Novel flavor modulating compounds

Abstract

The present invention relates to novel pyrazolo[1,5-a]pyrimidine derivatives and their uses as flavor modulating materials.

Description

[0001] NOVEL FLAVOR MODULATING COMPOUNDS

[0002] Status of Related Application

[0003] This application claims priority to U. S. Provisional Patent Application No. 63 / 709542, filed October 21, 2024, the contents hereby incorporated by reference as if set forth in its entirety.

[0004] Field of the Invention

[0005] The present invention relates to novel flavor modulating compounds and their use in providing flavor properties in flavor compositions.

[0006] Background of the Invention

[0007] Food industry has made significant effort to modify and harmonize taste in food products. The basic categories of taste include salty, sweet, sour, bitter and umami. The discovery of novel flavor modulating compounds that modify these basic tastes enables the creation of desirable flavors.

[0008] Those with skill in the art appreciate how small differences in molecular structures can result in significant differences in compound notes and flavor properties. These distinctive properties can be highly valuable as they provide unique and distinguished characters to flavor compositions. However, many of these distinctive properties can also be undesirable and, thus, would render molecules not suited for flavor use. Thus, those skilled in the art would recognize that the discovery and development of a novel modulator suitable for flavor use is unpredictable. Summary of the Invention

[0009] The present invention provides novel chemicals, and their use to modulate the flavor of foodstuff, chewing gums, dental and oral hygiene products, medicinal products and the like.

[0010] Specifically, the present invention relates to a novel flavor modulating compound, a pyrazolo[1,5-a]pyrimidine derivative, represented by Formula I set forth below:

[0011]

[0012] Formula I

[0013] wherein R1represents H, a C1-20 alkyl, a C3-10 cycloalkyl, a C3-10 heterocyclyl, a C3-10 aryl or a C3-10 heteroaryl, wherein the C1-10 alkyl, the C3-10 cycloalkyl, the C3-10 heterocyclyl, the C3-10 heterocyclyl ary l or the C3-10 heterocyclyl heteroaryl is optionally substituted with one or more substituents selected from the group consisting of a halogen, a chalcogen, an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;

[0014] R2represents a piperazinyl, a piperidinyl or an amino ethyl sulfonamide, wherein the piperazinyl is selected from the group consisting of a sulfonyl piperazinyl, an acyl piperazinyl, an alkoxyl piperazinyl, a carboxy alkyl piperazinyl and an amino piperazinyl; the piperidinyl is selected from the group consisting of a sulfonyl piperidinyl, an acyl piperidinyl, an alkoxyl piperidinyl, a carboxy alkyl piperidinyl and an amino piperidinyl; and

[0015] R3represents H, a C1-20 alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0-(Ci-io)alkyl. More specifically, the present invention relates to a novel flavor modulating compound, a pyrazolo[l,5-«]pyrimidine derivative, represented by Formula II. a subset of Formula I, set forth below:

[0016]

[0017] Formula II

[0018] wherein R1represents a benzene or a pyridine, wherein the benzene or the pyridine is optionally substituted with one or more substituents selected from the group consisting of an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;

[0019] R2represents a C1-10 alkyl, a C3-10 cycloalkyl and a C3-10 aryl; and

[0020] R3represents H, a Ci-io alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0-(Ci-io alkyl).

[0021] Another embodiment of the present invention relates to a flavor composition comprising an olfactory acceptable amount of a compound of Formula I.

[0022] Another embodiment of the present invention relates to a method of modulating a flavor composition comprising the step of adding to the flavor composition an olfactory acceptable amount of a compound of Formula I.

[0023] Another embodiment of the present invention relates to a flavor product comprising an olfactory acceptable amount of a compound of Formula I.

[0024] These and other embodiments of the present invention will be apparent by reading the following specification. Detailed Description of the Invention

[0025] The present invention relates to novel compounds represented by Formula I and Formula II set forth above and their advantageous use in modulating taste in flavor compositions.

[0026] The present invention relates to, for example, but not limited to, the following structures:

[0027]

[0028]

[0029]

[0030]

[0031] Those with skill in the art will recognize that the compounds of the present invention may contain chiral centers, thereby providing a number of stereoisomers of the claimed compounds. It is intended herein that the compounds of the present invention include isomeric mixtures as well as individual isomers that may be separated using techniques known to those having skill in the art. Suitable techniques include chromatography such as high performance liquid chromatography, referred to as HPLC, particularly silica gel chromatography, and gas chromatography trapping known as GC trapping. Yet, commercial versions of such products are mostly offered as mixtures.

[0032] The pyrazolo[1,5-a]pyrimidine derivatives of Formula I can be prepared, for example, via a general scheme depicted as follows:

[0033]

[0034] wherein t-BuOK represents potassium tert-butoxide; and wherein R’, R3and R3are defined the same as above.

[0035] Tire present invention has identified novel pyrazolo[l,5-<7]pyrimidine derivatives and their inventive use in providing and / or enhancing umami perception of meatiness, savory deliciousness, richness, saltiness, sweetness and / or kokumi sensation in consumables. Pyrazolo[ 1,5 -a] pyrimidine derivatives can each be used alone, in combinations thereof or in further combinations with additional umami compounds. Pyrazolo[ 1,5 -a ]pyrimidine derivatives can also be used with other flavor compositions, solvents, adjuvants and the like.

[0036] Additional umami compounds may include, for example, but not limited to, glutamate, ribonucleotides and salts thereof. Glutamate includes, for example, but not limited to, monosodium glutamate (MSG) (CAS No. 142-47-2), potassium glutamate and calcium glutamate. Ribonucleotides such as 5 ’-ribonucleotides include, for example, but not limited to. guanosine 5’-monophosphate (GMP), inosine 5 ’-monophosphate (IMP), adenosine 5 ’-monophosphate (AMP) and 5 '-ribonucleotide sodium (CAS No. 80702-47-2) (disodium 5′-GMP and disodium 5'-IMP). Some other umami compounds include N-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]cyclopropanecarboxamide (CAS No. 744251-93-2), 2-methyl-2-(l-methylcyclohexyl)propenamide and 1-tert-butylcyclohexane carboxamide (WO 2024123607). When the compounds of the present invention are used in a flavoring composition, they can be combined with other conventional flavoring materials or adjuvants, which are well known in the art and have been extensively described in the past. Conventional flavoring materials include saturated fatty acids, unsaturated fatty acids, amino acids; alcohols including primary and secondary alcohols; esters; carbonyl compounds including ketones; aldehydes; lactones; cyclic organic materials including benzene derivatives, acyclic compounds, heterocyclies such as furans, pyridines, pyrazines and the like; sulfur-containing compounds including thiols, sulfides, disulfides and the like; proteins; lipids; carbohydrates; so-called flavor potentiators such as monosodium glutamate; magnesium glutamate, calcium glutamate, guanylates and inosinates; natural flavoring materials such as hydrolyzates, cocoa, vanilla and caramel: essential oils and extracts such as anise oil, clove oil and the like; and artificial flavoring materials such as vanillin, ethyl vanillin and the like. Requirements for adjuvants include: (1) that they be non-reactive with the compounds of the present invention; (2) that they be organoleptically compatible with the compounds of the present invention, whereby the flavor of tire ultimate consumable product to which the compounds of the present invention are added is not detrimentally affected by the use of the adjuvants; and (3) that they be ingestible acceptable and thus nontoxic or otherwise non -deleterious. In addition, other flavor materials, vehicles, stabilizers, thickeners, surface active agents, conditioners and flavor intensifiers can also be included.

[0037] The term "foodstuff as used herein includes both solid and liquid ingestible materials for man or animals, which materials usually do, but need not, have nutritional value. Thus, foodstuffs include meats, gravies, soups, convenience foods, malt, alcoholic and other beverages, milk and dairy products, seafood, including fish, crustaceans, mollusks and the like, candies, vegetables, cereals, soft drinks, snacks, dog and cat foods, other veterinary products and the like.

[0038] The terms "‘flavor composition;’ “flavor formulation,” “flavor modulating composition” and "‘flavor modulating formulation” mean the same and refer to a composition that produces a pleasant or desired flavor. The flavor composition contains a compound or a mixture of compounds. The flavor composition of the present invention comprises a compound of Formula I of the present invention.

[0039] The term “flavor product” means a product containing a compound of the present invention and further a foodstuff, a chewing gum, a dental product, an oral hygiene product or a medicinal product. As used herein, the term “a” or “an” is understood to mean one or more. The term “a compound” is understood to mean one or more of the compounds represented by Formula I. The term “a substituent” is understood to mean one or more substitutes in Formula I as described herein.

[0040] The term “modulating” is understood to mean improving, enhancing and / or modifying, wherein the term “improving” is understood to mean raising a flavor composition to a more desirable character, the term “enhancing” is understood to mean making the flavor composition greater in effectiveness or providing the flavor composition with an improved character, and the term “modifying” is understood to mean providing the flavor composition with a change in character.

[0041] Tire tenns “synergistic flavor effect” or “synergistic umami” mean the same and refer to the interaction between two or more components or chemicals when the combined umami effect is larger than the sum of the umami effect of the individual components. In one embodiment, the synergistic flavor effect of the present invention refers to the synergistic umami effect of two or more pyrazolo[l,5-«]pyrimidine derivatives of Formula I. In another embodiment, the synergistic flavor effect of the present invention refers to the synergistic umami effect of a pyrazolo[l,5-o]pyrimidine derivative of Formula I and an additional umami compound such as a glutamate, for example, monosodium glutamate (MSG): a ribonucleotide, for example, inosine monophosphate (IMP), guanosine monophosphate (GMP). disodium inosinate or disodium guanylate; N-[(2E)-3,7-dimethyl-2,6-octadien-1-yl]cyclopropanecarboxamide. 2-methyl-2-(l-methylcyclohexyl)propenamide and 1-tert-butylcyclohexane carboxamide, a salt thereof and / or a mixture thereof.

[0042] The term “olfactory acceptable amount” is understood to mean the amount of a compound in a flavor composition, wherein the compound will contribute its individual olfactory characteristics. However, the olfactory effect of the flavor composition will be the sum of effect of each of the flavor ingredients. Thus, the compound of the present invention can be used to improve or enhance the aroma characteristics of the flavor composition, or by modifying the olfactory reaction contributed by other ingredients in tire composition. Tire olfactory’ acceptable amount may vary depending on many factors including other ingredients, their relative amounts and the olfactory effect that is desired. Generally, the olfactory acceptable amount of the compounds of the present invention employed in a flavor composition is greater than about 10 parts per trillion by weight, preferably from about 1 part per billion to about 500 parts per million by weight and more preferably from about 10 parts per billion to about 50 parts per million by weight. Those with skill in the art will be able to employ the desired amount to provide desired flavor effect and intensity. In addition to the compounds of the present invention, other materials can also be used in conjunction with the flavor composition to encapsulate and / or deliver the flavor. Some well-known materials are, for example, but not limited to, polymers, oligomers, other non-polymers such as surfactants, emulsifiers, lipids including fats, waxes and phospholipids, organic oils, mineral oils, petrolatum, natural oils, perfume fixatives, fibers, starches, sugars and solid surface materials such as zeolite and silica.

[0043] Some preferred polymers include polyacrylate, polyurea, polyurethane, polyacrylamide, polyester, polyether, polyamide, poly(acrylate-co-acrylamide), starch, silica, gelatin and gum Arabic, alginate, chitosan, polylactide, poly(melamine-formaldehyde), poly(urea-formaldehyde), or a combination thereof.

[0044] The following are provided as specific embodiments of the present invention. Other modifications of this invention will be readily apparent to those skilled in the art. Such modifications are understood to be within the scope of this invention. As used herein all percentages are weight percent unless otherwise noted, ppt is understood to stand for parts per trillion, ppb is understood to stand for parts per billion, ppm is understood to stand for parts per million, L is understood to be liter, mL is understood to be milliliter, Kg is understood to be kilogram, g is understood to be gram, mol is understood to be mole, mmol is understood to be millimole, and M is understood to be molar. IFF as used in the examples is understood to mean International Flavors & Fragrances Inc.. New York. NY, USA. EXAMPLE I

[0045]

[0046] 1-(o-tolyl)ethan-1-one ethyl 3-oxo-3-(o-tolyl)propanoate ethyl 3-hydroxy-3-(o-tolyl)acrylate

[0047] Preparation of ethyl 3-oxo-3-(o-tolyl)propanoate and ethyl 3-hydroxy-3-(o-tolyl)acrylate mixture: To a 2-L flame dried flask was charged with anhydrous toluene (600 mL) and potassium tert-butoxide (t-BuOK) (90.0 g, 0.80 mol) at room temperature. After the suspension was stirred at room temperature for 15-30 minutes, diethyl carbonate ((C₂H₅O)₂CO) (95.0 g, 0.80 mol) was added dropwise via an additional funnel. The speed of adding diethyl carbonate was controlled and external cooling was applied to keep the reaction temperature below 30 °C. The reaction mixture was subsequently stirred at room temperature for 15-20 minutes and heated to 80 °C. 1-(o-Tolyl)ethan-l-one (C₉H₁₀O) (54.0 g, 0.40 mol) was added dropwise via an additional funnel over a period of 1 hour. The reaction mixture was then heated under reflux for 1 hour. After the reaction completed as indicated by GC, liquid chromatography-mass spectrometry (LC-MS) and thin layer chromatography (TLC), the reaction mixture was cooled down to room temperature, quenched with acetic acid (CH3COOH) (52.8 g, 0.88 mol, 1.1 equivalent) with an ice water bath and diluted with brine. The organic layer was separated, washed twice with brine, dried over sodium sulfate (Na2SO4) and filtered. After evaporation of the solvent, the residue was purified by distillation under reduced pressure to provide a mixture of ethyl 3-oxo-3-(o-tolyl)propanoate and ethyl 3-hydroxy-3-(o-tolyl)acrylate with a weight ratio of about 4: 1 as a clear liquid (103-105 °C at 0.4 torr) (79.0 g).

[0048] ¹H NMR (400 MHz, CDCl₃) δ: 12.51 (s, 0.2H), 7.65 (m, 0.8H), 7.39 (m, 1H), 7.26 (m, 2H), 7.19 (m, 0.2H), 5.28 (s, 0.2H), 4.16-4.28 (m, 2H), 3.83 (s, 1.6H), 2.53 (s, 3H), 1.23-1.31 (m, 3H). MS 207 (MH⁺). EXAMPLE II

[0049]

[0050] ethyl 3-oxo-3-(o-tolyl) ethyl 3-hydroxy-3-(o-tolyl) 2-propyl-5-(o-tolyl)pyrazolo[1,5-a] propanoate acrylate pyrimidin-7(4H)-one

[0051] Preparation of 2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one: To an acetic acid solution of the ethyl 3-oxo-3-(o-tolyl)propanoate and ethyl 3 -hydroxy-3 -(o-tolyl)acrylate mixture (10.31 g, 50.0 mmol; obtained in Example I) (100 mL) was added 3-propyl-1H-pyrazol-5-amine (6.27 g, 50.0 mmol) in small portions at room temperature. The reaction mixture was stirred at room temperature for 2 hours, heated to 80 °C and stirred for 3 hours, and then heated under reflux at 130 °C with an oil bath for 6-10 hours. After the reaction completed as indicated by LC-MS and TLC, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure to remove most of the solvent. The resultant reaction mixture was left at room temperature overnight. The precipitate was then collected by filtration, washed with hexane in ethyl acetate (EtOAc) (25%). and dried under vacuum overnight to provide 2-propyl-5-(o-tolyl)pyrazolo[l,5-a]pyrimidin-7(4 / 7)-one as a white solid (10.61 g).

[0052] ¹H NMR (400 MHz, DMSO-d₆) δ: 12.12 (s, 1H), 7.43-7.47 (m, 4H), 5.71 (s, 1H), 5.51 (s, 1H), 2.74 (t, 2H), 2.33 (s, 3H), 1.79 (m, 2H), 0.96 (t, 3H). MS 268 (MH+). EXAMPLE III

[0053]

[0054] 2-propyl-5-(o-tolyl)pyrazolo[1,5-a] 7-chloro-2-propyl-5-(o-tolyl)pyrazolo[1,5- pyrimidin-7(4 / - / )-one a]pyrimidine

[0055] Preparation of 7-chloro-2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine: To an anhydrous acetonitrile solution of 2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (2.68 g, 10.0 mmol; obtained in Example II) (20 mL) was added anhydrous pyridine (0.80 g, 10.0 mmol). Phosphorus oxychloride (POCl₃) (1.54 g, 10.0 mmol) was then added dropwise via a syringe at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction completed as indicated by LC-MS and TLC, the reaction mixture was quenched with crushed ice using an ice-water bath and the suspension was stirred at 0 °C for 30 minutes. The solid was subsequently collected by filtration, washed with cold water and dried under vacuum overnight to provide the crude product of 7-chloro-2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine as a pale yellow solid (2.79 g). EXAMPLE IV

[0056]

[0057] 7-chloro-2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine 7-(4-(methylsulfonyl)piperazin-1-yl)-2-propyl-5-(o- tolyl)pyrazolo[1,5-a]pyrimidine Preparation of 7-(4-(methylsulfonyl)piperazin-l-yl)-2-propyl-5-(o-tolyl)pyrazolo[l,5-ajpyrimidine (Compound 3): To a 250-mL dry flask was added 7-chloro-2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (2.86 g, 10.0 mmol; obtained in Example III) and anhydrous dimethylformamide (DMF) (50 mL). l-(Methylsulfonyl)-piperazine (1.65 g, 10.0 mmol) and N,N-diisopropylethylamine (DIPEA) (2.59 g, 20.0 mmol) were subsequently added at room temperature. The reaction mixture was stirred at room temperature overnight. After the reaction completed as indicated by LC-MS and TLC, the reaction mixture was concentrated under reduced pressure, the residue was titrated with EtOAc (500 mL) and brine (100 ml). The organic layer was separated, washed with brine three times, dried over Na₂SO₄ and filtered. The solvent was evaporated. The resultant residue was purified by crystallization from hexane in EtOAc and further recrystallization from EtOH in water to provide 7-(4-(methylsulfonyl)piperazin-l-yl)-2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine as a white or pale yellow solid (3.70 g).

[0058] ¹H NMR (400 MHz, DMSO-d₆) δ: 7.50 (d, J=7.96 Hz, 1H), 7.33 (m, 3H), 6.53 (s, 1H), 6.49 (s, 1H), 3.86 (m, 4H), 3.36 (m, 4H), 2.97 (s, 3H), 2.71 (m, 2H), 2.40 (s, 3H), 1.71 (m, 2H), 0.94 (m, 3H). MS 414 (MH+). EXAMPLE V

[0059] A series of water solutions of Compound 3 (prepare as in EXAMPLE IV) were prepared and evaluated for flavor. The flavor profile is reported in the following:

[0060]

[0061] EXAMPLE VI

[0062] A monosodium glutamate (MSG) solution (5000 ppm) was prepared in water. The flavor profile of the MSG solution with added Compound 3 is reported in the following:

[0063]

[0064] EXAMPLE VII

[0065] A salt solution containing sodium chloride (75%), MSG (16.8%), Ribotide® (0.7%) and maltodextrin (7.5%) was prepared in water. The flavor profile of the salt solution with added Compound 3 is reported in the following:

[0066]

[0067] EXAMPLE VIII

[0068] The following compounds were similarly prepared.

[0069] 7-(4-(Methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 1) ¹H NMR (400 MHz, DMSO-d₆) δ: 8.20 (d, J=2.2 Hz, 1H), 7.52 (m, 1H), 7.34 (m, 3H), 6.62 (d, J=2.2 Hz, 1H), 6.51 (s, 1H), 3.90 (m, 4H), 3.37 (m, 4H), 2.97 (s, 3H), 2.41 (s, 3H). MS 372 (MH+). Compound 1 (15 ppm in water) exhibited umami taste.

[0070] 2-Methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 2) ¹H NMR (400 MHz, DMSO-d₆) δ: 7.50 (m, 1H), 7.33 (m, 3H), 6.42 (s, 1H), 6.39 (m, 1H), 3.88 (m, 4H), 3.36 (m, 4H), 2.97 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H). MS 386 (MH+).

[0071] Compound 2 (3 ppm in water) exhibited strong umami taste.

[0072] 2-Isopropyl-7-(4-(methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 4) ¹H NMR (400 MHz, DMSO-d₆) δ: 7.49 (m, 1H), 7.33 (m, 3H), 6.43 (s, 1H), 6.42 (s, 1H), 3.89 (m, 4H), 3.36 (m, 4H), 3.10 (sep, J=6.9 Hz, 1H), 2.96 (s, 3H), 2.40 (s, 3H), 1.33 (d, J=6.9 Hz, 6H). MS 414 (MH+).

[0073] Compound 4 (375 ppb) enhanced the umami taste of the above base solution (0.5%).

[0074] 2-(tert-Butyl)-7-(4-(methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 5) ¹H NMR (500 MHz, DMSO-d₆) δ: 7.49 (m, 1H), 7.32 (m. 3H), 6.47 (s, 1H), 6.41 (s, 1H), 3.91 (m, 4H), 3.37 (m, 4H), 2.97 (s, 3H). 2.40 (s. 3H), 1.39 (s, 9H). MS 428 (MH+).

[0075] Compound 5 (375 ppb) enhanced the umami taste of the above base solution (0.5%).

[0076] 2-Methoxy-7-(4-(methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 6) ¹H NMR (400 MHz, DMSO-d₆) δ: 7.49 (m, 1H), 7.32 (m, 3H), 6.41 (s, 1H), 6.02 (s, 1H), 3.96 (s, 3H), 3.86 (m, 4H), 3.35 (m, 4H), 2.96 (s, 3H). 2.40 (s. 3H). MS 402 (MH+).

[0077] Compound 6 (50 ppb in water) exhibited umami taste. 2-Ethoxy-7-(4-(methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 7) ¹H NMR (400 MHz, DMSO-d₆) δ: 7.49 (m. 1H), 7.32 (m, 3H). 6.40 (s. 1H), 6.01 (s, 1H). 4.30 (q, J=7.0 Hz, 2H), 3.85 (m, 4H), 3.34 (m, 4H), 2.96 (s, 3H), 2.40 (s, 3H), 1.39 (t, J=7.0 Hz, 3H). MS 416 (MH+).

[0078] Compound 7 (375 ppb in water) exhibited superior umami taste. Compound 7 (350 ppb) also enhanced the umami taste of the above base solution (0.5%).

[0079] 2-Isopropoxy-7-(4-(methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 8) ¹H NMR (600 MHz, CDCl₃) δ: 7.44 (m, 1H), 7.34 (m, 1H), 7.31 (m, 2H), 6.17 (s, 1H), 6.00 (s, 1H), 4.87 (sep, J=6.1 Hz, 1H), 3.83 (m, 4H), 3.52 (m, 4H), 2.88 (s, 3H), 2.44 (s, 3H), 1.48 (d, J=6.1 Hz, 6H). MS 430 (MH+).

[0080] Compound 8 (375 ppb) enhanced the umami taste of the above base solution (0.5%).

[0081] 2-Bromo-7-(4-(methylsulfonyl)piperazin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 9) ¹H NMR (500 MHz, DMSO-d₆) δ: 7.37 (m, 4H), 6.78 (s, 1H), 6.57 (s, 1H), 3.87 (m, 4H), 3.36 (m, 4H), 2.97 (s, 3H), 2.41 (s, 3H). MS 451. 453 (MH+).

[0082] 7-(4-(Methylsulfonyl)piperazin-1-yl)-5-(m-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 10) ¹H NMR (400 MHz, DMSO-d₆) δ: 8.18 (d, J=2.3 Hz, 1H), 8.01 (m, 2H), 7.38 (m, 2H), 6.90 (s, 1H), 6.64 (d, J=2.3 Hz, 1H), 3.95 (m, 4H), 3.39 (m, 4H), 2.98 (s, 3H), 2.43 (s, 3H). MS 372 (MH+).

[0083] 7-(4-(Methylsulfonyl)piperazin-1-yl)-5-(p-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 11) ¹H NMR (400 MHz, DMSO-d₆) δ: 8.16 (d, J=2.2 Hz, 1H), 8.11 (m. 2H), 7.34 (m, 2H). 6.89 (s, 1H), 6.61 (d, J=2.2 Hz, 1H), 3.94 (m, 4H), 3.38 (m, 4H), 2.97 (s, 3H), 2.39 (s, 3H). MS 372 (MH+).

[0084] 5-(2-Ethylphenyl)-7-(4-(methylsulfonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (Compound 12) ¹H NMR (400 MHz, DMSO-d₆) δ: 8.19 (d, J=2.3 Hz, 1H), 7.38 (m, 4H), 6.60 (d, J=2.3 Hz, 1H), 6.47 (s, 1H), 3.90 (m, 4H), 3.36 (m, 4H), 2.97 (s. 3H), 2.77 (q. J=7.5 Hz, 2H), 1.11 (t. J=7.5 Hz, 3H). MS 386 (MH+).

[0085] Compound 12 (5 ppm in water) exhibited strong umami taste. 5-(2-Methoxyphenyl)-7-(4-(methylsulfonyl)piperazin-l-yl)pyrazolo[1,5-a]pyrimidine (Compound 13)

[0086] 'H NMR (400 MHz, DMSO-de) 8: 13.65 (br s, 1H). 8.21 (d. J=2.3 Hz, 1H), 8.17 (m, lH).7.38 (m, 1H), 6.97 (m, 3H), 6.69 (d, J=2.3 Hz, 1H), 4.02 (m, 4H), 3.39 (m, 4H), 2.97 (s, 3H). MS 388 (MH+). Compound 13 (15 ppm in water) exhibited umami taste.

[0087] 2-Isopropyl-5 -(2-methoxyphenyl)-7-(4-(methylsulfonyl)piperazin- 1 -yl)pyrazolo [ 1,5 -a] pyrimidine (Compound 14)

[0088] 'H NMR (400 MHz, DMSO-d6) 5: 7.82 (m, 1H). 7.43 (m, 1H), 7.10 (m. 1H), 7.03 (m. 1H), 6.69 (s, 1H), 6.49 (s, 1H), 3.89 (s, 3H), 3.86 (m, 4H), 3.55 (m, 4H), 3.19 (sep, J=6.9 Hz, 1H), 2.88 (s, 3H), 1.39 (d, J=6.9 Hz, 6H). MS 430 (MH+).

[0089] Compound 14 (375 ppb) enhanced the umami taste of tire above base solution (0.5%).

[0090] 2-Cyclopropyl-5-(2-methoxyphenyl)-7-(4-(methylsulfonyl)piperazin-l-yl)pyrazolo[1.5-a]pyrimidine (Compound 15)

[0091] 'H NMR (400 MHz, DMSO-d6) 8: 7.75 (m, 1H), 7.45 (m, 1H), 7.17 (m, 1H), 7.07 (m, 1H), 6.77 (s, 1H), 6.30 (s, 1H), 3.88 (s, 3H), 3.82 (m, 4H), 3.38 (m, 4H), 2.97 (s, 3H), 2.09 (m, 1H), 1.03 (m, 2H), 0.87 (m, 2H). MS 428 (MH+).

[0092] Compound 15 (375 ppb) enhanced the umami taste of the above base solution (0.5%).

[0093] 5-(2-ethoxyphenyl)-7-(4-(methylsulfonyl)piperazin-l-yl)pyrazolo[l,5-a]pyrimidine (Compound 16)

[0094] 'H NMR (500 MHz, DMSO-de) 8: 8.18 (m, 1H), 7.87 (m, 1H), 7.45 (m, 1H), 7.18 (m, 1H), 7.08 (m, 1H), 7.03 (s, 1H), 6.64 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.83 (m, 4H), 3.39 (m, 4H), 2.98 (s, 3H), 1.41 (t. J=7.0 Hz, 3H)). MS 402 (MH+).

[0095] Compound 16 (15 ppm in water) exhibited umami taste.

[0096] 5-(2-fluorophenyl)-7-(4-(methylsulfonyl)piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (Compound 17)

[0097] 'HNMR (500 MHz, DMSO-de) 8: 8.23 (m, 1H), 7.97 (m, 1H), 7.56 (m, 1H), 7.37(Compound 17) (m, 2H), 6.74 (m, 1H), 6.68 (m, 1H), 3.91 (m, 4H), 3.38 (m, 4H), 2.97 (s, 3H). MS 376 (MH+). Compound 17 (15 ppm in water) exhibited strong umami taste. 7-(4-(Methylsulfonyl)piperazin-l-yl)-5-(2-(methylthio)phenyl)pyrazolo[l,5-a]pyriniidine (Compound 18)

[0098] 'H NMR (400 MHz, DMSO-d6) 5: 8.21 (d, J=2.2 Hz, 1H). 7.58 (m, 1H), 7.45 (m. 2H), 7.29 (m, 1H), 6.62 (d, J=2.2 Hz, 1H), 6.58 (s, 1H), 3.90 (m, 4H), 3.37 (m, 4H), 2.97 (s, 3H), 2.41 (s, 3H). MS 404 (MH+).

[0099] Compound 18 (15 ppm in water) exhibited umami taste.

[0100] 7-(4-(Methylsulfonyl)piperazin-1-yl)-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine (Compound 19) 'H NMR (400 MHz, DMSO-d6) 5: 8.75 (m, 1H), 8.46 (m. 1H), 8.23 (d, J=2.2 Hz. 1H), 8.00 (m, 1H), 7.54 (m, 1H), 7.42 (s, 1H), 6.73 (d, J=2.2 Hz, 1H), 3.93 (m, 4H), 3.41 (m, 4H), 2.98 (s, 3H). MS 359 (MH+).

[0101] 7-(4-(Ethylsulfonyl)piperazin- 1 -yl)-2 -methyl -5 -(o-tolyl)pyrazolo [ 1,5 -a] pyrimidine (Compound 20)

[0102] 'H NMR (400 MHz, DMSO-d6) 5: 7.49 (m, 1H), 7.33 (m, 3H), 6.42 (s, 1H), 6.39 (m, 1H), 3.85 (m, 4H), 3.42 (m, 4H), 3.15 (q, J=7.3 Hz, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 1.26 (t, J=7.3 Hz, 3H). MS 400 (MH+).

[0103] Compound 20 (15 ppm in water) exhibited umami taste.

[0104] 2-Methyl-7-(4-(propylsulfonyl)piperazin-l-yl)-5-(o-tolyl)pyrazolo[l,5-a]pyrimidine (Compound 21)

[0105] 'H NMR (400 MHz, DMSO-d6) 5: 7.50 (m, 1H), 7.33 (m, 3H), 6.42 (s, 1H), 6.39 (m, 1H), 3.85 (m, 4H), 3.40 (m, 4H), 3.11 (m, 2H), 2.43 (s, 3H), 2.40 (s, 3H), 1.73 (m, 2H), 1.00 (t, J=7.3 Hz, 3H). MS 414 (MH+).

[0106] Compound 21 (15 ppm in water) exhibited strong umami taste.

[0107] 7-(4-(Butylsulfonyl)piperazin-l-yl)-2-methyl-5-(o-tolyl)pyrazolo[l,5-a]pyrimidine (Compound 22)

[0108] 'H NMR (500 MHz, DMSO-d6) 8: 7.49 (m, 1H), 7.32 (m, 3H), 6.38 (m, 2H), 3.88 (m, 4H), 3.43 (m, 4H), 3.11 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H), 1.71 (m, 2H), 1.45 (m, 2H), 0.93 (t, J=7.3 Hz, 3H). MS 428 (MH+).

[0109] Compound 22 (15 ppm in water) exhibited umami taste. 7-(4-(Phenylsulfonyl)piperazin-l-yl)-5-(o-tolyl)pyrazolo[l,5-a]pyrimidine (Compound 23) 'H NMR (500 MHz, DMSO-d6) 5: 8.14 (m, 1H). 7.81 (m, 2H), 7.77 (m, 1H), 7.69 (m. 2H), 7.45 (m, 1H), 7.32 (m, 3H), 6.58 (m, 1H). 6.45 (s. 1H), 3.87 (m, 4H). 3.13 (m, 4H), 2.35 (s, 3H). MS Compound 23 (15 ppm in water) exhibited umami taste.

[0110] l-(4-(5-(2-Fluorophenyl)pyrazolo[l,5-a]pyrimidin-7-yl)piperazin-l-yl)ethan-l-one (Compound 24)

[0111] 'H NMR (500 MHz, DMSO-d6) 5: 8.22 (m, 1H). 7.97 (m, 1H), 7.55 (m, 1H), 7.37 (m. 2H), 6.70 (m, 1H), 6.67 (m, 1H), 3.77 (m. 8H), 2.09 (s, 3H). MS 340 (MH+).

[0112] 7-(1-(Methylsulfonyl)piperidin-4-yl)-2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 25)

[0113] 'H NMR (400 MHz, DMSO-d6) 8: 7.53 (m, 1H), 7.35 (m, 3H), 7.03 (s, 1H), 6.58 (s, 1H), 3.74 (m, 2H), 3.64 (m, 1H), 2.99 (m. 2H), 2.94 (s, 3H), 2.78 (t, J=7.3 Hz, 2H), 2.42 (s, 3H). 2.22 (m, 2H), 1.92 (m. 2H), 1.75 (m, 2H). 0.98 (t. J=7.3 Hz. 3H). MS 413 (MH+).

[0114] Compound 25 (375 ppb) enhanced the umami taste of the above base solution (0.5%).

[0115] N-( l-(5-(o-Tolyl)pyrazolo[ l,5-a]pyrimidin-7-yl)piperidin-4-yl)methanesulfonamide (Compound 26)

[0116] 'H NMR (400 MHz, DMSO-d6) 8: 8.17 (d, J=2.2 Hz, 1H). 7.49 (m, 1H), 7.33 (m. 3H), 7.24 (m, 1H), 6.56 (d, J=2.2 Hz, 1H), 6.42 (s, 1H), 4.41 (m, 2H), 3.50 (m, 1H), 3.21 (m, 2H), 2.98 (s, 3H), 2.40 (s, 3H), 2.02 (m, 2H), 1.67 (m, 2H). MS 386 (MH+).

[0117] 7-(4-Methoxypiperidin-1-yl)-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine (Compound 27)

[0118] 'H NMR (400 MHz, DMSO-d6) 8: 8.16 (d, J=2.2 Hz, 1H), 7.49 (m, 1H), 7.33 (m, 3H), 6.56 (d, J=2.2 Hz, 1H), 6.42 (s, 1H), 4.10 (m, 2H), 3.48 (m. 3H), 3.30 (s, 3H), 2.39 (s, 3H). 2.02 (m, 2H), 1.66 (m, 2H). MS 323 (MH+).

[0119] 1-(5-(o-Tolyl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxylic acid (Compound 28) 'H NMR (400 MHz, DMSO-d6) 8: 12.32 (s, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.49 (m, 1H), 7.33 (m, 3H), 6.55 (d, J=2.2 Hz, 1H), 6.42 (s, 1H), 4.38 (m, 2H), 3.20 (m, 2H), 2.59 (m, 1H), 2.40 (s, 3H), 2.01 (m. 2H), 1.78 (m, 2H). MS 337 (MH+). N-Ethyl-1-(5-(o-tolyl)pyrazolo[1,5-a]pyrimidin-7-yl)piperidine-4-carboxamide (Compound 29) 'H NMR (400 MHz, DMSO-d6) 5: 8.16 (d, J=2.2 Hz, 1H). 7.84 (m, 1H), 7.49 (m. 1H), 7.33 (m, 3H), 6.55 (d, J=2.2 Hz, 1H). 6.42 (s, 1H). 4.51 (m, 2H). 3.08 (m, 4H). 2.40 (m, 4H), 1.82 (m, 4H), 1.02 (t, J=7.2 Hz, 3H). MS 364 (MH+).

[0120] N-(2-((5-(o-tolyl)pyrazolo[l,5-a]pyrimidin-7-yl)amino)ethyl)methanesulfonamide (Compound 30) 'H NMR (400 MHz, DMSO-d6) 5: 8.12 (d, J=2.2 Hz, 1H). 8.01 (m, 1H), 7.47 (m, 1H), 7.32 (m, 4H), 6.45 (d, J=2.2 Hz, 1H), 6.30 (s, 1H), 3.55 (m, 2H), 3.24 (m. 2H), 2.90 (s, 3H), 2.39 (s, 3H). MS 346 (MH+).

[0121] Compound 30 (15 ppm in water) exhibited umami taste.

[0122] 2-((2-Ethoxy-5-(o-tolyl)pyrazolo[1,5-a]pyrimidin-7-yl)amino)-N,N-dimethylethane-1-sulfonamide (Compound 31)

[0123] 'H NMR (400 MHz, DMSO-de) 5: 7.67 (m. 1H), 7.45 (m. 1H), 7.31 (m. 3H), 6.21 (s, 1H), 5.87 (s, 1H), 4.31 (q, J=7.0 Hz, 2H), 3.80 (m. 2H), 3.45 (m. 2H), 2.78 (s. 6H), 2.39 (s, 3H), 1.38 (t, J=7.0 Hz, 3H). MS 404 (MH+).

[0124] Compound 31 (375 ppb) enhanced the umami taste of the above base solution (0.5%).

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:5Formula Iwherein R1represents H, a C1-20 alkyl, a C3-10 cycloalkyl, a C3-10 heterocyclyl, a C3- 10 aryl or a C3-10 heteroaryl, wherein the C1-10 alkyl, the C3-10 cycloalkyl, the C3-10 heterocyclyl, the C3-10 heterocyclyl aryl or the C3-10 heterocyclyl heteroaryl is optionally substituted with one or more substituents selected from the group consisting of a halogen, a chalcogen, an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;R2represents a piperazinyl. a piperidinyl or an amino ethyl sulfonamide, wherein the piperazinyl is selected from the group consisting of a sulfonyl piperazinyl, an acyl piperazinyl, an alkoxyl piperazinyl, a carboxy alkyl piperazinyl and an amino piperazinyl: the piperidinyl is selected from the group consisting of a sulfonyl piperidinyl, an acyl piperidinyl, an alkoxyl piperidinyl, a carboxy alkyl piperidinyl and an amino piperidinyl; andR3represents H, a C1-20 alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0- (Ci.io)alkyl.

2. Tire compound of claim 1, wherein the compound is represented by Formula II:wherein R1represents a benzene or a pyridine, wherein the benzene or the pyridine is optionally substituted with one or more substituents selected from the group consisting of an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;R2represents a C1-10 alkyl, a C3-10 cycloalkyl and a C3-10 and; andR3represents H, a C1-10 alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0- (C1-10 alkyl).

3. The compound of claim 2, wherein the compound is 7-(4-(methylsulfonyl)piperazin-l-yl)- 2-propyl-5 -(o-tolyl)pyrazolo [ 1,5 -r?]pyrimidine.

4. A flavor composition comprising an olfactory acceptable amount of a compound of Formula I:Formula Iwherein R1represents H, a C1-20 alkyl, a C3-10 cycloalkyl, a C3-10 heterocyclyl, a C3- 10 aryl or a C3-10 heteroaryl, wherein the C1-10 alkyl, the C3-10 cycloalkyl, the C3-10 heterocyclyl, the C3-10 heterocyclyl aryl or the C3-10 heterocyclyl heteroaryl is optionally substituted with one or more substituents selected from the group consisting of a halogen, a chalcogen, an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;R2represents a piperazinyl, a piperidinyl or an amino ethyl sulfonamide, wherein the piperazinyl is selected from the group consisting of a sulfonyl piperazinyl. an acyl piperazinyl, an alkoxyl piperazinyl, a carboxy alkyl piperazinyl and an amino piperazinyl; the piperidinyl is selected from the group consisting of a sulfonyl piperidinyl, an acyl piperidinyl, an alkoxyl piperidinyl, a carboxy alkyl piperidinyl and an amino piperidinyl; andR3represents H, a C1-20 alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0- (Ci.io)alkyl.

5. The flavor composition of claim 4, wherein the compound is represented by Formula II:Formula IIwherein R1represents a benzene or a pyridine, wherein the benzene or the pyridine is optionally substituted with one or more substituents selected from the group consisting of an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;R2represents a C1-10alkyl, a C3-10cycloalkyl and a C3-10aryl; and R3represents H, a C1-10 alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0- (C1-10 alkyl).

6. The flavor composition of claim 5, wherein the compound is 7-(4- (methylsulfonyl)piperazin-l-yl)-2-propyl-5-(o-tolyl)pyrazolo[l,5-<7]pyrimidine.

7. Tire flavor composition of claim 4, wherein the olfactory acceptable amount is greater than about 10 ppt by weight of the flavor composition.

8. The flavor composition of claim 4, wherein the olfactory acceptable amount is from about 10 ppt to about 10 ppm by weight of the flavor composition.

9. A method of modulating a flavor composition comprising the step of adding to the flavor composition an olfactory acceptable amount of a compound of Formula I:Formula Iwherein R1represents H, a C1-20 alkyl, a C3-10 cycloalkyl, a C3-10 heterocyclyl, a C3- 10 aryl or a C3-10 heteroaryl, wherein the C O alkyl, the C3-10 cycloalkyl, the C3-10 heterocyclyl, the C3-10 heterocyclyl aryl or the C3-10 heterocyclyl heteroaryl is optionally substituted with one or more substituents selected from the group consisting of a halogen, a chalcogen, an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;R2represents a piperazinyl, a piperidinyl or an amino ethyl sulfonamide, wherein the piperazinyl is selected from the group consisting of a sulfonyl piperazinyl, an acyl piperazinyl, an alkoxyl piperazinyl, a carboxy alkyl piperazinyl and an amino piperazinyl; the piperidinyl is selected from the group consisting of a sulfonyl piperidinyl, an acyl piperidinyl, an alkoxyl piperidinyl, a carboxy alkyl piperidinyl and an amino piperidinyl; andR3represents H, a C1.20 alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0- (Ci.io)alkyl.

10. The method of claim 9, wherein the compound is represented by Formula II:wherein R1represents a benzene or a pyridine, wherein the benzene or the pyridine is optionally substituted with one or more substituents selected from the group consisting of an alkyl, an -O-alkyl, a -S-alkyl, an alkenyl and an alkynyl;R2represents a C1-10 alkyl, a C3-10 cycloalkyl and a C3-10 aryl; and R3represents H, a C1-10 alkyl, a C3-10 cycloalkyl, a C3-10 aryl, a halogen or an -0- (C1-10 alkyl).

11. Tire method of claim 10, wherein the compound is 7-(4-(methylsulfonyl)piperazin-l-yl)- 2-propyl-5 -(o-tolyl)pyrazolo [ 1,5 -rz] pyrimidine.

12. The method of claim 9, wherein the olfactory acceptable amount is greater than about 10 ppt by weight of the flavor composition.

13. Tire method of claim 9, wherein the olfactory acceptable amount is from about 10 ppt to about 10 ppm by weight of the flavor composition.

14. A flavor product comprising the compound of claim 1.

15. A flavor product comprising the compound of claim 2.

16. A flavor product of claim 15. wherein the compound is 7-(4-(methylsulfonyl)piperazin-1-yl)-2-propyl-5-(o-tolyl)pyrazolo[1,5-a]pyrimidine.

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