CN117777050A

CN117777050A - Febuxostat 4-position ether derivative and pharmaceutical composition, preparation method and application thereof

Info

Publication number: CN117777050A
Application number: CN202311680155.XA
Authority: CN
Inventors: 唐海涛; 潘英明; 朱宇; 秦锦涛
Original assignee: Guangxi Normal University
Current assignee: Guangxi Normal University
Priority date: 2023-12-07
Filing date: 2023-12-07
Publication date: 2024-03-29

Abstract

The present invention provides a compound having a structure represented by formula I, II or III or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitrogen oxide, metabolite, or a pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof. The febuxostat 4-position ether derivative has good xanthine oxidase activity inhibition activity.

Description

Febuxostat 4-position ether derivative and pharmaceutical composition, preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and particularly relates to a febuxostat 4-position ether derivative, a pharmaceutical composition, a preparation method and application thereof.

Background

In recent years, with the increasing proportion of high-purine foods in dietary structures, people suffering from hyperuricemia and gout have a trend of increasing year by year. In 2017, the number of hyperuricemia patients in China has reached 1.7 hundred million, with gout patients exceeding 8000 ten thousand, and the annual growth rate of 9.7% per year has rapidly increased.

Febuxostat (febuxostat), chemical name 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylic acid, was developed by the Japanese Di people (Teijin) group in early 2004, and is mainly used clinically for treating gout and hyperuricemia. Febuxostat was approved for sale by the European Medicines Agency (EMA) at month 10 of 2008 and was approved for sale by the united states Food and Drug Administration (FDA) at month 2 of the next year. Febuxostat is a novel non-purine Xanthine Oxidase (XO) selective inhibitor, and the highly selective inhibition of XO by febuxostat determines that it does not affect the synthesis and metabolism of other purines, pyrimidines, at conventional therapeutic concentrations, while febuxostat is not limited by meals and foods. Febuxostat can act by reducing the concentration of blood uric acid salt, and the application of the febuxostat can improve the vascular endothelial cell function, inhibit platelet aggregation, reduce lipid peroxidation, inhibit xanthine oxidase circulation and reduce inflammatory reaction. The medicine is the first medicine approved by the FDA for treating gout for 50 years, has definite action mechanism and definite curative effect, is used as a novel anti-uric acid medicine, and febuxostat initiates a new era of gout treatment. Common adverse effects of febuxostat include liver dysfunction, diarrhea, headache, nausea, rash, and the like, 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 febuxostat synthesis, hundreds of derivatives have been synthesized and used in drug screening studies (Li Wen, na, macrorepair, etc.. Xanthine oxidase inhibitor febuxostat derivatives have been developed [ J ]. Pharmaceutical journal, 2021,56 (12): 3401-3413.).

To date, gout has become the second most metabolic disease next to diabetes, and for the intermittent period of gout attack and the chronic period, the treatment mainly comprises uric acid reduction treatment and alkalization urine, and the first-line administration comprises: allopurinol, febuxostat, benzbromarone and colchicine. The drugs cannot meet the existing demands, so that more effective drugs are required to be developed for clinical application.

Disclosure of Invention

In order to solve the technical problems in the prior art, the invention provides a febuxostat 4-position ether derivative, which has excellent xanthine oxidase activity inhibition activity.

Specifically, the invention provides a compound, which has a structure shown in a formula I or an enantiomer, a diastereomer, a racemate, a stereoisomer, a geometric isomer, nitrogen oxide, a metabolite or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically-labeled compound or prodrug thereof;

wherein,

n is 1, 2 or 3;

R ¹ is C _1-10 Alkyl, halogenated C _1-10 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl or C _3-6 Cycloalkyl;

R ² is C _1-10 Alkyl, halogenated C _1-10 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl or C _3-6 Cycloalkyl groups.

In some embodiments of the present invention, in some embodiments,

R ¹ Is C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-4 Alkyl or C _3-6 Cycloalkyl;

R ² is C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-4 Alkyl or C _3-6 Cycloalkyl groups.

In some embodiments of the present invention, in some embodiments,

R ¹ methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl;

R ² is methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl.

In another aspect, the present invention provides a compound having a structure represented by formula II or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

wherein,

m is 1, 2 or 3;

R ³ is hydrogen, C _1-10 Alkyl, halogenated C _1-10 Alkyl, C _3-6 cycloalkyl-C _1-6 Alkyl or C _3-6 Cycloalkyl groups.

In some embodiments of the present invention, in some embodiments,

R ³ is hydrogen, C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-4 Alkyl or C _3-6 Cycloalkyl groups.

In some embodiments of the present invention, in some embodiments,

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

In another aspect, the present invention also provides a compound having a structure represented by formula III or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

R ³ Is halogenated C _1-6 Alkyl, halogenated C _3-6 cycloalkyl-C _1-4 Alkyl or halo C _3-6 Cycloalkyl groups.

In some embodiments of the present invention, in some embodiments,

R ³ is trifluoromethyl, difluoromethyl or monofluoromethyl.

In another aspect, the present invention also provides a compound having one of the structures shown below or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

on the other hand, the invention also provides a method for synthesizing the febuxostat 4-position ether derivative, which comprises the following steps:

(1) Dispersing ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methyl-1, 3-thiazole-5-carboxylate and a first base in a first organic solvent, then dropwise adding a halogenated compound into 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 the protection of argon, then dropwise adding an alcohol compound into the mixture solution, dropwise adding DEAD, and reacting at room temperature to obtain an intermediate product; preferably, the molar ratio of the first base to the halide a or the alcohol compound B is 1: (2-5): (1.5-3); preferably, the molar ratio of the first base to the halide a or the alcohol compound B is 1:3:2;

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

wherein R is ¹ 、R ² 、R ³ 、R ⁴ N and m have the definitions indicated in the present invention;

the halogenated compound a has the following structure:

x is halogen;

the alcohol compound B has the following structure:

in some embodiments of the present invention, in some embodiments,

the first organic solvent or the second organic solvent is N, N-dimethylformamide, N-dimethylacetamide or tetrahydrofuran;

the third organic solvent is a combination of deionized water and absolute ethyl alcohol;

the first base is potassium carbonate and cesium carbonate;

the heating condition of the step (1) is 80-120 ℃;

the heating reaction in the step (2) is 80-100 ℃.

On the other hand, the invention also provides a pharmaceutical composition which is characterized by comprising the compound and pharmaceutically acceptable auxiliary materials.

In another aspect, the invention also provides the use of a compound of the invention or a pharmaceutical composition of the invention for inhibiting xanthine oxidase.

In another aspect, the invention also provides application of the compound or the pharmaceutical composition in preparation of medicines for hyperuricemia or gout.

Another aspect of the invention relates to methods for the preparation, isolation and purification of compounds of formula I, II, III.

Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.

The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully below. All references in this specification are incorporated herein by reference in their entirety.

Detailed Description

The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the concepts of the present disclosure. Such structures and techniques are also described in a number of publications.

Definition of the definition

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structural and chemical formulas. The invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.

It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

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 invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato: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.

The articles "a," "an," and "the" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.

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

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

The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.

When substituents are described by conventional formulas written from left to right, the substituents also include chemically equivalent substituents obtained when writing formulas from right to left. For example, -CH ₂ O-is equivalent to-OCH ₂ -。

The term "enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.

The term "diastereoisomer" refers to a stereoisomer that has two or more chiralities and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The term "racemate", "racemate" or "racemic mixture" refers to an equimolar mixture of two enantiomers lacking optical activity.

The term "tautomer" or "tautomeric form" refers to structural isomers having different energies that can be interconverted by a low energy barrier (lowenergy barrier). If tautomerism is possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as proton transfer tautomers (prototropic tautomer)) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence tautomers (valance tautomers) include interconversions by recombination of some of the bond-forming electrons. Specific examples of keto-enol tautomerism are tautomerism of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomer. Another example of tautomerism is phenol-ketone tautomerism. One specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

The term "stereoisomer" refers to a compound having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like.

The term "geometric isomer" is also referred to as "cis-trans isomer" as an isomer resulting from the inability of a double bond (including olefinic double bonds, c=n double bonds, and n=n double bonds) or a single bond of a ring carbon atom to rotate freely.

The stereochemical definitions and rules used in the present invention generally follow S.P. Parker, ed., mcGraw-Hill Dictionary ofChemical Terms (1984) Mc Graw-Hill Book Company, new York; and Eliel, E.and Wilen, S, "Stereochemistry ofOrganic Compounds", john Wiley & Sons, inc., new York,1994. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One particular stereoisomer is an enantiomer, and a mixture of such isomers is referred to as an enantiomeric mixture. A50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, 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 in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may be present in the form of one of the possible isomers or mixtures thereof, for example racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.

Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by methods familiar to those skilled in the art, e.g., by separation of the diastereoisomeric salts thereof obtained, using known methods. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racematesand 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 (Subramannian, G.ed., wiley-VCH Verlag GmbH & Co.K GaA, weinheim, germany, 2007).

The term "nitroxide" refers to the oxidation of 1 or more than 1 nitrogen atom to form an N-oxide when the compound contains several amine functions. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method L.W.Deady (Syn.Comm.1977, 7, 509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example in an inert solvent, for example methylene chloride.

The term "metabolite" refers to a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.

The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. Preferably, the term "pharmaceutically acceptable" as used herein refers to use in animals, particularly humans, approved by the federal regulatory agency or a state government or listed in the U.S. pharmacopeia or other generally recognized pharmacopeia.

The term "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: s.m. berge et al, j.pharmaceutical Sciences,66:1-19,1977. Pharmaceutically acceptable salts include salts of the compounds with acids including, but not limited to, inorganic acid salts (e.g., hydrochloride, hydrobromide, phosphate, sulfate, nitrate, perchlorate) and organic acid salts (e.g., acetate, glycolate, oxalate, maleate, tartrate, citrate, succinate, fumarate, mandelate, sulfosalicylate), or by other methods described in the literature such as ion exchange. More, the Many pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphoric acid salts, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate, lactobionic aldehyde acid salts, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts also include salts of the compounds with bases including, but not limited to, inorganic base salts (e.g., alkali metal salts, alkaline earth metal salts, ammonium salts, and n+ (C1-4 alkyl) 4 salts), alkali metal or alkaline earth metal salts including sodium, lithium, potassium, calcium, magnesium, and the like. The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C _1-8 Sulfonate and aromatic sulfonate. Organic base salts (such as primary, secondary and tertiary amine salts, substituted amines (including naturally occurring substituted amines, cyclic amines, basic ion exchange resins) salts), certain organic amine salts include, for example, isopropyl amine salts, benzathine (benzathine) salts, choline salts (choline salts), diethanolamine salts, diethylamine salts, lysine salts, meglumine (meglumine) salts, piperazine salts and tromethamine salts.

Pharmaceutically acceptable acid addition salts may be formed by the reaction of a compound of the invention with an inorganic or organic acid and pharmaceutically acceptable base addition salts may be formed by the reaction of a compound of the invention with an inorganic or organic base. Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).

The term "solvate" refers to an association of one or more solvent molecules with a compound of the invention. The solvent may 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 in a volume ratio of 10:90 to 90:10, acetone, methyl isobutyl ketone, acetonitrile, benzene, chloroform, carbon tetrachloride, methylene chloride, dimethyl sulfoxide, 1, 4-dioxane, ethanol, ethyl acetate, ethylene glycol, N-butanol, tert-butanol, sec-butanol, N-dimethylacetamide, N-dimethylformamide, formamide, formic acid, N-hexane, cyclohexane, N-heptane in a volume ratio of 1:5 to 5:1, methyl ethyl ketone, l-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, N-propanol, isopropanol, 2-acetone, 4-methyl-2-pentanone, pyridine, tetrahydrofuran, methyl ethyl ketone, xylene, cumene, isopropyl benzene, or a mixture thereof, etc.

The term "hydrate" refers to an association of one or more water molecules with a compound of the invention.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include solvated and unsolvated forms.

The term "ester" is represented by the formula-OC (O) R OR-C (O) OR, wherein R may be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, OR heteroaryl as described herein.

The term "isotopically-labeled compound" means that the compound of the present invention is isotopically labeled. Which are identical to those described in the present invention, except for the fact that: one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number common in nature. Exemplary isotopes that can also be incorporated into compounds of the invention include 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 F ³⁷ Cl。

Other isotopically-labeled compounds of the present invention which contain the aforementioned isotopically-labeled and/or other atoms, and pharmaceutically acceptable salts of said compounds, are intended to be encompassed within the scope of the present invention. Isotopically-labelled compounds of the invention, e.g. radioisotope-labelled compounds, e.g ³ H and ¹⁴ c incorporation into the compounds of the present invention may be useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³ h, and carbon-14, i.e ¹⁴ C, isotopes are particularly preferred. In addition, isotopes having a relatively large mass number, e.g. deuterium, i.e ² H substitution may provide therapeutic advantages of some greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Thus, it may be preferable in some situations.

In addition, heavier isotopesThe other is deuterium (i.e., ² substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the context of the present invention is considered a substituent for the compounds of formulae I to III. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for 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). Pharmaceutically acceptable solvates of the invention include those wherein the crystallization solvent may be isotopically substituted, e.g. D ₂ O, acetone-d 6, DMSO-d 6.

The term "prodrug" as used herein, means a compound that is converted in vivo to a compound of formula I. Such conversion is effected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C _1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following documents: 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。

Unless explicitly indicated otherwise, the description used in this disclosure that "each … is independently" and "… is each independently" and "… is independently" are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.

The term "optional," "optionally," or "optionally," means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, "optionally substituted with … …" means that the substitution may or may not be present.

The terms "independent of each other" and "optionally" when used in combination, for example, "independent of each other optionally substituted with …" mean that the specific options are not mutually affected by each other, are not substituted with … or are not substituted with ….

The term "unsaturated" or "unsaturated" means that the moiety contains one or more unsaturations.

In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C _1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed ₃ Alkyl, C ₄ Alkyl, C ₅ Alkyl and C ₆ An alkyl group.

In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.

The term "cycloalkyl" means a mono-or polyvalent, mono-cyclic, bicyclic or tricyclic ring system containing carbon atoms (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [ 1.1.1)]Amyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalyl, etc.), may be fully saturated or contain one or more unsaturations, but none of the aromatic rings. In one embodiment, the cycloalkyl group contains 3 to 6 carbon atoms, e.g. C _3-6 Saturated or partially unsaturated cycloalkyl groups. 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: saturated monocyclic cycloalkyl, saturated bicyclic cycloalkyl, saturated tricyclic cycloalkyl, partially unsaturated monocyclic cycloalkyl, partially unsaturated bicyclic cycloalkyl, and partially unsaturated tricyclic cycloalkyl. C (C) _4-7 Cycloalkyl means cycloalkyl having 4 to 7 ring atoms. C (C) _3-6 Cycloalkyl means cycloalkyl having 3 to 6 ring atoms.

The term "hydrogen" refers to ¹ H is formed; "deuterium" means ² H。

The terms "halogen" and "halo" refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "alkyl" or "alkyl group" means a saturated, straight or branched chain hydrocarbon group containing carbon atoms. In one embodiment, the alkyl group contains 1 to 6 carbon atoms, i.e. C _1-6 An alkyl group; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms, i.e. C _1-4 An alkyl group; in one embodiment, the alkyl group contains 1 to 3 carbon atoms, i.e. C _1-3 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentylRadicals, n-hexyl radicals and similar alkyl radicals.

When two groups are used in combination, one group is attached to the remainder of the molecule through the other group, e.g., arylalkyl, and aryl is attached to the molecule through alkyl; c (C) _6-10 Aryl C _1-6 Alkyl means aryl having 6 to 10 carbon atoms and alkyl having 1 to 6 carbon atoms.

The term "comprising" is synonymous with "including", "containing" or "characterized by", which is inclusive or open-ended and does not exclude additional, unrecited elements or components from the medicament (or steps in the case of a method). The phrase "consisting of … …" does not include any element, step or component not specified in the medicament (or step in the case of a method). The phrase "consisting essentially of … …" refers to the materials indicated and those materials that do not materially affect the basic and novel characteristics of the medicament (or step in the case of a method).

Unless otherwise indicated, substitutions or combinations of groups referred to herein as markush structures are those that are stable or chemically realizable.

Pharmaceutical compositions and methods of administration

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

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 excipients, binders, fillers, and the like, and additional therapeutic agents such as antidiabetic agents, antihyperglycemic agents, antiobesity agents, antihypertensive agents, antiplatelet agents, antiatherosclerotic agents, or lipid lowering agents. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

As used herein, the term "pharmaceutically acceptable carrier" refers to a substance that can be used to prepare or use a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption delaying agents, salts, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof, as known to those skilled in the art (see, e.g., remington TheScience and Practice of Pharmacy [ leimington: pharmaceutical science and practice ], 22 nd edition, pharmaceutical press [ pharmaceutical press ],2013, pages 1049 to 1070).

The present invention also relates to pharmaceutical compositions comprising as active ingredient a compound having the formula I, II-1, II-2, III or a pharmaceutically acceptable salt thereof, which may be used, inter alia, for the treatment of neoplastic diseases, in particular cancer, as described herein. The compositions may be formulated for parenteral administration, e.g. nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ocular, or in particular for oral administration, e.g. in the form of oral solid dosage forms, e.g. granules, pills, powders, tablets, film coated or sugar coated tablets, effervescent tablets, hard and soft capsules or hydroxypropyl methylcellulose (HPMC) capsules (suitably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, e.g. intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, especially humans, e.g. in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. These compositions may comprise the active ingredient alone, or preferably, in combination with a pharmaceutically acceptable carrier.

The compounds having the formulas I, II, III or pharmaceutically acceptable salts thereof may be processed with pharmaceutically inert inorganic or organic excipients for the production of oral solid dosage forms, such as granules, pills, powders, tablets, film coated or sugar coated tablets, effervescent tablets, hard or HPMC capsules or orally disintegrating tablets. 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, glidants such as fumed silica, can be used as such excipients for the formulation and manufacture of oral solid dosage forms such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.

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

Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithins, surfactants and the like.

In addition, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.

The dosage can vary within wide limits and, of course, in each particular case meets the individual requirements. Generally, in the case of oral administration, a dosage of about 1 to 1000mg of a compound of formula I per person per day should be appropriate, although the lower or upper limit mentioned above may also be exceeded if necessary.

The compounds of formulae I, II, III may also be used in combination with one or more other pharmacologically active compounds which are also effective against the same disease, preferably in different modes of action, or in reducing or preventing the possible undesired side effects of the compounds of formulae I, II-, III. The combination partners may be administered simultaneously in such a treatment, e.g. by incorporating them into a single pharmaceutical formulation or sequentially by administration of two or more different dosage forms, each dosage form containing one or more than one combination partner.

The term "therapeutically effective amount" of a compound of the invention refers to an amount of a compound of the invention that will elicit a biological or medical response (e.g., a decrease or inhibition of enzymatic or protein activity, or an improvement in symptoms, alleviation of a condition, slowing or delaying the progression of a disease, or preventing a disease, etc.) in a subject. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that is effective, when administered to a subject, to at least partially alleviate, inhibit, prevent and/or ameliorate diseases or disorders of hyperuricemia and gout.

The term "treatment" as used herein in the context of treating a disease or disorder relates generally to treatment and therapy of a human or animal (e.g., in veterinary applications), wherein some desired therapeutic effect is obtained, e.g., inhibiting the progression of the disease or disorder, and includes reducing the rate of progression, stopping the rate of progression, alleviating symptoms of the disease or disorder, ameliorating the disease or disorder, and curing the disease or disorder. Treatment (i.e., prevention) as a precaution is also included. For example, a patient for whom the disease or disorder has not yet developed, but is at risk of developing the disease or disorder, is encompassed by the term "treatment". For example, treatment includes prevention of hyperuricemia or gout, reduction of symptoms of hyperuricemia or gout, reduction of incidence of hyperuricemia or gout, reduction of uric acid levels, and the like.

In some embodiments, the present invention provides the use of a compound of formula I, II, III or a pharmaceutical composition or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of hyperuricemia and gout.

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

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

Synthesis method

The compounds of the formulae I, II, III can be synthesized by the methods given below, by the methods given in the experimental section below or by analogous methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds having formulas I, II, III; conversely, other techniques known to the skilled chemist may be used for compound synthesis.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. The NMR was performed using a Bruker Advance III-400M nuclear magnetic resonance spectrometer with deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD) or deuterated dimethyl sulfoxide (DMSO-d) ₆ ) The internal standard is Tetramethylsilane (TMS). When multiple peaks occur, the following abbreviations will be used: s (single, singlet), d (doublet ), t (triplet, multiplet), m (multiplet ), br (broadened, broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet), td (triplet of doublets, triplet), brs (broadened singlet, broad singlet). Coupling constant J, in units of hertz (Hz).

Liquid chromatography (LC-MS) was detected using an Agilent mass spectrometer (Agilent 1260,Agilent 6125B). High Performance Liquid Chromatography (HPLC) was performed using a Gilson high pressure liquid chromatograph (Gilson GX-281), a C18 column (10. Mu.M, 19 mm. Times.250 mm), UV detection bands of 220 and 254nm, and elution conditions of 5-95% acetonitrile (0.05% v/v formic acid or ammonium bicarbonate) gradient elution for 15 minutes.

The thin layer chromatography silica gel plate is Qingdao GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15-0.20mm, and the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.4-0.5 mm. Silica gel column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to literature reported in the art.

The following examples are provided to aid in the understanding of the present invention. It is to be understood that these examples are illustrative of the present invention only and are not to be construed as limiting in any way. The actual scope of the invention is set forth in the following claims. It will be understood that any modifications and variations may be made without departing from the spirit of the invention.

Example 1: synthesis of Compound 2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (d 1)

Ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methyl-1, 3-thiazole-5-carboxylate (0.2883 g,1mmol,1 eq) was placed in a 50mL round bottom flask, 3mL ln, n-dimethylformamide was added thereto with sufficient stirring, then 0.2mL deionized water was added to the solution, stirred well, sodium difluorochloroacetate (0.3089 g,2mmol,2 eq) was weighed for pre-dissolution in 2mL ln, n-dimethylformamide, then slowly dropped into the round bottom flask, and finally cesium carbonate (0.4887 g,1.5mmol,1.5 eq) was added to the round bottom flask in one portion, and the oil bath was heated to 100 ℃ for reaction for 0.5h. After the reaction was completed, 20mL of deionized water was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was spin-dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=10:3), to give a white solid (d 6): 2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid ethyl ester (0.2050 g, yield: 60%). ¹ H NMR(500MHz,CDCl ₃ )δ8.29(d,J＝2.2Hz,1H),8.15(dd,J＝8.8,2.3Hz,1H),7.41(d,J＝8.8Hz,1H),6.71(t,J＝71.2Hz,1H),4.36(q,J＝7.1Hz,2H),2.77(s,3H),1.39(t,J＝7.1Hz,3H). ¹³ C NMR(126MHz,CDCl ₃ )δ165.70,161.94,161.41,153.15(t,J＝2.5Hz),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.

The product (d 6) obtained in the previous step is: 2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid ethyl ester (0).1692g,0.5mmol,1 eq.) and lithium hydroxide monohydrate (0.0462 g,1.1mmol,2.2 eq.) were placed in a 50mL round bottom flask, deionized water 5mL, absolute ethanol 5mL were added, thoroughly stirred and mixed, and the reaction was carried out for 1h at 90℃with heating in an oil bath. After the completion of the reaction, 20mL of deionized water was added to the reaction mixture to terminate the reaction, the aqueous phase was extracted 3 times (15 mL each time) with ethyl acetate, the aqueous phase was retained, the pH of the aqueous phase was adjusted to be acidic (ph=3 to 4) with a 1N aqueous hydrochloric acid solution, at this time, a white solid was precipitated, the aqueous phase was extracted 3 times again (15 mL each time) with ethyl acetate, the organic phase was retained, the organic phase was washed 1 time with saturated saline, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:10), to give the title compound (d 1) as a white solid (0.0800 g, yield: 51%). ¹ H NMR(400MHz,DMSO-d ₆ )δ13.51(s,1H),8.48(d,J＝2.3Hz,1H),8.35(dd,J＝8.8,2.3Hz,1H),7.58(d,J＝8.8Hz,1H),7.55(t,J＝72.1Hz,1H),2.67(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ165.16,162.76,159.65,153.63,133.03,132.08,129.55,124.10,118.73,115.84(t,J＝261.8Hz),114.31,104.55,17.04.

Example 2: synthesis of Compound 2- (3-cyano-4- (2-methoxypropoxy) phenyl) -4-methylthiazole-5-carboxylic acid (d 3)

Ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methyl-1, 3-thiazole-5-carboxylate (0.2883 g,1mmol,1 eq.) was placed in a 50mL round bottom flask, argon was replaced 3 times, 2mL of ultra-dry tetrahydrofuran was then added thereto and stirred for dissolution, after mixing well, 2-methoxy-1-propanol (0.29 mL,3mmol,3 eq.) was slowly added dropwise to the mixture solution and stirred well at room temperature for 10min, and then DEAD (0.19 mL,1.2mmol,1.2 eq.) was slowly added dropwise thereto and reacted at room temperature for 1h. After the completion of the reaction, the solvent was dried under reduced pressure, the residue was redissolved with 5mL of ethyl acetate, 20mL of deionized water was added thereto, and the aqueous phase was extracted 3 times with ethyl acetate (1 each time 5 mL), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase for drying, the solvent was spin-dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=10:3), to give a pale yellow solid (d 8): 2- (3-Isocyano-4- (2-methoxypropoxy) phenyl) -4-methylthiazole-5-carboxylic acid ethyl ester (0.1100 g, yield: 30%). ¹ H NMR(400MHz,CDCl ₃ )δ8.16(d,J＝2.3Hz,1H),8.07(dd,J＝8.8,2.3Hz,1H),7.03(d,J＝8.9Hz,1H),4.34(q,J＝7.1Hz,2H),4.13(dd,J＝9.6,6.4Hz,1H),4.02(dd,J＝9.6,4.4Hz,1H),3.81(td,J＝6.4,4.4Hz,1H),3.48(s,3H),2.74(s,3H),1.37(t,J＝7.1Hz,3H),1.30(d,J＝6.4Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ167.04,162.24,162.12,161.17,132.65,132.12,126.49,122.12,115.45,112.92,103.20,75.16,73.28,61.49,57.71,17.56,16.67,14.42.

The product (d 8) obtained in the previous step is: ethyl 2- (3-isocyano-4- (2-methoxypropoxy) phenyl) -4-methylthiazole-5-carboxylate (0.1802 g,0.5mmol,1 eq.) and lithium hydroxide monohydrate (0.0462 g,1.1mmol,2.2 eq.) are placed in a 50mL round bottom flask, deionized water 5mL, absolute ethanol 5mL are added, thoroughly stirred and mixed, and the reaction is carried out for 1 hour at 90 ℃ with heating in an oil bath. After the completion of the reaction, 20mL of deionized water was added to the reaction mixture to terminate the reaction, the aqueous phase was extracted 3 times (15 mL each time) with ethyl acetate, the aqueous phase was retained, the pH of the aqueous phase was adjusted to be acidic (ph=3 to 4) with a 1N aqueous hydrochloric acid solution, at this time, a white solid was precipitated, the aqueous phase was extracted 3 times again (15 mL each time) with ethyl acetate, the organic phase was retained, the organic phase was washed 1 time with saturated saline, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:10), to give the title compound (d 3) as a white solid (0.0812 g, yield: 48%). ¹ H NMR(400MHz,DMSO-d ₆ )δ13.42(s,1H),8.27(d,J＝2.4Hz,1H),8.20(dd,J＝8.9,2.3Hz,1H),7.38(d,J＝9.0Hz,1H),4.22(dd,J＝10.3,3.9Hz,1H),4.16(dd,J＝10.4,6.0Hz,1H),3.72(td,J＝6.2,3.9Hz,1H),3.35(s,3H),2.65(s,3H),1.20(d,J＝6.4Hz,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ166.13,162.87,161.95,159.51,133.01,131.56,125.53,123.01,115.44,113.99,101.61,74.40,72.39,56.50,17.05,16.15.

Example 3: synthesis of Compound 2- (3-cyano-4- (3-methoxypropoxy) phenyl) -4-methylthiazole-5-carboxylic acid (d 4)

Ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methyl-1, 3-thiazole-5-carboxylate (0.2883 g,1mmol,1 eq.) and potassium carbonate (0.4146 g,3mmol,3 eq.) were placed in a 50ml round bottom flask, 15mLN, N-dimethylformamide was added thereto and stirred for dissolution, after which 3-bromopropyl methyl ether (0.23 mL,2mmol,2 eq.) was slowly added dropwise to the mixture solution and the reaction was carried out with heating in an oil bath at 85℃for 2h. After the reaction was completed, 20mL of deionized water was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was spin-dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give a white solid: 2- (3-cyano-4- (3-methoxypropoxy) phenyl) -4-methylthiazole-5-carboxylic acid ethyl ester (0.2662 g, yield: 73%). ¹ H NMR(400MHz,CDCl ₃ )δ8.13(d,J＝2.3Hz,1H),8.05(dd,J＝8.9,2.3Hz,1H),7.03(d,J＝8.9Hz,1H),4.32(q,J＝7.1Hz,2H),4.22(t,J＝6.2Hz,2H),3.58(t,J＝5.9Hz,2H),3.34(s,3H),2.72(s,3H),2.11(p,J＝6.1Hz,2H),1.36(t,J＝7.1Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ167.06,162.32,162.06,161.09,132.64,132.04,126.15,121.99,115.49,112.73,102.93,68.47,66.42,61.43,58.84,29.26,17.51,14.38.

The product obtained in the last step is: ethyl 2- (3-cyano-4- (3-methoxypropoxy) phenyl) -4-methylthiazole-5-carboxylate (0.2662 g,0.74mmol,1 eq.) and lithium hydroxide monohydrate (0.0682 g,1.63mmol,2.2 eq.) were placed in a 50mL round bottom flask, deionized water 5mL and absolute ethanol 5mL were added, stirred well and heated in an oil bath to 90 ℃ for reaction for 1h. After the reaction was completed, 20mL of deionized water was added to the reaction mixture The reaction was terminated, the aqueous phase was extracted 3 times (15 mL each) with ethyl acetate, the aqueous phase was retained, the aqueous phase was adjusted to be acidic (ph=3 to 4) with a 1N aqueous hydrochloric acid solution, at this time, a white solid was precipitated, the aqueous phase was extracted again 3 times (15 mL each) with ethyl acetate, the organic phase was retained, the organic phase was washed 1 time with saturated saline, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase for drying, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:10) to give the title compound (d 4) as a white solid (0.0600 g, yield: 24%). ¹ H NMR(400MHz,DMSO-d ₆ )δ13.41(s,1H),8.27(d,J＝2.4Hz,1H),8.21(dd,J＝8.9,2.3Hz,1H),7.37(d,J＝9.0Hz,1H),4.26(t,J＝6.3Hz,2H),3.50(t,J＝6.2Hz,2H),3.26(s,3H),2.65(s,3H),2.05-1.97(m,2H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ166.17,162.86,161.88,159.54,133.09,131.59,125.44,122.94,115.43,113.85,101.56,68.06,66.53,58.02,28.55,17.05.

Example 4: synthesis of Compound 2- (3-cyano-4- (2-methoxyethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (d 5)

Ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methyl-1, 3-thiazole-5-carboxylate (0.2883 g,1mmol,1 eq.) and potassium carbonate (0.4146 g,3mmol,3 eq.) were placed in a 50ml round bottom flask, 15mLN, N-dimethylformamide was added thereto and stirred for dissolution, after which 2-bromoethyl methyl ether (0.19 mL,2mmol,2 eq.) was slowly added dropwise to the mixture solution and the oil bath was heated for reaction at 85℃for 2h. After the reaction was completed, 20mL of deionized water was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was spin-dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give a white solid: 2- (3-cyano-4- (2-methoxyethoxy) phenyl) -4-methylthiazole-5-carboxylic acid ethyl ester (0.3230 g, yield: 93%). ¹ H NMR(400MHz,CDCl ₃ )δ8.17(d,J＝2.2Hz,1H),8.09(dd,J＝8.9,2.4Hz,1H),7.07(d,J＝8.9Hz,1H),4.35(q,J＝7.1Hz,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＝7.1Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ167.08,162.29,162.13,161.15,132.68,132.22,126.50,122.16,115.51,113.05,103.27,70.64,69.38,61.52,59.71,17.56,14.44.

The product obtained in the last step is: ethyl 2- (3-cyano-4- (2-methoxyethoxy) phenyl) -4-methylthiazole-5-carboxylate (0.3464 g,1mmol,1 eq.) and lithium hydroxide monohydrate (0.0923 g,2.2mmol,2.2 eq.) are placed in a 50mL round bottom flask, 10mL of deionized water, 10mL of absolute ethanol are added, thoroughly stirred and mixed, and the oil bath is heated to 90 ℃ for reaction for 1h. After the completion of the reaction, 20mL of deionized water was added to the reaction mixture to terminate the reaction, the aqueous phase was extracted 3 times (15 mL each time) with ethyl acetate, the aqueous phase was retained, the pH of the aqueous phase was adjusted to be acidic (ph=3 to 4) with a 1N aqueous hydrochloric acid solution, at this time, a white solid was precipitated, the aqueous phase was extracted 3 times again (15 mL each time) with ethyl acetate, the organic phase was retained, the organic phase was washed 1 time with saturated saline, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:10), to give the title compound (d 5) as a white solid (0.0700 g, yield: 22%). ¹ H NMR(400MHz,DMSO-d ₆ )δ13.40(s,1H),8.27(d,J＝2.3Hz,1H),8.21(dd,J＝8.9,2.4Hz,1H),7.38(d,J＝9.0Hz,1H),4.42-4.30(m,2H),3.77-3.69(m,2H),3.34(s,3H),2.65(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ166.09,162.87,161.88,159.47,133.02,131.65,125.53,123.07,115.51,113.96,101.56,69.96,68.97,58.44,17.04.

Example 5: synthesis of Compound (5-methyl-2-oxo-1, 3-dioxolan-4-yl) 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylic acid methyl ester (d 9)

5mLDMAC was placed in a 50ml round bottom flask, preheated to 30℃Followed by the addition of febuxostat (0.3164 g,1mmol,1 eq.) and 4- (hydroxymethyl) -5-methyl- [1,3]Dioxacyclopenten-2-one (0.12 mL,1.3mmol,1.3 eq.) was stirred and mixed, and then potassium carbonate (0.2073 g,1.5mmol,1.5 eq.), tsCl (0.2478 g,1.3mmol,1.3 eq.) and DMAP (0.0183 g,0.15mmol,0.15 eq.) were added thereto and stirred to react for 3 hours at 30 ℃. After the completion of the reaction, the reaction was terminated by adding 20mL of deionized water to the reaction mixture, and the aqueous phase was adjusted to be acidic (ph=5) with a 1N aqueous hydrochloric acid solution, at which time a white solid was precipitated, and the title compound (d 9) was obtained as a pale yellow solid (0.2183 g, yield: 51%). ¹ H NMR(400MHz,CDCl ₃ )δ8.18(d,J＝2.3Hz,1H),8.07(dd,J＝8.9,2.3Hz,1H),7.01(d,J＝8.9Hz,1H),5.05(s,2H),3.90(d,J＝6.5Hz,2H),2.75(s,3H),2.24(s,3H),2.24-2.14(m,1H),1.08(d,J＝6.7Hz,6H). ¹³ C NMR(101MHz,CDCl ₃ )δ168.25,162.81,162.65,161.40,152.14,140.58,133.33,132.79,132.30,125.79,120.34,115.42,112.80,103.18,75.86,54.40,28.26,19.16,17.74,9.63.

Example 6: synthesis of Compound 2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxamide (d 12)

2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.4654 g,1.5mmol,1 eq.) CDI (0.2432 g,1.5mmol,1 eq.) was placed in a 50mL round bottom flask, 10mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which 25% ammonia (2 mL) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:5) to give the title compound (d 12) as a white solid (0.07 g, yield: 15%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.42(d,J＝2.3Hz,1H),8.30(dd,J＝8.9,2.3Hz,1H),7.72(s,2H),7.59(d,J＝8.8Hz,1H),7.54(t,J＝72.2Hz,1H),2.62(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ162.69,162.47,155.09,153.30,132.77,131.70,129.80,128.13,118.90,118.45,115.85,114.33,113.24,104.62,17.01.

Example 7: synthesis of Compound 2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxamide (d 13)

2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.4654 g,1.5mmol,1 eq.) CDI (0.2432 g,1.5mmol,1 eq.) was placed in a 50mL round bottom flask, 10mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which hydrazine monohydrate (0.5 mL) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction mixture to terminate the reaction, the aqueous phase was extracted 3 times (15 mL each time) with ethyl acetate, the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, ethyl acetate) to give the title compound (d 13) as a white solid (0.07 g, yield: 14%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.64(s,1H),8.43(d,J＝2.3Hz,1H),8.30(dd,J＝8.8,2.4Hz,1H),7.59(d,J＝8.8Hz,1H),7.54(t,J＝72.2Hz,1H),4.59(s,2H),2.60(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ163.20,161.24,155.16,153.76,133.24,132.19,130.22,119.37,118.92,116.31,114.81,113.71,105.09,17.38.

Example 8: synthesis of Compound 2- (3-cyano-4- (difluoromethoxy) phenyl) -N, N, 4-trimethylthiazole-5-carboxamide (d 14)

2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.4654 g,1.5mmol,1 eq.) was added to the solution) CDI (0.2432 g,1.5mmol,1 eq.) was placed in a 50mL round bottom flask, 10mL of extra dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which a 2M/L in solution of dimethylamine in THF (0.9 mL,1.65mmol,1.1 eq.) was slowly added dropwise to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give the title compound (d 14) as a white solid (0.07 g, yield: 14%). ¹ H NMR(400MHz,CDCl ₃ )δ8.21(d,J＝2.0Hz,1H),8.07(dd,J＝8.7,2.2Hz,1H),7.37(d,J＝8.5Hz,1H),6.71(t,J＝71.4Hz,1H),3.09(s,6H),2.46(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ163.47,163.30,153.20,152.78,132.11,131.74,130.91,126.22,120.12,117.65,114.99,114.27,112.34,106.75,16.54.

Example 9: synthesis of Compound 2- (3-cyano-4- (difluoromethoxy) phenyl) -N-methoxy-N, 4-dimethylthiazole-5-carboxamide (d 15)

2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.3103 g,1mmol,1 eq.) CDI (0.1622 g,1mmol,1 eq.) was placed in a 50mL round bottom flask, 5mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which methoxymethylamine (0.0672 g,1.1mmol,1.1 eq.) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give the title compound (d 15) as a white solid (0.069 g, yield: 20％)。 ¹ H NMR(400MHz,CDCl ₃ )δ8.30(d,J＝1.9Hz,1H),8.21(dd,J＝8.8,2.1Hz,1H),7.41(d,J＝8.6Hz,1H),6.71(t,J＝71.3Hz,1H),3.75(s,3H),3.37(s,3H),2.80(s,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ165.61,162.63,162.54,152.98,132.28,132.07,131.12,120.33,119.85,117.68,115.02,114.38,112.35,106.95,61.98,33.02,18.68.

Example 10: synthesis of Compound 2- (3-cyano-4- (difluoromethoxy) phenyl) -N, 4-dimethylthiazole-5-carboxamide (d 16)

2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.3103 g,1mmol,1 eq.) CDI (0.1622 g,1mmol,1 eq.) was placed in a 50mL round bottom flask, 5mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which a 2M/L in solution of THF in methylamine (0.6 mL,1.1mmol,1.1 eq.) was slowly added dropwise to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give the title compound (d 16) as a white solid (0.015 g, yield: 5%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.43(d,J＝2.3Hz,1H),8.30(dd,J＝8.9,2.3Hz,1H),8.25(d,J＝5.0Hz,1H),7.59(d,J＝8.9Hz,1H),7.54(t,J＝72.2Hz,1H),2.77(d,J＝4.5Hz,3H),2.61(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ161.16,154.59,132.78,131.70,129.77,127.87,118.92,115.85,114.34,104.63,26.46,16.95.

Example 11: synthesis of Compound 2- (3-cyano-4- (difluoromethoxy) phenyl) -N- (2-hydroxyethyl) -4-methylthiazole-5-carboxamide (d 17)

2- (3-cyano-4- (difluoromethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.4654 g,1.5mmol,1 eq.) CDI (0.2432 g,1.5mmol,1 eq.) was placed in a 50mL round bottom flask, 10mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which ethanolamine (0.18 mL,3mmol,2 eq.) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:10) to give the title compound (d 17) as a white solid (0.069 g, yield: 20%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.43(d,J＝2.3Hz,1H),8.31(dd,J＝8.8,2.3Hz,1H),8.25(t,J＝5.6Hz,1H),7.59(d,J＝8.8Hz,1H),7.54(t,J＝72.2Hz,1H),4.75(t,J＝5.5Hz,1H),3.51(q,J＝6.0Hz,2H),3.34-3.28(m,4H),2.61(s,3H). ¹³ C NMR(101MHz,DMSO-d ₆ )δ162.52,160.81,154.65,153.28,132.76,131.68,129.79,128.01,118.93,118.44,115.84,114.33,113.24,104.64,59.50,42.26,16.98.

Example 12: synthesis of Compound 2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carboxamide (d 18)

2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.1572 g,0.5mmol,1 eq.) CDI (0.0811 g,0.5mmol,1 eq.) was placed in a 50mL round bottom flask, 3mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which 25% ammonia (1 mL) was added to the mixture solution and reacted at room temperature for 4h. After completion of the reaction, the reaction was terminated by adding 20mL of saturated saline, the aqueous phase was extracted 3 times (15 mL each time) with ethyl acetate, the organic phase was retained, the organic phase was washed 1 time with saturated saline, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry The solvent was dried, dried under reduced pressure, and the residue was purified by column chromatography (silica, ethyl acetate) to give the title compound (d 18) as a white solid (0.035 g, yield: 22%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.21(d,J＝2.3Hz,1H),8.14(dd,J＝8.9,2.4Hz,1H),7.64(s,2H),7.34(d,J＝9.0Hz,1H),4.08(d,J＝7.0Hz,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(101MHz,DMSO-d ₆ )δ163.72,162.65,161.73,155.02,132.78,131.28,126.86,125.51,115.67,114.07,101.50,73.81,17.05,9.75,3.15.

Example 13: synthesis of Compound 2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carbohydrazide (d 19)

2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.1572 g,0.5mmol,1 eq.) CDI (0.0811 g,0.5mmol,1 eq.) was placed in a 50mL round bottom flask, 3mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which hydrazine monohydrate (0.25 mL) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction mixture to terminate the reaction, the aqueous phase was extracted 3 times (15 mL each time) with ethyl acetate, the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, ethyl acetate) to give the title compound (d 19) as a yellow solid (0.015 g, yield: 9%). ¹ H NMR(400MHz,DMSO-d ₆ )δ9.57(s,1H),8.22(d,J＝2.3Hz,1H),8.15(dd,J＝8.9,2.4Hz,1H),7.35(d,J＝9.0Hz,1H),4.58(s,2H),4.08(d,J＝7.0Hz,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(101MHz,DMSO-d ₆ )δ163.73,161.70,160.97,154.57,132.76,131.29,125.45,124.94,115.65,114.06,101.50,73.79,16.94,9.73,3.13.

Example 14: synthesis of Compound 2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -N, N, 4-trimethylthiazole-5-carboxamide (d 20)

2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.1572 g,0.5mmol,1 eq.) CDI (0.0811 g,0.5mmol,1 eq.) was placed in a 50mL round bottom flask, 3mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which a 2M/L in solution of dimethylamine in THF (0.3 mL,0.55mmol,1.1 eq.) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=5:4) to give the title compound (d 20) as a white solid (0.1677 g, yield: 98%). ¹ H NMR(400MHz,CDCl ₃ )δ8.11(d,J＝2.0Hz,1H),8.01(dd,J＝8.9,2.3Hz,1H),6.98(d,J＝8.7Hz,1H),3.98(d,J＝6.8Hz,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(101MHz,CDCl ₃ )δ164.97,163.68,162.06,152.88,132.43,131.97,126.21,124.99,115.75,112.95,103.08,74.20,16.63,9.95,3.50.

Example 15: synthesis of Compound 2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -N-methoxy-N, 4-dimethylthiazole-5-carboxamide (d 21)

2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.1572 g,0.5mmol,1 eq.) CDI (0.0811 g,0.5mmol,1 eq.) was placed in a 50mL round bottom flask, 3mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which methoxymethylamine (0.0336 g,0.55mmol,1.1 eq.) was added to the mixture solution and reacted at room temperature for 4h. After the reaction, add to the reaction solution The reaction was terminated with 20mL of saturated brine, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase for drying, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give the title compound (d 21) as a silvery white solid (0.0769 g, yield: 43%). ¹ H NMR(400MHz,CDCl ₃ )δ8.17(d,J＝2.0Hz,1H),8.15(dd,J＝8.8,2.3Hz,1H),7.00(d,J＝8.7Hz,1H),4.00(d,J＝6.8Hz,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(101MHz,CDCl ₃ )δ166.97,162.69,162.19,132.49,132.15,126.08,118.59,115.68,112.87,103.01,74.16,61.83,32.89,18.52,9.87,3.43.

Example 16: synthesis of Compound 2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -N, 4-dimethylthiazole-5-carboxamide (d 22)

2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.1572 g,0.5mmol,1 eq.) CDI (0.0811 g,0.5mmol,1 eq.) was placed in a 50mL round bottom flask, 3mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which a 2M/L in solution of THF in methylamine (0.3 mL,0.55mmol,1.1 eq.) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, 20mL of saturated brine was added to the reaction solution to terminate the reaction, the aqueous phase was extracted 3 times with ethyl acetate (15 mL each time), the organic phase was retained, the organic phase was washed 1 time with saturated brine, and an appropriate amount of anhydrous sodium sulfate was added to the organic phase to dry it, the solvent was dried under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=1:2) to give the title compound (d 22) as a white solid (0.08 g, yield: 48%). ¹ H NMR(400MHz,CDCl ₃ )δ8.11(d,J＝2.1Hz,1H),8.04(dd,J＝8.7,2.2Hz,1H),6.99(d,J＝8.8Hz,1H),5.89(s,1H),4.00(d,J＝6.8Hz,2H),3.00(d,J＝4.3Hz,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(101MHz,CDCl ₃ )δ164.54,162.32,155.88,132.61,132.17,126.10,126.02,115.73,112.98,103.14,74.30,27.12,17.46,9.97,3.55.

Example 17: synthesis of Compound 2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methyl-N- (2, 2-trifluoroethyl) thiazole-5-carboxamide (d 23)

2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.1572 g,0.5mmol,1 eq.) CDI (0.0811 g,0.5mmol,1 eq.) was placed in a 50mL round bottom flask, 3mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which 2, 2-trifluoroethylamine hydrochloride (0.0745 g,0.55mmol,1.1 eq.) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, the reaction was terminated by adding 20mL of saturated brine, extracting the aqueous phase with methylene chloride 3 times (15 mL each time), leaving the organic phase, washing the organic phase 1 time with saturated brine, and adding an appropriate amount of anhydrous sodium sulfate to the organic phase for drying, spinning the solvent under reduced pressure, and purifying the residue by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give the title compound (d 23) as a white solid (0.03 g, yield: 15%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.93(t,J＝6.3Hz,1H),8.25(d,J＝2.3Hz,1H),8.18(dd,J＝8.9,2.3Hz,1H),7.36(d,J＝9.0Hz,1H),4.09(d,J＝6.9Hz,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(101MHz,DMSO-d ₆ )δ164.44,161.88,161.59,156.07,132.90,131.46,125.27,125.01,123.30,115.61,114.11,101.56,73.83,17.06,9.73,3.13.

Example 18: synthesis of Compound 2- (3-cyano-4- (cyclopropylmethoxy) phenyl) -N- (2-hydroxyethyl) -4-methylthiazole-5-carboxamide (d 24)

2- (3-cyano-4- (cyclopropylmethane) Oxy) phenyl) -4-methylthiazole-5-carboxylic acid (0.1572 g,0.5mmol,1 eq.) CDI (0.0811 g,0.5mmol,1 eq.) was placed in a 50mL round bottom flask, 3mL of ultra-dry DCM was added thereto, stirred at room temperature for 1.5h for activation, after which ethanolamine (0.06 mL,1mmol,2 eq.) was added to the mixture solution and reacted at room temperature for 4h. After the completion of the reaction, the reaction was terminated by adding 20mL of saturated brine, extracting the aqueous phase with methylene chloride 3 times (15 mL each time), leaving the organic phase, washing the organic phase 1 time with saturated brine, and adding an appropriate amount of anhydrous sodium sulfate to the organic phase for drying, spinning the solvent under reduced pressure, and purifying the residue by column chromatography (silica, petroleum ether/ethyl acetate=1:1) to give the title compound (d 24) as a white solid (0.067 g, yield: 37%). ¹ H NMR(400MHz,DMSO-d ₆ )δ8.22(d,J＝2.4Hz,1H),8.18(d,J＝5.6Hz,1H),8.15(dd,J＝8.9,2.3Hz,1H),7.35(d,J＝9.0Hz,1H),4.75(t,J＝5.6Hz,1H),4.08(d,J＝7.0Hz,2H),3.51(q,J＝6.0Hz,2H),3.30(q,J＝6.1Hz,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(101MHz,DMSO-d ₆ )δ163.54,161.72,160.98,154.55,132.76,131.26,126.75,125.49,115.66,114.09,101.52,73.80,59.54,42.24,17.02,9.74,3.14.

In addition, d2, d10, d11 can be obtained using a similar method according to the invention.

Experimental example: in vitro Activity inhibition assay of xanthine oxidase by Compounds of the invention

1. Preparation of buffer solution

1xPBS was prepared and diluted with 10xPBS plus deionized water (100mL 10xPBS+900mL deionized water=1 xPBS).

2. Preparation of substrate (xanthine)

1.5mg of xanthine is weighed, 19.9mL of 1xPBS is added, and the solution is promoted by ultrasonic treatment for 3-5min, thus obtaining a substrate solution with the concentration of 0.5 mmol/L.

3. Preparation of enzyme solution (xanthine oxidoreductase)

The original Sigma enzyme solution was 13.4mg/mL, diluted to 10. Mu.g/mL with 1 XPBS (e.g., whole plate, about 4mL diluted enzyme solution, 2.99. Mu.L of original enzyme solution, 1 XPBS = 4 mL-2.99. Mu.L, mixed well).

4. Preparation of test Compounds

Accurately weighing the compound to be tested, preparing 1 mu mol/mL solution by using DMSO, storing the solution at 20 ℃ and storing the solution in a dark place. Before use, PBS is used for dilution to the required concentration, and the DMSO content is controlled within 5 percent so as to ensure that the DMSO content has no influence on the enzyme activity.

5. Experimental method and procedure

Sequentially adding the prepared 1 XPBS solution, sample (the compound of the invention), positive control (febuxostat), blank control group (the blank control group is PBS solution) and enzyme solution into a 96-well plate, and incubating for 30min at 37 ℃ in a shaking table (an air bath constant temperature oscillator); sequentially adding a substrate into the well hatched microplate, and incubating for 20-25min; finally, absorbance was read 1 time every 1min at 292nm wavelength. Each set of experiments was run in parallel 3 times.

The initial rate of the test compound at each concentration was converted to a percent (%) inhibition based on the initial rate in the absence of inhibitor, and IC was calculated ₅₀ Values. (inhibition test protocol is as in Table 1, results are shown in Table 2.)

TABLE 1 test protocol for inhibition of xanthine oxidase Activity by Compounds in vitro

TABLE 2 IC inhibition of xanthine oxidase Activity by Compounds in vitro ₅₀ Value (nM)

Note that: the experimental data are the average of three tests, IC ₅₀ Lower values indicate that the compound is yellow in vitroThe stronger the purine oxidase inhibitory activity.

The technical scheme of the invention is not limited to the specific embodiment, and all technical modifications made according to the technical scheme of the invention fall within the protection scope of the invention.

Claims

1. A compound having the structure shown in formula I or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

wherein,

n is 1, 2 or 3;

2. A compound according to claim 1, wherein,

R ² is C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-4 Alkyl or C _3-6 Cycloalkyl;

preferably, the method comprises the steps of,

R ¹ methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl, cyclopropylmethyl;

R ² is methyl, ethyl, trifluoromethyl, isopropyl, cyclopropyl,Cyclopropylmethyl.

3. A compound having a structure represented by formula II or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

wherein,

m is 1, 2 or 3;

4. A compound according to claim 3, wherein,

R ³ is hydrogen, C _1-6 Alkyl, halogenated C _1-6 Alkyl, C _3-6 cycloalkyl-C _1-4 Alkyl or C _3-6 Cycloalkyl;

preferably, the method comprises the steps of,

5. A compound having a structure represented by formula III or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

R ³ Is halogenated C _1-6 Alkyl, halogenated C _3-6 cycloalkyl-C _1-4 Alkyl or halo C _3-6 Cycloalkyl;

preferably, the method comprises the steps of,

R ³ is trifluoromethyl, difluoromethyl or monofluoromethyl.

6. A compound having one of the structures shown below or an enantiomer, diastereomer, racemate, stereoisomer, geometric isomer, nitroxide, metabolite, or pharmaceutically acceptable salt, ester, solvate, hydrate, isotopically labeled compound or prodrug thereof;

7. a method for synthesizing a febuxostat 4-position ether derivative comprises the following steps:

(1) Dispersing ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methyl-1, 3-thiazole-5-carboxylate and a first base in a first organic solvent, then dropwise adding a halogenated compound A into 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 the protection of argon, then dropwise adding an alcohol compound B into the mixture solution, dropwise adding DEAD, and reacting at room temperature to obtain an intermediate product; preferably, the molar ratio of the first base to the halide a or the alcohol compound B is 1: (2-5): (1.5-3);

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

wherein R is ¹ 、R ² 、R ³ 、R ⁴ N and m have the definitions as indicated in any of claims 1 to 5;

the halogenated compound a has the following structure:

x is halogen;

the alcohol compound B has the following structure:

8. the synthesis method according to claim 7, wherein,

the first organic solvent or the second organic solvent is N, N-dimethylformamide, N-dimethylacetamide or tetrahydrofuran independently;

the third organic solvent is a combination of deionized water and absolute ethyl alcohol; preferably, the volume ratio of deionized water to absolute ethanol is 1:1, a step of;

the first base is potassium carbonate and cesium carbonate;

the heating condition of the step (1) is 80-120 ℃;

the heating reaction in the step (2) is 80-100 ℃.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable adjuvant.

10. Use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 9 for inhibiting xanthine oxidase or for the preparation of a medicament for hyperuricemia or gout.