub stituents 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-n-amyl, 3-pheny1-2-butyl, 2-pyridinylmethyl, 2-(2-pyridinypethyl, and the like.
The term "substituted arylalkyl" denotes an arylalkyl group substituted on the alkyl portion with one or more, and preferably one or two, groups preferably chosen from halogen, hydroxy, oxo, amino, (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, Ci to C6 alkyl, C1 to C6 substituted alkyl, C1 to C7 alkoxy, C1 to C7 substituted alkoxy, alkoxy-alkyl, C1 to C7 acyl, Ci to C7 substituted acyl, C1 to C7 acyloxy, nitro, earboxy, alkoxycarbonyl, carbamoyl, carboxamide, N-(C1 to C6 alkyl)carboxamide, N,N-(C1 to C6 dialkyl)carboxamide, cyano, N-(C1 to C6 alkylsulfonyl)amino, thiol, Ci to C4 alkylthio, C1 to C4 alkylsulfonyl groups;
and/or the phenyl group may be substituted with one or more, and preferably one or two, sub stituents preferably chosen from halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C1 to Cg alkyl, C1 to Cg substituted alkyl, C1 to C7 alkoxy, C1 to C7 substituted alkoxY, alkoxy-alkyl, C1 to C7 acyl, C1 to C7 substituted acyl, C1 to C7 acyloxy, carboxY, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(Ci to Cg alkyl) carboxamide, N,N-di(Ci to C6 alkyl)carboxamide, trifluoromethyl, N-((C1 to Cg alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino, cyclic C2 to C7 alkylene or a phenyl group, substituted or unsubstituted, for a resulting biphenyl group. The substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents which can be the same or different.
Examples of the term "substituted arylalkyl" include groups such as 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl)ethyl, 4-(2,6-dihydroxypheny1)-n-hexyl, 2-(5-cyano-3-methoxypheny1)-n-pentyl, 3-(2,6-dimethylphenyl)propyl, 4-chloro-3-aminobenzyl, 6-(4-methoxypheny1)-3-carboxy-n-hexyl, 5-(4-aminomethylpheny1)-3-(aminomethyl)-n-pentyl, 5-pheny1-3-oxo-n-pent-1-y1 and the like.
The term "arylalkylene" specifies an arylalkyl, as defined above, where the 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 arylalkylene as defined above that is further substituted preferably by halogen, hydroxy, protected hydroxy, C1 to C4 alkylthio, C1 to C4 alkylsulfoxide, C1 to alkylsulfonyl, C1 to C4 substituted alkylthio, C1 to C4 substituted alkylsulfoxide, C1 to C4 substituted alkylsulfonyl, C1 to Cg alkyl, C1 to C7 alkoxy, CI to C6 substituted alkyl, C1 to C7 alkoxy-alkyl, oxo, (monosubstituted)amino, (disubstituted)amino, trifluoromethyl, carboxy, alkoxycarbonyl, phenyl, substituted phenyl, phenylthio, phenylsulfoxide, phenylsulfonyl, amino, or protected amino group on the phenyl ring or on the alkyl group.
The term "substituted phenyl" specifies a phenyl group substituted with one or more, and preferably one or two, moieties preferably chosen from the groups consisting of halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C1 to C6 alkyl, C1 to C6 substituted alkyl, C1 to C7 alkoxy, C1 to C7 substituted alkoxy, alkoxy-alkyl, C1 to C7 acyl, CI to C7 substituted acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(C1 to C6 alkyl)carboxamide, N,N-di(Ci to C6 alkyl)carboxamide, trifluoromethyl, N-((C1 to C6 alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or phenyl, wherein the phenyl is substituted or unsubstituted, such that, for example, a biphenyl results. In many embodiments of substituted phenyl groups, the substituted cycloalkyl group will have 1, 2, 3, or 4 substituent groups independently selected from hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, CO2CH3, SH, SC2H5, SO3H, SCH3, P0311, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

P CT/ J S Eit 12;31443 01 The term "phenoxy" denotes a phenyl bonded to an oxygen atom. The term "substituted phenoxy" specifies a phenoxy group substituted with one or more, and preferably one or two, moieties chosen from the group consisting of halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C1 to C6 alkyl, C1 to C7 alkoxy, C1 to C7 substituted alkoxy, alkoxy-alkyl, C1 to C7 acyl, CI to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(C1 to Cg alkyl)carboxamide, N,N-di(Ci to C6 alkyl)carboxamide, trifluoromethyl, N-(( C1 to C6 alkyl)sulfonyl)amino, and N-phenylsulfonyl)amino.
The term "substituted phenylalkoxy" denotes a phenylalkoxy group wherein the alkyl portion is substituted with one or more, and preferably one or two, groups selected from halogen, hydroxy, protected hydroxy, oxo, amino, (monosubstituted)amino, (disubstituted)amino, guanidino, heterocyclic ring, substituted heterocyclic ring, C1 to C7 alkoxy, alkoxy-alkyl, C1 to C7 acyl, C1 to C7 acyloxy, nitro, carboxy, alkoxycarbonyl, carbamoyl, carboxamide, N-(C1 to C6 alkyl)carboxamide, N, N-(C1 to C6 dialkyl)carboxamide, cyano, N-(C1 to C6 alkylsulfonyl)amino, thiol, C1 to C4 alkylthio, Ci to C4 alkylsulfonyl groups; and/or the phenyl group can be substituted with one or more, and preferably one or two, substituents chosen from halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, Ci to C6 alkyl, C1 to C7 alkoxy, alkoxy-alkyl, C1 to C7 acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(C1 to C6 alkyl) carboxamide, N,N-di(Ci to C6 alkyl)carboxamide, trifluoromethyl, N-((C1 to C6 alkyl)sulfonyl)amino, N-(phenylsulfonyflamino, or a phenyl group, substituted or =substituted for a resulting biphenyl group. The substituted alkyl or phenyl groups may be substituted with one or more, and preferably one or two, substituents that can be the same or different.
The term "substituted naphthyl" specifies a naphthyl group substituted with one or more, and preferably one or two, moieties either on the same ring or on different rings chosen from the group consisting of halogen, hydroxy, protected hydroxy, thio, alkylthio, cyano, nitro, C1 to C6 alkyl, C1 to C7 alkoxy, alkoxy-alkyl, C1 to C7 acyl, C1 to C7 acyloxy, carboxy, alkoxycarbonyl, carboxymethyl, hydroxymethyl, amino, (monosubstituted)amino, (disubstituted)amino, carboxamide, N-(C1 to C6 alkyl)carboxamide, N,N-di(Ci to alkyl)carboxamide, trifluoromethyl, N-((C1 to C6 alkyl)sulfonyl)amino, or N-(phen.ylsulfonyl)amino.

C T /13 Si r.3 ..." IF 31441 n The fermi l'halo and "halogen" refer to the fluor , chloro, bromo or iodo atoms.
There can be one or more halogen, which are the same or different. Preferred halogens are chloro and fluor .
The term "(monosubstituted)amino" refers to an amino (NHR) group wherein the R
group is chosen from the group consisting of phenyl, C6-C10 substituted phenyl, C1 to C6 alkyl, C1 to C6 substituted alkyl, C1 to C7 acyl, Ci to C7 substituted acyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C2 to C7 alkynyl, C2 to C7 substituted alkynyl, C. to C12 phenylalkyl, C7 to C12 substituted phenylalkyl, and heterocyclic ring. The (monosubstituted)amino can additionally have an amino-protecting group as encompassed by the term "protected (monosubstituted)amino."
The term "(disubstitated)amino" refers to an amino group (NR2) with two substituents independently chosen from the group consisting of phenyl, C6-C10 substituted phenyl, C1 to C6 alkyl, C1 to C5 substituted alkyl, C1 to C7 acyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C7 to C12 phenylalkyl, and C7 to C12 substituted phenylalkyl. The two substituents can be the same or different.
The term "amino-protecting group" as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule. The term "protected (monosubstituted)amino"
means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
In addition, the term "protected carboxamide" means there is an amino-protecting group on the carboxamide nitrogen. Similarly, the term "protected N-(C1 to C6 alkyl)carboxamide"
means there is an amino-protecting group on the carboxamide nitrogen.
The term "alkylthio" refers to -SR groups wherein R is an optionally substituted C1-C7 or C1-C4organic group, preferably an alkyl, cycloalkyl, aryl, or heterocyclic group, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio, and like groups.
The term "alkylsulfoxide" indicates ¨S(0)R groups wherein R is an optionally substituted C1-C7 or C1-C4 organic group, preferably an alkyl, cycloalkyl, aryl, or heterocyclic group, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, t-butylthio and like groups, such as methylsulfoxide, ethylsulfoxide, n-propylsulfoxide, isopropylsulfoxide, n-butylsulfoxide, sec-butylsulfoxide, and the like.
The term "alkylsulfonyl" indicates ¨S(0)2R groups wherein R is an optionally substituted C1-C7 or C1-C4 organic group, which include for example groups such as methylsultonyl, ethylsultonyl, n-propylsulfonyl, isopropylsulfonyi, n-butylsulfonyl, t-butylsulfonyl, and the like.
The terms "phenylthio," "phenylsulfoxide," and "phenylsulfonyl" specify a sulfoxide (--S(0)-R), or sulfone (-SO2R)wherein the R group is a phenyl group.
The terms "substituted phenylthio," "substituted phenylsulfoxide," and "substituted phenylsulfonyl"
means that the phenyl of these groups can be substituted as described above in relation to "substituted phenyl."
The term "alkoxycarbonyl" means an "alkoxy" group attached to a carbonyl group, (-C(0)-0R, wherein R is an alkyl group, preferably a C1-C4 alkyl group. The term "substituted alkoxycarbonyl" denotes a substituted alkoxy bonded to the carbonyl group, which alkoxy may be substituted as described above in relation to substituted alkyl.
The term "phenylene" means a phenyl group where the phenyl radical is bonded at two positions connecting together two separate additional groups. Examples of "phenylene" include 1,2-phenylene, 1,3-phenylene, and 1,4-phenylene.
The term "substituted alkylene" means an alkyl group where the alkyl radical is bonded at two positions connecting together two separate additional groups and further bearing an additional sub stituent. Examples of "substituted alkylene"
includes aminomethylene, 1-(amino)-1,2-ethyl, 2-(amino)-1,2-ethyl, 1-(acetamido)-1,2-ethyl, 2-(acetamido)-1,2-ethyl, 2-hydroxy-1,1-ethyl, and 1-(amino)-1,3-propyl.
The term "substituted phenylene" means a phenyl group where the phenyl radical is bonded at tvvo positions connecting together two separate additional groups, wherein the phenyl is substituted as described above in relation to "substituted phenyl."
The terms "cyclic alkylene," "substituted cyclic alkylene," "cyclic heteroalkylene,"
and "substituted cyclic heteroalkylene," defmes such a cyclic group or radical bonded ("fused") to a phenyl radical, resulting in a fused bicyclic ring group or radical. The non-fused members of the cyclic alkylene or heteroalkylene ring may contain one or two double bonds, or often are saturated. Furthermore, the non-fused members of the cyclic alkylene or heteroalkylene ring can have one or two methylene or methine groups replaced by one or two oxygen, nitrogen, or sulfur atoms, or NH, NR, S(0) or SO2 groups, where R
is a lower alkyl group.
The cyclic alkylene or heteroalkylene group may be substituted once or twice by the same or different substituents preferably selected from the group consisting of the following moieties: hydroxy, protected hydroxy, carboxy, protected carboxy, oxo, protected oxo, C1 to P C, 1F / 1,11 E3Ij/iF3Mijt0 0 C4 acyloxy, fo rmyl, C1 to C7 acyl, C1 to Cg alkyl, C1 to C7 alkoxy, C1 to C4 alkylthio, Ci to C4 alkylsulfoxide, C1 to C4 alkylsulfonyl, halo, amino, protected amino, (monosubstituted)amino, protected (monosubstituted)a.mino, (disubstituted)amino, hydroxymethyl, and a protected hydroxymethyl. The cyclic alkylene or heteroalkylene group fused onto the benzene radical can contain two to ten ring members, but it preferably contains three to six members. Examples of saturated cyclic alkylene groups are 2,3-dihydro-indanyl and a tetralin ring systems. When the cyclic groups are unsaturated, examples include a naphthyl ring or indolyl group or radical. Examples of fused cyclic groups which each contain one nitrogen atom and one or more double bond, preferably one or two double bonds, are when the benzene radical is fused to a pyridyl, pyranyl, pyrrolyl, pyridinyl, dihydropyrolyl, or dihydropyridinyl groups or radicals. Examples of fused cyclic groups that each contain one oxygen atom and one or two double bonds are illustrated by a benzene radical ring fused to a furanyl, pyranyl, dihydrofuranyl, or dihydropyranyl 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 thienyl, thiopyranyl, dihydrothienyl, or dihydrothiopyranyl ring. Examples of cyclic groups which contain two heteroatoms selected from sulfur and nitrogen and one or two double bonds are when the benzene radical ring is fused to a thiazolyl, isothiazolyl, dihydrothiazolyl, or dihydroisothiazolyl ring. Examples of cyclic groups which contain two heteroatoms selected from oxygen and nitrogen and one or two double bonds are when the benzene ring is fused to an oxazolyl, isoxazolyl, dihydrooxazolyl or dihydroisoxazolyl ring. Examples of cyclic groups which contain two nitrogen heteroatoms and one or two double bonds occur when the benzene ring is fused to a pyrazolyl, imidazolyl, dihydropyrazolyl or dihydroimidazolyl ring or pyrazinyl.
The term "carbamoyl" refers to a carbamate group or radical, which often derived from the reaction of an organic isocyanate compound R1-NCO with an alcohol R2-OH, to yield a carbamate compound having the structure R1-NH-C(0)-0R2 wherein the nature of the R1 and R2 radicals are further defined by the circumstances.
One or more of the compounds of the invention may be present as a salt. The term "salt" encompasses those salts that form with the carboxylate anions and amine nitrogens and include salts formed with the organic and inorganic anions and cations discussed below.
Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as nitrogen containing heterocycles or amino groups) and organic or inorganic P C T/"Urdi 0145 / ji7,1;731)-11- Li!
acids. Such acids include hydrochloric, hydrofluoric, trifluoroacetic, sulfuric, phosphoric, acetic, succinic, citric, lactic, rnaleic, furnarie, palmitic, cholic, pamoic, mueic, D-glutarnic, D-camphoric, glutaric, plithalic, tartaric, lauric, stearic, salicyoic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and like acids.
The term "organic or inorganic cation" refers to positively charged counter-ions for the carboxylate anion of a carboxylate salt. Inorganic positively charged counter-ions include but are not limited to the alkali and alkaline earth metals, (such as lithium, sodium, potassium, calcium, magnesium, etc.) and other divalent and trivalent metallic cations such as barium, aluminum and the like, and ammonium (NH4)4. cations. Organic cations include ammonium cations derived from acid treatment or alkylation of primary, secondary, or tertiary amines such as trimetlaylamine and eyclohexylamine. Examples of organic cations include dibenzylammonium, benzylarnmonium, 2-hydroxyethylatnmonium, bis(2-hydroxyethyl)armnoniturn phenylethylbenzylarnmonium, dibenzylethylenediarrunonium, and like cations. See, for example, "Pharmaceutical Salts,"
Berge et at, J Pharm. Sci. (1977) 66:1-19.
Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of bask amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. For example, a cation for a carboxylate anion will exist when R5 is substituted with a (quaternary ammonium)methyl group. A preferred cation for the carboxylate anion is the sodium cation.
The compounds of the invention can also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention.
The term "amino acid" includes any one of the twenty naturally-occurring amino acids or the 1)-form of any one of the naturally-occurring amino acids. In addition, the term "amino acid" also includes other non-naturally occurring amino acids besides the 1)-amino acids, which are functional equivalents of the naturally-occurring amino acids. Such non-naturally-occurring amino acids include, for example, norleucine ("Nle"), norvaline ("Nva"), L- or D- naplithalanine, omithine ("Om"), homoarginine (homoArg) and others well known in the peptide art, such as those described in M. Bodanzsky, "Principles of P CT/Uri /12:594.nn .
no& synthesis, 1st ano 2nd Revised Ed., Spnnger-Verlag, New York, NY, 1984 and 1993, and Stewart and Young, "Solid Phase Peptide Synthesis," 2nd Ed., Pierce Chemical Co., Rockford, IL, 1984. ' Amino acids and amino acid analogs can be purchased commercially (Sigma Chemical Co.;
Advanced Cheintech) or synthesized using methods known. in the art.
"Amino acid side chain" refeis to any side chain from the above-described "amino acids."
"Substituted" harem refers to a substituted moiety, such as a hydrocarbon, e.g , substituted alkyl or benzyl wherein at least one element or radical, eg, hydrogen, is replaced by another, e.g., a halogen, as in chlorobeuzyl.
A. residue of a chemical species, as used in the specification and concludittg claims, refers to a structural fragment or a moiety that is the resulting product of the chemical .
species in a particular reaction scheme or subsequent formulption or chemical product, regardless of whether the structural fragment or moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one orrnore ¨
OCH2C1120- repeat units in the polyester, regardless of whetter ethylene glycol is used to prepare the polyester.
The term "organic residue" or "organic grotty" defines a carbort containing residue or group, 1. e., a residue comprising at least one carbon atom. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatorn, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited to alkyl or substituted alkyls, alkoxy or substituted alkoxy, hydroxyalkyls and aikoxyarkyls, mono or di-substituted amino, amide. groups, CN, COB, CHO, COR6, CO2R6, SR6, S(0)R6, S(0)2R6, alkenyl, cycloEtlityl, cycloalkenyl, aryl, and heteroaryl, wherein R6 is an alkyl. More specific examples of species of organic groups or residues include but are not limited to, NHCI-13, N(013)2, CO2C,I13, SC2Hs, sat%
S(0)CH3, S(0)2CH3, methyl, ethyl, isopropyl, vinyl, triftuoromethyl, methoxy, etboxy, isopropoxy, trifluorornethoxy, C}120C143, CH20-11, CH2NH2, CH2NHCH3, or CH2N(C113)2 groups or residues. Organic resides can comprise 1 to 18 carbon atoms, Ito 15 carbon atoms, 1 to 12 ao carbon atoms, 1 to 8 carbon atoms, 1 to 6 -carbon atoms, or 1 to 4 carbon atoms.
By the term "effective amount' of a compound as provided herein is meant a sufficient amount of one or more compounds in a composition that is sufacient to provide the desired regulation of a desired biological function, such as gene expression. protein P T,/ 111 foi 1,41 function, or more Farticidgily the induction of sweet taste perception in an animal or a human. 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 comestible composition, etc. Thus, it is not possible to specify an exact "effective amount." However, an appropriate effective amount can be determined by one of ordinary skill in the art using only routine experimentation.
It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an aromatic compound"
includes 10_ mixtures of aromatic compounds.
Often, ranges are expressed herein as from "about" one pditicular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value.
Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "optionally substituted lower alkyl" means that the lower alkyl group may or may not be substituted and that the description includes both unsubstituted lower alkyl and lower alkyls where there is substitution.
Further, unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as racemic or scalemic mixtures.
The Amide Compounds of the Invention The compounds of the invention are all organic (carbon containing) compounds that have at least one "amide" group therein and have the following general structure, which will be hereinafter referred to as the amide compounds having Formula (I):

P C T / S el 2314 113 (R2)m, R3 (R1 )m¨ Arl ¨Ar2 L

(I) Also, disclosed are comestibly acceptable salts of compounds of Formula (I).
The amide compounds of Formula (I) do not include amide compounds that are known to naturally occur in biological systems or foods, such as for example naturally occuring amino acids, peptides, proteins, nucleotides, nucleosides, nucleic acids, polysaccharide, certain amino sugars and/or amino polysaccharides, glycopeptides or glycoproteins, or the like. Neither does the present invention relate to compounds that are synthetic close structural analogs of amino acids, peptides, proteins, nucleotides, nucleosides, nucleic acids, certain amino sugars and/or amino polysaccharides, glycopeptidea or glycoproteins, or the like, such as for example the peptide analog sweeteners such as aspartame and neotame, or saccharide analog sweeteners such as Sucralose. The amide compounds of Formula (I) of the invention are man-made and artificial synthetic amide compounds that typically do not comprise peptide or saccharide residues.
For the various embodiments of the compounds of Formula (I), the Ari, Ar2, L, R2, R3, R4, and R5 groups can be and are independently further defined and/or limited in various ways, as will now be further detailed hereinbelow, so as to define and/or include a substantial number of structurally related subgenera and/or species of the compounds of Formula (I), and hence the various inventions disclosed herein are related because of their relationship to the compounds of Formula (I).
It is hereby specifically contemplated that any of the subgenuses and/or species of compounds of Formula (I) described herein can, either in their specified form or as one or more comestibly acceptable salts, be combined in an effective amount with one or more comestible or medicinal products or precursors thereof by the processes and/or methods described elsewhere herein, or by any such other processes as would be apparent to those of ordinary skill in preparing comestible or medicinal products or precursor thereof, to form one or more sweet flavor modified comestible or medicinal products, or one or more precursors or sweetener concentrate compositions thereof.

PCT /US int -31111:. El i As on,"." e oibrdmary skill n the art can discern, the compounds of Formula (I) comprise a ¨C(0)NH- group, which is well known to those of ordinary skill in the art as an "amide" group. Moreover, the compounds of Formula (I) as disclosed and claimed herein typically comprise a common and linked core of molecular/structural features that at least include an R5 group which is bonded to the nitrogen atom of the "amide" group, which amide group is additionally linked from its carbonyl carbon atom to the L, Arl, and Ar2 groups, as illustrated above. The RI, R2, R3, and R4 groups can be hydrogen, or optional substituent groups as disclose hereinbelow. Without wishing to be bound by any scientific theory, it is believed that this core of structural features (the amide, R5, and L groups, and the An and Ar2 aryl or heteroaryl groups) together form a "scaffold" of suitable size, shape, and polarity so as to promote binding of the compounds as a whole to the relevant biological receptors such as sweet taste T1R2/T1R3 receptors. The R2, R3, and R4 groups, and optional substituents on R5, on the periphery of the common core can also also be of suitable size, shape, and polarity to allow binding to the relevant biological receptors, and/or optimize other parameters such as solubility, but can in some embodiments be optional, i.e., present or absent, and can comprise substituent groups having substantial chemical and structural diversity. The R1, R2, R3, and R4 groups can be selected for suitable combinations of size , polarity, and/or molecular weight to promote binding to the relevant biological receptors, such as for example, being limited to selected ranges of carbon atoms per substituent. The overall molecular weight and/or number of carbon atoms of the compounds of Formula (I) can also be selelected or limited as is farther discussed below.
In some embodiments of the compounds of Formula (I), Arl and Ar2 are independently selected from monocyclic, aryl, fused bicyclic aryl, monocyclic heteroaryl or fused bicyclic heteroaryl rings; m is selected from the integers 0, 1, 2, 3, 4, or 5; m' is selected from the integers 0, 1, 2, 3, or 4; each R1 and R2 is independently selected from the group consisting of OH, NH2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical; L is a carbon or nitrogen atom; R3 is hydrogen, oxygen, hydroxy, halogen, or a CI-C6 organic radical; R4 is absent, or hydrogen, oxygen, hydroxy, halogen, or a Ci-C6 organic radical; R5 a Ci-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 or C3-C10 organic radical, such as an optionally substituted C3-C10 alkyl or cycloalkyl radical.

P S,fir.1 it gad' gom bthe e iments, alternative, and/or additional and optional limitations on the chemical and physical characteristics of the Arl,,Ar2 L, R2, R3, .k-4, and R5 groups are further described below.
Ar groups In some embodiments of the compounds of Formula (I), Ari and Ar2 are independently selected from monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, and fused bicyclic heteroaryl groups. In some embodiments, Art and Ar2 are independently selected from a monocycle aryl rings (such as phenyl), and monocycle heteroaryl rings having five or six ring atoms.
The monocycle aryl groups include at least phenyl rings, and can be substituted (m or m' are not zero) or unsubstituted (m or m' are zero). The fused bicyclic aryl groups include at least napthyl rings, tetrahydronapthyl, and indanyl rings, and can be substituted (m or m' are not zero) or unsubstituted (m or m' are zero). The monocyclic heteroaryl groups can include hetero aromatic rings with either five or six ring atoms, wherein at least one ring atom is carbon and at least one ring heteroatom is selected from nitrogen, oxygen, and sulfur. Such monocycle heteroaryls include but are not limited to pyridinyl, pyrazinyl, pyrazolyl, pyrrolyl, furanyl, thiofuranyl, oxazoloyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, and like hetero aromatic ring groups. The monocycle heteroaryl groups and can be substituted (m or m' are not zero) or unsubstituted (m or m' are zero). The fused bicyclic heteroaromatic groups comprise two fused rings wherein at least one ring is aromatic, such an aryl ring or heteroaryl ring, and at least one of the two fused rings has at least one ring heteroatom selected from nitrogen, oxygen, and sulfur.
Example of fused bicyclic hetero aromatic groups include quinolinyl, isoquinolinyl, indolyl, benzofuran, dihydrobenzofuran, benzothiofuran, dihydrobenzothioftiran, phthalimido, thiazolyl, and like fused ring groups. The fused bicyclic heteroaryl groups and can be substituted (m or m' are not zero) or unsubstituted (m or m' are zero).
To further illustrate the inventions disclosed herein, in some embodiments, the invention relates to compounds where Ari is a monocyclic aryl group such as a phenyl group, and Ar2 is selected from a monocyclic aryl such as a phenyl group, a fused bicyclic aryl such as a napthyl group, a monocyclic heteroaryl group such as a pyridyl group, or a fused bicyclic heteroaryl group such as a quinolinyl group. In other embodiments, Ari can be a fused bicyclic aryl group such as a napthyl or indanyl group, and Ar2 is selected from a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl PETSUSD õs 31:5-rit group. in yet other examples, Ari can be a monocyclic heteroaryl group such a pyridyl, pyrimidyl, furanyl, or thiofuranyl group, and Ar2 is a monocyclic aryl such as a phenyl, fused bicyclic aryl such as napthyl group, a monocyclic heteroaryl group, or fused bicyclic heteroaryl group. In yet additional examples, Arl can be a fused bicyclic heteroaryl group such as a quinolinyl or benzofuranyl group, and Ar2 is a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl group.
Alternatively, in some embodiments, Ar2 can be a monocyclic aryl group such as a phenyl group, and Arl is selected a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl ring. In yet another example, Ar2 can be a fused bicyclic aryl group such as a napthyl or tetrahydronapthyl group, and Arl is a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl ring. In yet another example, Ar2 can be a monocyclic heteroaryl group such as a pyridyl group, and Arl is a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl ring. In still another example, Ar2 can be a fused bicyclic heteroaryl group such a quinolinyl or benzofuran group, and Ail is a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl ring.
In one particular aspect of the invention, the Arl and Ar2 groups can be independently selected from the group consisting of phenyl, napthyl, indole, pyridyl, pyrimidyl, furan, thiofuran, benzofuran, triazolyl, and benzothiofuran groups, or alternatively, Arl and Ar2 groups can be independently selected from a phenyl, pyridyl, pyrimidyl, pyrizinyl, pyrrolyl, pyrazolyl, furanyl, thiofuranyl, or triazolyl ring.
In some aspects of the compounds of the invention, Arl can be a phenyl ring.
In many related aspects, Ar2 can be a phenyl ring. In aspects, Arl and Ar2 are both phenyl rings. In many aspects of the compounds of Formula (I), Ar2 is a phenyl ring, and Arl is a five or six membered monocyclic heteroaryl ring, such as for example a pyridyl, pyrimidyl, pyrazinyl, furanyl, thiofuranyl, pyrrolyl, imidazolyle, thiazolyly, oxazolyl, or like five or six-membered heteroaryl rings.
In some embodiments, the Arl and Ar2 groups of Formula (I) comprise an aryl ring, i.e., they each contain somewhere within their ring structures at least one six-membered aromatic phenyl ring. The aryls can include benzene and napthalene rings, which may not, but in many embodiments are, further substituted with at least 1, 2, 3, 4, or 5 independentely selected R1 or R2 substituent groups, which can be any of the alternatives recited below.

P T , 11 1111:11E, / 3 NI- 0 11:11 Ail The Arl ring radical, which is bonded to the Ar2 ring radical, can be a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl group, which can be substituted (m is not zero) or unsubstituted (m is zero). In many embodiments, the Arl ring radical plus all of its le substituents comprise from 3 to 18 carbon atoms, or from 4 to 12 carbon atoms, or from 5 to 10 carbon atoms.
In some aspects of the compounds of Formula (I), Arl can be a monocyclic aryl ring such as 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 tii-, tetra-, or penta-substituted phenyl, wherein the substituent groups (i.e., le) can be defined as recited elsewhere herein. In some embodiments, the R' substituentsof the Arl ring can be independently selected from any of the groups described hereinbelow, including for example inorganic substituents such as hydrogen, OH, NH2, NO2, SH, SO3H, PO3H, or halogens (e.g., fluor and chloro), the RI
substituents of the Ari ring can be independently selected from various Cl-C6 or Cl-C4 organic radicals as described hereinbelow, includcing for example NHCH3, N(CH3)2, CO2CH3, SC2H5, SCH3, S(0)CH3, S(0)2CH3, S(0)2NHCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy, In some aspects, two adjacent substituents on Arl may together form a heterocyclic ring fused to An, such as for example a methylenedioxy or ethylenedioxy ring fused to two adjacent carbons on the aromatic Arl ring. In other aspects, two adjacent positions on the Arl ring can be substituted so that the two substituents together form a five to seven membered saturated carbocyclic or heterocyclic ring that may optionally comprise one or two ring heteroatoms selected from oxygen, nitrogen, or sulfur ring atoms.
In some other embodiments, Ari can be a monocyclic heteroaryl such as a pyridyl ring. Further examples of monocyclic heteroaryl rings for Ari are pyrimidyl, pyrizinyl, or pyridazinyl rings having the following formulas:
N
ij or ic _A or (R1),(R A :9 1),õ N (R1),, wherein m is selected from the integer 0, 1, 2, or 3.
Additional examples of monocyclic heteroaryl groups for Arl include, but are not limited to, five membered heteroaryl rings having one of the following formulae:

, C11 B / iq;3111-11:11 ID zo, /13 (R1),,---\C3 --1 , (R1)m----c i , N--- IN ' -..... ij..., i/
__ssss (Ri)mS(_,. L7-j ----\\ --s5SS , (R1)m 2 s555 , (R16 ______ _(\ii , N----"
vvv-Lp v-vvv, alrulf, /N ,N N
(R1)m , (R1)m ¨C--J ---ccil , (R1) õ,----\\-( \---N N---"
R1 VVV11, 1 1 1/41-1.1W
N N
./.
N./
N \ Nhi (R1),--s5S5 , (R16--"\-C) (Ri),---cr õI
N---"
z,S zS
zr.S
.. (R1) --Tr-ss-6 sgS5 , ,, \\
(R1)m---____ _ll --ss.'55 (R1 , N N------N ' S, N
/ =-,,,, R1--___N/
N
(R1)m,¨% --------, , (R1 )m \ J¨ (R1 )nr , (R1 )m N i c S\
(R1 )m---"\--1.- _ j----------ss55 , or \ 2/1.555-wherein m is 0, 1, 2, or 3. In such compounds of Formula (I), each RI can be as defined elsewhere herein. In some preferred embodiments of the monocyclic heteroaryl amide compounds Arl is a furan, thiofuran, or oxazole ring, which may be either substituted or unsubstituted.
In some aspects of the invention, two adjacent substituents for Arl can together form a five to eight membered bicyclic carbocyclic or heterocyclic ring fused to Arl, such as for pT / Lit SKI / VP =
exarripie a metnyldne y nng. In some examples, the Arl group of the compounds of Formula (I) can have the following fused bicyclic heterocyclic structures:
0 or R12¨K or 1101 '217-0 0100 Rlb Rib 0=

c22z, Ria 110 or Rib 0 Rib wherein Rla and Rib are independently chosen from any of the Ri substituents defined elsewhere herein.
In additional embodiments of the compounds of Formula (I), Ari is a substituted heteroaryl ring comprising 5 to 12 carbon atoms, with optional Ri substituent groups as described further elsewhere herein.
Ar2 The Ar2 ring radical, is bonded to the Ari ring and the L atom, and can be a monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, and fused bicyclic heteroaryl ring, which can be substituted (m' is not zero) or unsubstituted (m' is zero).
In many embodiments, Ar2 is a monocyclic aryl ring, such as a phenyl ring, or any of a variety of five-membered or six-membered heteroaryl rings, as is further described below.
In many embodiments, the Ar2 ring radical plus all of its R2 substituents comprise from 3 to 18 carbon atoms, or from 4 to 12 carbon atoms, or from 5 to 10 carbon atoms.
In some embodiments of the compounds of Formula (I), Ar2 can be a monocyclic aryl ring such as 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- or tetra-substituted phenyl wherein the substituent groups (i.e., R2) can be independently selected from the various alternatives described elsewhere herein, such as for example inorganic sub stitents such as hydrogen, OH, NH2, NO2, SH, SO3H, PO3H, halogens (e.g., fluor and chloro), or C1-C6 or C,-C4 organic radicals as recited below. In some aspects of the invention, two adjacent substituents for Ar2 can together form a five to eight membered carbocyclic or heterocyclic ring fused to Ar2, such as for example a methylenedioxy ring. In some aspects of the invention, two adjacent substituents for Ari can together form a five to eight membered bicyclic carbocyclic or heterocyclic ring fused to Ari, such as for example a methylenedioxy ring.

, P CT Tilj El; g Irot,etriFgaotarelts, Ar2 can be a monocyclic heteroaryl group such as a pyridyl ring. Some specific examples of other monocyclic heteroaryl rings for Ar2 have the following formulae:
N.., N"...--"..:'-`,..
or Q or I I

7,-..
(R26. N (R2)m, N
(R2)m, 4'144st' wherein m' is selected from the integers 0, 1, or 2. Additional examples of monocyclic heteroaryl rings for Ar2, include, but are not limited to five-membered heteroaryl rings having at least one ring carbon atom and at least one ring heteroatom selected from oxygen, sulfur, and nitrogen, examples of such heteroaryls having the following exemplary formulae:
II
(R2 -4) --1¨N
, 6, H (R26 (R26 \ ,k (R2)m,\/ NN
\C
'/\N_/ , 1¨

..rvvv, ,rtitAr, ulfliV, 6. IN
(R26 (R2 \, N N.' N (R2) \,,NN
\N--N , I(R2)m, Ni (R2),,f, (R2)m, N
\\,, N N)--µ=

N
'111_ N¨N cll.(N¨N

C: TSUI Si CI 2 3 11-11-4:11 cs ,L7 (R2),. (R2)rn.
N
jõN
S
or (R2),, (R2)m, (R2)m, cl ¨
\
(R2),, wherein m' is 0, 1, or 2. In such compounds of Formula (I), each R2 can be as defined elsewhere herein.
In additional embodiments of the compounds of Formula (I), Ar2 can be a substituted heteroaryl ring comprising 5 to 12 carbon atoms and wherein the optional substituent groups (R2) are independently selected from any of the alternatives listed elsewhere hereinbelow.
R1 and R2 In the compounds of Formula (I), the groups Arl and/or Ar2 can be substituted with various substituents disclosed herein. Specifically, Arl can have 0, 1, 2, 3, 4, or 5 substituents, denoted in Formula (I) as 121 (i.e., (RI)õõ where m is selected from the integers 0, 1, 2, 3, 4, or 5). Ar2 can have 0, 1,2, 3, or 4 substituents, denoted in Formula (I) as R2 (i.e., (R2)õ,,, where m' is selected from the integers 0, 1, 2, 3, or 4. In some specific examples, m and m' are independently selected from the integers 0, 1, or 2. In other examples, m and m' are independently 0 or 1. It will be understood by those of ordinary skill in the art that if m or m' are zero, any carbon atom in a ring that could be substituted an Ri or an R2 substituent is assumed to carry a hydrogen substituent.
In many embodiments of the compounds of Formula (I), the substituents Rl and can be independently selected from the group consisting of an inorganic radical such as OH, NH2, SH, NO2, SO3OH, PO3H, halogen, and C1-C6 organic radical, or C1-C4 organic jijP C: gills R1 and R2 for can be independently selected from, for example, alkyl, alkoxy, alkoxy-alkyl, hydroxyalkyl, NHR6, NR6R6', CN, CO2H, CO2R6, C(0)H, C(0)R6, C(0)NHR6, C(0)NR6 R6', OC(0)R6, NHC(0)R6, SR6, S(0)R6, S(0)2R6, S(0)NHR6, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl, where R6 and R6'can be a C1-C6 or C1-C4 alkyl, or methyl. The organic radicals RI and R2 radical can also be independently selected from alkyl, haloalkyl, haloalkoxy, alkoxyl, alkoxy-alkyl, hydroxy-alkyl, aryl, heteroaryl, CN, C(0)H, CO2H, NHR6, NR62, CO2R6, COR6, C(0)R6, SR6, S(0)R6, S(0)2R6, S(0)2NHR6, and C(0)NHR6, wherein R6 is Ci-C4 alkyl.
In some aspects of the compounds of Formula (I), each R1 and R2 can be independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, CN, OC(0)CH3, SCH3, S(0)CH3, S(0)2CH3, S(0)2NHCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, CH2OH, CH2OCH3, CH2OCH2CH3, C(0)H, C(0)CH3, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, cyclopentyl, cyclhexyl, phenyl, pyridyl, pyrimidyl, pyrrolyl, furanyl, and thiofuranyl groups. In related aspects of the compounds of Formula (I), each R1 and R2 can be independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH02, COOCH3, SCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, S(0)CH3, S(0)2C113, S(0)2NHCH3, CN, CH2OH, C(0)H, C(0)CH3, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy groups.
In additional related aspects of the compounds of Formula (I), each 12.1 and/or each R2 can be independently selected from alkyl, allwxy, alkoxy-alkyl, hydroxyalkyl, OH, CN, CO211, CO2R6, CHO, COR6, CONHR6, SR6, S(0)R6, S(0)2R6, S(0)NHR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl, where R6 is C1-C6 alkyl.
In some related but alternative embodiments of the compounds of Formulas (I), each RI
and/or each R2 can be independently selected from the group consisting of OH, NH2, SH, NO2, SO3H, PO3H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 alkoxyl, C1-C4 alkoxy-alkyl, C1-C4 hydroxy-alkyl, NHR6, NR62, CN, CO2H, CO2R6, CHO, COR6, SH, SR6, s(o)R6, sp.2-- 6, ) 1( or S(0)2NHR6wherein R6 is C1-C4 alkyl. In many aspects of the compounds of Formulas (I), each RI and/or each R2 can be independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NO2, SO3H, PO3H, CN, NHCH3, N(CH3)2, OC(0)CH3, SCH3, S(0)CH3, S(0)2CH3, S(0)NHCH3, SC2H5, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, t-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

PCT 11,11 n Fat -3 1.1, ct Eit "`"
1 group In other embodiments of the compounds of Formula (I), L can be a carbon or nitrogen atom. In many embodiments of the invention, L is a carbon atom.
R3 and R4 In some embodiments of the compounds of Formula (I), R3 can be hydrogen, oxygen, hydroxy, amino, halogen, or a C1-C6 organic radical. In some specific examples, R3 can be a hydrogen, a C1-C4 alkyl, C1-C4 alkoxy, Ci-C4 hydroxyalkyl, C1-C4 alkoxyalkyl, C1-C4 monoalkylamino, or C1-C4 dialkylamino. In many aspects, R3 can be a methyl.
In related embodiments of the compounds of Formula (I), R4 can be absent (for example, when L is a nitrogen atom), or be a hydrogen, oxygen, hydroxy, amino, halogen, or a C1-C6 organic radical. In some specific examples, R4 can be a hydrogen, a C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 alkoxyalkyl, C1-C4 monoalkylamino, or Ci-C4 dialkylamino. In many aspects, R4 can be methyl.
In other related aspects, R3 and R4 together can form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl ring. Also, R3 and R4 can together form an ethylenedioxy or a trimethylenedioxy ring. Independently, R3 and R4 can also be selected from C1-C4 alkyls.
In many aspects, R3 and R4 are both methyl.
Still further examples of combinations of R3 and R4 include where one of R3 and R4 is a CI-Ca alkyl (methyl, ethyl, n-propyl, i-propyl, n-buytl, i-butyl, or t-butyl) and the other of R3 and R4 is hydrogen. Also included are where one of R3 and R4 is methyl and the other of R3 and R4 is hydrogen. In another example, R3 and R4 together can be an oxygen atom and L can be a carbon atom, thus forming a pyruvate derivative.
In some embodiments of the compounds of Formula (I), R4 can be absent, for example, when L is a nitrogen atom. In these examples, R3 can be any of the R3 disclosed herein. For example, R3 can be a C1-C4 alkyl and R4 can be absent. In another example, R3 can be a methyl and R4 can be absent.
In some preferred embodiments of the compounds of Formula (I), L is a carbon atom and both R3 and R4 are methyl groups.

In many embodiments of the compounds of Formula (I), the substituent R5 can be a C1-C14 organic radical, a Ci-Cio organic radical, a C3-C10 organic radical, or a C1-C6 organic radical.
The organic radicals can comprise monocyclic aryl, fused bicyclic aryl, monocyclic PICT ieeigP341VEZ It:AL heteroaryl rings, which may be optionally substituted with 1, 2, 3, 4, or 5 substituent groups independently selected from the group consisting of OH, NH2, SH, NO2, SO3H, PO3H, halogen, C1-C4 alkyl, C1-C4 haloalkyl, Ci-C4 haloalkoxy, alkoxyl, C1-C4 alkoxy-alkyl, C1-C4 hydroxy-alkyl, NHR6, NR62, CN, CO2H, CO2R6, CHO, COR6, SH, SR6, S(0)R6, S(0)2NHR6, or S(0)2R6, wherein R6 is C1-C4 alkyl. In some embodiments, the substituent groups are independently selected from the group consisting of hydroxy, fluor , ehloro, NH2, NO2, SO3H, PO3H, NHCH3, N(CH3)2, COOCH3, SCH3, S(0)CH3, S(0)NHCH3, S(0)2CH3, SC2H5, methyl, ethyl, isopropyl, n-propyl, n-butyl, 1-methyl-propyl, isobutyl, t-butyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trffluoromethoxy groups.
The organic radicals can also comprise a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl can optionally comprise one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical. In some specific examples, R5 can be C1-C6 branched alkyl or cycloalkyl. In other examples, R5 can be a C1-C10nounal or branched alkyl or cycloalkyl, substituted with 1, 2, or 3 sub stituents independently selected from the group consisting of hydroxy, fluor , chloro, NH2, NO2, NHCH3, N(CH3)2, COOCH3, SCH3, S(0)CH3, S(0)2CH3, S(0)2NHCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
In other embodiments of the amide compounds of Formula (I), R5 can be a "benzylic" radical having the structure:
Ar3-(R7)mo Ar3-(R7)mo Ne/
H2 or R5a wherein A.r3 is an aromatic or heteroaromatic ring such as phenyl, pyridyl, furanyl, thiofuranyl, pyrrolyl, or similar aromatic ring systems, m" is 0,1, 2, or 3, and each RT is independently selected from hydroxy, fluor , chloro, NH2, NO2, NHCH3, N(CH3)2, CO2CH3, CONH2, SC2H5, SCH3, S(0)CH3, S(0)2CH3, S(0)2NHCH3, SO3H, PO3H, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifiuoromethoxy, and each R5a substituent group can be independently selected from the group consisting of an alkyl, alkoxy-alkyl, alkenyl, cycloalkenyl, cycloalkyl, -R8OH, -R80 R5, -R8CN, -R8CO2H, -R8CO2R5, -R8COR5, -R8SR5, and -R8S02R5group, where R8 is a C1-C6 organic radical.

P s rot / 3111-n113 hi Still other embodiments of the compounds of Formula (I), R5 can be a C3-Cio branched alkyl. These C3-C10 branched alkyls have been found to be highly effective R5 groups for producing sweet amide compounds of Formula (I). In some embodiments, R5 can be a C4-C8 branched alkyl. Examples of such branched alkyls include the following structures:
or ( or or or or _______ or or In further embodiments the branched alkyls may optionally contain, inserted into what would have been an alkyl chain, one or two heteroatoms such as nitrogen, oxygen, or sulfur atoms to form amines, ethers, and/or thioethers, sulfoxides, or sulfones respectively, or one, two, or three hetero atomic sub stituents bonded to the alkyl chains independently selected from a hydroxy, fluor , chloro, bromo, NH2, NO2, NHCH3, N(CH3)2, CO2CH3, SCH3, SC2H5, SO3H, PO3H, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
In further embodiments of the compounds of Formula (I), R5 can be an a-substituted carboxylic acid or a-substituted carboxylic acid lower alkyl ester. For example, R5 can be an a-substituted carboxylic acid lower alkyl (especially methyl) ester. In some such 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, or its opposite enantiorner.
In many embodiments of the compounds of Formula (I), R5 can be 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 hydroxyl, NH2, SH, halogen, or a CI-CI
organic radical. In related embodiments, the substituents for the aryl or heteroaryl ring are selected from alkyl, alkoxy, alkoxy-alkyl, OH, CN, CO2H, CHO, COR6, CO2R6, SR6, halogen, alkenyl, cycloalkyl, cycloalkenyl, aryl, and heteroaryl, wherein and R6 is C1-C6 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, NH2, NO2, NHCH3, N(CH3)2, P fr; "6621N kileatWS(0)2CH3, S(0)2NHCH3, SC2H5, SO3H, PO3H, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.
In some embodiments of the compounds of Formula (I), R5 can be a phenyl, pyridyl, furanyl, thiofuranyl, or pyrrolyl ring optionally substituted with one or two substituents independently selected from hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, CO2CH3, SCH3, S(0)CH3, S(0)2CH3, S(0)2NHCH3, SC2H5, SO3H, PO3H, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
In many embodiments of the compounds of Formula (I), R5 can be a cycloalkyl, cycloalkenyl, or saturated heterocyclic ring having 3 to 10 ring carbon atoms, optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of NH2, NO2, SO3H, PO3H, NHCH3, N(CH3)2, CO2CH3, SC2H5, SCH3, S(0)CH3, S(0)2CH3, S(0)2NHCH3, C1-C4 alkyl, Ci-C4 haloalkyl, Ci-C4 alkoxy, Ci-C4 haloalkoxy, hydroxy, and halogen. In some further embodiments, R5 can be a cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl ring, or piperidyl ring optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NO2, SO3H, PO3H, NHCH3, N(CH3)2, CO2CH3, SC2H5, SCH3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
In some other embodiments, R5 can be a cyclohexyl ring, optionally substituted with 1, 2, or 3 substitutent groups selected from N112, NO2, SO3H, PO3H, NHCH3, N(CH3)2, CO2CH3, SC2H5, SCH3,Ci-C4 alkyl, C1-C4 haloalkyl, Ci-C4 alkoxy, Ci-C4 haloalkoxY, hydroxy, and halogen groups. For example, in some such embodiments, R5 can have one of the following structures:
R5c' R5e R5c"
or wherein R5c' and R5c" are independently selected from hydroxy, fluoro, chloro, bromo, NH2, NO2, SO3H, PO3H, NHCH3, N(CH3)2, COOCH3, SCH3, SC2H5, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups, or preferably methyl groups. Examples of such methyl substituted cyclohexyl rings have the formula:

C T/113 Si / 311.1I- II:11 or In many embodiments of the compounds of Formula (I), especially compounds having enhancer activity for other sweeteners, R5 can be a cyclopentyl or cyclohexyl ring having a phenyl ring fused thereto, i.e., a 141,2,3,4) tetrahydronapthalene ring radical or an 2,3-dihydro-1H-indene ring radical having the structures:

(R5a)n (R5a)n wherein n is 0,1, 2, or 3, and each R5a can be bonded to either the aromatic or non-aromatic ring. In other embodiments, each R5a can be bonded to the aromatic ring as is shown below:
ul.rt c??
or /a2_ I
(R5a)n (R5a)n (R5a)n In the tetrahydronapthalenyl and indanyl embodiments shown above, each R5a can be independently selected from the group consisting of hydroxyl, NH2, SH, halogen, or a C1-C4 organic radical. In alternative but related embodiments, each R5a can be independently selected from the group consisting of hydroxyl, NH2, SH, halogen, C1-C4 alkyl, C1-C4 haloalkyl, haloalkoxy, Ci-C4 alkoxyl, C1-C4 alkoxy-alkyl, C1-hydroxy-alkyl, OH, N112, NHR6, NR62, CN, CO2H, CO2R6, CHO, COR6, SH, SR6, S(0)R6, S(0)2R6, S(0)2N11R6, and halogen, wherein R6 is Ci-C4 alkyl. In some embodiments, each R5a can be independently selected from the group consisting of hydroxy, fluor , chloro, N112, NIICH3, N(CH3)2, CO2CH3, SCH3, SC2H5, NO2, SO3H, PO3H, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy.
In some embodiments R5 can be a 141,2,3,4) tetrahydronapthalene ring with certain preferred substitution patterns. In particular, in some embodiments of the compounds of Formula (1) R5 can be a cyclohexyl ring having one of the formulas:

F."1E: T / Ili 5 016 El 73 1,11- el 1E11 se, Or 001Jv (-4 R5a00 or SO
or R5a R5a ,Arld Or Oil or R5a R5a R5a %AA' %.1" rk.=
R5a R5a10$ R5a or SO or R5a R5a wherein each R5a can be independently selected from the groups described above. Similarly, in some preferred embodiments, R5 can include one of the structures:
..rvt v-vµ.
%AA %Aft Sill or so, Or 000 Or knit. try\
Or CH30 0:111101 or lel In some embodiments R5 can be an unsubstituted 1-(1,2,3,4) tetrahydronapthalene ring in racemic or optically active form, as shown below:
VW%
=
1411111111 or is, or 41:111111 P CT "'LIS Eli 15 õ/ 7,D 11-11.11,1111:::11 Similarly in the innanyl series R5 can have the structures:
JJ
R5a or R5a, or the R5a substituents can bound to the aromatic ring as show below:
%AMP
(R5a)n or in more specific embodiments, R5 can have one of the exemplary structures show below:
O

r Ole or R5a R5a R5a rv Rsa R5 or R5a op* or 01.
a 411 R5a R5a R5a In some embodiments of the amide compounds of the invention, the tetrahydronapthalene and indane ring systems of the R5 groups described above can be modified to comprise one or more heteroatoms or heteroatomic groups into the bicyclic ring systems, to form new heterocyclic and bicyclic analogs of the tetrahydronapthalene and indane ring systems, so as to form new R5 groups. For example, it is possible to substitute a nitrogen atom for one of the aromatic rings of a tetrahydronapthalenyl group to form new tetrahydroquinolinyl or tetrahydroisoquinolinyl radicals having the structures shown below:
tAftlIf .IVVV
N 410 or N
R
(5a), (R5a)õ

P IC II ..''' iii 5 ul EA 7 El 311+113113 tililAt ovvy N r 1 0 ooN
or (R5a)n (R5a), , wherein the R5a groups can be bonded to either the aromatic or non-aromatic rings, and can be defined in any of the ways described above in connection with the tetrahydronapthalenyl groups. It will be apparent to those of ordinary skill in the art that at least one additional nitrogen atom could be similarly inserted to form additional and isomeric heteroaryl groups, such as the following exemplary R5 groups:
..A.W
or r_pN)6 or .,,Io.N
1, 1 N -. I
or N / ,,,.. I
N/
(R5a) N /
, (R5a),/ (R5a), (R5a),/
The indanyl R5 groups described above can be similarly modified with one or more nitrogen atoms to form additional bicyclic heteroaryl R5 groups, such as for example the following structures:

N r 1 e or or ::3 or i :,-I
-, /
(R"õ )n N / N /
/
(R5a)h (R5a)n (R'a)n .
Additionally, one or more heteroatoms or substituted heteratomic groups can be inserted into the cyclopentyl or cyclohexyl groups of the tetrahydronapthalenyl or indanyl groups described above to form additional fused bicyclic heteroaryls, which include but are not limited to the exemplary structures listed below:
el / Xh (R5a)n Pi c-r u Ei, -911141,E.Dn 5a wherein n 0, c,"2`, or 3, each R can be defined in any of the ways described above, and Xi, is 0, S, SO, SO2, NH, nr NRh, wherein Rh is a C1-C4 organic radical.
Examples of such R5 groups are listed below:
J111.111 LAW
(R5a)n¨i or (R5a1 ¨ I
in =
(R5a) I or (R5a)n-I
n ~Al (R5a or (R5a)-17-1 Rh / 0 or 40. or or (R5a) s (R5a) (R5a) (R5a)2 0 or s or SO or so2 ) (R5a) (R5a) (R5a) (R5a) .tru, 00 or N_Rh (R54)/ :II or NH or / 1\1 (R5a) (R5a) Rh (R5a) It will also be understood by those of ordinary skill in the art that optical and/or diastereomeric isomerism can occur on the unsaturated five and six membered rings of the R5 groups described above, and in many other of the R1, R2, R3, and R4 groups disclosed herein, and that the differing optical isomers (enantiomers) and/or diastereomers can have differing biological activities with respect to the relevant sweet and savory taste receptors.
Prediction of which diastereomer or enantiomer of a particular R.5 group is most likely to be biologically effective can be difficult, and the finding that one particular isomer is more P 71.11 5 Ell Eir / 2 73 14..113 0 effective for one ring system may not necessarily mean that an analogous isomer of a differently substituted group will be similarly effective.
In still other embodiments of compounds of Formula (1), R5 can be a cyclic alkyl group for example, a cycloproryl, cyclobutyl, cyclopentyl, or cyclohexyl, including substituted derivatives thereof.
Also, R5 can be alkylalkoxyl groups, such as those shown below:
or 0 Or 0\
Organic Radicals In addition to the above described general physical and chemical characteristics and/or limitations, which can be shared by the various subgenuses of the sweet compounds of Formula (I), the compounds of Formula (I) can also share more specifically definable chemical structural features or chemical groups or residues, as is further described below.
For example, in some embodiments, R1, R2, R3, R4, and R5 can be independently selected from C1-C6 organic radicals. In one aspect, a C1-C6 organic radical can be 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 carbonyl, amino groups, hydroxyl, or chlorine, or fluorine groups. A preferred set of optional substituent groups can be substituents independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, CO2CH3, SC2115, SCH3, S(0)C113, S(0)2CH3, S(0)2NHCH3, SO3H, PO3H, methyl, ethyl, isopropyl, vinyl, frifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy substituent groups. In other examples, the organic radicals can be C1-C4 organic radicals. In still other examples, the C1 -C6 organic radicals can independently be selected from the group consisting of alkyl, haloalkyl, haloalkoxy, alkoxyl, alkoxy-alkyl, hydroxy-alkyl, aryl, heteroaryl, CN, C(0)H, CO2H, NHR6, NR62, COR6, C(0)R6, SR6, S(0)R6, S(0)2R6, S(0)2NHR6, and C(0)NHR6, wherein R6 is Ci-C4 alkyl.
The compounds of Formula (I) are relatively "small molecules" as compared to many biological molecules, and can often have a variety of limitations on their overall absolute physical size, molecular weight, and physical characteristics, so that they can be at P C:T s nu lLi1ri1 ei least somewhat soluble in aqueous media, and are of appropriate size to effectively bind to the heterodimeric T1R2/T1R3 taste receptors.
As an example of the physical and chemical properties. and/or physical/chemical limitations on the sweet amides of Formula (I), in most embodiments of the compounds of Formula (I), the molecular weight of the compounds of Foimula (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 mole, 450 grams per mole, 400 grams per mole, 350 grams per mole, or 300 grams per mole.
Similarly, the compounds of Formula (I) can have preferred ranges of molecular weight, such as for example from about 175 to about 500 grams per mole, from about 200 to about 450 grams per mole, from about 225 to about 400 grams per mole, from about 250 to about 350 grams per mole.
As discussed above, the amide compounds employed in the inventions described herein can have any combination of the structural features and groups discussed hereinabove.
The subgenera of aromatic or heteroaromatic amide compounds of Formula (I) described immediately above contain many excellent agonists of T1R2/T1R3 sweet taste receptors, at very low concentrations of the amide compound on the order of micromolar concentrations or less, and can significantly supplement enhance the effectiveness of a variety of known sweeteners, especially saccharide based sweeteners, so as to allow the formulation of comestible products with reduced concentrations of saccharide based sweeteners.
Accordingly, many of the aromatic or heteroaromatic amide compounds of Formula (I) can be utilized as sweet flavoring agents or sweet flavor enhancers when contacted with a wide variety of comestible products and/or compositions, or their precursors, to produce taste modified comestible or medicinal compositions, as is described elsewhere herein.
The amide compounds of the invention can be present in the form of enantiomers when the R3 and R4 groups are different, or when any of the "R" groups comprise an optically active carbon atom. When the specification, claims, and/or drawings of this document indicate that a compound is present in optically active form, as is implied by the discussion and drawings immediately above, it is to be understood that the indicated compounds of Formula (I) are present in at least a small enantiomeric excess (i.e. more than about 50% of the molecules have the indicated optical configuration). Further embodiments P C.: T ILI 5 n / 3141-0 preterably compnse an enantiomeric excess of the indicated isomer of at least 75%, or 90%, or 95%, or 98%, or 99%, or 99.5%. Depending on the difference in the biological activities, the cost of production, and/or any differences in toxicity between the two enantiomers, for a given compound it may be advantageous to produce and sell for human consumption a racemic mixture of the enantiomers, or a small or large enantiomeric excess one of the enantiomers of a given compound.
One preferred subgenus of the compounds of Formula (I) are compounds of subgenus Formula (II) wherein the various groups are defined as follows:

(R1)m¨Arl¨Ar2¨L

(II) wherein i) Arl and Ar2 are independently selected from monocyclic aryl or fused bicyclic aryl monocyclic heteroaryl or fused bicyclic heteroaryl rings;
ii) m is selected from the integers 0, 1, 2, 3, 4, or 5;
iii) m' is selected from the integers 0, 1, 2, 3, or 4;
iv) each Rl and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
L is a carbon or nitrogen atom;
vi) R3 is hydrogen, oxygen, hydroxy, halogen, or a Ci-C6 organic radical;
vii) R4 is absent, or hydrogen, oxygen, hydroxy, halogen, or a Ci-C6 organic radical;
viii) R5 is a C1-C organic radical comprising a normal or branched alkyl Or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.

P C T ii.. El 40 11:11 AnOtherTieferred subgenus of the compounds of Formula (I) are compounds wherein L is a carbon atom, L e. the amide compound has subgenus Formula (III):

(R2)m' R3 (R1)m¨Ar1¨Ar2¨C

wherein i) Arl and Ar2 are independently selected from phenyl, napthyl, indolyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrazolyl, furanyl, thiofuranyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, benzofuranyl, triazolyl, tetrazolyl, and benzothiofuranyl groups;
ii) m is selected from the integers 0, 1, 2, or 3;
iii) m' is selected from the integers 0, 1, or 2;
iv) each Rl and R2 is independently selected from the group consisting of a hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, COOCH3, SCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, S(0)CH3, S(0)2CH3, S(0)2NHCH3, CN, CH2OH, C(0)H, C(0)CH3, trifluoromethyl, niethoxy, ethoxy, isopropoxy, and trifluoromethoxy radical;
v) R3 is a C1-C4 alkyl;
vi) R4 is hydrogen, or a Ci-C4 alkyl;
vii) R5 is a C1-C10 normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to or two substituents independently selected from hydroxy, fluor , chloro, NH2, NO2, NHCH3, N(CH3)2, COOCH3, SCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, S(0)CH3, S(0)2CH3, CN, CH2OH, C(0)H, C(0)CH3, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy radical;
or one or more comestibly acceptable salts thereof.
In yet additional aspects, the amide compounds of the invention can have the structure:

P T SILITS Ell Et 311+0 0 (R2)m, R3 (R1)m¨Arl¨Ar2¨C

(IV) wherein i) Arl and Ar-2 are independently selected from a phenyl, or monocyclic heteroaryl rings;
ii) m and m' are independently selected from the integers 0, 1, or 2;
iii) each 121 and R2 is independently selected from the group consisting of OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C4 organic radical;
iv) R3 and R4 are independently selected from hydrogen and a Ci-C4 alkyl, v) R5 is a C3-C10 branched alkyl optionally comprising one, two, or three sub stituents independently selected from OH, NH2, a halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.
Comestibly or Pharmaceutically Acceptable Compounds Many of the amide compounds of Formula (I) or its various enumerated subgenuses comprise acidic or basic groups, so that depending on the acidic or basic character ("pH") of the comestible or medicinal compositions in which they are formulated, they may be present as salts, which are preferably comestibly acceptable (i.e., designated as generally recognized as safe, or GRAS) or pharmaceutically acceptable salts (many of which have been recognized by the Federal Food and Drug Administration).
The amide compounds of Formula (I) having acidic groups, such as carboxylic acids, will tend (at near neutral physiological pH) to be present in solution in the form of anionic carboxylates such as acetates, lactates, fumarates, succinates, salts of fatty acids, etc., and therefore will in preferred embodiments have an associate comestibly and/or pharmaceutically acceptable cation, many of which are known to those of ordinary skill in the art. Such comestibly and/or pharmaceutically acceptable cations include alkali metal cations (lithium, sodium, and potassium cations), alkaline earth metal cations (magnesium, calcium, and the like), or ammonium (14114+ or organically substituted ammonium cations such as (R-N113)+, (NPI2R.2) , (NNW, or (NRarcations, wherein the ammonium "R"

groups can be independently selected and can be a variety or organic groups, including Cl-C113 alkyls, hydroxyalkyls, or alkoxyalkyl groups.
The amide compounds of Formula (I) having ba.sic subsiituent groups, such as amino or nitrogen containing heterocyclic groups, will tend. (at near neutral physiological pH, or at the acidic pH common in many ihods) to be present in solution in the form of cationic ammonium eroups, and therefore will in preferred embodiments have an associate comestibly and/or pharmaceutically acceptable anion, many of which are known to those of ordinary skill in the art Such comestibly and/or pharmaceutically acceptable anionic groups include the anionic form of a variety a carboxylic acids (acetates, citrates, tartrates, anionic salts of fatty acids, etc.), halides (especially fluorides or chlorides), nitrates, and the like.
The amide compounds of Familia (1) and its various subgenuses should preferably be comestibly acceptable, i.e., deemed suitable for consumption in food or drink, and should also be pharmaceutically acceptable. A well known method of demonstrating that a flavorant compound is comestibly acceptable is to have the compound tested and/or evaluated by an Expert Panel ofthe Flavor and Extract Manufacturers Association and declared as to be "Generally Recognized As Safe" ("GRAS"). The PEMA/GRAS
evaluation process for flavarant compounds is complex but well known to those of ordinary sldll 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), pp. 46-59, May 200.
When being evaluated in the FEMA/GRAS process, anew flavorant compound is typically tested for any adverse toxic effects on laboratory rats when fed to such rats for at least about 91) days at a concentration 100-fold, or 1000-fold, or even higher concentrations than the proposed maximum allowable concentration of the compound in a particular category of food products being considered for approval. For example, such testing of the amide compounds of the invention might involve combining the zunicle compound with rat chow and feeding it to laboratory rats such as Crl:CD(SMIGS 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 amide compound of Formula (I) causes no adverse toxic effects on the rats.

;
PCT/ UStlitS/11,1õ:3Lan The compotmots of the invention as Sweet Tastants and/or Sweet Taste Enhancers The amide compounds of Formula (I) and its various compound sub-genuses and species, as described above are intended to be sweet taste flavorant compounds or flavor modifiers for comestible or medicinal products As is apparent from the teachings and Examples herein, many compounds of Formula (1) are agonists of an hT1112/11T1R3 sweet receptor, at concentrations on the order of from about 0.001 to about 100 micrornolar, or higher. Accordingly many OT all of the amide compounds of Formula (I) can have utility as sweet flavorants or flavor enhancers, in their own right. In many favored aspects of the invention, inclusion of such concentrations of the amide compounds of the present inventions in a comestible composition can permit a significant reduction in the amount of known caloric or carbohydrate sweeteners, especially sucrose, fructose, glucose, and sugar alcohols that are necessary to obtain the desired degree of sweetness in comestible compositions.
Nevertheless, it is deairahte to minimize the concentration of the compounds of the invention, 90 as to minimize cost, any possible "off tastes," and any unknown or undesirable side effects of the use of the cqmpounds of Formula (I) at high concentration levels. Accordingly, it is desirable to test the compounds of Formula (1) for their effectiveness as taste receptor agonist.s at lower concentration levels, so as to identify the best and most effective amide compounds within the genus of compounds desmibed by Formula (1). and so that lower limits of concentrations for the practical use of each compound can be identified. 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 tuill.T1R2ihT1R3 sweet receptors. Such measurement ........................................................... methods typically measure an "E050", 4e., the conoentration at which the compound causes 50% activation of the relevant receptor, i.e. such ECse measurements can be a measure of the agonist activity of the amide compounds with respect to ItT1R2/11T1R3 smet receptor&
Preferably, the amide compotm.ds of Fonnula (1) are sweet flavor modifiers or sweet flavor enhancers have an ECsa for the hTIR.2/11T11Z3 receptor of less than about 100 Ai, OT
leas than about 10 micromolar. Ideally, such amide compounds have an ECK, for the hT1It2/11TIR3 receptor of less than about 5 gM, 3 ulY1, 2 at/I, 1 p/V1, or 0.5 ulai.
The amide compounds of Formula (I) can in some cues modulate the binding of a known sweetener such as for example sucrose, fructose, glucose, erythritol, isomalt, lactitol, P C:T U 5 0 õ/ -3111- Eli El mannitol, sorbitOl, xylitol, maltodextrin, or the like, a known natural terpenoid, flavonoid, or protein sweetener, aspartame, saccharin, acesulfame-K, cyclamate, Sucralose, alitame or erythritol to an hT1R2/hT1R3 receptor.
The above identified assays are useful in identifying the most potent of the amide compounds of Formula (I) for sweet taste modifier or enhancer properties, and the results of such assays correlate reasonably well with actual sweet taste perception in animals and humans, but ultimately the results of the assays can be confirmed, at least for the most potent of the compounds of Formula (I), by human taste testing. Such human taste testing experiments can be well quantified and controlled by tasting the candidate compounds in aqueous solutions, as compared to control aqueous solution, or alternatively by tasting the amides of the inventions in actual food compositions. Examples of human taste test experiments in the form of both aqueous solutions that can be a model for sweet beverage compositions, and actual examples of comestible compositions such as ice cream, sweetener coated breakfast cereals, and actual beverage compositions can be found hereinbelow.
Preferred sweet taste modifiers of Formula (I) can be identified when a modified comestible or medicinal product has a sweeter taste than a control comestible or medicinal product that does not comprise the amide compound, as judged by the majority of a panel of at least eight human taste testers.
Preferred sweet taste enhancers of Formula (I) can be identified when a water 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, maltodextrin,a known natural terpenoid, 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 (preferably about 30, 10, 5, 2, 1, or less than 1 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 gums/100 milliliters, or a 50:50 mixture of glucose and fructose would preferably be present at a concentration of about 6 grams/100 milliliters, or 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 1P T /11,11 5 Eli B 4.1C3 present at a Condentration of about 0.4 mM, or alitame would preferably be present at a concentration of about 0.2 mM.
Nevertheless the agonist activity for the compounds of the invention is not however the only factor to be considered when selecting one or more amide compounds disclosed herein for formulating a particular comestible composition. For example, the solubility of the amide compound in water or other common precursors of comestible compositions, such as milk, sweetener concentrates containing sweeteners such as sucrose or fructose, such as corn syrup, edible oils, etc, should also be considered. The compounds of the invention are typically soluble to the extent of at least about 1 ppm in water, but many of the amide compounds have desirably increased solubility in common organic liquid precursors of comestible compositions, and can be soluble to the extent of at least about 5, 10, 20, 50, 100, or 1000 ppm in water, or other common precursors of sweet comestible compositions, such as for example sweet syrups such as corn syrup, milk, edible oils, etc.
or mixtures thereof Using the Compounds of Formula (I) to Prepare Comestible Compositions Many of the amide compounds of Formula (I) and/or its various subgenuses of amide compounds are potent T1R2/T1R3 receptor agonists at concentrations as low as 0.001 micromolar. In some such embodiments, the amide compounds of Formula (I) can have at surprisingly low sweet flavoring agent amounts, a sweet flavor when tasted in isolation, which is independent of the presence of other sweeteners, and therefore can be employed at very low concentrations as stand alone sweeteners in a comestible or medicinal composition, or a precursor thereof.
In many embodiments of the invention, the amide compounds disclosed herein can be used at very low concentrations on the order of a few parts per million, in combination with one or more known sweeteners, natural or artificial, so as to reduce the concentration of the known sweetener required to prepare a comestible composition having the desired degree of sweetness. The reduction of the concentrations of the natural saccharide sweeteners is particularly desirable, because of the reduction of caloric intake and/or tooth decay associated with the reduction of the use of such sweeteners.
Commonly used known or artificial sweeteners for use in such combinations of sweeteners include but are not limited to the common saccharide sweeteners sucrose, fructose, glucose, and sweetener compositions comprising those natural sugars, such as corn syrup or other syrups or sweetener concentrates derived from natural fruit and vegetable P T,/ Si Eli Et /12171littlEig, sources, or semi-synthetic sugar alcohol" sweeteners such as erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, and the like, or well known artificial sweeteners such as aspartame, saccharin, acesulfame-K, cyclamate, Sucralose, and alitame;
or any mixture thereof. Such use of a few parts per million of the amide compounds of the invention in combination with known saccharide sweeteners can be particularly beneficial in that it can allows for a reduction of the concentration of the saccharide sweeteners (and their associated calories) by 30-50%, while maintaining the basic taste of the saccharide sweeteners, and allowing for continuation of some of the other functions of the saccharide sweeteners in maintaining desirable physical properties (such as melting point, "bulking,"
and "browning") of the comestible product.
Some of the amide compounds of Formula (I), while having imperceptibly little or perhaps no sweet flavor when tasted in isolation at relevant concentrations can surprisingly be employed at very low sweet flavor enhancing amounts in order to significantly enhance, (i.e., potentiate or multiply) the sweetness of one or more other sweet flavor agents in a comestible or medicinal composition, or a precursor thereof, such as sucrose, fructose, glucose, and other like and well known natural saccharide-based sweeteners, or known artificial sweeteners such as saccharine, cyclamate, aspartame, and the like.
The inventions described herein also relate in many embodiments to the flavor-modified comestible or medicinal products that contain sweet flavor enhancing amounts of one or more of the amide compounds disclosed herein.
In other words, some of the amide compounds of Formula (I) are not perceived by human beings as being sweet tastants in isolation from other sweeteners, but can perceptibly enhance, potentiate, modulate or induce the perception in humans of the sweet taste of other natural, semi-synthetic, or synthetic sweet flavoring agents, such as for example sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, certain known natural terpenoids, flavonoids, or protein sweeteners, aspartame, saccharin, acesulfame-K, cyclamate, Sucralose, and alitame, and the like, or mixtures thereof. In some preferred embodiments, the amide compounds of the invention enhance the sweet taste of certain naturally occurring sweeteners that comprise one or more of sucrose, fructose, and glucose, or mixtures thereof.
Flavors, flavor modifiers, flavoring agents, flavor enhancers, sweet flavoring agents and/or flavor enhancers, the compounds of Formula (I) and its various subgenuses and species of compounds have application in foods, beverages, and medicinal compositions P CIF / 11J ,11,5 El i Eit lii wherein sweet compounds are conventionally utilized. These compositions include compositions for human and animal consumption. This includes foods for consumption by agricultural animals, pets and zoo animals.
Those of ordinary skill in the art of preparing and selling comestible compositions (i.e., edible foods or beverages, or precursors or flavor modifiers thereof) are well aware of a large variety of classes, subclasses and species of the comestible compositions, and utilize well-known and recognized terms of art to refer to those comestible compositions while endeavoring to prepare and sell various of those compositions. Such a list of terms of art is enumerated below, and it is specifically contemplated hereby that the various subgenuses and species of the compounds of Formula (I) could be used to modify or enhance the sweet flavors of the following list comestible compositions, either singly or in all reasonable combinations or mixtures thereof:
One or more confectioneries, chocolate confectionery, tablets, countlines, bagged selflines/softlines, boxed assortments, standard boxed assortments, twist wrapped miniatures, seasonal chocolate, chocolate with toys, alfaj ores, 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, chewing gum, sugarized gum, 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, savory biscuits and crackers, bread substitutes, breakfast cereals, rte cereals, family breakfast cereals, flakes, muesli, other rte cereals, children's breakfast cereals, hot cereals, ice cream, impulse ice cream, single portion dairy ice cream, single portion water ice cream, multi-pack dairy ice cream, multi-pack water ice cream, take-home ice cream, take-home dairy ice cream, ice cream desserts, bulk ice cream, take-home water ice cream, frozen yoghurt, artisanal ice cream, dairy products, milk, fresh/pasteurized milk, full fat fresh/pasteurized milk, semi skimmed fresh/pasteurized 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, P T / Si Ell Ei P 11-11.10 flavored, functional and other condensed milk, flavored milk drinks, dairy only flavored milk drinks, flavored milk drinks with fruit juice, soy milk, sour milk drinks, fermented dairy drinks, coffee whiteners, powder milk, flavored 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, flavored yoghurt, fruited yoghurt, probiotic yoghurt, drinking yoghurt, regular drinking yoghurt, 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, flavored fromage frais and quark, savory fromage frais and quark, sweet and savory snacks, fruit snacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn, pretzels, nuts, other sweet and savory snacks, snack bars, granola bars, breakfast bars, energy bars, fruit bars, other snack bars, meal replacement products, slimming products, convalescence drinks, ready meals, canned ready meals, frozen ready meals, dried ready meals, chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup, canned soup, dehydrated soup, instant soup, chilled soup, uht soup, frozen soup, pasta, canned pasta, dried pasta, chilled/fresh pasta, noodles, plain noodles, instant noodles, cups/bowl instant noodles, pouch instant noodles, chilled noodles, snack noodles, canned food, canned meat and meat products, canned fish/seafood, canned vegetables, canned tomatoes, canned beans, canned fruit, canned ready meals, canned 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 bakery products, frozen desserts, frozen ready meals, frozen pizza, frozen soup, frozen noodles, other frozen food, dried food, dessert mixes, dried ready meals, dehydrated soup, instant soup, dried pasta, plain noodles, instant noodles, cups/bowl instant noodles, pouch instant noodles, chilled food, chilled processed meats, chilled fish/seafood products, chilled processed fish, IP C T/ S Eit 5 õ/ 3 IUD Eli chilled coated fish, chilled smoked fish, chilled lunch kit, chilled 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 purées, bouillon/stock cubes, stock cubes, gravy granules, liquid stocks and fonds, herbs and spices, fermented sauces, soy based sauces, pasta sauces, wet sauces, dry sauces/powder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low fat salad dressings, vinaigrettes, dips, pickled products, other sauces, dressings and condiments, baby food, milk formula, standard milk formula, follow-on milk formula, toddler milk formula, hypoallergenic milk formula, prepared baby food, dried baby food, other baby food, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads.
Preferably, the compounds of Formula (I) can be used to modify or enhance the sweet flavor of one or more of the following subgenuses of comestible compositions:
confectioneries, bakery products, ice creams, dairy products, sweet and savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, or spreads, or a mixture thereof In some favored aspects of the inventions described herein, one or more of the amide compounds disclosed herein can be added to ice creams, breakfast cereals, sweet beverages or solid or liquid concentrate compositions for preparing beverages, ideally so as to enable the reduction in concentration of previously known saccharide sweeteners, or artificial sweeteners.
In general an ingestible composition will be produced that contains a sufficient amount of at least one compound within the scope of Formula (I) or its various subgenuses described hereinabove to produce a composition having the desired flavor or taste characteristics such as "sweet" taste characteristics.
Typically at least a sweet flavor modulating amount, a sweet flavoring agent amount, or a sweet flavor enhancing amount of one or more of the compounds of Formula (I) will be added to the comestible or medicinal product, optionally in the presence of known sweeteners, so that the sweet flavor modified comestible or medicinal product has pc an an increased sweet taste as compared to the comestible or medicinal product prepared without the amide compound, as judged by human beings or animals in general, or in the case of formulations testing, as judged by a majority of a panel of at least eight human taste testers, via procedures described elsewhere herein.
The concentration of sweet flavoring agent needed to modulate or improve the flavor of the comestible or medicinal product or composition will of course depend on many variables, including the specific type of comestible composition and its various other ingredients, especially the presence of other known sweet flavoring agents and the concentrations thereof, the natural genetic variability and individual preferences and health conditions of various human beings tasting the compositions, and the subjective effect of the particular compound on on the taste of such sweet compounds. As noted, a significant application of the compounds of Formula (I) is for modulating (inducing, enhancing or inhibiting) the sweet taste or other taste properties of other natural or synthetic sweet tastants, and comestible compositions made therefrom. A broad but also low range of concentrations of the amide compounds of Formula (I) would typically be required, i.e., from about 0.001 ppm to 100 ppm, or narrower alternative ranges from about 0.1 ppm to about 10 ppm, from about 0.01 ppm to about 30 ppm, from about 0.05 ppm to about 10 ppm, from about 0.01 ppm to about 5 ppm, or from about 0.02 ppm to about 2 ppm, or from about 0.01 ppm to about 1 ppm.
Examples of foods and beverages wherein compounds according to the invention may be incorporated included by way of example the Wet Soup Category, the Dehydrated and Culinary Food Category, the Beverage Category, the Frozen Food Category, the Snack Food Category, and seasonings or seasoning blends.
"Wet Soup Category" means wet/liquid soups regardless of concentration or container, including frozen Soups. For the purpose of this definition soup(s) means a food prepared from meat, poultry, fish, vegetables, grains, fruit and other ingredients, cooked in a liquid which may include visible pieces of some or all of these ingredients.
It may be clear (as a broth) or thick (as a chowder), smooth, pureed or chunky, ready-to-serve, semi-condensed or condensed and may be served hot or cold, as a first course or as the main course of a meal or as a between meal snack (sipped like a beverage). Soup may be used as an ingredient for preparing other meal components and may range from broths (consommé) to sauces (cream or cheese-based soups).
=

P T:11 p Dehydrated and Culinary Food Category means: (i) Cooking aid products such as: powders, granules, pastes, concentrated liquid products, including concentrated bouillon, bouillon and bouillon like products in pressed cubes, tablets or powder or granulated form, which are sold separately as a finished product or as an ingredient within a product, sauces and recipe mixes (regardless of technology); (ii) Meal solutions products such as:
dehydrated and freeze dried soups, including dehydrated soup mixes, dehydrated instant soups, dehydrated ready-to-cook soups, dehydrated or ambient preparations of ready-made dishes, meals and single serve entrees including pasta, potato and rice dishes; and (iii) Meal embellishment products such as: condiments, marinades, salad dressings, salad toppings, dips, breading, batter mixes, shelf stable spreads, barbecue sauces, liquid recipe mixes, concentrates, sauces or sauce mixes, including recipe mixes for salad, sold as a finished product or as an ingredient within a product, whether dehydrated, liquid or frozen.
"Beverage Category" means beverages, beverage mixes and concentrates, including but not limited to, alcoholic and non-alcoholic, ready to drink beverages, liquid concentrate formulations for preparing beverages such as sodas, and dry powdered beverage precursor mixes.
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, chewing gums, gelatins, ice creams, sorbets, puddings, jams, jellies, salad dressings, and other condiments, cereal, and other breakfast foods, canned fruits and fruit sauces and the like. The amide compounds of Formula (I) can also be of value for producing reduced sugar or reduced calorie formulations of sweet coatings, frostings, or glazes for comestible productes comprising a mixture of the at least one amide compound of Formula (1) in an amount from about 0.1 to about 10 ppm, and one or more other sweeteners independently selected from sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, neotame, saccharin, acesulfame-K, cyclamate, Sucralose, and alitame, or a mixture thereof.
Additionally, the subject compounds can be used in flavor preparations to be added to foods and beverages. In preferred instances the composition will comprise another flavor or taste modifier such as a sweet tastant.

T 71135 0 IS ,/ 2! :rig 1111- El 0 Methods for Modifying the Taste of Comestible or Medicinal Compositions In many embodiments, the inventions relate to methods for modulating (e.g., increasing) the sweet taste of a comestible or medicinal product comprising:
a) providing at least one comestible or medicinal product, or at least one precursor thereof, and b) combining the at least one comestible or medicinal product or at least one precursor thereof with at least a sweet flavor modulating amount of at least one bi-aromatic amide compound, or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product;
wherein the amide compound has the structure:

(R2)m, R3 (R1)m¨Ar1¨Ar2¨ L

(I) Examples of such methods include but are not limited to the methods embodied below.
As disclosed herein, the amide compound is the amide of Formula (I), or any of its various subgenuses or species compounds described herein, wherein Arl, Ar2, R1, R2, R3 R4, R5, and L, can be defined in the many ways also described hereinabove. For example, in some aspects of the methods of the invention, Arl and Ar2 can be independently selected from monocyclic or fused bicyclic aryl and monocyclic or fused bicyclic heteroaryl rings; m is selected from the integers 0, 1, 2, 3, 4, or 5; m' is selected from the integers 0, 1, 2, 3, or 4; each RI and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical; L is a carbon or nitrogen atom; R3 is hydrogen, oxygen, hydroxy, halogen, or a C1-C6 organic radical; R4 is absent, or hydrogen, oxygen, hydroxy, halogen, or a C1-C6 organic radical; R5 is a Cl-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, P03H, halogen, and a Cl-C6 organic radical; or a comestibly acceptable salt thereof.

Fl` CT,/ Us / F 3 11-11-113 fn iciainnal embodiments, the invention relates to methods for enhancing the sweet taste of a comestible or medicinal product comprising:
a) providing at least one comestible or medicinal product, or at least one precursor thereof, and b) combining the at least one comestible or medicinal product or at least one precursor thereof with at least about 0.001 ppm of at least one bi-aromatic amide compound of Formula (I), or a comestibly acceptable salt thereof, so as to form a modified comestible or medicinal product, and wherein the modified comestible or medicinal product optionally comprises one or more known sweeteners or a mixture thereof.
Preferably, the known sweeteners are selected from sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, a known natural terpenoid, flavonoid, or protein sweetener, aspartame, saccharin, acesulfame-K, cyclamate, Sucralose, alitame, and a mixture thereof. Even more preferably, the known sweeteners are selected from sucrose, fructose, glucose, and a mixture thereof.
The invention also relates to the modified comestible or medicinal products produced by the processes disclosed above.
The invention also relates to 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 combined with or applied to the comestible or medicinal products or precursor thereof in any of innumerable ways known to cooks, food preparers the world over, or producers of comestible or medicinal products.
Nevertheless, the amide compounds disclosed herein are typically far higher intensity sweeteners than previously known sweeteners, even previously known sweeteners such as aspartame, neotame, acesulfame K, and the like. Only a few ppm, or less of the amide compounds of the invention are typically needed to impart the desired sweet tast in a comestible composition, and concentrations substantially higher than 10-20 ppm on either an overall basis or in a localized area of the comestible compositions can impart an undesirable level of sweetness, or perhaps even off-tastes.
Accordingly, it can therefore be desirable that the amide compounds of the invention are highly dispersed and/or dissolved in one or more suitable precursors for the comestible compostions that can also serve as diluents for the amide compounds of the inventions, to prepare "sweetener concentrate compositions" comprising from about 10 to about 100,000 P / 2314zri E.11 .
ppm o one or more o: the amide compounds. In such sweetener concentrate compostions, the amide compounds are typically well and homogeneously dispersed in the the one or more suitable precursors for the comestible compositions, then the sweetener concentrate compositions are used to prepare the final comestible compositions, in which the amide compounds are typically also well and homogeneously dispersed. As a result of this high degree of dispersion, the amide compounds used efficiently and not present in the final comestible compositions in either bulk or local concentrations that are much higher than necessary in order to saturate the available sweet taste receptors. Such high dispersion and/or dilution of the amide compounds described herein is also desirable so as to avoid any off-tastes or other side-effects that can sometimes result if the amide compounds of the invention are present at concentrations that are higher than necessary.
For example, the amide compounds of Formula (I) could be dissolved in water or sugary aqueous solution, to form a sweetener concentrate composition, then the liquid sweetener concentrate composition used to disperse the amide into the comestible compositions. Water does not always constitute the optimum dilluent, especially for storage or stability purposes. Alternatively, the amide compounds of Formula (I) can be dissolved in or highly dispersed with one or more of many comestibly acceptable precursors, or mixtures thereof, such as liquids, solids, or other comestibly acceptable carriers, to form a sweetener concentrate concentration with particularly suitable properties. In such sweetener concentrate compositions, the amide compounds can be well dissolved dispersed, or emulsified in the carrier, and often can be more easily handled in bulk food processing operations than the pure amide compound itself. Such solutions, dispersions or emulsions can be generated by various mixing, grinding, milling, and/or homogenization procecesses well known to those of ordinary skill in the art. In such sweetener concentrate compositions, the amide compound can be typically present at significantly higher concentration than is desired in the ultimate comestible composition, for example from about 10 to about 100,000 ppm, or from about 20 to about 10,000 ppm, or from about 100 to about 1000 ppm, or from about 10 to about 1000 ppm of one or more of the amide compounds.
Examples of the many suitable precursor liquids, solids, or other comestibly acceptable carriers suitable for the practice of the inventions disclosed herein include water at neutral, acidic, or basic pH, fruit or vegetable juices, vinegar, marinades, beer, wine, natural water/fat emulsions such as milk or condensed milk, edible oils and shortenings P C. T/ ilj Sf1 E t 213 R+01 comprising fatty acid esters of glycerol, fatty acids or esters thereof, certain low molecular weight oligomers of propylene glycol, glyceryl esters of fatty acids, and dispersions or emulsions of such hydrophobic substances in aqueous media. Suitable liquid carriers or diluents can also include comestibly acceptable solvents such as ethanol, propylene glycol, certain low molecular weight oligomers of propylene glycol and their ethyl ethers or acetates. Solid commestibly acceptable precursors, carriers, or diluents can include salts such as sodium chloride, vegetable flours and powders; flavor concentrates and extracts, spices, seasonings, saccharide sugars such as sucrose, fructose, glucose/dextrin, lactose and the like, or polysaccharides such as starch, modified starches, dextrins, maltodextrins, celluloses and modified celluloses, and the like, or emulsifying and stabilizing polysaccharides such as pectins, alginates, chitosan and chitosan derivatives, gum Arabic, carrageenans, locust bean gum, guar gum, and the like, common anti-oxidants or stabilizers or bulking agents,or mixtures of the precursors of the comestible composition, as exemplified above.
The compounds of the invention typically have sufficient solubility in water and/or polar organic substances, and mixtures thereof, for formulation at the desired concentration ranges by simply dissolving them in the appropriate liquids. Concentrate compositions comprising solid but water soluble substances such as sugars or polysaccharides, and the amide compounds described herein can be prepared by dissolving or dispersing the amide compound and soluble carrier in water or polar solvents, then drying the resulting liquid, via well know processes such as spray drying.
The solubility of the amide compounds of the invention may however be limited in less polar or apolar liquid carriers, such as oils or fats. In such embodiments it can be desirable to prepare a very fine dispersion or emulsion of the solid amide compound in the carrier, by grinding, milling, or homogenizing a physical mixture of the amide compound and the liquid carrier. The amide compounds can therefore in some cases be formulated as sweetner concentrate compositions comprising dispersions of solid microparticles the amide compound in the precursor substances. For example, some of the amide compounds of the invention can have limited solubility in non-polar substances such as edible fats or oils, and therefore can be formulated as sweetener concentrate compositions by milling or grinding the solid amide compound to microparticle size and mixing with the edible fat or or oil, or by homogenizing a dispersion of the solid amide compound and the edible fat or oil, or a C T 11.11 El; 0 / 11-11-commestibl; acceptable analog thereof, such as the NeobeeTM triglyceride ester based oils sold by Stephan Corporation of Northfield Illinois, U.S.A.
It is also possible to prepare solids coated, frosted, or glazed with the well dispersed compounds of the invention by dissolving the amide compound in water or a polar solvent, then spraying the solid carrier or composition onto the solid comestible carrier or substrate, as exemplified below in connection with frosted cereals.
By means of the methods described above, many well known and valuable comestible compositions that currently contain sugar and/or equivalent saccharide sweeteners can be reformulated to comprise a few ppm of one or more of the amide compounds described herein, with a concomitant ability to reduce the concentration of the sugar and/or equivalent saccharide sweeteners by as much as 30 to 50%, with a corresponding drop in the caloric content of the comestible compositions.
For example, carbohydrate and/or saccharide sweeteners have long been used to sweeten and modify the melting point, texture, and palatability of ice cream formulations.
Examples of carbohydrate sweeteners that are typically used in ice cream formulation include, but are not limited to, sugar, corn syrups, corn syrup solids, maltodextrin, and mixtures thereof. While such sweeteners add sweetness and calories, they also affect the texture and freezing and melting points of the frozen ice cream. Disclosed herein are examples of methods for reducing the amount of carbohydrate and/or saccharide sweeteners by using the compounds disclosed herein. By means of such methods and the ice cream formlations that result, the concentration of carbohydrate sweeteners required to achieve the desired sweetness can be reduced, along with calories. Moreover, the texture, freezing, and melting points of the resulting ice cream formulation can be adjusted in view of the lower sweeteners levels, by use of other known stabilizers, diluents, or more healthful natural incredients, to achieve a high quality ice cream product with reduced calories, as is well known to those of skill in the art, in view of the reduced sweetener ice creams already on the market.
The sweet enhancers disclosed herein can also be used with reduced calorie ice cream formulations that utilize artificial sweeteners (Sucralose, aspartame, acesulfame K, etc.) and/or sugar alcohol sweeteners (xylitol, sorbitol, erythritol, etc.).
There are potential cost benefits that are associated with the use of the compounds of the invention to allow the reduction of these types of sweeteners, and there can also be some textural improvements as 1P S Et ,7 3 413 ET
well as decreased gastrointestinal side effects associated with the usage of sugar alcohol sweeteners.
The amide compounds disclosed herein can be used at any desired concentration, and are effective sweeteners at concentrations of from about 0.0-1 to about 20 ppm, but are often optimally effective in ice cream formulation at levels of from about 0.1 to about 6.0 ppm. When properly formulated, the concentrations of sugar and carbohydrate type sweeteners can be effectively reduced by up to 50% while maintaining the desired degree of sweet flavor of the ice cream. Artificial sweeteners and sugar alcohols can also be effectively and optimally reduced up to 50% by using the disclosed sweet enhancers at levels of from about 0.1 to about 8 ppm.
Carbohydrate sweeteners have also long been used to coat processed cereals such as snacks and frosted breakfast cereals, to provide sweetness and texture.
Typical sugar contents range from about 20 to 60% in known finished cereals, and the high sugar content of the cereal gives the cereals a "frosted" white appearance. The use of the amide compounds described herein in such cereal coatings allows for the reduction of sweetener levels and/or calories of the frosted cereals, and can also improve the appearance and/or marketability of the cereal. Similar approaches can be taken to form reduced sugar formulations of a wide variety of sweet coatings, frostings for baked goods, glazes, or sauces for other comestible products.
Carbohydrate sweeteners (typically sucrose, fructose, glucose/dextrose, dried corn syrup, etc.) have also long been used to formulate both liquid and dry beverage concentrate compositions, to provide for sweet taste and/or desirable mouthfeel. The use of a combination of disclosed amide compounds and significantly lower levels of existing sweeteners in liquid or solid beverage concentrate compositions allows the reduction unwanted calories in the final beverages, while maintaining similar taste, sweet flavor profile, and mouthfeel of the beverage. By use of the amide compounds of the invention at optimum 0.5 to 2.0 ppm concentrations, concentrations of the existing sweeteners can be reduced up to 50%, while achieving similar sweetness levels of the full sugar product. The sweet enhancers can also be used with reduced calorie and or sugar-free liquid beverages, dry beverage base formulations, or liquid concentrate formulations that utilize artificial sweeteners (Sucralose, aspartame, ace K, etc.) and or sugar alcohol sweeteners (xylitol, sorbitol, erythritol, etc.). There are potential cost benefits that are associated with the reduction of carbohydrate sweeteners, artificial sweeteners and sugar alcohol sweeteners.

C:T./ UStinie" al3141.3 Qualitatively similar results and/or improvements can be made in many other comestible composition formulations by use of one or more of the amide compounds described 'herein.
Carbohydrate sweeteners (HFSC, corn syrups, sucrose/sugar, fructose, glucose/dextrose, dried corn syrup, eta) are also used to sweeten soda flavor concentrate syrups, which are typically mixed with carbonated water in a 1;5 ratio to prepare the fountain soda drinks commonly sold in fast food restaurants and convenience stores. The most commonly used sweetener in soda syrup formulations is HFCS 55 (corn syrup comprising about 55% fructose), The use of 1117CS in fountain syrups and carbonated beverages (soda) has been criticized for contributing to the rise in both child and adult obesity, but its usage can be lowered by the use of the amide compounds described herein.
The arnide compounds can also be used in reduced calorie and or sugar-free soda syrup base formulations that utilize artificial sweeteners (Sucralose, aspartame, ace K, etc.). There are potential cost benefits that are associated with the reduction of carbohydrate sweeteners and artificial sweeteners. =
Making The Amide Compounds of Formula (1) 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 equipped to prepare any of the necessary starting materials and/or claimed compounds. In sonic 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.
It is recognized that the skilled artisan in the art of organic chemistry canteadily 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, Bravado substitutions, both electrophilic and nucleophilic, etherifications, esterification, saponification, nitrations, hydrogenations, reduetive amination and the like.
These manipulations are discussed in standard texts such as March's Advanced Organic Chemistry (3d Edition, 1985, Wiley-Interscience, New York), Feiser and Feiser's Reagents for Organic Synthesis, Carey and Sundberg, Advanced Organic Chemisiq and the like.

:1L1IS CitE IP 34E4 11,",:11 The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons (1999).
The following abbreviations have the indicated meanings:
CH3CN = acetonitrile HC1= hydrochloric acid CHC13 = chloroform H2SO4 = sulfuric acid DIC = N,Nt-diisopropylcarbodiimide HOBt = 1-hydroxybenzotriazole DIPEA = diisopropylethylamine Me0H = methyl alcohol DMAP = 4-(dimethylamino)-pyridine MgS0.4 = magnesium sulfate DMF = N,N-dimethylfonnamide NaHCO3 = sodium bicarbonate EDC = 1-(3-dimethylaminopropy1)-3- NaOH = sodium hydroxide ethylcarbodiimide hydrochoride Fmoc = N-(9- Na2SO4 = sodium sulfate fluorenylmethoxycarbonyl DCM= dichloromethane Ph = phenyl DME-1,2-dimethoxyethane ESEVIS = electron spray mass r.t. = room temperature spectrometry Et3N triethylamine SPOS = solid phase organic synthesis Et0Ac = ethyl acetate THF = tetrahydrofuran Et0H = ethyl alcohol TLC = thin layer chromatography Alkyl group abbreviations Me = methyl i-Bu = isobutyl Et = ethyl t-Bu = tertiary butyl n-Pr = normal propyl s-Bu = secondary butyl i-Pr = isopropyl n-Pen = normal pentyl n-Bu = normal butyl i-Pen = isopentyl P C T of a 3.400 .
inc ionowing example schemes are provided for the guidance of the reader, arid represent preferred methods for making the compounds of Formula (I). These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds Such methods specifically include solid phase based chemistries, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare the necessary and/or clainted eompounds by those methods given the literature and this disclosure.
The starting materials used in preparing the compounds Formula (I) and their synthetic precursors, especially the substituted or unsubstituted aryls and lieterotnyls, organic carboxylic acids and benzoic acids, isocyanates, and the various amities, anilines, .=
alcohols, amino acids, eta, are often known compounds, OT can be readily made by known methods of the literature, or are commercially available from various sources well known to those of ordinary skill in the art, such as for example, Sigma-.Aldrich Corporation of St Louis, Missouri USA, and their subsidiaries Fluke and Riedel-de Haen, at their various other worldwide offices, and other well know suppliers such as Fisher Scientific, TCI
America of Philadelphia PA, CheanDiv of San Diego, CA, Cheralnidge of San Diego, California, Asinex of Moscow, Russia, SPECS/BIOSPECS of the Netherlands, Maybridge otComwall, England, Acres, TimTec of Russia, Comgenex of South San Francisco, California, and ASDI Biosciences of Newark, Delaware,.
Well known organic reactions useful in the synthesis of the compounds of Formula (1) include halogenations, esterificatioris and de-esterifications, the reduction of carbonyl compounds to their corresponding alcohols, the condensation of carboxylic acids with amines to form amides, oxidations, alkylations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, estelification, saponification, nitrations, hydrogenations, reductive amination, palladium catalyzed coupling reactions, and the like.
These and many more well known to those of ordinary skill are discussed in standard texts such as March's Advanced Organic Chemistry (3d Edition, 1985, Wiley-Interseience, New York), Feiser and Feiser's Reagents for Organic Synthesis, Carey and Sundberg, Advanced Organic Chemistry and the like .
A representative synthetic pathway for'' producing the compounds of Formula wherein L is carbon are shown in Scheme 1:

P C T Ili 5 Eli Ej/$3iiO Ei Scheme 1 (R2)m, (R26 (R26, R 1. aq. NaOH

I R-_____________________________________________________ (R16¨Ari¨Ar2--/'-N-R5 R¨Ar2--)(c! 2. R5NH2 R¨Ar- N-R5 iv (R1)m¨Arl¨X
(R2)m.
R60, I R3?
R.
B¨Ar2 R6d The methods of Scheme 1 begin with monoaromatic carboxylic acid esters of structure i, whose synthesis will be further described below. The monoaromatic carboxylic acid esters are hydrolyzed, typically under basic conditions, to give the parent carboxylic acids, which are condensed with primary amine precursors of the R5 group (R5NH2) in presence of a variety of well known dehydrating/coupling reagents, such as 1-ethy1-3-(3-dimethylaminopropy1)-carbodiimide hydrochloride, to yield the amide compound of structure ii. The amide compound of structure ii is then coupled with a precursor of the Arl group, by one of the known variations of palladium catalyzed "Suzuki" coupling of boronic acids iii or v (see Suzuki, Pure & Applied Chem., (1994) 66:213-222, Miyaura and Suzuki, Chem. Rev. (1995) 95:2457-2483, Watanabe et al., Synlett. (1992) 207-210). In such Suzuki coupling reactions, precursors such as (ii) and (iii) may be employed wherein R6 is either alkyl or hydrogen, and R is a halide (such as, iodo, bromo, or chloro) or triflate.
Alternatively, the aryl borate v can be prepared by lithiation of a precursor aryl halide (e.g., iodo, bromo) ii, followed by treatment with a boric acid triester or can be prepared by palladium-catalyzed cross coupling reaction of a precursor aryl halide (e.g., iodo, bromo, or chloro) or a triflate ii with pinacol borane. Coupling reactions to produce biaryls such as iv may be conducted using either aryl boronic acids or aryl boronic esters, including cyclic esters in which two of the R6 groups together with the boron atom from a pinacol borate ester (formation of pinacol borane esters: Ishyama et al., J. Org. Chem.
(1995)60:7508-7510; coupling pinacol borane esters: Firooznia et al., Tetrahedron Lett.
(1999) 40:213-216).

P C] Lit !1:7,i; E, 311,11- (1.11 113 Sheme I a ,OR6 2 , (R1)rn¨Ar1-13 ( ),r , (R2),n. 0 I __R!,KN-R5 I F23A iii R31 R6-NH2 __________________________________________________________ m(R1)-Arl-Ar2 R-Ar2 OH m(R1)-Arl-Ar2--' -OH

R4 i ha v ia (R1)m¨Arl¨X
(R2),, _IfL' ,I3-A)L
r2 OH

ilia Alternatively, according to the Scheme la, the synthesis of compounds of Formula (I) can start with monoaromatic carboxylic acid or ester precursors ia wherein R is a halogen or triflate, that can be directly coupled under "Suzuki coupling"
conditions with boronic acids iii to give the biaryl acid iia. Alternatively iia can be prepared from the aryl borate ilia which can be prepared by lithiation of a precursor aryl halide (e.g., iodo, bromo) ia, followed by treatment with a boric acid triester or can be prepared by palladium-catalyzed cross coupling reaction of a precursor aryl halide (e.g., iodo, bromo, or chloro) or a triflate ia with pinacol borane followed by Suzuki coupling with a precursor of the Arl group [(R1)m-Ar1-X] wherein X is either alkyl, halogen or triflate. The biaryl acids iiia can be then condensed with primary amine precursors of R5 group (R5NH2) typically in presence of a carbodiimide type of reagent to yield the amide-biaryl compounds of structure iv.
Scheme 2 discloses a method that can be used to prepare urea compounds of Formula (I) wherein L is a nitrogen atom:
Scheme 2 (R2)m. (R2)m. 0 R5, Dioxane PS-NCO/PS-NH2 R-¨NCO + NH2 R¨Ar2¨NH NHR5 rt, o/n 50 C, 5h vi vii viii (R2)m. R3 (R2)nn, / Dioxane PS-NCO/PS-NH2 R¨Ar2--NH + R5-NCO
rt, o/n 50 C, 5h NHR5 via ix PC1r/USIINeST'itialigialompounds of Formula (I) wherein L is nitrogen can begin with readily available aryl isocyanates (vi). Aryl isocyanates can also be prepared by the phosphogenation of aryl amines by treatment with phosgene. In another method that avoids the use of phosgene, aryl isocyanates (vi) can be prepared by treating an aryl amine with a diallcyldicarbonate(e.g., di-tert-butyldicarbonate (i.e., (Boc)02) in the presence of a base (see e.g., Angew. Chem, Int. Ed. Engl. (1995) 34:2497.
In yet another route to aryl isocyanates (vi), an aryl carboxylic acid OT aryl acid chloride, upon treatment with diphenyphosphoryl azide or sodium azide, respectively, can undergo the Curtius rearrangement to provide the aryl isocyanate (vi). Alternatively, to synthesize a starting material via that will produce a final compound of Formula (I) having a non-hydrogen R3 substitutent, the N-substituted aromatic precursor compound XV can be condensed with an isocyanate precursor of the R.5 group vi.
With the desired aryl isocyanate starting material (vi) in hand, it can be treated with amine (vii) in dioxane, followed by treatment with methylisocyanate polystyrene and polystyrene amine, two polymer supported reagents, to yield the desired urea starting materials. The result is precursor (viii) (where R3 is hydrogen and R4 is absent), which can = be functionalized with aryl substituent Arl¨(RI)õõ as shown above in Scheme 1.
Various methods for synthesizing precursors of starting materials such as compound i are illustrated in Scheme 3. A representative synthetic method for synthesizing precursors i can start using bromination of readily available substituted totyl compounds of structure x , followed by substitution by cyanide providing the nitrite intermediate xi.
Hydrolysis of the nitrile under either basic or acidic conditions followed by esterification can provide various phenyl acetic acid esters xii, that can be alkylated on their activated methylene groups by treatment with a base (such as Nall, lithium diisopropyl amide (LDA), or K2CO3) then alkyl halides (e.g., iodo, chloro, bromo), providing depending on reaction stoichiometry and reaction conditions, either monoalkylated )(ill or dialkylated precursors i, where R3 is the same as R4. Subsequent alkylation of precursor (xii) can give compound i, where R.3 is not the same as R4. These reactions were described for example by Beckett et al.
Tetrahedron (1968) 24:6093-6109, by Duan et aL J. Med. Chem. (2002) 45:4954-4957, and by Obrnoto et al. J. Med Chem. (2001) 44:1268-1285.
In other aspects, a new R4 substituent bonded through an oxygen, nitrogen, or sulfur atom can be introduced onto compound xiii by brotuination at the activated methylene r, 1 01 n P E: 11 /gW3,9(iiidca ilV"iuµ iostitution of the bromide by nucleophiles such as alkoxides, organic amines, thiols, and the like.
Scheme 3 I
(RI26 NBS NaCN
(R26 (R2) (R) 2 J.1 R¨Ar2¨Me R¨Ar2___,- Br RAr2___,CN 0 R¨Ar2----- -OH
xi x 1 Br C)11 (R26 --)( R¨Ar2--xii 1 NBS NaH
3 1 Or R X KOtBu IC
or WA
I
(R )m (R2.
R ? R 6 < I 0 aH
R¨Ar2 N
¨4-- --e R¨Ar2¨r-k-o.
or R3 KOtBu R3 i or xiii LDA
Specifically, methods for the synthesis of acetic acid methyl ester starting materials having 5-membered heteroaromatic Arl rings, represented by general formula ii, are described in Scheme 4. N-Alkylation of xiv with NaH/BrCH2CO2Me can give carboxy methyl substituted heterocycles compounds xv. Similar a-C-alkylations or a-C-functionalization as described above gave the key precursors ic.

P C T / 12311+D
Scheme 4 (R2),õ, (R2),õ.
NaH..R3X

/X4Vµi Y., BrCH2CO2Me )5).< = NaH or KOtBu or LDA
õ/"= Z 0 R Z R
xiv xv W, X, Y, Z = CH, N
(R2),õ, (R2),õ, (R2)m.
X- .w NBS X: -IN 0 ,0 0 yõ Ri yõ R3ll yõ R 3 ,N ,N
R Z R Z R Z
AO
Br ic R4 R4X, NaH or KOtBu or LOA
An alternative route for the convenient synthesis of methyl phenylacetic acid esters i is described in Scheme 5, which employs a Palladium-catalyzed coupling of silylketene acetals with aryl halides developed by Hartwig, J. F. et al (Liu, X. and Hartwig, J. F. J. Am.
Chem. Soc. 2004, 126, 5182).
Scheme 5 OSiMe3 OMe RL VII (R26, (R2)m,R4 I 30 Ar.2 R It Ar2 R
Br Pd(dba)2, t-Bu3P, ZnF2 0 Methods for the synthesis of methyl phenylacetic acid ester precursors i having one of R3 and R4 being alkoxy or amino substitutions is described in Scheme 6. a-Hydroxy-phenylacetic acid derivatives B can be obtained by reaction of the corresponding benzaldehyde derivatives A with Me3SiCN, followed by hydrolysis with HC1, and subsequent esterification. O-Alkylation, followed by a-C-alkylation provided the precursors i. The a-amino-phenylacetic acid derivatives C can be similarly obtained via the Strecker synthesis, followed by esterification. The subsequent N-alkylation or N-protection, followed by a-C-alkylation, provided the precursors i.

P C T 7 113 S ia Et / 2 3 1,110 Eli Eli Scheme 6 (R2),,, (R2),,, (R2)m.
I 1. (a) Me3SiCN; (b) HCI or Me0H I 0 I 0 RCHOAry, 2. (a) KCN, NH4CI; (b)HCI. HCI Fr- e or alkylation or protection or (R26, (R2)m.
reductive annination R I 0 R4X I 30 1 Ary0 NaH or KOtBu or LDA R 0 D R3 iR4 Methods for the synthesis of phenyl acetic acid methyl ester precursors i with more functionalized R3 and R4 substitutions are described in Scheme 7. a-C-Alkylation or Aldol reaction of methyl phenylacetic acid esters E gave the corresponding a-C-mono-substituted methyl phenylacetic acid esters F. The subsequent base catalyzed condensation with esters or aldehydes provides the more functionalized phenylacetic acid methyl ester precursors i.
Condensation of methyl phenylacetic acid esters E with formaldehyde in the presence of K2CO3 gave a-phenyl methyl acrylate intermediates G. Asymmetric dihydroxylation, followed by selective alkylation of the resultant two hydroxyls (see Kolb, H.C., Chem Rev.
1994, vol 94, 2483-2547) can provide a variety of the phenylacetic acid methyl ester precursors wherein R3 and R4 are different.
Scheme 7 Et0Na, RCHO
1 1' (R2),, (R2)õ, (R2)m.
R3X or RCHO I 0 LiHMDS I 30 , Ary1,.
,.,,,IN NaH or R 0' RCO2Me or RCHO R 0 R 0 KotBu or LDA R3 E F i 1 HCHO, K2CO3 (R26 elongation of two-OH
(R2)m, I 0 by selective alkylation, I 0 AD-a or AD-P, 2 OHil ., protection, etc.
R

-,.
G H OH
Disclosed below are methods for synthesizing compounds wherein Arl is an oxadiazole heterocycle:

P C:T/ U S1Eti23Hfl Scheme 8 0, 0 1. NH2HCMCI

+ 7-0 N a H CO 3 OH 2. Br2 Br Br Br N
R3x NoarH
KOtBu or LDA
0 /¨ s\ r-fq 0 NBS
N-0 -C) li //' _____________________________ Br A.>
¨N R3 Br N R3 NaH
R4X K8trBu or LDA

N0\ ____________________________ NH 1. aq. NaOH

A ______________________________________________ 2. R5N H2 Br N R3 Br NO R3 (R1),-Ar¨B,,0 R6 0 ,R5 -0 '\'-NH (RI )m-Arl-X -0 \-NH

R60-- N R3 Ar N R3 0 R6 (R1), The methods of Scheme 8 begin with formation of dibromoformaldoxime I from glyoxylic acid J, as described by Rohloff et al. Tetrahedron Lett. (1992) 33:3113-3116.
Cyclization with ethyl cyanoacetate K under basic conditions provides the 3-brominated-1,2,4-oxadiazole intermediate L (see Humphrey, et al. J. Heterocyclic Chem.
(1989) 26:23-24), which can be further functionalized by treatment with a strong base (such as NaH, lithium diisopropyl amide (LDA), KOtBu) and alkyl halides (e.g., iodo, chloro, bromo) providing either monoalkylated M or dialkylated precursors N, where R3 is the same as R4.
Sequential alkylation of precursor (M) can give compounds N, where R3 is not the same as R4. These reactions were described for example by Beckett et al. Tetrahedron (1968) 24:6093-6109, by Duan et al. J. Med. Chem. (2002) 45:4954-4957, and by Ohmoto et al. J.
Med Chem. (2001) 44:1268-1285.

P C:11- Ult'inaltriati.ic carboxylic acid esters N are hydrolyzed, typically under basic conditions, to give the parent carboxylic acid, which is condensed with primary amine precursors of the R5 group (R5NH2) in the presence of a dehydrating/coupling reagent such as 1-ethyl-3-(3-dimethylaminopropy1)-carbodiimide hydrochloride, to yield the amide compound of structure 0. The amide compound of structure 0 is then coupled with a precursor of the Ar group, by palladium catalyzed "Suzuki" coupling of boronic acids P (see Suzuki, Pure & Applied Chem., (1994) 66:213-222, Miyaura and Suzuki, Chem.
Rev.
(1995) 95:2457-2483, Watanabe et al., Synlett. (1992) 207-210). In this Suzuki coupling reaction, precursors such as P may be employed wherein R6 is either alkyl or hydrogen.
Scheme 9 HO
1. HOBt, EDCI -0 Ar NH2 2. CH3CN Ar N
,(R1),õ (R1), R3X NoarH
KOtBu or LDA
I 0 / 0, /
NBS )1... __ Ar N R3 Air N R3 (R1)m (R1)m T
NaH
or IT+X KO tB u or LDA

-0 NH 1. aq. NaOH
______________________________________________________ R4 \Ls,1 __________________ R4 - ________ Ar N R3 2. R5NH2 Ar N R3 (R1) (R1)m id Alternatively, 1,2,4-oxadiazole-containing biaryl amides of Formula id may be synthesized as described in Scheme 9 from aryl hydroxybenzimidamides Q by cyclization with 3-methoxy-3-oxopropanoic acid R in two steps to provide the biaryl esters of structure S (see Wang et al. Org. Lett. (2005) 7:925-928). Further modification of the cyclized tfrol .
P C iilatightµ to arm a substituted structures T and U, followed by saponification and amide formation.
Scheme 10 provides for synthesis of other compounds of Formula (I) wherein Ail is an isoxazole heterocycle. The methods of Scheme 10 begin with reduction of the bisaromatic isoxazole aldehyde of structure V with sodium borohydride, followed by mesylation and substitution with the oyano group to give compound W.
Punctionalization cdpha to the cya.no substituent can be carried out base catalyzed alkylations as described in Scheme 10, to provide intermediates X and Y. Subsequent hydrolysis of the nittile functionality under acidic conditions, and condensation with an amine of formula R5N112 using coupling reagents (1-ethyl-3-(3-dirnethylaminopropyl)-carbodiimide hydrochloride and 1-hydroxybenzotriazole) provide the bia.ryl isoxazole amides Z.
So 10 tks...1 1. Nal,' Ft X
Wiel Nall 4# RI-"'NI P1)61 Kg3u 011)/1 oka kro Of V W WA =it X Nei NE1.9 feX taltt Alr 14t1 031)m els Y
aq-ReNilz . 44 Measuring the Biological Activity of the Compounds of Foraind*
Cell based technologies and assays, such as those disclosed in WO 02/064631, and WO 03/001876, and U.S. Patent Publication US 2003-0232407 Al were used both to initially .. screen amide compoun.ds for agonist or antagonist activity for T1R2/T1R3 "sweet"

P c T ,/ it "3 Cit El, 311-1- 117,It t See* receptors`that _iad been expressed in appropriate cell lines. Once initial "hits"
corresponding to interesting levels of agonist activity of compounds of Formula (I) had been obtained in assays using such cell lines, the same assays and also certain cell and/or receptor-based assays for the ability to enhance the sweet taste of known sweeteners such as sucrose, fructose, and the like were used to provide data to guide an iterative process of synthesizing and testing structural variants of the amide compounds of Formula (I), in combination with occasional human taste testing of high interest compounds, so aa to design, test, and identify species and genera of compounds with increased and optimized levels of desirable biological activities.
Some aspects of the inventions relate to the quantification of the degree of activity of specific compounds and classes of the amide compounds of Formula (I) that are agonists of, or modulate (increase or decrease) the activity of the T1R2/T1R3 sweet taste receptors, alone or in combination with another compound that activates hT1R2/hT1R3, e.g., sucrose or fructose. Particularly, in many embodiments the invention relates to the amides of Formula (I) that are agonists for, or modulate the activity of hT1R2/hT1R3 (human sweet 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, when added to a comestible or medicinal product or composition.
Prior to conducting "swish and spit" taste testing by human volunteers, compounds of Formula (I) that met desired activity criteria in the receptor-based screening assays, as well as suitable purity, solubility and other physical properties requirements, undergo a preliminary safety assessment. The preliminary safety assessment involves a preliminary toxicity review from the literature and a structure search and a substructure search, as well as searches on potential break-down products or metabolites. This safety assessment process is intended to identify structural alerts (described by Ashby and Tennant in "Chemical Structure, Salmonella Mutagenicity and Extent of Carcinogenicity as Indicators of Genotoxic Carcinogenesis Among 222 chemicals Tested in Rodents by the U.S.
NCl/NTP," Mutation Research, 204:17-115 (1988), "Definitive Relationships Among Chemical Structure, Carcinogenicity and Mutagenicity for 301 Chemicals Tested by the U.S. NT?," Mutation Research, 257:229-306 (1991), and by Cramer, Ford, and Hall, "Estimation of toxic hazard ¨ A decision tree approach," Food and Cosmetic Toxicology 16, 255-276 (1978)) using the principles outlined by Munro et al. ("A Procedure for the Safety PT

.bVamation ot Flavouring Substances." Food and Chemical Toxicology, 37:207-232 (1999)). Searches include chemical structures and reactions, associated chemical and physical properties, scientific literature, and detailed pharmacological, toxicological, and ecological data. A committee reviews a summary of relevant information, and if approved, compounds of Formula (I) whose chemical structure permits no strong initial presumption of safety (Class III) were tasted at or below the human exposure threshold of microgram/day describe by Munro et al.
As a result of the iterative process of making and assaying the activity of compounds of Fonnula (I), and selected human taste tests, it has been unexpectedly discovered that at the amide compounds of Formula (I) are agonists of hT1R2/hT1R3 (human sweet receptor) in vitro and/or in vivo at concentrations significantly below the millimolar level, and often are agonists at concentrations of a few micromolar or less. Moreover it has been discovered that many of the amide compounds of Formula (I) can, at concentrations significantly below the millimolar level, and often are agonists at concentrations of a few micromolar or less modulate the human perception of sweet taste, alone or in combination with another compound or flavorant compound or composition, when added to a comestible or medicinal product or composition, or a precursor thereof.
In vitro hT1R2/hT1R3-HEK293 taste receptor activation assay An HEK293 cell line derivative (Chandrashekar et al., Cell (2000) 100:703-711) that stably expresses Gal5 and hT1R2/hT1R3 (Li et al., Proc Nat! Acad Sci US A
(2002) 99:4692-4696), see also PCT Publication No. WO 03/001876 A2) was used to identify compounds with sweet taste enhancing properties.
Compounds covered in this document were initially selected based on their activity on the hT1R2/hT1R3-HEK293-Gal5 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 FLIPR assay). Cells from one clone (designated S-9 cells) were seeded into 384-well plates (at approximately 50,000 cells per well) in a medium containing DMEM Low Glucose (Invitrogen, Carlsbad, CA), 10% dialyzed fetal bovine serum (Invitrogen, Carlsbad, CA), 100 Units/m.1 Penicillin G, and 100 gig/ml Streptomycin (Invitrogen, Carlsbad, CA) (Li et al. vide supra) see also PCT Publication No. WO 03/001876 A2). S-9 cells were grown for 24 hours at 37 C. S-9 cells were then loaded with the calcium dye Fluo-3AM

(Molecular Probes, Eugene, OR), 41..1,M in a phosphate buffered saline (D-PBS) (Invitrogen, F" C 11.11 1L11. al CarIgnad, CA)i!, for 1 hour at room temperature. After replacement with 25 il D-PBS, stimulation was performed in the FLIPR instrument and at room temperature by the addition of 25 l D-PBS supplemented with different stimuli at concentrations corresponding to twice the desired final level. Receptor activity was quantified by determining the maximal fluorescence increases (using a 480 rim excitation and 535 rim emission) after normalization to basal fluorescence intensity measured before stimulation.
For dose-responses analysis, stimuli were presented in duplicates at 10 different concentrations ranging from 60 nM to 30 uM. Activities were normalized to the response obtained with 400 mM D-fructose, a concentration that elicits maximum receptor response.
EC50s were determined using a non-linear regression algorithm (using a Senomyx, Inc.
software), where the Hill slope, bottom asymptotes and top asymptotes were allow to vary.
Identical results were obtained when analyzing the dose-response data using commercially available software for non-linear regression analysis such as GraphPad PRISM
(San Diego, CA).
In order to determine the dependency of hT1R2/hT1R3 for the cell response to different stimuli, selected compounds were subjected to a similar analysis on Ga15 cells (not expressing the human sweet receptor). The HEK293-Ga15 cells do not show any functional response in the FLIPR assay to D-fructose or any other known sweeteners. Similarly, compounds covered in this document do not induce any functional response when using HEK293-Gal5 cells in the FLIPR assay.
Sweet Flavor and Sweet Flavor Enhancement Measurement Using Human Panelists Difference from Reference Human Taste Test Procedures To determine how the intensity of a test sample of an experimental compound differs from that of a reference sample in terms of sweetness, the following assay can be used. This type of study can use a larger number of evaluations in order to obtain statistically significant data, so the test can be repeated with the same or additional panelists.
Generally, a group of preferably 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 compound). Subjects rate the difference in intensity of the test sample compared to the reference sample for the key attribute on a scale of-5 (much less sweet than the reference) P T,'"' 11.11 rip 5 / 2 3 11.11. 0 0 ' to -P5` much sweeter than the reference). A score of 0 indicates the test sample is equally as sweet as the reference.
Ten or more subjects can be used for the Difference from Reference tests.
Preferably subjects have been previously familiarized with the key attribute taste and are trained to use the -5 to +5 scale. It can also be helpful to have subjects refrain from eating or drinking (except water) for at least 1 hour prior to the test. Subjects can eat a cracker and rinse with water four times to clean the mouth.
Test solutions can include the experimental compound in water, the experimental compound plus a key tastant (e.g., 4% sucrose, 6% sucrose, 6% fructose, 6%
fructose/glucose, or 7% fructose/glucose, at pH 7.1 or 2.8), and a range of key tastant only solutions as references.
Samples of the key tastant without the experimental compound can be used to determine if the panel is rating accurately; i.e., the reference is tested against itself (blind) to =
determine how accurate the panel is rating on a given test day. The solutions can be dispensed in 10 ml volumes into 1 oz. sample cups and served to the subjects at room temperature. The subjects are instructed to thoroughly "swish" a sample of the aqueous liquid containing the compounds to be tested around in their mouths, then "spit" out the bulk of the aqueous solution, so as to minimize the amount of compound actually ingested, and to minimize cross-contamination with subsequent test samples.
Typically, subjects first taste the reference sample then immediately taste the test sample and rate the difference in intensity of the key attribute on the Difference from Reference scale (-5 to +5). All samples are usually expectorated. Subjects may retaste the samples but can only use the volume of sample given. Subjects should rinse at least twice with water between pairs of samples. Eating a cracker between sample pairs may be required depending on the samples tasted.
The scores for each test are averaged across subjects and standard error is calculated.
Panel accuracy can be determined using the score from the blind reference test. ANOVA
and multiple comparison tests (such as 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-test (paired, two-tailed; alpha = 0.05) can be used to determine if there is any difference in the ratings between sessions.

PCT/US EtiCV
A numbr e or anterent reference sweeteners can be used for the measurement of sweet taste enhancement. A 6% fructose/glucose mixture can 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, for example, 6%
fructose/glucose at pH 7.1, studies can shift to evaluating the performance of the compound in a product prototype more similar to a cola beverage, i.e., higher concentrations of sweetener and lower pH.
EXAMPLES
The following examples are given to illustrate a variety of exemplary embodiments 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 1-57 and corresponding Table A comprising compound examples s Al-A93 can be referred to in shorthand by the number of the Example. For example, as shown immediately bellow, Example 1 discloses a synthesis of a particular compound 2-(4-(furan-3-yl)pheny1)-N-isobutyl-2-methylpropanamide, and the results of experimental assays of its biological effectiveness, which compound is and can be referred to herein in shorthand form as Compound 1. Similarly, the first compound illustrated in Table A can be referred to elsewhere herein as Compound Al.
Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for.
Unless indicated otherwise, parts are parts by weight, temperature is in C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions that can be used to optimize the sensitivity and resolution of analyses, product purity, and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions.
Example 1: 2-(4-(Furan-3-yl)pheny1)-N-isobutyl-2-methylpropanamide N
2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) (850 mg, 2,85 mmol) was dissolved in 30 ml of toluene, 6 ml of Et0H and 4.5 ml of water followed by F.' IF; '11/31187iRCEria)% Neal and 560 mg (5mmol) of 3-furanboronic acid. The suspension was degassed using argon stream and sonication (30 min). Then 1.16 g (lmmol) of tetrakis(triphenylphosphine)palladium was added under argon and the mixture was stirred at 80 C overnight. The solution was dried down on vacuum, diluted with Et0Ac and extracted with water. The organic phase was dried over MgSO4 and evaporated on vacuum providing a crude product that was further purified using RP HPLC yielding 300 mg (41%) of the title compound as a white solid. 1H NMR (400 MHz, dDMS0): 5 0.74-0.75 (d 6H), 1.45 (s, 611), 1.67-1.70 (in,1H), 2.83-2.86 (dd, 2H), 6.94-6.95 (dd, 1H), 7.30-7.32 (m, 311), 7.54-7.57 (m, 211), 7.72-7.73 (t, 111), 8.15-8.16 (t, 111). MS (M+H, 286).
Example la: 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide: Methyl 2-(4-bromopheny1)-2-methylpropanoate (1.29 ml, 5 mmol) was added to 30 ml of 1M
aq.
NaOH and the mixture was stirred at 60 C overnight. The solution was acidified with 6M
aq. HC1 (pH 2) and extracted with Et0Ac. The organic extract was washed with brine, dried over MgSO4 and concentrated on vacuum. The crude 2-(4-bromopheny1)-2-methylpropanoic acid was coupled without further purification with 2-methylpropan-1-amine (0.5 ml, 5 mmol) in presence of EDC (1.1 g, 5.5 mmol) and HOBt (675 mg, 5 mmol) in 8 ml of DMF at rt overnight. The mixture was dried down on vacuum and extracted with Et0Ac and washed with saturated NaHCO3, 10% citric acid and brine. Organic extracts were dried over MgSO4 and concentrated on vacuum to give 2-(4-bromopheny1)-N-isobuty1-2-methylpropanamide as a white solid (1.4g, 94%). (M+H, 298).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.34 Example 2: N-Isobuty1-2-methy1-2-(4-(4-methylthiophen-3-yl)phenyl)propanamide S
le 0 Prepared in a similar manner to Example 1 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 4-methylthiophen-3-ylboronic acid.Yield:
67%. 1H
NMR (400 MHz, dDMS0): (5 0.73-0.79 (d, 6H), 1.48 (s, 6H), 1.67-1.74 (in, 1H), 2.23 (s, 311), 2.84-2.87 (m, 211), 7.26-7.27 (m, 111), 7.34-7.40 (m, 511), 7.43-7.44 (d, 1H). MS(M+H, 316).

P CT ,tuS E ;II 11 ile16.0;r1'30Ut EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.85 RM.
Example 3: 2-(2-fluorobipheny1-4-y1)-N-isobutylpropanamide F

N
To a solution of 2-(2-fluorobipheny1-4-yl)propanoic acid (Aldrich) (172.3 mg), HOBt (133.2 mg, 1.4 eq) and triethylamine (196.5 mL, 2 eq) in dichoromethane (7 mL) was added at room temparature EDC (270.4 mg, 2.0 eq). The reaction was stired at room temperature for 30 minutes and 2-methylpropan-1-amine (0.1 mL, 1.5 eq) was added. The solution was stirred overnight then diluted with dichlorometahne and washed successively with aqueous NaHCO3, water, aqoueous HCL (1N), water, dried over MGS04, filtered and evaporated. Chromatogarphy on silica gel (eluent: ethyl acetate/hexane 1:1) afforded 170 mg of 2-(2-fluorobipheny1-4-y1)-N-isobutylpropanamide. Yield: 80%. 1H NMR (500 MHz, CDC13): 5 0.83-0.79 (d, 611), 1.55-1.56 (d, 3.H), 1.69-1.74 (m, 1H), 3.04-3.07 (m, 2H), 3.56-3.58 (m, 111), 5.4 (s br, 1H), 7.11-7.16 (m, 2H), 7.37-7.46 (m, 4H), 7.53-7.55 (m, 2H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 2.8 RM.
Example 4: 2-(2-fluorobipheny1-4-y1)-N-(furan-2-ylmethyl)propanamide F

HrO
Prepared in a similar manner to Example 3 from 2-(2-fluorobipheny1-4-yl)propanoic acid and furan-2-ylmethanamine. Yield: 75%. 1H NMR (500 MHz, CDC13): 5 1.55-1.56 (d, 311), 3.56-3.58 (m, 1H), 4.35-4.40 (dd, 111,11= 5.3 Hz, J2= 15.5 Hz), 4.45-4.49 (dd, 111, Ji=
5.7 Hz, ./2= 15.6 Hz), 5.72 (s br, 111), 6.16 (d, 1H, J= 2.7 Hz), 6.39 (in, 1H), 7.10-7.15 (m, 211), 7.25-7.45 (m, 5H), 7.54 (m, 2H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 4.55 RM.

qhalagalituorobipheny1-4-y1)-N-(2-methoxyethyl)propanamide F

Prepared in a similar manner to Example 3 from 2-(2-fluorobipheny1-4-yl)propanoic acid and 2-methoxyethanamine. Yield: 50%. 1H NMR (500 MHz, CDC13): 5 1.54-1.56 (d, 3H), 3.30 (s, 3H), 3.38-3.45 (m, 4H), 3.55 (q, 111), 5.58 (s br, 1H), 7.11-7.16 (m, 2H), 7.36-7.45 (m, 511), 7.54 (m, 2H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 6.5 M.
Example 6: 2-(2-fluorobipheny1-4-y1)-N-(1-methoxybutan-2-y1)-2-methylpropanamide F

Prepared in a similar manner to Example 3 from 2-(2-fluorobipheny1-4-yl)propanoic acid and 1-methoxybutan-2-amine. Yield: 67%. 1H NMR. (500 MHz, CDC13): 6 0.83 (t, 3H), 1.40 (m, 111), 1.51 (m, 1H), 1.55 (s, 311), 1.58 (s, 311), 3.25 (s, 3H), 3.26 (dd, 111), 3.35 (dd, 1H), 3.95 (m, 1H), 5.38 (d br, 114), 7.15-7.22 (m, 2H), 7.37-7.54 (m, 411), 7.54 (m, 2H).
m.p. 81-82 C.
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 3.81 M.
Example 7: N-isobuty1-2-methyl-2-(4-(thiophen-3-yflphenyflpropanamide r-Y
Prepared in a similar manner to Example 1 from 2-(4-Bromopheny1)-N-isobuty1-2-Methylpropanamide (Example la) and thiophen-3-ylboronic acid. MS (M+H, 302).

P CT 43 5 9hEg 'C'XpituriViall an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.24 uM.
Example 8: N-isobuty1-2-methyl-2-(3'-nitrobiphenyl-4-yl)propanamide 1411) SO
NH 'y 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) (100 mg, 0.33 mmol) was weigh out in a microwave vial and dissolved in 3 ml of DME, 2 ml of Et0H and 1.5 ml of water followed by addition of Na2CO3 (70mg, 0.66mmol) and 3-nitrophenylboronic acid (67mg, 0.4mmol). Pd(PPh3)4 (8mg, 6.6p,mol) was then added and the tube was immediately sealed. The reaction mixture was heated in a Smith Synthesizer at 150 C for 5 min. The solution was filtered and the compound purified by preparative HPLC to yield 75 mg (67%) of the title compound as a white solid. 1H NMR (400 MHz, CDC13): 6 0.8 (d, 611), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (dd, 2H), 5.2 (broad, 111), 7.5(d, 211), 7.6 (d, 311), 7.9 (d, 1H), S.2 (dd, 111), 8.4 (d, 1H). MS (M+H, 341).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in 1HEK293 cell line of 0.4 uM.
Example 9: 2-(3'-cyanobipheny1-4-y1)-N-isobuty1-2-methylpropanamide CN

N
Prepared in a similar manner to example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 3-cyanophenylboronic acid. Yield: 63%. 1H
NMR
(400 MHz, CDC13): 6 0.8 (d, 611), 1.65 (s, 611), 1.67-1.70 (m,1H), 3 (dd, 2H), 5.2 (broad, 1H), 7.45 (d, 2H), 7.55 (d, 311), 7.65 (d, 111), 8.2 (dd, 111), 8.4 (d, 1H).
MS (M+H, 321).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.2 M.
Example 10: Methyl 4'-(1-(isobutylamino)-2-methy1-1-oxopropan-2-yl)bipheny1-3-carboxylate IP C Elt 11+1E11 W,3 CO2Me Ny Prepared in a similar manner to Example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 3-(methoxycarbonyl)phenylboronic acid.Yield: 65%.
1H NMR (400 MHz, CDC13): 5 0.8 (d, 611), 1.65 (s, 6H), 1.67-1.70 (m, 111), 3 (t, 2H), 3.9 (s, 1H), 5.2 (broad, 1H), 7.4-7.56 (m, 311), 7.6 (d, 211), 7.8 (d, 111), 8.1 (dd, 111), 8.3 (d, 111).
MS (M+H, 354).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.9 M.
Example 11: 2-(3'-hydroxybipheny1-4-y1)-N-isobuty1-2-methylpropanamide OH
1 ) 1101 0 N
Prepared in a similar manner to example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 3-hydroxyphenylboronic acid. Yield: 70%. MS
(M+H, 312).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.9 M. =
Example 12: N-isobuty1-2-methyl-2-(2'-methylbiphenyl-4-yl)propanamide * = 0 Prepared in a similar manner to Example 8 from 2-(4-BromophenyI)-N-isobuty1-2-methylpropanamide (Example 1a) and o-tolylboronic acid. Yield: 80%. IHNMR (400 MHz, CDC13): 8 0.8 (d, 6H), 1.65 (s, 614), 1.67-1.70 (m,1H), 2.3 (s, 3H), 3 (t, 2H), 5.2 (broad, 1H), 7.2-7.25 (m, 4H), 7.3 (d, 2H), 7.4 (d, 211). MS (M+H, 310).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.9 P 1E: T /ijj1Ei; 113IE/ 3111-11- ID ID
Example 13: 2-(2'-aminobipheny1-4-y1)-N-isobuty1-2-methylpropanamide w.0 HN
Prepared in a similar manner to example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 2-aminophenylboronic acid. Yield: 65%. 1H
NMR
(400 MHz, CDC13): 5 0.8 (d, 611), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 214), 6.65-6.75 (m, 1H), 6.9 (m, 114), 7.0 (m, 1H), 7.2 (m, 1H), 7.4 (d, 2H), 7.55 (d, 211). MS
(M+H, 311).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 2.2 M.
Example 14: 2-(2'-eyanobipheny1-4-y1)-N-isobuty1-2-methylpropanamide CN
fa 0 Prepared in a similar manner to Example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 2-cyanophenylboronic acid. Yield: 60%. 1H
NMR
(400 MHz, CDC13): 5 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 211), 7.4-7.55 (m, 3H), 7.6 (d, 211), 7.65 (td, 2H), 7.8 (d, 114). MS (M+H, 321).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in 11EK293 cell line of 1.9 M.
Example 15: N-isobuty1-2-methyl-2-(3'-methylbiphenyl-4-yl)propanamide Olt fa Prepared in a similar manner to Example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and m-tolylboronic acid. Yield: 60%. 1H NMR
(400 MHz, CDC13): 5 0.8 (d, 6H), 1.65 (s, 611), 1.67-1.70 (m,1H), 2.3 (s, 3H), 3(t, 2H), 7.18 (d, 1H), 7.34 (t, 1H), 7.42 (m, 411), 7.6 (dd, 2H). MS (M+H, 310).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 3 M.

c: 11.11 S ;:E1 111.,101 11:11 Example 16: Ethyl 4'-(1-(isob utylamino)-2-methy1-1-oxopropan-2-yl)biphenyl-3-carb oxylate CO2Et ry Prepared in a similar manner to Example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanatnide (Example la) and 3-(ethoxycarbonyl)phenylboronic acid.
Yield: 65%.
1H NMR (400 MHz, CDC13): (3 0.8 (d, 6H), 1.4 (t, 3H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 4.4 (t, 2H), 7.48 (d, 2H), 7.54 (d, 1H), 7.64 (d, 2H), 7.8 (d, 1H), 8.04 (d, 1H), 8.3 (t, 1H). MS (M+H, 368).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 2.6 M.
Example 17: 2-(3'-((dimethylamino)carbonyObipheny1-4-y1)-N-isobuty1-2-methylpropanamide coNme2 Olt ik Ny Prepared in a similar manner to Example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example 1a) and 3-((dimethylamin.00xy)carbonyl)phenylboronic acid.
Yield: 60%. 1HNMR (400 MHz, CDC13): 3 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m, 1H), 3 (m, 5H), 3.15 (s, 3H), 7.38 (d, 1H), 7.54 (d, 1H), 7.46 (m, 3H), 7.6 (m, 4H).
MS (M+H, 383).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 2.7 M.
Example 18: N-isobuty1-2-(3'-isopropoxybipheny1-4-y1)-2-methylpropanamide Fl` ts s õ" i2 *la el Prepared in a similar manner to Example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 3-isopropoxyphenylboronic acid. Yield: 60%.

NMR (400 MHz, CDC13): 5 0.8 (d, 6H), 1.35 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (m, 2H), 4.6 (m, 1H), 6.9 (dd, 1H), 7.1 (t, 1H), 7.15 (d, 111), 7.35 (t, 1H), 7.45 (d, 2H), 7.6 (d, 2H). MS (M+H, 354).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 4.2 M.
Example 19: N-isobuty1-2-(3'-methoxybipheny1-4-y1)-2-methylpropanamide OMe SI So Prepared in a similar manner to example 8 from 2-(4-Bromopheny1)-N-isobuty1-2-methylpropanamide (Example la) and 3-methoxyphenylboronic acid. Yield: 60%. 1H

NMR (400 MHz, CDC13): 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 3.85 (s, 3H), 6.9 (dd, 1H), 7.1(s, 1H), 7.2(d, 111), 7.4 (t, 1H), 7.45 (d, 2H), 7.6 (d, 2H). MS (M+H, 326).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 4.3 M.
Example 20: 2-(4-(6-eyanopyrazin-2-yl)pheny1)-N-isobutyl-2-methylpropanamide CN

2-(4-(6-Cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid (example 20a) (267 mg, 1 minol) was placed in microwavable tube and dissolved in acetonitrile (3 mL) and DMF
(0.2 mL). Then HOBt (153 mg, 1 mmol) and EDC (211 mg, 1.1 mmol) were added followed by isobutyl amine (0.1 mL, 1 mmol) and the tube was sealed and irradiated in a microwave at 150 C for 5 min. The solvents were removed under reduced pressure and the mixture was purified using preparative RP HPLC (water/acetonitrile). The product was co-evaporated with Et0H to give 2-(4-(6-cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid as a white solid (166 mg, 62%).1H NMR (400 MHz, dMS0): 6 0.74-0.75 (d, 6H), 1.49 (s, 6H), 1.69 (m, 1H), 2.83-2.87 (t, 2H), 7.42-7.51 (d, 2H), 8.12-8.14 (d, 2H), 9.16 (s, 1H), 9.56 (s, 1H); M+H(323.2).
Example 20a: 2-(4-(6-Cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid: 6-Chloropyrazine-2-carbonitrile (example 20b) (890 mg, 6.4 mmol) was dissolved in DME
(24 mL) and water (6 mL) followed by 2-methy1-2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (1.86 g, 6.4 mmol) and (1.76 g, 12.7 mmol). The mixture was degassed using an argon stream, Pd(PP104.
(369 mg, 0.32 mmol) was added and the mixture was heated (80 C) overnight. The solvents were removed under reduced pressure and a residue was suspended in 1M aq. NaOH (10 mL) and washed with Et0Ac. The aqueous phase was then acidified to pH 4-5 using 6N aq.
HCI and extracted with Et0Ac (3x 60 mL). The organic extracts were combined, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (5% Me0H in DCM) to give 1.2 g (70%) of the pure intermediate 2-(4-(6-cyanopyrazin-2-yl)phenyI)-2-methylpropanoic acid. 1H NMR (400 MHz, dMS0): 3 1.50 (s, 6H), 1.69 (m, 1H), 7.54-7.56 (d, 2H), 8.13-8.15 (d, 2H), 9.17 (s, 1H), 9.56 (s, 1H), 12.50 (s, 1H).
Example 20b: 6-Chloropyrazine-2-carbonitrile: Pyrazine-2-earboxamide-4-N-oxide (example 20c) (2 g, 14.4 mmol) was suspended in dry DMF (20mL) and cooled to 0 C, then POCI3 (6 mL) was added. The mixture was stirred at room tempearture for 24 h and then poured in water/ice (100 mL). The product was extracted with Et0Ac (3x 100 ml).
The extracts were combined, washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 890 mg of 6-chloropyrazine-2-carbonitrile as brown oil. 1H NMR (400 MHz, dMS0): 6 9.16 (s, 1H), 9.26 (s, 1H); 13C NMR (400 MHz, dMS0): 6 115.62, 129.02, 147.75, 149.09, 149.67.
Example 20c: pyrazine-2-carboxamide-4-N-oxide: A mixture of pyrazine-2-carboxamide (10 g, 81 mmol) in 43 mL of glacial acetic acid and 38 mL of 30%
H202 was heated at 55 C for 30 h. The mixture was cooled to rt and filtered. The solid was washed with n-butanol and dried in vacuo to yield 6.18 g (54%) of pyrazine-2-carboxamide-4-N-oxide.1H NMR (400 MHz, dMS0): 6 8.02 (bs, 1H), 8.31 (bs, 1H), 8.48-8.50 (dd, 1H), 8.54 (b, 1H), 8.57-8.58 (d, 1H).
Example 20d: 2-methy1-2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-ybphenyl)propanoic acid: A solution of 2-(4-bromopheny1)-2-methylpropanoic acid (160 g, 0.66 mol), AcOK (196 g, 1 mol) and bis(pinaeolato)diboron.

C:T ILI Si 113 / 12 :3 11-11-113 113 (168.8 g, 0.66 mol) in dry DMF (1.6 L) was degassed at room temperature.
Pd(dppf)C12 (24 g, 32 mmol) was added under N2 atmosphere. The reaction was stirred at 60 C overnight. The solution was diluted with Et0Ac (2 L) and filtrated through a celite pie. The filtrate was washed with water (1Lx2) and brine (1 Lx2), dried over MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized in Et0Ac to give 2-methy1-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (110 g, yield 57.8 %).1H NMR (dMS0): 6 12.35 (s,1H), 7.61 (d, J = 6.8 Hz, 2H), 7.322 (d, J = 7.2 Hz,2H), 1.43 (s, 6H), 1.25 (s, 12H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.02 M.
Example 21: 2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methyl-N-(pentan-3-yl)propanamide CN
, Prepared in a similar manner to Example 3 from 2-(4-(5-cyanopyridin-3-yl)ph.eny1)-2-methylpropanoic acid (example 21a) and 3-pentanamine. Yield 55%. 1H NMR (400 MHz, DMS0): & 0.69-0.73 (t, 6H), 1.27 (m, 2H), 1.36 (m, 2H), 1.47 (s, 6H), 3.56 (m, 1H), 6.90-6.93 (d, 1H), 7.43-7.45 (d, 2H), 7.77-7.79 (d, 2H), 8.63-8.64 (t, 1H), 8.96-8.98 (d, 1H), 9.17-9.18 (d, 111). MS (M+H, 336).
Example 21a: 2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methylpropanoic acid: 5-bromonicotinonitrile (8.8 g, 48.08 mmol), 2-(4-boronopheny1)-2-methylpropanoic acid (example 21b) (11. 50 g, 52.89 mmol) and K2CO3 (13.3 g, 96.16 mmol were dissolved in a mixture of DME (120 mL) and water (30 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (2.7 g, 2.40 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure.
The residue was diluted with aq. 0.5 N NaOH (100 mL) and stirred for about 30 mm., and then the mixture was extracted with ether (30 mL x 3). The aqueous layer was cooled to 0 C, acidified with 2 N HC1, and then extracted with Et0Ac. The combined organic layers were washed successively with water and brine, dried over MgSO4., filtered and evaporated. The residue was triturated with hexane, filtered and dried to give 9.4 g of 2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methylpropanoic acid as a white solid in 73% yield.

P CT /13 S 6 72 3 11-11.. Lit 113 111 NMR (400 MHz, DMS0): & 1.49 (s, 6H), 7.46-7.48 (d, 2H), 7.76-7.78 (d, 2H), 8.63 (s, 111), 8.98 (s, 1H), 9.17 (s, 1H), 12.43 (s, 1H). MS (M+H, 267).
Example 21b: 2-(4-boronopheny1)-2-methylpropanoic acid: To a solution of 2-(4-bromopheny1)-2-methylpropanoic acid (15 g, 61.7 mmol) in anhydrous THF (150 mL) was added at -78 C under argon a 2.5 M solution of n-butyllithium in hexane (37 ml, 92.6 mmol) dropwise, followed by triisopropyl borate (43 ml, 185.1 mmol). After the addition, the reaction mixture was stirred at -50 C for 2 his and allowed to warm up to room temperature and stirred over night. The reaction mixture was quenched with 1 N
HC1 then extracted with Et0Ac and washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 13 g of product as a white solid in 99% yield.
111NMR (400 MHz, DMS0): ô 1.41 (s, 6H), 7.25-7.27 (d, 2H), 7.29-7.47 (dd, 1H), 7.68-7.70 (d, 111), 12.31 (s, 1H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in 11EK293 cell line of 0.07 M.
Example 22: (R)-N-sec-buty1-2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methylpropanamide CN
, N ik 0 77 F\rY
Prepared in a similar manner to Example 3 from 2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methylpropanoic acid (example 21a) and (R)-3-Methyl-2-butylamine. Yield 48%.

NMR (400 MHz, DMS0): ô 0.71-0.73 (d, 3H), 0.74-0.76(d, 3H), 0.91-0.93 (d, 311), 1.46 (s, 311), 1.47 (s, 3H), 1.59 (m, 1H), 3.58 (m, 111), 6.98-7.01 (d, 1H), 7.42-7.44 (d, 2H), 7.77-7.79 (d, 2H), 8.64 (s, 111), 8.98 (s, 111), 9.17 (s, 1H). MS (M+H, 336).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in 11EK293 cell line of 0.14 M.
Example 23: 2-(4-(5-cyanopyridin-3-yl)pheny1)-N-isobutyl-2-methylpropanamide CN
, m I
ik 0 cl"õ/ LIT Eit 5 õ/ 311-11- at N-isobuiy1-2-methy1-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-y1)phenyl)propanamide (example 23a) (14.86 g, 43.03 mmol), 5-bromonicotinonitrile (7.50 g, 40.98 mmol) and potassium carbonate (11.33 g, 81.96 mmol) were mixed in toluene (75 mL), ethanol (15 mL) and water (11.25 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (950 mg, 0.82 mmol) was added. The reaction mixture was heated to reflux for 16 hr and cooled to room temperature then diluted with Et0Ac/water, washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (eluant 40% Et0Ac in hexane) twice, then recrystallized from EtOAC/hexane and co-evaporated with ethanol to give 11.6 g of the product as a white solid in 88% yield. 1H NIVIR (400 MHz, DMSO-d6): 6 0.75 (d, 6H)), 1.48 (s, 6H), 1.70 (m, 1H), 2.85 (t, 2H), 7.45 (m, 3H), 7.8 (d, 2H), 8.65 (t, 11{), 9 (d, 1H), 9.2 (d, 111). MS(M+H, 322).
Example 23a: N-isobuty1-2-methy1-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide: 2-methy1-2-(4-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid (example 20d) (10 g, 34.46 mmol), EDC
(7.26 g, 37.91 mmol) and HOBt (5.12 g, 37.91 mmol) were mixed in DCM (350 mL) and stirred for 5 minutes then 2-methylpropan-1-amine (3.6 mL, 36.19 mmol) was added. The reaction mixture was stirred at room temperature overnight then diluted with dichloromethane and washed successively with aq. HC1 (0.5N), water, aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was crystallized from Et0Ac/hexane to give 11.8 g of product as a white solid in 99% yield. 1H NMR (400 MHz, CDC13): 3 0.76-0.78 (d, 6H), 1.35(s, 1211), 1.57 (s, 6H), 1.62 (m, 1H), 2.97 (t, 2H), 5.15 (br-s, 111), 7.38-7.40 (d, 2H), 7.79-7.81 (d, 2H). MS (M+H, 346).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.15 JAM.
Example 24: tert-butyl 1-(bipheny1-4-y1)-2-(isobutylamino)-2-oxoethylcarbamate >0).L.NH
o Prepared in a similar manner to Example 20 from 2-(bipheny1-4-y1)-2-(tert-butoxycarbonylarnino)acetic acid and isobutyl amine. Yield: 55%. 1H NMR (400 MHz, dMS0): 0.76-0.78 (d, 6H), 1.38 (s, 9H), 1.63-1.66 (m, 111), 2.84-2.92 (m, 211), 5.30-5.22 (d, 1H), 7.25-7.27 (d, 111), 7.35-7.37 (m, 111), 7.43-7.51 (m, 411), 7.61-7.66 (m, 411), 8.14-8.17 (t, 111); MS+H (383).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 7.54 M.
Example 25: 2-methyl-N-(2-methylbuty1)-2-(4-(pyrimidin-5-yl)phenyl)propanamide J/

LN
Prepared in a similar manner to Example 20 from 2-methy1-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and 2-methylbutan-l-amine. Yield: 58%.

(400 MHz, dMS0): (50.72-0.74 (d, 3H), 0.79-0.84 (m, 311) 0.97-1.00 (m, 111), 1.24-1.27 (m, 111), 1.47 (m, 111), 1.48 (s, 611), 2.81-2.87 (m, 111), 2.93-2.98 (m, 1H), 7.37-7.39 (t, 111), 7.44-7.47 (d, 211), 7.76-7.79 (d, 211), 9.13 (s, 1H), 9.18 (s, 1H); MS+H
(312.1).
Example 25a: 2-Methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid: 2-(4-Bromopheny1)-2-methylpropanoic acid (5.71g, 23.5 mmol) was dissolved in DME
(140 mL) and water (35 mL) and pyrimidin-5-ylboronic acid (2.92 g, 23.5 mmol) and potassium carbonate (11.4 g, 82.2 mmol) were added to the solution. The mixture was degassed using an argon stream, and Pd(PPh3)4 (1.35 g, 1.17 mmol) was added. The mixture was heated (80 C) under argon overnight then cooled to room temperature. The solution was diluted with 1M NaOH (20 mL) and washed with Et0Ac. The aqueous phase was acidified with 6N
aq. HC1 to pH 4-5 and extracted with Et0Ac (3x). The combined extract was successively washed with water and brine, dried over MgSO4, filtered and evaporated to yield 4.2 g (74%) of the crude 2-Methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (MS+H, 243) that was used in the next step without further purification.
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.23 M.
Example 26: 2-(4-(5-(ethoxymethyl)pyridin-3-yl)pheny1)-N-isobutyl-2-methylpropanamide F' C T 5; 01 is le 14.11,,,it , 1110 N

Prepared in a similar manner to Example 3 from 2-(4-(5-(ethoxymethyl)pyridin-3-yl)pheny1)-2-methylpropanoic acid (example 26a) and isobutylamine. Yield: 80%.

(400 MHz, dMS0): 6 0.72 (s, 3H); 0.74 (s, 31.1); 1.15 (t, 311, J= 6.8); 1.46 (s, 6H); 1.68 (m, 111); 2.83 (t, 2H, J=5.6); 3.51 (q, 211, J= 7.2); 4.54 (s, 211); 7.4 (t, 1H);
7.41 (d, 2H, J=6.4);
7.66 (d, 2H, J=6.8); 7.95 (t, 111, J=2.4); 8.49 (d, 111, J=1.6); 8.78 (d, 111, J=2.8). MS (M+H, 355).
Example 26a: 2-(4-(5-(ethoxymethyl)pyridin-3-yl)pheny1)-2-methylpropanoic acid: Prepared in a similar manner as example 21a starting from 3-Bromo-5-(ethoxymethyl)pyridine (example 26b) and 2-(4-boronopheny1)-2-methylpropanoic acid (example 21b). Yield: 90 %. MS (M+H, 300).
Example 26b: 3-Bromo-5-(ethoxymethyl)pyridine: To a mixture of powdered KOH (5.96 g, 106.4 mmol) in anhydrous DMSO (20 mL) was added under argon a solution of (5-bromopyridin-3-yl)methanol (example 26c) (5 g, 26.6 mmol) in anhydrous DMSO (20 mL), followed by EtI (2.6 mL, 31.9 mmol). The reaction mixture was stirred at room temperature for 1 hour then diluted with water and extracted with Et0Ac. The organic phase was washed with water and brine, dried over MgSO4, filtered and evaporated to give 5.6 g of 3-bromo-5-(ethoxymethyl)pyridine as a dark brown oil in 97% yield. 1H NMR
(400 mHz,cpc3): 1.27 (t, 311), 3.57-3.59 (q, 211), 4.50 (s, 2H,),8.48 (s, 111), 8.60 (s, 1H).
Example 26c: (5-bromopyridin-3-yOmethanol: A suspension of 5-bromo-nicotinic acid methyl ester (example 26d) (10 g, 46.29 mmol) in anhydrous Et0H
(100 ml) was cooled to 0 C and NaBH4 (4.03 g, 106.47 mmol) was added in portions within 15 min.
After stirred at 0 C for 1 hour the ice bath was removed and stirring was continued at room temperature for 3 hours, then the reaction mixture was heated to reflux overnight. The solvent was evaporated and acetone (50 mL) was added and the solution stirred for 30 minutes then the acetone was evaporated. Saturated aqueous K2CO3 (50 mL) was added and the mixture was refluxed for 1 hour then diluted with water (100 mL) and extracted with DCM. The organic phase was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel (5% Me0H in DCM) to give 4.78 g of pure (5-bromopyridin-11:"' T S 314E11 El 3-yl)methanol as a light yellow oil. Yield 55%. 1H NMR (400 MHz,CDC13): 2.60 (t, 1H);
4.73-4.74 (d, 2H), 7.90 (s, 111,), 8.47 (s, 1H), 8.57 (s, 1H).
Example 26d: 5-Bromo-nicotinic acid methyl ester: To a suspension of 5-bromonicotinic acid (20 g, 99.0 mmol) in anhydrous Me0H (100 mL), was carefully added conc. 112504 (12 mL) via a syringe. After the addition the reaction mixture was heated to reflux overnight, then cooled to room temperature and concentrated on rotary evaporator.
Ice-water (200 mL) was added and a white solid crashed out. The solid was collected by filtration, dissolved in Et0Ac (300 mL), washed with aq. NaHCO3, water and brine, dried over MgSO4, filtered and evaporated to give 18 g of 5-Bromo-nicotinic acid methyl ester as a white powder. Yield 84%. 1H NMR (400 MHz,DMS0): 3.88 (s, 311); 0.74 (s, 313), 8.43 (s, 111,), 8.96 (s, 111), 9.02 (s, 1H). MS (M+H, 217).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.26 M.
Example 27: N-isobuty1-2-(2-methoxy-3'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanamide To a solution of 2-(2-methoxy-5'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanoic acid (example 27a) (315 mg, 1 mmol) in DCM (10 mL) and DMF (1 mL) were added HOBt (135mg, 1 mmol) and isobutyl amine (98pL, 1 mmol) followed by EDC
(197 mg, 1 mmol). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was dissolved in Et0Ac, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative RP HPLC (water-acetonitrile) to give a colorless oil that was further evaporated from Et0H (3X) and dried to yield 150 mg (41%) of the product. 111NMR (400 MHz, dMS0): 5 0.76-0.77 (t, 311), 1.49 (s, 611), 1.10-1.72 (m, 111), 2.85-2.88 (t, 211), 3.30 (s, 311), 3.74 (s, 311), 4.44 (s, 211), 6.96-6.98 (m, 2H), 7.22-7.26 (m, 211), 7.36-7.38 (m, 411); MS+H
(370.2).
Example 27a: 2-(2-Methoxy-S'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanoic acid: Ethyl 2-(2-methoxy-5'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanoate (example 27b) (986 mg, 2.88 mmol) was suspended in Et0H (10 mL) and 1M aq. NaOH (15 mL) and stirred at 100 C for 3 h. Et0H was removed under reduced P C T / S / 2 :314 Eli Eli pressure and the residue was diluted with water (10 mL) and acidified with 6N
aq. HC1 to pH 2-3. The product was extracted with Et0Ac, washed with water and brine, dried over MgSO4, filtered and evaporated to give 900 mg (99%) of 2-(2-Methoxy-5'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanoic acid. 111 NMR(400 MHz, dMS0):

1.48 (s, 6H), 3.29 (s, 3H), 4.45 (s, 2H), 7.40-7.61 (m, 811), 12.44 (s, 111).
Example 27b: Ethyl 2-(2-methoxy-5'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanoate: Ethyl 2-(2-methoxy-5'-(methoxymethyl)bipheny1-4-yl)acetate (example 27c) (1.38 g, 4.39 mmol) was 'dissolved in dry THF (10 mL) and transferred under argon into a suspension of NaH (518 mg, 13.2 mrnol).in dry THF (40 mL). The suspension was stirred under argon for 30 min and Mel (686 j.tL, 10 98 mmol) was added drop-wise and the mixture was stirred at room temperature overnight then quenched with water (15 mL) and extracted with Et0Ac. The organic phase was successively washed with water and brine, dried over MgSO4, filtered and evaporated to give 986 mg (66%) of Ethyl 2-(2-methoxy-5'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanoate. 111NMR(400 MHz, dMS0): t5 1.11-1.15 (t, 3H), 1.51 (s, 611), 3.28 (s, 3H), 3.73 (s, 3H), 4.01-4.09 (q, 211), 4.41 (s, 2H), 6.94 (d, 2H), 7.21-7.22 (m, 2H), 7.34-7.36 (m 3H).
Example 27c: Ethyl 2-(2-methoxy-5'-(methoxymethyl)bipheny1-4-yl)acetate:
To a solution of Ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate (example 27d) (2 g, 5.8 mmol) in DME (36 mL) and water (9 mL) was added potassium carbonate (1.61 g, 11.6 mmol) and 3-(methoxymethyl)phenylboronic acid (962 mg, 5.8 mmol) and the mixture was degassed using argon stream for 30 minutes.
Pd[PPh3]4 (330 mg, 0.29 mmol) was added and the mixture was heated at 80 C under argon overnight. The solvents were removed under reduced pressure and the residue extracted with Et0Ac, washed with water and brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (20% Et0H/hexanes) to yield 1.38 g (76%) of ethyl 2-(2-methoxy-5'-(methoxymethyl)bipheny1-4-ypacetate._114 NMR(400 MHz, dMS0): 5 1.16-1.20 (t, 311), 3.27 (s, 3H), 3.68 (s, 2H), 3.72 (s, 3H), 4.06-4.11 (q, 2H) 4.41 (s, 211) 6.89 (d, 1H), 7.00 (s, 1H) 7.19-7.24 (m, 2H), 7.34- 7.36 (m, 311).
Example 27d: Ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate:
Ethyl hommovanilate (4g, 19 mmol) was dissolved in DCM (40 mL) and dry pyridine (3 mL, 38 mmol) was added. The mixture was cooled to 0 C and triflic anhydride (3.78 mL, 22.8 mmol) was added drop-wise. The mixture was stirred at room temperature overnight, diluted with DCM and washed successively with water, sat. Na.HCO3, water and P I/ S et / 2 3 40 Cli orine, dried over MgSO4, filtered and evaporated to give 6.4 g (98%) of ethyl 2-(3-inethoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate.
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.26 W.
Example 28: 2-(4-(1H-pyrrol-1-yl)pheny1)-N-isobutyl-2-methylpropanamide To a solution of 2-(4-bromopheny1)-N-isobuty1-2-methylpropanamide (example la) (100 mg, 0.33 mmol) in DMF (5 mL) was added 1-H-pyrrole (0.66 mmol, 44 mg), (2.4 eq., 115 mg) and catalytic CuI (3 mg). The reaction tube was sealed, and heated in a microwave at 195 C for 3 hours. The solution was extracted with ethyl acetate and washed with cold water. The product was purified twice by reverse phase HPLC (10 to 95%
acetonitrile/water). The compound was re-dissolved in ethanol and evaporated to dryness.
1H NMR (400 MHz, DMSO-d6): ô 0.75 (d, 6H)), 1.48 (s, 6H), 1.70 (m, 1H), 2.85 (t, 2H), 6.1 (d, 2H), 7.3 (m, 5H), 7.5 (d,2H). MS: WEI= 285.
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.35 ptM.
Example 29: N-isobuty1-2-(4-(6-(methoxymethyppyrazin-2-yl)pheny1)-2-methylpropanamide 2-(4-(6-(Hydroxymethyl)pyrazin-2-yl)pheny1)-N-isobuty1-2-methylpropanamide (example 29a) (37 mg, 0113 mmol) in DMSO (1mL) was added under argon to a solution of KOH (9.5 mg, 0.169 mmol) in DMSO (1 mL) and the mixture was stirred for 5 min then cooled to 0 C. Mel (7.7 ptL, 0.124 mmol) in DMSO (1 mL) was added dropwise and the mixture was stirred at room temperature for 20 min. The reaction was quenched with water (1004) and the product was purified by RP HPLC (water-acetonitrile) to give 19 mg (50%) of the product. 1H NMR (400 MHz, dMS0): 8 0.73-0.75 (d, 6H), 1.49 (s, 6H), 1.68-P El: 1" ../ 11õ11 !!:llii 0 Eit / 2 31 11-11- Ell 1.71 (m, 1H), 2.83-2.86 (m, 2H), 3.37 (s, 3H), 4.63 (s, 211), 7.37 (t, 111), 7.45-7.48 (d, 2H), 8.07-8.09 (d, 2H), 8.60 (s, 111), 9.16 (s, 1H); MS+H (342).
Example 29a: 2-(4-(6-(Hydroxymethyl)pyrazin-2-yl)pheny1)-N-isobutyl-2-methylpropanamide: Prepared in a similar manner to Example 26c starting from ethyl 6-(4-(1-(isobutylamino)-2-methyl-1-oxopropan-2-yl)phenyl)pyrazine-2-carboxylate (example 29b). Yield: 32%. MS+H(328).
Example 29b: ethyl 6-(4-(1-(isobutylamino)-2-methyl-l-oxopropan-2-yl)phenyl)pyrazine-2-earboxylate: 2-(4-(6-Cyanopyrazin-2-yl)pheny1)-N-isobutyl-methylpropanamide (example 20) (110 mg, 0.34 mmol) was dissolved in 1.5M HC1 in Et0H (3 mL) and heated at 80 C for 12 h. The mixture was concentrated in vacuo and purified on silica gel (50% Et0Ac-hexanes) to yield 122 mg (97%). MS+H (371).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.26 M.
Example 30: N-isobuty1-2-(3'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanamide Prepared in a similar manner to Example 1 from 2-(4-bromopheny1)-N-isobuty1-2-methylpropanamide (example la) and 3-(methoxymethyl)phenylboronic acid. Yield:
91%.
NMR (400 MHz, DMS0): ô 0.72-0.74 (d, 6H), 1.46 (s, 611), 1.68 (m, 1H), 2.83 (1,211), 3.29 (s, 3H), 4.45 (s, 211), 7.27-7.29 (d, 1H), 7.33 (t, 111), 7.36-7.38 (d, 211), 7.41 (t, 111), 7.53-7.55 (d, 2H), 7.58-7.60 (d, 2H). MS (M+H, 340).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.61 M.
Example 31: N-isobuty1-2-methyl-2-(1-phenyl-1H-pyrazol-4-yppropanamide 11:73)0( Prepared in a similar manner to Example 21a from 2-(4-bromo-1H-pyrazol-1-y1)-N-isobuty1-2-methylpropanamide (example 31a) and phenylbronic acid. Yield: 89%.

Cli Eit 2 311.11- i1:11113 (400 MHz, C'DC13): 5 0.81 (d, 311, .1= 6.8 Hz), 1.64-1.69 (m, 111), 1.90 (s, 6H), 3.00 (t, 2H, J= 6.8 Hz), 6.29 (br, 111), 7.26 (d, 1H, J= 7. 6 Hz), 7.38 (t, 211, J= 7.6 Hz), 7.50 (d, 2H, J
= 7.6 Hz), 7.86 (s, 1H), 7.92 (s, 1H). MS(MH) 286.
Example 31a: 2-(4-Bromo-1H-pyrazol-1-y1)-N-isobuty1-2-methylpropanamide:
Prepared in a similar manner to Example 3 from 2-(4-bromo-1H-pyrazol-1-y1)-2-methylpropanoic acid and isobutylamine. Yield: 95%. 1H NMR (400 MHz, CDC13):
0.81 (d, 311, J= 6.8 Hz), 1.63-1.67 (m, 1H), 1.84 (s, 6H), 2.99 (t, 211, J= 6.8 Hz), 6.19 (br, 1H), 7.61 (s, 1H), 7.64 (s, 111). MS(MH) 288, 290.
The compound had an EC50- for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 14.88 M.
Example 32: N-isobuty1-2-(4-(5-(methoxymethyl)pyridin-3-yl)pheny1)-2-methylpropanamide 1.1 0 N

Prepared in a similar manner to example 3 from 2-(4-(5-(methoxymethyl)pyridine-yl)pheny1)-2-methylpropanoic acid (example 32a) and isobutylamine. Yield 73 %.

(400 MHz, DMS0): (50.72-0.74 (d, 611), 1.46 (s, 611), 1.68 (m, 1H), 2.83 (t, 211), 3.32 (s, 311), 4.5 (s, 211), 7.36 (t,111), 7.39-7.42 (d, 211), 7.66-7.68 (d, 211), 7.95 (t, 1H), 8.48-8.49 (d,1H), 8.78-8.79 (d, 1H). MS (M+H, 341).
Example 32a: 2-(4-(5-(methoxymethyl)pyridine-3-yl)pheny1)-2-methylpropanoic acid: 3-bromo-5-(methoxymethyl)pyridine (example 32b) (4.8 g, 23.56 mmol), 2-(4-boronopheny1)-2-methylpropanoic acid (example 21b) (5.4 g, 25.92 mmol) and K2CO3 (6.5 g, 47.12 mmol) were mixed in DME (60 mL) and 15 ml of water (15 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (0.55 g, 0.47 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure. The residue was diluted with aqueous NaOH
(0.5 N, 60 mL) and stirred for 30 min., and the solution extracted with ether (20 mL x 3). The aqueous phase was cooled to 0 C, acidified with 2 N HC1 to PH = 5-6 , then extracted with Et0Ac.
The organic phase was washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane, filtered and evaporated to give 5.9 g of 2-(4-(5-(methoxymethyl)pyridine-3-yl)pheny1)-2-methylpropanoic acid as a IP if:: -11" 11õ,11 Si Eli Fif 7311.11-113 Eli light brown 'solid in 88% yield. ,NMR (400 MHz, CDC13): 6 1.66 (s, 611), 3.44 (s, 311), 4.54 (s, 211), 7.54-7.56 (d, 4H), 7.92 (s, 111), 8.56 (s, 1H), 8.76 (s, 111).
MS (M+H, 286).
Example 32b: 3-bromo-5-(methoxymethyl)pyridine: Prepared in a similar manner to Example 26a starting from (5-bromopyridin-3-yl)methanol (example 26d) and iodoethane. Yield: 89 %. 1H NMR (400 MHz, CDC13): 33.43 (s, 311), 4.46 (s, 211), 7.85 (s, 111), 8.47 (s, 1H), 8.61 (s, 1H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.91 111\4.
Example 33: N-isobuty1-2-methyl-2-(3-phenylisoxazol-5-yl)propanamide ,0 N

Prepared in a similar manner to Example 68 from 2-methy1-2-(5-phenylisoxazol-3-yl)propanoic acid (example 33a) and isobutylatnine. Yield: 24%. 111 NMR (500 MHz, DMSO-d6): 6 0.78-0.79 (d, 6H, J= 6.7 Hz), 1.53 (s, 6H), 1.68-1.78 (sept, 111, J= 6.7 Hz), 2.86-2.89 (t, 211, J= 6.7 Hz), 7.00 (s, 111), 7.48-7.57 (m, 411), 7.84-7.87 (m, 2H). MS(M+H, 287).
Example 33a: 2-methyl-2-(5-phenylisoxazol-3-yl)propanoic acid: To a solution of 2-methyl-2-(5-phenylisoxazol-3-yl)propanenitrile (example 33b) (45.9 mg, 0.22 mmol) in dioxane (3 mL), was added a 1N HC1 solution (2.2 mL, 2.2 mmol). The reaction was stirred at reflux for 24h, diluted with 1120(10 mL) and extracted with Et0Ac (3x). The organic layers were combined and washed with brine, dried over MgSO4 and concentrated to yield a yellow syrup, carried onto the next step without further purification.
Example 33b: 2-methyl-2-(5-phenylisoxazol-3-yl)propanenitrile: To a solution of 2-(5-phenylisoxazol-3-yl)acetonitrile (example 33c) (209 mg, 1.13 'mop in anhydrous THF (5 mL), was added a solution of NaH (60% in mineral oil, 136 mg, 3.40 mmol) in anhydrous THF (8 mL) under Ar. The reaction was stirred at room temperature for 30 min, at which time methyl iodide (150 !IL, 2.71 mmol) was added dropwise. The reaction was stirred at room temperature for 3 h under Ar, quenched with 1 drop of 1120 and diluted with Et0Ac. The mixture was washed with 1120 (1x), saturated NaHCO3 (2x), 10%
citric acid solution (1x) and brine. The organic layers were dried over MgSO4, filtered, concentrated and purified by flash-chromatography, (0-50% Et0Ac in Hexane) to yield a yellow solid WO 2006/138512 =

P C: 117,11 Eii / Eli Ell (88.1mg, 37%). 111NMR (DMSO-d6, 400 MHz): 1.77 (s, 6H), 7.35 (s, 1H), 7.55-7.59 (m, 3H), 7.87-7.89 (m, 2H).
Example 33c: 2-(5-phenylisoxazol-3-y1)acetonitrile: To a solution of (5-phenylisoxazol-3-yl)methyl methanesulfonate (example 33d) (261 mg, 1.03 mmol) in anhydrous DMSO (8 mL) was added NaCN (252 mg, 5.15 mmol). The reaction mixture was heated at 80 C under N2 for 15 hours, then diluted with Et0Ac and washed with 1120 (5x). The combined organic layers were dried over MgSO4, filtered and concentrated to yield a yellow solid (209 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): 4.30 (s, 2H), 7.12 (s, 1H), 7.55-7.57 (m, 3H), 7.89-7.92 (m, 2H).
Example 33d: (5-phenylisoxazol-3-yl)methyl methanesulfonate: To a solution of 5-phenylisoxazole-3-carbaldehyde (500 mg, 2.89 mmol) in Me0H (10 mL) at 0 C, was added NaBH4 (327 mg, 8.67 mmol). The reaction was slowly warmed to room temperature, stirred for 15 h and concentrated in vacuo. The solid obtained was dissolved in Et0Ac, washed with H20 (1x) and saturated NH4C1 (3x). The organic layers were combined, dried over MgSO4, filtered, concentrated and dissolved in anhydrous CH2C12(8 mL).
The mixture was cooled to 0 C, followed by addition of Et3N (1.02 mL, 7.25 mmol) and methanesulfonyl chloride (337 L, 4.35 mmol). The reaction was slowly warmed to room temperature and stirred for 15 h. Upon completion, the reaction was quenched with aqueous NaHCO3 (5 mL) and extracted with Et0Ac. The combined organic layers were washed with NaHCO3 (2x), dried over MgSO4, filtered, concentrated and carried onto the next step without further purification.
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 6.75 M.
Example 34: N-isobuty1-2-methyl-2-(4-(1-methyl-111-pyrrol-2-yl)phenyl)propanamide \ I
To a solution of N-isobuty1-2-methy1-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanamide (example 23a) (19.04 g, 55.14 mmol), K2CO3 (22.86 g, 165.4 mmol), and N-methyl-2-bromopyrrole (7.50 g, 93.74 mmol) in DME/H20 (4/1, 300 mL) was added Pd(PPh3)4 (3.20 g, 2.76 mmol) at RT under argon and the reaction mixture was stirred at 85 C overnight. After it was cooled down to room temperature, the reaction F" 11,-; T CI 6 / :3 11-11-mixture was diluted with brine, and extracted with Et0Ac (3X). The combined organic layers were washed with brine, and dried over Na2SO4. After evaporation of the solvent under reduced pressure, the residue was purified twice by chromatography on silica gel eluting with Et0Ac/Hexanes (1/9) to give the title compound as off-white white solid, which was further purified by recrystallization from hexanes, and dried under vacuum overnight. mp: 59-60 C. 1H NMR (400 MHz, DMSO-d6) ô 7.35 (d, J = 7.2 Hz, 2H), 7.31 (d, J = 7.2 Hz, 2H), 6.79 (m, 1H), 6.09 (m, 1.11), 6.01 (m, 1H), 3.60 (s, 311), 2.82 (t, J = 6.4 Hz, 2H), 1.7 (m, 111), 1.44 (s, 6H), 0.2 (d, J = 7.2 Hz, 6H). MS 299 (MH+).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.96 gM.
Example 35: 2-(3-hydroxy-4-(4-methylthiophen-3-yl)pheny1)-N-isobutyl-2-methylpropanamide HO
la 0 S ---N-isobuty1-2-(3-methoxy-4-(4-methylthiophen-3-yl)pheny1)-2-methylpropanamide (example 35a) (103mg, 0.3 mmol) was dissolved in dry DCM (5 mL), the mixture was under argon cooled to -78 C and BBr3 (1.69 mL of 1M solution in DCM) was added drop-wise and the mixture was stirred at room temperature for 72 hrs. The solution was diluted with DCM and treated with 1M aq. HC1. The organic phase was washed with water and brine, dried over MgSO4 filtered and evaporated. The residue was purified on preparative RP HPLC (acetonitrile/water) and on silica gel (Et0Ac/hexanes) and the product was co-evaporated with ethanol to give 2-(3-hydroxy-4-(4-methylthiophen-3-yl)pheny1)-N-isobuty1-2-methylpropanamide (69 mg, 70%). 1H NMR (400 MHz, dMS0): 6 0.74-0.76 (d, 6H), 1.42 (s, 6H), 1.67-1.74 (m, 1H), 2.09 (s, 3H), 2.83-2.86 (t, 2H), 6,76-6.78 (dd, 1H), 6.87-6.88 (d, 1H), 7.01-7.03 (d, 111), 7.13-7.14 (m, 1H), 7.21-7.22 (d, 111), 7.27-7.29 (t, 1H), 9.38-9,39 (b, 1H); MS (332).
Example 35a: N-isobuty1-2-(3-methoxy-4-(4-methylthiophen-3-yl)pheny1)-2-methylpropanamide: To a solution of 2-(3-methoxy-4-(4-methylthiophen-3-yl)pheny1)-2-methylpropanoic acid (example 35b) (630 mg, 2.2 mmol) in DMF (7 mL) were added HOBt (297 mg, 2.2 intnol), EDC (434 mg, 2.2 mmol) and isobutyl amine (214 pi, 2.2 mmol). The mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in Et0Ac and successively washed with water, 10% citric acid, sat. NaHCO3 and water, dried over MgSO4, filtered and evaporated. The residue was chromato graphed on silica gel (30% Et0Ac-hexanes) to give 190 mg (37%) of N-isobuty1-2-(3-methoxy-4-(4-inethylthiophen-3-yl)pheny1)-2-methylpropanamide.

NMR (400 MHz, dMS0): 6 0.73-0.75 (d, 6H), 1.48 (s, 6H), 1.69-1.72 (m, 111), 2.00 (s, 3H), 2.49-2.50 (m, 2H), 3.71 (s, 3H), 6.91-6.94 (m, 2H), 7.08-7.10 (d, 1H), 7.18 (s, 1H), 7.24-7.25 (d, 1H), 7.34-7.35 (t, 1H).
Example 35b: 2-(3-methoxy-4-(4-methylthiophen-3-yl)pheny1)-2-methylpropanoic acid: Prepared in a similar manner to example 27a from ethyl 2-(3-methoxy-4-(4-methylthiophen-3-yl)pheny1)-2-methylpropanoate (example 35c).
Yield:
92%. 1H NMR (400 MHz dMS0): 51.51 (s, 6H), 2.01 (s, 3H), 3.73 (s, 3H), 6.89-6.99 (m, 2H), 7.10-7.12 (d, 1H), 7.16-7.17 (d, 1H), 7.26-7.27 (d, 2H), 12.31 (s, 1H).
Example 35c: Ethyl 2-(3-methoxy-4-(4-methylthiophen-3-yl)pheny1)-2-methylpropanoate: Prepared in a similar manner to example 27b from ethyl 2-(3-methoxy-4-(4-methylthiophen-3-yl)phenypacetate (example 35d). Yield: 94%.
Example 35d: Ethyl 2-(3-methoxy-4-(4-methylthiophen-3-yl)phenyl)acetate:
Prepared in a similar manner to example 1 from ethyl 2-(3-methoxy-4-(trifluoromethylsulfonyloxy)phenyl)acetate (example 27d) and 4-methylthiophen-ylboronic acid. Yield: 72%.1H NMR (400 MHz, dMS0): 5 1.19-1.22 (m, 3H), 2.00 (s, 3H), 3.62 (s, 211), 3.69-3.73 (m, 3H), 4.08-4.13 (m, 2H), 6.86-6.88 (d, 1H), 6.98-6.99 (d, 1H), 7.08-7.10 (d, 1H), 7.16-7.17 (t, 1H), 7.26-7.27 (d,1H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.04 M.
Example 36: 2-(2'-(hydroxymethyl)bipheny1-4-y1)-N-isobuty1-2-methylpropanamide HO

2-(2'-Formylbipheny1-4-y1)-N-isobuty1-2-methylpropanamide (example 37) (190 mg, 0.59 mmol) was dissolved in anhydrous Me0H (6 mL) and the mixture was cooled to 0 C. A solution of NaBH4 (45 mg, 1.2 mmol) in anhydrous Me0H (4 mL) was then added to the solution. The mixture was stirred for 4 hrs at room temperature and then evaporated.
The residue was dissolved in Et0Ac and washed successively with water and brine, dried P CT./ U 5 El EL / 3111-0 0 over MgSO4, filtered and evaporated. The residue was successively purified on preparative RP HPLC (acetonitrile/water) and on silica gel (Et0Ac/hexanes) and co-evaporated with ethanol to give 119 mg (62 %) of white crystals. 111 NMR (400 MHz, dMS0): ô
0.72-0.74 (d, 611), 1.47 (s, 6H), 1.67-1.70 (m, 1H), 2.82-2.86 (t, 2H), 4.37-4.38 (d, 2H), 5.01-5.1 (t, 111), 7.17 (d, 111), 7.27-7.36 (m, 7H), 7.53-7.55 (d, 111); MS+H (326).
The compound had an BCH) for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.05 u.M.
Example 37: 2-(2'-formylbipheny1-4-y1)-N-isobuty1-2-methylpropanamide o 10 Prepared in a similar manner to Example 1 from 2-(4-bromopheny1)-N-isobuty1-2-methylpropanamide (example la) and 2-formylphenylboronic acid. Yield: 59%. 111 NMR
(400 MHz, dMS0): 6 0.72-0.75 (d, 611), 1.49 (s, 6H), 1.65-1.72 (m, 1H), 2.80-2.85 (t, 211), 7.35-7.44 (m, 5H), 7.47-7.50 (d, 111), 7.55-7.65 (t, 1H), 7.70-7.75 (t, 111), 7.85-7.90 (d,1H), 9.9 (s, 1H); MS+H (324).
15 The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in 11EK293 cell line of 0.81 M.
Example 38: N-isobuty1-2-methyl-2-(1-phenyl-1H-pyrazol-4-yl)propanamide Fl la 0 /
Prepared in a similar manner to Example 1 starting from 4-(1-20 (isobutylcarbamoyl)cyclopropyl)phenyl trifluoromethanesulfonate (example 38a) and 4-methylthiophen-3-ylboronic acid. Yield: 69%. 1H NMR (400 MHz, dMS0): 6 0.73-0.75 (d, 611), 0.97-1.00 (m, 211), 1.31-1.33 (m, 2H), 1.64-1.67 (m, 1H), 2.24 (s, 3H), 2.83-2.86 (m, 211), 6.72-6.75 (t, 111), 7.27-7.47 (m, 6H); MS+H (411).
Example 38a: 4-(1-(isobutylearbamoyl)cyclopropyl)phenyl 25 trifluoromethanesulfonate: Prepared in a similar manner to Example 27d starting from 1-(4-hydroxypheny1)-N-isobutylcyclopropanecarboxamide (example 38b). Yield: 98%.

MS+H (366).

P T / :tIEiI/ Ell 3 111.= Lit Example 38b: 1-(4-hydroxypheny1)-N-isobutylcyclopropanecarboxamide:
Prepared in a similar manner to Example 35 starting from N-isobuty1-1-(4-methoxyphenyl)cyclopropanecarboxamide (example 38c). Yield: 91%. MS+H(234).
Example 38c: N-isobuty1-1-(4-methoxyphenyl)cyclopropanecarboxamide:
Prepared in a similar manner to Example 35a starting from 1-(4-methoxyphenyl) cyclopropanecarboxylic acid and isobutyl amine. Yield: 97%. MS+H (248).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 3.36 11M.
Example 39: (S)-N-(1-hydroxybutan-2-y1)-2-(3'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanamide OH
dith Prepared in a similar manner to Example 27 from 2-(3'-(methoxyrnethyl)bipheny1-y1)-2-methylpropanoic acid (example 39a) and (S)-2-aminobutan-1-ol. Yield:
52%. 111 NMR (DMSO-d6, 400 MHz) 8 7.61 (m, 4H), 7.44 (m, 311), 7.31 (d, 111, J= 7.2 Hz), 6.83 (d, 111, J= 8.5 Hz), 4.57 (t, 1H, J= 5.8 Hz), 4.84 (s, 2H), 3.68 (m, 1H), 3.34 (m, 1H), 3.33 (s, 3H), 3.22 (m, 111), 1.56 (m, 1H), 1.49 (s, 6H), 1.29 (m, 1H), 0.76 (t, 3H, J= 7.3 Hz). 13C
NMR (DMSO-d6, 100 MHz) 8 175.5, 145.8, 139.8, 139.2, 137.8, 128.9, 126.5, 126.5, 126.4, 125.6, 125.6, 73.6, 63.0, 57.6, 52.5, 46.1, 27.1, 27.0, 23.5, 10.6. M+H
= 356, m.p.
73-75 C.
Example 39a: 2-(3'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanoic acid:
Prepared in a similar manner to Example 1 starting from 3-(methoxymethyl)phenylboronic acid and 2-(4-bromopheny1)-2-methylpropanoic acid. Yield: 82%. 1H NMR (400 MHz, DMS0): 3 1.48 (s, 6H), 4.46 (s, 2H), 7.27-7.29 (d, 111), 7.40-7.44 (m, 3H), 7.54-7.56 (d, 2H), 7.60-7.62 (d, 2H), 12.40 (s, 1H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.87 M.
Example 40: 2-(5'-cyano-2,3'-bipyridin-5-y1)-N-isobuty1-2-methylpropanamide , / 11-11 S 113 6 / 147:114-0 ID
Prepared in a similar manner to Example 23 from 2-(6-bromopyridin.-3-y1)-N-isobuty1-2-methylpropanamide (example 40a) and 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-Anicotinonitrile. Yield: 47%. 111 NMR (400 MHz, dMS0): 5 0.72-0.74 (d, 611), 1.51 (s, 6H), 1.66-1.69 (m, 111), 2.82-2.86 (m, 2H), 7.62-7.64 (m, 111), 7.82-7.85 (m, 1H), 8.10-8.12 (d, 114), 8.65-8.66 (d, 111), 8.89-8.90 (t,1H), 9.05-9.06 (d, 1H), 9.50-9.51 (d, 1H); MS+H (323).
Example 40a: 2-(6-bromopyridin-3-y1)-N-isobuty1-2-methylpropanamide:
Prepared in a similar manner to Example 35a from 2-(6-Bromopyridin-3-y1)-2-methylpropanoic acid (example 40b) and isobutyl amine. Yield: 93%. MS+H (300).
Example 40b: 2-(6-Bromopyridin-3-y1)-2-methylpropanoic acid: To a solution of LiOH (252 mg, 10.5 mmol) in Me0H (15 mL) and water (5 mL) was added 2-(6-bromopyridin-3-y1)-2-methylpropanenitrile (example 40c) (800 mg, 3.5 mmol) and the reaction mixture was heated at 85 C for 48 hrs. The methanol was evaporated and aqueous NaOH (1N, 10 mL) was added and the solution was washed with Et0Ac, acidified with aq.
HC1 (6N) to pH-4-5 and extracted with Et0Ac. The organic layer was suuccessively washed with water and brine, dried over MgSO4, filtered and evaporated to give 700 mg (96%) of 2-(6-Bromopyridin-3-y1)-2-methylpropanoic acid (MS +El, 243.8).
Example 40c: 2-(6-Bromopyridin-3-y1)-2-methylpropanenitrile: Prepared in a similar manner to Example 27b from 2-(6-bromopyridin-3-yl)acetonitrile (example 40d).
Yield: 71%.1H NMR (400 MHz, dMS0): 5 1.73 (s, 6H), 7.73-7.75 (d, 1H), 7.91-7.94 (dd, 1H), 8.57-8.59 (d, 111). MS+H (226).
Example 40d: 2-(6-Bromopyridin-3-yl)acetonitrile: A solution of 2-bromo-5-(bromomethyl)pyridine (example 40e) (6g, 24 mmol) and NaCN (1.42 g, 29 mmol) in absolute Et0H (50 mL) was heated at 80 C for 8 h. The mixture was then cooled to room temperature then evaporated. The residue was suspended in water and extracted with Et0Ac. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by chromatography on silica gel (5- 30%
Et0Ac/hexanes) to give 2.89 g (63%) of 2-(6-Bromopyridin-3-ypacetonitrile. 1H
NMR
(400 MHz, dMS0): 5 4.07 (s, 2H), 7.66-7.68 (d, 111), 7.72-7.73 (dd, 111), 8.36-8.37 (d, 1H).
Example 40e: 2-Bromo-5-(bromomethyl)pyridine: To a solution of 2-bromo-5-methylpyridine (5g, 29 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (7.79 g, 44 mmol). The mixture was heated to 80 C, then dibenzoyl peroxide (53 mg, 0.22 mmol) was added and the mixture was stirred at 80 C for 4 h then P T Ei; 5 re i? 34.0 0 cooled to room temperature, washed with water and brine, dried over Na2SO4, filtered and evaporated. The residue was chromatographed on silica gel (30%
Et0A.c/heaxanes) to give 6 g of 2-Bromo-5-(bromomethyl)pyridine (MS+H, 251.8).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 2.19 M.
Example 41: N-isobuty1-2-methy1-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanamide ,0 yVy N

To a solution of 2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanoic acid (example 41a) (307 mg, 1.32 mmol) in CH2C12 (10 mL) were added HOBt (196 mg, 1.45 mmol), EDCHICI (278 mg, 1.45 mmol) and isobutylamine (146 L, 1.45 mmol). The reaction was stirred at room temperature under N2 for 18 h. Upon completion, the reaction was concentrated and purified by flash-chromatography (0-75% Et0Ac in Hexane) to yield N-isobuty1-2-methy1-2-(3-phenyl-1,2,4-oxadiazol-5-Apropanamide (198 mg, 52%) as a white solid. 1H NMR (500 MHz, DMSO-d6): ô 0.81-0.83 (d, 6H, J= 6.7 Hz), 1.66 (s, 6H), 1.70-1.80 (sept, 1H, J= 6.7 Hz), 2.89-2.92 (t, 2H, J= 6.4 Hz), 7.56-7.61 (m, 3H), 7.92-7.95 (t, 1H, J= 5.6 Hz), 8.01-8.03 (m, 2H). MS(M+H, 288).
Example 41a: 2-Methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanoic acid: To a solution of methyl 2-(3-pheny1-1,2,4-oxadiazol-5-ypacetate (example 41b) (700 mg, 3.2 mmol) dissolved in THF (10 mL) under Ar, were added a solution of NaH (60%
dispersion in mineral oil, 385 mg, 9.6 mmol) dissolved in THF (6 mL) and methyl iodide (480 L, 7.68 mmol). The reaction was stirred for 16 h at room temperature under Ar.
Upon completion, the reaction was quenched with Me0H (15 mL) and H20 (15 mL). The solution was adjusted to pH 12 with a concentrated NaOH solution, and the resulting mixture was stirred at room temperature for 8 h. Upon completion, the reaction was adjusted to pH 2 with 6N HC1, and extracted with Et0Ac (4x). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated to yield 2-methy1-2-(3-pheny1-1,2,4-oxadiazol-5-yl)propanoic acid as a yellow oil (731 mg, 98%). 1H
NMR (500 MHz, DMSO-d6): 1.68 (s, 6H), 7.56-7.62 (m, 311), 8.01-8.04 (m, 2H), 13.4 (br.
s, 1H).
MS(M+H, 247).

IP C T,/ 11.3 si Eli / iiT4?; Lali iJ
Example 41b: Methyl 2-(3-phenyl-1,2,4-oxadiazol-5-ybacetate: A mixture of 2,2-dimethy1-1,3-dioxane-4,6-dione (5.0 g, 34.6 mmol) and Me0H (1.4 mL, 34.6 mmol) was heated at 80 C for 18k The reaction was concentrated, the residue (2.05 g, 17.3 mmol) was dissolved in CH3CN (10 mL) and added to a solution of HOBt (2.3 g, 17.3 mmol), EDCIITC1 (3.3 g, 17.3 mmol), N,N-diisopropylethylamine (3.01 mL, 17.3 mmol) and /V1-hydroxybenzimidamide (2.0 g, 8.5 mmol) in CH3CN (5 mL). The reaction was stirred at 40 C for 18 h under N2, and upon completion, diluted with Et0Ac and washed with H20 (2x).
The combined organic layers were dried over Na2SO4, concentrated and purified by flash-chromatography (0-50% Et0Ac in Hexane>. The resulting residue was dissolved in (10 mL), and heated in a microwave reactor (110 C, 3G min). Upon completion, the solvent was removed in vacuo and the residue was purified by flash-chromatography (0-50 %
Et0Ac in Hexane) to yield methyl 2-(3-phenyl-1,2,4-oxadiazol-5-yl)acetate as a yellow oil (700 mg, 38%). 111NMR (500MHz, DMSO-d6): S 3.72 (s, 3H), 4.41 (s, 211), 7.56-7.62 (m, 311), 8.01-8.04 (m, 2H). MS(M+H, 219).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in 11EK293 cell line of 6.53W.
Example 42: 2-(5'-cyano-3,3'-bipyridin-6-y1)-N-isobuty1-2-methylpropanamide N

Prepared in a similar manner to Example 23 from 2-(5-bromopyridin-2-y1)-N-isobuty1-2-methylpropanamide (example 42a) and 5-(4,4,5,5-tetramethy1-1,3,2-dioxaborolan-2-yDnicotinonitrile. Yield 49%. 1H NMR (400 MHz, acetonitrile-d6): 6 0.80-0.81 (d, 611), 1.63 (s, 6H), 1.71-1.77 (m, 1H), 2.97-3.00(t, 211), 7.01 (bs, 111), 7.59-7.62 (d, 1H), 8.18-8.21 (dd, 111), 8.59-8.60 (t, 1H), 8.99 (d, 111), 9.20-9.21 (d, 111); MS+H (323).
Example 42a: 2-(5-Bromopyridin-2-y1)-N-isobuty1-2-methylpropanamide:
Prepared in a similar manner to example 27 from 2-(5-bromopyridin-2-y1)-2-methylpropanoic acid (example 46b) and isobutyl amine. Yield 32%. MS+H (301).
Example 42b: 2-(5-Bromopyridin-2-y1)-2-methylpropanoic acid: Methyl 245-bromopyridin-2-y1)-2-methylpropanoate (514 mg, 2 mmol) was dissolved in dry DCM (10 mL) and cooled to -10 C. BBr3 (20 mL of 1M solution in DCM) was added drop-wise under argon to the solution. The reaction mixture was stirred 30 min at -10 C and then at room IEIT/ li3 2 3 1.11- Ell Ell temperature for 72 h and evaporated to give 2-(5-Bromopyridin-2-y1)-2-methylpropanoic acid used in the next step without further purification. MS+H (244, 246).
Example 42c: Methyl 2-(5-bromopyridin-2-y1)-2-methylpropanoate: Prepared in similar manner to Example 27b from methyl 2-(5-bromopyridin-2-ypacetate (example 46d). Yield 67%. 1H NMR (400 MHz, dMS0): 3 1.50 (s, 6H), 3.57 (s, 3H), 7.39-7.41 (d, 1H), 8.01-8.04 (dd, 1H), 8.62-8.63 (d, 1H); MS+H (258, 259).
Example 42d: Methyl 2-(5-bromopyridin-2-yl)acetate: 2-(5-Bromopyridin-2-yl)acetic acid hydrochloride (example 42e) (2.34 g, 9.3 mmol) was dissolved in Me0H (18 mL) and conc. H2SO4 (1.5 mL). The mixture was stirred at 80 C overnight. The solvent was removed under reduced pressure and the mixture was treated with sat. NaHCO3 then extracted with Et0Ac, washed with brine, dried over MgSO4, filtered and evaporated to give methyl 2-(5-bromopyridin-2-yl)acetate as a yellow oil (1.97 g, 92%). 1H
NMR (400 MHz, dMS0): 6 3.60 (s, 3H), 3.83 (s, 2H), 7.34-36 (d, 1H), 7.99-8.02 (dd, 1H), 8.60-8.61 (d, 1H); MS+H (230, 231).
Example 42e: 2-(5-Bromopyridin-2-yBacetic acid hydrochloride: 545-Bromopyridin-2(1H)-ylidene)-2,2-dimethy1-1,3-dioxane-4,6-dione (example 42f) (3.55g, 11.87 mmol) was suspended in conc. HC1 (55 mL) and refluxed for 3 h. The solution was concentrated under reduced pressure and a residue was triturated with Et0H to provide white crystals that were filtered off and washed with Et0H (2.34 g, 78%). 1H
NMR (400 MHz, dMS0): 5 3.81 (s, 2H), 7.44-7.46 (d, 111), 8.12-8.15 (dd, 1H), 8.70-8.71 (d, 1H), 11.30 (bs, 1H); MS+H (218).
Example 42f: 5-(5-Bromopyridin-2(1H)-ylidene)-2,2-dimethy1-1,3-dioxane-4,6-dione: 3-Bromopyridine N-oxide (10 g, 57.5 mmol) was slowly added into a solution of 2,2-dimethy1-1,3-dioxane-4,6-dione (Meldrum's acid, 8.28g, 57.5 mmol) in acetic anhydride (58 mL) at 0 C. The temperature was allowed to come to room temperature overnight. The mixture was filtered and yellow crystals were washed with small amount of acetic anhydride and dried in vacuo. The residue was triturated with warm chloroform and insoluble residue was filtered off. The chloroform soluble fraction was evaporated and the residue triturated with 5% Me0H in DCM. The solid material was filtered off and the soluble fraction was evaporated to give 3.55 g (20%) of 5-(5-Bromopyridin-2(1H)-ylidene)-2,2-dimethy1-1,3-dioxane-4,6-dione. 1H NMR (400 MHz, dMS0): 1.61 (s, 6H), 1.64 (s, 1H), 8.20-8.23 (dd, 1H), 8.51-8.52 (d, 1H), 8.62-8.65 (d, 1H).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor 1P CF,,.'Ei11IIF1.ti3tilI EA
expressed in HEK293 cell line of 10.64 M.
Example 43: N-isobuty1-2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanamide I
Prepared in a similar manner to Example 1 from 2-(4-bromopheny1)-N-isobuty1-2-methylpropanamide (example la) and pyrimidin-5-ylboronic acid. Yeld: 64%. 1H
NMR
(400 MHz, dMS0): 5 0.75-0.77 (d, 6H), 1.49(s, 6H), 1.69-1.72 (m, 1H), 2.84-2.87(t, 2H), 7.41 (t, 1H), 7.45-7.47 (d, 3H), 7.77-7.79 (d, 2H), 9.14 (s, 2H), 9.18 (s, 1H); MS+H (297.7).
The compound had an EC50 for activation of a hT1R2/hTIR3 sweet receptor expressed in HEK293 cell line of 1.01 12M.
Example 44: (R)-2-methyl-N-(3-methylbutan-2-y1)-2-(4-(pyrimidin-5-yl)phenyl)propanamide N
I
Prepared in a similar manner to Example 20 from 2-methy1-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and (R)-3-methylbutan-2-amine.Yield 60%. 1H
NMR (400 MHz, dMS0): 0.74-0.79 (m, 6H), 0.94-0.96 (d, 3H), 1.48-1.49 (d, 6H), 1.59-1.64 (m, 1H), 3.59-3.65 (m, 1H), 6.99-7.02 (d, 1H), 7.44-7.45 (d, 2H), 7.77-7.80 (d, 2H), 9.14 (s, 1H), 9.18 (s, 1H); MS+H (312.1).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.6511M.
Example 45: 2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(2-methoxypropy1)-2-methylpropanamide NC 1\1. 0 Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid (example 20a) and 2-methoxypropan-1-amine.Yield 70%. 1H NMR (400 MHz, dMS0): 0.93-0.94 (d, 3H), 1.48-1.49 (d, 6H), 2.99-3.11 (m, P C sr / / 311+0 0 211), 3.17 (s, 3H), 3.29 -3.30 (m, 111), 7.41-7.42 (m, 111), 7.49-7.51 (d, 2H), 8.11-8.14 (d, 211), 9.15 (s, 1H), 9.55 (s, 1H); MS+H (339).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.92 M.
Example 46: 2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(2-(furan-2-y1)-2-hydroxyethyl)-2-methylpropanamide OH

I
Prepared in a similar manner to Example 3 starting from 2-(4-(5-oyanopyridin-3-yl)pheny1)-2-methylpropanoic acid (example 21a) and 2-amino-1-(furan-2-ypethanol.
Yield: 75 %. 1H NMR (400 MHz, DMS0): 6 1.41 (s, 6H), 3.26 (m, 1H), 3.41 (m, 1H), 4.63 (t, 1H), 5.45 (br-s, 1H), 6.21-6.22 (d, 1H), 6.35 (t, 1H), 7.34 (t, 311), 7.35-7.37 (dd, 211), 7.54-7.55 (d, 1H), 7.71-7.73 (dd, 214), 8.61 (t, 1H), 8.97-8.98 (d, 1H), 9.15-9.16 (d, 111). MS
(M+H, 358).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.19 M.
Example 47: (R)-N-sec-buty1-2-(4-(6-cyanopyrazin-2-yl)pheny1)-2-methylpropanamide fait I
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid (example 20a) and (R)-butan-2-amine.Yield 43%.
1H NMR (400 MHz, dMS0): 6 0.70-0.74 (m, 311), 0.95-0.97 (d, 311), 1.31-1.35 (m, 2H), 1.47 (s, 611), 3.70-3.73 (m, 1H), 7.04-7.06 (d, 111), 7.48-7.50 (dd, 211), 8.11-8.13 (dd, 2H), 9.14 (s, 1H), 9.55 (s, 111); MS+H (323).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.14 M.
Example 48: 2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(1-(furan-2-yl)ethyl)-2-methylpropanamide P T ID Si 113 Li L3 111-113 N
NCN 0 no Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid (example 20a) and 1-(furan-2-yl)ethanamine.
Yield 35%. 1H NMR (400 MHz, dMS0): 6 1.32-1.33 (d, 311), 1.49-1.52 (d, 6H), 5.09 (m, 111), 6.06 (d, 111), 6.33-6.35 (dd, 1H), 7.49-751 (d, 211), 7.54 (d, 111), 8.12-8.14 (d, 211), 9.16 (s, 1H), 9.56 (s, 1H); MS+H (361).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.19 M.
Example 49: 2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(furan-2-ylmethyl)-2-1 0 methylpropanamide Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid (example 20a) and furan-2-ylmethanamine.
Yield 30%.
1H NMR (400 MHz, dMS0): 6 1.51 (s, 611), 4.23-4.25 (d, 211), 6.06-6.07 (d, 111), 6.34-6.35 (t, 111), 7.48-7.50 (d, 211), 7.53 (t, 111), 7.97-8.00 (t, 1H), 9.16 (s, 111), 9.56 (s, 1H); MS+H
(347).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.47 1AM.
Example 50: N-isobuty1-2-methyl-2-(2-methylbiphenyl-4-yl)propanamide N

Prepared in a similar manner to Example 1 from 4-(1-(isobutylamino)-2-methyl-1-oxopropan-2-y1)-2-methylphenyl trifluoromethanesulfonate (example 50a) and phenyl boronic acid. Yield: 75%.111NMR (400 MHz, dMS0): 5 0.76-0.77 (d, 611), 1.46 (s, 6H), 1.72-1.73 (m, 1H), 2.21 (s, 311), 2.84-2.8-7 (m, 211), 7.13-7.21 (m, 3H), 7.30-7.37 (m, 411), 7.41-7.45 (m, 2H); MS+H (310).

'PICT/ 1j Eli tii 6 / 31141-0 Example 50a: 4-(1-(Isobutylamino)-2-methy1-1-oxopropan-2-y1)-2-methylphenyl trifluoromethanesulfonate: Prepared in a similar manner to Example 27d starting from 2-(4-hydroxy-3-methylpheny1)-N-isobuty1-2-methylpropanamide (example 50b). Yield: 94%. MS+H (382) Example 50b: 2-(4-hydroxy-3-methylpheny1)-N-isobuty1-2-methylpropanamide:
Prepared in a similar manner to Example 35 starting from N-isobuty1-2-(4-methoxy-3-methylpheny1)-2-methylpropanamide (example 50c). Yield: 60%. MS+H (250).
Example 50c: N-isobuty1-2-(4-methoxy-3-methylpheny1)-2-methylpropanamide:
Prepared in a similar manner to Example 35a starting from 2-(4-methoxy-3-methylpheny1)-2-methylpropanoic acid (example 50d) and isobutylamine. Yield: 64%. MS+H
(264).
Example 50d: 2-(4-methoxy-3-methylpheny1)-2-methylpropanoic acid:
Prepared in a similar manner as example 27b starting from methyl 2-(4-methoxy-methylphenyl)acetate (example 50e) followed by hydrolysis using 1M NaOH (50 mL) at 60 C overnight. The mixture was cooled to room temperature and acidified with 6N aq. HC1 to pH 2. The product was extracted to Et0Ac, washed with water and brine, dried over MgSO4, filtered and evaporated to give 1.82g (79%) of the product. 1H NMR (400 MHz, solMS0): ô 1.44 (s, 6H), 2.14 (s, 3H), 3.76 (s, 3H), 6.86-6.88 (d, 1H), 7.11-7.14 (m, 2H);
MS+H (209).
Example 50e: 2-(4-methoxy-3-methylphenyl)acetate: Prepared in a similar manner to Example 42d starting from 2-(4-methoxy-3-methylphenyl)acetic acid.
Yield 98%.
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.42 1.1M.
Example 51: (S)-2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(1-hydroxybutan-2-y1)-2-methylpropanamide NC N 161 0 ..OH
f\r Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)pheny1)-2-methylpropanoic acid (example 20a) and 2-aminobutan-1-ol. Yield 37%.
1H NMR (400 MHz, clMS0): (5 0.70-0.74 (t, 3H), 1.02-1.06 (m, 111), 1.48-1.56 (m, 7H), 3.18-3.22 (m, 1H), 3.28-3.33 (m, 2H), 3.64-3.68 (m, 1H), 4.53-4.56 (m, 1H), 6.86-6.88 P =

Hi- 0 11:,1 (a, 2H), 8.10-8.13 (d, 211), 9.14 (s, 1H), 9.55 (s, 111); MS+H (339).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 1.03 M
Example 52: 2-methyl-N-(pentan-3-y1)-2-(4-(pyrimidin-5-. 5 yl)phenyl)propanamide N
Prepared in a similar manner to Example 20 starting from 2-methy1-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and pentan-3-amine. Yield: 67 %. 1H
NMR (400 MHz, dMS0): 8 0.71-0.75 (m, 611), 1.26-1.42 (m, 411), 1.49 (s, 6H), 3.57-3.59 (m, 111), 6.91-6.93 (d, 1H), 7.45-7.48 (d, 2H), 7.77-7.79 (d, 211), 9.14 (s, 211), 9.17 (s, 111); MS+H
(312).
The compound had an EC50 for activation of a hT1R2/hT1R3 sweet receptor expressed in HEK293 cell line of 0.38 M.
Numerous amide compounds of Formula (I) were also synthesized and experimentally tested for effectiveness as activator of a hT1R2/hT1R3 "sweet"
receptor expressed in an HEK293 cell line. The results of that testing are shown below in Table A.
Table A
COMPOUND C SWEET
OMPOUND
NO. EC50 tM
F
Al o 3.52 N-cyclopropy1-2-(2-fluorobipheny1-4-Apropanamide F
A2 (11101 =
N 2.38 -H
(2 S)-N-sec-butyI-2-(2-fluorobipheny1-4-yl)propanamide F

N 1.71 2-(2-fluorobipheny1-4-y1)-N-isobuty1-2-methylpropanamide P Ti" uF:i; T.) Pi, 311-11- T.1 tril COMPOUND SWEET
COMPOUND
NO. ECso 11M
F

A4 3.19 2-(2-fluorobipheny1-4-y1)-N-(1-methoxypropan-2-y1)-2-methylpropanamide AS 4.26 2-(biphenyl-4-y1)-N-isobutylpropanamide A6 1411 10 0 1.80 ' 2-(31-fluorobipheny1-4-y1)-N-isobutylpropanamide A7 0 5.58 N-isobuty1-2-(3'-methoxybipheny1-4-yl)propanamide AS 7.5 2-(2-fluorobipheny1-4-y1)-N-isobutylacetamide 1.66 N-isobuty1-2-methy1-2-(4-(pyridin-4-y1)pheny1)propanamide _ N
A10 0 3.36 2-(4-(1H-indo1-5-Apheny1)-N-isobutyl-2-methylpropanamide IP C T / 11,õ11 0 El 3111-11-0 COMPOUND SWEET
COMPOUND
NO. EC50 rN
H
N

All 2.13 N -N-isobuty1-2-methy1-2-(4-(pyrimidin-5-yl)phenyl)propanamide SF
OMe 0 K' Al2 4.5 N-cyclopropy1-2-(2-fluorobipheny1-4-yl)propanamide Al3 7.0 2-(2'-ethylbipheny1-4-y1)-N-isobuty1-2-methylpropanamide A14 9.0 N-isobuty1-2-methyl-2-(2'-(methylthio)bipheny1-4-yl)propanamide S0, Al5 0 4.0 Methyl 4'-(1-(isobutylamino)-2-methyl- 1 -oxopropan-2-yl)bipheny1-2-carboxylate Al6 6.0 N-isobuty1-2-(3'-isopropylbipheny1-4-y1)-2-methylpropanamide el Al7 5.6 N-isobuty1-2-methy1-2-(3'-propoxybipheny1-4-y1)propanamide COMPOUND SWEET
COMPOUND
NO. EC50piM

A18 6.6 2-(2',3'-dimethoxybipheny1-4-y1)-N-isobuty1-2-methylpropanamide A19 0 7.1 2-(2',4'-dimethoxybipheny1-4-y1)-N-isobuty1-2-methylpropanamide CN
N

110, 0 A20 0.71 2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methyl-N-(1-phenylethyl)propanamide CN

0.94 N
2-(4-(5-cyanopyridin-3-yl)pheny1)-N-isopentyl-2-methylpropanamide CN
A22 N I o 0.94 N
2-(4-(5-eyanopyridin-3-yl)pheny1)-N-isopropyl-2-methylpropanamide A23 41140 0 1.10 N
= 2-(3'-formy1-21-((methoxymethoxy)methyl)bipheny1-4-y1)-N-isobuty1-2-methylpropanamide VoUft all+ 0 SWEET
COMPOUND
NO. ECso 11M

A24 0 1.17 N
2-(2'-acetylbipheny1-4-y1)-N-isobuty1-2-methylpropanamide \

N 1.23 2-(4-(imidazo{1,2-a]pyridin-3-yl)pheny1)-N-isobutyl-2-methylpropanamide H N

A26 2.02 N
2-(4-(1H-indo1-4-yl)pheny1)-N-isobutyl-2-methylpropanamide CN
N So A27 2.06 N
(S)-2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methyl-N-((teirahydrofuran-2-y1)methyl)propanamide CN
i A28 2.06 (S)-2 -(4 -(5-cyanopyridin-3-yl)pheny1)-N-(hydroxy(phenyl) methyl)-2-methylpropanamide 0 \
= ON 0 A29 2.91 N
2-(4-(5-(methoxymethyl)pyridin-3-yl)pheny1)-2-methyl-N-propylpropanamide P C 1121 oM12ti.N42 "
(51 5 SWEET
COMPOUND
NO. EC50 ViM
./C) 3.05 N-isobuty1-2-(5-(3-(methoxymethyl)phenyl)pyridin-2-y1)-2-methylpropanamide 3.79 N-isobuty1-2-(6-(3-(methoxymethyl)phenyl)pyridin-3-y1)-2-methylpropanamide A32 N 0 5.40 N-isobuty1-2-methy1-2-(4-(thiazol-4-yl)phenyl)propanamide N
A33 N 0 5.40 N
N-isobuty1-2-methyl-2-(4-(pyrimidin-4-yl)phenyl)propanamide N
A34 10.10 2-(4-(1H-imidazol-1-yl)pheny1)-N-isobutyl-2-methylpropanamide A35 0 0 11.49 N-isobuty1-2-methyl-2-(4-(oxazol-5-yl)phenyl)propanamide 0 1.28 2-(bipheny1-4-y1)-N-isobuty1-2-methy1propanamide 1P ET/ It VriagyiNa 3 It 11 o , COMPOUND SWEET
NO. EC50iM
A370.76 (:)=
2-(3'4ormy1bipheny1-4-y1)-N-isobuty1-2-methy1propanamide o .0 ' 401 A38 S 0 1.49 N-isobuty1-2-methy1-2-(3'-(methylsulfonyl)bipheny1-4-yl)propanamide N

A39 01 1.1 0 1.54 2-(bipheny1-4-y1)-N-isobuty1acetamide N

0.03 2-(4-(6-cyanopyrazin-2-yl)pheny1)-2-methyl-N-(pentan-3-yl)propanamide N

A41 0.05 2-(4-(6-eyanopyrazin-2-yl)pheny1)-2-methyl-N-(2-methylbutyl)propanamide H
A42 NC N 101 0 0.10 2-(4-(6-eyanopyrazin-2-yl)pheny1)-N-(1-(furan-2-yl)ethyl)-2-methylpropanamide 0.13 2-(4-(6-eyanopyrazin-2-yl)pheny1)-N-eyelopentyl-2-methylpropanamide r" C Elf 111- El! IDE
COMPOUND SWEET
COMPOUND
NO. EC50 0.21 (R)-2-(4-(6-cyanopyrazin-2-yl)pheny1)-2-methyl-N-(3-methylbutan-2-yl)propanamide IF\

0.27 (2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(cyclopropylmethyl)-2-methylpropanamide N

0.31 (S)-2-(4-(6-cyanopyrazin-2-y1)pheny1)-2-methyl-N-(3-methy1butan-2-yl)propanamide V

A47 0.32 2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-cyclopropyl-2-methylpropanamide NC = A48 0 0.32 /

2-(4-(4-cyanofuran-3-yl)pheny1)-N-isobuty1-2-methylpropanamide 0.37 2-(4-(6-cyanopyrazin-2-yl)phenyI)-N-cyclobutyl-2-methylpropanamicle 1\1 0.37 (R)-N-sec-buty1-2-(4-(6-cyanopyrazin-2-yl)pheny1)-2-methylpropanamide COMPOUND
NO. EC50 A51 NC o 0.41 2-(4-(5-cyanopyridin-3-Apheny1)-N-cyclobuty1-2-methylpropanamide A52 NC 1\L IP 0 0.47 I
2-(4-(6-cyanopyrazin-2-y1)pheny1)-2-methy1-N-propy1propanamide N
IP
A53 0 0.55 (R)-N-sec-buty1-2-(3?-(methoxymethyl)bipheny1-4-y1)-2-rnethylpropanamide FNi j0 A54 NC N.,. 11, 0 0.59 I
2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(furan-3-ylmethyl)-2-methylpropanamide N

0.65 2-(4-(6-cyanopyrazin-2-yl)pheny1)-N-(furan-3-ylmethyl)-2-methylpropanamide Ed, =A56N 0 0.77 N-isobuty1-2-methyl-2-(4-(pyridin-3-ypphenyl)propanamide A57 o 0.92 N-isopropy1-2-(3'-(methoxymethyl)bipheny1-4-y1)-2-methylpropanamide P C T 11,11 EapV5iiii,i'D;i2 NI, SWEET
COMPOUND
NO. EC50tM
110 0 \
1.05 (R)-N-sec-buty1-2-(4-(5-(methoxymethyl)pyridin-3-yl)pheny1)-2-methylpropanamide N N
A59 / 0 1.05 N-isobuty1-2-methy1-2-(6-(4-methylthiophen-3-yl)pyridin-3-yl)propanamide N

1110 0 H 1.10 (R)-2-(bipheny1-4-y1)-N-(1-hydroxybutan-2-y1)-2-methylpropanamide OH
N

NC 0 1101 1.17 2-(4-(5-cyanopy.ridin-3-yl)pheny1)-N-(2-hydroxy-2-phenylethyl)-2-methylpropanamide N

0 1.22 2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(1-methoxybutan-2-y1)-2-methylpropanamide A63 0 11101 0 1.29 NC \ I
2-(4-(5-cyanofuran-2-yl)pheny1)-N-isobutyl-2-methylpropanamide N

1.29 (S)-N-sec-buty1-2-(4-(5-(methoxymethyl)pyridin-3-yl)pheny1)-2-methylpropanamide P CT/113 W16.1312113 " Ell SWEET
COMPOUND
No. EC50 tt114 OH

1.31 2-(4-(6-cyanopyrazin-2-y1)pheny1)-N-(2-(thran-2-y1)-2-hydroxyethyl)-2-methylpropanamide Ol 0 1.37 4-(4-(1-(isobuty1amino)-2-methy1-1-oxopropan-2-yl)phenylguran-2-carboxylic acid HO N
A67 0 1.42 2-(2-hydroxybipheny1-4-y1)-N-isobuty1-2-methylpropanamide N

1.59 2-(4-(5-ethoxypyridin-3-yl)pheny1)-N-isobutyl-2-methylpropanamide A69 0 1.66 (S)-2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(1-hydroxypentan-2-y1)-2-methylpropanamide 0.51 2-(4-(5-(methoxymethyl)pyridin-3-yl)pheny1)-2-methyl-N-(2-methylbutyl)propanamide HO
N, 0.75 /

(E)-2-(4-(4-((hydroxyimino)methyl)furan-3-yl)pheny1)-N-isobutyl-2-methylpropanamide P fr; T /1 s n El, F!! 7;1! WO T3 COMPOUND SWEET
COMPOUND
NO. EC50tM
0 \

NC \ 1.1 0 0.18 2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(furan-2-ylmethyl)-2-methylpropanamide A73 o 0.54 ' ,-N
methyl 5-(4-(1-(isobutylamino)-2-methyl-1 -oxoprop an-2-yl)phenyl)nicotinate .
NC H 0.68 . (S)-2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(1-hydroxybutan-2-y1)-2-methylpropanamide 0 0.96 N-isobuty1-2-(2-methoxybipheny1-4-y1)-2-methylpropanamide 0H 1.25 (S)-2-(4-(furan-3-yl)pheny1)-N-(1-hydroxybutan-2-y1)-2-methylpropanamide 0.67 2-(3'-(methoxymethyl)bipheny1-4-y1)-2-methyl-N-propylpropanamide 0 0.67 2-(4-(1,5-dihydrob enzo [el [1,31dioxepin-6-yl)pheny1)-N-is obuty1-2-methylpropana mide C: T 11 1 Si CI
COMPOUNDSWEET
COMPOUND
NO. ECsolIM
HO
A80 NC 1101 0 0.67 2-(3?-cyano-21-(hydroxymethylpipheny1-4-y1)-N-isobuty1-2-methylpropanamide A81 NC N 1101 0 0.67 2-(4-(6-cyanopyridin-2-y1)pheny1)-N-isobuty1-2-methy1propanamide A82 NCN ir 0 0.03 2-(4-(6-cyanopyridin-2-yflpheny1)-N-isobutyl-2-methylpropanamide A83 NC 0 0.11 \
2-(4-(6-cyanopyridin-2-y1)pheny1)-N-isobuty1-2-methy1propanam1de I 0.11 N
2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(cyclopropylmethyl)-2-methylpropanamide \ 0.15 2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(cyclopropylmethyl)-2-methylpropanamide \ 0.18 2-(4-(5-cyanopyridin-3-yl)pheny1)-N-cyclohexyl-2-methylpropanamide k.OMPu'unD SWEET
COMPOUND
NO. EC50 ttM
N

A87 01 0 0.21 N-isobuty1-2-(4-(5-isopropoxypyridin-3-yl)pheny1)-2-methylpropanamide A88 N 0 0.37 .
(R)-N-(1-(4-methoxyphenypethyl)-2-methy1-2-(4-(pyrimidin-5-yl)phenyl)propanamide 0 -10 0.41 N-cyc1ohexy1-2-methy1-2-(4-(pyrimidin-5-y1)pheny1)propanamide N
A90 NC 0 0.48 2-(4-(5-cyanopyridin-3-yl)pheny1)-2-methyl-N-pro ylpropanamide N

NC 0 0.62 \
2-(4-(5-cyanopyridin-3-yl)pheny1)-N-(2-ethylbuty1)-2-methylpropanamide N
A92 HO 0 SI 0.63 CHO
2-(21-formy1-51-(hydroxymethyphipheny1-4-y1)-N-isobuty1-2-methylpropanamide N
A93 lel0 0.90 =
2-(biphenyl-4-y1)-N-isobutylbutanamide P TS_Elt / 7,1E1E11 1117,11 Example n: Sweet Flavor and Sweet Flavor Enhancement Measurement Using Human Panelists: Difference from Reference Human Taste Test Procedures Purpose: To determine how the intensity of a test sample of an experimental compound differs from that of a reference sample in terms of sweetness. This type of study requires a larger number of evaluations in order to obtain statistically significant data, so the test may be repeated with the same or additional panelists.
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 compound). Subjects rate the difference in intensity of the test sample compared to the reference sample for the key attribute on a scale of-5 (much less sweet than the reference) to +5 (much sweeter than the reference). A score of 0 indicates the test sample is equally as sweet as the reference.
Procedure: Ten or more Subjects are used for the Difference from Reference tests.
Subjects have been previously familiarized with the key attribute taste and are trained to use the -5 to +5 scale. Subjects refrain from eating or drinking (except water) for at least 1 hour prior to the test. Subjects eat a cracker and rinse with water four times to clean the mouth.
Test solutions can include the experimental compound in water, the experimental compound plus a key tastant (e.g., 4% sucrose, 6% sucrose, 6% fructose, 6%
fructose/glucose, or 7% fructose/glucose, at pH 7.1 or 2.8), and a range of key tastant only solutions as references.
Samples of the key tastant without the experimental compound are used to determine if the panel is rating accurately; i.e., the reference is tested against itself (blind) to determine how accurate the panel is rating on a given test day. The solutions are dispensed in 10 ml volumes into 1 oz. sample cups and served to the Subjects at room temperature.
Subjects first taste the reference sample then immediately taste the test sample and rate the difference in intensity of the key attribute on the Difference from Reference scale (-5 to +5). All samples are expectorated. Subjects may retaste the samples but can only use the volume of sample given. Subjects must rinse at least twice with water between pairs of samples. Eating a cracker between sample pairs may be required depending on the samples tasted.
The scores for each test are averaged across Subjects and standard error is Pr C 11,1 'S Eat El 31 LIM r.3 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-test (paired, two-tailed; alpha = 0.05) can be used to determine if there is any difference in the ratings between sessions.
A number of different reference sweeteners have been utilized for the measurement of sweet taste enhancement. 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 a product prototype more similar to a cola beverage, i.e., higher concentrations of sweetener and lower pH.
The results of some human taste tests of the sweet compounds of the invention in aqueous compositions intended to model the composition of a carbonated beverage are shown below in Table B.
Table B. Sweet Taste Test Results CompoundPerceived Equivalent Contents of Solution pH
No. Sweet Solution 5 AM Compound 1 7.1 Greater than 6% but less than 1 or equal to 8% fructose/
6% fructose/glucose glucose 5 uM Compound 2 7.1 Greater than or equal to 2 9% fructose/glucose 6% fructose/glucose =
Example 53a: Sweet Flavor and Sweet Flavor Enhancement Measurement Using Human Panelists Line Scale Sensory Testing for Human Taste Test Procedures Purpose: To create a dose-response curve for perceived sweetness intensity of fructose-glucose concentrations. Test samples containing experimental compound are compared to this dose-response curve to determine equivalent sweetness intensity. This type of study requires a number of evaluations in order to obtain statistically significant data, so the test may be repeated with the same or additional panelists.
Overview: A group of eight or more panelists taste solutions including fructose-glucose at various concentrations, as well as the experimental compound, both with and PETS )1,,3 Eli 314-U11E1i without ak ed fructose-glucose. Panelists rate sweetness intensity of all samples on an unstructured horizontal line scale, anchored from 0 to 10, where 0 equals no sweetness and equals intense sweetness. Scores for sweetness intensity are averaged across panelists.
Then using the average scores and/or equation of the line for the fructose-glucose dose-5 response curve, equivalent sweetness fructose-glucose concentrations are determined for the samples containing experimental compound.
Procedure: Eight or more subjects are used for the Line Scale tests. Subjects have been previously familiarized with the key attribute taste and are trained to use the 0 to 10 unstructured line scale. Subjects refrain from eating or drinking (except water) for at least 1 10 hour prior to the test. Subjects eat a cracker and rinse with water several times to clean the mouth.
Fructose-glucose solutions are provided at a wide range of concentrations, such as 0%, 2%, 4%, 6%, 8%, and 10% fructose-glucose, in order to create the dose-response curve.
Samples containing experimental compound are prepared both alone and in a 6%
fructose-glucose solution. All samples are made up in low sodium buffer pH 7.1. In order to aid dispersion, solutions can also be made up in 0.1% ethanol.
The solutions are dispensed in 20 ml volumes into 1 oz. sample cups and served to the subjects at room temperature. All samples are presented in randomized counterbalanced order to reduce response bias. Further, two sessions of testing may be used to check panel precision.
Subjects taste each sample individually and rate sweetness intensity on the line scale prior to tasting the next sample. All samples are expectorated. Subjects may retaste the samples but can only use the volume of sample given. Subjects must rinse with water between samples. Eating an unsalted cracker between sample pairs may be required depending on the samples tasted.
The scores for each sample are averaged across subjects and standard error is calculated. The dose-response curve is plotted graphically, and this may be used to ensure the panel is rating accurately; i.e. increasing the concentration of fructose-glucose should correspond to increased average scores for sweetness. A 2-way ANOVA (factors being samples and panelists) and multiple comparison tests (such as Tukey's Honestly Significant Difference test) can be used to determine differences among samples and/or panelists. A 3-way ANOVA, with sessions as the third factor, can be used to determine if there is any difference in the ratings between sessions.

PL T UF.1; n -3Dirrji The fesuitg"o some human taste tests of the sweet compounds of the invention in aqueous compositions intended to model the composition of a carbonated beverage are shown below in Table C.
CompoundPerceived Equivalent Contents of Solution No. Sweet Solution NI Compound 20 Equal to 10% fructose/
20 glucose 6% fructose/glucose 20 10 OW Compound 20 Equal to 6% fructose/
glucose 5 M Compound 21 Greater than 10% but less than 21 or equal to 12% fructose/
- 6% fructose/glucose glucose 5 M Compound 21 Greater than 6% but less than 21 or equal to 8% fructose/
glucose 5 I.LM Compound 22 Greater than 8% but less than 22 or equal to 9% fructose/
6% fructose/glucose glucose - 5 M Compound 23 Equal to 10% fructose/
23 glucose 6% fructose/glucose - 2 jiM Compound 23 Greater than 2% but less than 23 or equal to 4% fructose/
glucose 10 M Compound 25 Equal to 10% fructose/
25 glucose 6% fructose/glucose 10 M Compound 26 Greater than 8% but less than 26 10% fructose/
6% fructose/glucose glucose 5 M Compound 27 Equal to 8% fructose/
27 glucose 6% fructose/glucose 5 juM Compound 30 Equal to 10% fructose/
30 glucose 6% fructose/glucose 5 M Compound 30 Greater than 4% but less than 30 6% fructose/
glucose 10 0\4 Compound 32 Equal to 8% fructose/
32 glucose 6% fructose/glucose 04 Compound 39 Equal to 8% fructose/
39 glucose 6% fructose/glucose P T /11_11 101 ,i." il-2:3'711 'Er El CompoundPerceived Equivalent Contents of Solution No. Sweet Solution A4 Compound 43 Equal to 8% fructose/
43 glucose 6% fructose/glucose 5 uM Compound 34 Equal to 8% fructose/
34 glucose 6% fructose/glucose Example 54: Reduced Sugar Ice Cream To illustrate the use of the disclosed amide compounds to reduce the sugar content of ice cream, comparable fully sugared and 2/3 sugared ice cream formulations containing the an amide compound of the invention (the compound of Example 23) were prepared with 5 the composition shown in the following table, and taste tested by humans.
Table D:
Fully Sugared Ice 2/3 Sugared Ice Cream Cream plus amide compound Ingredients (% wt/wt) (% wt/wt) Cream, Heavy, 36% butterfat 39.37 39.37 Milk, Whole, 3.25% butterfat 38.62 44.58 Sugar, granulated 18.11 12.07 Egg yolks, pasteurized 3.00 3.00 Natural Vanilla Flavor 0.60 0.60 Stabilizer* 0.30 0.38 Amide Compound, Example 23** 0.00 6.6 ppm * IC Premium Stabilizer, commercially available from Danisco Inc., New Century, Kansas, USA, comprises Dextrose, Locust Bean Gum, Guar Gum and Carageenan.
** Added via liquid sweetener concentrate solution in ethanol, see below.
10 Preparation of Fully Sugared Ice Cream:
The fully sugared ice cream formualtion was formulated to weigh a total of 3000.00 g. Ingredients were weighed on a calibrated balance and all dairy ingredients were keep cold (40 F (4 C) or below) until processing.
The commercially available stabilizer composition was mixed into half of the granulated sugar using the whip attachment on a KITCHEN AIDETm Mixer, at speed 2.
This mixture was set aside.
The heavy cream and whole milk were placed into a 5000 mL stainless steel cylinder and mixed using a LIGHTNINTM Mixer at from 500 to 650 rpms using a 2.5 inch (6.36 cm) impeller with three straight blades. A vortex was created by positioning the impeller blades at a 30 to 450 angle. The sugar/stabilizer mixture was slowly added to the vortex of the mixing milk/cream solution, and mixed for 10 minutes until the sugar P T1TJ 111 Ft / IR- Ft ra dissoiv-ed and trie¨Stabifiz6r rehydrated. Care was taken to ensured that no lumps or undissolved stabilizer existed in the solution. The remaining sugar was added to the vortex and mixing continued for an additional 10 minutes. Egg yolks and vanilla flavor were added next to the mixture and mixing was continued for 5 more minutes.
The brix of the resulting ice cream base was determined to be from 32.0 to 34.0 .
The density of the resulting ice cream base was determined to be from 110.0 to 111.0 g/100 mL
The ice cream base liquid was placed in an electric steam jacketed kettle and pasteurized to a temperature of 180 to 185 F (82 to 85 C) and held for 1 minute. The product was poured into a sanitized container and placed into an ice bath where the temperature was brought down to 50 to 60 F (10 to 16 C) and placed in the refrigerator to bring the temperature down to 40 F (4 C).
The cold ice cream base (40 F (4 C) or below), which can be homogenized if desired, was added to a batch ice cream freezer and was frozen to an overrun (volume increase) of 34 to 38%. The final product was placed into quart ice cream containers and placed into the freezer to set to - 5 F (- 21 C).
Preparation of 2/3 Sugared Ice Cream Comprising Amide Compound 23:
The ice cream batch was 3000.00g total formula weight. Ingredients were weighed on a calibrated balance and all dairy ingredients were kept cold (40 F (4 C) or below) until processing.
A water soluble liquid sweetener concentrate composition comprising 0.1% by weight of Example 23 in USP grade propylene glycol can be prepared by mixing the amide compound and propylene glycol by stirring the composition while warming to about 50 C, then milling the resulting liquid in a Silverson mill with a square basket cage at 300 ¨ 600 rpms, to farther ensure homogeneity of the liquid. An alternative method actually used was that the amide compound was dissolved in ethanol (1:1000 dilution), sonicated for 20 minutes, and 19.80 grams of the diluted sweet enhancer sample was added to the vanilla flavoring (which contains 20 ¨ 30% ethyl alcohol) and sonicate that sample for an additional 20 minutes.
The stabilizer was mixed into half of the granulated sugar using the whip attachment on the KITCHEN AIDETM Mixer at speed 2 and set aside.
Heavy cream and whole milk were placed into a 5000 mL stainless steel cylinder and mixed using a LIGHTNINTm Mixer at 500 to 650 rpms using a 2.5 inch (6.35 cm) P C T 1.11 ut Epy -0,13 ro Impeller with three straight blades. A vortex was created by positioning the impeller blades at a 30 to 45 angle. The sweet enhancer was added using the vanilla/ethanol mixture.
Some milk/cream was added back to the weigh dish of the sweet enhancer to ensure all the amide compound was removed from the weigh dish. The sugar/stabilizer mixture was slowly added to the vortex of the mixing milk/cream solution. The resulting solution was mixed for 10 minutes until the sugar dissolved and the stabilizer rehydrated.
Care was taken to ensured that no lumps or undissolved stabilizer existed in the solution. The remaining sugar was added to the vortex and mixing was continued for an additional 10 minutes. Egg yolks and vanilla flavor were next added and the mixing continued for 5 more minutes.
The brix of the resulting ice cream base was determined to be from 28.5 to 30.5 .
The density of the resulting ice cream base was determined to be from 110.0 to 111.0 g /
100 mL.
The ice cream base was placed in an electric steam jacketed kettle and pasteurized to a temperature of 180 to 185 F (82 to 85 C) and held for I minute. The product was poured into a sanitized container and placed into an ice bath, where the temperature was brought down to between 50 to 60 F (10 to 16 C) and placed in the refrigerator to bring the temperature down to 40 F (4 C). The cold ice cream base (40 F (4 C) or below), was added to a batch ice cream freezer and was frozen to an overrun of 34 to 38%.
The final product was placed into quart ice cream containers and placed into the freezer to set to - 5 F
(- 21 C).
Sensory Evaluation:
Ice cream samples were evaluated by tasters, using a rank rating design.
Tasters used an anchored scale from 1 to 10 (1 being no sweetness, 10 being intense sweetness).
Three digit coded samples were randomized and the following samples were given to tasters: full sugar version, 2/3 sugared version, 2/3 sugared + 3.3 ppm or 6.6 ppm of compound 23. Tasters were instructed to hold the ice cream samples in their mouth for at least 5 seconds, expectorate the sample, and evaluate/rank the "peak" of sweetness intensity.
See Table E:

C T./ S ra,./ F314,191 Ell fable E: Sensory Evaluation Results Product Average Sweet Intensity Score Fully Sugared Control 7.857 2/3 Sugared Control 3.643 2/3 Sugared +
3.3 ppm Compound 23 5.143 2/3 Sugared + 6.6 ppm Compound 23 7.357 Both levels of compound 23 (3.3 ppm and 6.6ppm) scored higher in sweetness than the 2/3 sugared control sample. The 2/3 sugared + 6.6 ppm compound 23 ice cream sample was nearly as sweet as the fully sugared ice cream. Qualitative feedback included comments about a "slight lingering" and "slight delay of sweetness" in the samples that contained compound 23.
Example 55: Reduced Sugar Frosted Breakfast Cereal To illustrate the use of the amide compounds of the invention in reducing the sugar content of frosted breakfast cereals, fully sugared and 2/3 sugared cereal frosting containing compound 23 were prepared according to, the formulations in the following table.
Table F
Cereal Frosting Cereal Frosting 2/3 Sugared Fully Sugared + Compound 23 Ingredients (% wt/wt) (% wt/wt) Sugar, granulated 64.00 59.01 HFCS 42, 71% solids* 14.08 12.98 Sugar, 20X powdered 5.00 4.61 Water 15.61 21.59 Tapioca Dextrin 0.75 1.04 Gum Arabic, pre-hydrated 0.56 0.77 Sweetener concencentrate 0.00 As indicated below compostion *HFCS: High Fructose Corn Syrup The reduced sugar cereal had a less "white/sugary" appearance and more of a desirable natural cereal appearance.
Fully Sugared Cereal Processing 500.00g of a fully sugared cereal frosting was formulated for coating frosted corn flake prototypes. Specifically, a KITCHEN AIDETm Mixer with a wire whip attachment at speed 3 was used to mix the granulated sugar, powdered sugar, gum Arabic, and dextrin.
Water and HFCS corn syrup were placed into a 1000 mL stainless steel cylinder and were mixed using a LIGHTNINTm Mixer at 500 to 650 rpms using a 2.5 inch (6.35 cm) impeller IP C: T ...`" 11 õ11 rit Eit int rit With -air& straigtirb`ladeS iffitil the HFCS was dissolved (5 minutes). A
vortex was created by positioning the impeller blades at a 30 to 45 angle. The sugar/gum/dextrin dry mixture was added to the vortex very slowly and allowed to mix until the sugar dissolved and the gum rehydrated. Mixing was continued for 10 minutes after the last of the dry blend was added to form the frosting.
The resulting frosting was heated in a two quart stainless steel heating vessel to between 210 to 230 F (99 to 110 C), until the sugar was liquefied. The following proportions were used to coat the cereal.
Fully Sugared 2/3 Sugared Frosting Frosting Fortified Corn Flakes 644.30g 714.70g Frosting 355.70g 285.30g The warm frosting was drizzled onto the corn flakes while mixing with a spatula.
An alternative method can be to drizzle small amounts of frosting in front of a curtain of compressed air (at least 30 to 40 psi) while mixing with a spatula.
The coated cereals were transferred to a stainless steel. drum (20 quart (19 L)) and placed onto the rollers of a vacuum tumbler that was angled at 45 . The cereal was tumbled at low speed (10 to 20 rpm) as a heat gun with hot air at 170 to 220 F (77 to 104 C) was blown onto the flakes to evenly coat the flakes and to drive off some moisture.
The cereal was tumbled and hot air was applied to the tumbling cereal for 10 minutes. The temperature of the surface of the flakes was maintained at 200 to 220 F (93-104 C) as measured by a calibrated infrared thermometer.
The frosted corn flakes were transferred to a half sheet bake pan and baked in a 200 F (93 C) convection oven for 50 minutes to a moisture level below 4%. The baked frosted corn flakes were allowed to cool to 70 F (21 C) at ambient temperatures and was packaged and stored in double ZIPLOCTM plastic bags.
Processing Cereal with 2/3 Sugared Cereal Frosting Comprising Compound 23 A 100 gram sample of a solid sweetener concentrate composition was prepared from 1.000 g of compound 23 and 99.000 g of 10 D.E. maltodextrin. "DE" i.e.
"Dextrin Equivalents" is a measure of the degree of depolymerization of the corn starches used to manufacture maltodextrins. Fifty grams of the maltodextrin was placed on the bottom of a clean and dried mortar and the 1.000 gr of compound 23 was added to the maltodextrin and slowly ground and mixed into the maltodextrin. The remaining 50 grams of maltodextrin was added to a planetary mixer with a wire whip attachment (KITCHEN AIDETM
Mixer), P II ItS i2roi then the content's' of the mortar were placed into the mixer and the mixer was turned on to a slow speed (setting 3), and allowed to mix for 10 minutes. A rubber spatula was used to scrap the walls and bottom of the bowl, then the mixture was blended on low for another 15 minutes. The 100 x diluted solid sweetener concentrate composition was stored in an air tight amber glass container. The contents were mixed in the glass container before taking out aliquots of the dry diluted sweet enhancer.
Using the KITCHEN AIDETM Mixer with the wire whip attachment, the granulated sugar, powdered sugar, gum arabic, dextrin, and the 1:100 diluted sweetener concentrate composition were mixed at speed 3. Water and the HFCS were placed into a 1000 mL
stainless steel cylinder and mixed using a LIGHTNINTm Mixer at 500 to 650 rpms using a 2.5 inch (6.35 cm) impeller with three straight blades until the HFCS was dissolved (5 minutes). A vortex was created by positioning the impeller blades at a 30 to 45 angle. The dry/sugar/gum dry blend was added to the vortex very slowly and allowed to mix until the sugar dissolved and the gum rehydrated. An additional 10 minute mixing time was allowed after the last of the dry blend was added, to form the frosting.
The resulting liquid frosting was added to a two quart (2 L) stainless steel heating vessel, and heated to 210 to 230 F (99 to 110 C) until liquefied. To coat the cereal, the following proportions were used.
2/3 Sugared +
Full Sugar Compound 23 Fortified Corn Flakes 644.30g 714.0372g Frosting 355.70g 285.30g Sweetener Concentrate 0 0.6628 grams The warm frosting was drizzled onto the corn flakes while mixing with a spatula, and then transferred to a stainless steel drum (20 quart (19 L)), which was placed onto the rollers of the vacuum tumbler angled at 45 . The cereal was tumbled at low speed (10 to 20 rpm) as a heat gun with hot air at 170 to 220 F (77 to 104 C) was blown onto the flakes to evenly coat the flakes and to drive off some moisture. The cereal was tumbled and hot air was applied to the tumbling cereal for 10 minutes. The temperature of the surface of the flakes was maintained at 200 to 220 F (93 to 104 C).
The frosted corn flakes were transferred to a half sheet bake pan and baked in a 200 F (93 C) convection oven for 50 minutes to a moisture level of 4% or less.
The baked frosted corn flakes were allowed to cool to 70 F (21 C) at ambient temperatures and was packaged and stored into double ZIPLOCTM plastic bags.

S Ell El! 3 Ivo Sensory tN7a1uation:
Frosted corn flake cereal samples were evaluated using a rank rating design by tasters. Tasters use an anchored scale from 1 to 10 (1 being no sweetness, 10 being intense sweetness). Three digit coded samples were randomized and the following samples were given to tasters: fully sugared corn flakes, 2/3 sugared corn flakes, and corn flakes comprising 2/3 sugared frosting comprising 3.3 ppm or 6.6 ppm of compound 23.
Tasters were instructed to hold the cereal samples in their mouth for at least 5 seconds, expectorate the sample, and evaluate/rank the "peak" of sweetness intensity. See Table E.
Table E: Sensory Evaluation Results Product Avgage Sweet Intensity Score 2/3 sugared flakes 5 Fully sugared flakes 8 2/3 sugared + 6.6 ppm compound 23 7.5 2/3 sugared + 9.6 ppm compound 23 7.81 All the frosted corn flake samples comprising the amide compounds described herein scored higher sweetness intensity scores than the 2/3 sugared cornflake control. The cornflakes comprising frostin with 9.6 ppm of compound 23 had almost as much sweetness as the fully sugar frosted cornflake control.
Example 56: Reduced Sugar Dry Beverage Mixes To exemplify the use of the disclosed amide compounds to reduce sugar content in dry beverage mixes or "bases," fully sugared and 2/3 sugared beverage bases simulating a powdered strawberry beverage mix containing compound 23, and appropriate control mixes were prepared according to the formulations in the following table.
Table F:
Beverage Base Beverage Base Fully Sugared 2/3 Sugared +
Compound 23 Ingredients (% wt/wt) (% wt/wt) Sugar, granulated 7.17 4.90 Citric Acid, granulated 0.20 0.21 Ascorbic Acid, granulated 0.03 0.03 Water 92.39 94.65 Red Dye #40, dry 0.0025 0.0025 Artificial Strawberry Flavor*** 0.13 0.13 Calcium Silicate** 0.03 0.03 Malic Acid, granulated* 0.05 0.05 Compound 23**** 0.00 1.3 ppm * Flavoring acid. Others (such as tartaric, phosphoric, etc., and combinations) can used if other fruit or non-fruit flavors are used.

P E:11,3 Uli F13 40 *'*Anti-caking aient. Others can be used ( silicon dioxide, Tricalcium phosphate, etc.) ***Other fruit flavors (Natural or N&A) can used at levels of 0.15¨ 1.00%.
**** Added via a solid sweetener concentrate composition in maltodextrin, see below.
Fully Sugared Beverage Base Processing 1000.00g of the finished beverage was formulated in the following manner.
Granulated ingredients (sugar, acids) were mixed slowly in a KITCHEN AIDETm mixer at speed 2 using the wire whip attachment for 3 minutes. Calcium silicate was added to the granulated ingredients and was allowed to mix for another 5 minutes until the silicate was evenly dispersed. The dry strawberry flavor and dry color were added last and allowed to mix for another 10 minutes. A plastic spatula was used to scrape the inside of the mixing bowl to ensure even mixing, and produce the dry beverage mix.
The water was placed in a stainless steel 3 L cylinder and a LIGHTNINTm Mixer set at 500 to 650 rpms using a 2.5 inch (6.25 cm) impeller with three straight blades. This was used to create a vortex in the water. The impeller blades were positioned at a 30 to 450 angle. The dry beverage was slowly added to the vortex of the water and was mixed for an additional 5 minutes until all the sugar and acids had dissolved. This resulted in a liquid beverage with a pH of 2.96 and brix of 7.70 .
2/3 Sugared Beverage Base Comprising Compound 23 1000.00g of the finished beverage was formulated. Compound 23 was diluted with maltodextrin (1:100) to form a sweetener concentrate composition prior to addition to the other dry beverage base ingredients. 50g of the maltodextrin was placed on the bottom of a clean and dried mortar and 1.0000g of compound 23 was added and slowly ground into the maltodextrin with the pestle. The remaining maltodextrin was added to a planetary mixer with a wire whip attachment (KITCHEN AIDETM Mixer), and the contents of the mortar were placed into the mixer and the mixer was turned on to a slow speed (setting 3) and allowed to mix for an additional 10 minutes.
A rubber spatula was used to scrap the walls and bottom of the mortar. The mixture was blended on low for another 15 minutes. The 100 x diluted sweetener concentrate composition was stored in an air tight amber glass container.
The contents of the glass container were re-mixed in the glass container before taking out aliquots of the dry diluted sweet enhancer. Using the KITCHEN
AIDETM Mixer with the wire whip attachment, the granulated ingredients of the beverage base (sugar, acid) were mixed slowly at speed 2 using the wire whip attachment for 3 minutes and 0.13 grams =
of the 1:100 diluted solid sweetener concentrate composition was added and mixed at speed P IC:T/11_1i S P 4.1,11 3 for 5 minutes. taiciurii silicate was added and allowed to mix for another 5 minutes until the silicate was evenly dispersed. The dry flavor and dry color were added last and allowed to mix for another 10 minutes. A plastic spatula was used to scrape the inside of the mixing bowl to ensure complete recovery of the dry beverage base composition.
The water was placed in a stainless steel 3 L cylinder and a LIGHTNINTTm Mixer was set at 500 to 650 rpms using a 2.5 inch (6.35 cm) impeller with three straight blades.
This was used to create a vortex in the water. The impeller blades were positioned at a 30 to 45 angle. The dry beverage base (53.525 grams) was slowly added to the vortex of the water and was mixed for an additional 5 minutes until all the sugar and acids had dissolved.
This resulted in a beverage with a pH of 2.90 and brix of 7.70 .
Sensory Evaluation Samples of control sugared strawberry beverages containing sugar at the full level indicated above (50, 66.67, 80, 90, and 100% of fall sugar), and the strawberry beverage comprising 2/3 sugar + 1.3 ppm compound 23 were given to tasters in randomized order.
Tasters used an anchored scale from 1 to 10 (1 being no sweetness, 10 being intense sweetness). Tasters were instructed to hold the beverage in their mouth for at least 5 seconds, expectorate the sample, and evaluate/rank the "peak" of sweetness intensity of their various samples. They were allowed to re-taste and re-position their samples on the physical line scale. Once satisfied with their rankings, they wrote down their code and corresponding rank score.
Table G: Sensory Evaluation Results Sweet Score from Individual Tastors Average % Sugar -#1 #2 #3 #4 #5 #6 #7 #8 Scores 50% 2 2 1 1 1 1 1.5 1.5 1.375 66.67% 3 3 3.5 3 2 2 3.5 3 2.875 80% 4 6 4 6 3 5 6 4 4.75 90% 6.5 9 7 8 7 7 8 7.5 7.5 100% 6.5 9 8 6 7 7 9 9 7.688 2/3 Sugared + 8 7 7 8 7.5 7 8 8 7.56 1.3 ppm Cmpd 23 It was concluded that 1.3 ppm of compound 23 in a 2/3 sugared formulation had similar sweet intensity ratings to the 100% sugar formulation.
Example 57: Reduced Sugar Soda Syrup Concentrate To demonstrate the use of the disclosed amide compounds to reduce the concentration of saccharide sugars in soda syrups, the concentrates used to dispense P õ,c IS Si Eli /1213111"n fountain soda drinks, a fully sugared strawberry soda syrup (such as those comprising high fructose corn syrups, HFCS) and 2/3 fully sugared HFCS soda syrups also containing the amide compound of Example 23 were prepared according to the formulations in the following table, and human taste tested.
Table H
Soda Syrup Soda Syrup Fully Sugared with 2/3 Sugared with HFCS HFCS + Compound 23 Ingredients (%wt/wt) (%wt/wt) Water 25.0595 49.6665 HFCS 55, 77 Brix 74.00 49.33 Sodium Benzoate 0.05 0.05 Phosphoric Acid, 75% 0.32 0.37 Citric Acid, granulated* 0.02 0.02 Red Dye #40, dry** 0.0005 0.0005 Natural Strawberry Flavor*** 0.50 0.50 Potassium Sorbate 0.05 0.05 Compound 23 **** 0.00 1.3 ppm (0.013 gr sweetener concentrate) *Other flavoring acids (such as tartaric acid, ascorbic acid, malic acid, etc.) and combinations can be used if other fruit or non-fruit flavors are used.
**Other colors (such as yellow #5, #6, caramel color, etc.) can be used.
***Other flavors (Natural or N&A) can be used such as cola, cherry, orange, lemon, citrus or non-fruit type flavors at levels of 0.15 to 1.00%
**** Added in form of sweetner concentrate composition described below.
Fully Sugared HFCS Soda Syrup Processing The soda syrup was formulated then mixed with carbonated water at a 5:1 throw ratio (volume to volume of carbonated water: soda syrup) and then tasted.
1000.00 g of the fully sugared syrup was formulated in the following manner.
Water was placed into a 2000 mL stainless steel cylinder and equiped with_a LIGHTNINTm Mixer at 500 to 650 rpms using a 2.5 inch (6.35 cm) impeller with three straight blades. A
vortex was created by positioning the impeller blades at a 30 to 45 angle.
Sodium benzoate and potassium sorbate was added to the water vortex and mixed for 5 minutes until both were dissolved. The HFCS was added, followed by the Red Dye #40, and strawberry flavor. The acids were added last, phosphoric followed by the citric acid, and the syrup was allowed to mix for another 10 minutes until the colors and acids were well dispersed.
The resulting soda syrup was made into a carbonated strawberry soda by using a throw ratio of 5:1 (vol/vol) of carbonated water to soda syrup. The resulting strawberry ro" T / Eli Eir 3 11+ la 113 soda had a brix of 10.0 (target was 9.5 to 10.5 ) and a pH of 2.95 (target pH
range was 2.80 to 3.10).
2/3 Sugared Soda Syrup Comprising HFCS + Compound 23 1000.00g of the 2/3 sugared syrup comprising compound 23 was formulated in the following manner. Compound 23 was diluted with maltodextrin (1:100) to make a sweetener concentrate composition for addition to the soda syrup formulation.
An alternative method is to make a solution of amide compound in propylene glycol that can be added directly into the liquid soda syrup formulation. A 100g batch of dry sweetener concentrate composition was produced by weighing 1.000 g of the enhancer and 99.0000 g of 10 D.E. maltodextrin. 50g of the maltodextrin was placed on the bottom of a clean and dried mortar and the 1.0000g of amide compound was added and slowly mixed into the maltodextrin. In a planetary mixer with a wire whip attachment (KITCHEN AIDE
Mixer), the rest of the maltodextrin was added to the mixing bowl, and the contents of the mortar was placed into the mixer and the mixer was turned on to a slow speed (setting 3). A
rubber spatula was used to remove the contents of the mortar and the contents were allowed to mix for an additional 10 minutes. A rubber spatula was used to scrap the walls and bottom of the bowl. The mixture was blended on low for another 15 minutes. The 1000 x sweetener concentrate composition was stored in an air tight amber glass container.
Using the KITCHEN AIDETM Mixer with the wire whip attachment, the granulated ingredients (sugar, acids) were mixed slowly at speed 2 using the wire whip attachment for 3 minutes.
Water was placed into a 2000 mL stainless steel cylinder of a LIGHTNINTm Mixer having a 2.5 inch (6.35 cm) impeller with three straight blades, and stirred at 500 to 650 rpm. A vortex was created by positioning the impeller blades at a 30 to 45 angle. Sodium benzoate and potassium sorbate was added to the water vortex and was mixed for 5 minutes until both were dissolved. The dry diluted sweet concentrate composition was slowly added and mixed for 5 minutes. The HFCS was added, followed by the Red#40 and strawberry flavor. The acids were added last, phosphoric followed by the citric and the syrup was allowed to mix for another 10 minutes until the colors and acids were well dispersed. The resulting soda syrup was made into a carbonated strawberry soda by using a throw ratio of 5:1 (vol/vol) of carbonated water to soda syrup. The resulting strawberry soda had a brix of 7.10 (target was 6.3 to 7.3 ) and a pH of 2.98 (target pH range was 2.80 to 3.10).

Pc-rf usius/ 4324-0 Sensory Evaluation The test strawberry beverage compositions were given to eight tasters in randomized order. Tasters used an anchored scale from Ito 10(1 being no sweetness, 10 being intense sweetness). Tasters were instructed to hold the strawberry soda in their mouth for at least 5 '5 seconds, expectorate the sample, and evaluate/rank the "peak" of sweetness intensity of their various samples. They were allowed to re-taste and re-position their samples on the physical line scale. Once satisfied with their rankings, they wrote down their code and corresponding rank score.
Table I: Sensory Evaluation 1Zestifts Product Average Sweet Intensity - Score 2/3 Sugared with HFCS 4.214 ¨
' Fully Sugared with FRCS 7.357 2/3 Sugared with 11FCS + 6.429 1.0 ppra compound 23 2/3 Sugared with HFCS 7.214 1.3gun compound 23 Tasters could easily discriminate between the 100% HFCS soda and the 2/3 Sugared RFC& Soda comprising 2/3 Fully Sugared HFCS +13 ppm of compound 23 had similar sweetness intensity to the 100% HFCS strawberry soda.
While particular embodiments of the present invention have been illustrated and described, the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole,

Claims (132)

1. A method for increasing the sweet taste of a comestible or medicinal product comprising:
a. providing at least one comestible or medicinal product, or at least one precursor thereof, and b. combining the at least one comestible or medicinal product or at least one precursor thereof with at least a sweet flavor modulating amount of at least one bi-aromatic amide compound, or one or more comestibly acceptable salts thereof, so as to form a modified comestible or medicinal product;
wherein, the amide compound has the structure:
wherein i) Ar1 and Ar2 are independently selected from monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl rings;
ii) m is selected from the integers 0, 1, 2, 3, 4, or 5;
iii) m' is selected from the integers 0, 1, 2, 3, or 4;
iv) each R1 and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH,SO3H, PO3H, halogen, and a C1-C6 organic radical;
v) L is a carbon atom;
vi) R3 is hydrogen, hydroxy, halogen, or a C1-C6 organic radical;
vii) R4 is hydrogen, hydroxy, halogen, or a C1-C6 organic radical;
viii) R5 is a C1-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.

2. The method of claim 1, wherein m and m' are independently selected from the integers 0, 1, or 2.

3. The method of claim 1, wherein m and m' are independently 0 or 1.

4. The method of claim 1, wherein the organic radicals are C1-C4 organic radicals.

5. The method of claim 1, wherein the C1-C6 organic radicals are independently selected from the group consisting of alkyl, alkoxy, alkoxy-alkyl, hydroxyalkyl, NHR6, NR6R6', CN, CO2H, CO2R6, C(O)H, C(O)R6, C(O)NHR6, C(O)NR6R6', OC(O)R6, NHC(O)R6, SR6, S(O)R6, S(O)2R6, S(O)NHR6, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl, wherein R6 is C1-C4 alkyl.

6. The method of claim 1, wherein each R1 and R2 is independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NHCH3, N(CH3)2, CN, OC(O)CH3, SCH3, S(O)CH3, S(O)2CH3, S(O)2NHCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, alkyl, CH2OH, CH2OCH3, CH2OCH2CH3, C(O)H, C(O)CH3, methoxy, ethoxy, and isopropoxy groups.

7. The method of claim 1, wherein Ar1 and Ar2 are independently selected from the group consisting of monocyclic aryl, and monocycle heteroaryl rings.

8. The method of claim 1, wherein Ar1 and Ar2 are independently selected from the group consisting of phenyl, napthyl, indole, pyridyl, pyrimidyl, benzofuran, and benzothiofuran rings.

9. The method of claim 1, wherein Ar1 is a phenyl ring.

10. The method of claim 1, wherein Ar2 is a phenyl ring.

11. The method of claim 10, wherein Ar1 is a phenyl, pyridyl, pyrimidyl, or pyrazinyl ring.

12. The method of claim 1, wherein Ar1 and Ar2 are phenyl rings,

13. The method of claim 1, wherein Ar1 is a pyridyl ring.

14. The method of claim 1, wherein Ar1 has the formula:

15. The method of claim I, wherein Ar1 has the formula:

16. The method of claim 1, wherein Ar1 has the formula:

17. The method of claim 1, wherein Ar2 is a pyridyl ring.

18. The method of claim 1, wherein Ar1 and Ar2 are pyridyl rings.

19. The method of claim 1, wherein Ar2 has the formula:

20. The method of claim 1, wherein Ar2 has the formula:

21. The method of any one of claims 4-20, wherein m and m' are independently selected from the integers 0, 1, or 2.

22. The method of claim 1, wherein R3 and R4 are independently selected from hydrogen and a C1-C4 organic radical.

23. The method of claim 1, wherein R3 and R4 are independently selected from hydrogen, a C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, or C1-C4 alkoxyalkyl

24. The method of claims 1, wherein R3 and R4 are independently selected from hydrogen and C1-C4 alkyls.

25. The method of claim 1, wherein at least one of R3 and R4 are methyl.

26. The method of claim 1, wherein one of R3 and R4 is a C1-C4 alkyl and the other of R3 and R4 is hydrogen.

27. The method of claim 1, wherein one of R3 and R4 is methyl and the other of R3 and R4 is hydrogen.

28. The method of any one of claims 1-21, wherein R3 and R4 are methyl.

29. The method of any one of claims 1-28, wherein R5 is a C3-C10 branched alkyl.

30. The method of claim 1, wherein R5 is a C1-C10 normal or branched alkyl or cycloalkyl, optionally substituted with 1, 2, or 3 aryl or hetereroaryl rings.

31. The method of claim 1; wherein R5 is a C1-C10 normal or branched alkyl or cycloalkyl, substituted with 1, 2, or 3 substituents independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, COOCH3, SCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups.

32. The method of claim 1, wherein:
a. Ar1 and Ar2 arc independently selected from phenyl or 5 or 6 membered monocyclic heteroaryl rings, b. each R1 and R2 is independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NHCH3, N(CH3)2, CN, OC(O)CH3, SCH3, S(O)CH3, S(O)2CH3, S(O)2NHCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, CH2OH, CH2OCH3, CH2OCH2CH3, C(O)H, C(O)CH3, methoxy, ethoxy, and isopropoxy groups, c. R3 and le are methyl, and d. R5 is a C3-C10 branched alkyl.

33. The method of any one of claims 1-32, wherein the modified, comestible or medicinal product further comprises at least a sweet flavoring agent amount of one or more additional natural, semi-synthetic, or synthetic sweet flavoring agents, or a mixture thereof

34. The method of claim 33, wherein the one or more natural, semi-synthetic, or synthetic sweet flavoring agents comprise sucrose, fructose, glucose, crythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, neotame, saccharin, acesulfame-K, cyclamate, Sucralose, alitame or a mixture thereof.

35. The method of any of claims 1 -32, wherein the modified comestible or medicinal product further comprises a sweet flavoring agent amount of sucrose.

36. The method of any of claims 1-32, wherein the modified comestible or medicinal product further comprises a sweet flavoring agent amount of fructose.

37. The method of any one of claims 1-34, wherein the modified comestible or medicinal product has a sweeter taste than a control comestible or medicinal product that does not comprise the amide compound, as judged by the majority of a panel of at least eight human taste testers.

38. The method of any one of claims 1-36, 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, and snack bars.

39. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is selected from the group consisting of meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, and spreads.

40. The method of any one of claims 1-36, wherein the modified comestible or medicinal product comprises one or more of meats, poultry, fish, vegetables, grains, or fruits.

41. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a frozen food, an uncooked food, or a fully or partially cooked food.

42. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a snack food.

43. The method of any one of claims 1-36, 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.

44. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a cake, cookie, pie, candy, chewing gum, gelatin, ice cream, sorbet, pudding, jam, jelly, salad dressing, condiment, cereal, canned fruit, or fruit sauce.

45. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a beverage, a beverage mix, or a beverage concentrate.

46. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a solid beverage mix also comprising a saccharide sweetener.

47. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a liquid beverage concentrate composition also comprising a saccharide sweetener.

48. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a soda.

49. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a fruit or vegetable juice.

50. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is an alcoholic beverage.

51. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is ice cream.

52. The method of any one of claims 1-36, wherein the modified comestible or medicinal product is a cereal.

53. The method of any one of claims 1-36, wherein the modified comestible or medicinal product comprises a sweet coating, frosting, or glaze comprising a mixture of the at least one amide compound and one or more other sweeteners independently selected from sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, neotame, saccharin, acesulfame-K, cyclamate, Sucralose, and alitame, or a mixture thereof.

54. The method of any one of claims 1-36, wherein the amide compound is present in the modified comestible or medicinal product in a concentration from about 0.001 ppm to about 30 ppm.

55. The method of any one of claims 3-36, wherein the modified comestible or medicinal product has a sweeter taste than a control comestible or medicinal product that does not comprise the amide compound, as judged by the majority of a panel of at least eight human taste testers.

56. The method of any one of claims 1-36, wherein the amide compound has an EC50 for binding an hT1R2/hT1R3 receptor expressed in an HEK293-G.alpha.15 cell line of less than about 2 µM.

57. The method of any one of claims 1-36, wherein the one or more amide compounds are contacted or mixed with one or more precursors of the comestible or medicinal product to form a sweetener concentrate composition comprising from about 10 to about 100,000 ppm of the one or ore amide compounds, then the sweetener concentrate composition is used to prepare the comestible or medicinal product.

58. The method of claim 57 wherein from about 100 to about 1000 ppm of the one or more amide compounds are present in the sweetener concentrate composition.

59. The method of claim 57 wherein the sweetener concentrate composition is a liquid solution, dispersion, or emulsion of the amide compound in one or more precursors of the comestible or medicinal product.

60. The method of claim 57 wherein the sweetener concentrate composition is a solid.

61. A comestible or medicinal product produced by the process of any one of claims 1-56,

62. A method for increasing the sweet taste of a comestible or medicinal product comprising:
a. providing at least one comestible or medicinal product, or at least one precursor thereof, and b. combining the at least one comestible or medicinal product or at least one precursor thereof with from About 0.01 to about 100 ppm of at least one bi-aromatic amide compound, or a comestibly acceptable salt thereof, and a sweet flavoring agent amount of sucrose, fructose, glucose, or a mixture thereof, so as to form a modified comestible or medicinal product;
wherein the amide compound has the structure:
wherein i) Ar1 and Ar2 are independently selected from phenyl, napthyl, indolyl, pyridyl, pyrimidyl, pyrrolyl, furanyl, thiofuranyl, quinolinyl, benzofuranyl, triazolyl, and benzothiofuranyl rings;
ii) in is selected from the integers 0, 1, 2, or 3, iii) m' is selected from the integers 0, 1, or 2;
each R1 and R2 is independently selected from the group consisting of a hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, COOCH3. SCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, S(O)CH3, S(O)2CH3, CN, CH2OH, C(O)H, C(O)CH3, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy radical;
v) R3 is a C1-C4 vi) R4 is hydrogen, or a C1-C4 alkyl;

vii) R5 is a C1-C10 normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one or two-substituents independently selected from hydroxy, fluoro, chloro, NH2, NO2, NHCH3, N(CH3)2, COOCH3, SCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, S(O)CH3, S(O)2CH3, CN, CH2OH, C(O)H, C(O)CH3, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy radical;
or a comestibly acceptable salt thereof.

63. The method of claim 62, wherein R3 and R4 are methyl, and R5 is a C3-C10 branched alkyl.

64. A comestible or medicinal product produced by the process of claims 62 or 63.

65. A sweet comestible or medicinal product comprising from about 0.01 to about 100 ppm of at least one bi-aromatic amide compound, or a comestibly acceptable salt thereof, and at least a sweet flavoring agent amount of one or more natural, semi-synthetic, or synthetic sweet flavoring agents, or a mixture thereof;
wherein the amide compound has the structure:
wherein i) Ar1 and Ar2 are independently selected from a phenyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl, furanyl, thiofuranyl, triazolyl, isoxazolyl, oxadiazolyl, or indolyl ring;
ii) m and m' are independently selected from the integers 0, 1, or 2, iii) each R1 and R2 is independently selected from the group consisting of OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C4 organic radical, iv) R3 and R4 are independently selected from hydrogen and methyl, v) R5 is a C3-C10 branched alkyl optionally comprising one, two, or three substituents independently selected from OH, NH2, a halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.

66. The sweet comestible or medicinal product of claim 65 wherein Ar1 is a phenyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrazolyl, furanyl, thiofuranyl, or indolyl ring.

67. The sweet comestible or medicinal product of claim 65 wherein Ar2 is a phenyl, pyridyl, pyrimidyl, pyrazinyl, pyrazolyl, furanyl, thiofuranyl, isoxazolyl, oxadiazolyl, or triazolyl ring.

68. The sweet comestible or medicinal product of claim 65, wherein each R1 and R2 is independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NHCH3, N(CH3)2, CN, OC(O)CH3, SCH3, S(O)CH3, S(O)2CH3, S(O)2NHCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, CH2OH, CH2OCH3, CH2OCH2CH3, C(O)H, C(O)CH3, methoxy, ethoxy, and isopropoxy groups.

69. The sweet comestible or medicinal product of claim 65, wherein the one or more natural, semi-synthetic, or synthetic sweet flavoring agents comprising sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, neotame, saccharin, acesulfame-K, cyclamate, Sucralose, or alitame, or a mixture thereof.

70. The sweet comestible or medicinal product of claim 65 that is a confectionery, bakery product, ice cream, dairy product. sweet snack, cereal, beverage, beverage mix, or beverage concentrate.

71. An amide compound having the structure:

wherein i) Ar1 and Ar2 are independently selected from a phenyl or monocyclic heteroaryl rings;
ii) m and m' are independently selected from the integers 0, 1, or 2;
iii) each R1 and R2 is independently selected from the group consisting of OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C4 organic radical;
iv) R3 and R4 arc independently selected from hydrogen and methyl;
v) R5 is a C3-C10 branched alkyl; or vi) R5 is a C3-C10 substituted alkyl, wherein the substituents are bonded to the alkyl chains and are independently selected from fluoro, chloro, bromo, NH2, NO2, NHCH3, N(CH3)2, SCH3, SC2H5, SO3H, trifluoromethyl, methoxy, ethoxy, isopropoxy, and trifluoromethoxy groups;
or a comestibly acceptable salt thereof;
provided Ar1 is not thiofuranyl.

72. The amide compound of claim 71 or a comestibly acceptable salt thereof, wherein Ar1 is phenyl.

73. The amide compound of claim 71 or a comestibly acceptable salt thereof, wherein Ar2 is phenyl.

74. The amide compound of claim 71 or a comestibly acceptable salt thereof, wherein Ar1 is a pyridyl, pyrimidyl or pyrazinyl ring.

75. The amide compound of claim 71 or a comestibly acceptable salt thereof, wherein Ar1 has the structure

76. The amide compound of claim 71 or a comestibly acceptable salt thereof, wherein each R1 and R2 is independently selected from the group consisting of hydroxy, fluoro, chloro, NH2, NHCH3, N(CH3)2, CN, OC(O)CH3, SCH3, S(O)CH3, S(O)2CH3, S(O)2NHCH3, SC2H5, methyl, ethyl, propyl, isopropyl, vinyl, allyl, CH2OH, CH2OCH3, CH2OCH2Ch3, C(O)H, C(O)CH3, methoxy, ethoxy, and isopropoxy groups.

77. The amide compound of claim 71 or a comestibly acceptable salt thereof, wherein R3 and R4 are methyl.

78. the amide compound of claim 71 or a comestibly acceptable salt thereof, wherein R5 is a C3-C10 branched alkyl.

79. A comestible composition comprising from about 0.001 to about 10 ppm of one or more of the compounds of claim 71, and one or more comestibly acceptable carriers.

80. A sweetener concentrate composition comprising from about 10 to about 100,000 ppm of one or more of the amide compounds of claim 71, and one or more comestibly acceptable carriers.

81. The sweetener concentrate composition of claim 80 comprising a solution, dispersion, or emulsion of the amide compound in the one or more comestibly acceptable liquids.

82. The sweetener concentrate composition of claim 81 wherein the comestibly acceptable liquids are selected from a water, a comestibly acceptable organic solvent, or comestibly acceptable oils or melted fats, or a mixture thereof.

83. The sweetener concentrate composition of claim 82 wherein the comestibly acceptable organic solvents are selected from ethanol, propylene glycol, dipropylene glycol and methyl, ethyl, and acetate esters thereof, glycerol, and corn syrup.

84. The sweetener concentrate composition of claim 82 wherein the comestibly acceptable oils or melted fats comprise triacetylesters of glycerol.

85. The sweetener concentrate composition of claim 80 wherein the one or more comestibly acceptable carriers is a comestibly acceptable solid.

86 The sweetener concentrate composition of claim 85 wherein the comestibly acceptable solid comprises a saccharide or polysaccharide.

87. The sweetener concentrate composition of claim 85 wherein the comestibly acceptable solid comprises sucrose, fructose, or glucose.

88. The sweetener concentrate composition of claim 85 wherein the comestibly acceptable solid comprises starch, modified starches, dextrins, maltodextrins, celluloses, modified celluloses, pectins, alginates, chitosan, chitosan derivatives, gum Arabic, carrageenans, locust bean gum, and guar gum.

89. A compound having the formula:
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-isobutyl-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methyl-N-(pentan-3-yl)propanamide;
(R)-N-sec-butyl-2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanamide;
2-(4-(5 -cyanopyridin-3-yl)phenyl)-N-isobutyl-2-methylpropanamide, 2-methyl-N-(2-methylbutyl)-2-(4-(pyrimidin-5-yl)phenyl)propanamide;
2-(4-(5-(ethoxymethyl)pyridin-3-yl)phenyl)-N-isobutyl-2-methylpropanamide;
N-isobutyI -2-(2-methoxy-3 ' -(methoxymethyl)bipheny-4-yl)-2 -methylpropanamide;
N-isobutyl-2-(4-(6-(methoxymethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;
N-isobutyl-2-(3'-(methoxymethyl)biphenyl-4-yl)-2-methylpropanamide, N-isobutyl-2-(4-(5 -(methoxymethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;
N-isobutyl-2-methyl-2-(4-(1-methyl-1H-pyrrol-2-yl)phenyl)propanamide;
2-(2'-(hydroxymethyl)biphenyl-4-yl)-N-isobutyl-2-methylpropanamide (S)-N-(1-hydroxybutan-2-yl)-2-(3 '-(methoxymethyl)biphenyl-4-yl)-2-methylpropanamide:
N-isobutyl-2-methyl -2-(4-(pyrimidin-5-yl)phenyl)propanamide;
2 -(4-(6-cyanopyrazin-2-yl)phenyl )-N-(2-methoxypropyl)-2-methylpropanamide;
(R)-N-see-butyl-2-(4-(6-cyanopyrazin-2-yl)phenyI)-2-methylpropanamide; or a comestibly acceptable salt thereof.

90. A comestible composition comprising at least a sweet flavor modulating amount of at least one of the compounds of claim 89, and one or more comestibly acceptable carriers.

91. A method for increasing the sweet taste of a comestible or medicinal product comprising:
a. providing at least one comestible or medicinal product, or at least one precursor thereof, and b. combining the at least one comestible or medicinal product or at least one precursor thereof with at least a sweet flavor modulating amount of at least one bi-aromatic amide compound, or one or more comestibly acceptable salts thereof, so as to form a modified comestible or medicinal product;
wherein the amide compound has the structure:
wherein i) Ar1 and Ar2 are independently selected from monocyclic aryl, fused bicyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl rings, ii) m is selected from the integers 0, 1, 2, 3, 4, or 5;
iii) m' is selected from the integers 0, 1, 2, 3, or 4;
iv) each R1 and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
v) L is a carbon or nitrogen atom;
vi) R3 is hydrogen, hydroxy, halogen, or a C1-C6 organic radical:
vii) R4 is absent, or hydrogen, hydroxy, halogen, or a C1-C6 organic radical;
viii) R5 is a C1-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or branched alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof.

92. An amide compound having the structure:

wherein ix) Ar1 and Ar2 are independently selected from a phenyl or monocyclic heteroaryl rings, ii) m and m' are independently selected from the integers 0,1, or 2;
iii) each R1 and R2 is independently selected from the group consisting of OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C4 organic radical;
R3 and R4 are both methyl;
v) R5 is a C3-C10 branched alkyl optionally comprising one, two, or three substituents independently selected from OH, NH2, a halogen, and a C1-C6 organic radical;
or a comestibly acceptable salt thereof,

93. A sweet comestible or medicinal product comprising:
(a) at least one amide compound, or a comestibly acceptable salt thereof, and (b) at least one natural, semi-synthetic, or synthetic sweet flavoring agents, or a mixture thereof:
wherein the at least one amide compound has the following structure:
wherein Ar1 and Ar2 are independently monocyclic aryl, monocyclic heteroaryl, or fused bicyclic heteroaryl;

ii) m is selected from the integers 0, 1, 2, 3, 4, or 5, iii) m' is selected-from the integers 0, 1, 2, 3, or 4;
iv) each R1 and R2 is independently selected from the group consisting of an OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical;
v) L is a carbon atom;
vi) R3 is hydrogen or a C1-C6 organic radical;
vii) R4 is hydrogen or a C1-C6 organic radical;
viii) R5 is a C1-C14 organic radical comprising a normal or branched alkyl or cycloalkyl, wherein the normal or brandied alkyl or cycloalkyl optionally comprises one to four substituents independently selected from OH, NH2, NO2, SH, SO3H, PO3H, halogen, and a C1-C6 organic radical; or a comestibly acceptable salt thereof.

94. The sweet comestible or medicinal product of claim 93, wherein Ar1 and Ar2 are independently monocyclic aryl.

95. The sweet comestible or medicinal product of claim 94, wherein Ar1 is phenyl.

96, The sweet comestible or medicinal product of claim 93, wherein Ar1 is monocyclic heteroaryl or fused bicyclic heteroaryl, and Ar2 is monocyclic aryl.

97, The sweet comestible or medicinal product of claim 96, wherein Ar1 is pyridinyl or a heteroaryl unit having the formula.

98. The sweet comestible or medicinal product of claim 93, wherein Ar1 is monocyclic aryl, and Ar2 is monocyclic heteroaryl, or fused bicyclic heteroaryl

99. The sweet comestible or medicinal product of claim 98, wherein Ar2 is pyridinyl, pyrimidinyl, pyrazinyl, or a heteroaryl unit having the formula:

100. The sweet comestible or medicinal product of claim 93, wherein Ar1 and Ar2 are independently monocyclic heteroaryl, or fused bicyclic, heteroaryl.

101. The sweet comestible or medicinal product of claim 100, wherein Ar1 is pyridinyl or a heteroaryl unit haying the formula:

102 The sweet comestible or medicinal product of claim 100, wherein Ar2 is pyridinyl, pyrimidinyl, pyrazinyl, or a heteroaryl unit having the formula:

103. The sweet comestible or medicinal product of claim 93, wherein R3 and R4 are independently hydrogen or methyl.

104. The sweet comestible or medicinal product of claim 93, wherein R3 and R4 are both methyl.

105. The sweet comestible or medicinal product of claim 93, wherein R3 is methyl and R4 is hydrogen.

106. The sweet comestible or medicinal product of claim 93, wherein m and m' are independently 0 or 1.

107. The sweet comestible or medicinal product of claim 93, wherein R5 is C1-C6, normal or branched alkyl.

108. The sweet comestible or medicinal product of claim 93, wherein R5 is selected from propyl, cyclopropyl, isobutyl, 1-methoxypropan-2-yl, 1-methoxybutan-2-yl, isopentyl, pentan-3-yl, 2-methylbutyl, cyclopentyl, (R)-3-methylbutan-2-yl, (S)-3-methylbutan-2-yl, cyclopropylmethyl, see-butyl, cyclobutyl, isopropyl, 1-hydroxybutan-2-yl, 1 -hydroxypentan-2-yl, cyclohexyl, 2-ethylbutyl, furan-2ylmethyl, 2-methoxyethyl, methoxypropyl, 2-(furan-2-yl)-2-hydroxyethyl, 1-phenylethyl, tetrahydrofuran-2-yl, hydroxy(phenyl)methyl, 1-(furan-2-yl)ethyl, furan-3ylmethyl2-hydroxy-2-phenylethyl, cyclohexyl, and 1-(4-methoxyphenyl)ethyl.

109. The sweet comestible or medicinal product of claim 93, wherein the one or more natural, semi-synthetic, or synthetic sweet flavoring agents comprise sucrose, fructose, glucose, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, aspartame, neotame, saccharin, acesulfame-K, cyclamate, sucralose, alitame, or a mixture thereof.

110, The sweet comestible product of claim 93, that is selected from the group consisting of confectioneries, bakery products, ice creams, dairy products, sweet or savory snacks, snack bars, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, and spreads

111. The sweet comestible product of claim 91, comprising one or more meats, poultry, fish, vegetables, grains, or fruits.

112. The sweet comestible product of Claim 93, that is a frozen food, an uncooked food, or a fully or partially cooked food.

113. The sweet comestible product of claims 93, that is a soup, a dehydrated or concentrated soup, or a dry soup.

114. The sweet comestible product of claim 93, that is a snack food.

115. The sweet comestible product of claim 93, that is a cooking aid product, a meal solution product, a meal enhancement product, a seasoning, or a seasoning blend.

116. The sweet comestible product of claim 93, that is a beverage, a beverage mix, or a beverage concentrate,

117. The sweet comestible product of claim 93, that is a soda, juice, or alcoholic beverage,

118. The sweet comestible or medicinal product of claim 93, further comprising at least a savory flavor modulating amount of monosodium glutamate.

119. The sweet comestible or medical product of claim 93, wherein the amide compound is present in a concentration from about 0.01 ppm to about 100 ppm.

120. The sweet comestible or medical product of claim 93, that has an increased sweet taste as compared to the comestible composition prepared without the compound, as judged by a majority of a panel of at least eight human taste testers.

121. The sweet comestible of claim 93, that is selected from one or more confectioneries, chocolate confectionery, tablets, countlines, bagged selflines/softlines, boxed assortments, standard boxed assortments, twist wrapped miniatures, seasonal chocolate, chocolate with toys. alfajores, other chocolate confectionery, mints, standard minis, power mints, boiled sweets, pastilles, gums, jellies and chews, toffees, caramels and nougat, medicated confectionery, lollipops, liquorice, other sugar confectionery, gum, chewing gum, sugarised gum. 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 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, take-home dairy ice cream, ice cream desserts, bulk ice cream, take-home water ice cream, frozen yoghurt, artisanal ice cream, dairy products, milk, fresh/pasteurised milk, 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, functional 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 milk, flavoured powder milk drinks, cream, cheese, processed cheese, spreadable processed cheese, unspreadable processed cheese, unprocessed cheese, spreadable unprocessed cheese, hard cheese, packaged hard cheese, unpackaged hard cheese, yoghurt, plain/natural yoghurt, flavoured yoghurt; fruited yoghurt, probiotic yoghurt, drinking yoghurt, regular drinking yoghurt, probiotic 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 frontage frais and quark, sweet and savoury snacks, fruit snacks, chips/crisps, extruded snacks, tortilla/corn chips, popcorn, pretzels, nuts, other sweet and savoury snacks, snack bars, granola bars, breakfast bars. energy bars, fruit bars, other snack bars, meal replacement products, slimming products, convalescence drinks, ready meals, canned ready meals, frozen ready meals, dried ready meals. chilled ready meals, dinner mixes, frozen pizza, chilled pizza, soup, canned soup, dehydrated soap, instant soup, chilled soup, uht soup, frozen soup, pasta, canned pasta, dried pasta, chilled/fresh pasta, noodles, plain noodles, instant noodles, cups/bowl instant noodles, pouch instant noodles, chilled noodles, snack noodles, canned food, canned meat and meat products, canned fish/seafood, canned vegetables, canned tomatoes, canned beans, canned fruit, canned ready meals, canned 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 bakery products, frozen desserts, frozen ready meals, frozen pizza, frozen soup, frozen noodles, other frozen food, dried food, dessert mixes, dried ready meals, dehydrated soup, instant soup, dried pasta, plain noodles, instant noodles, cups/bowl instant noodles, pouch instant noodles, chilled food, chilled processed meats, chilled fish/seafood products, chilled processed fish, chilled coated fish, chilled smoked fish, chilled lunch kit, chilled ready meals, chilled pizza, chilled soup, chilled/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 pur6es, bouillon/stock cubes, stock cubes, gravy granules, liquid stocks and fonds, herbs and spices, fermented sauces, soy based sauces, pasta sauces, wet sauces, dry sauces/powder mixes, ketchup, mayonnaise, regular mayonnaise, mustard, salad dressings, regular salad dressings, low fat salad dressings, vinaigrettes, dips, pickled products, other sauces, dressings and condiments, baby food, milk formula, standard milk formula, follow-on milk formula, toddler milk formula, hypoallergenic milk formula, prepared baby food, dried baby food, other baby food, spreads, jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads.

122. A method for increasing the sweet taste of a comestible or medicinal product comprising:
a) providing at least one comestible or medicinal product, or at least one precursor thereof, and b) combining the at least one comestible or medicinal product or at least one precursor thereof with at least one amide compound of claim 93, or one or more comestibly acceptable salts thereof, so as to form a modified comestible or medicinal product.

123, The method of claim 122, wherein the at least one amide compound is in a concentration from about 0.01 ppm to about 100 ppm.

124. A compound selected from the group consisting of:
2-(4-(Furan-3-yl)phenyl)-N-isobutyl-2-methylpropanamide;
N-Isobutyl-2-methyl-2-(4-(4-methylthiophen-3-yl)phenyl)propanamide;
2-(2-fluorobiphenyl-4-yl)-N-isobutylpropanamide;
2-(2-fluorobiphenyl-4-yl)-N-(furan-2-ylmethyl)propanamide;
2-(2-fluorobiphenyl-4-yl)-N-(2-methoxyethyl)propanamide;
2-(2-fluorobiphenyl-4-yl)-N-(1-methoxybutan-2-yl)-2-methylpropanamide;
N-isobutyl-2-methyl-2-(4-(thiophen-3-yl)phenyl)propanamide;
N-isobutyl-2-methyl-2-(3'-nitrobiphenyl-4-yl)propanamide;
2-(3'-cyanobiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
Methyl 4'-(1-(isobutylamino)-2-methyl-1-oxopropan-2-yl)biphenyl-3-carboxylate;

2-(3'-hydroxybiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(2'-methylbiphenyl-4-yl)propanamide;
2-(2'-aminobiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
2-(2'-cyanobiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(3'-methylbiphenyl-4-yl)propanamide;
Ethyl 4'-(1-(isobutylamino)-2-methyl-1-oxoptopan-2-yl)biphenyl-3-carboxylate;
2-(3'((dimethylamino)carbonyl)biphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-(3'-isopropoxybiphenyl-4-yl)-2-methylpropanamide, N-isobutyl-2-(3'-methoxybiphenyl-4-yl)-2-methylpropanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-isobutyl-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methyl-N-(pentan-3-yl)propanamide;
(R)-N-sec-butyl-2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-isobutyl-2-methylpropanamide;
tert-butyl 1-(biphenyl-4-yl)-2-(isobutylamino)-2-oxoethylcarbamate;
2-methyl-N-(2-methylbutyl)-2-(4-(pyrimidin-5-yl)phenyl)propanamide;
2-(4-(5-(ethoxymethyl)pyridin-3-yl)phenyl)-N-isobutyl 2-methylpropanamide, N-isobutyl-2-(2-methoxy-3'-(methoxymethyl)biphenyl-4-yl)-2-methylpropanamide, 2-(4-(1H-pyrrol-1-yl)phenyl)N-isobutyl-2-methylpropanamide;
N-isobutyl-2-(4-(6-(methoxymethyl)pyrazin-2-yl)phenyl)-2-methylpropanamide;
N-isobutyl-2-(3'-(methoxymethyl)biphenyl-4-yl)-2-methylpropanamide, N-isobutyl-2-methyl-2-(1-phenyl-1H-pyrazol-4-yl)propanamide;
N-isobutyl-2-(4-(5-(methoxymethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;
N-isobutyl-2-methyl-2-(3-phenylisoxazol-5-yl)propanamide;
N-isobutyl-2-methyl-2-(4-(1-methyl-1H-pyrrol-2-yl)phenyl)propanamide;
2-(3-hydroxy-4-(4-methylthiophen-3-yl)phenyl)-N-isobutyl-2-methylpropanamide;
2-(2'-(hydroxymethyl)biphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
2-(2'-formylbiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(1-phenyl-1H-pyrazol-4-yl)propanamide;
(S)-N-(1-hydroxybutan-2-yl)-2-(3'-(methoxymethyl)biphenyl-4-yl)-2-methylpropanamide;
2 -(5'-cyano-2,3 '-bipyridin-5-yl-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(3-phenyl-1,2,4-oxadiazol-5-yl)propanamide;
2-(5'-cyano-3,3'-bipyridin-6-yl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanamide;
(R)-2-methyl-N-(3 -methylbutan-2-yl)-2-(4-(pyrimidin-5-yl)phenyl)propanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(2-methoxypropyl)-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(2-(furan-2-yl)-2-hydroxyethyl)-2-methylpropanamide;
(R)-N-sec-butyl-2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methylpropanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(1-(furan-2-yl)ethyl)-2-methylpropanamide;

2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(furan-2-ylmethyl)-2-methyl propanamide;
N -isobutyl-2-methyl-2-(2-methylbiphenyl-4-yl)propanamide;
(S)-2-(4-(6-cyanopyrazin-2-)yl)phenyl)-N-(1-hydroxybutan-2-yl)-2-methylpropanamide;
2-methyl-N-(pentan-3-yl)-2-(4-(pyrimidin-5-yl)phenyl)propapamide, N-cyclopropyl-2-(2-fluorobiphenyl-4-yl)propanamide;
(2S)-N-sec-butyl -2-(2-fluorobiphenyl-4-yl)propanamide;
2-(2-fluorobiphenyl-4-yl)-N-isobutyl-2-methylpropanamide:

2-(2-fluorobiphenyl-4-yl)-N-(1-methoxypropan-2-yl)-2-methylpropanamide;
2-(biphenyl-4-yl)-N-isobutylpropanamide;
2-(3'-fluorobiphenyl-4-yl)-N-isobutylpropanamide;
N-isobutyl-2-(3-methoxybiphenyl-4-yl)propanamide;
2-(2-fluorobiphenyl-4-yl)-N-isobutylacetamide;
N-isobutyl-2-methyl-2-(4-(pyridin-4-yl)phenyl)propanamide;
2-(1H-indol-5 -yl)phenyl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanamide;
N-cyclopropyl-2-(2-fluorobiphenyl-4-yl)propanamide;
2-(2'-ethylbiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(2'-(methylthio)biphenyl-4-yl)propanamide;
Methyl 4'-(1-(isobutylamino)-2-methyl-1-oxopropan-2-yl)biphenyl-2-carboxylate;

N-isobutyl-2-(3'-isopropylbiphenyl-4-yl)-2-methylpropanamide;
N-isobutyl-2-methyl-2-(3'-propoxybiphenyl-4-yl)propanamide;
2-(2',3'-dimethoxybiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
2-(2',4'-dimethoxybiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methyl-N-(1-phenylethyl)propanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-isopentyl-2-methylpropanamide;
2-(4-(5-cyanopyridin -3-yl)phenyl)-N-isopropyl-2-methylpropanamide, 2-(3'-formyl-2'-((methoxymethoxy)methyl)biphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
2-(2'-acetylbiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
2-(4-(imidazo[1,2-a]pyridin-3-yl)phenyl)-N-isobutyl-2-methylpropanamide;
2-(4-(1H-indol-4-yl)phenyl)-N-isobutyl-2-methylpropanamide;
(S)-2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methyl-N-((tetrahydrofuran-2-yl)methyl)propanamide;
(S)-2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(hydroxy(phenyl)methyl)-2-methylpropanamide:
2-(4-(5-(methoxymethyl)pyridin-3-yl)phenyl)-2-methyl-N-propylpropanamide;
N-Isobutyl-2-(5-(3-(methoxymethyl)phenyl)pyridin-2-yl)-2-methylpropanamide;
N-isobutyl-2-(6-(3-(methoxymethyl)phenyl)pyridin-3-yl)-2-methylpropanamide;

N-isobutyl-2-methyl-2-(4-(thiazol-4 -yl)phenyl)propanamide, N-isobutyl-2-methyl-2-(4-(pyrimidin-4-yl)phenyl)propanamide;
2-(4-(1II-imidazol-1-yl)phenyl)-N-isobutyl-2-methylpropanamide, N-isobutyl-2-methyl-2-(4-(oxazol-5-yl)phenyl)propanamide;
2-(biphenyl-4-yl)-N-isobutyl)-2-methyIpropanamide;
2-(3'-formylbiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
N-isobutyl-2-methyl-2-(3'-(methylsulfonyl)biphenyl-4-yl)propanamide;
2-(biphenyl-4-yl)-N-isobutylamamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methyl-N-(pentan-3-yl)propanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methyl-N-(2-methylbutyl)propanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(1-furan-2-yl)ethyl)-2-methylpropanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-cyclopentyl-2-methylpropanamide;
(R)-2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methyl-N-(3-methylbutan-2-yl)propanamide;
(2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(cyclopropylmethyl)-2-methylpropanamide;
(S)-2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methyl-N-(3-methylbutan-2-yl)propanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-cyclopropyl-2-methylpropanamide;
2-(4-(4-cyanofuran-3-yl) phenyl)-N-isobutyl-2-methylpropanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-cyclobutyl-2-methylpropanamide;
(R)-N-sec-butyl-2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-cyclobutyl-2-methylpropanamide;
2-(4-( 6-cyanopyrazin-2-yl)phenyl)-2-methyl-N-propylpropanamide, (R)-N-sec-butyl-2-(3'-(methoxymethyl)biphenyl-1-yl)-2-methylpropanamide, 2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(furan-3-ylmethyl)-2-methylpropanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(furan-3-ylmethyl)-2-methylpropanamide;
N-isobutyl-2-methyl-2-(4-(pyridin-3-yl)phenyl)propanamide, N-isopropyl-2-(3'-(methoxymethyl)biphenyl-4-yl)-2-methylpropanamide;
(R)-N-sec-hutyl-2-(4-(5-methoxymethyl)pyridin-3-yl)phenyl)-2-methyIpropanamide;
N-isobutyl-2-methyl-2-(6-(4-methylthiophen-3-yl)pyridin-3-yl )propanamide;
(R)-2-(biphenyl-4-yl)-N-(1-hydroxybutan-2-yl)-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(2-hydroxy-2-phenylethyl)-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(1-methoxybutan-2-yl)-2-methylpropanamide;

2-(4-(5-cyanofuran-2-yl)phenyl)-N-isobutyl-2-methylpropanamide;
(S) N-sec-butyl-2-(4-(5-(methoxymethyl)pyridin-3-yl)phenyl)-2-methylpropanamide;
2-(4-(6-cyanopyrazin-2-yl)phenyl)-N-(2-(furan-2-yl)-2-hydroxyethyl)-2-methylpropanamide;
4-(4-(1-(isobutylamino)-2-methyl-1-oxopropan-2-yl)phenyl)furan-2-carboxylic acid;
2-(2-hydroxybiphenyl-4-yl)-N-isobutyl-2-methylpropanamide;
2-(4-(5-ethoxypyridin-3-yl)phenyl)-N-isobutyl-2-methylpropanamide;
(S)-2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(1-hydroxypentan-2-yl)-2-methylpropanamide, 2-(4-(5-(methoxymethyl)pyridin-3-yl)phenyl)-2-methyl-N-(2-methylbutyl)propanamide;
(E)-2-(4-(4-((hydroxyimino)methyl)furan-3-yl)phenyl)-N-isobutyl-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(furan-2-ylmethyl)-2-methylpropanamide;
methyl 5-(4-(1-(isobutylamino)-2-methyl-1-oxopropan-2-yl)phenyl)nicotinate;
(S)-2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(1-hydroxybutan-2-yl)-2-methylpropanamide;
N-isobutyl-2-(2-methoxybiphenyl-4-yl)-2-methylpropanamide;
(S)-2-(4-(furan-3-yl)phenyl)-N-(1-hydroxybutan-2-yl)-2-methylpropanamide;
2-(3'-(methoxymethyl)biphenyl-4-yl)-2 -methyl-N-propylpropanamide;
2-(4-(1,5-dihydrobenzo[e][1,3]dioxepin-6-yl)phenyl)-N-isobutyl-2-methylpropanamide;
2-(3'-cyano-2 '-(hydroxymethyl)biphenyl-4-yl)-N-isobutyl-2-methylpropanamide, 2-(4-(6-cyanopyridin-2-yl)phenyl)-N-isobutyl-2-methylpropanamide, (S)-2-(4-(6-cyanopyrazin-2-yl)phenyl)-2-methyl-N-(2-methylbutyl)propanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methyl-N-(2-methylbutyl)propanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(cyclopropylmethyl)-2-methylpropanamide;
(R)-N-sec-butyl-2-(4-(5 -cyanopyridin-3-yl)phenyl)-2-methylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-cyclohexyl-2-methylpropanamide;
N-isobutyl-2-(4-(5-isopropoxypyridin-3-yl)phenyl)-2-methylpropanamide;
(R)-N-(1-(4-methoxyphenyl)ethyl)-2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanamide, N-cyclohexyl-2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-2-rnethyl-N-propylpropanamide;
2-(4-(5-cyanopyridin-3-yl)phenyl)-N-(2-ethylbutyl)-2-methylpropanamide, 2-(2'-formyl-5'-(hydroxymethyl)biphenyl)-N-isobutyl-2-methyIpropanamide; and 2-(biphenyl-4-yl)-N-isobutylbutanamide, or comestibly acceptable salt thereof.

125. The method of claim 1, wherein Ar1 has the formula:
wherein m is selected from the integers 0, 1, 2, or 3.

126. The method of claim 1, wherein Ar1 has the formula:
wherein m is selected from the integers 0, 1, 2, or 3,

127. The method of claim 1, wherein Ar2 has the formula:
wherein m' is selected from the integers 0, 1, or 2.

128. The amide compound of claim 71 or a comestibly acceptable salt thereof, wherein Ar1 has the structure:
wherein m is selected from the integers 0 or 1.

129. The sweet comestible or medicinal product of claim 96, wherein Ar1 is pyridinyl or a heteroaryl unit having the formula:

wherein m is selected from the integers 0, 1, 2, or 3.

130, The sweet comestible or medicinal product of claim 98, wherein Ar2 is pyridinyl, pyrimidinyl, pyrazinyl, or a heteroaryl unit having the formula:
wherein m is selected from the integers 0, 1, or 2.

131. The sweet comestible or medicinal product of claim 100, wherein Ar1 is pyridinyl or a heteroaryl unit having the formula:

wherein m is selected from the integers 0, 1, 2 or 3,

132, The sweet comestible or medicinal product of claim 100, wherein Ar2 is pyridinyl, pyrimidinyl, pyrazinyl, or a heteroaryl unit having the formula:
wherein rn is selected from the integers 0, 1, or 2.