Fragrance and flavor compositions comprising pyrazole derivatives

Abstract

The present application relates to 1, 3-dimethyl-5-pyrazole carboxylic acid esters and related compounds, methods for their preparation and methods of their use as perfume and flavor ingredients in food, cosmetic, pharmaceutical, consumer and other compositions and products.

Description

[0001] Cross-references to related applications This application is an international application and claims priority and benefit to U.S. Provisional Application No. 63 / 535,715, filed August 31, 2023, and U.S. Provisional Application No. 63 / 624,741, filed January 24, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application relates to 1,3-dimethyl-5-pyrazole carboxylate and related compounds, methods for their preparation, and methods for using them as flavoring and flavoring ingredients in food, cosmetics, pharmaceuticals, consumer products, and other compositions and products. Background Technology

[0003] Scent is a crucial factor in creating anticipation, a sense of quality, palatability, and security in many consumer products. Flavor is especially important for food. Choosing the right aromas and flavors for a product is a key element of its success, crucial for product marketing, improving customer satisfaction, and maintaining customer loyalty. Sweet, vanilla, waffle, floral, woody, warm, chocolate, light woody, iris, and soft leather notes may be particularly suitable for certain flavors and fragrances and can be used in toiletries, cosmetics, household cleaners, room sprays, laundry detergents, and premium fragrance products such as perfumes and eau de toilettes, oral hygiene products (such as toothpaste and mouthwash), oral medications, and food.

[0004] Many scientists are dedicated to finding new substances, either alone or in combination, to impart or enhance the aroma or flavor of various consumer materials, such as cosmetics, detergents, and foods. While there are some trends in the correlation between the chemical structure of a molecule and the flavor or aroma it produces—for example, low molecular weight aldehydes and alcohols are often used as flavoring agents and fragrances—the specific aroma produced by a particular molecule is extremely difficult to predict. Even minute structural changes, such as the addition or removal of a functional group containing only one carbon atom, can have profound and unexpected effects on the flavor or aroma characteristics of a compound. The development of techniques for predicting the flavor and aroma of compounds is still in its early stages.

[0005] Using their proprietary predictive method, the inventors also identified ethyl 1,3-dimethyl-5-pyrazole carboxylate as a novel ingredient that can be used as a flavoring and fragrance component. It is believed that this compound had not previously been identified as a flavor or fragrance component, and its odor had not been described.

[0006] This application describes the surprising and unexpected olfactory properties of 1,3-dimethyl-5-pyrazole carboxylate and its analogues and derivatives, as well as their use as flavor and fragrance ingredients and their potential applications. Invention Overview In one aspect, the application relates to a compound of Formula I: Formula I wherein: R 1 is H, C 1-6 alkyl (e.g., CH3), C 1-3 haloalkyl (e.g., CF3), or C 3-6 cycloalkyl (e.g., cyclopropyl); R 2 , R 3 , and R 4 are each independently selected from H, C 1-6 alkyl (e.g., CH3), C 3-6 cycloalkyl (e.g., cyclopropyl), C 1-3 haloalkyl (e.g., CF3), OC 1-6 alkyl (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR', C(O)R, and CHO, or wherein R 2 and R 3 , or R 3 and R 4 , together with the carbon atom to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein the heterocycloalkyl ring comprises at least one ring atom selected from O, S, N(H), and N(R a ); provided that at least one of R 2 , R 3 , and R 4 is COOH, COOR, CONHR, CONRR', C(O)R, or CHO; each R and R' can each independently be C 1-6 alkyl (e.g., methyl or ethyl), or C 3-6 cycloalkyl (e.g., cyclopropyl); and R a is C 1-6 alkyl (e.g., methyl or ethyl), or C 3-6 cycloalkyl (e.g., cyclopropyl); optionally provided that the compound is not ethyl 1,3-dimethyl-5-pyrazolecarboxylate.

[0008] In some embodiments, the compound of Formula I is ethyl 1,3-dimethyl-5-pyrazolecarboxylate.

[0009] In another aspect, the present application relates to a flavor and fragrance composition comprising a compound of Formula I, which composition can optionally comprise one or more additives, other flavor or fragrance ingredients, or a combination of additives and other flavor or fragrance ingredients. In some embodiments, the present application relates to a flavor and fragrance composition comprising 1,3-dimethyl-5-pyrazole carboxylic acid ethyl ester.

[0010] In another aspect, the present application relates to a product, such as a consumer product, comprising a flavor and fragrance composition comprising a compound of Formula I. For example, a product comprising 1,3-dimethyl-5-pyrazole carboxylic acid ethyl ester.

[0011] In another aspect, the present disclosure provides a method of making a compound of Formula I.

[0012] The following detailed description describes one or more embodiments of the present application. 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 case of any conflict, the present description will prevail.

[0013] Other features and advantages of the present application will be seen from the following detailed description, examples and claims.

[0014] DETAILED DESCRIPTION The inventors have unexpectedly discovered that 1,3-dimethyl-5-pyrazole carboxylic acid ethyl ester has a unique aroma and flavor characterized by floral, chocolate, light woody, iris, and soft leather notes, and a unique style. Accordingly, it was determined that this compound can be used to impart a desirable aroma and / or flavor to a product. It is expected that other compounds of Formula I also have a pleasing or desirable aroma and / or flavor. Accordingly, such compounds can be suitable for use in products where the addition of a pleasing aroma or flavor is desired, including but not limited to perfumes, home products, laundry products, personal care products, cosmetics, oral hygiene products, oral pharmaceuticals, and food products. The amount of a compound of Formula I used can vary depending on the particular flavor or fragrance product application, the nature and amount of other fragrance ingredients, and the aroma and / or flavor desired for the product.

[0015] A first aspect of the present disclosure provides a compound of Formula I (Compound 1): Formula I wherein: R 1 is H, C 1-6 alkyl (e.g., CH3), C 3-6 cycloalkyl (e.g., cyclopropyl), or C 1-3 haloalkyl (e.g., CF3); R2, R3, and R4are each independently selected from H, C 1-6 alkyl (e.g., CH3), C3-6 cycloalkyl (e.g., cyclopropyl), C 1-3 haloalkyl (e.g., CF3), OC 1-6 alkyl (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR', C(O)R, and CHO, or wherein R 2 and R 3 , or R 3 and R 4 , together with the carbon atom to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein the heterocycloalkyl ring includes at least one ring atom selected from O, S, N(H), and N(R a ); provided that at least one of R 2 , R 3 , and R 4 is COOH, COOR, CONHR, CONRR', C(O)R, or CHO; each R and R' can each independently be C 1-6 alkyl (e.g., methyl or ethyl) or C 3-6 cycloalkyl (e.g., cyclopropyl); and R a is C 1-6 alkyl (e.g., methyl or ethyl) or C 3-6 cycloalkyl (e.g., cyclopropyl); optionally provided that the compound is not ethyl 1,3-dimethyl-5-pyrazolecarboxylate.

[0016] In one aspect, in further embodiments of the disclosure, the disclosure provides: 1.1 Compound 1, wherein the compound is not ethyl 1,3-dimethyl-5-pyrazolecarboxylate; 1.2 Compound 1, wherein the compound is not: (a) R 1 is methyl or ethyl, R 2 is methyl or ethyl, R 3 is H, and R 4 is COOH; (b) R 1 is methyl or ethyl, R 2 is methyl or ethyl, R 3 is H, and R 4 is COOR, and R is methyl or ethyl; 1.3 Compound 1, or any one of Compounds 1.1-1.2, wherein R 1 is H; 1.4 Compound 1, or any of Compounds 1.1-1.2, wherein R 1 is CH3; 1.5 Compound 1, or any of Compounds 1.1-1.4, wherein R 2 is H; 1.6 Compound 1, or any of Compounds 1.1-1.4, wherein R 2 is C 1-6 alkyl (e.g., CH3), C 3-6 cycloalkyl (e.g., cyclopropyl), C 1-3 haloalkyl (e.g., CF3), or OC 1-6 alkyl (e.g., OCH3); 1.7 Compound 1, or any of Compounds 1.1-1.4, wherein R 2 is CH2OR, COOH, CONHR, CONRR', or COOR; 1.8 Compound 1, or any of Compounds 1.1-1.4, wherein R 2 is C(O)R or CHO; 1.9 Compound 1, or any of Compounds 1.1-1.8, wherein R 3 is H; 1.10 Compound 1, or any of Compounds 1.1-1.8, wherein R 3 is C 1-6 alkyl (e.g., CH3), C 3-6 cycloalkyl (e.g., cyclopropyl), C 1-3 haloalkyl (e.g., CF3), or OC 1-6 alkyl (e.g., OCH3); 1.11 Compound 1, or any of Compounds 1.1-1.8, wherein R 3 is CH2OR, COOH, CONHR, CONRR', or COOR; 1.12 Compound 1, or any of Compounds 1.1-1.8, wherein R 3 is C(O)R or CHO; 1.13 Compound 1, or any of Compounds 1.1-1.12, wherein R 4 is H; 1.14 Compound 1, or any of Compounds 1.1-1.12, wherein R 4 is C 1-6 alkyl (e.g., CH3), C 3-6 cycloalkyl (e.g., cyclopropyl), C 1-3 haloalkyl (e.g., CF3), or OC 1-6alkyl (e.g., OCH3); 1.15 Compound 1, or any one of Compounds 1.1-1.12, wherein R 4 is CH2OR, COOH, CONHR, CONRR', or COOR; 1.16 Compound 1, or any one of Compounds 1.1-1.12, wherein R 4 is C(O)R or CHO; 1.17 Compound 1, or any one of Compounds 1.1-1.16, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form an optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl ring, wherein the heterocycloalkyl ring includes at least one ring atom selected from O, S, N(H), and N(R 3 ); 4 a 1.18 Compound 1.17, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form an unsubstituted 5-8 membered (C 5-8 ) cycloalkyl ring; 1.19 Compound 1.17, wherein R 3 and R 4 , together with the carbon atom to which they are attached, form an unsubstituted 5-8 membered (C 5-8 ) cycloalkyl ring; 1.20 Compound 1.17, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 5-8 membered (C 5-8 ) cycloalkyl ring, which ring is substituted with one or more groups R b (e.g., methyl); 1.21 Compound 1.17, wherein R 3 and R 4 , together with the carbon atom to which they are attached, form a 5-8 membered (C 5-8 ) cycloalkyl ring, which ring is substituted with one or more groups R (e.g., methyl); 1.22 Compound 1.17, or any one of Compounds 1.18-1.21, wherein the 5-8 membered (C 5-8 ) cycloalkyl ring is selected from cyclopentyl and cyclohexyl; 1.23 Compound 1.17, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form an unsubstituted heterocycloalkyl ring, wherein the heterocycloalkyl ring includes at least one ring atom selected from O, S, N(H), and N(R​​a ) ring atoms; Compound 1.24, 1.17, wherein R 3 and R 4 Together with the carbon atoms they are attached to, they form an unsubstituted heterocyclic alkyl ring, wherein the heterocyclic alkyl ring comprises at least one selected from O, S, N(H) and N(R). a ) ring atoms; Compound 1.25, 1.17, wherein R 2 and R 3 Together with the carbon atoms they are attached to, they form a heterocyclic alkyl ring, which is bound by one or more R groups. b The substitution, wherein the heterocyclic alkyl ring comprises at least one selected from O, S, N(H) and N(R) a ) ring atoms; Compound 1.26, 1.17, wherein R 3 and R 4 Together with the carbon atoms they are attached to, they form a heterocyclic alkyl ring, which is bound by one or more R groups. b The substitution, wherein the heterocyclic alkyl ring comprises at least one selected from O, S, N(H) and N(R) a ) ring atoms; 1.27 Compound 1.17 or any one of compounds 1.22-1.26, wherein the heterocyclic alkyl ring comprises a group selected from O, N(H) and N(R). a One or more ring atoms; 1.28 Compound 1.17 or any one of compounds 1.22-1.27, wherein the heterocyclic alkyl ring is selected from pyrrolidine, tetrahydrofuran, piperidine, piperazine and morpholine; 1.29 Compound 1.17 or any one of compounds 1.18-1.28, wherein the cycloalkyl ring or heteroalkyl ring is surrounded by one, two, three, or four R... b (e.g., methyl) substitution; 1.30 Compound 1.17 or any one of compounds 1.18-1.28, wherein the cycloalkyl ring or heteroalkyl ring is formed by two R b (e.g., methyl) substitution; 1.31 Compound 1.17 or any one of compounds 1.18-1.30, wherein each R b Selected independently from C 1-6 Alkyl (e.g., methyl or ethyl), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 1-3 Halogenated alkyl groups (e.g., CF3) or OC 1-6 Alkyl groups (e.g., OCH3); 1.32 Compound 1, or any one of compounds 1.1-1.31, wherein R a C 1-6 Alkyl (e.g., methyl or ethyl); 1.33 Compound 1, or any one of compounds 1.1-1.32, wherein R is C 1-6 Alkyl (e.g., methyl or ethyl); 1.34 Compound 1, or any one of compounds 1.1-1.32, wherein R is C 3-6 Cycloalkyl (e.g., cyclopropyl); 1.35 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 For H or C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl); 1.36 Compound 1, or any one of compounds 1.1-1.35, wherein R 2 C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C 1-3 Halogenated alkyl groups (e.g., CF3 or CHF2); 1.37 Compound 1, or any one of compounds 1.1-1.36, wherein R 3 C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C 1-3 Halogenated alkyl groups (e.g., CF3 or CHF2); 1.38 Compound 1, or any one of compounds 1.1-1.37, wherein R 4 C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C 1-3 Halogenated alkyl groups (e.g., CF3 or CHF2); 1.39 Compound 1, or any one of compounds 1.1-1.38, wherein R 2 R 3 or R 4 One of them is C(O)R or CHO; 1.40 Compound 1.39, wherein R is selected from methyl, ethyl, propyl and isopropyl; 1.41 Compound 1, or any one of compounds 1.1-1.38, wherein R 2 R 3 or R 4One of them is COOH, COOR, CONHR, or CONRR'; 1.42 Compound 1.41, wherein R and R' in each example are independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and isobutyl; 1.43 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 C 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl) or C 1-3 Halogenated alkyl groups (e.g., CF3), R 2 C 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl) or C 1-3 Halogenated alkyl groups (e.g., CF3), R 3 For H, R 4 It is COOH or COOR, and R is C. 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); 1.44 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 C 1-6 Alkyl (e.g., CH3) or C 3-6 Cycloalkyl (e.g., cyclopropyl), R 2 C 1-6 Alkyl (e.g., CH3) or C 3-6 Cycloalkyl (e.g., cyclopropyl), R 3 For H, R 4 It is COOH or COOR, and R is C. 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); 1.45 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 C 1-6 Alkyl (e.g., CH3), R 2 C 1-6 Alkyl (e.g., CH3) or C 3-6 Cycloalkyl (e.g., cyclopropyl), R 3 For H, R 4 It is COOH or COOR, and R is C. 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); 1.46 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 C1-6 Alkyl (e.g., CH3), R 2 C 1-6 Alkyl (e.g., CH3), R 3 For H, R 4 It is COOH or COOR, and R is C. 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); 1.47 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 C 1-6 Alkyl (e.g., CH3), R 2 C 1-6 Alkyl (e.g., CH3), R 3 For H, R 4 COOR, R is C 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); 1.48 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 C 1-6 Alkyl (e.g., CH3), R 2 C 1-6 Alkyl (e.g., CH3), R 3 For H, R 4 COOR, R is C 1-6 Alkyl groups (e.g., methyl or ethyl); 1.49 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 It is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl, R 2 It is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl, R 3 For H, R 4 It is COOR, and R is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, or cyclobutyl; 1.50 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 It is methyl, ethyl, propyl or isopropyl, R 2 It is methyl, ethyl, propyl or isopropyl, R 3 For H, R 4 COOR, where R is methyl, ethyl, propyl, isopropyl, cyclopropyl, or cyclobutyl; 1.51 Compound 1, or any one of compounds 1.1-1.34, wherein R 1It is methyl or ethyl, R 2 It is methyl or ethyl, R 3 For H, R 4 COOR, where R is methyl, ethyl, propyl, isopropyl, or cyclopropyl; 1.52 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 For methyl, R 2 It is methyl, R 3 For H, R 4 For COOR, R is methyl, ethyl, propyl, isopropyl, or cyclopropyl; 1.53 Compound 1, or any one of compounds 1.1-1.34, wherein R 1 For H or C 1-6 Alkyl (e.g., CH3), R 3 and R 4 Together with the carbon atoms they are attached to, they form a 5-8 quinary (C) group. 5-8 ) A cycloalkyl ring, wherein the ring is separated by one or two R groups b Replace, R 2 It is COOH or COOR, where R and R b Each is independently selected from C 1-6 Alkyl groups (e.g., CH3); Compound 1.54, 1.53, wherein the cycloalkyl ring is formed by two C2C ... 1-6 Alkyl (e.g., CH3) geminal disubstituted; 1.55 Compound 1, or any one of compounds 1.1-1.54, wherein the compound of formula I is a compound of formula Ia: Formula Ia Where R 2 and R 3 As defined in any of the preceding formulas; 1.56 Compound 1, or any one of compounds 1.1-1.54, wherein the compound of formula I is a compound of formula Ib: Formula Ib Where R 1 R 2 and R 4 As defined in any of the preceding formulas; 1.57 Compound 1, or any one of compounds 1.1-1.54, wherein the compound of formula I is: Where R is defined as in any of the aforementioned equations; 1.58 Compound 1.57, wherein R is methyl, ethyl, propyl, isopropyl or cyclopropyl; Compound 1.59, 1.57, wherein R is an ethyl group; 1.60 Any of the aforementioned compounds, wherein the substituent R of compound I is... 1 R 2 R 3 and R 4 It can be any one or more combinations of the following: Where Me is methyl, Et is ethyl, n-Pr is n-propyl, and iPr is isopropyl; 1.61 Any of compound 1.60, wherein R may be independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and isobutyl; 1.62 Any of the aforementioned compounds, wherein the molecular weight of the compound is selected from the following ranges: 90 to 500, or 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; 1.63 Any of the aforementioned compounds, wherein the compounds are selected from: , , , , , , , , , , , , , , , ,, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， ， , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ; 1.64 Any of the aforementioned compounds, wherein the compounds are selected from: , , , , , , , and ; 1.65 Any of the aforementioned compounds is a salt if it has an acidic or basic atom or functional group, for example, a base addition salt or an acid addition salt; 1.66 Any of the aforementioned compounds, wherein the compound has a pleasant taste and / or aroma, for example, as determined by a trained spice or flavor chemist or chief perfumer (e.g., the aroma and / or taste of roasted coconut or other nuts).

[0017] It should be understood that substituted pyrazoles exhibit tautomerism, and conventional organic chemical synthesis methods typically yield a mixture of substituted pyrazole isomers. Therefore, the structural formulas drawn according to the following nomenclature in this paper should be understood to contain any one or two isomers of the substituted compound, and the ratio of the two isomers can be arbitrary; however, for any given compound, it is also possible to contain only one purified isomer, and this isomer may be chosen.

[0018] In a second aspect, this disclosure provides a flavor composition and / or fragrance composition (composition 1) comprising compound 1 or any one of compounds 1.1-1.66, and mixed with one or more non-toxic, orally acceptable, pharmaceutically acceptable, cosmetically acceptable, or suitable for household products carriers or excipients. In a particular embodiment, this second aspect of the disclosure provides: 1.1 Composition 1, wherein the composition is a fragrance composition.

[0019] 1.2 Composition 1, wherein the composition is a flavor composition.

[0020] 1.3 Composition 1 or any one of compositions 1.1-1.2, wherein the composition comprises compound 1 or any one of compounds 1.1-1.66 in an amount of 0.1% to 100% by weight of the composition, for example, 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%... Up 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.

[0021] 1.4 Composition 1, or any one of compositions 1.1-1.3, wherein the composition further comprises one or more other spices or flavors.

[0022] 1.5 Composition 1, or any one of compositions 1.1-1.4, wherein the composition further comprises one or more solvents.

[0023] 1.6 Composition 1.5, wherein 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, glycerol, triethyl citrate, triacetin, triglycerides, liquid waxes, propylene glycol derivatives (e.g., polypropylene glycol or ethylene oxide / propylene oxide copolymers), ethylene glycol derivatives (e.g., polyethylene glycol or ethylene oxide / propylene oxide copolymers), other alcohols or ethers, or any combination thereof.

[0024] 1.7 Composition 1, or any one of compositions 1.1 to 1.6, wherein the composition is a liquid.

[0025] 1.8 Composition 1, or any one of compositions 1.1 to 1.6, wherein the composition is a soft or waxy solid.

[0026] 1.9 Composition 1, or any one of compositions 1.1 to 1.8, wherein the composition further comprises one or more polymers, gelling agents, powder matrices, surfactants, emollients, plasticizers, wetting agents, swelling agents, or active ingredients (e.g., oral care active ingredients or pharmaceutical active ingredients), or any other additives described herein.

[0027] 1.10 Composition 1, or any one of compositions 1.1 to 1.9, wherein the composition does not contain any ingredient or component that is unsafe for ingestion, oral application or topical application to skin or hair; 1.11 Composition 1, or any one of compositions 1.1 to 1.10, wherein the composition does not contain any ingredient or component that is unsafe or unapproved for use in food, cosmetic, pharmaceutical, oral care, or consumer cleaning compositions.

[0028] As used herein, the term "fragrance composition" refers to a mixture of fragrance ingredients (e.g., including compounds of Formula I) with one or more non-toxic, cosmetically acceptable, or household product acceptable carriers or excipients (e.g., solvents). For example, the fragrance ingredient may be dissolved in a suitable solvent or mixed with a powdered matrix, and other auxiliary substances (e.g., additives) may be added as needed. Fragrance compositions are used (and are intended to be used) to provide or impart a desired odor or aroma to products (e.g., cosmetics or household products, such as household cleaners). Therefore, fragrance compositions are used as ingredients or components of final products (e.g., cosmetics or consumer products) to meet the need for a specific fragrance. Products containing fragrance ingredients include, but are not limited to, perfumes, soaps, insect repellents and pesticides, detergents, household cleaners, air fresheners, room sprays, fragrance pills, candles, cosmetics, eau de toilette, preshave and aftershave lotions, talcum powder, hair care products, body deodorants, antiperspirants, and pet bedding. The fragrance ingredient should contain sufficient fragrance to effectively impart the desired scent or aroma to the final product, which depends on the concentration of the fragrance ingredient in the formulation and the concentration of that formulation in the product.

[0029] As used herein, the term "flavor composition" refers to a mixture of a flavor component (e.g., including compounds of Formula I) with one or more non-toxic, orally acceptable, or pharmaceutically acceptable carriers or excipients (e.g., solvents). For example, the flavor component may be soluble in a suitable solvent or mixed with a suitable solid, semi-solid, or liquid excipient, and other excipients (e.g., additives) may be added as needed. Flavor compositions are used (and are intended to be used) to provide or impart a desired flavor and aroma to a product (e.g., a food or oral medication). Therefore, flavor compositions are used as ingredients or components of a final product (e.g., a food or oral medication) to impart a specific flavor to that product. Examples of products containing flavor compositions include, but are not limited to, oral care compositions (e.g., oral hygiene products such as mouthwash, toothpaste, dental floss, and breath fresheners), pharmaceutical compositions (e.g., oral medications including liquids, tablets, or capsules), and foods. Flavor compositions should contain sufficient flavor components to effectively provide the desired flavor and aroma to the final product, depending both on the concentration of the flavor component in the composition and the concentration of the composition used in the product.

[0030] Flavoring components and flavoring components, and mixtures thereof, which can be combined with the disclosed compounds for the manufacture of flavor and flavor compositions, include, but are not limited to, natural products such as extracts, animal products and essential oils, absolutes, resinous compounds, resins and gels, and synthetic flavoring materials, including, but not limited to, alcohols, aldehydes, ketones, ethers, acids, esters, acetals, phenols, ethers, lactones, furans, nitriles, acids and hydrocarbons, including saturated or unsaturated compounds and aliphatic carbocyclic, heterocyclic compounds and animal products. In this document, "flavoring component" and "flavoring component" refer to components other than compounds of Formula I used to impart flavor or aroma to a composition or product.

[0031] Examples of esters that can be used as flavoring or fragrance components in the compositions and products disclosed herein include, but are not limited to: acrylates (methyl ester, ethyl ester, etc.), acetoacetate esters (methyl ester, ethyl ester, etc.), anisyl esters (methyl ester, ethyl ester, etc.), benzoates (allyl ester, isoamyl ester, ethyl ester, geraniol ester, linalool ester, phenethyl ester, hexyl ester, cis-3-hexenyl ester, benzyl ester, methyl ester, etc.), anthranilates (cinnamyl ester, cis-3-hexenyl ester, methyl ester, ethyl ester, linalool ester, isobutyl ester, etc.), N-methyl anthranilates (methyl ester, ethyl ester, etc.), isovalerates (pentyl ester, allyl ester, isoamyl ester, isobutyl ester, isopropyl ester, ethyl ester, octyl ester, geraniol ester, cyclohexyl ester, citronellol ester, terpene esters, linalool ester, cinnamyl ester, phenethyl ester, butyl ester, propyl ester, etc.). Esters, hexyl esters, benzyl esters, methyl esters, rhodane esters, etc.), isobutyrates (isoamyl esters, geraniol esters, citronellol esters, terpenoid esters, cinnamyl esters, octyl esters, nerolithyl esters, phenethyl esters, phenylpropyl esters, phenoxyethyl esters, butyl esters, propyl esters, isopropyl esters, hexyl esters, benzyl esters, methyl esters, ethyl esters, linalool esters, rhodane esters, etc.), undecenoate esters (allyl esters, isoamyl esters, butyl esters, ethyl esters, methyl esters, etc.), octanoate esters (allyl esters, isoamyl esters, ethyl esters, octyl esters, hexyl esters, butyl esters, methyl esters, linalool esters, etc.), octenate esters (methyl esters, ethyl esters, etc.), octyryne carboxylic acid esters (methyl esters, ethyl esters, etc.), hexanoate esters (allyl esters, pentyl esters, isoamyl esters, methyl esters, ethyl esters, isobutyl esters, propyl esters, hexyl esters, cis-3-hexenyl esters, trans-2-hexenyl esters, linalool esters, geraniol esters, cyclohexyl esters, etc.), hexyl esters, etc. Acrylates (methyl ester, ethyl ester, etc.), valerates (pentyl ester, isopropyl ester, isobutyl ester, ethyl ester, cis-3-hexenyl ester, trans-2-hexenyl ester, cinnamate, phenethyl ester, methyl ester, etc.), formates (anisyl ester, isoamyl ester, isopropyl ester, ethyl ester, octyl ester, geraniol, citronellol ester, cinnamate, cyclohexyl ester, terpene esters, phenethyl ester, butyl ester, propyl ester, hexyl ester, cis-3-hexenyl ester, benzyl ester, linalool, rhodane ester, etc.), crotonates (isobutyl ester, ethyl ester, cyclohexyl ester, etc.), cinnamic acid esters (allyl ester, ethyl ester, methyl ester, isopropyl ester, propyl ester, 3-phenylpropyl ester, benzyl ester, cyclohexyl ester, methyl ester, etc.), succinates (monomethyl ester, diethyl ester, dimethyl ester, etc.), acetates (anisyl ester, pentyl ester, α-pentylcinnamate, isoamyl ester, isobutyl ester). Isopropyl ester, isoborneol ester, isoeugenol ester, eugenol ester, 2-ethylbutyl ester, ethyl ester, 3-octyl ester, p-cresol ester, o-cresol ester, geraniol ester, α- or β-santalyl ester, cyclohexyl ester, cycloneryl ester, dihydrocumyl ester, dimethyl benzyl methanol ester, cinnamic acid ester, styrax ester, decyl ester, dodecyl ester, terpene ester, guaiac ester, nerolithyl ester, nonyl ester, phenethyl ester, phenylpropyl ester, butyl ester, furfuryl ester, propyl ester, hexyl ester, cis-3-hexenyl ester, trans-2-hexenyl ester, cis-3-nonenyl ester, cis-6-nonenyl ester, cis-3-cis-6-nonadienyl ester, 3-methyl-2-butenyl ester, heptyl ester, benzyl ester, borneol ester, myrcene ester, dihydromyrcene ester, myrtyl ester, methyl ester, 2-methylbutyl ester, menthyl ester, linalool ester, rhodane ester, etc.Salicylate esters (allyl, isoamyl, phenyl, ethyl, benzyl, ethyl, methyl, etc.), cyclohexylalkyl esters (ethyl cyclohexyl, allyl cyclohexylpropionate, allyl cyclohexylbutyrate, allyl cyclohexylhexanoate, allyl cyclohexyldecanoate, allyl cyclohexylvalerate, etc.), stearates (ethyl, propyl, butyl, etc.), sebacate esters (diethyl, dimethyl, etc.), decanoate esters (isoamyl, ethyl, butyl, methyl, etc.), dodecanoate esters (isoamyl, ethyl, butyl, etc.), lactate esters (isoamyl, ethyl, butyl, etc.), nonanoate esters. (Ethyl acetate, phenethyl acetate, methyl acetate, etc.), nonenolates (allyl acetate, ethyl acetate, methyl acetate, etc.), hydroxyhexanoates (ethyl acetate, methyl acetate, etc.), phenylacetic acids (isoamyl acetate, isobutyl acetate, ethyl acetate, geraniol acetate, cis-3-hexenyl acetate, methyl acetate, etc.), phenoxyacetic acids (allyl acetate, ethyl acetate, methyl acetate, etc.), furan carboxylic acid esters (ethyl furan carboxylate, methyl furan carboxylate, hexyl furan carboxylate, isobutylfuran neopentyl glycol diacetate dipropionate, etc.), propionates (anesinyl acetate, allyl acetate, ethyl acetate, pentyl acetate, isoamyl acetate, propyl acetate, butyl acetate, isobutyl acetate, isopropyl acetate). Benzyl ester, Geraniol ester, Cyclohexyl ester, Citronellol ester, Cinnamyl ester, Tetrahydrofurfuryl ester, Tricyclodecenyl ester, Heptanyl ester, Borneol ester, Methyl ester, Menthyl ester, Linaloyl ester, Terpenyl ester, α-Methylpropionyl ester, β-Methylpropionyl ester, etc.), Heptanyl esters (allyl ester, ethyl ester, octyl ester, propyl ester, methyl ester, etc.), Heptanyl carboxylic esters (allyl ester, ethyl ester, propyl ester, methyl ester, etc.), Myristyl esters (isopropyl ester, ethyl ester, methyl ester, etc.), Phenyl glycidyl esters (ethyl phenyl glycidyl acid, ethyl 3-methylphenyl glycidyl acid, ethyl p-methyl-β-phenyl glycidyl acid, etc.). 2-Methylbutyrates (methyl, ethyl, octyl, phenethyl, butyl, hexyl, benzyl, etc.), 3-methylbutyrates (methyl, ethyl, etc.), butyrates (anesinyl, amyl, allyl, isoamyl, methyl, ethyl, propyl, octyl, guaiacol, linaloyl, geraniol, cyclohexyl, citronellol, cinnamic acid ester, nerol, terpene esters, phenylpropyl, β-phenethyl, butyl, hexyl, cis-3-hexenyl ester, trans-2-hexenyl ester, benzyl, rhodane, etc.), and hydroxybutyrates (methyl, ethyl, menthyl, etc. of 3-hydroxybutyrate).

[0032] Examples of alcohols that can be used as flavoring or seasoning ingredients or as solvents in the compositions and products disclosed herein include, but are not limited to: fatty alcohols (isoamyl alcohol, 2-ethylhexanol, 1-octanol, 3-octanol, 1-octen-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-1-pentanol, etc.). Terpenoid alcohols (borneol, isoborneol, carvacrol, geraniol, α- or β-santalol, citronellol, 4-thujol, terpineol, 4-terpineol, nerol, myrceneol, myrtol, dihydromyrceneol, tetrahydromyrceneol, nerolidol, hydroxycitronellol, farnesol, perillol, rhodaneol, linalool, etc.); and aromatic alcohols (anisinol, α-pentylcinnamyl alcohol, isopropylbenzylmethanol, carvacrol, cuminol, dimethylbenzylmethanol, cinnamyl alcohol, phenylpropanol, phenethyl alcohol, β-phenylethanol, 3-phenylpropanol, benzyl alcohol, etc.).

[0033] Examples of aldehydes that can be used as flavoring or flavoring ingredients in the compositions and products disclosed herein include, but are not limited to: aliphatic aldehydes (acetaldehyde, octanal, nonanal, decanal, undecanal, 2,6-dimethyl-5-heptanal, 3,5,5-trimethylhexanal, cis-3-cis-6-nonadienal, trans-2-cis-6-nonadienal, pentanal, propanal, isopropanal, hexanal, trans-2-hexenal, cis-3-hexenal, 2-pentenal, dodecanal, tetradecanal, trans-4-decenal, trans-2-tetrenal, trans-2-dodecenal, trans-2-undecenal, 2,4-hexadienal, cis-6-nonenal, trans-2-nonenal, 2-methylbutanal, etc.). Aromatic aldehydes (anisaldehyde, α-pentylcinnamaldehyde, α-methylcinnamaldehyde, cyclamate aldehyde, p-isopropylphenylacetaldehyde, ethyl vanillin, cuminaldehyde, salicylaldehyde, cinnamaldehyde, o-tolualdehyde, m-tolualdehyde or p-tolualdehyde, vanillin, piperaldehyde, phenylacetaldehyde, jasmine aldehyde, benzaldehyde, 4-methyl-2-phenyl-2-pentenal, p-methoxycinnamaldehyde, p-methoxybenzaldehyde, etc.); and terpene aldehydes (geranialdehyde, citral, citronellol, α-sweet orange aldehyde, β-sweet orange aldehyde, perillaldehyde, hydroxycitronellol, tetrahydrocitronellol, myrtol, cyclocitronellol, isocyclocitronellol, citronoxyacetaldehyde, neraldehyde, α-methylenecitronellol, citric acid aldehyde, vernaldehyde, saffron aldehyde, etc.).

[0034] Examples of ketone compounds that can be used as flavoring or fragrance ingredients in the compositions and products disclosed herein include, but are not limited to: cyclic ketones (1-acetyl-3,3-dimethyl-1-cyclohexene, cis-jasmone, α-, β- or γ-irone, ethyl maltol, cycloenone, dihydronorcaconone, 3,4-dimethyl-1,2-cyclopentanedione, sotorone, α-, β-, γ- or δ-damasconone, α-, β- or γ-damasconone, nocaconone, 2-sec-butylcyclohexanone, maltol, α-, β- or γ-ionone, α-, β- or γ-methyl Ionone, α-, β- or γ-isomethyl ionone, furanol, camphor, etc.; aromatic ketones (acetylnaphthone, acetophenone, anisidine acetone, raspberry ketone, p-methyl acetophenone, anisyl acetone, p-methoxyacetophenone, etc.); and chain ketones (diacetyl, 2-nonanone, diacetyl, 2-heptanone, 2,3-heptanedione, 2-pentanone, methylpentyl ketone, methyl nonyl ketone, β-methylnaphthyl ketone, methyl heptanone, 3-heptanone, 4-heptanone, 3-octanone, 2,3-hexanedione, 2-undecaneone, dimethyloctenone, 6-methyl-5-hepten-2-one, etc.).

[0035] Examples of acetals that can be used as flavoring or fragrance ingredients in the compositions and products disclosed herein include, but are not limited to: acetaldehyde diethyl acetal, acetaldehyde dipentyl acetal, acetaldehyde dihexyl acetal, acetaldehyde propylene glycol acetal, acetaldehyde ethyl cis-3-hexenyl acetal, benzaldehyde glycerol acetal, benzaldehyde propylene glycol acetal, citral dimethyl acetal, citral diethyl acetal, citral propylene glycol acetal, citral ethylene glycol acetal, phenylacetaldehyde dimethyl acetal, citronellol methyl acetal, acetaldehyde phenylethylpropyl acetal, and hexaldehyde 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-methylundecanoal dimethyl acetal, citronellol dimethyl acetal, Ambes (produced by Givaudan), ethyl acetoacetate ethylene glycol acetal, and 2-phenylpropanal dimethyl acetal.

[0036] Examples of phenolic compounds that can be used as flavoring or seasoning ingredients in the compositions and products disclosed herein include, but are not limited to: eugenol, isoeugenol, 2-methoxy-4-vinylphenol, thymol, carvacrol, guaiacol, piperol, and vanillin.

[0037] Examples of ethers and epoxides that can be used as flavoring or flavoring ingredients in the compositions and products disclosed herein include, but are not limited to: anethole, 1,4-cineole, dibenzyl ether, linalool oxide, limonene oxide, nerol oxide, rose oxide, methyl isoeugenol, methyl guanylic acid, isopentylphenyl ethyl ether, β-naphthylmethyl ether, phenylpropyl ether, p-cresol methyl ether, vanillyl butyl ether, α-terpinel methyl ether, citronellol ethyl ether, geraniol ethyl ether, rose furan, theanosterane, decyl methyl ether, and methyl phenyl methyl ether.

[0038] Examples of lactones that can be used as flavoring or fragrance ingredients in the compositions and products disclosed herein include, but are not limited to: γ- or δ-decyl lactone, γ-heptyl lactone, γ-nonyl lactone, γ- or δ-caprolactone, γ- or δ-octyl lactone, γ- or δ-undecyl lactone, δ-dodecyl lactone, δ-2-decenyl lactone, methyl lactone, 5-hydroxy-8-undecenoic acid δ-lactone, jasmine lactone, menthol lactone, dihydrocoumarin, octahydrocoumarin, and 6-methylcoumarin.

[0039] Examples of furan compounds that can be used as flavoring or seasoning ingredients in the compositions and products disclosed herein 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-furanyl)-2-methyl-2-propenal, 5-(hydroxymethyl)furfural, 2,5-dimethyl-4-hydroxy-3(2H)-furanone (furanol), 4,5-dimethyl-3-hydroxy-2(5H)-furanone (solanol). Tolone), 2-ethyl-4-hydroxy-5-methyl-3(2H)-furanone (high furanol), 5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone (high isotorone), 3-methyl-1,2-cyclopentanedione (cycloenone), 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.

[0040] Examples of hydrocarbon compounds that can be used as flavoring or flavoring ingredients in the compositions and products disclosed herein include, but are not limited to: α- or β-bisabolene, β-caryophyllene, p-cymene, terpinene, terpinene oil, carbidesene, cedrene, longleafene, farnesene, limonene, ocimene, myrcene, α- or β-pinene, 1,3,5-undecanetriene, and valenene.

[0041] Examples of acids that can be used as flavoring or flavoring ingredients in the compositions and products disclosed herein include, but are not limited to: geranilic acid, lauryl 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.

[0042] The spice and flavor compositions of this application may contain one or more natural extracts or oils as additional spice or flavor ingredients, including but not limited to: fennel, orange, lemon, lime, citrus, petitgrain, bergamot, lemon balm, grapefruit, elemi, frankincense, lemongrass, neroli oil, marjoram, angelica root, star anise, basil, bay leaf, calamus, chamomile, caraway, cardamom, cinnamon, bark, pepper, perilla, cypress, oregano, cassia, ginger, parsley, pine needles, sage, hyssop, tea tree, mustard, horseradish, clary sage, cloves, dried... Cilantro, coriander, tarragon, eucalyptus, fennel, guaiac wood, dill, melaleuca, sophora flavescens, allspice, juniper, fenugreek, garlic, bay leaf, nutmeg peel, myrrh, nutmeg, spruce, geranium, lemongrass, lavender, bright lavender, palmarosa, rose, rosemary, sandalwood, oakmoss, cedarwood, vetiver, camphor, rosewood, patchouli, rockrose, cumin, thyme, ylang-ylang, birch, chili, celery, toluene, broom, immortelle, benzoin, jasmine, acacia, tuberose, mignonette, marigold, mimosa, frankincense, iris, vanilla, and licorice. Each natural extract or oil contains a complex mixture of chemical compounds, which may include the compounds mentioned above. Other fragrance components can be isolated from natural products; for example, geraniol and citronellol can be isolated from citronella oil, citral from lemongrass oil, eugenol from clove oil, and linalool from rosewood oil. Animal products used in the fragrance compositions include, but are not limited to, musk, ambergris, civet, and castoreum. The natural ingredients described herein can also be synthesized and may include the compounds disclosed herein, and may be used as fragrance and / or flavoring components in the fragrance and flavor compositions of this application.

[0043] Examples of fragrance ingredients used in perfumes, air fresheners, laundry detergents, pet bedding, cleaning products, liquid and solid soaps, shampoos and conditioners, cosmetics, deodorants, and personal hygiene products include, but are not limited to: hexylcinnamaldehyde; pentylcinnamaldehyde; amyl salicylate; hexyl salicylate; terpineol; 3,7-dimethyl-cis-2,6-octadien-1-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-1-ol; 3,7-dimethyl-6-octen-1-ol; 3,7-dimethyl-1-octanol; 2-methyl-3-(p-tert-butylphenyl)propanal; 4-(4-hydroxy-4-methylpentyl)-3-cyclohexen-1-carboxaldehyde; tricyclodecenyl propionate; tricyclodecenyl acetate; anisaldehyde; 2-methyl-2-(p-isopropylphenyl)propionaldehyde; ethyl 3-methyl-3-phenyl glycidyl ester; 4-(p-hydroxyphenyl)but-2-one; 1-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-buten-1-one; p-methoxyacetophenone; p-methoxy-α-phenylpropene; 2-n-hexyl-3-oxocyclohexane Methyl pentane carboxylate; γ-undecyl lactone; geraniol; geraniol acetate; linalool; linalool acetate; tetrahydrolinalool; citronellol; citronellol acetate; dihydromyrceneol; dihydromyrceneol acetate; tetrahydromyrceneol; terpineol acetate; nopodium; nopodium acetate; 2-phenylethanol; 2-phenylethyl acetate; benzyl alcohol; benzyl acetate; benzyl salicylate; benzyl benzoate; styrax ester acetate; dimethylbenzyl methanol; trichloromethylphenyl methanol; methylphenylmethanol acetate; isononyl ethyl alcohol Ester; Vetiveryl acetate; Vetiverol; 2-Methyl-3-(p-tert-butylphenyl)propanal; 2-Methyl-3-(p-isopropylphenyl)propanal; 3-(p-tert-butylphenyl)propanal; 4-(4-methyl-3-pentenyl)-3-cyclohexenaldehyde; 4-acetoxy-3-pentyltetrahydropyran; Methyl dihydrojasmonate; 2-n-heptylcyclopentanone; 3-methyl-2-pentylcyclopentanone; n-Decanal; n-Dodecanoal; 9-Decanol-1; Phenoxyethyl isobutyrate; Phenylacetaldehyde Dimethyl acetal; phenylacetaldehyde diethyl acetal; geraniol; citronellol; cedrol acetal; 3-isocamphorcyclohexanol; cedrol methyl ether; isolongaenolide; obeppine nitrile; obeppine; heliotropin; eugenol; vanillin; diphenyl ether; hydroxycitronellol ionone methyl ionone; isomethyl ionone; ionone; cis-3-hexenol and its esters; indaminom musk fragrance; tetrahydronaphthalene musk fragrance; isochromic musk fragrance; macrocyclic ketones; macrocyclic lactone musk fragrances; and tridecanoic acid glycol ester.

[0044] The flavoring and flavoring ingredients in the flavoring and flavoring compositions of a particular product are selected based on the product’s intended use and desired aroma. For example, flavoring ingredients used in toothpaste, mouthwash, and oral hygiene products may be designed to give the product a “fresh” feel, including but not limited to spearmint oil, peppermint oil, star anise oil, lemon oil, and menthol.

[0045] Flavor compositions can be used to mask unpleasant tastes in oral medications. For example, if a medication is salty, flavorings containing cinnamon, raspberry, orange, maple syrup, caramel, or licorice (Eurasian licorice) flavors can be used to mask the taste. If a medication is too sweet, flavorings containing berry, vanilla, or acacia flavors can be used to improve its palatability. For bitter medications, flavoring compositions containing cocoa, chocolate mint, wild cherry, walnut, licorice (Eurasian licorice), and sage flavors can be used; while for sour medications, flavorings containing fruit, citrus, or cherry flavors can be used to improve their palatability. These flavors can be provided by the natural or synthetic flavoring ingredients discussed herein.

[0046] Examples of flavoring ingredients used in food flavor compositions include, but are not limited to: glucosylstevioside, isomenthyl alcohol, thiocarboxylic acid, cathinone, 1,5-octadien-3-ol, 2-mercaptoheptane-4-ol, 4,3-(methylthio)decaldehyde, (4Z,7Z)-tetadecano-4,7-dienal, Polygonum hydropiper oil, Amacha leaf extract, glutamyl-2-aminobutyric acid, glutamyl-2-aminobutyric acid, glutamyl-n-valine-glycine, glutamyl-n-valine, N1-(2,3-dimethoxybenzyl)-N2-(2-(pyridin-2-yl)ethyl)oxalamide, 1-(2-hydroxy-4-methylcyclohexyl)acetone, lime oil, Persian lime oil, 6-methoxy-2,6-dimethylheptaldehyde, 3,5-undecadien-2-one 2,5-Undecadien-1-ol, Triethylthiazide, 4-Methylpentyl-4-methylvalerate, (R)-N-(1-methoxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide, 2-N-acetylglutamic acid, 1,3-propanediol, Zanthoxylum bungeanum extract, Piper tamarind extract, Peppermint oil, Mangosteen distillate, Ethyl 3-(2-hydroxyphenyl)propionate, 1-cyclopropanemethyl-4-methoxybenzene, Isopentenylthioisobutyrate, Isopentenylthioisovalerate, Podocarpus resin, Stevioside, 1-(2,4-dihydroxyphenyl)-3-(3-hydroxy-4-methoxyphenyl)prop-1-one, Ethyl 5-formyloxydecanoate, Ethyl 3-[3-(2-isopropyl-5-methylcyclohexyl)ureo]butyrate, 2-Isopropyl-4-methyl-3-thiazoline, 2,6,10-trimethyl-9-undecenal, 5-mercapto-5-methyl-3-hexanone, Mayer lemon oil, stevia glycoside extract, stevia, lebodiin 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 peppermint oil. See LJ Marnett et al., GRAS Flavorings 26, Food Technology, 44-45 (2013).

[0047] Solvents and excipients preferably used in the compositions and products disclosed herein 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).

[0048] The amount of spices or flavorings used in a spice or flavor composition cannot be generalized, as it depends on the type of product to which the spices or flavorings are added, the intended use of the product, and the desired aroma and / or flavor. The amount of spices or flavorings used in a spice or flavor composition typically ranges from 1% to 99% of the composition's mass. If too little spice or flavoring is used, a sufficiently rich aroma or flavor may not be achieved. Furthermore, if too much spice or flavoring is used, a larger amount of reagent may be required to dissolve the ingredients, which in turn reduces the desired aroma or flavor characteristics of the final product. Enhancing the effect of flavorings or flavorings can be achieved by suppressing the diffusion of volatile or other flavorings during use or consumption. Therefore, the amount of each spice and flavoring in the spice or flavor composition must be selected based on the aroma and / or flavor characteristics of the selected ingredients, the overall composition of the product, and the desired aroma and / or flavor effect.

[0049] The flavor and fragrance compositions disclosed herein may use additives. These additives include, but are not limited to, solvents, surfactants, pH adjusters, buffers, thickeners, drying agents, emulsifiers, foaming agents, stabilizers, antioxidants, and disintegrants. Other additives for the flavor and fragrance compositions will be selected according to the intended use of the composition.

[0050] Solvents that can be used in the fragrance and flavor compositions disclosed herein, such as water-soluble organic solvents, 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, butanediol, hexanediol, glycerol, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, and dipropylene glycol monomethyl ether. These water-soluble solvents can be used alone or in combination. The content of water-soluble organic solvents in the compositions of this application can be determined according to the desired composition properties, and is typically from about 1% to about 99% by mass.

[0051] Oil-soluble organic solvents that can be used in the flavor and fragrance compositions of this application include, but are not limited to: isoparaffins, paraffin, limonene, pinene, triethyl citrate, benzyl benzoate, isopropyl myristate, triacetin, and silicones.

[0052] Preferred solvents include, but are not limited to, triethyl citrate, triacetin, glycerol, ethanol, water, triglycerides, liquid waxes, propylene glycol derivatives, and ethylene glycol derivatives.

[0053] In some embodiments, the flavor and fragrance compositions and products disclosed herein may also contain other substances, including but not limited to chelating agents, preservatives, antioxidants, deodorants, bactericides, ultraviolet absorbers, pH adjusters, insecticides, insect repellents, insecticides, colorants, excipients, and buffers. The substances used or added to the flavor and fragrance compositions of this application may vary depending on the product containing the composition. When used in a flavor and fragrance composition, the substance may function as an additive. When used with a flavor and fragrance composition, the substance may be considered part of a product composition containing the flavor and fragrance composition.

[0054] The excipients that may be used in the flavor and fragrance compositions and products disclosed herein may vary depending on the intended use of the product and its overall composition. In some cases, the excipient may be included in the flavor or fragrance composition or may be independent of the composition. Excipients used in flavoring compositions for oral pharmaceuticals include, but are not limited to, tablet coatings (e.g., cellulose ether hydroxypropyl methylcellulose), synthetic polymers, shellac, corn gluten (e.g., zein or other polysaccharides), and gelatin. In contrast, cosmetic excipients may include, but are not limited to: carbomer 940 ETD, triethanolamine, purified water, glycerin, imidazolidinyl urea, EDTA, polyvinyl alcohol, methylparaben, phenoxyethanol, ethanol, PEG-7 glyceryl cocoate, PEG-6 triglyceride hexanoate, Acemulogar LAM V, isopropyl myristate, Tegosoft CT, xanthan gum, Sepicide CL, polyquaternium-7, and petrolatum oil. Those skilled in the art can readily select other suitable excipients for use with the flavor and fragrance compositions of the products described.

[0055] Buffers that can be used with the flavor and flavor compositions of this application may vary depending on the intended use of the product and its overall composition. In some cases, buffers may be included in the flavor or flavor composition or may be separate from the composition. Examples of buffers that can be used in the flavor and flavor compositions of this application include, but are not limited to, citrates, acetates, and phosphates. For example, trisodium citrate is known to impart a sour taste to a product and can also be used as a buffer. Trisodium citrate is an ingredient in many soft drinks and other beverages, beverage mixtures, and German sausages. In cosmetics, disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and citric acid can be used to buffer the pH of a product. In toothpaste, calcium carbonate and / or dicalcium phosphate can be used as pH buffers. Those skilled in the art can readily select other buffers suitable for use in or with the flavor and / or flavor compositions of said products.

[0056] Thirdly, this disclosure provides a product comprising compound 1 or any one of compounds 1.1-1.69, or composition 1 or any one of compositions 1.1 to 1.11. In some embodiments, the product may be selected from: personal care products (e.g., soap, skin cream or lotion, balm, shampoo, shower gel, body gel, moisturizer, deodorant, antiperspirant, aftershave, cologne, perfume or other hair or skin care products), sunscreen, insect repellents and pesticides, detergents, household cleaners (e.g., surface cleaners, metal cleaners, wood cleaners, glass cleaners, body cleaners (e.g., soap), dishwashing liquid or laundry detergent), air fresheners, room sprays, fragrance pills, candles, cosmetics (e.g., perfume, cologne, nail polish, eyeliner, mascara, lipstick, foundation, concealer, blush, bronzer, eyeshadow, lip liner, lip balm), eau de toilette, talcum powder, and pet bedding.

[0057] The foregoing has described some embodiments of this application. Those skilled in the art should understand that the above descriptions are merely examples and not restrictive. Therefore, embodiments of this application may take other specific forms without departing from its spirit or essential characteristics.

[0058] Those skilled in the art should recognize or be able to determine, through conventional experiments, equivalents of specific embodiments of this application. Therefore, it should be understood that the embodiments described herein are merely examples, the scope of this application is defined by the appended claims and their equivalents, and this application may be implemented in ways different from those specifically described in the foregoing specification.

[0059] When used to describe a composition in an application, the term "about" refers to a listed percentage of ±5%, ±4%, ±3%, ±2.5%, ±2%, ±1.5%, ±1%, ±0.75%, ±0.5%, ±0.25%, or ±0.1%. In one embodiment, "about" refers to a listed percentage of ±5%. For example, "about 50%" refers to a range of 45% to 55%. In one embodiment, "about" refers to a listed percentage of ±2.5%. In one embodiment, "about" refers to a listed percentage of ±1%. In one embodiment, "about" refers to a listed percentage of ±0.5%. In one embodiment, "about" refers to a listed percentage of ±0.1%.

[0060] The singular forms “a,” “an,” and “the” used in this article all include plural references unless the context clearly specifies otherwise. For example, “spice ingredient” includes not only a single spice ingredient but also a combination or mixture of two or more different spice ingredients; “additive” includes both a single additive and two or more additives, and so on.

[0061] The phrases “for example,” “to illustrate,” “likely,” or “including” used herein are intended to introduce examples to further clarify more general topics. These examples are only used to aid understanding of this disclosure and are not intended to be limiting in any way. Furthermore, the terms “may,” “optional,” “selectively,” or “may selectively” used herein indicate that the situation described below may or may not occur; therefore, the description includes both examples where the situation occurs and examples where the situation does not occur. For example, “selectively exist” means that an object may or may not exist; therefore, the description includes both examples where the object exists and examples where the object does not exist.

[0062] As used herein, "optional substitution" means that the indicated core group or functional group is not substituted, or is substituted by one or more groups, wherein the number of substituents does not exceed the maximum allowed by the valence bond rules, and wherein the groups are selected from: halogens, hydroxyl groups, cyano groups, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl 、 C 1-6 Alkyl groups, -O-Si(R) x ) 3 -OR x -C(O)H, -C(O)-R x -C(O)-OR x -C(O)-NH- R x -C(O)-N-(R) x ) ( R x -OC(O)-R x、 -NH(R x )-C(O)-R x -N (R) x (R) x )-C(O)-R x -NH(R) x ), -N(R x (R) x ), heterocyclic alkyl, aryl, heteroaryl; wherein, the C 1-6 Alkyl, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups may be further optionally converted to one or more halogens, hydroxyl groups, cyano groups, or C groups. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 1-6 Halogenated alkyl groups, -O-Si(R) x )3 -OR x -C(O)H, -C(O)-R x -C(O)-OR x -C(O)-NH- R x -C(O)-N-(R) x (R) x -OC(O)-R x -NH(R) x )-C(O)-R x -N(R) x (R) x ) -C(O)-R x -NH(R) x ), - N (R x ) (R x ), heterocyclic alkyl, aryl and heteroaryl substitutions; wherein each R x All are independently selected from hydrogen and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0063] As used in this article, "C" 1-6 "Alkyl" refers to a saturated straight-chain or branched radical consisting primarily of 1 to 6 carbon atoms and a corresponding number of hydrogen atoms. An example C 1-6 Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and tert-hexyl. Based on this disclosure, those skilled in the art will understand that other C... 1-6 -alkyl. The term "C" 1-3 -alkyl", C 1-4 "-alkyl" and similar terms have the same meaning, referring to saturated straight-chain or branched free radicals mainly composed of 1 to 3 (or 4) carbon atoms and a corresponding number of hydrogen atoms. Similar terms include "C..." 2-6 -alkenyl", C 2-6 -alkynyl group", C 3-6 -cycloalkyl", C 1-6 -haloalkyl", "C" 1-6"-alkoxy" and similar terms refer to the corresponding functional groups having the stated number of carbon atoms. "Alkenyl" refers to an unsaturated straight-chain or branched radical having at least one double bond; "alkynyl" refers to an unsaturated straight-chain or branched radical having at least one triple bond; "haloalkyl" refers to at least one halogen atom bonded to a carbon atom; "alkoxy" refers to at least one oxygen atom bonded to an alkyl group, with the functional group's connection point being an oxygen atom (i.e., forming an ether). Exemplary alkenyl groups include vinyl and allyl. Exemplary alkynyl groups include ethynyl and propynyl. Typical haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, 3,3,3-trifluoroethyl, and similar groups containing chlorine, bromine, or iodine. "Cycloalkyl" refers to a carbon ring linked by a ring of carbon atoms. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0064] As used herein, the term "heteroaryl" refers to an aromatic radical having 5 to 20 atoms (i.e., ring atoms) forming a ring, wherein at least one ring atom (e.g., 1 to 5) is a carbon atom, and at least one of the remaining ring atoms is a nitrogen, sulfur, or oxygen atom. Heteroaryl rings include monocyclic, bicyclic fused rings, and polycyclic fused ring systems, provided that at least one ring in the system contains at least one heteroatom (N, S, or O), and all rings are aromatic rings. Exemplary five-membered heteroaryl groups include furanyl, thiopheneyl (thiophene group), pyrroleyl, oxazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, imidazoleyl, triazolyl, oxadiazolyl, thiazolyl, and tetrazolyl. Typical six-membered heteroaryl groups include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and 1,2,4-triazinyl. Typical fused heteroaryl groups include benzoxazolyl, benzothiazolyl, benzoisothiazolyl, benzoisothiazolyl, benzoimidazolyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl. Other heteroaryl groups will be understood by those skilled in the art based on this disclosure. Typically, heteroaryl groups are attached to the host structure via carbon atoms. However, those skilled in the art will understand that certain other atoms, such as heterocyclic atoms, can also be attached to the host structure.

[0065] As used in this article, the term "aryl" refers to an aromatic radical having five or six atoms (i.e., ring atoms) forming a ring in which all ring atoms are carbon atoms. Typical aryl radicals include phenyl and naphthyl.

[0066] As used herein, the term "heterocyclic alkyl" refers to an aromatic radical having 3 to 20 atoms (i.e., ring atoms) forming a ring, wherein at least one ring atom (e.g., 1 to 5) is a carbon atom, at least one of the remaining ring atoms is a nitrogen, sulfur, or oxygen atom, and at least one ring is a non-aromatic ring. Heterocyclic alkyl rings include monocyclic, bicyclic fused, bicyclic spirocyclic, polycyclic bridging, and polycyclic fused ring systems, provided that at least one ring in the ring system has at least one heteroatom (N, S, or O), and at least one ring in the ring system is a non-aromatic ring (e.g., a saturated ring). Exemplary saturated heterocyclic alkyl groups include aziridine alkyl, aziridine alkyl, ethylene oxide, oxadienoyl alkyl, tetrahydrofuran alkyl, pyrrole alkyl, piperidinyl alkyl, piperazine alkyl, morpholinyl alkyl, and thiomorpholinyl alkyl. Heterocyclic alkyl ring systems include ring systems in which aromatic and non-aromatic rings are fused, for example, ring systems obtained by partial reduction of polycyclic aromatic ring systems. Typical examples of such ring systems include indolinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Other heterocyclic alkyl groups will be understood by those skilled in the art based on this disclosure. Heterocyclic alkyl groups can be attached to the main structure via carbon or nitrogen atoms on the ring.

[0067] Unless otherwise stated, the term "compound" as used herein means any particular chemical compound disclosed herein, including tautomers, regioisomers, geometric isomers, and, where applicable, stereoisomers, including their optical isomers (enantiomers) and other stereoisomers (diastereomers), and, where applicable, their pharmaceutically acceptable salts and derivatives. In this context, the term "compound" generally refers to a single compound, but may also include other compounds, such as stereoisomers, regioisomers, and / or optical isomers (including racemic mixtures), and specific enantiomers or enantiomer-enriched mixtures of disclosed compounds. In this context, the term also refers to prodrug forms of compounds that are modified to facilitate delivery of the compound to the active site. The term also refers to any particular chemical compound in which one or more atoms have been substituted with one or more different isotopes of the same element.

[0068] The entire contents of every patent document and scientific article mentioned herein are incorporated herein by reference. The following non-limiting embodiments will help to provide a more complete understanding of the functionality and advantages of these and other embodiments. These embodiments are intended to be illustrative and should not be considered as limiting the scope of the embodiments discussed herein.

[0069] Example Several other known synthetic routes can prepare polysubstituted pyrazoles by reacting hydrazine and hydrazone with carbonyl compounds and their 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).

[0070] The functional groups on the pyrazole core can be further modified according to standard methods, such as ester hydrolysis, Grignard addition, ketone reduction, alcohol oxidation, ester formation, N-alkylation, etc.

[0071] Ethyl 1,3-dimethyl-5-pyrazolecarboxylate was obtained, and its olfactory properties were investigated. The compound was analyzed in pure liquid form and in a 10% ethanol dilution by an experienced fragrance chemist (chief perfumer). The results showed that the compound possesses unique aroma characteristics including floral, chocolate, light woody, iris, and soft leather notes.

[0072] Synthesis Examples The compounds in Examples 1 to 164 can be prepared according to the following method.

[0073] Recording at 400 MHz using a Bruker Avance AV-I-400 or Bruker Avance AV-II-400 MRI scanner. 1 H₂NMR spectra. Unless otherwise specified, chemical shift values ​​are expressed in ppm with tetramethylsilane as an internal standard. The following abbreviations or combinations thereof are used to indicate the multiplicity of the NMR signal: br = broad peak, d = doublet, m = multiplet, q = quartet, quintet = quintet, s = singlet, t = triplet.

[0074] Purification method information: Method A: Mass spectrometer type: ACQ-SQD2; High-performance liquid chromatograph type: Waters modular preparative high-performance liquid chromatography system; Column: Waters XSelect (C18, 100x30mm, 10µm); Flow rate: 55 mL / min preparative pump; Column temperature: room temperature; Mobile phase A: 10mM ammonium bicarbonate aqueous solution, pH=9.5; Mobile phase B: 100% acetonitrile; Linear gradient: t=0 min 2% B, t=4 min 2% B, t=13 min 30% B, t=14.5 min 100% B, t=17 min 100% B; Detector: DAD (220-320 nm); Detector: MSD (ESI positive / negative); Mass range: 100 – 800; Fraction collection based on MS and DAD.

[0075] Method B: Rapid column chromatography (SiO2, 0-40% EtOAc heptane solution) Method C: Mass spectrometer type: Agilent Technologies G6130B quadrupole mass spectrometer; High-performance liquid chromatograph type: Agilent Technologies 1290 preparative liquid chromatograph; Column: Waters XSelect CSH (C18, 100x30mm, 10µm); Flow rate: 55 mL / min; Column temperature: room temperature; Mobile phase A: 10mM ammonium bicarbonate aqueous solution (pH=9.5); Mobile phase B: 100% acetonitrile; Linear 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; Detector: DAD (220-320 nm); Detector: MSD (ESI positive / negative ion mode), mass range: 100 – 1000; Fraction collection was performed based on MS and DAD.

[0076] Method D: Rapid column chromatography (SiO2, 0-30% EtOAc heptane solution) Method E: Rapid column chromatography (SiO2, 0-50% EtOAc heptane solution) Method F: Rapid column chromatography (SiO2, 0-60% EtOAc heptane solution) Method G: Instrument: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Amylose-3 (250x21.2 mm, 5 µm); Column temperature: 40°C; Flow rate: 100 mL / min; ABPR: 120 bar; Mobile phase A: CO2, Mobile phase B: 20 ​​mM ammonia-ethanol solution; Isocratic elution: 50% B, duration 8 min; Detection: UV 210; Collection: timed collection.

[0077] Method H: Rapid column chromatography (SiO2, 0-100% EtOAc heptane solution) Method I: Instrument: Sepiatec Prep 250 SFC; Column: Phenomenex Lux i-Cellulose-5 (250x21.2 mm, 5 µm); Column temperature: 40°C; Flow rate: 100 mL / min; ABPR: 120 bar; Mobile phase A: CO2, Mobile phase B: 20 ​​mM ammonia-methanol solution; Isocratic elution: 50% B, duration 8 min; Detection: UV 210; Collection: timed collection.

[0078] Method J: Instrument: Sepiatec Prep 250 SFC; Column: Phenomenex Lux Amylose-1 (250x21mm, 5µm); Column temperature: 40°C; Flow rate: 100 mL / min; ABPR: 120 bar; Mobile phase A: CO2, Mobile phase B: 20 ​​mM ammonia-ethanol solution; Isocratic elution: 50% B, duration 8 min; Detection: UV 210; Collection: timed collection.

[0079] Method K: Instrument: Sepiatec Prep 250 SFC; Column: Phenomenex Lux Cellulose-2 (250 x 21.2 mm, 5 µm); Column temperature: 40°C; Flow rate: 100 mL / min; ABPR: 120 bar; Mobile phase A: CO2; Mobile phase B: 20 ​​mM ammonia-ethanol solution; Linear gradient: t = 0 min 10% B, t = 6.5 min 50% B; t = 7.5 min 50% B; Detection: UV 210; Collection: Timed.

[0080] Method L: Rapid column chromatography (SiO2, 0-70% EtOAc heptane solution) Method M: Rapid column chromatography (SiO2, 0-80% EtOAc heptane solution) Method N: Mass spectrometer type: Agilent Technologies G6130B quadrupole mass spectrometer; High-performance liquid chromatograph type: Agilent Technologies 1200 preparative liquid chromatograph; Column: Waters Sunfire (C18, 150x19mm, 10µm); Flow rate: 25 mL / min; Column temperature: room temperature; Mobile phase A: 0.1% formic acid aqueous solution; Mobile phase B: 100% acetonitrile; Linear 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; Detector: DAD (220-320 nm); Detector: MSD (ESI positive / negative), mass range: 100 – 1000; Fraction collection was performed based on MS and DAD.

[0081] LCMS analysis method information: Method 1: UPLC: Waters I-Class, acquisition method: UPLC_AN_ACID, column: XSelect CSHC18 XP (50x2.1mm 2.5µm), flow rate: 0.6 mL / min; column temperature: 40°C, mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid acetonitrile solution, gradient: t=0 min 5% B, t=2.0 min 98% B, t=2.7 min 98% B, post-processing time: 0.3 min, PDA detection: 210-320nm and 215nm.

[0082] Method 2: UPLC: Waters I-Class, Acquisition method: UPLC_AN_BASE, Column: XSelect CSHC18 XP (50x2.1mm 2.5µm), Flow rate: 0.6 mL / min; Column temperature: 25°C, Mobile phase A: 10mM ammonium bicarbonate aqueous solution (pH 9.5), Mobile phase B: Acetonitrile, Gradient: t=0 min 5% B, t=2 min 98% B, t=2.7 min 98% B, Post-processing time: 0.3 min, Detection PDA: 210-320nm.

[0083] Method 3: Acquisition method: U_T3_ACID_00-20, System: Agilent 1290 (equipped with SQ-MSD), Column: XSelect HSS T3 XP (50×2.1mm, 2.5µm), Flow rate: 0.8 mL / min; Column temperature: 40°C, Mobile phase A: 0.1% formic acid aqueous solution; Mobile phase B: 0.1% formic acid acetonitrile solution, Linear gradient: t=0 min 0% B, t=4.5 min 20% B, t=5 min 20% B, Post-processing time: 1 min, Detection: DAD (210, 215, 210-320nm), Detection: PDA (210-320nm), Detection: MSD (ESI positive / negative) mass range 90-1500.

[0084] Method 4: Acquisition method: U_AN_ACID, System: Agilent 1290 mass spectrometer (equipped with SQ-MSD), Column: XSelect CSH XP C18 (50x2.1mm, 2.5µm), Flow rate: 0.8 mL / min, Column temperature: 40°C, Mobile phase A: 0.1% formic acid aqueous solution, Mobile phase B: 0.1% formic acid acetonitrile solution, Linear gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min 98% B; t=5 min 98% B, Post-processing time: 0.5 min, Detection: DAD (210-320nm, 215nm), Detection: PDA (210-320nm), Detection: MSD (ESI positive / negative), Mass range 90-1500.

[0085] Method 5: Acquisition method: UPLC_AN_BASE, column: XSelect CSH C18 XP (50x2.1mm, 2.5µm), flow rate: 0.6 mL / min; column temperature: 25°C, mobile phase A: 10mM ammonium bicarbonate aqueous solution (pH=9.5), mobile phase B: 100% acetonitrile, gradient: t=0 min 5% B, t=2 min 98% B, t=2.7 min 98% B, post-processing time: 0.3 min, PDA detector: 210-320nm, ELSD detector: gas pressure 40 psi, drift tube temperature: 50°C.

[0086] Method 6: Acquisition method: U_AN_BASE, System: Agilent 1290 mass spectrometer (equipped with SQ-MSD), Column: XSelect CSH XP C18 (50x2.1mm, 2.5µm), Flow rate: 0.8 mL / min, Column temperature: 25°C, Mobile phase A: 10mM ammonium bicarbonate aqueous solution (pH 9.5), Mobile phase B: Acetonitrile, Linear gradient: t=0 min 5% B, t=0.5 min 5% B, t=4.5 min 98% B; t=5 min 98% B, Post-processing time: 0.5 min, Detection: DAD (210-320nm, 215nm), Detection: PDA (210-320nm), Detection: MSD (ESI positive / negative), Mass range: 90-1500.

[0087] Method 7: UPLC_SC_ACID, Instrument: Waters I-Class UPLC, Binary Solvent Manager (BSM), Sample Manager-FTN (SM-FTN) and Sample Preparer (SO), Column Manager (CM-A), PDA 210-320nm, QDaESI 100-800 (positive) 100-800 (negative), Column: XSelect CSH C18 XP (50x2.1mm 2.5µm), Flow rate: 0.6 mL / min; Column temperature: 40°C, Mobile phase A: 0.1% formic acid aqueous solution, Mobile phase B: 0.1% formic acid acetonitrile solution, Gradient: t=0 min 5% B, t=1.3 min 98% B, t=1.7 min 98% B, Run: 0.3 min.

[0088] Method 8: Method: SC_BASE.M, Instruments: Agilent 1260 Infinity, 1260 G1312B injection pump, 1260 G1367E WPS, 1260 TCC G1316A, Column: 1260 G1315C, DAD (210-320 nm, 210 and 220 nm), PDA (210-320 nm), G6130B MSD ESI positive / negative (mass range 100-1000), Column: WatersXSelect CSH C18 (30x2.1mm 3.5µm), Flow rate: 1 mL / min; Column temperature: 25°C, Mobile phase A: 10 mM ammonium bicarbonate aqueous solution (pH 9), Mobile phase B: acetonitrile, Gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, run again: 1.3 min.

[0089] Method 9: Method: SC_ACID.M, Instruments: Agilent 1260 Infinity II, 1260 G7112B box pump, 1260 G7167A multiplexer, 1290 MCT G7116B column packing. 1260 G7115A DAD (210, 220 and 210-320 nm), PDA (210-320 nm), G6135B MSD (ESI positive / negative) mass range 90-1500, 1290G7102A ELSD (evaporation: 50°C, nebulization: 50°C, gas flow rate: 1.3 mL / min), column: XSelect CSH C18 (30x2.1 mm 3.5 µm), flow rate: 1 mL / min, column temperature: 40°C, mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid acetonitrile solution, gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, run: 1.3 min.

[0090] Method 10: Method: SC_BASE.M, Instruments: Agilent 1260 Infinity, 1260 G1312B box pump, 1260 G1367E WPS, 1260 TCC G1316A column packing. 1260 G1315C DAD (210-320 nm, 210 and 220 nm), PDA (210-320 nm), G6130B MSD (ESI positive / negative) mass range: 100 - 1000, column: WatersXSelect CSH C18 (30x2.1 mm, 3.5 µm), flow rate: 1 mL / min, column temperature: 25°C, mobile phase A: 10 mM ammonium bicarbonate aqueous solution (pH=9), mobile phase B: acetonitrile, gradient: t=0 min 5% B, t=1.6 min 98% B, t=3 min 98% B, run: 1.4 min.

[0091] Example 1: N,1,3,5-Tetramethyl-1H-pyrazole-4-carboxamide 1,3,5-Trimethylpyrazole-4-carboxylic acid (750 mg, 1 Eq, 4.86 mmol) was dissolved in DMF (24.3 mL), and methylaminetetrahydrofuran (THF) solution (3.65 mL, 2.0 mol / L, 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) were added. The mixture was stirred at 50 °C for 16 hours. Purification was performed using method C to obtain the target compound: 578.1 mg (yield 71.1%, purity 96.37%). LCMS: Method 1, 0.61 min, M+H = 168.07; calculated value 168.212. 1 H NMR (400 MHz, CDCl3) δ 5.54 (s, 1H), 3.72 (s, 3H), 2.96 (d, J = 4.8 Hz, 3H), 2.48 (s, 3H), 2.39 (s, 3H).

[0092] Example 2: N,1,3-Trimethyl-1H-pyrazole-4-carboxamide 1,3-Dimethylpyrazole-4-carboxylic acid (1000 mg, 1 Eq, 7.136 mmol) was dissolved in DMF (35.68 mL), and methylaminetetrahydrofuran (THF) solution (5.352 mL, 2.0 mol / L, 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) were added. The mixture was stirred at 50 °C for 16 hours. Purification was performed using method N to give the target compound: 670.9 mg (yield 61.3%, purity 100%). LCMS: Method 1, 0.59 min, M+H = 154.05; calculated value 154.185. 1 H NMR (400 MHz, CDCl) 3) δ 7.67 (s, 1H), 5.61 (s, 1H), 3.83 (s, 3H), 2.95 (d, J = 4.8Hz, 3H), 2.46 (s, 3H).

[0093] Example 3: N,N,1,3-Tetramethyl-1H-pyrazole-4-carboxamide 1,3-Dimethylpyrazole-4-carboxylic acid (1000 mg, 1 Eq, 7.136 mmol) was dissolved in DMF (35.68 mL), and 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) were added. The mixture was stirred at 50 °C for 16 hours. Purification was performed using method C to give the target compound: 679.9 mg (yield 56.9%, purity 100%). LCMS: Method 1, 0.66 min, M+H = 168.06; calculated value 168.212. 1 H NMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 3.84 (s, 3H), 3.07 (s, 6H), 2.33 (s, 3H).

[0094] Example 4: Ethyl 2-methyl-2,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate Cyclopentanone (53 mL, 1 Eq, 594.4 mmol) and diethyl oxalate (81.54 mL, 1.01 Eq, 600.3 mmol) were dissolved in ethanol (250 mL). Sodium ethoxide (21% ethanol solution) (0.20 L, 21% by weight, 1.01 Eq, 600.3 mmol) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 16 hours and then concentrated. Acetic acid (12.5 mL) was added to the resulting crude product, sodium 2-(2-ethoxy-2-oxoacetyl)cyclopent-1-en-1-ol (5.0 g, 0.041 Eq, 24 mmol), and the gel mixture was cooled to 0 °C. Methylhydrazine (1.40 mL, 0.0444 Eq, 26.4 mmol) was added dropwise. After the addition was complete, the gel was warmed to room temperature, gently vortexed to form a suspension, and stirred at room temperature for 16 hours. The solid was filtered, and the filtrate was concentrated under reduced pressure and extracted with dichloromethane and a saturated aqueous solution of sodium bicarbonate and sodium hydroxide (6 M) (approximately 9:1; total water volume approximately 100 mL), and the mixture was vigorously stirred. The layers were separated, and the aqueous layer was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid column chromatography (silica gel, 5-60% ethyl acetate / heptane) to give the target compound (672 mg, 3.46 mmol, yield 14.2%). LCMS: Method 1, 1.45 min, M+H = 195.11; calculated value 195.234. 1 H NMR(400 MHz, DMSO) δ 4.25 (q, J = 7.1 Hz, 2H), 4.00 (s, 3H), 2.71 (t, J = 7.2Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.39 – 2.28 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0095] Example 5: Ethyl 5-isopropyl-1H-pyrazole-4-carboxylate Ethyl 4-methyl-3-oxovalerate (10.0 g, 1 Eq, 63.2 mmol) and 1,1-dimethoxy-N,N-dimethylmethylamine (10.1 mL, 1.2 Eq, 75.9 mmol) were dissolved in 2,2,2-trifluoroethanol (50.0 mL). A solution of hydrazine hydrate (3.07 mL, 1 Eq, 63.2 mmol) in 2,2,2-trifluoroethanol (50.0 mL) was added dropwise at 0 °C, and the mixture was heated to room temperature and stirred for 18 hours. The reaction mixture was concentrated, and water (100 mL) was added to the residue, followed by extraction with ethyl acetate (2 × 100 mL). The organic phase was washed successively with saturated sodium bicarbonate aqueous solution and water, dried over anhydrous magnesium sulfate, filtered, and concentrated. Purification was achieved by rapid column chromatography (SiO2, 0-100% EtOAc / heptane). ， The title compound was obtained (8.67 g, 44 mmol, 69% yield). ¹H NMR (400 MHz, CDCl3) δ 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).

[0096] Example 6: Ethyl 3-isopropyl-1-methyl-1H-pyrazole-4-carboxylate Ethyl 5-isopropyl-1H-pyrazole-4-carboxylate (1.0 g, 92% by weight, 1 Eq, 5.0 mmol) was dissolved in N,N-dimethylformamide (10 mL), and potassium carbonate (0.84 g, 1.2 Eq, 6.1 mmol) and methyl iodoformane (0.38 mL, 1.2 Eq, 6.1 mmol) were added. The mixture was stirred at room temperature for 5 hours. After concentration, the solution was redissolved in a dichloromethane / water mixture, the organic layer was separated, and the N,N-dimethylformamide aqueous layer was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed using method G to give ethyl 3-isopropyl-1-methyl-1H-pyrazole-4-carboxylate: 460.3 mg (yield 46%, purity 100%). LCMS: Method 1, 1.33 min, M+H = 197.06; calculated value 197.25. 1 H NMR (400 MHz, CDCl3) δ7.79 (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).

[0097] Example 7: Ethyl 1,3,4-trimethyl-1H-pyrazole-5-carboxylate Step 1: Ethyl 4-(chloromethyl)-1,3-dimethyl-1H-pyrazole-5-carboxylate 1,4-Dioxane (10 mL), paraformaldehyde (357 mg, 2 Eq, 11.9 mmol), and ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (893 μL, 1 Eq, 5.95 mmol) were added sequentially to hydrochloric acid (1.10 mL, 6 Eq, 35.7 mmol) and sulfuric acid (31.7 μL, 0.1 Eq, 595 μmol), and the mixture was refluxed and heated for 5 hours. The mixture was concentrated, ice water was added, and it was extracted with ethyl acetate. The aqueous phase was extracted once with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 4-(chloromethyl)-1,3-dimethyl-1H-pyrazole-5-carboxylate (1.05 g, 4.85 mmol, yield 81.5%). LCMS: Method 8, 1.91 minutes, M+H = 217.0; calculated value 217.66.

[0098] Step 2: Ethyl 1,3,4-trimethyl-1H-pyrazole-5-carboxylate Under nitrogen protection, ethyl 4-(chloromethyl)-1,3-dimethyl-1H-pyrazole-5-carboxylate (1.05 g, 1 Eq, 4.85 mmol) was added to ethanol (20 mL), followed by palladium on carbon catalyst (516 mg, 5% by weight, 0.05 Eq, 242 μmol). The mixture was subjected to three vacuum hydrogen cycles and then placed in a hydrogen atmosphere with stirring at room temperature for 18 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated. Purification was achieved by rapid column chromatography (silica gel, 0-100% ethyl acetate / heptane). ， Ethyl 1,3,4-trimethyl-1H-pyrazole-5-carboxylate was obtained (439 mg, 2.41 mmol, yield 49.7%). LCMS: Method 1, 1.38 min, M+H = 183.1; calculated value 183.223. 1 H NMR (400 MHz, CDCl3) δ 4.36 (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).

[0099] Example 8: Ethyl 6,6-dimethyl-1,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate Step 1: Ethyl 2-(2-hydroxy-3,3-dimethylcyclopent-1-en-1-yl)-2-oxoethyl acetate Diethyl oxalate (12.25 g, 1 Eq, 84.97 mmol) and 2,2-dimethylcyclopentan-1-one (10.8 mL, 1.01 Eq, 85.82 mmol) were dissolved in ethanol (30 mL), and sodium ethoxide (32.0 mL, 21% by weight, 1.01 Eq, 85.82 mmol) was added. The mixture was stirred at room temperature for 16 hours. Ice water (200 mL) was added, and the pH of the mixture was adjusted to 4–5 with concentrated acetic acid, followed by extraction with diethyl ether. The aqueous layer was extracted once with diethyl ether, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give ethyl 2-(2-hydroxy-3,3-dimethylcyclopentan-1-en-1-yl)-2-oxoethyl acetate (15.16 g, 71.43 mmol, yield 84.06%). LCMS: Method 8, 1.91 min, M+H = 213.0; calculated value 213.24.

[0100] Step 2: Ethyl 6,6-dimethyl-1,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate Ethyl 2-(2-hydroxy-3,3-dimethylcyclopent-1-en-1-yl)-2-oxoethyl acetate (8.50 g, 1 Eq, 40.0 mmol) was dissolved in ethanol (75 mL), and hydrazine hydrate (3.20 mL, 64% by weight, 1.05 Eq, 42.1 mmol) was added. The mixture was refluxed for 16 hours. Acetic acid (5.0 mL, 2.2 Eq, 87 mmol) was added, and the mixture was refluxed for 1 hour and concentrated. The concentrate was dissolved in dichloromethane, washed successively with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by rapid column chromatography (SiO2, 0-100% EtOAc / heptane). ，Ethyl 6,6-dimethyl-1,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate was given (3.88 g, 18.6 mmol, yield 46.5%). LCMS: Method 1, 1.38 min, M+H = 209.1; calculated 209.261. ¹H NMR (400 MHz, CDCl3) δ 10.47 (brs, 1H), 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).

[0101] Examples 9 and 10: Ethyl 2-methyl-2,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate and ethyl 1-methyl-1,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate Ethyl 1,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate (10.00 g, 1 Eq, 55.49 mmol) was dissolved in DMF (75 mL), and potassium carbonate (15.34 g, 2 Eq, 111.0 mmol) and methyl iodoform (4.164 mL, 1.20 Eq, 66.59 mmol) were added. The mixture was stirred at room temperature for 16 hours. The solution was diluted with deionized water and ethyl acetate, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Ethyl 2-methyl-2,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate (5.28 g, 27.2 mmol, yield 49.0%) was purified by rapid column chromatography (SiO2, 0-100% EtOAc / heptane), LCMS: Method 1, 1.45 min, M+H = 195.1; calculated value 195.234. 1 ¹H NMR (400 MHz, CDCl₃) δ 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 1-methyl-1,4,5,6-tetrahydrocyclopentano[c]pyrazole-3-carboxylate (3.99 g, 20.5 mmol, yield 37.0%). LCMS: Method 1, 1.2 min, M+H = 195.1; calculated 195.234. 1H NMR (400 MHz, CDCl3), δ 4.36 (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-1-methyl-1H-pyrazole-5-carboxylate and ethyl 5-isopropyl-1-methyl-1H-pyrazole-3-carboxylate Ethyl 5-methyl-2,4-dioxohexanoate (12.50 g, 1 Eq, 67.13 mmol) was dissolved in ethanol (100 mL), and methylhydrazine (3.75 mL, 1.05 Eq, 70.48 mmol) was added. The mixture was refluxed and stirred for 2 hours, concentrated, and suspended in dichloromethane. The solid was removed by filtration. Purification by rapid column chromatography (silica gel, 0-100% ethyl acetate / heptane) yielded ethyl 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (3.69 g, 18.8 mmol, yield 28.0%). LCMS: Method 1, 1.55 min, M+H = 197.1; calculated value 197.25. 1 ¹H NMR (400 MHz, CDCl₃) δ 6.65 (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-1-methyl-1H-pyrazole-3-carboxylate (7.53 g, 38.4 mmol, yield 57.2%). LCMS: Method 1, 1.29 min, M+H = 197.1; calculated 197.25. 1 H NMR(400 MHz, CDCl3) δ 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).

[0103] Examples 13 and 14: Ethyl 5-propyl-1H-pyrazole-3-carboxylate and ethyl 4-ethyl-5-methyl-1H-pyrazole-3-carboxylate Step 1: Ethyl 2,4-dioxonium ester.

[0104] Pentyl-2-one (30.9 mL, 1 Eq, 290.3 mmol) and diethyl oxalate (39.42 mL, 1 Eq, 290.3 mmol) were dissolved in ethanol (150 mL), and sodium ethoxide (109 mL, 21% by weight, 1.01 Eq, 293.2 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours, then concentrated, acidified with 1M hydrochloric acid aqueous solution, and extracted twice with dichloromethane. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. ， filter ， Concentration yielded ethyl 2,4-dioxanone (47.16 g, 253.3 mmol, 87.25% yield). LCMS: Method 9, 1.81 min, M+H = 187.0; calculated value 187.21.

[0105] Step 2: Ethyl 5-propyl-1H-pyrazole-3-carboxylate and ethyl 4-ethyl-5-methyl-1H-pyrazole-3-carboxylate Ethyl 2,4-dioxane-heptanoate (20.00 g, 1 Eq, 107.4 mmol) was dissolved in ethanol (175 mL), and hydrazine hydrate (8.581 mL, 64% by weight, 1.05 Eq, 112.8 mmol) was added. The mixture was refluxed and heated for 3 hours. After concentration, the mixture was suspended in dichloromethane and filtered to remove the solid. The solid was purified by rapid column chromatography (SiO2, heptane / ethyl acetate gradient elution 0-100%, twice), followed by purification by Method J (twice) to give ethyl 5-propyl-1H-pyrazole-3-carboxylate (5.09 g, 27.9 mmol, yield 26.0%). LCMS: Method 1, 1.22 min, M+H = 183; calculated value 183.223. 1¹H NMR (400 MHz, CDCl₃) δ 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-1H-pyrazole-3-carboxylate (873 mg, 4.79 mmol, yield 4.46%). LCMS: Method 1, 1.21 min, M+H = 183.1; calculated value 183.223. 1 ¹H NMR (400 MHz, CDCl₃) δ 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). Missing. 1 H signal.

[0106] Examples 15, 16, 17 and 18: Ethyl 1-methyl-3-propyl-1H-pyrazole-5-carboxylate, ethyl 4-ethyl-1,3-dimethyl-1H-pyrazole-5-carboxylate, ethyl 1-methyl-5-propyl-1H-pyrazole-3-carboxylate and ethyl 4-ethyl-1,5-dimethyl-1H-pyrazole-3-carboxylate Ethyl 2,4-dioxonium ester (26.90 g, 1 Eq, 144.5 mmol) was dissolved in ethanol (200 mL), and methylhydrazine (8.06 mL, 1.05 Eq, 151.7 mmol) was added. The mixture was refluxed and stirred for 5 hours. After concentration, the mixture was suspended in dichloromethane, and the solid was removed by filtration. Purification was performed by rapid column chromatography (SiO2, heptane / ethyl acetate gradient elution, 0-100%) to give ethyl 1-methyl-3-propyl-1H-pyrazole-5-carboxylate (7.33 g, 37.4 mmol, yield 25.9%). LCMS: Method 1, 1.54 min, M+H = 197.1; calculated value 197.25. 1¹H NMR (400 MHz, CDCl₃) δ 6.62 (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-1,3-dimethyl-1H-pyrazole-5-carboxylate (1.02 g, 5.20 mmol, yield 3.60%). LCMS: Method 1, 1.49 min, M+H = 197.1; calculated 197.25. 1 ¹H NMR (400 MHz, CDCl₃) δ 4.36 (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 1-methyl-5-propyl-1H-pyrazole-3-carboxylate (13.05 g, 66.50 mmol, yield 46.03%). LCMS: Method 1, 1.31 min, M+H = 197.1; calculated 197.25. 1 ¹H NMR (400 MHz, CDCl₃) δ 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-1,5-dimethyl-1H-pyrazole-3-carboxylate (purified by method K) (463.7 mg, 2.363 mmol, yield 1.636%). LCMS: Method 1, 1.27 min, M+H = 197.1; calculated value 197.25. 1H NMR (400MHz, CDCl3) δ 4.39 (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).

[0107] Example 19: Ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (10 g, 1 Eq, 71 mmol) was dissolved in ethanol (150 mL), and sulfoxide chloride (16 mL, 3 Eq, 0.21 mol) was added dropwise. The mixture was stirred at room temperature for 4 hours, concentrated, alkalized with saturated sodium bicarbonate solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate. ， Filter and concentrate. Purify by rapid column chromatography (SiO2, 0-30% ethyl acetate / heptane) to give ethyl 1,5-dimethyl-1H-pyrazole-3-carboxylate (10.2 g, 60.6 mmol, 85% yield). LCMS: Method 1, 1 min, M+H = 122.87 (fragmentation); calculated value 169.196. 1 H NMR (400 MHz, CDCl3)δ 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).

[0108] Examples 20 and 21: Ethyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylate and ethyl 5-ethyl-1-methyl-1H-pyrazole-3-carboxylate Ethyl 2,4-dioxane (25.00 g, 1 Eq, 145.2 mmol) was dissolved in ethanol (250 mL), and methylhydrazine (8.10 mL, 1.05 Eq, 152.5 mmol) was added. The mixture was refluxed and stirred for 3 hours, then concentrated. Purification was performed by rapid column chromatography (SiO2, heptane / ethyl acetate gradient elution, 0-100%) to give ethyl 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (7.76 g, 42.6 mmol, yield 29.3%). LCMS: Method 1, 1.4 min, M+H = 183; calculated value 183.223. 1¹H NMR (400 MHz, CDCl₃) δ 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-1-methyl-1H-pyrazole-3-carboxylate (17.86 g, 98.01 mmol, yield 67.50%). LCMS: Method 1, 1.16 min, M+H = 183; calculated 183.223. 1 H NMR (400 MHz, CDCl3) δ 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).

[0109] Example 22: 1,5-Dimethyl-1H-pyrazole-3-carboxaldehyde Under nitrogen protection, lithium aluminum hydride (5.35 mL, 2.4 M, 2.2 Eq, 12.8 mmol) was added to a tetrahydrofuran solution (58.4 mL) of N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide (1.07 g, 1 Eq, 5.84 mmol) at -78 °C and stirred for 1 hour at -78 °C. The mixture was then poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3 times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by rapid column chromatography (SiO2, gradient elution with heptane and ethyl acetate, 0-100%) yielded 1,5-dimethyl-1H-pyrazole-3-carboxaldehyde (167.8 mg, 1.352 mmol, yield 23.1%). LCMS: Method 1, 0.77 min, M+H = 124.92; calculated value 125.143. 1 H NMR (400MHz, CDCl3) δ 9.88 (s, 1H), 6.56 (s, 1H), 3.88 (s, 3H), 2.32 (s, 3H).

[0110] Example 23: Ethyl 5-ethyl-1,4-dimethyl-1H-pyrazole-3-carboxylate Step 1: Ethyl 4-bromo-5-ethyl-1-methyl-1H-pyrazole-3-carboxylic acid Ethyl 5-ethyl-1-methyl-1H-pyrazole-3-carboxylate (1.00 g, 1 Eq, 5.49 mmol) was dissolved in dichloroethane (20 mL), and NBS (1.95 g, 2 Eq, 11.0 mmol) was added. The mixture was heated at 80 °C for 3 hours. After cooling to room temperature, it was further diluted with dichloromethane and water. The mixture was filtered through a phase separator, and the aqueous layer was extracted twice with dichloromethane. The organic phases were combined, concentrated, and purified by rapid column chromatography (SiO2, 0-100% ethyl acetate / heptane) to give ethyl 4-bromo-5-ethyl-1-methyl-1H-pyrazole-3-carboxylate (1.53 g, 5.86 mmol, 100% yield). LCMS: Method 9, 1.76 min, M+H = 261.0; calculated value 261.01.

[0111] Step 2: Ethyl 5-ethyl-1,4-dimethyl-1H-pyrazole-3-carboxylate: Under argon protection, potassium carbonate (2.27 g, 3 Eq, 16.4 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (1.54 mL, 2 Eq, 11.0 mmol), and the [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) complex dichloromethane (894 mg, 0.2 Eq, 1.10 mmol) were added to 20 mL of DMF containing ethyl 4-bromo-5-ethyl-1-methyl-1H-pyrazole-3-carboxylic acid ester (1.43 g, 1 Eq, 5.48 mmol) under argon protection. The mixture was stirred at 110 °C for 2 hours. After cooling to room temperature, the mixture was diluted with water and ethyl acetate. The aqueous phase was extracted once with ethyl acetate, and the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purified by rapid column chromatography (SiO2, 0-100% ethyl acetate / heptane), ethyl 5-ethyl-1,4-dimethyl-1H-pyrazole-3-carboxylate (615.70 mg, 3.1373 mmol, yield 57.3%) was obtained. LCMS: Method 2, 1.33 min, M+H = 197.1; calculated value 197.25. 1H NMR (400 MHz, CDCl3) δ 4.39 (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).

[0112] General Process 1: Examples 24-35 The compounds in Examples 24-35 were prepared by sulfuric acid-mediated esterification according to the following general procedure.

[0113] At 0°C, sulfuric acid (1Eq) was added to a carboxylic acid (1Eq) dissolved in a 0.3 M alcohol solution, and the mixture was heated under reflux until the reaction was complete. The reaction mixture was concentrated, alkalized with a saturated aqueous sodium bicarbonate solution, extracted with dichloromethane, filtered through a phase separator, and concentrated. Purification (see Methods) yielded the target product.

[0114] The following examples are all prepared according to general process 1, using the corresponding acids and alcohols as raw materials.

[0115] General Process 2: Example 36-116 The compounds in Examples 36-116 were prepared by thionyl chloride-mediated acyl halide formation and esterification reactions according to the following general procedure.

[0116] Carboxylic acid (1 Eq) was dissolved in an alcohol solution (0.3 M), and thionyl chloride (1.5–11.2 Eq) was added. The mixture was refluxed and heated until the reaction was complete. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was added to concentrate and alkalize the reaction solution. The solution was extracted with dichloromethane, filtered through a phase separator, and concentrated. The purified product was then obtained.

[0117] The following examples are all prepared according to general process 2, using the corresponding acids and alcohols as raw materials.

[0118] General Process 3: Examples 117-164 The compounds of Examples 117-164 were prepared by addition of a Grignard reagent (RMgX) to Weinreb amides according to the following general procedure.

[0119] Under a nitrogen atmosphere, Grignard reagent (2.5–5 Eq) was added dropwise to a 0.2 M solution of carboxamide (1 Eq) in tetrahydrofuran at 0 °C. The mixture was heated to room temperature and stirred until the reaction was complete. The reaction was terminated by adding a saturated aqueous solution of ammonium chloride, and the reaction mixture was concentrated. The solution was diluted with a saturated aqueous solution of ammonium chloride and dichloromethane, and the layers were separated. The aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The purified product was obtained (see Methods).

[0120] The following examples were prepared according to general procedure 3, using the corresponding carboxylamides and Grignard reagents (MeMgBr (3.0M ether solution), EtMgBr (1.0M THF solution), PrMgBr (1.0M THF solution), iPrMgBr (0.75M THF solution) as raw materials.

[0121] Synthetic intermediates The following steps provide the synthetic intermediates used in the general steps 1, 2, or 3 described above.

[0122] N-Methoxy-N,5-Dimethyl-1H-pyrazole-3-carboxamide N,O-dimethylhydroxylamine hydrochloride (5.7 g, 3 Eq, 58 mmol) was added to a tetrahydrofuran solution (19 mL) of 1H-pyrazole-3-carboxylic acid 5-methylethyl ester (3.0 g, 1 Eq, 19 mmol). The mixture was cooled to -30 °C, and a tetrahydrofuran solution of isopropyl magnesium chloride (90 mL, 1.3 mol / L, 6 Eq, 0.12 mol) was added, followed by stirring at -30 °C for 50 min. The reaction was quenched with 2 M hydrochloric acid aqueous solution. The layers were separated, and the aqueous phase was extracted with tetrahydrofuran and dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification was performed by column chromatography (SiO2, 0-5% MeOH / DCM) to give the target compound (1.4 g, 8.3 mmol, 43% yield). 1 H NMR (400 MHz, CDCl3) δ 10.83 (s, 1H), 6.59 (s, 1H), 3.78 (s, 3H), 3.38 (s, 3H), 2.35 (s, 3H).

[0123] N-Methoxy-N,1,5-Trimethyl-1H-pyrazole-3-carboxamide: 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (2.5 g, 1 Eq, 18 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.6 g, 1.5 Eq, 27 mmol) were dissolved in dichloromethane (180 mL), and HATU (7.5 g, 1.1 Eq, 20 mmol) and DIPEA (12 mL, 4 Eq, 71 mmol) were added. The mixture was stirred at room temperature for 15 minutes. The mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide (2.37 g, 12.9 mmol, 73% yield). 1 H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H), 3.42 (s, 3H), 2.29 (s, 3H).

[0124] N-Methoxy-N,4,5-Trimethyl-1H-pyrazole-3-carboxamide 4,5-Dimethyl-1H-pyrazole-3-carboxylic acid (5.00 g, 1 Eq, 35.7 mmol) was dissolved in dichloromethane (75 mL), and N,O-dimethylhydroxylamine hydrochloride (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) were added. The mixture was stirred at room temperature for 16 hours, concentrated, and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give the target compound (2.53 g, 11 mmol, yield 32%, purity 82%). LCMS: Method 8, 1.39 min, M+H = 184.1; calculated value 184.21.

[0125] 3-Isopropyl-1-methyl-1H-pyrazole-5-carboxylic acid hydrochloride Ethyl 3-isopropyl-1-methyl-1H-pyrazole-5-carboxylate (3.1 g, 1 Eq, 16 mmol) was dispersed in 35% hydrochloric acid aqueous solution (25 mL, 14 mol / L, 22 Eq, 0.35 mol) and stirred at 80 °C for 16 h. The resulting solution was concentrated to dryness and recrystallized from acetonitrile. The residue was washed with acetonitrile and concentrated to give the title compound (2.33 g, 11.4 mmol, yield 72%, purity 100%). LCMS: Method 9, 1.57 min, M+H = 169.0; calculated value 169.20.

[0126] 5-Isopropyl-1-methyl-1H-pyrazole-3-carboxylic acid Ethyl 5-isopropyl-1-methyl-1H-pyrazole-3-carboxylate (6.8 g, 1 Eq, 35 mmol) was dissolved in 6M sodium hydroxide aqueous solution (17 mL, 6.0 M, 3 Eq, 0.10 mol), water (200 mL), and ethanol (100 mL) and stirred at room temperature for 2 hours. The mixture was concentrated to remove most of the ethanol, washed with dichloromethane, acidified with 1 M hydrochloric acid aqueous solution, extracted with dichloromethane, and concentrated to give the target compound (5.33 g, 31.7 mmol, 91% yield). LCMS: Method 9, 1.53 min, M+H = 212.2; calculated value 212.27.

[0127] N-Methoxy-N,1,3-Trimethyl-1H-pyrazole-5-carboxamide 1,3-Dimethyl-1H-pyrazole-5-carboxylic acid (3.16 g, 1 Eq, 22.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.30 g, 1.5 Eq, 33.8 mmol) were dissolved in dichloromethane (100 mL), and HATU (9.43 g, 1.1 Eq, 24.8 mmol) and DIPEA (11.8 mL, 3 Eq, 67.6 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give the target compound (3.57 g, 19.5 mmol, yield 86.4%). LCMS: Method 10, 1.51 min, M+H = 184.2; calculated value 184.21.

[0128] 5-Isopropyl-N-methoxy-N,1-dimethyl-1H-pyrazole-3-carboxamide 5-Isopropyl-1-methyl-1H-pyrazole-3-carboxylic acid (1.9 g, 1 Eq, 11 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.7 g, 1.5 Eq, 17 mmol) were dissolved in dichloromethane (110 mL), and HATU (4.7 g, 1.1 Eq, 12 mmol) and DIPEA (7.9 mL, 4 Eq, 45 mmol) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give the target compound (2.44 g, 8.7 mmol, 77% yield, 75% purity). LCMS: Method 8, 1.39 min, M+H = 184.1; calculated value 184.21.

[0129] N-Methoxy-N,1,3,4-Tetramethyl-1H-pyrazole-5-carboxamide 1,3,4-Trimethyl-1H-pyrazole-5-carboxylic acid (3.80 g, 1 Eq, 24.6 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.61 g, 1.5 Eq, 37.0 mmol) were dissolved in dichloromethane (100 mL), and HATU (10.3 g, 1.1 Eq, 27.1 mmol) and DIPEA (17.2 mL, 4 Eq, 98.6 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give N-methoxy-N,1,3,4-tetramethyl-1H-pyrazole-5-carboxamide (6.20 g, 26 mmol, 110%, purity 83%). LCMS: Method 8, 1.49 min, M+H = 198.1; calculated value 198.24.

[0130] 5-Isopropyl-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide 5-Isopropyl-1H-pyrazole-3-carboxylic acid hydrochloride (2.25 g, 1 Eq, 11.8 mmol) and N,O-dimethylhydroxylamine hydrochloride (1.73 g, 1.5 Eq, 17.7 mmol) were dissolved in dichloromethane (118 mL), and HATU (4.49 g, 1 Eq, 11.8 mmol) and DIPEA (8.22 mL, 4 Eq, 47.2 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give 5-isopropyl-N-methoxy-N-methyl-1H-pyrazole-3-carboxamide (1.03 g, 3.3 mmol, 28% yield). 1 H NMR (400 MHz, CDCl3) δ10.64 (s, 1H), 6.63 (s, 1H), 3.79 (s, 3H), 3.38 (s, 3H), 3.10 – 2.96 (m, 1H), 1.30 (d, J = 6.9 Hz, 6H).

[0131] 3-Ethyl-N-methoxy-N,1-dimethyl-1H-pyrazole-5-carboxamide 3-Ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (3.00 g, 1 Eq, 19.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.85 g, 1.5 Eq, 29.2 mmol) were dissolved in dichloromethane (50 mL), and HATU (8.14 g, 1.1 Eq, 21.4 mmol) and DIPEA (10.2 mL, 3 Eq, 58.4 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give 3-ethyl-N-methoxy-N,1-dimethyl-1H-pyrazole-5-carboxamide (4.26 g, 21.6 mmol, 100% yield). LCMS: Method 10, 1.60 minutes, M+H = 198.2; calculated value 198.24.

[0132] 5-Ethyl-N-methoxy-N,1-dimethyl-1H-pyrazole-3-carboxamide 5-Ethyl-1-methyl-1H-pyrazole-3-carboxylic acid (3.44 g, 1 Eq, 22.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.26 g, 1.5 Eq, 33.5 mmol) were dissolved in dichloromethane (50 mL), and HATU (9.33 g, 1.1 Eq, 24.5 mmol) and DIPEA (11.7 mL, 3 Eq, 66.9 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% EtOH / EtOAc] / heptane) to give 5-ethyl-N-methoxy-N,1-dimethyl-1H-pyrazole-3-carboxamide (9.42 g, 47.8 mmol, 100% yield, containing residual HATU urea). LCMS: Method 10, 1.53 min, M+H = 198.1; calculated value 198.24.

[0133] N-Methoxy-N,1-Dimethyl-3-propyl-1H-pyrazole-5-carboxamide 1-Methyl-3-propyl-1H-pyrazole-5-carboxylic acid (2.95 g, 1 Eq, 17.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.57 g, 1.5 Eq, 26.3 mmol) were dissolved in dichloromethane (50 mL), and HATU (7.34 g, 1.1 Eq, 19.3 mmol) and DIPEA (9.17 mL, 3 Eq, 52.6 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give N-methoxy-N,1-dimethyl-3-propyl-1H-pyrazole-5-carboxamide (3.60 g, 17.0 mmol, 97.2% yield). LCMS: Method 8, 1.73 minutes, M+H = 212.1; calculated value 212.27.

[0134] N-Methoxy-N,1-Dimethyl-5-propyl-1H-pyrazole-3-carboxamide 1-Methyl-5-propyl-1H-pyrazole-3-carboxylic acid (4.07 g, 1 Eq, 24.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.54 g, 1.5 Eq, 36.3 mmol) were dissolved in dichloromethane (50 mL), and HATU (10.1 g, 1.1 Eq, 26.6 mmol) and DIPEA (12.6 mL, 3 Eq, 72.6 mmol) were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give N-methoxy-N,1-dimethyl-5-propyl-1H-pyrazole-3-carboxamide (7.75 g, 36.7 mmol, 100% yield). LCMS: Method 8, 1.66 minutes, M+H = 212.1; calculated value 212.27.

[0135] N-Methoxy-N,3-Dimethyl-1H-pyrazole-5-carboxamide 3-Methyl-1H-pyrazole-5-carboxylic acid hydrochloride (4.3 g, 1 Eq, 26 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.2 g, 2 Eq, 53 mmol) were dissolved in dichloromethane (110 mL), and DIPEA (23 mL, 5 Eq, 0.13 mol), EDC (6.1 g, 1.2 Eq, 32 mmol), and cyano(E)-2-(hydroxyimino)butyric anhydride (4.1 g, 1.1 Eq, 29 mmol) were added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give N-methoxy-N,3-dimethyl-1H-pyrazole-5-carboxamide (3.4 g, 20 mmol, 76% yield). ¹H NMR (400 MHz, CDCl3) δ 11.14 (brs, 1H), 6.59 (s,1H), 3.78 (s, 3H), 3.38 (s, 3H), 2.35 (s, 3H).

[0136] N-Methoxy-N-methyl-3-propyl-1H-pyrazole-5-carboxamide 3-propyl-1H-pyrazole-5-carboxylic acid hydrochloride (6.8 g, 84% by weight, 1 Eq, 30 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.8 g, 2 Eq, 60 mmol) were dissolved in dichloromethane (120 mL), and DIPEA (26 mL, 5 Eq, 0.15 mol), EDC (6.9 g, 1.2 Eq, 36 mmol), and cyano(E)-2-(hydroxyimino)butyric anhydride (4.7 g, 1.1 Eq, 33 mmol) were added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give N-methoxy-N-methyl-3-propyl-1H-pyrazole-5-carboxamide (4.5 g, 23 mmol, 76%). LCMS: Method 7, 0.80 min, M+H = 198.0; calculated value 198.24.

[0137] 3-Ethyl-N-methoxy-N-methyl-1H-pyrazole-5-carboxamide 3-Ethyl-1H-pyrazole-5-carboxylic acid hydrochloride (5.16 g, 90% by weight, 1 Eq, 26.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (5.13 g, 2 Eq, 52.6 mmol) were dissolved in dichloromethane (105 mL), and DIPEA (22.9 mL, 5 Eq, 131 mmol), EDC (6.05 g, 1.2 Eq, 31.6 mmol) and cyano(E)-2-(hydroxyimino)butyric anhydride (4.11 g, 1.1 Eq, 28.9 mmol) were added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give 3-ethyl-N-methoxy-N-methyl-1H-pyrazole-5-carboxamide (3.12 g, 16 mmol, yield 60%, purity 93%). LCMS: Method 7, 0.91 min, M+H = 184.0; calculated value 184.21.

[0138] 5-Ethyl-N-methoxy-N,1,4-trimethyl-1H-pyrazole-3-carboxamide 5-Ethyl-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (2.75 g, 1 Eq, 16.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.19 g, 2 Eq, 32.7 mmol) were dissolved in dichloromethane (50 mL), and DIPEA (11.4 mL, 4 Eq, 65.4 mmol), EDC (3.76 g, 1.2 Eq, 19.6 mmol) and cyano(E)-2-(hydroxyimino)butyric anhydride (2.56 g, 1.1 Eq, 18.0 mmol) were added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated and purified by rapid column chromatography (SiO2, 0-100% [30% ethanol / ethyl acetate] / heptane) to give 5-ethyl-N-methoxy-N,1,4-trimethyl-1H-pyrazole-3-carboxamide (2.34 g, 11 mmol, yield 64%, purity 95%). LCMS: Method 9, 1.47 min, M+H = 212.2; calculated value 212.27. ¹H NMR (400 MHz, CDCl3) δ 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).

[0139] N-Methoxy-N,1,5-Trimethyl-1H-pyrazole-3-carboxamide 1,5-Dimethyl-1H-pyrazole-3-carboxylic acid (2.0 g, 1 Eq, 14 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.1 g, 1.5 Eq, 21 mmol) were dissolved in dichloromethane (140 mL), and HATU (6.0 g, 1.1 Eq, 16 mmol) and DIPEA (9.9 mL, 4 Eq, 57 mmol) were added. The mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated and purified by rapid column chromatography (SiO2, 0-10% methanol / dichloromethane, then 0-100% ethyl acetate / heptane) to give N-methoxy-N,1,5-trimethyl-1H-pyrazole-3-carboxamide (1.68 g, 9.17 mmol, 64% yield). 1 H NMR (400 MHz, CDCl3) δ6.51 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 3.41 (s, 3H), 2.29 (s, 3H).

[0140] Example 165: Odor Characteristic Determination The odor characteristics of the selected compounds within this disclosure were determined through evaluation by a lead perfumer and 4–6 trained sensory evaluators. The sensory evaluators were trained in our internal classification system, referencing 11 major families and 62 subfamilies. Panel members were familiar with hundreds of other odor descriptors but had not received specific training. The evaluators were trained in the use of a rating scale, also incorporating internal references. Evaluators did not participate in the evaluation of the compounds until they completed and passed a final examination using a carefully designed classification system by our fragrance team.

[0141] The overall score for the sensory group was obtained by calculating the arithmetic mean of the scores from all group members. Alternatively, the overall score could be generated by fitting the scores from all group members to a model. This model could correct for differences in the latent function intercept or slope when each member rated based on the perceptual outcome, i.e., it corrected for differences in scores among group members.

[0142] The master perfumer possesses profound knowledge of fragrance components, exceptional technical expertise, and is highly regarded for their experience in crafting complex perfumes. Their comments may enhance the sensory panel's ratings, thereby improving accuracy.

[0143] Test samples were dissolved in ethanol at a concentration of 10% (w / v). At time 0 (t = 0), a new test fragrance strip (white paddle-shaped perfume test strip, 5 x 0.5 inches) was immersed in the 10% solution of the test compound. The odor description at t = 0 was recorded within 1–2 minutes after wetting the test strip to allow most of the ethanol solvent to evaporate, thus more accurately determining the odor of the test compound. Evaluations were conducted at room temperature in a laboratory benchtop environment. To determine the lasting power, the test strips were exposed to air on the laboratory benchtop between evaluations (without using jars or other sealed containers).

[0144] The results are shown in the table below: The embodiments provided herein are merely illustrative and are not intended to limit in any way the various aspects and embodiments of the invention described herein.

Claims

1. Compound of Formula I: Formula I in: R 1 For H, C 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl) or C 1-3 Haloalkyl groups (e.g., CF3); R 2 R 3 and R 4 Selected independently from H and C respectively 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 1-3 Halogenated alkyl groups (e.g., CF3), OC 1-6 Alkyl groups (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR', C(O)R, and CHO, or Where R 2 and R 3 , or R 3 and R 4 Together with the carbon atoms to which they are attached, they form optionally substituted 5-8 membered cycloalkyl or heterocycloalkyl rings, wherein the heterocycloalkyl ring comprises at least one selected from O, S, N(H) and N(R). a ) ring atoms; The condition is R 2 R 3 and R 4 At least one of them is COOH, COOR, CONHR, CONRR', C(O)R, or CHO; Each R and R' can be independently represented by C. 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 cycloalkyl (e.g., cyclopropyl); and R a It is C 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); The prerequisite is that the compound is not ethyl 1,3-dimethyl-5-pyrazolecarboxylate, and that the compound is not one of the following compounds: (a)R 1 It is methyl or ethyl, R 2 It is methyl or ethyl, R 3 For H, R 4 It is COOH; (b)R 1 It is methyl or ethyl, R 2 It is methyl or ethyl, R 3 For H, R 4 For COOR, R is methyl or ethyl.

2. Compound of Formula I: Formula I in: R 1 For H, C 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl) or C 1-3 Haloalkyl groups (e.g., CF3); R 2 R 3 and R 4 Selected independently from H and C respectively 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 1-3 Halogenated alkyl groups (e.g., CF3), OC 1-6 Alkyl groups (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR', C(O)R, and CHO, or Where R 2 and R 3 , or R 3 and R 4 Together with the carbon atoms they are attached to, they form arbitrarily substituted 5-8 membered cycloalkyl or heterocycloalkyl rings, wherein the heterocycloalkyl ring includes at least one selected from O, S, N(H) and N(R). a ) ring atoms; The condition is R 2 R 3 and R 4 At least one of them is COOH, COOR, CONHR, CONRR', C(O)R, or CHO; Each R and R' can be independently C 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 cycloalkyl groups (e.g., cyclopropyl); and R a It is C 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); It can be used as a flavor or spice ingredient.

3. A flavor composition and / or fragrance composition comprising a compound of formula I: Formula I in: R 1 For H, C 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl) or C 1-3 Haloalkyl groups (e.g., CF3); R 2 R 3 and R 4 Selected independently from H and C respectively 1-6 Alkyl (e.g., CH3), C 3-6 Cycloalkyl (e.g., cyclopropyl), C 1-3 Halogenated alkyl groups (e.g., CF3, OC) 1-6 Alkyl groups (e.g., OCH3), CH2OR, COOH, COOR, CONHR, CONRR', C(O)R, and CHO, or Where R 2 and R 3 , or R 3 and R 4 Together with the carbon atoms to which they are attached, they form arbitrarily substituted 5-8 membered cycloalkyl or heterocyclic alkyl rings, wherein the heterocyclic alkyl ring includes at least one selected from O, S, N(H) and N(R). a ) ring atoms; The condition is R 2 R 3 and R 4 At least one of them is COOH, COOR, CONHR, CONRR', C(O)R, or CHO; Each R and R' can be independently C 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); R a It is C 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl); Mixed with one or more non-toxic, orally acceptable, pharmaceutically acceptable, cosmetically acceptable, or household product acceptable carriers or excipients.

4. The composition of claim 3, wherein R 1 For H or C 1-6 Alkyl (e.g., methyl, ethyl, propyl or isopropyl), n-butyl, sec-butyl, isobutyl or tert-butyl.

5. The composition of claim 3, wherein R 2 C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C 1-3 Halogenated alkyl groups (e.g., CF3 or CHF2).

6. The composition of claim 3, wherein R 3 C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C 1-3 Halogenated alkyl groups (e.g., CF3 or CHF2).

7. The composition of claim 3, wherein R 4 C 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl), C 1-3 Halogenated alkyl groups (e.g., CF3 or CHF2).

8. The composition according to any one of claims 1-7, wherein R 2 R 3 Or R 4 One of them is C(O)R or CHO, wherein R is selected from methyl, ethyl, propyl and isopropyl.

9. The composition according to any one of claims 1-7, wherein R 2 R 3 Or R 4 One of them is COOH, COOR, CONHR, or CONRR', and optionally, R and R' are each independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and isobutyl.

10. The composition according to any one of claims 1-9, wherein the compound of formula I has one or more of the following substituent combinations R 1 R 2 R 3 and R 4 : Where 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: , , , , , , , and .

12. The composition of claim 3, wherein the compound of formula I is: Where R is C 1-6 Alkyl (e.g., methyl or ethyl) or C 3-6 Cycloalkyl (e.g., cyclopropyl).

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

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

15. The composition according to any one of claims 3-14, wherein the composition further comprises one or more other flavorings or flavorings.

16. A product comprising the compound of claim 1 or the composition of any one of claims 3 to 15, for example, selected from the following products: personal care products (e.g., soap, skin cream or lotion, lip balm, shampoo, shower gel, body gel, moisturizer, deodorant, antiperspirant, aftershave, cologne, perfume or other hair or skin care products), sunscreen, insect repellent and insecticide, detergent, household cleaner (e.g., surface cleaner, metal cleaner, wood cleaner, glass cleaner, body cleaner (e.g., soap), dishwashing liquid or laundry detergent), air freshener, room spray, fragrance pills, candle, cosmetics (e.g., perfume, cologne, nail polish, eyeliner, mascara, lipstick, foundation, concealer, blush, bronzer, eyeshadow, lip liner, lip balm), eau de toilette, talcum powder and pet bedding.

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