Non-bisant 4 ether derivatives and pharmaceutical compositions thereof, methods of preparation and uses

Abstract

The present application provides a compound having a structure shown in Formula I, II or III or its enantiomer, diastereoisomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite or its pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug. The non-fenofibrate 4-position ether derivative of the present application has an excellent xanthine oxidase activity inhibitory activity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to non-butyric ether derivatives and pharmaceutical compositions thereof, preparation methods and uses. BACKGROUND

[0002] In recent years, with the proportion of high purine food in the dietary structure increasing, the prevalence of hyperuricemia and gout has shown a trend of increasing year by year. In 2017, the number of patients with hyperuricemia in China reached 170 million, of which more than 80 million were gout patients, and the number was rapidly increasing at an annual growth rate of 9.7%.

[0003] Febuxostat, chemical name 2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, is developed by Teijin Group in Japan in early 2004, and is mainly used for the treatment of gout and hyperuricemia in clinic. Febuxostat was approved for marketing by the European Medicines Agency (EMA) in October 2008, and by the U.S. Food and Drug Administration (FDA) in February of the following year. Febuxostat is a new non-purine xanthine oxidase (XO) selective inhibitor. The high selectivity of febuxostat in inhibiting XO determines that it does not affect the synthesis and metabolism of other purines and pyrimidines at conventional treatment concentrations, and febuxostat is not limited by meals and food. Febuxostat can play a role by reducing blood urate concentration, and its application can improve vascular endothelial cell function, inhibit platelet aggregation, reduce lipid peroxidation, and at the same time inhibit the xanthine oxidase cycle and reduce inflammation. This drug is the first drug approved by FDA in nearly 50 years for the treatment of gout, and its mechanism is clear and its efficacy is accurate. As a new anti-uric acid drug, febuxostat has opened a new era of gout treatment. The common adverse reactions of febuxostat include abnormal liver function, diarrhea, headache, nausea and skin rash, and are dose-dependent (Frampton J E. Febuxostat: a review of its use in the treatment of hyperuricaemia in patients with gout [J]. Drugs, 2015, 75: 427-438.). Since the synthesis of febuxostat, hundreds of derivatives have been synthesized and used for drug screening research (Li W Y, Zhai N, Ju X L, et al. Research progress of xanthine oxidase inhibitor febuxostat derivatives [J]. Acta Pharmaceutica Sinica, 2021, 56(12): 3401-3413.).

[0004] Up to now, gout has become the second metabolic disease after diabetes, and the treatment of gout during the intermittent and chronic periods mainly includes uric acid reduction and urine alkalization. The first-line drugs include allopurinol, febuxostat, benzbromarone and colchicine. The existing drugs cannot meet the existing needs, and therefore more effective drugs need to be developed for clinical application. SUMMARY

[0005] In order to solve the above technical problems in the prior art, the present application provides a febuxostat 4-position ether derivative, which has an excellent xanthine oxidase activity inhibitory activity.

[0006] Specifically, the present application provides a compound having a structure shown in formula I or an enantiomer, diastereoisomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof.

[0007]

[0008] wherein,

[0009] n is 1, 2 or 3;

[0010] R 1 is C 1-10 alkyl, haloC 1-10 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl or C 3-6 cycloalkyl;

[0011] R 2 is C 1-10 alkyl, haloC 1-10 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl or C 3-6 cycloalkyl.

[0012] In some embodiments,

[0013] R 1 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl or C 3-6 cycloalkyl;

[0014] R 2 is C 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl or C 3-6cycloalkyl.

[0015] In some embodiments,

[0016] R 1 is hydrogen, methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl;

[0017] R 2 is hydrogen, methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl.

[0018] In another aspect, the present application provides a compound having a structure according to Formula II, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitro oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof:

[0019]

[0020] wherein,

[0021] m is 1, 2, or 3;

[0022] R 3 is hydrogen, methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl; 1-10 alkyl, haloC 1-10 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl or C 3-6 cycloalkyl.

[0023] In some embodiments,

[0024] R 3 is hydrogen, methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl; 1-6 alkyl, haloC 1-6 alkyl, C 3-6 cycloalkyl-C 1-4 alkyl or C 3-6 cycloalkyl.

[0025] In some embodiments,

[0026] R 3 is hydrogen, methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl.

[0027] In another aspect, the present application provides a compound having a structure according to Formula III, or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitro oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof:

[0028]

[0029] R3 halo-C1-C6-alkyl, 1-6 halo-C1-C6-alkyl, 3-6 cycloalkyl-C1-C6-alkyl, 1-4 halo-C1-C6-alkyl, 3-6 cycloalkyl.

[0030] In some embodiments,

[0031] R 3 halo-C1-C6-alkyl,

[0032] In another aspect, the present application also provides a compound having one of the following structures or an enantiomer, diastereoisomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof:

[0033]

[0034]

[0035] In another aspect, the present application also provides a method for synthesizing a non-bisat 4-position ether derivative, comprising:

[0036] (1) dispersing 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester and a first base in a first organic solvent, then adding dropwise a halogenated compound to the mixture solution, and reacting under heating to obtain an intermediate product; or dispersing 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester and triphenylphosphine in a second organic solvent under argon protection, then adding dropwise an alcohol compound to the mixture solution, and adding dropwise DEAD at room temperature to obtain an intermediate product; preferably, the molar ratio of 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester, the first base, and the halogenated compound A or the alcohol compound B is 1:(2-5): (1.5-3); preferably, the molar ratio of 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester, the first base, and the halogenated compound A or the alcohol compound B is 1:3:2;

[0037] (2) dissolving the intermediate product and lithium hydroxide monohydrate in a third organic solvent, and heating to react to obtain a non-bisat 4-position ether derivative; preferably, the molar ratio of the intermediate product and lithium hydroxide monohydrate is 1:(2-3); preferably, the molar ratio of the intermediate product and lithium hydroxide monohydrate is 1:2.2; wherein the non-bisat 4-position ether derivative has a structure shown in formula I, formula II, or formula III:

[0038]

[0039]

[0040] wherein R 1 , R 2 , R 3 , R 4 , n and m have the definitions as indicated in the present invention;

[0041] The halogenated compound A has the following structure:

[0042] X is halogen;

[0043] The alcohol compound B has the following structure:

[0044]

[0045] In some embodiments,

[0046] The first organic solvent or the second organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide or tetrahydrofuran;

[0047] The third organic solvent is a combination of deionized water and anhydrous ethanol;

[0048] The first base is potassium carbonate or cesium carbonate;

[0049] The heating condition of step (1) is 80-120℃;

[0050] The heating reaction of step (2) is 80-100℃.

[0051] In another aspect, the present application also provides a pharmaceutical composition, characterized by comprising the compound of the present application and pharmaceutically acceptable adjuvants.

[0052] In another aspect, the present application also provides the use of the compound of the present application or the pharmaceutical composition of the present application in inhibiting xanthine oxidase.

[0053] In another aspect, the present application also provides the use of the compound of the present application or the pharmaceutical composition of the present application in the preparation of a drug for hyperuricemia or gout.

[0054] Another aspect of the present application relates to the preparation, separation and purification method of the compound of formula I, II and III.

[0055] Any embodiment of any aspect of the present application can be combined with other embodiments, as long as they do not conflict with each other. In addition, any technical feature in any embodiment of any aspect of the present application can be applied to the technical feature in other embodiments, as long as they do not conflict with each other.

[0056] The foregoing summary only illustrates certain aspects of the application and is not intended to be limiting. These and other aspects will be more readily appreciated as the same becomes better understood by reference to the following detailed description and considered in connection with the accompanying drawings. DETAILED DESCRIPTION

[0057] In order to make the objects, technical solutions, and advantages of the present application clearer, the following further describes the present application in conjunction with embodiments. The specific embodiments described herein are only used to explain the present application and should not be used to constitute any limitation on the present application. In addition, in the following description, the description of well-known structures and techniques is omitted to avoid unnecessary confusion of the concepts of the present disclosure. Such structures and techniques are also described in many publications.

[0058] Definitions

[0059] Certain embodiments of the application now will be described in detail, with examples of the invention being illustrated by the accompanying structural and chemical formulas. All alternatives, modifications and equivalents as would be appreciated by those skilled in the art to which the application pertains are included herein and are within the scope of the present application as defined by the claims. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents for the specific embodiments described herein. The application is not intended to be limited to the embodiments described herein, but is to be accorded the full scope that resides in the art that is defined by the appended claims. In the event that any term is defined differently from or excluded from the definitions provided herein, the term has the definition provided in the document incorporated by reference, if any, or the term has the definition provided in the patent law.

[0060] It should further be appreciated that certain of the application's features, while described in the context of separate embodiments, might also be provided in combination in a single embodiment. Conversely, various features of the application, while described in the context of a single embodiment, might also be provided separately or in any suitable subcombination. It is therefore contemplated to this extent that every single feature disclosed for a single embodiment is also expressly disclosed as being combinable with every disclosed feature of every other embodiment and, additionally, every subcombination of every disclosed feature in at least one embodiment is expressly disclosed as being within the scope of the application.

[0061] Unless otherwise defined, 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. All patents and publications identified are incorporated herein by reference in their entirety.

[0062] The following definitions shall apply unless otherwise indicated. For the purposes of the present application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the American Chemical Society. Additionally, general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are incorporated herein by reference.

[0063] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to "at least one") of the grammatical object of the article. By way of example, "an element" means one or more elements, and thus, possibly, more than one element. Similarly, the term "the" is used herein to refer to one or to more than one (i.e., to "at least one") of the grammatical object of the article "the." By way of example, "the element" means one or more elements, and thus, possibly, more than one element.

[0064] The term "subject" refers to an animal. Typically the animal is a mammal. A subject, for example, also refers to a primate (e.g., human, male or female), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0065] The term "patient" refers to a human (including adults and children) or other animal. In some embodiments, "patient" refers to a human.

[0066] The term "comprising" is a broad term of inclusion, that also includes enclosures or things as well as stating the inclusion of whatever follows the term "comprising." Thus, the term "comprising" when used in this specification and claims is taken to specify the presence of stated features but does not preclude the presence or addition of one or more other features.

[0067] When a substituent is described as being "substituted" it is meant to include not only the indicated replacement of a hydrogen with the stated group, but also the replacement of a hydrogen with a variety of other groups. For example, a "substituted alkyl" is an alkyl group as defined herein wherein one or more hydrogen atoms have been independently replaced with a group other than hydrogen. Such substituted groups have not been enumerated, but they include the various substituents described below or otherwise available in the art.

[0068] The term "enantiomer" refers to two isomers of a compound that are non-superimposable mirror images of one another.

[0069] The term "diastereomers" refers to two or more stereoisomers having chirai neutral and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated by high resolution analytical techniques such as electrophoresis and chromatography, e.g., HPLC.

[0070] The term "racemate," "racemic" or "racemic mixture" refers to an equimolar mixture of two enantiomeric isomers lacking optical activity.

[0071] The term "tautomer" or "tautomerism" refers to structural isomers that differ in energy by a low energy barrier and can interconvert. If tautomerism is possible (as in solution), a chemical equilibrium of tautomers can be achieved. For example, protontautomer (also known as prototropic tautomer) includes interconversion by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomer includes interconversion by reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerism is phenol-keto tautomerism. A specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.

[0072] The term "stereoisomers" refers to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans isomers), atropisomers, and the like.

[0073] The term "geometric isomers" also known as "cis-trans isomers" are isomers due to the restricted rotation about a single bond (including double bonds of alkenes, C=N double bonds, and N=N double bonds) or a ring carbon atom.

[0074] The stereochemical definitions and rules used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc, New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of the rotation of plane-polarized light by the compound, i.e., (-) or 1 meaning that the compound is levorotatory. A compound, which is ( + ) or d is dextrorotatory. A specific stereoisomer of a particular compound is referred to as an enantiomer when there are one or more centers of chirality in the molecule. A mixture of such isomers is

[0075] Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in the form of a racemic or enantiomeric enrichment, e.g., in the (R)-, (S)-, or (R,S)-configurational form. In certain embodiments, each asymmetric atom is at least 50% enantiomeric excess in the (R)- or (S)- configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0076] Depending on the choice of starting materials and methods, the compounds of the present application can be synthesized as one of the possible isomers or a mixture of them, such as, for example, in the form of racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms), in the form of geometric isomers (E) or (Z), if appropriate, if the compound contains a double bond, in the form of cis- or trans- isomers, if appropriate, if the compound contains a cycloalkanediyl group, in the form of optical active compounds, such as, for example, as (R)- or (S)-isomers, if appropriate, if the compound contains one or more centers of chirality. The optically active compounds can be obtained by resolution of a racemic form of the compound using standard techniques, or by the use of chiral synthon or chiral reagent, or by the use of conventional techniques such as, for example, asymmetric synthesis.

[0077] Any mixture of stereoisomers can be separated into their individual components by conventional techniques, such as, for example, fractional crystallization and / or chromatography, if desired.

[0078] The racemates of any resulting end products or intermediates can be resolved into the optical antipodes by methods well known to those skilled in the art, e.g., by separation of the resulting diastereomeric salts thereof. The racemic products can also be separated by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent. In particular, the enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2nd Ed. Robert E. Gawley, Jeffrey Aube, Elsevier, Oxford, UK, 2012); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972); Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag Gmb H & Co. KGaA, Weinheim, Germany, 2007).

[0079] The term "nitrogen oxides" means that when a compound contains several amine functions, one or more than one nitrogen atom can be oxidized to form N-oxides. Particular examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen heterocycle ring nitrogen atoms. N-oxides can be formed by treatment of the corresponding amines with an oxidizing agent such as hydrogen peroxide or a peracid (e.g. peroxycarboxylic acids) (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages 504-505). In particular, N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514) wherein an amine compound is reacted with meta-chloroperoxybenzoic acid (MCPBA), for example in an inert solvent such as dichloromethane.

[0080] The term "metabolite" refers to a product produced through metabolism of a specified compound or salt thereof in the body. Metabolites of a compound can be identified using techniques known in the art and can be tested using test procedures described herein. Such products can be oxidized, reduced, hydrolyzed, aminated, deaminated, esterified, deesterified, cleaved, or the like. Accordingly, the present application includes metabolites of a compound of the application, including those produced following administration of the compound to a mammal for a period of time sufficient to yield a metabolic product.

[0081] The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated with it. Preferably, "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0082] The term "pharmaceutically acceptable salt" means an organic or inorganic salt of a compound of the present application. Pharmaceutically acceptable salts are well known in the art, e.g., S. M. Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977. Pharmaceutically acceptable salts include salts of acidic groups such as carboxylic acid groups with inorganic or organic bases, including but not limited to, sodium, potassium, calcium, magnesium, and ammonium salts, and salts of basic groups such as amino groups with inorganic or organic acids, including but not limited to, hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, perchloric, acetic, hydroxyacetic, oxalic, maleic, tartaric, citric, succinic, fumaric, mandelic, sulfosalicylic, and other salts as described in the literature. Further pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bicarbonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, sulfamate, sulfanilate, suberate, succinate, tannate, tartrate, teoclate, toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts further include salts of compounds of the present application formed with bases, including but not limited to, inorganic bases (e.g., sodium, potassium, calcium, magnesium, and ammonium salts, and salts of basic organic compounds such as amines. The present application also contemplates the quaternization of any basic nitrogen-containing groups of the compounds of the present application with a quaternizing agent such as a alkyl halide, dialkyl sulfates, and the like. Pharmaceutically acceptable salts further include suitable, nontoxic ammonium, quaternary ammonium, and amine cations formed by the inclusion of an appropriate, nontoxic counterion, such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C 1-8 sulfate, and arylsulfonate. Organic base salts (e.g., salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion-exchange resins) include, for example, salts of isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0083] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as para-toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene- 1, 5- disulfonic acid, oxalic acid and citric acid. Pharmaceutically acceptable base addition salts can be formed with inorganic bases such as ammonium hydroxide, ammonium bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, and magnesium hydroxide, and organic bases such as caffeine, meglumine, and 4-phenylcyclohexylamine. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where appropriate. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0084] The term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the application. The solvent can be water, acetic acid, diethyl ether, isopropyl ether, petroleum ether, ethyl formate, ethyl acetate, isopropyl acetate, n-propyl acetate, isobutyl acetate, n-butyl acetate, methyl tert-butyl ether (MTBE), n-heptane, a mixed solvent of ethanol and water at a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, ethylene glycol, n-butanol, tert-butanol, sec-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, n-hexane, cyclohexane, n-heptane, a mixed solvent of n-heptane and ethyl acetate at a volume ratio of 1:5 to 5:1, isopropyl alcohol, methanol, butanone, l-methyl-2-pyrrolidinone, mesitylene, nitromethane, polyethylene glycol, n-propanol, isopropanol, 2-propanone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methylethyl ketone, toluene, xylene, cumene, or a mixture thereof.

[0085] The term "hydrate" refers to an association or complex of one or more water molecules with a compound of the application.

[0086] Furthermore, the compounds disclosed in this invention, including their salts, can also be obtained in their hydrated form or in the form containing their solvents (e.g., ethanol, DMSO, etc.) for their crystallization. The compounds disclosed in this invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, this invention is intended to include both solvated and unsolvated forms.

[0087] The term "ester" is represented by the formula -OC(O)R or -C(O)OR, where R can be an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described in this invention.

[0088] The term "isotope-labeled compound" refers to compounds of the present invention labeled with isotopes. They are identical to those compounds described in the present invention except that one or more atoms are replaced by atoms with atomic masses or mass numbers different from those of naturally occurring common atoms. Exemplary isotopes may also be introduced in compounds of the present invention, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as... 2 H, 3 H, 13 C, 14 C, 15 N, 16 O, 17 O, 31 P, 32 P, 36 S, 18 F and 37 Cl.

[0089] Compounds of the present invention containing the aforementioned isotopic label and / or other isotopic labels, as well as pharmaceutically acceptable salts of said compounds, are included within the scope of this invention. Isotopically labeled compounds of the present invention, such as radioisotope-labeled compounds, are also included. 3 H and 14 The incorporation of tritium into the compounds of this invention can be used for drug and / or substrate tissue distribution analysis. Due to its ease of preparation and detection, tritium-substituted compounds, i.e., 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred. Additionally, isotopes with higher mass numbers, such as deuterium, are used. 2 H substitution can offer therapeutic advantages such as greater metabolic stability, including increased in vivo half-life or reduced dose requirements. Therefore, it may be preferred in some situations.

[0090] In addition, heavier isotopes, especially deuterium (i.e., 2Substitution of H or D) can provide certain therapeutic advantages that result from, for example, increased metabolic stability, or decreased dosing requirements, or improved therapeutic index. It will be appreciated that deuterium is regarded as a substituent in the compounds of the present application. The concentration of such heavier isotopes, particularly deuterium, can be defined in terms of an isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance of the specified isotope and the natural abundance. If a substituent of a compound of the present application is designated as deuterium, the compound has an isotopic enrichment factor at each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium atom. The pharmaceutically acceptable solvates of the present application include those in which the solvent can be isotopically substituted, e.g., D20, acetone-d6, DMSO-d6.

[0091] The term "prodrug" as used herein refers to a compound which in vivo is converted to a compound of Formula I. Such conversion is effected by the hydrolysis of the prodrug in the blood or by enzymatic conversion in the blood or tissues to the parent structure. The prodrug class of compounds of the present application can be esters, and in the present application esters which can act as prodrugs are benzoic acid esters, aliphatic (C 1-24) esters, acyloxymethyl esters, carbonates, carbamates, and amino acid esters. For example, a compound of the application containing a hydroxyl group can be acylated to provide a prodrug form of the compound. Other prodrugs include phosphate esters, such as those prepared by phosphorylating a hydroxyl group on the parent. A thorough discussion of prodrugs is provided in Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series; Roche et al., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345.

[0092] Unless explicitly stated otherwise, the description employed in the present application "each independently" and "each of" and "independently" are interchangeable and are to be interpreted broadly, meaning that the specific options expressed by the same symbol between different groups are independent of each other, and that the specific options expressed by the same symbol between the same groups are independent of each other.

[0093] The term "optionally," "optionally" or "any," "any" means that the event or circumstance subsequently described can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted" means that the substitution can or can not be present.

[0094] The term "each independently" is used in combination with "any," for example, "each independently optionally substituted" means that the specific options are independent of each other, either substituted or not substituted.

[0095] The term "unsaturated" or "unsaturated" means that the moiety contains one or more degrees of unsaturation.

[0096] Throughout the specification, substituents of compounds disclosed herein are presented by reciting a genus of groups or ranges. It is specifically intended that the application include each and every independent combination of members of the various groups or ranges recited. For example, the term "C 1-6 "alkyl" specifically refers to the individual disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups.

[0097] Throughout the specification, connecting substituents are described. When the structure clearly requires a connecting group, the Markush variable recited for that group should be understood to be a connecting group. For example, if the structure requires a connecting group and the Markush group definition recited for that variable lists "alkyl" or "aryl", then it should be understood that the "alkyl" or "aryl" respectively represents a connected alkylene or arylene group.

[0098] The term "cycloalkyl" means a monovalent or multivalent monocyclic, bicyclic, or tricyclic ring system (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring including spiro, fused, or bridged systems (such as bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), which contains carbon atoms, which can be fully saturated or contain one or more degrees of unsaturation, but not an aromatic ring. In one embodiment, the cycloalkyl contains 3-6 carbon atoms, such as C 3-6 saturated or partially unsaturated cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, and the like. In one embodiment, the saturated or partially unsaturated cycloalkyl is selected from the group consisting of saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, partially unsaturated tricyclic cycloalkyl.C 4-7 Cycloalkyl means cycloalkyl having 4-7 ring atoms.C 3-6 Cycloalkyl means cycloalkyl having 3-6 ring atoms.

[0099] The term "hydrogen" means 1 H; "deuterium" means 2 H.

[0100] The terms "halogen" and "halo" mean fluorine (F), chlorine (CI), bromine (Br), or iodine (I).

[0101] The term "alkyl" or "alkyl group" means a saturated straight-chain or branched hydrocarbon radical containing carbon atoms. In one embodiment, the alkyl group contains 1-6 carbon atoms, i.e., C 1-6 alkyl; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, i.e., C 1-4alkyl; and in one embodiment, the alkyl group contains 1 to 3 carbon atoms, i.e., C 1-3 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, n-pentyl, n-hexyl, and the like.

[0102] When two groups are used in conjunction, the term indicates that one group is attached to the remainder of the molecule through the other group, e.g., arylalkyl indicates that the aryl group is attached to the molecule through the alkyl group; C 6-10 aryl C 1-6 alkyl indicates that the aryl group has 6 to 10 carbon atoms and the alkyl group has 1 to 6 carbon atoms.

[0103] The terms "comprising" and "including," "containing" or "characterized by" are synonymous and are inclusive or open-ended and do not exclude additional, unrecited elements or method steps from the pharmaceutical (or steps in the method). The phrase "consisting of" excludes any element, step or ingredient not specified. The phrase "consisting essentially of" means that the specified materials and those that do not materially affect the basic and novel characteristic(s) of the pharmaceutical (or steps in the method).

[0104] Unless otherwise specified, references to substitution or combinations of groups herein are to those substitution or combinations that are stable or chemically feasible.

[0105] Pharmaceutical compositions and methods of administration

[0106] The present application relates to a pharmaceutical composition comprising a compound of the present application or an enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitroso, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound, or prodrug thereof; and a pharmaceutically acceptable carrier.

[0107] The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug thereof with other chemical components, such as physiologically / pharmaceutically acceptable carriers, diluents, further including excipients, binders, fillers, and the like adjuvants, as well as anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents, anti-platelet agents, anti-atherosclerotic agents, or lipid-lowering agents, and the like additional therapeutic agents. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0108] As used herein, the term "pharmaceutically acceptable carrier" refers to a material that is useful in preparing or administering a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegration agents, lubricants, wetting agents, sweetening agents, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., Remington The Science and Practice of Pharmacy, 22ndEd., Pharmaceutical Press, 2013, pp. 1049-1070).

[0109] The present application also relates to pharmaceutical compositions comprising, as active ingredient, a compound of formula I, II-1, II-2, III, or a pharmaceutically acceptable salt thereof, which can be particularly useful in the treatment of oncological diseases, in particular cancer, as described herein. The compositions can be formulated for parenteral administration, for example nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ocular, or especially for oral administration, for example in the form of oral solid dosage forms, such as granules, pellets, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules and soft capsules or hydroxypropyl methylcellulose (HPMC) capsules (coated as appropriate), buccal disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, in particular humans, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions can comprise the active ingredient alone, or preferably, together with a pharmaceutically acceptable carrier.

[0110] The compounds of formula I, II, III, or a pharmaceutically acceptable salt thereof, can be processed with pharmaceutically inert, inorganic or organic excipients for the production of oral solid dosage forms, such as granules, pellets, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or buccal disintegrating tablets, using, for example, conventional mixing or confectioning techniques. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or derivatives thereof, binders such as cellulose, starch, polyvinylpyrrolidone or derivatives thereof, glidants such as talc, stearic acid or salts thereof, flow agents such as, for example, calcined silicon dioxide, can be used as such excipients for the formulation and manufacture of oral solid dosage forms, such as granules, pellets, powders, tablets, film-coated tablets or sugar-coated tablets, effervescent tablets, hard capsules or HPMC capsules or buccal disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like.

[0111] Suitable excipients for the manufacture of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose, etc.

[0112] Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants, etc.

[0113] Furthermore, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

[0114] The dosage can vary within wide limits and will, of course, depend on the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 1 to 1000 mg of a compound of general formula I per person should suffice, although the above-mentioned upper limit can also be exceeded when necessary.

[0115] The compounds of the formulae I, II, III can also be used in combination with one or more other compounds having pharmacological activity which are also effective against the same disease, preferably using a different mode of action, or reducing or preventing possible unwanted side effects of the compounds of the formulae I, II, III. The combination partners can be administered simultaneously, e.g. by incorporating them in a single pharmaceutical formulation, or consecutively, by administering two or more different dosage forms each containing one or more combination partners.

[0116] The term "therapeutically effective amount" of a compound of the application refers to the amount of the compound of the application that will elicit the biological or medical response (e.g., reduction or inhibition of an enzyme or protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc.) in subjects. In one non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the application that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent and / or ameliorate a disease or condition of hyperuricemia and gout.

[0117] As used herein in the context of treating a disease or disorder, the term "treatment" generally refers to the treatment and therapy of humans or animals (e.g., in veterinary applications) in which some desired therapeutic effect is achieved, such as inhibiting the progression of the disease or disorder, and includes reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of the disease or disorder, improving the disease or disorder, and curing the disease or disorder. It also includes treatment as a preventative measure (i.e., prevention). For example, treatment for patients who have not yet developed the disease or disorder but are at risk of developing it is covered by the term "treatment." For example, treatment includes the prevention of hyperuricemia or gout, reducing the symptoms of hyperuricemia or gout, reducing the incidence of hyperuricemia or gout, lowering uric acid levels, etc.

[0118] In some embodiments, the present invention provides the use of compounds I, II, III or pharmaceutical compositions thereof or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of hyperuricemia and gout.

[0119] In some embodiments, the present invention provides a method for treating hyperuricemia and gout, the method comprising administering a therapeutically effective amount of compound I, II, III or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the present invention provides I, III compounds or pharmaceutical compositions for treating hyperuricemia and gout.

[0121] Synthetic methods Definitions Pharmaceutical compositions and methods of administration Synthetic methods Definitions Pharm

[0122] Compounds having formulas I, II, and III can be synthesized by the methods given below, by the methods given in the experimental section below, or by similar methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds having formulas I, II, and III; rather, other techniques known to a skilled chemist may also be used for compound synthesis.

[0123] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6NMR measurements were made on a Bruker Advance III-400M NMR spectrometer with deuterated chloroform (CDCI3), deuterated methanol (CD3OD) or deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard. When multiplets occur, the following abbreviations will be used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets), td (triplet of doublets), br s (broadened singlet). Coupling constants, J, are reported in Hertz (Hz).

[0124] Liquid chromatography-mass spectrometry (LC-MS) was detected using an Agilent mass spectrometer (Agilent 1260, Agilent 6125B). High performance liquid chromatography (HPLC) was measured using a Gilson high pressure liquid chromatograph (Gilson GX-281), C18 column (10 μM, 19 mm x 250 mm), UV detection wavelength of 220 and 254 nm, and elution conditions of 5-95% acetonitrile (containing 0.05% v / v formic acid or ammonium bicarbonate) gradient elution for 15 minutes.

[0125] Thin layer chromatography silica gel plates were used Qingdao GF254 silica gel plates, and the silica gel plates used in thin layer chromatography (TLC) had a specification of 0.15-0.20 mm, and the preparative thin layer chromatography used 0.4 mm-0.5 mm. Silica gel column chromatography generally used Qingdao silica gel 200-300 mesh silica gel as the carrier.

[0126] The starting materials in the embodiments of the present application are known and commercially available, or can be synthesized using or according to the literature reported in the art.

[0127] The following examples are provided to assist in understanding the present application. It should be understood that these examples are intended to be illustrative only and are not intended to limit the present application in any way. Rather, the scope of the present application is to be understood only as set forth in the Claims Section. Modifications and adaptations will occur to those skilled in the art (and within the spirit and scope of the present application) and it is intended to cover any and all adaptations or modifications.

[0128] Example 1: Synthesis of compound 2-(3-cyano-4-(difluoromethoxy)phenyl)-4- methylthiazole-5-carboxylic acid (d1)

[0129]

[0130] Ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-l,3-thiazole-5-carboxylate (0.2883 g, 1 mmol, 1 eq) was placed in a 50 ml round-bottom flask, 3 mL of N,N-dimethylformamide was added to it with sufficient stirring, then 0.2 mL of deionized water was added to the solution, stirred and mixed, and sodium difluorochloroacetate (0.3089 g, 2 mmol, 2 eq) was weighed in 2 mL of N,N-dimethylformamide and pre-dissolved, then slowly added dropwise to the round-bottom flask, and finally cesium carbonate (0.4887 g, 1.5 mmol, 1.5 eq) was added to the round-bottom flask at once, and the oil bath pot was heated to 100°C for 0.5 h. After the reaction was completed, 20 mL of deionized water was added to the reaction liquid to terminate the reaction, and the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 10:3) to obtain white solid (d6): ethyl 2-(3-cyano-4-(difluoromethoxy)phenyl)-4-methylthiazole-5-carboxylate (0.2050 g, yield: 60%). 1 H NMR (500 MHz, CDCI3) δ 8.29 (d, J = 2.2 Hz, 1 H), 8.15 (dd, J = 8.8, 2.3 Hz, 1 H), 7.41 (d, J = 8.8 Hz, 1 H), 6.71 (t, J = 71.2 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 2.77 (s, 3 H), 1.39 (t, J = 7.1 Hz, 3 H). 13 C NMR (126 MHz, CDCI3) δ 165.70, 161.94, 161.41, 153.15 (t, J = 2.5 Hz), 132.32, 132.11, 130.89, 123.47-116.89 (m), 114.97, 114.25, 112.84, 106.94, 61.70, 17.58, 14.43.

[0131] The product from the previous step (d6) 2-(3-cyano-4-(difluoromethoxy)phenyl)-4- methylthiazole-5-carboxylic acid ethyl ester (0.1692 g, 0.5 mmol, 1 eq) and lithium hydroxide monohydrate (0.0462 g, 1.1 mmol, 2.2 eq) were placed in a 50 mL round bottom flask, added 5 mL of deionized water, 5 mL of anhydrous ethanol, stirred well, and heated in an oil bath at 90 °C for 1 h. After the reaction was completed, 20 mL of deionized water was added to the reaction to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time), the aqueous phase was retained, the pH of the aqueous phase was adjusted to acidic (pH = 3-4) with 1 N aqueous hydrochloric acid, at this time white solid was precipitated, the aqueous phase was extracted with ethyl acetate three times again (15 mL each time), the organic phase was retained, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:10) to obtain the title compound (d1) white solid (0.0800 g, yield: 51%). 1 H NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.35 (dd, J = 8.8, 2.3 Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 7.55 (t, J = 72.1 Hz, 1H), 2.67 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.16, 162.76, 159.65, 153.63, 133.03, 132.08, 129.55, 124.10, 118.73, 115.84 (t, J = 261.8 Hz), 114.31, 104.55, 17.04.

[0132] Example 2: Synthesis of compound 2-(3-cyano-4-(2-methoxypropoxy)phenyl)-4- methylthiazole-5-carboxylic acid (d3)

[0133]

[0134] Ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate (0.2883 g, 1 mmol, 1 eq), triphenylphosphine (0.3147 g, 1.2 mmol, 1.2 eq) were placed in a 50 ml round bottom flask, replaced with argon 3 times, then 2 mL of super dry tetrahydrofuran was added to stir and dissolve, after mixing, 2-methoxy-1-propanol (0.29 mL, 3 mmol, 3 eq) was slowly added dropwise, stirred at room temperature for 10 min, then DEAD (0.19 mL, 1.2 mmol, 1.2 eq) was slowly added dropwise, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, the solvent was rotary evaporated under reduced pressure, the residue was redissolved with 5 mL of ethyl acetate, 20 mL of deionized water was added, the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time), the organic phase was retained, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase for drying, the solvent was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 10:3) to obtain a light yellow solid (d8): ethyl 2-(3-isocyano-4-(2-methoxypropoxy)phenyl)-4-methylthiazole-5-carboxylate (0.1100 g, yield: 30%). 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 8.8, 2.3 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.13 (dd, J = 9.6, 6.4 Hz, 1H), 4.02 (dd, J = 9.6, 4.4 Hz, 1H), 3.81 (td, J = 6.4, 4.4 Hz, 1H), 3.48 (s, 3H), 2.74 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.30 (d, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 167.04, 162.24, 162.12, 161.17, 132.65, 132.12, 126.49, 122.12, 115.45, 112.92, 103.20, 75.16, 73.28, 61.49, 57.71, 17.56, 16.67, 14.42.

[0135] The product from the previous step (d8): ethyl 2-(3-isocyano-4-(2- methoxypropoxy)phenyl)-4-methylthiazole-5-carboxylate (0.1802 g, 0.5 mmol, 1 eq) and lithium hydroxide monohydrate (0.0462 g, 1.1 mmol, 2.2 eq) were placed in a 50 ml round bottom flask, 5 mL of deionized water, 5 mL of anhydrous ethanol were added, and the mixture was stirred thoroughly, and heated in an oil bath at 90 °C for 1 h. After the reaction was completed, 20 mL of deionized water was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time), and the aqueous phase was retained. The pH of the aqueous phase was adjusted to acidic (pH = 3-4) using 1 N aqueous hydrochloric acid, at which time white solids were precipitated, and the aqueous phase was extracted with ethyl acetate three more times (15 mL each time), and the organic phase was retained. The organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:10) to obtain the title compound (d3) as a white solid (0.0812 g, yield: 48%). 1 H NMR (400 MHz, DMSO-d6) δ 13.42 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.9, 2.3 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.22 (dd, J = 10.3, 3.9 Hz, 1H), 4.16 (dd, J = 10.4, 6.0 Hz, 1H), 3.72 (td, J = 6.2, 3.9 Hz, 1H), 3.35 (s, 3H), 2.65 (s, 3H), 1.20 (d, J = 6.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.13, 162.87, 161.95, 159.51, 133.01, 131.56, 125.53, 123.01, 115.44, 113.99, 101.61, 74.40, 72.39, 56.50, 17.05, 16.15.

[0136] Example 3: Synthesis of compound 2-(3-cyano-4-(3-methoxypropoxy)phenyl)-4- methylthiazole-5-carboxylic acid (d4)

[0137]

[0138] Ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate (0.2883 g, 1 mmol, 1 eq), potassium carbonate (0.4146 g, 3 mmol, 3 eq) were placed in a 50 ml round bottom flask, 15 mL of N,N-dimethylformamide was added to stir and dissolve, then 3-bromopropyl methyl ether (0.23 mL, 2 mmol, 2 eq) was slowly added dropwise to the mixture solution, and the oil bath pot was heated to 85°C for 2h. After the reaction was completed, 20 mL of deionized water was added to terminate the reaction, and the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase for drying, the solvent was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to obtain a white solid: ethyl 2-(3-cyano-4-(3-methoxypropoxy)phenyl)-4-methylthiazole-5-carboxylate (0.2662 g, yield: 73%). 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 2.3 Hz, 1H), 8.05 (dd, J = 8.9, 2.3 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.22 (t, J = 6.2 Hz, 2H), 3.58 (t, J = 5.9 Hz, 2H), 3.34 (s, 3H), 2.72 (s, 3H), 2.11 (p, J = 6.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 167.06, 162.32, 162.06, 161.09, 132.64, 132.04, 126.15, 121.99, 115.49, 112.73, 102.93, 68.47, 66.42, 61.43, 58.84, 29.26, 17.51, 14.38.

[0139] The product from the previous step: 2-(3-cyano-4-(3-methoxypropoxy)phenyl)-4- methylthiazole-5-carboxylic acid ethyl ester (0.2662 g, 0.74 mmol, 1 eq) and lithium hydroxide monohydrate (0.0682 g, 1.63 mmol, 2.2 eq) were placed in a 50 ml round bottom flask, added 5 mL of deionized water, 5 mL of anhydrous ethanol, and stirred well, and heated in an oil bath at 90 °C for 1 h. After the reaction was completed, 20 mL of deionized water was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time), and the aqueous phase was retained, and the pH of the aqueous phase was adjusted to acidic (pH = 3-4) with 1 N aqueous hydrochloric acid solution, at which time white solids were precipitated, and the aqueous phase was extracted with ethyl acetate three times again (15 mL each time), and the organic phase was retained, and the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, and the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:10) to obtain the title compound (d4) as a white solid (0.0600 g, yield: 24%). 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.21 (dd, J = 8.9, 2.3 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 4.26 (t, J = 6.3 Hz, 2H), 3.50 (t, J = 6.2 Hz, 2H), 3.26 (s, 3H), 2.65 (s, 3H), 2.05-1.97 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 166.17, 162.86, 161.88, 159.54, 133.09, 131.59, 125.44, 122.94, 115.43, 113.85, 101.56, 68.06, 66.53, 58.02, 28.55, 17.05.

[0140] Example 4: Synthesis of compound 2-(3-cyano-4-(2-methoxyethoxy)phenyl)-4- methylthiazole-5-carboxylic acid (d5)

[0141]

[0142] Ethyl 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate (0.2883 g, 1 mmol, 1 eq), potassium carbonate (0.4146 g, 3 mmol, 3 eq) were placed in a 50 ml round bottom flask, 15 mL of N,N-dimethylformamide was added to stir and dissolve, then 2-bromoethyl methyl ether (0.19 mL, 2 mmol, 2 eq) was slowly added dropwise to the mixture solution, and the oil bath pot was heated to 85°C for 2h. After the reaction was completed, 20 mL of deionized water was added to terminate the reaction, and the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase for drying, the solvent was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to obtain white solid: ethyl 2-(3-cyano-4-(2-methoxyethoxy)phenyl)-4-methylthiazole-5-carboxylate (0.3230 g, yield: 93%). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 8.9, 2.4 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.31-4.27 (m, 2H), 3.86-3.79 (m, 2H), 3.47 (s, 3H), 2.75 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 167.08, 162.29, 162.13, 161.15, 132.68, 132.22, 126.50, 122.16, 115.51, 113.05, 103.27, 70.64, 69.38, 61.52, 59.71, 17.56, 14.44.

[0143] The product from the previous step: 2-(3-cyano-4-(2-methoxyethoxy)phenyl)-4- methylthiazole-5-carboxylic acid ethyl ester (0.3464 g, 1 mmol, 1 eq) and lithium hydroxide monohydrate (0.0923 g, 2.2 mmol, 2.2 eq) were placed in a 50 ml round bottom flask, 10 mL of deionized water, 10 mL of anhydrous ethanol were added, and the mixture was stirred thoroughly, and heated in an oil bath at 90 °C for 1 h. After the reaction was completed, 20 mL of deionized water was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time), and the aqueous phase was retained. The pH of the aqueous phase was adjusted to acidic (pH = 3-4) using 1 N aqueous hydrochloric acid solution, at which time white solids were precipitated, and the aqueous phase was extracted with ethyl acetate three times again (15 mL each time), and the organic phase was retained. The organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it. The solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:10) to obtain the title compound (d5) as a white solid (0.0700 g, yield: 22%). 1 H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 8.27 (d, J = 2.3 Hz, 1H), 8.21 (dd, J = 8.9, 2.4 Hz, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.42-4.30 (m, 2H), 3.77-3.69 (m, 2H), 3.34 (s, 3H), 2.65 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.09, 162.87, 161.88, 159.47, 133.02, 131.65, 125.53, 123.07, 115.51, 113.96, 101.56, 69.96, 68.97, 58.44, 17.04.

[0144] Example 5: Synthesis of compound (5-methyl-2-oxo-l,3-dioxolan-4-yl) 2-(3-cyano-4- isobutoxyphenyl)-4-methylthiazole-5-carboxylate (d9)

[0145]

[0146] Into a 50 ml round bottom flask, 5 mL of DMAC was placed and preheated to 30 °C, then nonivamide (0.3164 g, 1 mmol, 1 eq) and 4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one (0.12 mL, 1.3 mmol, 1.3 eq) were added, after stirring and mixing, potassium carbonate (0.2073 g, 1.5 mmol, 1.5 eq), TsCl (0.2478 g, 1.3 mmol, 1.3 eq), DMAP (0.0183 g, 0.15 mmol, 0.15 eq) were added and stirred, and the reaction was carried out at 30 °C for 3 h. After the reaction was completed, 20 mL of deionized water was added to the reaction solution to terminate the reaction, and the aqueous phase was adjusted to acidic (pH = 5) with 1 N aqueous hydrochloric acid solution, at which time white solid was precipitated, and the title compound (d9) was obtained as a light yellow solid (0.2183 g, yield: 51%) by filtration. 1 H NMR (400 MHz, CDC13) δ 8.18 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 8.9, 2.3 Hz, 1H), 7.01 (d, J = 8.9 Hz, 1H), 5.05 (s, 2H), 3.90 (d, J = 6.5 Hz, 2H), 2.75 (s, 3H), 2.24 (s, 3H), 2.24 - 2.14 (m, 1H), 1.08 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, CDC13) δ 168.25, 162.81, 162.65, 161.40, 152.14, 140.58, 133.33, 132.79, 132.30, 125.79, 120.34, 115.42, 112.80, 103.18, 75.86, 54.40, 28.26, 19.16, 17.74, 9.63.

[0147] Example 6: Synthesis of compound 2-(3-cyano-4-(difluoromethoxy)phenyl)-4- methylthiazole-5-carboxamide (d12)

[0148]

[0149] To a 50 mL round bottom flask was placed 2-(3-cyano-4- (difluoromethoxy)phenyl)-4-methylthiazole-5-carboxylic acid (0.4654 g, 1.5 mmol, 1 eq), CDI (0.2432 g, 1.5 mmol, 1 eq) and 10 mL of super dry DCM was added to it and stirred at room temperature for 1.5 h for activation. After that, 25% ammonia solution (2 mL) was added to the mixture and allowed to react at room temperature for 4 h. After completion of the reaction, 20 mL of saturated brine was added to the reaction mixture to stop the reaction. The aqueous phase was extracted with ethyl acetate three times (15 mL each time), the organic phase was retained, the organic phase was washed with saturated brine once and dried by adding an appropriate amount of anhydrous sodium sulfate to the organic phase. The solvent was distilled off under reduced pressure and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:5) to obtain the title compound (d12) as a white solid (0.07 g, yield: 15%). 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 8.9, 2.3 Hz, 1H), 7.72 (s, 2H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 72.2 Hz, 1H), 2.62 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.69, 162.47, 155.09, 153.30, 132.77, 131.70, 129.80, 128.13, 118.90, 118.45, 115.85, 114.33, 113.24, 104.62, 17.01.

[0150] Example 7: Synthesis of compound 2-(3-cyano-4-(difluoromethoxy)phenyl)-4- methylthiazole-5-carbohydrazide (d13)

[0151]

[0152] To a solution of 2-(3-cyano-4-(difluoromethoxy)phenyl)-4-methylthiazole-5- carboxylic acid (0.4654 g, 1.5 mmol, 1 eq) and CDI (0.2432 g, 1.5 mmol, 1 eq) in a 50 mL round-bottom flask, 10 mL of super dry DCM was added and stirred at room temperature for 1.5 h for activation. After that, hydrazine monohydrate (0.5 mL) was added to the mixture solution and reacted at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time). The organic phase was reserved, washed with saturated brine once, and dried by adding an appropriate amount of anhydrous sodium sulfate to the organic phase. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, ethyl acetate) to obtain the title compound (d13) as a white solid (0.07 g, yield: 14%). 1 H NMR (400 MHz, DMSO-d6) δ 9.64 (s, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 72.2 Hz, 1H), 4.59 (s, 2H), 2.60 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.20, 161.24, 155.16, 153.76, 133.24, 132.19, 130.22, 119.37, 118.92, 116.31, 114.81, 113.71, 105.09, 17.38.

[0153] Example 8: Synthesis of compound 2-(3-cyano-4-(difluoromethoxy)phenyl)-N,N,4- trimethylthiazole-5-carboxamide (d14)

[0154]

[0155] To a solution of 2-(3-cyano-4-(difluoromethoxy)phenyl)-4-methylthiazole-5- carboxylic acid (0.4654 g, 1.5 mmol, 1 eq) and CDI (0.2432 g, 1.5 mmol, 1 eq) in 50 mL round-bottom flask, 10 mL of super dry DCM was added and stirred at room temperature for 1.5 h for activation. After that, 2M / L of dimethylamine solution in THF (0.9 mL, 1.65 mmol, 1.1 eq) was added slowly dropwise to the mixture solution and reacted at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time). The organic phase was reserved, washed with saturated brine once, and dried by adding an appropriate amount of anhydrous sodium sulfate to the organic phase. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to obtain the title compound (d14) as a white solid (0.07 g, yield: 14%). 1 HNMR (400 MHz, CDC13) δ 8.21 (d, J = 2.0 Hz, 1H), 8.07 (dd, J = 8.7, 2.2 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.71 (t, J = 71.4 Hz, 1H), 3.09 (s, 6H), 2.46 (s, 3H). 13 C NMR (101 MHz, CDC13) δ 163.47, 163.30, 153.20, 152.78, 132.11, 131.74, 130.91, 126.22, 120.12, 117.65, 114.99, 114.27, 112.34, 106.75, 16.54.

[0156] Example 9: Synthesis of compound 2-(3-cyano-4-(difluoromethoxy)phenyl)-N- methoxy-N,4-dimethylthiazole-5-carboxamide (d15)

[0157]

[0158] Into a 50 mL round-bottom flask, 2-(3-cyano-4-(difluoromethoxy)phenyl)-4- methylthiazole-5-carboxylic acid (0.3103 g, 1 mmol, 1 eq), CDI (0.1622 g, 1 mmol, 1 eq) were placed, 5 mL of super dry DCM was added thereto, and stirring was performed at room temperature for 1.5 h to activate, after which methoxymethylamine (0.0672 g, 1.1 mmol, 1.1 eq) was added to the mixture solution, and reaction was performed at room temperature for 4 h. After the completion of the reaction, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to obtain the title compound (d15) as a white solid (0.069 g, yield: 20%). 1 H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 1.9 Hz, 1H), 8.21 (dd, J = 8.8, 2.1 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.71 (t, J = 71.3 Hz, 1H), 3.75 (s, 3H), 3.37 (s, 3H), 2.80 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.61, 162.63, 162.54, 152.98, 132.28, 132.07, 131.12, 120.33, 119.85, 117.68, 115.02, 114.38, 112.35, 106.95, 61.98, 33.02, 18.68.

[0159] Example 10: Synthesis of compound 2-(3-cyano-4-(difluoromethoxy)phenyl)-N,4- dimethylthiazole-5-carboxamide (d16)

[0160]

[0161] Into a 50 mL round bottom flask was placed 2-(3-cyano-4- (difluoromethoxy)phenyl)-4-methylthiazole-5-carboxylic acid (0.3103 g, 1 mmol, 1 eq), CDI (0.1622 g, 1 mmol, 1 eq) and 5 mL of super dry DCM was added to it and stirred at room temperature for 1.5 h for activation. After that, to the mixture solution was added slowly drop wise 2M / L of methylamine solution in THF (0.6 mL, 1.1 mmol, 1.1 eq) and allowed to react at room temperature for 4 h. After completion of the reaction, to the reaction was added 20 mL of saturated brine to quench the reaction and the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time) and the organic phase was retained, washed with saturated brine once and dried over anhydrous sodium sulfate by adding to the organic phase and the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to get the title compound (d16) as a white solid (0.015 g, yield: 5%). 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 2.3 Hz, 1H), 8.30 (dd, J = 8.9, 2.3 Hz, 1H), 8.25 (d, J = 5.0 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.54 (t, J = 72.2 Hz, 1H), 2.77 (d, J = 4.5 Hz, 3H), 2.61 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 161.16, 154.59, 132.78, 131.70, 129.77, 127.87, 118.92, 115.85, 114.34, 104.63, 26.46, 16.95.

[0162] Example 11: Synthesis of compound 2-(3-cyano-4-(difluoromethoxy)phenyl)-N-(2- hydroxyethyl)-4-methylthiazole-5-carboxamide (d17)

[0163]

[0164] Into a 50 mL round-bottom flask, 2-(3-cyano-4-(difluoromethoxy)phenyl)-4- methylthiazole-5-carboxylic acid (0.4654 g, 1.5 mmol, 1 eq), CDI (0.2432 g, 1.5 mmol, 1 eq) were placed, 10 mL of super dry DCM was added thereto, and stirring was performed at room temperature for 1.5 h to activate, after which ethanolamine (0.18 mL, 3 mmol, 2 eq) was added to the mixture solution, and reaction was performed at room temperature for 4 h. After the completion of the reaction, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:10) to obtain the title compound (d17) as a white solid (0.069 g, yield: 20%). 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 8.8, 2.3 Hz, 1H), 8.25 (t, J = 5.6 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 (t, J = 72.2 Hz, 1H), 4.75 (t, J = 5.5 Hz, 1H), 3.51 (q, J = 6.0 Hz, 2H), 3.34 - 3.28 (m, 4H), 2.61 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.52, 160.81, 154.65, 153.28, 132.76, 131.68, 129.79, 128.01, 118.93, 118.44, 115.84, 114.33, 113.24, 104.64, 59.50, 42.26, 16.98.

[0165] Example 12: Synthesis of compound 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4- methylthiazole-5-carboxamide (d18)

[0166]

[0167] To a solution of 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4-methylthiazole-5- carboxylic acid (0.1572 g, 0.5 mmol, 1 eq) and CDI (0.0811 g, 0.5 mmol, 1 eq) in a 50 mL round bottom flask, 3 mL of super dry DCM was added and stirred at room temperature for 1.5 h for activation. After that, 25% ammonia water (1 mL) was added to the mixture solution and reacted at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time). The organic phase was reserved, washed with saturated brine once, and dried by adding an appropriate amount of anhydrous sodium sulfate to the organic phase. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, ethyl acetate) to obtain the title compound (d18) as a white solid (0.035 g, yield: 22%). 1 H NMR (400 MHz, DMSO-d6) δ 8.21 (d, J = 2.3 Hz, 1H), 8.14 (dd, J = 8.9, 2.4 Hz, 1H), 7.64 (s, 2H), 7.34 (d, J = 9.0 Hz, 1H), 4.08 (d, J = 7.0 Hz, 2H), 2.60 (s, 3H), 1.34 - 1.24 (m, 1H), 0.65 - 0.59 (m, 2H), 0.42 - 0.37 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.72, 162.65, 161.73, 155.02, 132.78, 131.28, 126.86, 125.51, 115.67, 114.07, 101.50, 73.81, 17.05, 9.75, 3.15.

[0168] Example 13: Synthesis of compound 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4- methylthiazole-5-carbohydrazide (d19)

[0169]

[0170] To a solution of 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4-methylthiazole-5- carboxylic acid (0.1572 g, 0.5 mmol, 1 eq) and CDI (0.0811 g, 0.5 mmol, 1 eq) in a 50 mL round bottom flask, 3 mL of super dry DCM was added and stirred at room temperature for 1.5 h for activation. After that, hydrazine monohydrate (0.25 mL) was added to the mixture and reacted at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time). The organic phase was reserved, washed with saturated brine once, and dried by adding an appropriate amount of anhydrous sodium sulfate to the organic phase. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, ethyl acetate) to obtain the title compound (d19) as a yellow solid (0.015 g, yield: 9%). 1 H NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.15 (dd, J = 8.9, 2.4 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.58 (s, 2H), 4.08 (d, J = 7.0 Hz, 2H), 2.58 (s, 3H), 1.33-1.25 (m, 1H), 0.66-0.57 (m, 2H), 0.43-0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.73, 161.70, 160.97, 154.57, 132.76, 131.29, 125.45, 124.94, 115.65, 114.06, 101.50, 73.79, 16.94, 9.73, 3.13.

[0171] Example 14: Synthesis of compound 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-N,N,4- trimethylthiazole-5-carboxamide (d20)

[0172]

[0173] To a solution of 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4-methylthiazole-5- carboxylic acid (0.1572 g, 0.5 mmol, 1 eq) and CDI (0.0811 g, 0.5 mmol, 1 eq) in a 50 mL round-bottom flask, 3 mL of super dry DCM was added, and stirring was performed at room temperature for 1.5 h for activation. After that, dimethylamine solution (0.3 mL, 0.55 mmol, 1.1 eq) in THF (2 M / L) was added to the mixture solution, and reaction was performed at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time). The organic phase was reserved, and the organic phase was washed with saturated brine once, and then dried by adding an appropriate amount of anhydrous sodium sulfate to the organic phase. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 5:4) to obtain the title compound (d20) as a white solid (0.1677 g, yield: 98%). 1 HNMR (400 MHz, CDC13) δ 8.11 (d, J = 2.0 Hz, 1H), 8.01 (dd, J = 8.9, 2.3 Hz, 1H), 6.98 (d, J = 8.7 Hz, 1H), 3.98 (d, J = 6.8 Hz, 2H), 3.09 (s, 6H), 2.46 (s, 3H), 1.34 - 1.29 (m, 1H), 0.76 - 0.62 (m, 2H), 0.43 - 0.36 (m, 2H). 13 C NMR (101 MHz, CDC13) δ 164.97, 163.68, 162.06, 152.88, 132.43, 131.97, 126.21, 124.99, 115.75, 112.95, 103.08, 74.20, 16.63, 9.95, 3.50.

[0174] Example 15: Synthesis of compound 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-N- methoxy-N,4-dimethylthiazole-5-carboxamide (d21)

[0175]

[0176] Into a 50 mL round-bottom flask, 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4-methylthiazole-5-carboxylic acid (0.1572 g, 0.5 mmol, 1 eq), CDI (0.0811 g, 0.5 mmol, 1 eq) were placed, 3 mL of super dry DCM was added thereto, and stirring was performed at room temperature for 1.5 h to activate, after which methoxymethylamine (0.0336 g, 0.55 mmol, 1.1 eq) was added to the mixture solution, and reaction was performed at room temperature for 4 h. After the completion of the reaction, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted with ethyl acetate 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to obtain the title compound (d21) silver white solid (0.0769 g, yield: 43%). 1 H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 8.8, 2.3 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 4.00 (d, J = 6.8 Hz, 2H), 3.74 (s, 3H), 3.36 (s, 3H), 2.79 (s, 3H), 1.37-1.30 (m, 1H), 0.71-0.68 (m, 2H), 0.47-0.38 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 166.97, 162.69, 162.19, 132.49, 132.15, 126.08, 118.59, 115.68, 112.87, 103.01, 74.16, 61.83, 32.89, 18.52, 9.87, 3.43.

[0177] Example 16: Synthesis of compound 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-N,4-dimethylthiazole-5-carboxamide (d22)

[0178]

[0179] To a solution of 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4-methylthiazole-5- carboxylic acid (0.1572 g, 0.5 mmol, 1 eq) and CDI (0.0811 g, 0.5 mmol, 1 eq) in a 50 mL round-bottom flask, 3 mL of super dry DCM was added, and stirring was performed at room temperature for 1.5 h for activation. After that, a 2 M / L solution of methylamine in THF (0.3 mL, 0.55 mmol, 1.1 eq) was added to the mixture solution, and reaction was performed at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with ethyl acetate three times (15 mL each time). The organic phase was reserved, and the organic phase was washed with saturated brine once and dried by adding an appropriate amount of anhydrous sodium sulfate to the organic phase. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:2) to obtain the title compound (d22) as a white solid (0.08 g, yield: 48%). 1 H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 2.1 Hz, 1H), 8.04 (dd, J = 8.7, 2.2 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 5.89 (s, 1H), 4.00 (d, J = 6.8 Hz, 2H), 3.00 (d, J = 4.3 Hz, 3H), 2.71 (s, 3H), 1.35-1.29 (m, 1H), 0.72-0.67 (m, 2H), 0.44-0.40 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 164.54, 162.32, 155.88, 132.61, 132.17, 126.10, 126.02, 115.73, 112.98, 103.14, 74.30, 27.12, 17.46, 9.97, 3.55.

[0180] Example 17: Synthesis of compound 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4- methyl-N-(2,2,2-trifluoroethyl)thiazole-5-carboxamide (d23)

[0181]

[0182] To a solution of 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4-methylthiazole-5- carboxylic acid (0.1572 g, 0.5 mmol, 1 eq) and CDI (0.0811 g, 0.5 mmol, 1 eq) in a 50 mL round-bottom flask, 3 mL of super dry DCM was added and stirred at room temperature for 1.5 h for activation. After that, 2,2,2-trifluoroethylamine hydrochloride (0.0745 g, 0.55 mmol, 1.1 eq) was added to the mixture solution and reacted at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, and the aqueous phase was extracted with dichloromethane 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to obtain the title compound (d23) as a white solid (0.03 g, yield: 15%). 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 6.3 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.18 (dd, J = 8.9, 2.3 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 4.09 (d, J = 6.9 Hz, 4H), 2.60 (s, 3H), 1.34 - 1.25 (m, 1H), 0.66 - 0.59 (m, 2H), 0.43 - 0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.44, 161.88, 161.59, 156.07, 132.90, 131.46, 125.27, 125.01, 123.30, 115.61, 114.11, 101.56, 73.83, 17.06, 9.73, 3.13.

[0183] Example 18: Synthesis of compound 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-N-(2- hydroxyethyl)-4-methylthiazole-5-carboxamide (d24)

[0184]

[0185] Into a 50 mL round-bottom flask, 2-(3-cyano-4-(cyclopropylmethoxy)phenyl)-4- methylthiazole-5-carboxylic acid (0.1572 g, 0.5 mmol, 1 eq), CDI (0.0811 g, 0.5 mmol, 1 eq) were placed, 3 mL of super dry DCM was added, and stirring was performed at room temperature for 1.5 h for activation, after which ethanolamine (0.06 mL, 1 mmol, 2 eq) was added to the mixture solution, and reaction was performed at room temperature for 4 h. After the reaction was completed, 20 mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted with dichloromethane 3 times (15 mL each time), the organic phase was reserved, the organic phase was washed with saturated brine once, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was rotary evaporated under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether / ethyl acetate = 1:1) to obtain the title compound (d24) as a white solid (0.067 g, yield: 37%). 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 5.6 Hz, 1H), 8.15 (dd, J = 8.9, 2.3 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 4.75 (t, J = 5.6 Hz, 1H), 4.08 (d, J = 7.0 Hz, 2H), 3.51 (q, J = 6.0 Hz, 2H), 3.30 (q, J = 6.1 Hz, 2H), 2.59 (s, 3H), 1.31 - 1.25 (m, 1H), 0.66 - 0.58 (m, 2H), 0.43 - 0.36 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.54, 161.72, 160.98, 154.55, 132.76, 131.26, 126.75, 125.49, 115.66, 114.09, 101.52, 73.80, 59.54, 42.24, 17.02, 9.74, 3.14.

[0186] In addition, d2, d10, and d11 can be obtained by using a similar method of the present application.

[0187]

[0188] Experimental Example: In vitro activity inhibition experiment of the compound of the present application on xanthine oxidase

[0189] 1. Preparation of buffer

[0190] Prepare 1xPBS by diluting 10xPBS with deionized water (100 mL of 10xPBS + 900 mL of deionized water = 1xPBS).

[0191] 2. Preparation of substrate (xanthine)

[0192] Weigh 1.5 mg xanthine, add 19.9 mL 1x PBS, and ultrasonic for 3-5 min to dissolve, to obtain 0.5 mmol / L substrate solution.

[0193] 3. Preparation of enzyme solution (xanthine oxidoreductase)

[0194] The original Sigma enzyme solution is 13.4 mg / mL, which is diluted to 10 μg / mL with 1x PBS (for example, for the whole plate, about 4 mL of diluted enzyme solution is needed, 2.99 μL of original enzyme solution is needed, 1x PBS = 4 mL-2.99 μL, and mix well).

[0195] 4. Preparation of test compound

[0196] Weigh the test compound accurately, prepare a 1 μmol / mL solution with DMSO, and store it at 20°C away from light. Before use, dilute it to the required concentration with PBS, and control the DMSO content within 5% to ensure that it has no effect on enzyme activity.

[0197] 5. Experimental method and process

[0198] Add the above prepared 1x PBS solution, sample (compound of the present application), positive control (febuxostat), blank control group (blank control group is PBS solution), and enzyme solution to a 96-well plate in turn, and incubate in a shaking bed (air bath constant temperature shaker) at 37°C for 30 min; then add the substrate to the incubated microplate in turn, and incubate for 20-25 min; finally, read the absorbance at 292 nm wavelength every 1 min. Each group of experiments is determined in triplicate.

[0199] Convert the initial speed of the test compound at each concentration to the percentage (%) of inhibition rate based on the initial speed without inhibitor, and calculate the IC 50 value. (Inhibition test scheme as shown in Table 1, and results shown in Table 2.)

[0200] Table 1. Inhibition test scheme of each compound on xanthine oxidase activity in vitro

[0201]

[0202]

[0203] Table 2. IC 50 value (nM) of each compound on xanthine oxidase activity in vitro

[0204]

[0205] Note: The experimental data is the average value of three tests, and the IC50 The lower the value, the stronger the compound is in inhibiting xanthine oxidase in vitro.

[0206] The technical solutions of the present application are not limited to the above specific embodiments, and any technical variations made according to the technical solutions of the present application fall within the protection scope of the present application.

Claims

1. A compound having one of the following structures or an isotopically-labeled compound thereof: or a pharmaceutically acceptable salt thereof. 。 2.A method for synthesizing a non-bisat 4-position ether derivative, comprising: (1) dispersing 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester and a first base in a first organic solvent, then adding dropwise a halogenated compound A to the mixture solution, and reacting under heating to obtain an intermediate product; or dispersing 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester and triphenylphosphine in a second organic solvent under argon protection, then adding dropwise an alcohol compound B to the mixture solution, and adding dropwise DEAD at room temperature to obtain the intermediate product; (2) dissolving the intermediate product and lithium hydroxide monohydrate in a third organic solvent, and heating to react to obtain the non-bisat 4-position ether derivative; wherein the non-bisat 4-position ether derivative has the structure of any one of the compounds of claim 1; and the molar ratio of the intermediate product to lithium hydroxide monohydrate is 1: (2-3) ; the halogenated compound A has the following structure: ， ， ， ； the alcohol compound B has the following structure: 。 3. The method of synthesis according to claim 2, wherein, the molar ratio of 2-(3-cyano-4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylic acid ethyl ester, the first base, and the halogenated compound A to the alcohol compound B is 1: (2-5) : (1.5-3). 4.The method according to claim 2, wherein: the first organic solvent or the second organic solvent is independently N,N-dimethylformamide, N,N-dimethylacetamide, or tetrahydrofuran; the third organic solvent is a combination of deionized water and anhydrous ethanol; the first base is potassium carbonate or cesium carbonate; the heating condition in step (1) is 80-120 DEG C; and the heating reaction in step (2) is 80-100 DEG C. 5.The method according to claim 2, wherein: the volume ratio of the deionized water to the anhydrous ethanol is 1:

1. 7.The use of the compound of claim 1 or the pharmaceutical composition of claim 6 in the preparation of a drug for hyperuricemia or gout. ​ ​ ​ 5. The method of synthesis according to claim 4, wherein, ​ 6. A pharmaceutical composition, characterized by, ​ ​

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