Fragrance and flavor compositions comprising pyrazole derivatives

Abstract

The present application relates to 1,3-dimethyl-5-pyrazolecarboxylates, and related compounds, methods of making them, and methods of using them as flavor and fragrance ingredients in food, cosmetic, pharmaceutical, consumer, and other compositions and products.

Description

FRAGRANCE AND FLAVOR COMPOSITIONS COMPRISING PYRAZOLE DERIVATIVESCROSS-REFERENCE TO RELATED APPLICATIONSThis application is an international application which claims priority to, and the benefit of, U.S. Provisional Applic. Ser. No. 63 / 535,715, filed on Aug. 31, 2023, and U.S. Provisional Applic. Ser. No. 63 / 624,741, filed on Jan. 24, 2024, the contents of each of which are hereby incorporated by reference in their entireties.FIELD OF THE APPLICATION

[0001] The present application relates to l,3-dimethyl-5-pyrazole carboxylates, and related compounds, methods of making them, and methods of using them as flavor and fragrance ingredients in food, cosmetic, pharmaceutical, consumer, and other compositions and products.BACKGROUND

[0002] Scent is an important factor used to produce a sense of anticipation, quality, palatability, and security to many consumer products. Flavor is particularly important for foodstuffs. Identifying effective aromas and flavors to impart in a product is an element that contributes to the success of the product, and is useful in product marketing, consumer satisfaction, and consumer retention. Sweet, vanilla, waffle, floral, woody, warm, chocolate, blond wood, orris, and soft leather notes may be particularly desirable for certain flavors and fragrances and may be used in toiletries, cosmetics, household cleaners, room sprays, laundry, and fine fragrance applications, such as in perfumes and toilet water, dental hygiene products (such as toothpastes and mouthwashes), orally administered medications, and food products.

[0003] Considerable work is performed by many scientists relating to identifying new substances which can be used, alone or in combinations, to imparl to, or enhance, the aroma or flavor of various consumable materials, including, e.g., cosmetics, cleaners, and foodstuffs. While there may be some trends in the relationship between chemical structure and flavor or fragrance — such as common use of low molecular weight aldehydes and alcohols as flavors and fragrances — the precise aroma associated with a molecule is exceedingly difficult to predict. Small changes in structure, such a lengthening or shortening a functional group by just one carbon atom, can have profound and unexpected effects on a compound’s flavor or fragrance profile. The art of flavor and fragrance prediction is still in its infancy.

[0004] Using a proprietary predictive method, the inventors have also identified ethyl 1,3- dimethyl-5-pyrazolecarboxylate, as a new ingredient useful in flavors and fragrances. It is believed that this compound has not been previously identified as a flavor or fragrance ingredient, nor has it its smell or odor been previously described.

[0005] This application describes the surprising and unexpected olfactive qualities of 1,3- dimethyl-5-pyrazole carboxylates, and analogs and derivatives thereof, and their use as fragrance and flavor ingredients, and potential applications thereof.BRIEF SUMMARY

[0006] In one aspect, the application relates to compounds of Formula I:Formula I wherein;haloalkyl (e.g., CF3), or C3-6cycloalkyl (e.g., cyclopropyl);R2, R3, and R4are each independently selected from H, C1-6 alkyl (e.g., CH3), C3- 6cycloalkyl (e.g., cyclopropyl), C1-3haloalkyl (e.g., CF3), OC1-6alkyl (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR’, C(O)R, and CHO, or wherein R2and R3, or R3and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); provided that at least one of R2, R3, and R4is COOH, COOR, CONHR, CONRR’, C(O)R, or CHO; each R and R’ is independently C 1 -ealky 1 (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); andRais Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl);optionally provided that the compound is not ethyl l,3-dimethyl-5- pyrazolecarboxylate.

[0007] In some embodiments, the compound of Formula I is ethyl l,3-dimethyl-5- pyrazolecarboxylate.

[0008] In another aspect, the application relates to fragrance and flavor compositions comprising the compound of Formula I, optionally comprising one or more additives, additional fragrance or flavor ingredients, or a combination of additives and fragrance or flavor ingredients. In some embodiments, the application relates to fragrance and flavor compositions comprising ethyl l,3-dimethyl-5-pyrazolecarboxylate.

[0009] In another aspect, the application relates to products, such as consumer products, comprising such fragrance and flavor compositions comprising the compound of Formula I, e.g., products comprising ethyl l,3-dimethyl-5-pyrazolecarboxylate.

[0010] In another aspect, the present disclosure provides a method of making compound of Formula I.

[0011] The details of one or more embodiments of the application are set forth in the accompanying description below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the case of conflict, the present specification will control.

[0012] Other features and advantages of the application will be apparent from the following detailed description, examples, and claims.DETAILED DESCRIPTION

[0013] The inventors have unexpectedly found that ethyl l,3-dimethyl-5-pyrazolecarboxylate has a unique aroma and flavor characterized as having floral, chocolate, blond wood, orris, and soft leather notes, and a unique style. It has thus been determined that this compound would be useful in imparting and providing desirable aromas and / or flavors to the products to which it is added. Other Compounds of Formula I are expected to likewise have pleasant or desirable flavors and / or aromas. Such Compounds are therefore potentially useful for products where the inclusion of a pleasing fragrance or flavor is desired, including, but not limited to, perfumes, household products, laundry products, personal care products, cosmetics, dental hygiene products, orally administered medications, and food products. The Compounds of Formula I may be employed in varying amounts depending upon the specific fragrance or flavor product application, the nature and amount of other flavor or fragrance ingredients present, and the desired aroma and / or flavor of the product.

[0014] In a first aspect, the present disclosure provides a compound of Formula I (Compound1):wherein:R1is H, Ci-6 alkyl (e.g., CH3), C3-6cycloalkyl (e.g., cyclopropyl), or C1-3 haloalkyl (e.g., CF3);R2, R3, and R4are each independently selected from H, C1-6 alkyl (e.g., CH3), C3- ecycloalkyl (e.g., cyclopropyl), C1-3 haloalkyl (e.g., CF3), OC1-6alkyl (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR’, C(O)R, and CHO, or wherein R2and R3, or R3and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); provided that at least one of R2, R3, and R4is COOH, COOR, CONHR, CONRR’, C(O)R, or CHO; each R and R’ is independently C1-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); andRais Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); optionally provided that the compound is not ethyl l,3-dimethyl-5-pyrazolecarboxylate.

[0015] In further embodiments, of the first aspect, the present disclosure provides:1.1 Compound 1, wherein the compound is not ethyl l,3-dimethyl-5- pyrazolecarboxylate;1.2 Compound 1, wherein the compound is not a compound wherein:(a) R1is methyl or ethyl, R2is methyl or ethyl, R3is H, and R4is COOH;(b) R1is methyl or ethyl, R2is methyl or ethyl, R3is H, and R4is COOR, and R is methyl or ethyl;1.3 Compound 1, or any of 1.1 -1.2, wherein R1is H;Compound 1, or any of 1.1 -1.2, wherein R1is CH3; Compound 1, or any of 1.1 -1.4, wherein R2is H; Compound 1, or any of 1.1-1.4, wherein R2is C1-6 alkyl (e.g., CH3), C3- ecycloalkyl (e.g., cyclopropyl), C1-3 haloalkyl (e.g., CF3), or OC1-6alkyl (e.g., OCH3); Compound 1, or any of 1.1 -1.4, wherein R2is CH2OR, COOH, CONHR, CONRR’, or COOR; Compound 1, or any of 1.1-1.4, wherein R2is C(O)R or CHO; Compound 1, or any of 1.1 -1.8, wherein R3is H; Compound 1, or any of 1.1-1.8, wherein R3is C1-6 alkyl (e.g., CH3), C3- 6cycloalkyl (e.g., cyclopropyl), C1-3 haloalkyl (e.g., CF3), or OC1-6alkyl (e.g., OCH3); Compound 1, or any of 1.1-1.8, wherein R3is CH2OR, COOH, CONHR, CONRR’, or COOR; Compound 1, or any of 1.1 -1.8, wherein R3is C(O)R or CHO; Compound 1, or any of 1.1-1.12, wherein R4is H; Compound 1, or any of 1.1-1.12, wherein R4is C1-6 alkyl (e.g., CH3), C3- ecycloalkyl (e.g., cyclopropyl), C1-3 haloalkyl (e.g., CF3), or OC1-6alkyl (e.g., OCH3); Compound 1 , or any of 1.1 - 1.12, wherein R4is CH2OR, COOH, CONHR, CONRR’, or COOR; Compound 1, or any of 1.1-1.12, wherein R4is C(O)R or CHO; Compound 1, or any of 1.1-1.16, wherein R2and R3, or R3and R4, together with the carbon atoms to which they arc attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); Compound 1.17, wherein R2and R3, together with the carbon atoms to which they are attached, form an unsubstituted 5-8 membered (C5-8) cycloalkyl ring; Compound 1.17, wherein R3and R4, together with the carbon atoms to which they are attached, form an unsubstituted 5-8 membered (C5-8) cycloalkyl ring; Compound 1.17, wherein R2and R3, together with the carbon atoms to which they are attached, form a 5-8 membered (Cs-s) cycloalkyl ring substituted with one or more groups Rb(e.g., methyl);Compound 1.17, wherein R3and R4, together with the carbon atoms to which they are attached, form a 5-8 membered (Cs-s) cycloalkyl ring substituted with one or more groups Rb(e.g., methyl); Compound 1.17 or any of 1.18-1.21, wherein said 5-8 membered (Cs-s) cycloalkyl ring is selected from cyclopentyl and cyclohexyl; Compound 1.17, wherein R2and R3, together with the carbon atoms to which they are attached, form an unsubstituted heterocycloalkyl ring, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); Compound 1.17, wherein R3and R4, together with the carbon atoms to which they are attached, form an unsubstituted heterocycloalkyl ring, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); Compound 1.17, wherein R2and R3, together with the carbon atoms to which they are attached, form a heterocycloalkyl ring substituted with one or more groups Rb, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); Compound 1.17, wherein R3and R4, together with the carbon atoms to which they are attached, form a heterocycloalkyl ring substituted with one or more groups Rb, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); Compound 1.17, or any of 1.22- 1.26, wherein said heterocycloalkyl ring comprises one or more ring atoms selected from O, N(H), and N(Ra); Compound 1.17, or any of 1.22-1.27, wherein said hctcrocycloalkyl ring is selected from a pyrrolidine, tetrahydrofuran, piperidine, piperazine, and morpholine; Compound 1.17 or any of 1.18-1.28, wherein said cycloalkyl ring or heterocycloalkyl ring is substituted by one, two, three, or four groups Rb(e.g., methyl); Compound 1.17 or any of 1.18-1.28, wherein said cycloalkyl ring or heterocycloalkyl ring is substituted by two groups Rb(e.g., methyl);Compound 1.17 or any of 1.18- 1.30, wherein each Rbis independently selected from C1-6alkyl (e.g., methyl or ethyl), C3-6cycloalkyl (e.g., cyclopropyl), Ci-3 haloalkyl (e.g., CF3), or OC1-6alkyl (e.g., OCH3); Compound 1, or any of 1.1-1.31, wherein Rais C1-6alkyl (e.g., methyl or ethyl); Compound 1, or any of 1.1-1.32, wherein R is C1-6alkyl (e.g., methyl or ethyl); Compound 1, or any of 1.1-1.32, wherein R is C3-6cycloalkyl (e.g., cyclopropyl); Compound 1, or any of 1.1-1.34, wherein R1is H or C1-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl), n-butyl, sec -butyl, isobutyl, or tert-butyl; Compound 1, or any of 1.1-1.35, wherein R2is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C1-3 haloalkyl (e.g., CF3or CHF2); Compound 1, or any of 1.1-1.36, wherein R3is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C1-3 haloalkyl (e.g., CF3or CHF2); Compound 1, or any of 1.1-1.37, wherein R4is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C1-3 haloalkyl (e.g., CF3or CHF2); Compound 1, or any of 1.1-1.38, wherein one of R2, R3, or R4is C(O)R or CHO; Compound 1.39, wherein R is selected from methyl, ethyl, propyl and isopropyl; Compound 1, or any of 1.1-1.38, wherein one of R2, R3, or R4is COOH, COOR, CONHR, or CONRR’; Compound 1.41, wherein each instance of R and R’ is independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, and isobutyl; Compound 1, or any of 1.1-1.34, wherein R1is C1-6 alkyl (e.g., CH3), Cs- ecycloalkyl (e.g., cyclopropyl), or C1-3 haloalkyl (e.g., CF3), R2is C1-6 alkyl (e.g., CH3), C3-6cycloalkyl (e.g., cyclopropyl), or C1-3 haloalkyl (e.g., CF3), R3is H, R4is COOH or COOR, and R is C1-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl);Compound 1, or any of 1.1-1.34, wherein R1is Ci-6 alkyl (e.g., CH3) or C3- 6cycloalkyl (e.g., cyclopropyl), R2is C1-6 alkyl (e.g., CH3), or C3-ecycloalkyl (e.g., cyclopropyl), R3is H, R4is COOH or COOR, and R is Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); Compound 1, or any of 1.1-1.34, wherein R1is C1-6 alkyl (e.g., CH3), R2is Cu 6 alkyl (e.g., CH3), or C3-6cycloalkyl (e.g., cyclopropyl), R3is H, R4is COOH or COOR, and R is Ci^alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); Compound 1, or any of 1.1-1.34, wherein R1is C1-6 alkyl (e.g., CH3), R2is Cn 6 alkyl (e.g., CH3), R3is H, R4is COOH or COOR, and R is Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); Compound 1, or any of 1.1-1.34, wherein R1is C1-6 alkyl (e.g., CH3), R2is Cn 6 alkyl (e.g., CH3), R3is H, R4is COOR, and R is C1-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); Compound 1, or any of 1.1-1.34, wherein R1is Ci-6 alkyl (e.g., CH3), R2is Cn 6 alkyl (e.g., CH3), R3is H, R4is COOR, and R is Ci-6alkyl (e.g., methyl or ethyl); Compound 1, or any of 1.1-1.34, wherein R1is methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, cyclopropyl, or cyclobutyl, R2is methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, cyclopropyl, or cyclobutyl, R3is H, R4is COOR, and R is methyl, ethyl, propyl, isopropyl, n- butyl, s-butyl, isobutyl, t-butyl, cyclopropyl, or cyclobutyl; Compound 1, or any of 1.1-1.34, wherein R1is methyl, ethyl, propyl, or isopropyl, R2is methyl, ethyl, propyl, or isopropyl, R3is H, R4is COOR, and R is methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl; Compound 1, or any of 1.1-1.34, wherein R1is methyl or ethyl, R2is methyl or ethyl, R3is H, R4is COOR, and R is methyl, ethyl, propyl, isopropyl, or cyclopropyl; Compound 1, or any of 1.1-1.34, wherein R1is methyl, R2is methyl, R3is H, and R4is COOR, and R is methyl, ethyl, propyl, isopropyl, or cyclopropyl; Compound 1, or any of 1.1-1.34, wherein R1is H or C1-6 alkyl (e.g., CH3), R3and R4, together with the carbon atoms to which they are attached, form a 5-8 membered (C5-8) cycloalkyl ring substituted with one or two groups Rb, and R2isCOOH, or COOR, wherein R and Rbare each independently selected from Ci-6 alkyl (e.g., CH3); Compound 1.53, wherein said cycloalkyl ring is gem-disubstituted with two C1-6 alkyl (e.g., CH3); Compound 1, or any of 1.1-1.54, wherein the compound of Formula I is a compound of Formula la:Formula la wherein R2and R3are as defined in any preceding formula; Compound 1 , or any of 1.1 - 1.54, wherein the compound of Formula I is a compound of Formula lb:Formula lb wherein R1, R2, and R4are as defined in any preceding formula; Compound 1, or any of 1.1-1.54, wherein the compound of Formula I is:wherein R is as defined in any preceding formula;Compound 1.57, wherein R is methyl, ethyl, propyl, isopropyl, or cyclopropyl; Compound 1.57, wherein R is ethyl; Any preceding compound, wherein the compound of Formula I has any one or more the following combination of substituents R1, R2, R3, and R4:wherein Me is methyl, Et is ethyl, n-Pr is n-propyl, and iPr is isopropyl; Any of Compound 1.60, wherein R is independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and isobutyl; Any preceding compound, wherein the compound has a molecular weight selected from the range of to 90 to 500, 90 to 400, or 90 to 350, or 90 to 300, or 90 to 250, or 90 to 225, or 90 to 200, or 90 to 180; Any preceding compound, wherein the compound is selected from the group consisting of:Any preceding compound, wherein the compound is selected from the group consisting of:Any preceding compound wherein if the compound has an acidic or basic atom or functional group, then the compound is in the form of a salt, e.g., a base addition salt or an acid addition salt;1.66 Any preceding compound, wherein the compound has a pleasing taste and / or aroma, e.g., as judged by a trained flavor or fragrance chemist or master perfumer (e.g., toasted coconut or other nutty aromas and / or tastes).

[0016] It is understood that substituted pyrazoles are subject to tautomerism and, most commonly, isomeric mixtures of substituted pyrazoles are generated by normal organic chemical synthetic methodology. Therefore, as used herein, structures drawn according to the following nomenclature are understood to embrace either or both isomers of the substituted compound in any ratio, but for any particular a single purified isomer is also embraced and may be selected.

[0017] In a second aspect, the present disclosure provides a flavor composition and / or a fragrance composition (Composition 1) comprising Compound 1, or any of 1.1-1.66, in admixture with one or more non-toxic, orally acceptable, pharmaceutically acceptable, cosmetically acceptable, or acceptable for a household product, carriers or excipients. In particular embodiments, the second aspect provides:1.1 Composition 1, wherein the composition is a fragrance composition.1.2 Composition 1, wherein the composition is a flavor composition.1.3 Composition 1, or any of Compositions 1.1 -1.2, wherein the composition comprises the Compound 1, or any of 1.1-1.66, in an amount of 0.1 to 100% by weight of the composition, e.g., 0.1 to 90%, or 0.1 to 80%, or 0.1 to 70%, or 0.1 to 60%, or 0.1 to 50%, or 0.1 to 40%, or 0.1 to 30%, or 0.1 to 20%, or 0.1 to 15%, or 0.1 to 10%, or 0.1 to 7.5%, or 0.1 to 5%, or 0.1 to 4%, or 0.1 to 3%, or 0.1 to 2%, or 0.1 to 1%, or 10 to 100%, or 20 to 100%, or 30 to 100%, or 40 to 100%, or 50 to 100%, or 60 to 100%, or 70 to 100%, or 80 to 100%, or 90 to 100%, or 95 to 100%, or 25 to 75%, or 50 to 75%, or 75 to 95%, by weight of the composition.1.4 Composition 1, or any of Compositions 1.1-1.3, wherein the composition further comprises one or more other flavors or fragrances.1.5 Composition 1, or any of Compositions 1.1 -1.4, wherein the composition further comprises one or more solvents.1.6 Composition 1.5, wherein the one or more solvents are selected from water, methanol, ethanol, propanol, isopropanol, dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethylene glycol, propylene glycol, glycerin, triethyl citrate, triacetin,triglycerides, liquid waxes, propylene glycol derivatives (e.g., polypropylene glycols or ethylene oxide / propylene oxide copolymers), ethylene glycol derivatives (e.g., polyethylene glycols or ethylene oxide / propylene oxide copolymers), other alcohols or ethers, or any combination thereof.1.7 Composition 1, or any of composition 1.1 to 1.6, wherein the composition is a liquid.1.8 Composition 1, or any of compositions 1.1 to 1.6, wherein the composition is a soft or waxy solid.1.9 Composition 1, or any of compositions 1.1-1.8, wherein the composition further comprises one or more of a polymer, gelling agent, powdery substrate, surfactant, emollient, plasticizer, wetting agent, swelling agent, or active agent (e.g., an oral care active or a medicinal active agent), or any other additives as described herein.1.10 Composition 1, or any of Compositions 1.1 -1.9, wherein the composition does not comprise any ingredient or component that would not be safe for ingestion, application to the oral cavity, or topical application to the skin or hair;1.11 Composition 1, or any of Compositions 1.1-1.10, wherein the composition does not comprise any ingredient or component which is unsafe for, or not approved for, use in a food, cosmetic composition, pharmaceutical composition, oral care composition, or consumer cleaning composition.

[0018] As used herein, the term “fragrance composition” means a mixture of fragrance ingredients (e.g., including a Compound of Formula I) with one or more non-toxic, cosmetically acceptable, or acceptable for a household product, carriers or excipients, such as solvents. For example, the fragrance ingredient(s) may be dissolved in a suitable solvent or mixed with a powdery substrate, with additional auxiliary substances added (e.g., additives), if desired. A fragrance composition is used, and intended to be used, to provide or impart a desired odor or aroma to a product, such as a cosmetic product or household product (e.g., household cleaners). Thus, a fragrance composition is used as an ingredient or component in a final product, such as a cosmetic product or consumer product, for which a particular fragrance is desired. Examples of products having fragrance compositions include, but are not limited to, perfumes, soaps, insect repellants and insecticides, detergents, household cleaning agents, air fresheners, room sprays, pomanders, candles, cosmetics, toilet waters, pre- and aftershave lotions, talcum powders, hair-care products, body deodorants, anti-perspirants, and pet litter. A fragrance composition should have enough of its fragrance ingredients so that it is effective to provide the desired odor or aroma to the final product,and this depends both on the concentration of the fragrance ingredient(s) in the composition and the concentration of the composition used in the product.

[0019] As used herein, the term “flavor composition” means a mixture of flavor ingredients (e.g., including a Compound of Formula I) with one or more non-toxic, orally acceptable, or pharmaceutically acceptable, carriers or excipients, such as solvents. For example, the flavor ingredient(s) may be dissolved in a suitable solvent or mixed with a suitable solid, semi-solid, or liquid excipients, with additional auxiliary substances added (e.g., additives), if desired. A flavor composition is used, and intended to be used, to provide or impart a desired flavor and aroma to a product, such as a food product or oral pharmaceutical product. Thus, a flavor composition is used as an ingredient or component in a final product, such as a food or oral pharmaceutical product, for which a particular flavor is desired. Examples of products having flavor compositions include, but are not limited to, oral care compositions (e.g., dental hygiene products such as mouth wash, toothpaste, floss, and breath fresheners), pharmaceutical compositions (e.g., orally administered medications including liquids, tablets or capsules), and food products. A flavor composition should have enough of its flavor ingredients so that it is effective to provide the desired flavor and aroma to the final product, and this depends both on the concentration of the flavor ingredients in the composition and the concentration of the composition used in the product.

[0020] Fragrance and flavor ingredients and mixtures of fragrance and flavor ingredients that may be used in combination with the disclosed compound for the manufacture of fragrance and flavor compositions include, but are not limited to, natural products including extracts, animal products and essential oils, absolutes, resinoids, resins, and concretes, and synthetic fragrance materials which include, but are not limited to, alcohols, aldehydes, ketones, ethers, acids, esters, acetals, phenols, ethers, lactones, furansketals, nitriles, acids, and hydrocarbons, including both saturated and unsaturated compounds and aliphatic carbocyclic and heterocyclic compounds, and animal products. As used herein, the terms “fragrance ingredient” and “flavor ingredient” refer to ingredients other than the Compounds of Formula I which are used to impart a flavor or a fragrance to a composition or product.

[0021] Examples of esters which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, acrylic acid esters (methyl, ethyl, etc.), acetoacetic acid esters (methyl, ethyl, etc.), anisic acid esters (methyl, ethyl, etc.), benzoic acid esters (allyl, isoamyl, ethyl, geranyl, linalyl, phenylethyl, hexyl, cis-3- hexenyl, benzyl, methyl, etc.), anthranilic acid esters (cinnamyl, cis-3-hexenyl, methyl, ethyl, linalyl, isobutyl, etc.), N-methylanthranilic acid esters (methyl, ethyl, etc.), isovaleric acid esters (amyl,allyl, isoamyl, isobutyl, isopropyl, ethyl, octyl, geranyl, cyclohexyl, citronellyl, terpenyl, linalyl, cinnamyl, phenylethyl, butyl, propyl, hexyl, benzyl, methyl, rhodinyl, etc.), isobutyric acid esters (isoamyl, geranyl, citronellyl, terpenyl, cinnamyl, octyl, nellyl, phenylethyl, phenylpropyl, phenoxyethyl, butyl, propyl, isopropyl, hexyl, benzyl, methyl, ethyl, linalyl, rhodinyl, etc.), undecylenic acid esters (allyl, isoamyl, butyl, ethyl, methyl, etc.), octanoic acid esters (allyl, isoamyl, ethyl, octyl, hexyl, butyl, methyl, linalyl, etc.), octenoic acid esters (methyl, ethyl, etc.), octynecarboxylic acid esters (methyl, ethyl, etc.), caproic acid esters (allyl, amyl, isoamyl, methyl, ethyl, isobutyl, propyl, hexyl, cis-3-hexenyl, trans-2-hexenyl, linalyl, geranyl, cyclohexyl, etc.), hexenoic acid esters (methyl, ethyl, etc.), valeric acid esters (amyl, isopropyl, isobutyl, ethyl, cis-3- hexenyl, trans-2-hexenyl, cinnamyl, phenylethyl, methyl, etc.), formic acid esters (anisyl, isoamyl, isopropyl, ethyl, octyl, geranyl, citronellyl, cinnamyl, cyclohexyl, terpenyl, phenylethyl, butyl, propyl, hexyl, cis-3-hexenyl, benzyl, linalyl, rhodinyl, etc.), crotonic acid esters (isobutyl, ethyl, cyclohexyl, etc.), cinnamic acid esters (allyl, ethyl, methyl, isopropyl, propyl, 3-phenylpropyl, benzyl, cyclohexyl, methyl, etc.), succinic acid esters (monomethyl, diethyl, dimethyl, etc.), acetic acid esters (anisyl, amyl, a-amylcinnamyl, isoamyl, isobutyl, isopropyl, isobornyl, isoeugenyl, eugenyl, 2-ethylbutyl, ethyl, 3-octyl, p-cresyl, o-cresyl, geranyl, a- or -santalyl, cyclohexyl, cycloneryl, dihydrocuminyl, dimethyl benzyl carbinyl, cinnamyl, styralyl, decyl, dodecyl, terpenyl, guainyl, neryl, nonyl, phenyl ethyl, phenylpropyl, butyl, furfuryl, propyl, hexyl, cis-3-hexenyl, trans- 2-hexenyl, cis-3-nonenyl, cis-6-noneyl, cis-3-cis-6-nonadienyl, 3-methyl-2-butenyl, heptyl, benzyl, bornyl, myrcenyl, dihydromyrcenyl, myrtenyl, methyl, 2-methylbutyl, menthyl, linalyl, rhodinyl, etc.), salicylic acid esters (allyl, isoamyl, phenyl, phenylethyl, benzyl, ethyl, methyl, etc.), cyclohexylalkanoic acid esters (ethyl cyclohexylacetate, allyl cyclohexylpropionate, allyl cyclohexylbutyrate, allyl cyclohexylhexanoate, allyl cyclohexyldecanoate, allyl cyclohexylvalerate, etc.), stearic acid esters (ethyl, propyl, butyl, etc.), scbacic acid esters (diethyl, dimethyl, etc.), decanoic acid esters (isoamyl, ethyl, butyl, methyl, etc.), dodecanoic acid esters (isoamyl, ethyl, butyl, etc.), lactic acid esters (isoamyl, ethyl, butyl, etc.), nonanoic acid esters (ethyl, phenylethyl, methyl, etc.), nonenoic acid esters (allyl, ethyl, methyl, etc.), hydroxyhexanoic acid esters (ethyl, methyl, etc.), phenylacetic acid esters (isoamyl, isobutyl, ethyl, geranyl, citronellyl, cis-3-hexenyl, methyl, etc.), phenoxyacetic acid esters (allyl, ethyl, methyl, etc.), furancarboxylic acid esters (ethyl furancarboxylate, methyl furancarboxylate, hexyl furancarboxylate, isobutyl furancarboxylate, etc.), propionic acid esters (anisyl, allyl, ethyl, amyl, isoamyl, propyl, butyl, isobutyl, isopropyl, benzyl, geranyl, cyclohexyl, citronellyl, cinnamyl, tetrahydrofurfuryl, tricyclodecenyl, heptyl, bornyl, methyl, menthyl, linallyl, terpenyl, a- methylpropionyl, P-methylpropionyl, etc.), heptanoic acidesters (allyl, ethyl, octyl, propyl, methyl, etc.), heptanecarboxylic acid esters (allyl, ethyl, propyl, methyl, etc.), myristic acid esters (isopropyl, ethyl, methyl, etc.), phenylglycidic acid esters (ethyl phenylglycidate, ethyl 3-methylphenylglycidate, ethyl p-methyl-p-phenylglycidate, etc.), 2- methylbutyric acid esters (methyl, ethyl, octyl, phenyl ethyl, butyl, hexyl, benzyl, etc.), 3- methylbutyric acid esters (methyl, ethyl, etc.), butyric acid esters (anisyl, amyl, allyl, isoamyl, methyl, ethyl, propyl, octyl, guainyl, linallyl, geranyl, cyclohexyl, citronellyl, cinnamyl, nellyl, terpenyl, phenylpropyl, P-phenylethyl, butyl, hexyl, cis-3-hexenyl, trans-2-hexenyl, benzyl, rhodinyl, etc.), and hydroxybutyric acid esters (methyl, ethyl, menthyl or the like of 3-hydroxybutyric acid esters).

[0022] Examples of alcohols which may be used as fragrance ingredients or flavor ingredients, or as solvents, in the compositions and products of the present disclosure include, but are not limited to, aliphatic alcohols (isoamyl alcohol, 2-ethylhexanol, 1 -octanol, 3-octanol, 1- octene-3-ol, 1-decanol, 1-dodecanol, 2,6-nonadienol, nonanol, 2-nonanol, cis-6-nonenol, trans-2, cis- 6-nonadienol, cis-3, cis-6-nonadienol, butanol, hexanol, cis-3-hexenol, trans-2-hexenol, 1- undecanol, heptanol, 2-heptanol, 3-methyl-l -pentanol, etc.); terpene alcohols (borneol, isobomeol, carveol, geraniol, a- or P-santalol, citronellol, 4-thujanol, terpineol, 4-terpineol, nerol, myrcenol, myrtenol, dihydromyrcenol, tetrahydromyrcenol, nerolidol, hydroxy citronellol, farnesol, perilla alcohol, rhodinol, linalool, etc.); and aromatic alcohols (anisic alcohol, a-amylcinnamic alcohol, isopropylbenzylcarbinol, carvacrol, cumin alcohol, dimethylbenzylcarbinol, cinnamic alcohol, phenyl allyl alcohol, phenylethylcarbinol, P-phenylethyl alcohol, 3-phenylpropyl alcohol, benzyl alcohol, etc.).

[0023] Examples of aldehydes which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, aliphatic aldehydes (acetaldehyde, octanal, nonanal, decanal, undecanal, 2,6-dimcthyl-5-hcptanal, 3,5,5-trimethylhexanal, cis-3, cis-6-nonadienal, trans-2, cis-6-nonadienal, valeraldehyde, propanal, isopropanal, hexanal, trans-2-hexenal, cis-3-hexenal, 2-pentenal, dodecanal, tetradecanal, trans-4- decenal, trans-2-tridecenal, trans-2-dodecenal, trans-2-undecenal, 2,4-hexadienal, cis-6-nonenal, trans-2-nonenal, 2-methylbutanal, etc.); aromatic aldehydes (anisic aldehyde, a-amylcinnamic aldehyde, a-methylcinnamic aldehyde, cyclamen aldehyde, p-isopropylphenylacetaldehyde, ethylvanillin, cumin aldehyde, salicylaldehyde, cinnamic aldehyde, o-, m- or p-tolylaldehyde, vanillin, piperonal, phenylacetaldehyde, heliotropin, benzaldehyde, 4-methyl-2-pheny-2-pentenal, p- methoxycinnamic aldehyde, p-methoxybenzaldehyde, etc.); and terpene aldehydes (geranial, citral, citronellal, a-sinensal, P-sinensal, perillaldehyde, hydroxycitronellal, tetrahydrocitral, myrtenal,cyclocitral, isocyclocitral, citronellyloxyacetaldehyde, neral, a-methylenecitronellal, myrac aldehyde, vernaldehyde, safranal, etc.).

[0024] Examples of ketones which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, cyclic ketones (l-acetyl-3,3-dimethyl-l-cyclohexene, cis-jasmone, a-, 0- or y-irone, ethyl maltol, cyclotene, dihydronootkatone, 3,4-dimethyl-l,2-cyclopentadione, sotolon, a-, 0-, y- or 6-damascone, a-, 0- or y-damascenone, nootkatone, 2-sec -butylcyclohexanone, maltol, a-, 0- or y-ionone, a-, 0- or y-methylionone, a-, 0- or y-isomethylionone, furaneol, camphor, etc.); aromatic ketones (acetonaphthone, acetophenone, anisylideneacetone, raspberry ketone, p-methyl acetophenone, anisylacetone, p-methoxy acetophenone, etc.); and chain ketones (diacetyl, 2-nonanone, diacetyl, 2- heptanone, 2,3-heptanedione, 2-pentanone, methyl amyl ketone, methyl nonyl ketone, 0-methyl naphthyl ketone, methyl heptanone, 3-heptanone, 4-heptanone, 3-octanone, 2,3-hexanedione, 2- undecanone, dimethyloctenone, 6-methyl-5-hepten-2-one, etc.).

[0025] Examples of acetals which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, acetaldehyde diethyl acetal, acetaldehyde diamyl acetal, acetaldehyde dihexyl acetal, acetaldehyde propylene glycol acetal, acetaldehyde ethyl cis-3-hexenyl acetal, benzaldehyde glycerin acetal, benzaldehyde propylene glycol acetal, citral dimethyl acetal, citral diethyl acetal, citral propylene glycol acetal, citral ethylene glycol acetal, phenylacetaldehyde dimethyl acetal, citronellyl methyl acetal, acetaldehyde phenylethylpropyl acetal, hexanal dimethyl acetal, hexanal dihexyl acetal, hexanal propylene glycol acetal, trans-2-hexenal diethyl acetal, trans-2-hexenal propylene glycol acetal, cis-3-hexenal diethyl acetal, heptanal diethyl acetal, heptanal ethylene glycol acetal, octanal dimethyl acetal, nonanal dimethyl acetal, decanal dimethyl acetal, decanal diethyl acetal, 2- mcthylundccanal dimethyl acetal, citroncllal dimethyl acetal, Ambersage (manufactured by Givaudan), ethyl acetoacetate ethylene glycol acetal, and 2-phenylpropanal dimethyl acetal.

[0026] Examples of phenols which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, eugenol, isoeugenol, 2-methoxy-4-vinylphenol, thymol, carvacrol, guaiacol, and chavicol, and vanillin.

[0027] Examples of ethers and epoxides which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure, but are not limited to, anethole, 1,4-cineole, dibenzyl ether, linalool oxide, limonene oxide, nerol oxide, rose oxide, methyl isoeugenol, methyl chavicol, isoamyl phenyl ethyl ether, 0-naphthyl methyl ether, phenyl propylether, p-cresyl methyl ether, vanillyl butyl ether, a-terpinyl methyl ether, citronellyl ethyl ether, geranyl ethyl ether, rose furan, theaspirane, decylmethyl ether, and methylphenyl methyl ether.

[0028] Examples of lactones which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, y- or 8-decalactone, y-heptalactone, y-nonalactone, y- or 8-hexylactone, y- or 8-octalactone, y- or 8- undecalactone, 8-dodecalactone, 8-2-decenolactone, methyl lactone, 5-hydroxy-8-undecenoic acid 8- lactone, jasmine lactone, menthalactone, dihydrocoumarin, octahydrocoumarin, and 6- methy Icoumarin .

[0029] Examples of furans which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, furan, 2- methylfuran, 3-methylfuran, 2-ethylfuran, 2,5-diethyltetrahydrofuran, 3-hydroxy-2- methyltetrahydrofuran, 2-(methoxymethyl)furan, 2,3-dihydrofuran, furfural, 5-methylfurfural, 3-(2- furyl)-2-methyl-2-propenal, 5-(hydroxymethyl)furfural, 2,5-dimethyl-4-hydroxy-3(2H)-furanone (furaneol), 4,5-dim ethyl-3-hydroxy-2(5H)-furanone (sotolon), 2-ethyl-4-hydroxy-5-methyl-3(2H)- furanone (homofuraneol), 5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone (homosotolon), 3-methyl- 1 ,2-cyclopentanedione (cyclotene), 2(5H)-furanone, 4-methyl-2(5H)-furanone, 5-methyl-2(5H)- furanone, 2-methyl-3(2H)-furanone, 5-methyl-3(2H)-furanone, 2- acetylfuranone, 2-acetyl-5- methylfuran, furfuryl alcohol, methyl 2-furancarboxylate, ethyl 2-furancarboxylate, and furfuryl acetate.

[0030] Examples of hydrocarbons which may be used which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, a- or p-bisabolene, p-caryophyllene, p-cymene, terpinene, terpinolene, cadinene, cedrene, longifolene, farnesene, limonene, ocimene, myrcene, a- or P-pinene, 1,3,5- undccatricnc and valcnccnc.

[0031] Examples of acids that may be used which may be used as fragrance ingredients or flavor ingredients in the compositions and products of the present disclosure include, but are not limited to, geranic acid, dodecanoic acid, myristic acid, stearic acid, lactic acid, phenylacetic acid, pyruvic acid, trans-2-methyl-2-pentenoic acid, 2-methyl-cis-3-pentenoic acid, 2-methyl-4-pentenoic acid, and cyclohexanecarboxylic acid.

[0032] The fragrance and flavor compositions of the application may comprise as additional fragrance or flavor ingredients one or more natural extracts or oils including, but not limited to, anise, orange, lemon, lime, mandarin, petitgrain, bergamot, lemon balm, grapefruit, elemi, olibanum, lemongrass, neroli, marjoram, angelica root, star anise, basil, bay, calamus, chamomile, caraway,cardamom, cassia, cinnamon, pepper, perilla, cypress, oregano, cascarilla, ginger, parsley, pine needle, sage, hyssop, tea tree, mustard, horseradish, clary sage, clove, cognac, coriander, estragon, eucalyptus, fennel, guaiac wood, dill, cajuput, wormseed, pimento, juniper, fenugreek, garlic, laurel, mace, myrrh, nutmeg, spruce, geranium, citronella, lavender, lavandin, palmarosa, rose, rosemary, sandalwood, oakmoss, cedarwood, vetiver, linaloe, hois de rose, patchouli, labdanum, cumin, thyme, ylang ylang, birch, capsicum, celery, tolu balsam, genet, immortelle, benzoin, jasmine, cassie, tuberose, reseda, marigold, mimosa, opoponax, orris, vanilla and licorice. Each of these natural extracts or oils comprises a complex mixture of chemical compounds, which may include those compounds described above. Additional fragrance ingredients may be isolated from natural products, for example, geraniol and citronellal may be isolated from citronella oil, citral may be isolated from lemon-grass oil, eugenol may be isolated from clove oil, and linalool may be isolated from rosewood oil. Animal products used in fragrance compositions include, but are not limited to, musk, ambergris, civet and castoreum. The natural ingredients described herein may also be produced synthetically, and may include the compounds disclosed herein, and be used as fragrance and / or flavor ingredients in the fragrance and flavor compositions of the present application.

[0033] Examples of fragrance ingredients used in perfumes, air fresheners, laundry detergents, pet litters, cleaning products, liquid and bar soaps, shampoos and conditioners, cosmetics, deodorants, and personal hygiene products include, but are not limited to: hexyl cinnamic aldehyde; amyl cinnamic aldehyde; amyl salicylate; hexyl salicylate; terpineol; 3,7-dimethyl-cis-2,6- octadien-l-ol; 2,6-dimethyl-2-octanol; 2,6-dimethyl-7-octen-2-ol; 3,7-dimethyl-3-octanol; 3,7- dimethyl-trans-2,6-octadien- l-ol; 3,7-dimethyl-6-octen- l-ol; 3,7-dimethyl-l -octanol; 2-methyl-3- (para-tert-butylphenyl)-propionaldehyde; 4-(4-hydroxy-4-methylpentyl)-3-cyclohexene-l- carboxaldehyde; tricyclodecenyl propionate; tricyclodecenyl acetate; anisaldehyde; 2-methyl-2- (para-iso-propylphcnyl)-propionaldchydc; cthyl-3-mcthyl-3-phcnyl glycidatc; 4-(para- hydroxyphenyl)-butan-2-one; l-(2,6,6-trimethyl-2-cyclohexen-l-yl)-2-buten-l-one; paramethoxyacetophenone; para-methoxy-alpha-phenylpropene; methyl-2-n-hexyl-3-oxo-cyclopentane carboxylate; undecalactone gamma, geraniol; geranyl acetate; linalool; linalyl acetate; tetrahydrolinalool; citronellol; citronellyl acetate; dihydromyrcenol; dihydromyrcenyl acetate; tetrahydromyrcenol; terpinyl acetate; nopol; nopyl acetate; 2-phenylethanol; 2-phenylethyl acetate; benzyl alcohol; benzyl acetate; benzyl salicylate; benzyl benzoate; styrallyl acetate; dimethylbenzylcarbinol; trichloromethylphenylcarbinyl methylphenylcarbinyl acetate; isononyl acetate; vetiveryl acetate; vetiverol; 2-methyl-3-(p-tert-butylphenyl)-propanal; 2-methyl-3-(p- isopropylphenylj-propanal; 3-(p-tert-butylphenyl)-propanal; 4-(4-methyl-3-pentenyl)-3-cyclohexenecarbaldehyde; 4-acetoxy-3-pentyltetrahydropyran; methyl dihydrojasmonate; 2-n- heptylcyclopentanone; 3-methyl-2-pentyl -cyclopentanone; n-decanal; n-dodecanal; 9-decenol-l; phenoxyethyl isobutyrate; phenylacetaldehyde dimethylacetal; phenylacetaldehyde diethylacetal; geranonitrile; citronellonitrile; cedryl acetal; 3-isocamphylcyclohexanol; cedryl methyl ether; isolongifolanone; aubepine nitrile; aubepine; heliotropine; eugenol; vanillin; diphenyl oxide; hydroxycitronellal ionones; methyl ionones; isomethyl ionones; irones; cis-3-hexenol and esters thereof; indane musk fragrances; tetralin musk fragrances; isochroman musk fragrances; macrocyclic ketones; macrolactone musk fragrances; and ethylene brassylate.

[0034] The fragrance and flavor ingredients in a given product’s fragrance or flavor composition are selected based on the intended use of the product and the product’s desired aroma. For example, flavor ingredients used in toothpaste, mouth wash, and dental hygiene products may be selected to impart “freshness” and include, but are not limited to, spearmint oil, peppermint oil, star anise oil, lemon oil, and menthol.

[0035] Flavor compositions may be used to mask the unpleasant taste of orally administered medications. For example, if a medication is salty, a flavor composition that has cinnamon, raspberry, orange, maple, butterscotch, or glycyrrhiza (licorice) flavor may be used to mask the taste. If a medication is overly sweet, a flavor composition that has a berry, vanilla, or acacia flavor may render the medication more palatable. In the case of bitter tasting medications, flavor compositions that have cocoa, chocolate-mint, wild cherry, walnut, glycyrrhiza (licorice), and eriodictyon flavors might be used, whereas sour medications may be improved by flavor compositions that have fruity, citrus, or cherry flavors. These flavors may be provided by the natural or synthetic flavor ingredients discussed herein.

[0036] Examples of flavor ingredients used in flavor compositions for food products also include, but arc not limited to, glucosyl steviol glycosides, isomcnthols, carbonothoic acids, cassyrane, l,5-octadien-3-ol, 2-mercaptoheptan-4-ol, 4 3-(methylthio)decanal, (4Z,7Z)-trideca-4,7- dienal, persicaria odorata oil, Amacha leaves extract, glutamyl-2- aminobutyric acid, glutamyl-2- aminobutyric acid, glutamyl-norvalyl-glycine, glutamyl-norvaline, Nl-(2,3-Dimethoxybenzyl)-N2- (2-(pyridin-2-yl)ethyl) oxalamide, l-(2-hydroxy-4-methylcyclohexyl)ethanone, Mexican lime oil, Persian lime oil, 6-methoxy-2,6-dimethylheptanal, 3,5-undecadien-2-one, 2,5-undecadien-l-ol, triethylthialdine. 4-methylpentyl 4-methylvalerate, (R)-N-(l-methoxy-4-methylpentan-2-yl)-3,4- dimethylbenzamide, 2 N-acetyl glutamate, 1,3-propanediol, Szechuan pepper extract, Tasmannia lanceolata extract, Mentha longifolia oil, mangosteen distillate, ethyl 3-(2- hydroxyphenyl)propanoate, l-cyclopropanemethyl-4-methoxybenzene, prenyl thioisobutyrate,prenyl thioisovalerate, matairesinol, stevioside, l-(2,4-dihydroxyphenyl)-3-(3-hydroxy-4- methoxyphenyl)propan-l-one, ethyl 5-formyloxydecanoate, 3-[3-(2-isopropyl-5-methyl- cyclohexyl)ureido] butyric acid ethyl ester, 2-Isopropyl-4-methyl-3-thiazoline, 2,6,10-trimethyl-9- undecenal, 5-mercapto-5-methyl-3-hexanone, Meyer lemon oil, teviol glycoside extract, stevia rebaudiana, rebaudioside A 60%, rubescenamine, 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3- oxopropoxy)-2-methylquinoline-3-carboxylic acid, 3-methyl-5-(2,2,3-trimethylcyclopent-3-en- 1- yl)pent-4-en-2-ol, ( 1 -Methyl-2-( 1 ,2,2-trimethylbicyclo[3.1 ,0]hex-3-ylmethyl)cyclopropyl)methanol, erospicata oil, and curly mint oil. See L. J. Mamett et al., GRAS Flavoring Substances 26, Food Technology, 44-45 (2013).

[0037] Preferred solvents and excipients for use in the compositions and products of the present disclosure include, but are not limited to, triethyl citrate, triacetin, glycerol, propylene glycol, dipropylene glycol, isopropyl myristate, ethanol, water, triglycerides, liquid waxes, propylene glycol derivatives (e.g., polymers), and ethylene glycol derivatives (e.g., polymers).

[0038] The amount of a given fragrance or flavor ingredient in a fragrance or flavor composition cannot be categorically described because it varies depending on the type product being scented or flavored, the intended use of the product, and the desired aroma and / or taste of the product. The amount of a fragrance or flavor ingredient in a fragrance or flavor composition is usually in the range of from about 1% to about 99% by mass of the fragrance composition. When the amount of the ingredient is too small, a sufficient strength of the scent or flavor may not be obtained. Further, when the amount of the ingredient is too large, a larger amount of the agent(s) needed to solubilize the ingredient may be needed, which may in turn reduce the desired aromatic or flavor properties of the end product by inhibiting volatilization or other mechanisms by which the flavor or fragrance is dispersed when the product is used or consumed. The amount of each of the fragrance and flavor ingredients in a given fragrance or flavor composition must therefore be selected based upon the aromatic and / or flavor characteristics of the selected ingredient, the overall composition of the product, and the intended aromatic and / or flavor effect.

[0039] Additives may be used in the flavor and fragrance compositions of the present disclosure. Additives that may be used include, but are not limited to, solvents, surfactants, pH adjusters, buffers, thickening agents, desiccants, emulsifiers, foaming agents, stabilizers, antioxidants, and disintegrating agents. Other fragrance and flavor composition additives will be selected in accordance with the intended use of the composition.

[0040] Solvents, for example water-soluble organic solvents, which may be used in the flavor and fragrance compositions of the present disclosure include, but are not limited to, ethanol,propanol, isopropanol, butanol, 3-methoxy-3-methyl- 1 -butanol, benzyl alcohol, ethyl carbitol (diethylene glycol monoethyl ether), ethylene glycol, propylene glycol, dipropylene glycol, butylene glycol, hexylene glycol, glycerin, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, and dipropylene glycol monomethyl ether. These water- soluble solvents may be used solely or in combination. The content of the water-soluble organic solvent in the compositions of the application may be determined according to the desired composition properties, and is usually from about 1% to about 99% by mass.

[0041] Oil-soluble organic solvents which may be used with the flavor and fragrance compositions of the application include, but arc not limited to, isoparaffin, paraffin, limonene, pinene, triethyl citrate, benzyl benzoate, isopropyl myristate, triacetin, and silicone.

[0042] Preferred solvents include, but are not limited to, triethyl citrate, triacetin, glycerol, ethanol, water, triglycerides, liquid waxes, propylene glycol derivatives, and ethylene glycol derivatives.

[0043] In some embodiments, the flavor and fragrance compositions and products of the present disclosure may further comprise other substances, including, but not limited to, sequestering agents, preservatives, antioxidants, deodorizers, sterilization agents, ultraviolet absorbers, pH adjusters, insecticidal components, components for protection from insects, insect repellents, colorants, excipients, and buffers. The substances used in, or in addition to, the fragrance and flavor compositions of the present application may be determined by the product in which the composition is included. When the substance is used in a flavor or fragrance composition, it may be an additive. When the substance is used alongside a flavor or fragrance composition, it may be considered as part of a product composition that comprises a fragrance or flavor composition.

[0044] Excipients that may be used in the fragrance and flavoring compositions and products of the present disclosure may vary depending on the use of the intended product and its overall composition. In some instances, the excipient may be included in the fragrance or flavor composition or may, alternatively, be independent of the composition. Excipients used in or with flavoring compositions of an orally administered medication may include, but are not limited to, tablet coatings, such as a cellulose ether hydroxypropyl methylcellulose, synthetic polymer, shellac, corn protein zein or other polysaccharides, and gelatin. In contrast, cosmetic excipients may include, but are not limited to, Carbopol 940 ETD, triethanolamine, purified water, glycerin, imidazolidinyl urea, EDTA, polyvinyl alcohol, methyl parabens phenoxyethanol 0, ethyl alcohol 1, peg 7 glyceryl cocoate, peg 6 triglyceryl caproic glycerides, acemulogar LAM V, isopropyl myristate, tegosoft CT, xanthan gum, sepicide CI.,, polyquatenuum 7, and Vaseline oils. Additional suitable excipients foruse with or in a flavor and / or fragrance composition for a given product will be readily selected by those having ordinary skill in the art.

[0045] Buffers that may be used with the fragrance and flavoring compositions of the present application may vary depending on the use of the intended product and its overall composition. In some instances, the buffer may be included in the fragrance or flavor composition or may, alternatively, be independent of the composition. Examples of buffers that may be used in or with the fragrance and flavor compositions of the application include, but are not limited to, citrates, acetates, and phosphates. For example, trisodium citrate may be used as a flavor or as a preservative, and is known to impart tartness to a flavor, but also acts as a buffer. Trisodium citrate is an ingredient in a variety of sodas and other beverages, as well as drink mixes and bratwurst. In cosmetic products, disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate and, and citric acid may be used to buffer the pH of the product. In toothpaste, calcium carbonate and / or dicalcium phosphate may be used as pH buffers. Additional suitable buffers for use with or in a flavor and / or fragrance composition for a given product will be readily selected by those having ordinary skill in the art.

[0046] In a third aspect, the present disclosure provides a product which comprises Compound 1, or any of 1.1-1.69, or Composition 1 or any of 1.1 to 1.11. In some embodiments, the product may be selected from the following: personal care products (e.g., a soap, skin cream or lotion, balm, shampoo, body wash, shower gel, hydrating cream, deodorant, antiperspirant, aftershave lotion, cologne, perfume, or other hair care or skin care product), sunscreens, insect repellants and insecticides, detergents, household cleaning agents (e.g., a surface cleaner, a metal cleaner, a wood cleaner, a glass cleaner, a body cleaner such as a soap, a dish-washing detergent, or a laundry detergent), air fresheners, room sprays, pomanders, candles, cosmetics (e.g., perfumes, colognes, nail polish, eye liner, mascara, lipstick, foundation, concealer, blush, bronzer, eye shadow, lip liner, lip balm), toilet waters, talcum powders, and pet litter.

[0047] Having now described some embodiments of the application, it should be apparent to those skilled in the art that the foregoing is merely illustrative and not limiting, having been presented by way of example only. The embodiments of the application can therefore be in other specific forms without departing from the spirit or essential characteristics thereof.

[0048] Those skilled in the: art should recognize or be able to ascertain, using no more than routine experimentation, equivalents to the specific embodiments of the application. It is therefore to be understood that the embodiments described herein are presented by way of example only and that the scope of the application is thus indicated by the appended claims and equivalents thereto,and that the application may be practiced otherwise than as specifically described in the foregoing description.

[0049] The term “about,” when used to describe one of the compositions of the application, refers to a recited percentage ±5%, ±4%, ±3%, ±2.5%, ±2%, ±1.5%, ±1%, ±0.75%, ±0.5%, ±0.25%, or ±0.1%. In one embodiment, the term “about,” refers to a recited percentage ±5%. For example, “about 50%” refers to the range 45% to 55%. In one embodiment, the term “about,” refers to a recited percentage ±2.5%. In one embodiment, the term “about,” refers to a recited percentage ±1%. In one embodiment, the term “about,” refers to a recited percentage ±0.5%. In one embodiment, the term “about,” refers to a recited percentage ±0.1%.

[0050] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a fragrance ingredient” includes not only a single fragrance ingredient but also a combination or mixture of two or more different fragrance ingredients, reference to “an additive” includes a single additive as well as two or more additives, and the like.

[0051] As used herein, the phrases “for example,” “for instance,” “such as,” or “including” are meant to introduce examples that further clarify more general subject matter. These examples are provided only as an aid for understanding the disclosure, and are not meant to be limiting in any fashion. Furthermore, as used herein, the terms “may,” “optional,” “optionally,” or “may optionally” mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, the phrase “optionally present” means that an object may or may not be present, and, thus, the description includes instances wherein the object is present and instances wherein the object is not present.

[0052] As used herein, “optionally substituted” means that the indicated core or functional group is either unsubstituted or substituted by one or more groups up to the maximum permitted by the rules of valency, wherein said groups are selected from: halo, hydroxy, cyano, C1-6alkyl, C2- ealkenyl, Cz-ealkynyl, C3-6cycloalkyl, Ci-6haloalkyl, Ci-6-alkoxy, -O-Si(Rx)3, -O-Rx, -C(O)H, -C(O)- Rx, -C(O)-O-RX, -C(O)-NH-RX, -C(O)-N-(RX)(RX), -O-C(O)-RX, -NH(RX)-C(O)-RX, -N(RX)(RX)-C(O)- RX),-NH(RX), -N(RX)(RX), heterocycloalkyl, aryl, and heteroaryl; wherein each of said C1-6alkyl, C3- 6cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further optionally substituted by one or more halo, hydroxy, cyano, C1-6alkyl, C^-ealkenyl, C2-6alkynyl, C3-6cycloalkyl, Ci-ehaloalkyl, -O-Si(Rx)3, -O-Rx, -C(O)H, -C(O)-RX, -C(O)-O-RX, -C(O)-NH-RX, -C(O)-N-(RX)(RX), -O-C(O)-RX, -NH(RX)-C(O)-RX, - N(RX)(RX)-C(O)-RX),-NH(RX), -N(RX)(RX), heterocycloalkyl, aryl, and heteroaryl; and wherein eachRxis independently selected from hydrogen, C16alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, heterocycloalkyl, aryl and heteroaryl.

[0053] As used herein, the term “Ci-6-alkyl” means a saturated linear or branched free radical consisting essentially of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms. Exemplary Ci-6-alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and thexyl. Other Ci-6-alkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. The terms “Ci-3-alkyl”, “Ci-4-alkyl”, etc., have equivalent meanings, i.e., saturated linear or branched free radical consisting essentially of 1 to 3 (or 4) carbon atoms and a corresponding number of hydrogen atoms. The similar terms “C2-6-alkenyl,” “C2-6-alkynyl,” “C3-6-cycloalkyl,” “Ci-6 -haloalky 1,” “Ci-6- alkoxy,” and the like, refer to corresponding functional groups having the stated number of carbon atoms, wherein “alkenyl” refers to an unsaturated linear or branched free radical having at least one double bond, “alkynyl” refers to an unsaturated linear or branched free radical having at least one triple bond, “haloalkyl” refers to an alkyl radical having at least one halogen atom attached to a carbon atom, and “alkoxy” refers to an alkyl radical having at least one oxygen atom attached to the alkyl radical and wherein the attachment point of the functional group is through the oxygen (i.e., to form an ether). Exemplary alkenyl groups include vinyl and allyl. Exemplary alkynyl groups include ethynyl and propynyl. Exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluorethyl, and like groups with chlorine, bromine or iodine. “Cycloalkyl” refers to a carbocyclic ring attached via a ring carbon atom. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0054] As used herein, the term “heteroaryl” means an aromatic free radical having 5 to 20 atoms (i.e., ring atoms) that form a ring, wherein at least one atom (e.g., 1 to 5) of the ring atoms are carbon and at least one atom of the remaining ring atoms is a nitrogen, sulfur, or oxygen. Heteroaryl rings include monocyclic, bicyclic fused, and polycyclic fused ring systems provided that at least one ring of the ring system has at least one heteroatom (N, S, or O), and all rings are aromatic. Exemplary 5-membered heteroaryl groups include furyl, thienyl (thiophenyl), pyrrolyl, oxazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. Exemplary 6-membered heteroaryl groups include pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and 1,2,4-triazinyl. Exemplary fused heteroaryl groups include benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl. Other heteroaryl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. In general, the heteroaryl group typically isattached to the main structure via a carbon atom. However, those of skill in the art will realize that certain other atoms, e.g., hetero ring atoms, can be attached to the main structure.

[0055] As used herein, the term “aryl” means an aromatic free radical having 5 or 6 atoms (i.e., ring atoms) that form a ring, wherein all of the ring atoms are carbon. Exemplary aryl groups include phenyl and naphthyl.

[0056] As used herein, the term “heterocycloalkyl” means an aromatic free radical having 3 to 20 atoms (i.e., ring atoms) that form a ring, wherein at least one atom (e.g., 1 to 5) of the ring atoms are carbon and at least one atom of the remaining ring atoms is a nitrogen, sulfur, or oxygen, and wherein at least one ring is non-aromatic. Heterocycloalkyl rings include monocyclic, bicyclic fused, bicyclic spiro-joined, polycyclic bridged, and polycyclic fused ring systems, provided that at least one ring of the ring system has at least one heteroatom (N, S, or O) and at least one ring of the ring system is non-aromatic (e.g., saturated). Exemplary saturated heterocycloalkyl groups include azetidinyl, aziridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl. Heterocycloalkyl rings systems include ring systems in which an aromatic ring is fused to a nonaromatic ring, such as will be obtained by partial reduction of a polycyclic aromatic ring system. Exemplary ring systems of this category include indolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Other heterocycloalkyl groups will be readily apparent to those of skill in the art given the benefit of the present disclosure. A heterocycloalkyl groups can be attached to the main structure either through a carbon atom or a nitrogen atom of the ring.

[0057] The term “compound,” as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives thereof where applicable, in context. Within its use in context, the term compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and / or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds. The term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. The term also refers to any specific chemical compound in which one or more atoms have been replaced with one or more different isotopes of the same element.

[0058] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference in its entirety for all purposes. The function and advantages ofthese and other embodiments will be more fully understood from the following non-limiting examples. The examples are intended to be illustrative in nature and are not to be considered as limiting the scope of the embodiments discussed herein.EXAMPLES

[0059] There are also several known synthetic routes to provide polysubstituted pyrazoles from hydrazine and hydrazones by reacting with carbonyl compounds and carbonyl compound equivalents, for example:See: Katritsky et al., J. Het. Chem. 37(5): 1309- 14 (2000); Almirante, et al., Synlett 3:299-302 (1999); Gharbaoui et al., Bioorg. & Med. Chem. Lett. 17(17): 4914-19 (2007); Moir et al., Eur. J. Med. Chem. 210: 113087 (2021); Lee et al., Bioorg. & Med. Chem. Lett. 27(18): 4383-88 (2017); Suchankova et al., ACS Med. Chem. Lett. 13(6): 932-34 (2022).

[0060] Further elaboration of functional groups attached to the pyrazole core, may be carried out according to standard methods, e.g., ester hydrolysis, Grignard addition, ketone reduction, alcohol oxidation, ester formation, N-alkylation, etc.

[0061] Ethyl l,3-dimethyl-5-pyrazolecarboxylate is obtained and its olfactory qualities are studied. Both the neat liquid compound and a 10% dilution of the compound in ethanol are examined by an experienced fragrance chemist (a master perfumer). It is found that the compound exhibits an odor characterized as floral, chocolate, blond wood, orris, soft leather, and a unique style.

[0062] Synthetic Examples

[0063] The Compounds of Examples 1 to 164 may be prepared according to the procedures described hereinbelow.

[0064] 1H-NMR spectra were recorded at 400 MHz on a Bruker Avance AV-I-400 instrument or on a Bruker Avance AV-II-400 instrument. Chemical shift values arc expressed in ppm-values relative to tetramethylsilane unless noted otherwise. The following abbreviations or their combinations are used for multiplicity of NMR signals: br = broad, d = doublet, m = multiplet, q = quartet, quint = quintet, s = singlet and t = triplet.

[0065] Purification method information:Method A: MS instrument type: ACQ-SQD2; HPLC instrument type: Waters Modular Preparative HPLC System; column: Waters XSelect (Cl 8, 100x30mm, 10); flow: 55 ml / min prep pump; column temp: RT; eluent A: lOmM ammonium bicarbonate in water pl 1=9.5, eluent B: 100% acetonitrile; lin. gradient: t=0 min 2% B, t=4 min 2% B, t=I3 min 30% B, t=14.5 100% B, t=17 min 100% B; detection: DAD (220-320 nm); detection: MSD (ESI pos / neg) mass range: 100 - 800; fraction collection based on MS and DAD.Method B: Flash chromatography (SiO2, 0-40% EtOAc in heptanes)Method C: MS instrument type: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1290 preparative LC; Column: Waters XSelect CSH (C18, 100x30mm, lOp); Flow: 55 ml / min; Column temp: RT; Eluent A: lOmM ammonium bicarbonate in water pH=9.5; Eluent B: 100% acetonitrile lin. gradient: t=0 min 2% B, t=2 min 2% B, t=8.5 min 30% B, t=10 min 100% B, t=13 min 100% B; Detection: DAD (220- 320 nm); Detection: MSD (ESI pos / neg) mass range: 100 - 1000; Fraction collection based on MS and DAD.Method D: Flash chromatography (SiO2, 0-30% EtOAc in heptanes) Method E: Flash chromatography (SiO2, 0-50% EtOAc in heptanes) Method F: Flash chromatography (SiO2, 0-60% EtOAc in heptanes) Method G: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 pm); Column temp: 40°C; Flow: 100 ml / min; ABPR: 120 bar; Eluent A:C02, Eluent B: 20 mM Ammonia in Ethanol; Isocratic method: 50% B for 8 min; Detection: UV 210; Collection: Timed.Method H: Flash chromatography (SiO2, 0-100% EtOAc in heptanes)Method I: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Cellulose-5 (250x21.2 mm, 5 pm); Column temp: 40°C; Flow: 100 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Methanol; Isocratic method: 50% B for 8 min; Detection: UV 210; Collection: Timed.Method J: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux Amylose- 1 (250x21mm, 5pm); Column temp: 40°C; Flow: 100 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Ethanol; Isocratic method: 50% B for 8 min; Detection: UV 210; Collection: Timed.Method K: Apparatus: Sepiatec Prep 250 SFC; Column: Phenomenex Lux Cellulose-2 (250x21.2 mm, 5pm); Column temp: 40°C; Flow: 100 ml / min; ABPR: 120 bar; Eluent A: CO2, Eluent B: 20 mM Ammonia in Ethanol; Linear gradient: t=0 min 10% B, t=6.5 min 50% B; t=7.5 min 50% B; Detection: UV 210; Collection: Timed.Method L: Flash chromatography (SiO2, 0-70% EtOAc in heptanes)Method M: Flash chromatography (SiO2, 0-80% EtOAc in heptanes)Method N: MS instrument type: Agilent Technologies G6130B Quadrupole; HPLC instrument type: Agilent Technologies 1200 preparative LC; Column: Waters Sunfire (C18, 150x19mm, lOp); Flow: 25 mL / min; Column temp: RT; Eluent A: 0.1% formic acid in water; Eluent B: 100% acetonitrile; lin. gradient: t=0 min 2% B, t=2 min 2% B, t=8.5 min 30% B, t= 10 min 100% B, t=13 min 100% B; Detection: DAD (220-320 nm); Detection: MSD (ESI pos / neg) mass range: 100 - 1000; Fraction collection based on MS and DAD.

[0066] LCMS Analytical method information:Method 1: UPLC: Waters I-Class, Acq. Method: UPLC_AN_ACID, Column: XSelect CSH C18 XP (50x2.1mm 2.5pm), Flow: 0.6 ml / min; Column temp: 40°C, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile, Gradient: t=0 min 5% B, t= 2.0 min 98% B, t=2.7 min 98% B, Posttime: 0.3 min, Detection PDA: 210-320nm and 215nm.Method 2: UPLC: Waters I-Class, Acq. Method: UPLC_AN_BASE, Column: XSelect CSH C18 XP (50x2.1mm 2.5pm), Flow: 0.6 ml / min; Column temp: 25°C, Eluent A: lOmM ammonium bicarbonate in water (pH 9.5), Eluent B: acetonitrile, Gradient: t=0 min 5% B, t=2 min 98% B, t=2.7 min 98% B, Posttime: 0.3 min, Detection PDA: 210-320nm.Method 3: Acq. Method: U_T3_ACID_00-20, System: Agilent 1290 with SQ-MSD, Column: XSelect HSS T3 XP (50x2.1mm, 2.5p), Flow: 0.8 ml / min; Column temp 40°C, Eluent A: 0.1% Formic acid in WaterEluent B: 0.1% Formic acid in Acetonitrile, Lin. Gradient: t=0 min 0% B, t=4.5 min 20% B, t=5 min 20% B, Posttime: 1 min, Detection: DAD (210, 215, 210-320nm), Detection: PDA (210-320nm), Detection: MSD (ESI pos / neg) mass range 90-1500.Method 4: Acq. Method: U_AN_ACID, System: Agilent 1290 with SQ-MSD, Column: XSelect CSH XP C18 (50x2.1mm, 2.5p), Flow: 0.8 ml / min Column temp 40°C, Eluent A: 0.1% Formic acid in Water, Eluent B: 0.1% Formic acid in Acetonitrile, Lin. Gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min 98% B; t=5 min 98% B, Posttime: 0.5 min, Detection: DAD (210-320nm, 215 nm), Detection: PDA (210-320nm), Detection: MSD (ESI pos / neg) mass range 90-1500.Method 5: Acq. Method: UPLC_AN_BASE, Column: XSelect CSH C18 XP (50x2.1mm 2.5pm), Flow: 0.6 ml / min; Column temp: 25°C, Eluent A: lOmM ammonium bicarbonate in water (pH=9.5) , Eluent B: 100% acetonitrile, Gradient: t=0 min 5% B, t=2 min 98% B, t=2.7 min 98% B, Posttime: 0.3 min, Detection PDA: 210-320nm, Detection ELSD: gas pressure 40 psi, drift tube temp: 50°C.Method 6: Acq. Method: U_AN_BASE, System: Agilent 1290 with SQ-MSD, Column: XSelect CSH XP C18 (50x2.1mm, 2.5p), Flow: 0.8 ml / min Column temp 25°C, Eluent A: lOmM ammonium bicarbonate in Water (pH 9.5), Eluent B: Acetonitrile, Lin. Gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min 98% B; t=5 min 98% B, Posttime: 0.5 min, Detection: DAD (210-320nm, 215 nm), Detection: PDA (210-320nm), Detection: MSD (ESI pos / neg) mass range 90-1500.Method 7: UPLC_SC_ACID, Instrument: Waters I-Class UPLC, Binary Solvent Manager (BSM), Sample Manager-FTN (SM-FTN) and Sample Organizer (SO), Column Manager (CM-A), PDA 210-320nm, QDa ESI 100-800 (pos) 100-800 (neg), Column: XSelect CSH C18 XP (50x2.1mm 2.5pm) Flow: 0.6 ml / min; Column temp: 40°C, Eluent A: 0.1% formic acid in water, Eluent B: 0.1% formic acid in acetonitrile, Gradient: t=0 min 5% B, t=1.3 min 98% B, t=1.7 min 98% B, Postrun: 0.3 min.Method 8: Method: SC_BASE.M, Instrument: Agilent 1260 Infinity, 1260 G1312B Bin. Pump, 1260 G1367E WPS, 1260 TCC G1316A Column Comp. 1260 G1315C DAD (210- 320 nm, 210 and 220nm), PDA (210-320 nm), G6130B MSD ESI pos / neg (mass range 100- 1000), Column: Waters XSelect CSH C18 (30x2.1mm 3.5p), Flow: 1 ml / min; ColumnTemp: 25 °C, Eluent AMO mM ammonium bicarbonate in water (pH 9), Eluent B: Acetonitrile, Gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, Postrun: 1.3 min. Method 9: Method: SC_ACID.M, Instrument: Agilent 1260 Infinity II, 1260 G7112B Bin. Pump, 1260 G7167A Multisampler, 1290 MCT G7116B Column Comp. 1260 G7115A DAD (210, 220 and 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI pos / neg) mass range 90-1500, 1290 G7102A ELSD (Evap: 50°C, Neb: 50°C, gas flow: 1.3 ml / min), Column: XSelect CSH C18 (30x2.1mm 3.5p) Flow: 1 ml / min, Column temp.: 40°C, Eluent A: 0.1% Formic acid in Water, Eluent B: 0.1% Formic acid in Acetonitrile, Gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, Postrun: 1.3 min.Method 10: Method: SC_BASE.M, Instrument: Agilent 1260 Infinity, 1260 G1312B Bin. Pump, 1260 G1367E WPS, 1260 TCC G1316A Column Comp. 1260 G1315C DAD (210- 320 nm, 210 and 220nm), PDA (210-320 nm), G6130B MSD (ESI pos / neg) mass range: 100 - 1000, Column: Waters XSelect CSH C18 (30x2.1mm, 3.5p) , Flow: 1 ml / min Column temp: 25°C, Eluent A: lOmM ammonium bicarbonate in water (pH=9), Eluent B: Acetonitrile, Gradient: t=0min 5% B, t=1.6min 98% B, t=3 min 98% B, Postrun: 1.4 min.

[0067] Example 1: N.L3.5-tetramethyl-l II-pyrazole-4-carboxamide

[0069] To l,3,5-Trimethylpyrazole-4-carboxylic acid (750 mg, 1 Eq, 4.86 mmol) in DMF(24.3 mL) was added methylamine in THF (3.65 mL, 2.0 molar, 1.5 Eq, 7.30 mmol), EDCI (1.12 g,1.2 Eq, 5.84 mmol), Oxyma Pure (760 mg, 1.1 Eq, 5.35 mmol) and Triethylamine (2.03 mL, 3 Eq, 14.6 mmol). Stirred at 50 °C for 16 hours. Purified by purification Method C, afforded the title compound: 578.1 mg (71.1% yield, 96.37% purity). LCMS: Method 1, 0.61 min, M+H = 168.07; calcd. 168.212, 1H NMR (400 MHz, CDC13) 55.54 (s, 1H), 3.72 (s, 3H), 2.96 (d, J = 4.8 Hz, 3H),2.48 (s, 3H), 2.39 (s, 3H).

[0070] Example 2: N.L3-trimethyl- 1 H-pvrazole-4-carboxamide

[0071]

[0072] To l,3-Dimethylpyrazole-4-carboxylic acid (1000 mg, 1 Eq, 7.136 mmol) in DMF(35.68 mL) was added methylamine in THF (5.352 mL, 2.0 molar, 1.5 Eq, 10.70 mmol), EDCI(1.642 g, 1.2 Eq, 8.563 mmol), Oxyma Pure (1.115 g, 1.1 Eq, 7.849 mmol) and Triethylamine (2.98mL, 3 Eq, 21.41 mmol). Stirred at 50 °C for 16 hours. Purified by purification Method N, afforded the title compound: 670.9 mg (61.3% yield, 100% purity). LCMS: Method 1, 0.59 min, M+H = 154.05; calcd. 154.185, 1H NMR (400 MHz, CDC13) 5 7.67 (s, 1H), 5.61 (s, 1H), 3.83 (s, 3H), 2.95 (d, J = 4.8 Hz, 3H), 2.46 (s, 3H).

[0073] Example 3: N,N,l,3-tetramethyl-lH-pyrazole-4-carboxamide

[0075] To l,3-Dimethylpyrazole-4-carboxylic acid (1000 mg, 1 Eq, 7.136 mmol) in DMF (35.68 mL) was added dimethylamine hydrochloride (872.8 mg, 1.5 Eq, 10.70 mmol), EDCI (1.642 g, 1.2 Eq, 8.563 mmol), Oxyma Pure (1.115 g, 1.1 Eq, 7.849 mmol) and Triethylamine (2.98 mL, 3 Eq, 21 .41 mmol). Stirred at 50 °C for 16 hours. Purified by purification method C, afforded the title compound: 679.9 mg (56.9% yield, 100% purity). LCMS: Method 1, 0.66 min, M+H = 168.06; calcd. 168.212, 1H NMR (400 MHz, CDC13) 57.43 (s, 1H), 3.84 (s, 3H), 3.07 (s, 6H), 2.33 (s, 3H).

[0076] Example 4: ethyl 2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3- carboxylate

[0078] To cyclopentanone (53 mL, 1 Eq, 594.4 mmol) and diethyl oxalate (81.54 mL, 1.01 Eq, 600.3 mmol) in ethanol (250 mL) was added dropwise sodium ethoxide (21% in EtOH) (0.20 L, 21% Wt., 1.01 Eq, 600.3 mmol) over a period of 30 min. The mixture was stirred at room temperature for 16h and concentrated. To the crude sodium 2-(2-ethoxy-2-oxoacetyl)cyclopent-l-en- 1-olate (5.0 g, 0.041 Eq, 24 mmol) was added AcOH (12.5 mL) and the gel mixture was cooled to 0 °C. Dropwise was added Methylhydrazine (1.40 mL, 0.0444 Eq, 26.4 mmol) and after addition, the gel was allowed to warm to room temperature and gently vortexed forming a suspension, which was stirred at room temperate for 16h. Solids were filtered, the filtrated was concentrated in vacuo, partitioned between DCM and aq. sat. NaHCO3 + aq. NaOH (6 M) (ca. 9: 1; total water volume ca. 100 mL) and mixed vigorously. The layers were separated and the aqueous layer was extracted with DCM. Combined organics were dried over NaiSCU, filtered, concentrated and purified by flash column chromatography (SiCL, 5-60% EtOAc in heptanes), afforded the title compound (672 mg, 3.46 mmol, 14.2% yield). LCMS: Method 1, 1.45 min, M+H - 195.11; calcd. 195.234, 1H NMR(400 MHz, DMSO) 5 4.25 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.39 - 2.28 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0079] Example 5: ethyl 5-isopropyl-lH-pyrazole-4-carboxylate

[0080]

[0081] To ethyl 4-methyl-3-oxopentanoate (10.0 g, 1 Eq, 63.2 mmol) and 1,1-dimethoxy- N,N-dlmethylmethanamlne (10.1 mL, 1.2 Eq, 75.9 mmol) in 2,2,2-Trifluoroethanol (50.0 inL) at 0°C was added dropwise hydrazine hydrate (3.07 mL, 1 Eq, 63.2 mmol) in 2,2,2-Trifluoroethanol (50.0 mL) and mixture allowed to warm to room temperature and stirred for 18h. Concentrated, water (100 ml) added to the residue and mixture extracted with ethyl acetate (2x 100 ml). The organic phase was washed with sat. aq. NaHCCL, water, dried over MgSCL, filtered and concentrated. Purification by flash column chromatography (SiCL, 0-100% EtOAc in heptanes), afforded the title compound (8.67 g, 44 mmol, 69 % yield). 1H NMR (400 MHz, CDC13) 5 12.03 (s, 1H), 7.96 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.70 (hept, J = 7.0 Hz, 1H), 1.42 - 1.28 (m, 9H).

[0082] Example 6: ethyl 3-isopropyl-l-methyl-lH-pyrazole-4-carboxylate

[0084] To ethyl 5-isopropyl-lH-pyrazole-4-carboxylate (1.0 g, 92% Wt., 1 Eq, 5.0 mmol) in N,N-Dimethylformamide (10 mL) were added potassium carbonate (0.84 g, 1.2 Eq, 6.1 mmol) and iodomethane (0.38 mL, 1.2 Eq, 6.1 mmol) and the mixture was stirred at room temperature for 5 hours. Concentrated, redissolved in DCM / water, the organic layers were separated and the N, N aqueous layer was extracted with DCM (2x). The combined organics were dried over Na2SO4, filtered and concentrated. Purified by purification method G, affording ethyl 3-isopropyl-l-methyl- lH-pyrazole-4-carboxylate: 460.3 mg (46% yield, 100% purity). LCMS: Method 1, 1.33 min, M+H = 197.06; calcd. 197.25, 1H NMR (400 MHz, CDC13) 57.79 (s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.53 (hept, J = 6.9 Hz, 1H), 1.38 - 1.24 (m, 9H).

[0085] Example 7: ethyl l,3,4-trimethyl-lH-pyrazole-5-carboxylate

[0086]

[0087] Step 1: ethyl 4-(chloromethyl)-l,3-dimethyl-lH-pyrazole-5-carboxylate

[0088] To hydrochloric acid (1.10 mL, 6 Eq, 35.7 mmol) and sulfuric acid (31.7 pL, 0.1 Eq, 595 pmol) were added subsequently 1,4-Dioxane (10 mL), paraformaldehyde (357 mg, 2 Eq, 11.9 mmol) and ethyl l,3-dimethyl-lH-pyrazole-5-carboxylate (893 pL, 1 Eq, 5.95 mmol) and the mixture was heated under reflux for 5h. The mixture was concentrated, ice water was added and mixture extracted with EtOAc. The aqueous phase was extracted once with EtOAc and combined organics were washed with brine, dried over Na2SO4, filtered and concentrated, affording ethyl 4- (chloromethyl)-l,3-dimethyl-lH-pyrazole-5-carboxylate (1.05 g, 4.85 mmol, 81.5 % yield). LCMS: Method 8, 1.91 min, M+H = 217.0; calcd. 217.66.

[0089] Step 2: ethyl l,3,4-trimethyl-lH-pyrazole-5-carboxylate

[0091] To ethyl 4-(chloromethyl)-l,3-dimethyl-lH-pyrazole-5-carboxylate (1.05 g, 1 Eq, 4.85 mmol) in Ethanol (20 mL) under nitrogen atmosphere was added palladium on carbon (516 mg, 5% Wt., 0.05 Eq, 242 pmol) and the mixture was placed under hydrogen atmosphere via 3 vacuum hydrogen cycles and stirred at room temperature for 18h. Filtered over celite and the filtrate concentrated. Purification by flash column chromatography (SiCE, 0-100% EtOAc in heptanes), afforded ethyl l,3,4-trimethyl-lH-pyrazole-5-carboxylate (439 mg, 2.41 mmol, 49.7 % yield).LCMS: Method 1, 1.38 min, M+H = 183.1; calcd. 183.223, 1H NMR (400 MHz, CDC13) 54.36 (q, J = 7.1 Hz, 2H), 4.07 (s, 3H), 2.18 (d, J = 4.0 Hz, 6H), 1.39 (t, J = 7.2 Hz, 3H).

[0092] Example 8: ethyl 6,6-dimethyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3- carboxylate

[0094] Step 1: ethyl 2-(2-hydroxy-3,3-dimethylcyclopent-l-en-l-yl)-2-oxoacetate

[0095] To diethyl oxalate (12.25 g, 1 Eq, 84.97 mmol) and 2,2-dimethylcyclopentan-l-one (10.8 mL, 1.01 Eq, 85.82 mmol) in EtOH (30 mL) was added sodium ethoxide (32.0 mL, 21% Wt., 1.01 Eq, 85.82 mmol) and the mixture stirred at room temperature for 16h. Ice water (200 mL) was added, mixture brought to pH 4 -5 by addition of concentrated acetic acid and mixture extracted with Et O. The aqueous layer was extracted once with Et20 and combined organics were dried over Na2SO4, filtered and concentrated, affording ethyl 2-(2-hydroxy-3,3-dimethylcyclopent-l-en-l-yl)-2-oxoacetate (15.16 g, 71.43 mmol, 84.06 % yield). LCMS: Method 8, 1.91 min, M+H = 213.0; calcd. 213.24.

[0096] Step 2: ethyl 6,6-dimethyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate

[0098] To ethyl 2-(2-hydroxy-3,3-dimethylcyclopent-l-en-l-yl)-2-oxoacetate (8.50 g, 1 Eq, 40.0 mmol) in EtOH (75 mL) was added hydrazine hydrate (3.20 mL, 64% Wt., 1.05 Eq, 42.1 mmol) and mixture heated under reflux for 16h. acetic acid (5.0 mL, 2.2 Eq, 87 mmol) was added and the mixture was heated under reflux for Ih and concentrated. Dissolved in DCM and washed with sat aq NaHCO s, brine, dried over NaiSO-t, filtered and concentrated. Purification by flash column chromatography (SiO2, 0-100% EtOAc in heptanes), afforded ethyl 6,6-dimethyl-l ,4,5,6- tetrahydrocyclopenta[c]pyrazole-3-carboxylate (3.88 g, 18.6 mmol 46.5 % yield). LCMS: Method 1, 1.38 min, M+H = 209.1; calcd. 209.261, IH NMR (400 MHz, CDC13) 6 10.47 (brs, IH), 4.35 (q, J = 7.2 Hz, 2H), 2.78 (t, J = 7.0 Hz, 2H), 2.27 (t, J = 7.0 Hz, 2H), 1.46 - 1.26 (m, 9H).

[0099] Example 9 and 10: ethyl 2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3- carboxylate and ethyl l-methyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate

[0101] To ethyl l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (10.00 g, 1 Eq, 55.49 mmol) in DMF (75 mL) were added potassium carbonate (15.34 g, 2 Eq, 111.0 mmol) and iodomethane (4.164 mL, 1.20 Eq, 66.59 mmol) and mixture was stirred at room temperature for 16h. Diluted with water and EtOAc and layers separated. The aqueous was extracted with EtOAc (2x) and the combined organics were washed with brine, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (SiO2, 0-100% EtOAc in heptanes), afforded ethyl 2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (5.28 g, 27.2 mmol, 49.0 % yield.), LCMS: Method 1, 1.45 min, M+H = 195.1; calcd. 195.234. IH NMR (400 MHz, CDC13) 5 4.31 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 2.75 (dt, J = 26.4, 7.3 Hz, 4H), 2.46 - 2.35 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H), and ethyl l-methyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (3.99 g, 20.5 mmol, 37.0 % yield). LCMS: Method 1, 1.2 min, M+H = 195.1; calcd. 195.234, IH NMR (400 MHz, CDC13) 54.36 (qd, J = 7.1, 0.9 Hz, 2H), 3.82 (d, J = 0.8 Hz, 3H), 2.84 - 2.76 (m, 2H), 2.70 (t, J = 7.1 Hz, 2H), 2.65 - 2.52 (m, 2H), 1.37 (td, J = 7.1, 0.8 Hz, 3H).

[0102] Examples 11 and 12: ethyl 3-isopropyl-l-methyl-lH-pyrazole-5-carboxylate and ethyl 5-isopropyl-l-methyl-lH-pyrazole-3-carboxylate

[0103]

[0104] To ethyl 5-methyl-2,4-dioxohexanoate (12.50 g, 1 Eq, 67.13 mmol) in EtOH (100 mL) was added methylhydrazine (3.75 mL, 1.05 Eq, 70.48 mmol) and mixture stirred under reflux for 2h, concentrated, suspended in DCM and solids filtered off. Purification by flash column chromatography (SiO2, 0-100% EtOAc in heptanes), afforded ethyl 3-isopropyl-l-methyl-lH- pyrazole-5-carboxylate (3.69 g, 18.8 mmol, 28.0 % yield). LCMS: Method 1, 1.55 min, M+H = 197.1; calcd. 197.25, 1H NMR (400 MHz, CDC13) 86.65 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.12 (s, 3H), 2.97 (hept, J = 7.0 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H), 1.26 (d, J = 7.0 Hz, 6H), and ethyl 5- isopropyl-l-methyl-lH-pyrazole-3-carboxylate (7.53 g, 38.4 mmol, 57.2 % yield). LCMS: Method 1, 1.29 min, M+H = 197.1; calcd. 197.25, 1H NMR (400 MHz, CDC13) 8 6.59 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 2.94 (p, J = 6.8 Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H), 1.27 (d, J = 6.9 Hz, 6H).

[0105] Examples 13 and 14: ethyl 5-propyl-lH-pyrazole-3-carboxylate and ethyl 4- ethyl-5-methyl-lH-pyrazole-3-carboxylate

[0106]

[0107] Step 1: ethyl 2,4-dioxoheptanoate. To pentan-2-one (30.9 mL, 1 Eq, 290.3 mmol) and diethyl oxalate (39.42 mL, 1 Eq, 290.3 mmol) in EtOH (150 mL) was added dropwise sodium ethoxide (109 mL, 21% Wt., 1.01 Eq, 293.2 mmol) and the mixture was stirred at room temperature for 16h, then it was concentrated, acidified by addition of 1 M aq. HO and extracted with DCM (2x). Combined organics were washed with brine, dried over Na2SO4, filtered and concentrated, affording ethyl 2,4-dioxoheptanoate (47.16 g, 253.3 mmol, 87.25 % yield). LCMS: Method 9, 1.81 min, M+H = 187.0; calcd. 187.21.

[0108] Step 2: ethyl 5-propyl-lH-pyrazole-3-carboxylate and ethyl 4-ethyl-5-methyl-lH- pyrazole-3-carboxylate

[0109]

[0110] To ethyl 2,4-dioxoheptanoate (20.00 g, 1 Eq, 107.4 mmol) in EtOH (175 mL) was added hydrazine hydrate (8.581 mL, 64% Wt., 1.05 Eq, 112.8 mmol) and mixture heated underreflux for 3h. Concentrated, suspended in DCM and solids filtered off. Purification by flash column chromatography (SiO2, gradient 0-100% EtOAc in heptanes, 2x), followed by purification by method J (2x), affording ethyl 5-propyl-lH-pyrazole-3-carboxylate (5.09 g, 27.9 mmol, 26.0 % yield). LCMS: Method 1, 1.22 min, M+H = 183; calcd. 183.223, 1H NMR (400 MHz, CDC13) 5 10.20 (brs, 1H), 6.63 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.70 (h, J = 7.5 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H), and ethyl 4-ethyl-5-methyl-lH-pyrazole-3- carboxylate (873 mg, 4.79 mmol, 4.46 % yield). LCMS: Method 1, 1.21 min, M+H = 183.1; calcd. 183.223, 1H NMR (400 MHz, CDC13) 5 4.38 (q, J = 7.1 Hz, 2H), 2.70 (q, J = 7.5 Hz, 2H), 2.26 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.5 Hz, 3H). 1 H signal missing.

[0111] Examples 15. 16, 17, and 18: ethyl l-methyl-3-propyl-lH-pyrazole-5- carboxylate, ethyl 4-ethyl-l,3-dimethyl-lH-pyrazole-5-carboxylate, ethyl l-methyl-5-propyl- lH-pyrazole-3-carboxylate, and ethyl 4-ethyl-l,5-dimethyl-lH-pyrazole-3-carboxylate

[0112]

[0113] To ethyl 2,4-dioxoheptanoate (26.90 g, 1 Eq, 144.5 mmol) in EtOH (200 mL) was added methylhydrazine (8.06 mL, 1.05 Eq, 151.7 mmol) and the mixture was stirred under reflux for 5h. Concentrated, suspended in DCM and solids filtered off. Purified by flash column chromatography (SiO2, gradient 0-100% EtOAc in heptanes), affording ethyl l-methyl-3-propyl-lH- pyrazole-5-carboxylate (7.33 g, 37.4 mmol, 25.9 % yield). LCMS: Method 1, 1.54 min, M+H = 197.1; calcd. 197.25, 1H NMR (400 MHz, CDC13) 86.62 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 2.66 - 2.53 (m, 2H), 1.67 (dt, J = 15.0, 7.4 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 0.96 (t, J = 7.3 Hz, 3H), and ethyl 4-ethyl-l,3-dimethyl-lH-pyrazole-5-carboxylate (1.02 g, 5.20 mmol, 3.60 % yield). LCMS: Method 1, 1.49 min, M+H = 197.1; calcd. 197.25, 1H NMR (400 MHz, CDC13) 64.36 (q, J = 7.1 Hz, 2H), 4.06 (s, 3H), 2.64 (q, J = 7.5 Hz, 2H), 2.20 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.4 Hz, 3H), and ethyl l-methyl-5-propyl-lH-pyrazole-3-carboxylate (13.05 g, 66.50 mmol, 46.03 % yield). LCMS: Method 1, 1.31 min, M+H = 197.1; calcd. 197.25, 1H NMR (400 MHz, CDC13) 8 6.58 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 2.58 (t, J = 7.5 Hz, 2H), 1.69 (h, J = 7.4 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H), and ethyl 4-ethyl-l,5-dimethyl-lH-pyrazole-3- carboxylate (after purification method K,) (463.7 mg, 2.363 mmol, 1.636 % yield). LCMS: Method1, 1.27 min, M+H = 197.1; ealed. 197.25, 1H NMR (400 MHz, CDC13) 54.39 (q, J = 7.1 Hz, 2H),3.83 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 2.20 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.4 Hz, 3H).

[0114] Examples 19: ethyl l,5-dimethyl-lH-pyrazole-3-carboxylate

[0115]

[0116] To l,5-dimethyl-lH-pyrazole-3-carboxylic acid (10 g, 1 Eq, 71 mmol) in ethanol(150 mL) was added dropwise thionyl chloride (16 mL, 3 Eq, 0.21 mol). The mixture was stirred at room temperature for 4 hours, concentrated, basified by addition of sat. aq. NaHCOa, extracted with DCM, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (SiO2, 0-30% EtOAc in heptanes), afforded ethyl l,5-dimethyl-lH-pyrazole-3-carboxylate (10.2 g, 60.6 mmol, 85 % yield). LCMS: Method 1, 1 min, M+H = 122.87 (fragment); ealed. 169.196, 1H NMR (400 MHz, CDC13) 5 6.57 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 2.3 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H).

[0117] Examples 20 and 21 : ethyl 3-ethyl-l-methyl-lH-pyrazole-5-carboxylate and ethyl 5-ethyl-l-methyl-lH-pyrazole-3-carboxylate

[0118]

[0119] To ethyl 2,4-dioxohexanoate (25.00 g, 1 Eq, 145.2 mmol) in EtOH (250 mL) was added Methylhydrazine (8.10 mL, 1 .05 Eq, 152.5 mmol) and mixture stirred under reflux for 3h and concentrated. Purification by flash column chromatography (SiCL. gradient 0-100% EtOAc in heptanes), afforded ethyl 3-ethyl-l-methyl-lH-pyrazole-5-carboxylate (7.76 g, 42.6 mmol, 29.3 % yield). LCMS: Method 1, 1.4 min, M+H = 183; ealed. 183.223, 1H NMR (400 MHz, CDC13) 5 6.64 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.6 Hz, 3H), and ethyl 5-ethyl-l-methyl-lH-pyrazole-3-carboxylate (17.86 g, 98.01 mmol, 67.50 % yield). LCMS: Method 1, 1.16 min, M+H - 183; ealed. 183.223, 1H NMR (400 MHz, CDC13) 5 6.59 (d, J = 1.0 Hz, 1H), 4.39 (qd, J = 7.2, 1.0 Hz, 2H), 3.85 (d, J = 0.9 Hz, 3H), 2.62 (q, J = 7.5 Hz, 2H), 1.39 (td, J = 7.2, 0.9 Hz, 3H), 1.29 (td, J = 7.5, 0.9 Hz, 3H).

[0120] Example 22: l,5-dimethyl-lH-pyrazole-3-carbaldehyde

[0122] To N-methoxy-N,l,5-trimethyl-lH-pyrazole-3-carboxamide (1.07 g, 1 Eq, 5.84 mmol) in Tetrahydrofuran (58.4 mL) under Nitrogen atmosphere at -78 °C was added lithium aluminum hydride (5.35 mL, 2.4 molar, 2.2 Eq, 12.8 mmol) and the mixture was stirred at -78 °C for 1 hour. The mixture was then poured into sat. aq. NH4C1 and extracted with EtOAc (3x). The organic layers were combined, dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (SiO2, gradient 0-100% EtOAc in heptanes), afforded 1,5-dimethyl-lH- pyrazole-3-carbaldehyde (167.8 mg, 1.352 mmol, 23.1 % yield). LCMS: Method 1, 0.77 min, M+H = 124.92; calcd. 125.143, 1H NMR (400 MHz, CDC13) 8 9.88 (s, 1H), 6.56 (s, 1H), 3.88 (s, 3H),2.32 (s, 3H).

[0123] Example 23: ethyl 5-ethyl-l,4-dimethyl-lH-pyrazole-3-carboxylate

[0124]

[0125] Step 1: ethyl 4-bromo-5-ethyl-l-methyl-lH-pyrazole-3-carboxylate

[0126] To ethyl 5-ethyl-l-methyl-lH-pyrazole-3-carboxylate (1.00 g, 1 Eq, 5.49 mmol) inDCE (20 mL) was added NBS (1.95 g, 2 Eq, 11.0 mmol) and the mixture was heated at 80 °C for 3h.Allowed to cool to room temperature and further diluted with DCM and water. Mixture filtered over a phase separator and the aqueous layer extracted twice with DCM. Combined organics were concentrated, and purification by flash column chromatography (SiO2, 0-100% EtOAc in heptanes), afforded ethyl 4-bromo-5-ethyl-l-methyl-lH-pyrazole-3-carboxylate (1.53 g, 5.86 mmol, 100% yield). LCMS: Method 9, 1.76 min, M+H = 261.0; calcd. 261.01.

[0127]

[0128] Step 2: ethyl 5-ethyl-l,4-dimethyl-lH-pyrazole-3-carboxylate:

[0129] To ethyl 4-bromo-5-ethyl-l -methyl- lH-pyrazole-3-carboxylate (1.43 g, 1 Eq, 5.48 mmol) in DMF (20 mL) under argon atmosphere was added potassium carbonate (2.27 g, 3 Eq, 16.4 mmol), 2,4,6-Trimethyl-l,3,5,2,4,6-trioxatriborinane (1.54 mL, 2 Eq, 11.0 mmol) and [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Complex.Dichloromethane (894 mg, 0.2 Eq, 1.10 mmol) and the mixture was stirred at 110 °C for 2h. Allowed to cool to room temperature and diluted with water and EtOAc. The aqueous was extracted once with EtOAc and the combined organics were washed with brine (2x), dried over Na2SO4, filtered and concentrated. Purification byflash column chromatography (SiO2, 0-100% EtOAc in heptanes), afforded ethyl 5-ethyl-l,4- dimethyl-lH-pyrazole-3-carboxylate (615.70 mg, 3.1373 mmol, 57.3 % yield). LCMS: Method 2, 1.33 min, M+H = 197.1; calcd. 197.25, 1H NMR (400 MHz, CDC13) 54.39 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.22 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H).

[0130] General procedure 1: Examples 24-35

[0131] The Compounds of Examples 24-35 are made according to the following general procedure via sulfuric-acid mediated esterification.

[0132]

[0133] To carboxylic acid (1 Eq) in alcohol (0.3 M) at 0°C was added sulfuric acid (1 Eq) and the mixture was heated under reflux until completion. Reaction mixture concentrated and basified by addition of sat. aq. NaHCOa, extracted with DCM, filtered over a phase separator, and concentrated. Purification (see method) provided the target.

[0134] The following examples were prepared according to general procedure 1 , starting from their corresponding acid and alcohol.

[0135] General procedure 2: Examples 36-116

[0136] The Compounds of Examples 36-116 are made according to the following general procedure via thionyl chloride mediated acyl halide formation and esterification.

[0137]

[0138] To carboxylic acid (1 Eq) in alcohol (0.3 M) was added thionyl chloride (1.5 - 11.2Eq) and the mixture was heated under reflux until completion. Reaction concentrated and basified byaddition of sat. aq. NaHCCh, extracted with DCM, filtered over a phase separator, and concentrated. Purification provided the target.

[0139] The following examples were prepared according to general procedure 2, starting from their corresponding acid and alcohol.

[0140] General procedure 3: Examples 117-164

[0141] The Compounds of Examples 117-164 are made according to the following general procedure via Grignard reagent (RMgX) addition to Weinreb amides.

[0143] Under nitrogen atmosphere, Grignard solution (2.5 - 5 Eq) was added dropwise to a solution of carboxamide (1 Eq) in tetrahydrofuran (0.2 M) at 0°C. The mixture was allowed to warm to room temperature and stirred until completion. The reaction was quenched by addition of sat. aq. NH4CI solution and concentrated. Diluted with sat. aq. NH4CI and DCM and layers separated. The aqueous was extracted with DCM and combined organics were dried over Na2SO4, filtered and concentrated. Purification (see method) provided the target.

[0144] The following examples were prepared according to general procedure 3, starting from their corresponding carboxamide and Grignard reagent (MeMgBr (3.0M in diethyl ether),EtMgBr (EOM in THF), PrMgBr (1.0M in THF), iPrMgBr (0.75M in THF).

[0145] Synthetic Intermediates

[0146] The following procedures provide synthetic intermediates used in General Procedures 1, 2, or 3 shown above.

[0147] N-methoxy-N,5-dimethyl-lH-pyrazole-3-carboxamide

[0149] N,O-Dimethyl-hydroxylamine HC1 (5.7 g, 3 Eq, 58 mmol) was added to a solution of lH-pyrazole-3-carboxylic acid, 5-methyl-, ethyl ester (3.0 g, 1 Eq, 19 mmol) in Tetrahydrofuran (19 mL). The mixture was cooled to -30 °C, isopropylmagnesium chloride (90 mL, 1.3 molar, 6 Eq, 0.12 mol) in THF was added and the mixture was stirred at -30 °C for 50 min. The reaction was quenched by addition of aq. HC1 (2 M). Layers were separated and the aqueous phase was extracted with THF and DCM, combined organic phases were dried over Na2SO4, filtered and concentrated. Purification by column chromatography (SiO2, 0-5% MeOH in DCM) afforded the title compound (1.4 g, 8.3mmol, 43 % yield). 1H NMR (400 MHz, CDC13) 8 10.83 (s, 1H), 6.59 (s, 1H), 3.78 (s, 3H), 3.38 (s, 3H), 2.35 (s, 3H).

[0150] Vmetlwxy-N.l.S-trimethyl- 1 H-pyrazole-3-cai boxamide:

[0152] To l,5-Dimethyl-lH-pyrazole-3 -carboxylic acid (2.5 g, 1 Eq, 18 mmol) and N,O- dimethyl-hydroxylamine HO (2.6 g, 1.5 Eq, 27 mmol) in dichloromethane (180 mL) were added HATU (7.5 g, 1.1 Eq, 20 mmol) and DIPEA (12 mL, 4 Eq, 71 mmol) and the mixture was stirred at room temperature for 15 minutes. The mixture was concentrated and purified by flash chromatography (SiO2, 0-100% [30% EtOH in EtOAc] in heptanes) affording N-methoxy-N,l,5- trimethyl-lH-pyrazole-3-carboxamide (2.37 g, 12.9 mmol, 73 % yield). 1H NMR (400 MHz, CDC13) 5 6.51 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.42 (s, 3H), 2.29 (s, 3H).

[0153] N-methoxy-N,4,5-trimethyl-lH-pyrazole-3-carboxamide

[0154]

[0155] To 4,5-dimethyl-lH-pyrazole-3-carboxylic acid (5.00 g, 1 Eq, 35.7 mmol) in DCM (75 mL) were added N,O-dimethyl-hydroxylamine HC1 (5.22 g, 1.5 Eq, 53.5 mmol), DIPEA (24.9 mL, 4 Eq, 143 mmol) and HATU (14.9 g, 1.1 Eq, 39.2 mmol). The mixture was stirred at room temperature for 16h, concentrated, and purification by flash column chromatography (SiO2, 0-100% [30% EtOH in EtOAc] in heptanes) afforded the title compound (2.53 g, 11 mmol, 32 % yield, 82% Purity). LCMS: Method 8, 1.39 min, M+H = 184.1; calcd. 184.21.

[0156] 3-isopropyl-l-methyl-lH-pyrazole-5-carboxylic acid hydrochloride

[0158] Ethyl 3-isopropyl-l-methyl-lH-pyrazole-5-carboxylate (3.1 g, 1 Eq, 16 mmol) was dispersed in hydrochloric acid, 35% in water (25 mL, 14 molar, 22 Eq, 0.35 mol) stirred at 80 °C for 16 hours. The resulting solution was concentrated to dryness and recrystallized from MeCN. The residue was washed with MeCN and concentrated to give the title compound (2.33 g, 11.4 mmol, 72 %, 100% Purity). LCMS: Method 9, 1.57 min, M+H = 169.0; calcd. 169.20.

[0159] 5-isopropyl-l-methyl-lH-pyrazole-3-carboxylic acid

[0160]

[0161] Ethyl 5-isopropyl-1 -methyl-lH-pyrazole-3-carboxylate (6.8 g, 1 Eq, 35 mmol) in 6M aq. NaOH in water (17 mL, 6.0 molar, 3 Eq, 0.10 mol), water (200 mL) and ethanol (100 mL) were stirred at room temperature for 2 h. The mixture was concentrated to remove most of the EtOH, washed with DCM, acidified with 1 M aq. HC1, extracted with DCM and concentrated to give the title compound (5.33 g, 31.7 mmol, 91 % yield). LCMS: Method 9, 1.53 min, M+H = 212.2; calcd.212.27.

[0162] N-methoxy-N,l,3-triniethyl- 1 H-pyrazole-5-carboxaniide

[0163]

[0164] To l,3-dimethyl-lH-pyrazole-5-carboxylic acid (3.16 g, 1 Eq, 22.5 mmol) and N,O- dimethyl-hydroxylamine HC1 (3.30 g, 1 .5 Eq, 33.8 mmol) in dichloromethane (100 mL) were added HATU (9.43 g, 1.1 Eq, 24.8 mmol) and DIPEA (11.8 mL, 3 Eq, 67.6 mmol) and the mixture was stirred at room temperature for Ih. The mixture was concentrated and purification by flash column chromatography (SiO2, 0-100% [30% EtOH in EtOAc] in heptanes) afforded the title compound (3.57 g, 19.5 mmol, 86.4 % yield). LCMS: Method 10, 1.51 min, M+H = 184.2; calcd. 184.21.

[0165] 5-isopropyl-N-methoxy-N,l-dimethyl-lH-pyrazole-3-carboxamide

[0167] To 5-isopropyl-l-methyLlH-pyrazole-3-carboxylic acid (1.9 g, 1 Eq, 11 mmol) and N,O-dimethyl-hydroxylamine HC1 (1.7 g, 1.5 Eq, 17 mmol) in dichloromethane (110 mL) were added HATU (4.7 g, 1.1 Eq, 12 mmol) and DIPEA (7.9 mL, 4 Eq, 45 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated and purification by flash column chromatography (SiCL, 0-100% [30% EtOH in EtOAc] in heptanes) afforded the title compound (2.44 g, 8.7 mmol, 77 % yield, 75% Purity). LCMS: Method 8, 1.39 min, M+H = 184.1; calcd. 184.21.

[0168] N-methoxy-N,l,3,4-tetramethyl-lH-pyrazole-5-carboxamide

[0169]

[0170] To l,3,4-trimethyl-lH-pyrazole-5-carboxylic acid (3.80 g, 1 Eq, 24.6 mmol) and N,O-dimethyl-hydroxylamine HC1 (3.61 g, 1.5 Eq, 37.0 mmol) in dichloromethane (100 mL) were added HATU (10.3 g, 1.1 Eq, 27.1 mmol) and DIPEA (17.2 mL, 4 Eq, 98.6 mmol) and the mixture was stirred at room temperature for Ih. The mixture was concentrated and purification by flash column chromatography (SiCL, 0-100% [30% EtOH in EtOAc] in heptanes) afforded N-methoxy- N,l,3,4-tetramethyl-lH-pyrazole-5-carboxamide (6.20 g, 26 mmol, 110 %, 83% Purity). LCMS: Method 8, 1.49 min, M+H = 198.1; calcd. 198.24.

[0171] 5-isopropyl-N-methoxy-N-methyl-lH-pyrazole-3-carboxamide

[0173] To 5-isopropyl-lH-pyrazole-3-carboxylic acid hydrochloride (2.25 g, 1 Eq, 11.8 mmol) and N,O-dimethyl-hydroxylamine HC1 (1.73 g, 1.5 Eq, 17.7 mmol) in dichloromethane (118 mL) were added HATU (4.49 g, 1 Eq, 11.8 mmol) and DIPEA (8.22 mL, 4 Eq, 47.2 mmol) and the mixture was stirred at room temperature for Ih. The mixture was concentrated and purification by flash column chromatography (SiCE, 0-100% [30% EtOH in EtOAc] in heptanes) afforded 5- isopropyl-N-methoxy-N-methyl-lH-pyrazole-3-carboxamide (1.03 g, 3.3 mmol, 28 % yield). IH NMR (400 MHz, CDC13) 8 10.64 (s, IH), 6.63 (s, IH), 3.79 (s, 3H), 3.38 (s, 3H), 3.10 - 2.96 (m, IH), 1.30 (d, J = 6.9 Hz, 6H).

[0174] 3-ethyl-N-methoxy-N,l-dimethyl-lH-pyrazole-5-carboxamide

[0176] To 3-ethyl-l-methyl-lH-pyrazole-5-carboxylic acid (3.00 g, 1 Eq, 19.5 mmol) and N,O-dimethyl-hydroxylamine HC1 (2.85 g, 1.5 Eq, 29.2 mmol) in dichloromethane (50 mL) were added HATU (8.14 g, 1.1 Eq, 21.4 mmol) and DIPEA (10.2 mL, 3 Eq, 58.4 mmol) and the mixture was stirred at room temperature for 16h. The mixture was concentrated and purification by flash column chromatography (SiCL, 0-100% [30% EtOH in EtOAc] in heptanes) afforded 3-ethyl-N- methoxy-N,l-dimethyl-lH-pyrazole-5-carboxamide (4.26 g, 21.6 mmol, 100 % yield). LCMS: Method 10, 1.60 min, M+H = 198.2; calcd. 198.24.

[0177] 5-ethyl-N-methoxy-N,l-dimethyl-lH-pyrazole-3-carboxamide (

[0179] To 5-ethyl-l-methyl-lH-pyrazole-3-carboxylic acid (3.44 g, 1 Eq, 22.3 mmol) and N,O-dimethyl-hydroxylamine HCI (3.26 g, 1.5 Eq, 33.5 mmol) in dichloromethane (50 mL) were added HATU (9.33 g, 1.1 Eq, 24.5 mmol) and DIPEA (11.7 mL, 3 Eq, 66.9 mmol) and the mixture was stirred at room temperature for 16h. The mixture was concentrated and purification by flash column chromatography (SiO2, 0-100% [30% EtOH in EtOAc] in heptanes) afforded 5-ethyl-N- methoxy-N,l-dimethyl-lH-pyrazole-3-carboxamide (9.42 g, 47.8 mmol, 100% yield, residual HATU urea present). LCMS: Method 10, 1.53 min, M+H = 198.1; calcd. 198.24.

[0180] N-methoxy-N,l-dimethyl-3-propyl-lH-pyrazole-5-carboxamide

[0182] To l-methyl-3-propyl-lH-pyrazole-5-carboxylic acid (2.95 g, 1 Eq, 17.5 mmol) and N,O-dimethyl-hydroxylamine HCI (2.57 g, 1.5 Eq, 26.3 mmol) in Dichloromethane (50 mL) were added HATU (7.34 g, 1.1 Eq, 19.3 mmol) and DIPEA (9.17 mL, 3 Eq, 52.6 mmol) and the mixture was stirred at room temperature for 16h. The mixture was concentrated and purification by flash column chromatography (SiCL, 0-100% [30% EtOH in EtOAc] in heptanes) afforded N-methoxy- N,l-dimethyl-3-propyl-lH-pyrazole-5-carboxamide (3.60 g, 17.0 mmol, 97.2 % yield). LCMS: Method 8, 1.73 min, M+H - 212.1; calcd. 212.27.

[0183] N-methoxy-N,l-dimethyl-5-propyl-lH-pyrazole-3-carboxamide

[0185] To l-methyl-5-propyl-l H-pyrazole-3-carboxylic acid (4.07 g, 1 Eq, 24.2 mmol) and N,O-dimethyl-hydroxylamine HCI (3.54 g, 1.5 Eq, 36.3 mmol) in dichloromethane (50 mL) were added HATU (10.1 g, 1.1 Eq, 26.6 mmol) and DIPEA (12.6 mL, 3 Eq, 72.6 mmol) and the mixture was stirred at room temperature for 16h. The mixture was concentrated and purification by flash column chromatography (SiCL, 0-100% [30% EtOH in EtOAc] in heptanes) afforded N-methoxy- N,l-dimethyl-5-propyl-lH-pyrazole-3-carboxamide (7.75 g, 36.7 mmol, 100% yield). LCMS: Method 8, 1.66 min, M+H = 212.1; calcd. 212.27.

[0186] N-methoxy-N,3-dimethyl-lH-pyrazole-5-carboxamide

[0188] To 3-methyl-lH-pyrazole-5-carboxylic acid hydrochloride (4.3 g, 1 Eq, 26 mmol) and N,O-dimethyl-hydroxylamine HCI (5.2 g, 2 Eq, 53 mmol) in DCM (110 mL) were added DIPEA (23 mL, 5 Eq, 0.13 mol), EDC (6.1 g, 1.2 Eq, 32 mmol) and cyanic (E)-2- (hydroxyimino)butanoic anhydride (4.1 g, 1.1 Eq, 29 mmol) and the mixture was stirred at room temperature for Ih. The mixture was concentrated and purification by flash column chromatography (SiO2, 0-100% [30% EtOH in EtOAc] in heptanes) afforded N-methoxy-N,3-dimethyl-lH-pyrazole- 5-carboxamide (3.4 g, 20 mmol, 76 % yield). IH NMR (400 MHz, CDC13) 8 11.14 (brs, IH), 6.59 (s, IH), 3.78 (s, 3H), 3.38 (s, 3H), 2.35 (s, 3H).

[0189] N-methoxy-N-methyl-3-propyl-lH-pyrazole-5-carboxamide:

[0191] To 3-propyl-lH-pyrazole-5-carboxylic acid hydrochloride (6.8 g, 84% Wt., 1 Eq, 30 mmol) and N,O-dimethyl-hydroxylamine HCI (5.8 g, 2 Eq, 60 mmol) in DCM (120 mL) were added DIPEA (26 mL, 5 Eq, 0.15 mol), EDC (6.9 g, 1 .2 Eq, 36 mmol) and cyanic (E)-2- (hydroxyimino)butanoic anhydride (4.7 g, 1.1 Eq, 33 mmol) and the mixture was stirred at room temperature for 30 min. The mixture was concentrated and purification by flash column chromatography (SiCL, 0-100% [30% EtOH in EtOAc] in heptanes) afforded N-methoxy-N-methyl-3-propyl-lH-pyrazole-5-carboxamide (4.5 g, 23 mmol, 76 %). LCMS: Method 7, 0.80 min, M+H = 198.0; calcd. 198.24.

[0192] 3-ethyl-N-methoxy-N-methyl-lH-pyrazole-5-carboxamide:

[0194] To 3-cthyl-lH-pyrazolc-5-carboxylic acid hydrochloride (5.16 g, 90% Wt., 1 Eq, 26.3 mmol) and N,O-dimethyl-hydroxylamine HCI (5.13 g, 2 Eq, 52.6 mmol) in DCM (105 mL) were added DIPEA (22.9 mL, 5 Eq, 131 mmol), EDC (6.05 g, 1.2 Eq, 31.6 mmol) and cyanic (E)-2- (hydroxyimino)butanoic anhydride (4.11 g, 1.1 Eq, 28.9 mmol) and the mixture was stirred at room temperature for 3h. The mixture was concentrated and purification by flash column chromatography (SiO2, 0-100% [30% EtOH in EtOAc] in heptanes) afforded 3-ethyLN-methoxy-N-methyl-lH- pyrazole-5-carboxamide (3.12 g, 16 mmol, 60 % yield, 93% Purity). LCMS: Method 7, 0.91 min, M+H = 184.0; calcd. 184.21.

[0195] 5-ethyl-N-methoxy-N,l,4-trimethyl-lH-pyrazole-3-carboxamide:

[0196]

[0197] To 5-ethyl-l,4-dimethyl-lH-pyrazole-3-carboxylic acid (2.75 g, 1 Eq, 16.3 mmol) and N,O-dimethyl-hydroxylamine HC1 (3.19 g, 2 Eq, 32.7 mmol) in DCM (50 mL) were added DIPEA (11.4 mL, 4 Eq, 65.4 mmol), EDC (3.76 g, 1.2 Eq, 19.6 mmol) and cyanic (E)-2- (hydroxyimino)butanoic anhydride (2.56 g, 1.1 Eq, 18.0 mmol) and the mixture was stirred at room temperature for 3h. The mixture was concentrated and purification by flash column chromatography (SiO2, 0-100% [30% EtOH in EtOAc] in heptanes) afforded 5-ethyl-N-methoxy-N,l,4-trimethyl-lH- pyrazole-3-carboxamide (2.34 g, 11 mmol, 64 % yield, 95% Purity). LCMS: Method 9, 1.47 min, M+H = 212.2; calcd. 212.27. 1H NMR (400 MHz, CDC13) 5 3.81 (s, 3H), 3.78 (s, 3H), 3.41 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 2.12 (s, 3H), 1.15 (t, J = 7.6 Hz, 3H).

[0198] N-methoxy-N,l,5-trimethyl-lH-pyrazole-3-carboxamide:

[0200] To l,5-Dimethyl-lH-pyrazole-3 -carboxy licacid (2.0 g, 1 Eq, 14 mmol) and N,O- dimethyl-hydroxylamine HC1 (2.1 g, 1.5 Eq, 21 mmol) in dichloromethane (140 mL) were added HATU (6.0 g, 1.1 Eq, 16 mmol) and DIPEA (9.9 mL, 4 Eq, 57 mmol) and the mixture was stirred at room temperature for 15 min. The mixture was concentrated and purification by flash column chromatography (SiCE, 0-10% MeOH in DCM, followed by 0-100% EtOAc in heptanes) afforded N-methoxy-N,l,5-trimethyl-lH-pyrazole-3-carboxamide (1.68 g, 9.17 mmol, 64 % yield). 1H NMR (400 MHz, CDC13) 5 6.51 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.41 (s, 3H), 2.29 (s, 3H).

[0201] Example 165: Odor Profile Determination

[0202] Odor profile for selected compounds within the scope of the disclosure is determined using assessments by one Master Perfumer and 4-6 trained sensory panelists. Sensory panelists are trained on our internal taxonomy with reference materials that include 11 grand families, and 62 subfamilies. Panelists are experienced in, but not trained in, an additional several hundred odor descriptors. Panelists are trained on usage of a rating scale, which also includes internal references. Panelists arc not advanced to compound evaluation until they have completed and received a passing score on a Final Exam on the taxonomy that was curated by our perfumery team.

[0203] A single score is generated for the sensory panel by taking the arithmetic mean of all panelist scores for a given sample, for a given attribute. Alternatively, a single score may be generated by fitting all panelist scores to a model that can correct for differences in the intercept or slope of the latent function through which each panelist produces a rating given a percept, i.e. correction for inter-panelist variation.

[0204] The Master Perfumer, possessing a deep knowledge of fragrance ingredients, high level technical expertise, and who is recognized for their experience in creating complex perfumes, reviews, may augment sensory panel scores for improved accuracy.

[0205] Test samples are dissolved at a concentration of 10% w / v in ethanol. At time 0 (t = 0), new test blotters (White Paper Paddle Shaped Perfumery Blotters, measuring 5 x 0.5 inches) are dipped into the 10% solution of the text compound. Odor descriptions at time t = 0 are captured within 1-2 minutes of wetting the blotter to allow for evaporation of most of the ethanol solvent, permitting a more accurate determination of the test compound’s odor. Assessments are made at ambient temperature in a benchtop laboratory setting. For the longevity determination, blotters are stored in open air on the laboratory benchtop between assessments (no jar or other enclosure is used).

[0206] The results are shown in the table below:

[0207] The Examples provided herein are exemplary only and are not intended to be limiting in any way to the various aspects and embodiments of the invention described herein.

Claims

CLAIMSWhat is claimed:

1. A compound of Formula I:wherein:R1is H, Ci-6 alkyl (e.g., CH3), C3-6cycloalkyl (e.g., cyclopropyl), or C1-3 haloalkyl (e.g., CF3);R2, R3, and R4are each independently selected from H, C1-6 alkyl (e.g., CH3), C3- ecycloalkyl (e.g., cyclopropyl), C1-3 haloalkyl (e.g., CF3), OC1-6alkyl (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR’, C(O)R, and CHO, or wherein R2and R3, or R3and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein said heterocyclo alkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); provided that provided that at least one of R2, R3, and R4is COOH, COOR, CONHR, CONRR’, C(O)R, or CHO; each R and R’ is independently C1-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); andRais Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); provided that the compound is not ethyl l,3-dimethyl-5-pyrazolecarboxylate, and wherein the compound is not a compound wherein:(a) R1is methyl or ethyl, R2is methyl or ethyl, R3is H, and R4is COOH;(b) R1is methyl or ethyl, R2is methyl or ethyl, R3is H, and R4is COOR, and R is methyl or ethyl.

2. A compound of Formula I:Formula I wherein:R1is H, Ci-6 alkyl (e.g., CH3), C3-6cycloalkyl (e.g., cyclopropyl), or C1-3 haloalkyl (e.g., CF3);R2, R3, and R4are each independently selected from H, C1-6 alkyl (e.g., CH3), C3- ecycloalkyl (e.g., cyclopropyl), C1-3 haloalkyl (e.g., CF3), OC1-6alkyl (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR’, C(O)R, and CHO, or wherein R2and R3, or R3and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); provided that at least one of R2, R3, and R4is COOH, COOR, CONHR, CONRR’, C(O)R, or CHO; each R and R’ is independently Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); andRais Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); for use as a flavor or fragrance ingredient.

3. A flavor composition and / or fragrance composition comprising a compound of Formula I:Formula I wherein:R1is H, Ci-6 alkyl (e.g., CH3), C3-6cycloalkyl (e.g., cyclopropyl), or C1-3 haloalkyl (e.g., CF3);R2, R3, and R4are each independently selected from H, C1-6 alkyl (e.g., CH3), C3- ecycloalkyl (e.g., cyclopropyl), C1-3 haloalkyl (e.g., CF3), OC1-6alkyl (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR’, C(O)R, and CHO, or wherein R2and R3, or R3and R4, together with the carbon atoms to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein said heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(Ra); provided that at least one of R2, R3, and R4is COOH, COOR, CONHR, CONRR’, C(O)R, or CHO; each R and R’ is independently C1-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); andRais Ci-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl); in admixture with one or more non-toxic, orally acceptable, pharmaceutically acceptable, cosmetically acceptable, or acceptable for a household product, carriers or excipients.

4. The composition of claim 3, wherein R1is H or Ci-6alkyl (e.g., methyl, ethyl, propyl, or isopropyl), n-butyl, sec-butyl, isobutyl, or tert-butyl.

5. The composition of claim 3, wherein R2is Ci-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, isobutyl, or tert-butyl), C1-3 haloalkyl (e.g., CF3 or CHF2).

6. The composition of claim 3, wherein R3is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, isobutyl, or tert-butyl), C1-3 haloalkyl (e.g., CF3 or CHF2).

7. The composition of claim 3, wherein R4is C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl, isobutyl, or tert-butyl), C1-3 haloalkyl (e.g., CF3 or CHF2).

8. The composition of any one of claims 1-7, wherein one of R2, R3, or R4is C(O)R or CHO, optionally wherein R is selected from methyl, ethyl, propyl and isopropyl.

9. The composition of any one of claims 1-7, wherein one of R2, R3, or R4is COOH, COOR, CONHR, or CONRR’, optionally wherein R and R’ are independently selected from methyl, ethyl, propyl isopropyl, n-butyl, s-butyl, and isobutyl.

10. The composition of any one of claims 1-9, wherein the compound of Formula I has any one or more the following combination of substituents R1, R2, R3, and R4:wherein Me is methyl, Et is ethyl, n-Pr is n-propyl, and iPr is isopropyl.

11. The composition of claim 3, wherein the compound of Formula I is selected from the group consisting of:

12. The composition of claim 3, wherein the compound of Formula I is:wherein R is C1-6alkyl (e.g., methyl or ethyl) or C3-6cycloalkyl (e.g., cyclopropyl).

13. The composition of claim 12, wherein R is ethyl.

14. The composition of any one of claims 3-13, wherein the composition further comprises one or more solvents.

15. The composition of any one of claims 3-14, wherein the composition further comprises one or more other flavors or fragrances.

6. A product comprising the compound of claim 1 or the composition of any one of claims 3 to 15, e.g., a product selected from the following: personal care products (e.g., a soap, skin cream or lotion, balm, shampoo, body wash, shower gel, hydrating cream, deodorant, antiperspirant, after-shave lotion, cologne, perfume, or other hair care or skin care product), sunscreens, insect repellants and insecticides, detergents, household cleaning agents (e.g., a surface cleaner, a metal cleaner, a wood cleaner, a glass cleaner, a body cleaner such as a soap, a dish-washing detergent, or a laundry detergent), air fresheners, room sprays, pomanders, candles, cosmetics (e.g., perfumes, colognes, nail polish, eye liner, mascara, lipstick, foundation, concealer, blush, bronzer, eye shadow, lip liner, lip balm), toilet waters, talcum powders, and pet litter.

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