WO2022121222A1

WO2022121222A1 - Pyridine thioglycolic acid compound and preparation method therefor, pharmaceutical derivative or formulation thereof, and application thereof

Info

Publication number: WO2022121222A1
Application number: PCT/CN2021/091260
Authority: WO
Inventors: 陈洁; 黄绿; 谢福佳
Original assignee: 江苏正大清江制药有限公司
Priority date: 2020-12-09
Filing date: 2021-04-30
Publication date: 2022-06-16
Also published as: CN114621136B; CN114621136A

Abstract

A pyridine thioglycolic acid compound and a preparation method therefor, a pharmaceutical derivative or formulation thereof, and an application thereof. The pyridine thioglycolic acid compound has a structure represented by formula I, wherein Ar is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted phenyl, and substituted or unsubstituted pyridine, wherein the substituents are selected from one or more of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl; R1 and R2 are each independently selected from a hydrogen atom and C1-C6 alkyls or cycloalkyls, or R1 and R2 form a ring of C3-C6. The compound has good URAT1 inhibitory activity, and can be used for the treatment of gout and hyperuricemia.

Description

Pyridylthioacetic acid compound and its preparation method, pharmaceutical derivative or formulation and application

technical field

The invention relates to the field of medicine, in particular to a pyridinethioglycolic acid compound and a preparation method thereof, a pharmaceutical derivative or formulation and application thereof.

Background technique

Gout is a disease in which uric acid is deposited in tissues due to increased blood uric acid levels or decreased uric acid excretion due to purine metabolism disorders. Its clinical manifestations are recurrent acute and chronic arthritis and soft tissue damage caused by hyperuricemia and urate deposition, and gouty nephropathy caused by uric acid nephrolithiasis. It is a metabolic disease that seriously endangers human health. Disease, its onset is closely related to obesity, hyperlipidemia, diabetes, hypertension and cardiovascular and cerebrovascular diseases. In addition, the incidence of gout is also related to gender, age, geographical and genetic factors.

In western developed countries, the incidence of gout is on the rise. A survey data showed that between 1990 and 2015, the prevalence of gout in British adults rose from 1.0% to 3.9%, and the incidence of gout in American adult men rose from 1.8% to 4.5%. With the development of social economy and changes in people's lifestyles, the prevalence of gout is also increasing year by year in developing countries. For example, in 1980, gout cases were quite rare in China, but by 2015, the proportion of gout in the Chinese population was about 50%. was 1.14%. According to reports on the incidence of hyperuricemia in various places in recent years, it is conservatively estimated that there will be about 120 million hyperuricemia patients in my country by 2020, accounting for about 9.0% of the total population, and more than 12 million gout patients.

The pathogenesis of gout includes two stages: 1. The end product of purine metabolism in the body, uric acid, exists in the form of urate in the physiological environment. When its concentration in the blood exceeds the dissolution threshold (408 μmol/L or 6.8 mg) /dl), it can precipitate to form monosodium uric acid (monosodiumurate, MSU) crystals, which are deposited in joints and surrounding tissues; 2. The stimulation of joints and tissues by MSU crystals triggers an immune response leading to spontaneous inflammation. It can be said that gout is an inflammatory and immune disorder caused by metabolic diseases. The clinical symptoms of gout population mainly include: increased serum uric acid concentration (ie hyperuricemia); joint redness and swelling; repeated attacks of acute and chronic arthritis; long-term accumulation of MSU in the joints and around the joints to form tophi (tophi), which may result in severe cases. Patients with joint deformity or even disability; renal function damage, involving glomerular, renal tubulopathy and interstitial dorsiitis, and even renal failure; uric acid nephrolithiasis; and concomitant hyperlipidemia, hypertension, diabetes, arterial sclerosis and coronary heart disease.

Medications for gout include:

1. Reduce the production of uric acid in the body. Use xanthine oxidase inhibitor (XOIS). Xanthine oxidase inhibitor prevents the oxidation of xanthine and hypoxanthine to generate urate and hydrogen peroxide by inhibiting xanthine oxidase. Ancient anti-gout drugs, which are still used as first-line uric acid lowering drugs in gout treatment guidelines in many countries, mainly include allopurinol, febuxostat and topicastat. The use of XOIs will increase the serum urinary xanthine concentration, leading to xanthineuria, on the one hand, and increase the content of the toxic XO metabolites mercaptopurine and deoxyinosine in serum on the other hand.

2. Drugs that promote uric acid excretion: increase the amount of uric acid excreted in urine, belong to the second-line blood uric acid treatment drugs, and can selectively inhibit the organic anion transporters (OATs) expressed in proximal tubular cells, Such as URAT1 and GLUT9, thereby increasing the excretion of urate by the kidneys. This kind of drugs is the mainstream research and development direction of gout treatment drugs. The main ones on the market are probenecid, benzbromarone, sulfinazodone and the newly launched lesinurad.

3. Utilize recombinant uricase to convert uric acid into allantoin which is easy to dissolve and excrete.

Lesinurad (RDEA594), a newly marketed oral drug for the treatment of gout that increases uric acid excretion, inhibits the renal proximal tubule uric acid transporter URAT1. Lesinurad (Lesinurad) is an orally active URAT1 inhibitor. The results of Phase I and Phase II clinical studies have shown that the combination of Recinade and a xanthine oxidase inhibitor can effectively regulate the level of uric acid with high safety. Its molecular structure is as follows:

However, the compound has serious liver toxicity, so finding a new anti-gout drug that can replace it will be of great significance for clinical treatment.

SUMMARY OF THE INVENTION

The object of the present invention is to overcome the above-mentioned problems existing in the prior art, and to provide a new pyridinethioglycolic acid compound with the structure shown in formula I, the method for preparing the compound of the structure shown in formula I, and the structure shown in formula I Pharmaceutical derivatives or formulations of the compounds and their uses. The compounds of the present invention have good URAT1 inhibitory activity and can be used for the treatment of gout and hyperuricemia.

In order to achieve the above object, a first aspect of the present invention provides a pyridinethioacetic acid compound having the structure shown in formula I,

in,

Ar is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted phenyl, and substituted or unsubstituted pyridine, wherein the substituent is selected from halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxy one or more of alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl;

R ₁ and R ₂ are each independently selected from a hydrogen atom, a C1-C6 alkyl group or a cycloalkyl group; or, R ₁ and R ₂ form a C3-C6 ring;

R ₃ is selected from substituted or unsubstituted C1-C6 straight-chain alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl C4-C12 heterocyclic aryl and substituted or unsubstituted -NR ₄ R ₅ groups, wherein the heteroatom is selected from one or more of oxygen, sulfur and nitrogen, and the substituent is selected from halogen, cyano, nitro one or more of oxo, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heterocyclic aryl;

R ₄ and R ₅ are each independently selected from hydrogen atoms, C1-C4 alkyl groups, and R ₄ and R ₅ are not both hydrogen atoms.

The inventors of the present invention have found that the compound of the structure shown in the above formula I can achieve comparable or even better effects than the existing gout drugs. In order to further improve the curative effect, one or more of the following preferred embodiments can also be selected.

Regarding the Ar group:

Preferably, Ar is selected from the group consisting of pyridine (in the present invention, unless otherwise specified, when a group is not defined as "substituted", it means that the group is unsubstituted), substituted phenyl and substituted naphthyl;

Preferably, Ar is selected from pyridine and substituted phenyl.

Preferably, in the Ar group, the substituents are selected from halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl one or more of.

Preferably, in the Ar group, the substituents are selected from halogen, cyano, oxo, C1-C3 alkyl chains, C2-C4 alkyl groups cyclic with the substituted group, C1-C3 heterocyclic groups One or more of an alkyl chain and a C2-C4 heteroalkyl group that forms a ring with the substituted group; wherein the heteroatom in the heteroalkyl chain and the ring-forming heteroalkyl group is selected from oxygen, sulfur and nitrogen One or more of them, most preferably an oxygen atom. In the present invention, the term "substituted group" does not refer to an atom or group that has been substituted and no longer exists (such as a hydrogen atom), but refers to a modified target functional group, such as when a hydrogen on a phenyl group When an atom is substituted with a chlorine atom, the present invention refers to a phenyl group rather than a hydrogen atom when referring to a "substituted group".

Preferably, in the Ar group, the substituents are selected from the group consisting of halogen, cyano, methyl, ethyl, C2-C4 alkyl cyclic with the substituted group, C2-C4 cyclic with the substituted group and the heteroatom is an oxygen atom.

Preferably, the Ar group is selected from pyridine, phenyl, halogen substituted phenyl, alkyl substituted phenyl (more preferably C1-C3 alkyl), cycloalkyl substituted phenyl (more preferably C3-C6 alkyl) cycloalkyl), phenyl substituted by heterocycloalkyl (more preferably, the heteroatom in heterocycloalkyl is oxygen, and the number of atoms is 3-5), phenyl substituted by alkyl, phenyl substituted by heteroalkyl Phenyl, naphthyl, halogen-substituted naphthyl, and cyano-substituted naphthyl.

Preferably, the Ar group is selected from pyridine, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, alkyl-substituted cyclic phenyl (more preferably C3-C6 alkyl, and the two substitution sites are adjacent to position), heteroalkyl substituted cyclic phenyl (more preferably heteroalkyl with 3-6 atoms, the heteroatom is one or two oxygen atoms, and the two substitution sites are adjacent) and cyano substituted naphthyl.

Regarding the R ₁ group and the R ₂ group:

Preferably, R ₁ and R ₂ are each independently selected from a hydrogen atom, a C1-C3 alkyl group or a cycloalkyl group; alternatively, R ₁ and R ₂ form a C2-C4 ring.

According to a specific embodiment, R ₁ and R ₂ are each independently selected from hydrogen atoms, methyl groups, ethyl groups.

According to a specific embodiment, R ₁ is methyl and R ₂ is methyl.

According to a specific embodiment, one of R ₁ and R ₂ is a methyl group and the other is a hydrogen atom.

Regarding the _R3 group:

Preferably, R ₃ is selected from C1-C3 straight chain alkyl, C1-C4 branched chain alkyl, C3-C6 cycloalkyl, C3-C4 substituted cycloalkyl, phenyl, substituted phenyl , -NR ₄ R ₅ group, thiophene, C5-C6 heterocyclic aryl; wherein R ₄ and R ₅ are each independently selected from hydrogen atoms, methyl, ethyl, and R ₄ and R ₅ are not simultaneously hydrogen atom.

Preferably, the substituents in the _R3 group are selected from halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl.

According to one embodiment, the substituent in the _R3 group is halogen.

Preferably, the heterocyclic aryl group in the R ₃ group and the heteroatom in the heterocycloalkyl group are each independently selected from one or more of oxygen, sulfur and nitrogen, most preferably S.

Preferably, R ₃ is selected from a hydrogen atom, a C1-C4 straight-chain alkyl group, a C3-C5 cycloalkyl group, a dimethylamino group, a diethylamino group, a halophenyl group and an aromatic heterocycle.

Preferably, _R3 is selected from a hydrogen atom, methyl, cyclopropyl, dimethylamino, halophenyl (eg 4-fluorophenyl) and aromatic heterocycle (eg containing one heteroatom S).

The various embodiments of the above-mentioned Ar, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ of the present invention may be combined with each other. The present invention is equivalent to various combination forms of various embodiments of Ar, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ that have been disclosed, and to save text, they will not be repeated.

Several specific embodiments of the present invention are listed below, which are not intended to limit the protection scope of the present invention.

According to a first specific embodiment, in the structure shown in formula I:

Ar is selected from pyridine, substituted pyridine, phenyl, substituted phenyl, naphthyl and substituted naphthyl; wherein the substituent is selected from halogen, cyano, oxo, C1-C3 alkyl chain, C2-C4 One or more of the alkyl group that forms a ring with the substituted group, the heteroalkyl chain of C1-C3 and the heteroalkyl group that forms a ring with the substituted group of C2-C4; wherein the heteroalkyl chain and The heteroatom in the ring-forming heteroalkyl group is selected from one or more of oxygen, sulfur and nitrogen;

R ₁ and R ₂ are each independently selected from a hydrogen atom, a C1-C3 alkyl group or a cycloalkyl group; or, R ₁ and R ₂ form a C2-C4 ring;

R ₃ is selected from C1-C3 straight-chain alkyl, C1-C4 branched alkyl, C3-C6 cycloalkyl, C3-C4 substituted cycloalkyl, phenyl, substituted phenyl, -NR ₄ R ₅ group, thiophene, C5-C6 heterocyclic aryl group; wherein R ₄ and R ₅ are each independently selected from hydrogen atoms, methyl groups, ethyl groups, and R ₄ and R ₅ are not simultaneously hydrogen atoms; wherein Substituents are selected from halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl; the heteroatom in the heterocycloalkyl is selected from oxygen, sulfur and nitrogen one or more.

According to the second specific embodiment, in the structure shown in formula I:

Ar is selected from pyridine, substituted phenyl and substituted naphthyl; wherein the substituent is selected from halogen, cyano, methyl, ethyl, C2-C4 alkyl group cyclic with the substituted group, C2-C4 Heteroalkyl which forms a ring with the substituted group and the heteroatom is an oxygen atom;

R ₁ and R ₂ are each independently selected from a hydrogen atom, a methyl group, an ethyl group;

R ₃ is selected from C1-C3 straight-chain alkyl, C1-C4 branched alkyl, C3-C6 cycloalkyl, C3-C4 substituted cycloalkyl, phenyl, substituted phenyl, -NR ₄ R ₅ group, a C5-C6 heterocyclic aryl group; wherein R ₄ and R ₅ are each independently selected from hydrogen atoms, methyl groups, ethyl groups, and R ₄ and R ₅ are not simultaneously hydrogen atoms; wherein substituents is selected from halogen and methyl; the heteroatom in the heterocycloalkyl is S.

According to a third specific embodiment, in the structure shown in formula I:

Ar is selected from pyridine, phenyl, halogen substituted phenyl, alkyl substituted phenyl (more preferably C1-C3 alkyl), cycloalkyl substituted phenyl (more preferably C3-C6 cycloalkyl), Heterocycloalkyl-substituted phenyl (more preferably, the heteroatom in heterocycloalkyl is oxygen, and the number of atoms is 3-5), alkyl-substituted phenyl, ring-substituted phenyl, naphthyl , halogen-substituted naphthyl and cyano-substituted naphthyl;

R ₁ is a methyl group, and R ₂ is a methyl group; or one of R ₁ and R ₂ is a methyl group and the other is a hydrogen atom;

R ₃ is selected from a hydrogen atom, a C1-C4 straight-chain alkyl group, a C3-C5 cycloalkyl group, a dimethylamino group, a diethylamino group, a halogenated phenyl group and an aromatic heterocycle.

According to the fourth specific embodiment, in the structure shown in formula I:

Ar is selected from pyridine, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, alkyl-substituted cyclic phenyl (more preferably C3-C6 alkyl, the two substitution sites are peri-position), heteroalkane phenyl group substituted into a ring (more preferably a heteroalkyl group with 3-6 atoms, the heteroatom is one or two oxygen atoms, and the two substitution sites are adjacent) and cyano-substituted naphthyl;

R ₁ is a methyl group, and R ₂ is a methyl group; or one of R ₁ and R ₂ is a methyl group, and the other is a hydrogen atom;

_R3 is selected from hydrogen atom, methyl group, cyclopropyl group, dimethylamino group, halophenyl group and aromatic heterocycle containing one S atom.

In the present invention, the term "Cn (n is a specific positive integer)" means "composed of n carbons". The term "Cx-Cy (x<y, where x, y are specific positive integers)" represents an optional range of "consisting of x carbons" to "consisting of y carbons". "C1-C6" is specifically listed as C1, C2, C3, C4, C5, C6. "C3-C6" is specifically listed as C3, C4, C5, C6. "C3-C7" is specifically listed as C3, C4, C5, C6, C7. "C4-C12" is specifically listed as C4, C5, C6, C7, C8, C9, C10, C11, C12. "C1-C4" is specifically listed as C1, C2, C3, C4. "C1-C3" is specifically listed as C1, C2, and C3. "C2-C4" is specifically listed as C2, C3, C4. "C3-C5" is specifically listed as C3, C4, and C5.

Some specific compounds are listed below, which are not intended to limit the protection scope of the present invention. These compounds are coded in the form of five letters, and are coded as M ₁ M ₂ M ₃ M ₄ M ₅ , wherein the first M ₁ is fixed as I, representing the compound of formula I; the second M ₂ corresponds to an Ar group, The 3rd position M ₃ corresponds to the R ₁ group, the 4th position M ₄ corresponds to the R ₂ group, and the 5th position M ₅ corresponds to the R ₃ group. The codes corresponding to specific functional groups in each group are shown in Table 1. For example, a substance coded as Iaaaa indicates that in the structure of formula I, Ar is a benzene ring, R ₁ is H, R ₂ is H, and R ₃ is H. Please note that each code is not limited to represent only one compound, but may also represent a group of compounds, for example Ibaaa represents the structure of formula I where Ar is a benzene ring substituted by X (fluorine or chlorine or bromine or iodine or methyl) at any position , R ₁ is H, R ₂ is H, R ₃ is H; but it is understandable that when 1 code represents a group of compounds, this group of compounds has similar structures and properties.

In Table 1, the small black dots "·" marked on the functional group only represent the site connected to the structure of formula I (and no longer produce any meanings of this symbol in the chemical structural formula), when a functional group is marked on the When there are multiple black dots, it means that these marked sites can be used as the site to connect to the structure of formula I; X in the functional group represents fluorine, chlorine, bromine, iodine or methyl; when the substituent points to the ring When inside, it means that neither the substitution site nor the number of substitutions is limited; R ₄ represents H, methyl or ethyl, R ₅ represents H, methyl or ethyl, and R ₄ and R ₅ are not H at the same time.

Table 1

Through Table 1, the present invention has specifically disclosed at least 1200 compounds coded as IM ₂ M ₃ M ₄ M ₅ , wherein M ₂ is taken from any one of a to t, and M ₃ is taken from any one of a to e , M ₄ is taken from any one of a to e, M ₅ is taken from any one of a to l, and the specific structures of the obtained compounds are shown in Table 1. The compounds represented by these codes may be a compound or a group of compounds, but their structures are exact based on the records in Table 1. Due to space limitations, the specific codes are not listed one by one, but are regarded as shown in Table 1. All coded compounds obtained have been listed one by one in the present invention. The compounds of these specific structures can solve the technical problems of the present invention and achieve better effects.

Further, some compounds of the specific structure of formula I are listed in the following table 2, this table 2 mainly exemplifies some optional groups of Ar and R ₃ , and R ₁ and R ₂ take methyl groups only as examples and not limited to a preferred way. . This Table 2 is not used to limit the protection scope of the present invention.

Table 2

By way of example only, the structures of specific compounds in Table 2 above are shown below.

The second aspect of the present invention provides a method for preparing the compound represented by the formula I of the first aspect of the present invention, the method comprising: subjecting the compound represented by the formula II to a sulfonamidation reaction,

The compound of formula II is the structure of formula II-1, formula II-2 or formula II-3, wherein,

In formula II-1, Y ₁ is halogen, and Y ₂ is methyl or ethyl;

In formula II-2, Y ₁ is an Ar group in formula I, and Y ₂ is methyl or ethyl;

In formula II-3, Y ₁ is an Ar group in formula I, and Y ₂ is H;

R ₁ and R ₂ are R ₁ and R ₂ in formula I.

The structure of formula II-1 can be expressed as:

The structure of formula II-2 can be represented as:

The structure of formula II-3 can be represented as:

According to a specific embodiment of the present invention, the compound represented by the formula I is obtained from the compound represented by the formula II-3 through a sulfonamidation reaction.

According to a specific embodiment of the present invention, the compound represented by the formula I is obtained from the compound represented by the formula II-2 through a hydrolysis reaction (to obtain the compound represented by the formula II-3) and a sulfonamidation reaction in sequence.

According to a specific embodiment of the present invention, the compound of formula I is sequentially subjected to Suzuki coupling reaction (to obtain the compound of formula II-2), hydrolysis reaction (to obtain the compound of formula II-3) from the compound of formula II-1 ) and sulfonamidation.

The sulfonamidation reaction can be carried out in a conventional manner in the art. Preferably, the process of the sulfonamidation reaction comprises: in a solvent (such as dichloromethane), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 4- In the presence of dimethylaminopyridine (DMAP), the compound shown in II-3 is contacted with the sulfonamide compound.

Preferably, in the sulfonamidation reaction, the compound shown in II-3 is first mixed with a solvent, then EDC, DMAP and the sulfonamide compound are added at a temperature of -2°C to 5°C, and the temperature is raised to room temperature ( 20℃～30℃).

The hydrolysis reaction can be carried out in a conventional manner in the art. Preferably, the process of the hydrolysis reaction includes: contacting the solution of the compound represented by formula II-2 with an alkaline aqueous solution and heating to reflux.

Preferably, in the hydrolysis reaction, the solvent of the solution of the compound represented by formula II-2 is an organic solvent, such as methanol.

Preferably, in the hydrolysis reaction, the alkaline aqueous solution is a 25-35 wt% NaOH solution.

Preferably, in the hydrolysis reaction, after the reaction is complete (as judged by TLC monitoring), it is cooled (preferably simultaneously diluted, eg by adding cold water) and the pH is adjusted to weakly acidic or neutral (eg pH=6-7).

Preferably, in the hydrolysis reaction, the pH-adjusted material is subjected to extraction, washing, drying, concentration, separation, etc. to obtain the compound of the structure represented by formula II-3.

The Suzuki coupling reaction can be carried out in a conventional manner in the art. Preferably, the process of the Suzuki coupling reaction comprises: in potassium fluoride, dioxane, water and a catalyst [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd In the presence of (dppf)Cl ₂ ), the compound of formula II-1 is subjected to reflux reaction with arylboronic acid.

Preferably, in the Suzuki coupling reaction, the reflux reaction is carried out under the protection of an inert gas (eg, nitrogen).

Preferably, in the Suzuki coupling reaction, the reflux reaction time is 12-24 hours.

Preferably, in the Suzuki coupling reaction, the material at the end of the reaction (judged by TLC monitoring) is subjected to extraction, washing, drying, concentration, separation, etc. to obtain the compound of formula II-2.

The compound represented by the formula II-1 can be obtained by preparation, preferably, the preparation method of the compound represented by the formula II-1 comprises: (1) 3-bromo-4-chloropyridine and sodium sulfide in N,N-dimethyl sulfide; The contact reaction is carried out in the presence of DMF to obtain the intermediate compound int1; (2) the intermediate compound int1 is contacted with 2-halogen-fatty acid ethyl ester in the presence of DMF and carbonate.

Preferably, in step (1), the contact reaction is carried out under the protection of an inert gas (eg nitrogen).

Preferably, in step (1), the temperature of the contact reaction is 90-105° C., and the time is 1.5-2.5 hours.

Preferably, in step (1), a mixed solution of ethyl acetate and petroleum ether in a weight ratio of 1:(4-8) is used as a developing agent.

Preferably, the material obtained from the contact reaction in step (1) is subjected to cooling, extraction, pH adjustment (to 5-6), and solid-liquid separation to obtain the intermediate compound int1.

Preferably, in step (2), a mixed solution of ethyl acetate and petroleum ether in a weight ratio of 1:(0.8-1.2) is used as a developing agent.

Preferably, the material obtained from the contact reaction in step (2) is cooled, extracted, washed, dried, concentrated and separated to obtain the intermediate compound int1.

According to a specific embodiment of the present invention, the compound represented by formula I is prepared by the reaction scheme shown below.

The third aspect of the present invention provides the pharmaceutical derivatives or formulations of the compound of formula I of the first aspect of the present invention, and/or the pharmaceutical derivatives or formulations of the compounds prepared by the method described in the second aspect of the present invention , the pharmaceutical derivatives or formulations include pharmaceutically acceptable salts, compositions, solvates, hydrates and pharmaceutically acceptable prodrugs.

The pharmaceutical derivatives or formulations of the third aspect of the present invention can be obtained by adding one or more pharmaceutically acceptable carriers, adjuvants and excipients conventional in the art and by conventional preparation methods in the art.

Such pharmaceutically acceptable salts include, but are not limited to, Na, K, Li, Mg, Ca, Zn salts, for example.

Examples of such pharmaceutically acceptable prodrugs include, but are not limited to, esters, carbonates, enacbitate, thiocarbonates, N-acyl derivatives, N-acyloxy derivatives, amino acid conjugates, and the like.

The pharmaceutical derivatives or formulations may contain carriers, such as, but not limited to, mannitol, sorbitol, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine , vitamin C, disodium EDTA, calcium sodium EDTA, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, sodium chloride, potassium chloride, sodium lactate , xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and its derivatives, alginate, gelatin, polyvinylpyrrolidone, glycerol, Tween 80, agar, calcium carbonate, calcium bicarbonate, surfactant, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipid materials, kaolin, talc, calcium stearate, magnesium stearate Wait. For example in solid oral administration formulations.

The pharmaceutical derivatives or formulations may contain excipients such as, but not limited to, binders, fillers, diluents, tableting agents, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents, Tablets may be coated if necessary. For example in solid oral administration formulations.

The pharmaceutical derivatives or formulations may contain fillers such as, but not limited to, cellulose, mannitol, lactose. For example in solid oral administration formulations.

Disintegrants such as, but not limited to, starch, polyvinylpyrrolidone, and starch derivatives such as sodium starch glycolate may be included in the drug derivative or formulation. For example in solid oral administration formulations.

The pharmaceutical derivatives or formulations may contain lubricants such as, but not limited to, magnesium stearate. For example in solid oral administration formulations.

The pharmaceutical derivatives or formulations may contain wetting agents, such as, but not limited to, sodium lauryl sulfate. For example in solid oral administration formulations.

The pharmaceutical derivatives or formulations may contain suspending agents such as, but not limited to, sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, Hydrogenated edible fats. For example, in liquid preparations for oral administration (which may be, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs) or in a dry product for constitution with water or other suitable vehicle before use middle.

The pharmaceutical derivatives or formulations may contain emulsifiers such as, but not limited to, lecithin, sorbitan monooleate, acacia. For example, in liquid oral administration formulations or in dry products.

The pharmaceutical derivatives or formulations may contain non-aqueous carriers (which may include edible oils) such as, but not limited to, almond oil, fractionated coconut oil, oily esters such as glycerol esters, propylene glycol, ethanol. For example, in liquid oral administration formulations or in dry products.

The pharmaceutical derivatives or formulations may contain preservatives such as, but not limited to, methylparaben, propylparaben, sorbic acid. For example, in liquid oral administration formulations or in dry products.

The pharmaceutical derivatives or formulations may contain sterile carriers, such as in injections. Depending on the carrier and concentration, the compounds of the present invention can be suspended or dissolved. Solutions are generally prepared by dissolving the compound in a carrier, filter sterilizing before filling into a suitable vial or ampoule, and sealing. Adjuvants such as a local anesthetic, preservatives and buffering agents can also be dissolved in the carrier. To improve its stability, the composition can be frozen after filling into a vial and the water removed under vacuum.

The present invention may be in any pharmaceutically acceptable dosage form, including: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal preparations , granules, granules, pills, powders, ointments, pills, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches. The preparation of the present invention is preferably an oral dosage form, such as capsules, tablets, oral liquids, granules, pills, powders, elixirs, ointments and the like.

The route of administration of the present invention may be oral, parenteral or topical, with oral and injectable forms of administration being preferred. Oral administration formulations suitable for pharmaceutical use may be tablets, capsules, granules or other formulations in liquid form suitable for pharmaceutical use such as solutions, emulsions, suspensions and the like. The preferred oral formulation is a tablet, and the tablet may be formulated in a coated, enteric, sustained or metered release form. Solid oral compositions can be prepared by conventional methods such as mixing, filling, tableting, and the like. Repeated mixing allows the active to be distributed throughout those compositions where large amounts of fillers are used.

The fourth aspect of the present invention provides the use of the compound represented by formula I and its pharmaceutical derivatives or formulations in the preparation of medicines for regulating uric acid levels and/or treating gout-related indications.

The relevant indications include, but are not limited to, hyperuricemia, gout, gouty arthritis, inflammatory arthritis, nephropathy, nephrolithiasis, joint inflammation, deposition of urate crystals in joints, urolithiasis, uric acid Deposition of salt crystals in renal parenchyma, gout flare, tophi gout, or a combination thereof.

The compound represented by formula I and its pharmaceutical derivatives or formulations of the present invention have good URAT1 inhibitory activity, can be used for the treatment of gout and hyperuricemia, and provide a new kind of new method for clinical treatment of diseases related to abnormal URAT1 activity. medicinal potential.

A fifth aspect of the present invention provides a method of modulating uric acid levels and/or treating gout-related indications, comprising administering to a subject a compound of formula I or a pharmaceutical derivative or formulation thereof.

The endpoints of ranges and any values disclosed herein are not limited to the precise ranges or values, which are to be understood to encompass values proximate to those ranges or values. For ranges of values, the endpoints of each range, the endpoints of each range and the individual point values, and the individual point values can be combined with each other to yield one or more new ranges of values that Ranges should be considered as specifically disclosed herein.

Detailed ways

The present invention will be described in detail below by means of examples. The described embodiments of the present invention are only a part of the embodiments of the present invention, but not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

The raw materials used in the following examples are all commercially available analytical grades unless otherwise specified.

The following takes the preparation process of compound 1-compound 26 as an example, and the reaction scheme is as an example with the following formula.

Example 1 Synthesis of Int2 (formula II-1) compound

Synthesis of compound int1: To a 1000 ml round bottom flask was added 3-bromo-4-chloropyridine (38.4 g, 0.2 mol), Na2S _· _9H2O (95.84 g, 0.4 mol) and 500 ml of N,N-bismuth Methylformamide (DMF), the reaction mixture was under nitrogen protection, slowly heated to 100 ° C under nitrogen protection, continued to stir, keeping the reaction temperature at 100 ° C for 2 h, the reaction progress was monitored by thin layer chromatography (TLC), Use ethyl acetate:petroleum ether (1:6) as a developing solvent, after TLC detects that the reaction reaches the end point, after the reaction mixture is cooled, pour it into 1000 ml of ice water, stir, and the system is extracted twice with 500 ml of dichloromethane, and the water is reserved. phase, and then the aqueous phase was adjusted to pH 5-6 with concentrated hydrochloric acid, continued to stir at room temperature for 1 h, filtered with suction, and the solid was collected. 24.5 g of product was obtained with a yield of 64%, which was directly used in the next reaction without purification.

Synthesis of compound int2: Add compound int1 (19 g, 0.1 mol) to a 1000 ml round-bottomed flask, stir with 150 ml of N,N-dimethylformamide (DMF) at room temperature, dissolve and add K ₂ CO ₃ (27.6 g, 0,2mol), ethyl 2-bromo-2-methylpropionate (23.4g, 0.12mol), the mixture was stirred at room temperature, and the reaction was monitored by TLC (ethyl acetate: petroleum ether=1:1 as a developing solvent) , after the reaction is complete, pour the mixture into 1000 ml of ice water, stir, extract 3 times with 200 ml of dichloromethane, combine the organic phases, wash the organic phase once with 5% NaCl aqueous solution, and dry the organic phase with anhydrous Na ₂ SO ₄ , filtered, the filtrate was taken, the solvent was concentrated to dryness, purified by column chromatography, eluted with ethyl acetate: petroleum ether=1:5 as the eluent, and the eluent was concentrated to obtain compound int2 as a colorless liquid, Weighed 28.5g.

LCMS: calcd for C ₁₁ H ₁₄ BrNO ₂ S([M+H]), found 304.

Preparation of Example 2 Compound 1:

Synthesis of compound A1: Compound int2 (5.0 g, 16.4 mmol), compound p-chlorobenzeneboronic acid (compound A, 3.75 g, 24 mmol), Pd(dppf)Cl ₂ (0.73 g, 1 mmol), fluorinated Potassium (3.72g, 64mmol), 90ml of dioxane, 10ml of water, the reaction mixture was protected with nitrogen, heated and refluxed for reaction under nitrogen protection, after 16h of reaction, TLC detected the reaction progress, after reaching the end of the reaction, stopped heating, stirred , after the reaction system was cooled, 50ml of water and 100ml of dichloromethane were added to it, the organic phase was separated, the aqueous phase was extracted with 100ml of dichloromethane, the organic phases were combined, and the organic phase was washed with 5% NaCl aqueous solution, and then used Dry over anhydrous sodium sulfate for 15 minutes, remove the desiccant by filtration, and concentrate the filtrate. The obtained material was passed through a silica gel column by rotary evaporation, and eluted with ethyl acetate: petroleum ether (1:5) to obtain 4.36 g of an oily liquid of compound A1. rate 81.14%.

Synthesis of compound A2: Compound A1 (4.0 g, 12 mmol) was added to a round-bottomed flask, 50 ml of methanol was added to dissolve, and then 30% NaOH (2 ml, 15 mmol) solution was added, and heated and refluxed for 1 h. After the reaction was monitored by TLC, the heating was stopped. After cooling, add 50 ml of cold water, adjust the pH of the system to 6-7 with concentrated hydrochloric acid, extract with 100 ml of ethyl acetate, wash the organic phase with 5% NaCl aqueous solution, then dry with anhydrous Na ₂ SO ₄ , filter to remove the desiccant, The filtrate was concentrated, and the concentrated material was separated by a Biotage column machine to obtain 2.33 g of pure product with a yield of 63%.

Synthesis of compound 1: Add compound A2 (0.75g, 2.44mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.7 g, 3.66 mmol), 4-dimethylaminopyridine DMAP (0.45 g, 3.66 mmol) and cyclopropanesulfonamide (0.45 g, 3.66 mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to obtain product 1 (0.25 g, 0.61 mmol) with a yield of 25%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.55(d,1H), 8.45(s,1H), 7.48(d,2H), 7.34(d,2H), 7.18(d,1H), 2.94(m, 1H), 1.64(s, 6H), 1.30(q, 2H), 1.11(q, 2H). LCMS: calcd for C ₁₈ H ₁₉ ClN ₂ O ₂ S ₂ ([M+H]), found 410.9.

Example 3, the preparation of compound 2

Compound 2 is obtained by replacing cyclopropanesulfonamide in the step of preparing compound 1 in Example 2 with N,N-dimethylsulfonamide in the same molar amount.

Synthesis of compound 2: Add compound A2 (0.75g, 2.44mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system Propyl)carbodiimide hydrochloride EDC (0.7 g, 3.66 mmol), 4-dimethylaminopyridine DMAP (0.45 g, 3.66 mmol) and N,N-dimethylsulfonamide (0.45 g, 3.66 mmol) , the reaction was slowly raised to room temperature, detected by TLC, until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to obtain the product (0.27 g, 0.65 mmol) with a yield of 27%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.55(d,1H), 8.45(s,1H), 7.48(d,2H), 7.34(d,2H), 7.18(d,1H), 2.95(s, 6H), 1.62(s, 6H). LCMS: calcd for C ₁₇ H ₂ 0ClN ₃ O ₃ S ₂ ([M+H]), found 414.0.

Preparation of Example 4 Compound 3

Compound 3 is obtained by replacing cyclopropanesulfonamide in the step of preparing compound 1 in Example 2 with ethylsulfonamide in the same molar amount.

Synthesis of compound 3: add compound A2 (0.75g, 2.44mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.7 g, 3.66 mmol), 4-dimethylaminopyridine DMAP (0.45 g, 3.66 mmol) and ethylsulfonamide (0.4 g, 3.66 mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was purified by column separation to obtain the product (0.23 g, 0.58 mmol) with a yield of 23%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.55(d,1H), 8.45(s,1H), 7.48(d,2H), 7.34(d,2H), 7.18(d,1H), 3.40(q, 2H), 1.95(s, 1H), 1.56(s, 6H), 1.25(t, 3H). LCMS: calcd for C ₁₇ H ₁₉ ClN ₂ O ₂ S ₂ ([M+H]), found 399.0.

Example 5 Preparation of Compound 4

Compound 4 is obtained by replacing cyclopropanesulfonamide in the step of preparing compound 1 in Example 2 with 4-fluorobenzenesulfonamide in the same molar amount.

Synthesis of compound 4: add compound A2 (0.75g, 2.44mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.7 g, 3.66 mmol), 4-dimethylaminopyridine DMAP (0.45 g, 3.66 mmol) and 4-fluorobenzenesulfonamide (0.64 g, 3.66 mmol), slowly The reaction was raised to room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were carried out to obtain the product (0.3 g, 0.65 mmol) with a yield of 30%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.50(s, 2H), 8.15(d, 1H), 8.01(m, 2H), 7.48(d, 2H), 7.34(d, 2H), 7.23(d, 1H), 6.77(d, 1H), 1.56(s, 6H). LCMS: calcd for C ₂₁ H ₁₈ ClFN ₂ O ₃ S ₂ ([M+H]), found 465.0.

Example 6 Preparation of Compound 5

Compound 5 is obtained by replacing cyclopropanesulfonamide in the step of preparing compound 1 in Example 2 with 2-thiophenesulfonamide in the same molar amount.

Synthesis of compound 5: add compound A2 (0.75g, 2.44mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system Propyl)carbodiimide hydrochloride EDC (0.7 g, 3.66 mmol), 4-dimethylaminopyridine DMAP (0.45 g, 3.66 mmol) and 2-thiophenesulfonamide (0.60 g, 3.66 mmol), slowly add The reaction was carried out at room temperature, detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was purified by column separation to obtain the product (0.29 g, 0.64 mmol) with a yield of 29%.

¹ H NMR (CDCl ₃ , 400MHz) δ: 8.39(s, 1H), 8.15(d, 1H), 7.85(d, 2H), 7.75(d, 2H), 7.48(d, 2H), 7.23(m, 1H), 6.62(d, 1H), 1.56(s, 6H). LCMS: calcd for C ₁₉ H ₁₇ ClN ₂ O ₃ S ₃ ([M+H]), found 452.7.

The preparation of embodiment 7 compound 6

Compound 6 is obtained by replacing cyclopropanesulfonamide in the step of preparing compound 1 in Example 2 with methylsulfonamide in the same molar amount.

Synthesis of compound 6: Compound A2 (1.8 g, 5.86 mmol) and 100 ml of dichloromethane were added to the reaction flask, the system was cooled to 0 degrees Celsius, and 1-ethyl-(3-dimethylaminopropyl) was added to the reaction solution base) carbodiimide hydrochloride EDC (1.13 g, 5.90 mmol), 4-dimethylaminopyridine DMAP (0.72 g, 5.90 mmol) and methylsulfonamide _MsNH2 (0.613 g, 6.42 mmol), slowly liter The reaction was carried out at room temperature and detected by TLC until the raw materials disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was separated and purified to obtain 0.58 g of the product with a yield of 25.8%.

¹ H NMR (CDCl ₃ , 400MHz) δ: 8.55(d, 1H), 8.45(s, 1H), 7.48(d, 2H), 7.34(d, 2H), 7.18(d, 1H), 3.21(s, 3H), 1.56 (s, 6H). LCMS: calcd for C ₁₆ H ₁₇ ClN ₂ O ₃ S ₂ ([M+H]), found 385.0.

Preparation of Example 8 Compound 7

Synthesis of compound B1: Compound int2 (5.0 g, 16.4 mmol), compound 4-trifluoromethylbenzeneboronic acid (compound B, 4.56 g, 24 mmol), Pd(dppf)Cl ₂ (0.73 g, 1 mmol) were added to a round-bottomed flask ), potassium fluoride (3.72g, 64mmol), dioxane 90ml, water 10ml, the reaction mixture was protected with nitrogen, and the temperature was raised to reflux under nitrogen protection. Stop heating, stir, and after the reaction system is cooled, add 50 ml of water and 100 ml of dichloromethane to it, separate the organic phase, extract the aqueous phase with 100 ml of dichloromethane, combine the organic phases, and use 5% NaCl aqueous solution for the organic phase. Washed, dried with anhydrous sodium sulfate for 15 minutes, filtered to remove the drying agent, the filtrate was concentrated, the obtained material was passed through a silica gel column by rotary evaporation, and eluted with ethyl acetate:petroleum ether (1:5) to obtain a pale yellow compound B1. 4.82 g of oily matter, yield 79.4%.

Synthesis of compound B2: Add compound B1 (4.0 g, 11 mmol) to a round-bottomed flask, add 50 ml of methanol to dissolve, then add 30% NaOH (2.93 g, containing 0.88 g of sodium hydroxide, 22 mmol) solution, heat under reflux and stir for 1 h, TLC After monitoring the reaction, stop heating, add 50 ml of cold water after cooling, adjust the pH of the system to 6-7 with concentrated hydrochloric acid, extract with 100 ml of ethyl acetate, wash the organic phase with 5% NaCl aqueous solution, and then use anhydrous Na ₂ SO ₄ After drying, the desiccant was removed by filtration, the filtrate was concentrated, and the concentrated material was separated by a Biotage column machine to obtain 2.95 g of pure product with a yield of 79.73%.

Synthesis of compound 7: Add compound B2 (1.0 g, 2.93 mmol) to a round-bottomed flask, then add 50 ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.8g, 4.2mmol), 4-dimethylaminopyridine DMAP (0.5g, 4.2mmol) and cyclopropanesulfonamide (0.5g, 4.2mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were carried out to obtain the product (0.36 g, 0.81 mmol) with a yield of 28%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.55(d,1H), 8.45(s,1H), 7.75(d,2H), 7.51(d,2H), 7.25(d,1H), 2.94(m, 1H), 1.63(s, 6H), 1.30(q, 2H), 1.11(q, 2H). LCMS: calcd for C ₁₉ H ₁₉ F ₃ N ₂ O ₃ S ₂ ([M+H]), found 433.1 .

Preparation of Example 9 Compound 8

Compound 8 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 7 in Example 8 with N,N-dimethylsulfonamide in the same molar amount.

Synthesis of compound 8: Add compound B2 (1 g, 2.93 mmol) to a round-bottomed flask, then add 50 ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylaminopropane to the reaction system) base) carbodiimide hydrochloride EDC (0.8 g, 4.2 mmol), 4-dimethylaminopyridine DMAP (0.5 g, 4.2 mmol) and N,N-dimethylsulfonamide (0.5 g, 4.2 mmol), The reaction was slowly raised to room temperature, detected by TLC, until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to obtain product 8 (0.42 g, 0.94 mmol) with a yield of 32%.

¹ H NMR (CDCl ₃ , 400MHz) δ: 8.55(d, 1H), 8.45(s, 1H), 7.75(d, 2H), 7.51(d, 2H), 7.25(d, 1H), 2.95(s, 6H), 1.55(s, 6H). LCMS: calcd for C ₁₈ H ₂₀ F ₃ N ₃ O ₃ S ₂ ([M+H]), found 448.0.

Example 10 Preparation of Compound 9

Compound 9 was obtained by replacing cyclopropanesulfonamide with ethylsulfonamide in the step of preparing compound 7 in Example 8.

Synthesis of compound 9: add compound B2 (1 g, 2.93 mmol) to a round-bottomed flask, then add 50 ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylaminopropane to the reaction system) base) carbodiimide hydrochloride EDC (0.8 g, 4.2 mmol), 4-dimethylaminopyridine DMAP (0.5 g, 4.2 mmol) and ethylsulfonamide (0.46 g, 4.2 mmol), slowly warmed to room temperature The reaction was detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were carried out to obtain the product (0.32 g, 0.74 mmol) with a yield of 25%.

¹ H NMR (CDCl ₃ , 400MHz) δ: 8.55(d, 1H), 8.45(s, 1H), 7.75(d, 2H), 7.51(d, 2H), 7.25(d, 1H), 3.48(q, 2H), 1.62(s, 6H), 1.34(t, 3H). LCMS: calcd for C ₁₈ H ₁₉ F ₃ N ₂ O ₃ S ₂ ([M+H]), found 433.1.

Example 11 Preparation of Compound 10

Compound 10 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 7 in Example 8 with 4-fluorobenzenesulfonamide in the same molar amount.

Synthesis of compound 10: Add compound B2 (1 g, 2.93 mmol) to a round-bottomed flask, then add 50 ml of dichloromethane, cool to 0 degrees Celsius, and add 1-ethyl-(3-dimethylaminopropane to the reaction system) base) carbodiimide hydrochloride EDC (0.8 g, 4.2 mmol), 4-dimethylaminopyridine DMAP (0.5 g, 4.2 mmol) and 4-fluorobenzenesulfonamide (0.7 g, 4.2 mmol), slowly rise The reaction was carried out at room temperature, detected by TLC, until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to obtain the product (0.4 g, 0.8 mmol) with a yield of 27%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.37(s, 1H), 8.15(d, 1H), 8.01(m, 2H), 7.75(d, 2H), 7.49(d, 2H), 7.23(m, 2H), 6.67(d, 1H), 1.52(s, 6H). LCMS: calcd for C ₂₂ H ₁₈ F ₄ N ₂ O ₃ S ₂ ([M+H]), found 498.9.

Example 12 Preparation of Compound 11

Compound 11 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 7 in Example 8 with 2-thiophenesulfonamide in the same molar amount.

Synthesis of compound 11: Add compound B2 (1 g, 2.93 mmol) to a round-bottomed flask, then add 50 ml of dichloromethane, cool to 0 degrees Celsius, and add 1-ethyl-(3-dimethylaminopropane to the reaction system) base) carbodiimide hydrochloride EDC (0.8 g, 4.2 mmol), 4-dimethylaminopyridine DMAP (0.5 g, 4.2 mmol) and 2-thiophenesulfonamide (0.68 g, 4.2 mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was purified by column separation to obtain the product (0.38 g, 0.78 mmol) with a yield of 27%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.39(s, 1H), 8.15(d, 1H), 7.85(d, 1H), 7.75(m, 3H), 7.48(d, 2H), 7.23(m, 1H), 6.62(d, 1H), 1.56(s, 6H). LCMS: calcd for C ₂₀ H ₁₇ F ₃ N ₂ O ₃ S ₃ ([M+H]), found 486.8.

Example 13 Preparation of Compound 12

The cyclopropanesulfonamide in the step of preparing compound 7 in Example 8 was replaced with the same molar amount of methylsulfonamide, and compound 6 was obtained.

Synthesis of Compound 12: Compound B2 (1.8 g, 5.30 mmol) and 100 ml of dichloromethane were added to the reaction flask, the system was cooled to 0 degrees Celsius, and 1-ethyl-(3-dimethylaminopropyl) was added to the reaction solution base) carbodiimide hydrochloride EDC (1.01 g, 5.30 mmol), 4-dimethylaminopyridine DMAP (0.64 g, 5.30 mmol) and methylsulfonamide _MsNH2 (0.55 g, 5.8 mmol), slowly liter The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were carried out to obtain 0.9 g of crude product, 0.6 g of the product, and a yield of 27%.

¹ H NMR (CDCl ₃ , 400MHz) δ: 8.55(d, 1H), 8.45(s, 1H), 7.75(d, 2H), 7.47(d, 2H), 7.25(d, 1H), 3.12(s, 3H), 1.53(s, 6H). LCMS: calcd for C ₁₇ H ₁₇ F ₃ N ₂ O ₃ S ₂ ([M+H]), found 419.1.

Example 14 Preparation of Compound 13

Synthesis of compound C1: Compound int2 (5.0 g, 16.4 mmol), compound 3,4-(methylenedioxy)benzeneboronic acid (compound C, 3.98 g, 24 mmol), Pd(dppf)Cl ₂ were added to a round-bottomed flask (0.73g, 1mmol), potassium fluoride (3.72g, 64mmol), 90ml of dioxane, 10ml of water, the reaction mixture was protected with nitrogen, heated and refluxed under nitrogen protection, after 16h of reaction, TLC detected the reaction progress, After reaching the reaction end point, stop heating, stir, and after the reaction system is cooled, add 50 ml of water and 100 ml of dichloromethane to it, separate the organic phase, extract the aqueous phase with 100 ml of dichloromethane, combine the organic phases, and use the Washed with 5% NaCl aqueous solution, then dried with anhydrous sodium sulfate for 15 minutes, filtered to remove the desiccant, the filtrate was concentrated, the material obtained by rotary evaporation was passed through a silica gel column, and eluted with ethyl acetate: petroleum ether (1:5) to obtain The light yellow oily substance of compound C1 was 5.42 g, and the yield was 95.42%.

Synthesis of compound C2: Compound C1 (5.0 g, 14.5 mmol) was added to the round-bottomed flask, 50 ml of methanol was added to dissolve, and then 30% NaOH (3.87 g, containing 1.16 g of sodium hydroxide, 29 mmol) solution was added, and the mixture was heated under reflux and stirred for 1 h. After the reaction was monitored by TLC, the heating was stopped, 50 ml of cold water was added after cooling, the pH value of the system was adjusted to 6-7 with concentrated hydrochloric acid, extracted with 100 ml of ethyl acetate, the organic phase was washed with 5% NaCl aqueous solution, and then washed with anhydrous Na ₂ SO _4. Dry, remove the desiccant by filtration, concentrate the filtrate, and separate the concentrated material with a Biotage column machine to obtain 3.84 g of pure product with a yield of 83.66%.

Synthesis of compound 13: Add compound C2 (0.75g, 2.36mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.68g, 3.55mmol), 4-dimethylaminopyridine DMAP (0.43g, 3.55mmol) and cyclopropanesulfonamide (0.43g, 3.55mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was purified by column separation to obtain the product (0.28 g, 0.67 mmol) with a yield of 28%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(m, 2H), 7.15(d, 1H), 6.91(d, 1H), 6.85(m, 2H), 6.05(s, 2H), 2.93(m, 1H), 1.63(s, 6H), 1.30(q, 2H), 1.11(q, 2H). LCMS: calcd for C ₁₉ H ₂₀ N ₂ O ₅ S ₂ ([M+H]), found 421.2.

Example 15 Preparation of Compound 14

Compound 14 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 13 in Example 14 with N,N-dimethylsulfonamide in the same molar amount.

Synthesis of compound 14: Add compound C2 (0.75g, 2.36mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system Propyl)carbodiimide hydrochloride EDC (0.68 g, 3.55 mmol), 4-dimethylaminopyridine DMAP (0.43 g, 3.55 mmol) and N,N-dimethylsulfonamide (0.43 g, 3.55 mmol) , the reaction was slowly raised to room temperature, detected by TLC, until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to obtain the product (0.3 g, 0.71 mmol) with a yield of 30%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.50(m, 2H), 7.35(d, 1H), 6.95(d, 1H), 6.85(m, 2H), 6.05(s, 2H), 2.95(s, 6H), 1.55(s, 6H).LCMS: calcd for C ₁₈ H ₂₁ N ₃ O ₅ S ₂ ([M+H]), found 424.2.

Example 16 Preparation of Compound 15

Compound 15 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 13 in Example 14 with ethylsulfonamide in the same molar amount.

Synthesis of compound 14: Add compound C2 (0.75g, 2.36mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.68 g, 3.55 mmol), 4-dimethylaminopyridine DMAP (0.43 g, 3.55 mmol) and ethylsulfonamide (0.39 g, 3.55 mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was purified by column separation to obtain the product (0.26 g, 0.64 mmol) with a yield of 26%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(m, 2H), 7.30(d, 1H), 6.95(d, 1H), 6.85(m, 2H), 6.05(s, 2H), 3.47(q, 2H), 1.62(s, 6H), 1.32(t, 3H). LCMS: calcd for C ₁₈ H ₂₀ N ₂ O ₅ S ₂ ([M+H]), found 409.2.

Example 17 Preparation of Compound 16

Compound 16 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 13 in Example 14 with 4-fluorobenzenesulfonamide in the same molar amount.

Synthesis of compound 16: add compound C2 (0.75g, 2.36mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.68 g, 3.55 mmol), 4-dimethylaminopyridine DMAP (0.43 g, 3.55 mmol) and 4-fluorobenzenesulfonamide (0.62 g, 3.55 mmol), slowly The reaction was raised to room temperature, detected by TLC, until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and subjected to column separation and purification to obtain the product (0.36 g, 0.76 mmol) with a yield of 32%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(s, 1H), 8.15(d, 1H), 8.01(m, 1H), 7.76(m, 3H), 6.85(m, 2H), 6.82(m, 2H), 6.05(s, 2H), 1.52(s, 6H). LCMS: calcd for C ₂₂ H ₁₉ FN ₂ O ₅ S ₂ ([M+H]), found 475.0.

Example 18 Preparation of Compound 17

Compound 17 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 13 in Example 14 with thiophenesulfonamide in the same molar amount.

Synthesis of compound 17: Compound C2 (0.75 g, 2.36 mmol) was added to a round-bottomed flask, then 50 ml of dichloromethane was added, cooled to 0 degrees Celsius, and 1-ethyl-(3-dimethylamino) was added to the reaction system Propyl)carbodiimide hydrochloride EDC (0.68g, 3.55mmol), 4-dimethylaminopyridine DMAP (0.43g, 3.55mmol) and thiophenesulfonamide (0.62g, 3.55mmol), slowly warm to room temperature The reaction was detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were carried out to obtain the product (0.36 g, 0.76 mmol) with a yield of 32%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.40(s, 1H), 8.05(d, 1H), 7.85(d, 1H), 7.76(d, 1H), 7.16(m, 1H), 6.85(m, 2H), 6.82(m, 2H), 6.05(s, 2H), 1.56(s, 6H). LCMS: calcd for C ₂₀ H ₁₈ N ₂ O ₅ S ₃ ([M+H]), found 463.0.

Example 19 Preparation of Compound 18

Compound 18 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 13 in Example 14 with the same molar amount of methylsulfonamide.

Synthesis of compound 18: Compound C2 (1.12 g, 3.53 mmol) and 100 ml of dichloromethane were added to the reaction flask, the system was cooled to 0 degrees Celsius, and 1-ethyl-(3-dimethylaminopropyl) was added to the reaction solution base) carbodiimide hydrochloride EDC (0.68 g, 3.53 mmol), 4-dimethylaminopyridine DMAP (0.43 g, 3.53 mmol) and methylsulfonamide _MsNH2 (0.37 g, 3.90 mmol), slowly liter Reaction at room temperature, TLC detection, until the raw material disappears, stop the reaction, concentrate the reaction solution, carry out separation and purification to obtain 1.1 g of crude product, continue to carry out Biotage column separation to obtain 0.35 g of product with a yield of 25%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.43(m, 2H), 7.25(d, 1H), 6.85(d, 1H), 6.75(m, 2H), 6.05(s, 2H), 3.12(s, 3H), 1.53(s, 6H). LCMS: calcd for C ₁₇ H ₁₈ N ₂ O ₅ S ₂ ([M+H]), found 395.1.

Example 20 Preparation of Compound 19

Synthesis of compound D1: Compound int2 (5.0 g, 16.4 mmol), compound benzo-1,4-dioxane-6-boronic acid (compound D, 4.44 g, 24 mmol), and Pd (dppf) were added to a round-bottomed flask. Cl ₂ (0.73g, 1mmol), potassium fluoride (3.72g, 64mmol), 90ml of dioxane, 10ml of water, the reaction mixture was protected with nitrogen, heated and refluxed under nitrogen protection, after 16h of reaction, TLC detected the reaction Process, after reaching the end of the reaction, stop heating, stir, and after the reaction system is cooled, add 50 ml of water and 100 ml of dichloromethane to it, separate the organic phase, and extract the aqueous phase with 100 ml of dichloromethane, combine the organic phases, and combine the organic phases. The phase was washed with 5% NaCl aqueous solution, then dried over anhydrous sodium sulfate for 15 minutes, filtered to remove the desiccant, the filtrate was concentrated, the obtained material was passed through a silica gel column by rotary evaporation, and eluted with ethyl acetate: petroleum ether (1:5) , to obtain 5.57 g of compound D1 as a pale yellow oily liquid with a yield of 94.25%.

Synthesis of compound D2: Compound D1 (5.0 g, 13.9 mmol) was added to the round-bottomed flask, 50 ml of methanol was added to dissolve, and then 30% NaOH (3.70 g, containing 1.11 g of sodium hydroxide, 28.9 mmol) solution was added, and the solution was heated under reflux and stirred for 1 h. , after the reaction was monitored by TLC, the heating was stopped, 50 ml of cold water was added after cooling, the pH value of the system was adjusted to 6-7 with concentrated hydrochloric acid, extracted with 100 ml of ethyl acetate, the organic phase was washed with 5% NaCl aqueous solution, and then washed with anhydrous Na ₂ Dry with _SO4 , remove the desiccant by filtration, concentrate the filtrate, and separate the concentrated material with a Biotage column machine to obtain 3.35 g of pure product with a yield of 72.67%.

Synthesis of compound 19: add compound D2 (0.85g, 2.57mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.74g, 3.85mmol), 4-dimethylaminopyridine DMAP (0.47g, 3.85mmol) and cyclopropanesulfonamide (0.47g, 3.85mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was purified by column separation to obtain the product (0.27 g, 0.66 mmol) with a yield of 24%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(m, 2H), 7.15(d, 1H), 6.91(d, 1H), 6.85(d, 1H), 6.80(d, 1H), 4.33(s, 4H), 2.93(m, 1H), 1.63(s, 6H), 1.30(q, 2H), 1.11(q, 2H). LCMS: calcd for C ₂₀ H ₂₂ N ₂ O ₅ S ₂ ([M+H ]), found 435.1.

Example 21 Preparation of Compound 20

Compound 20 is obtained by replacing cyclopropanesulfonamide in the step of preparing compound 19 in Example 20 with N,N-dimethylsulfonamide in the same molar amount.

Synthesis of compound 20: Add compound D2 (0.85g, 2.57mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system Propyl)carbodiimide hydrochloride EDC (0.74 g, 3.85 mmol), 4-dimethylaminopyridine DMAP (0.47 g, 3.85 mmol) and N,N-dimethylsulfonamide (0.47 g, 3.85 mmol) , the reaction was slowly raised to room temperature, detected by TLC, until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were carried out to obtain the product (0.29 g, 0.66 mmol) with a yield of 26%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(m, 2H), 7.15(d, 1H), 6.91(d, 1H), 6.85(d, 1H), 6.80(d, 1H), 4.34(s, 4H), 2.93(s, 6H), 1.55(s, 6H). LCMS: calcd for C ₁₉ H ₂₃ N ₃ O ₅ S ₂ ([M+H]), found 438.1.

Example 22 Preparation of Compound 21

Compound 21 is obtained by replacing cyclopropanesulfonamide in the step of preparing compound 19 in Example 20 with ethylsulfonamide in the same molar amount.

Synthesis of compound 21: add compound D2 (0.85g, 2.57mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.74g, 3.85mmol), 4-dimethylaminopyridine DMAP (0.47g, 3.85mmol) and ethylsulfonamide (0.42g, 3.85mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was purified by column separation to obtain the product (0.25 g, 0.59 mmol) with a yield of 23%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(m, 2H), 7.15(d, 1H), 6.91(d, 1H), 6.85(d, 1H), 6.80(d, 1H), 4.34(s, 4H), 3.47(q, 2H), 1.66(s, 6H), 1.32(t, 3H). LCMS: calcd for C ₁₉ H ₂₂ N ₂ O ₅ S ₂ ([M+H]), found 423.1.

Example 23 Preparation of Compound 22

Compound 22 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 19 in Example 20 with 4-fluorobenzenesulfonamide in the same molar amount.

Synthesis of compound 22: Add compound D2 (0.85g, 2.57mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system propyl)carbodiimide hydrochloride EDC (0.74g, 3.85mmol), 4-dimethylaminopyridine DMAP (0.47g, 3.85mmol) and 4-fluorobenzenesulfonamide (0.67g, 3.85mmol), slowly The reaction was raised to room temperature, detected by TLC, until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and subjected to column separation and purification to obtain the product (0.36 g, 0.74 mmol) with a yield of 29%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.40(s, 1H), 8.01(m, 3H), 7.74(m, 1H), 6.85(d, 2H), 6.82(m, 2H), 6.51(d, 1H), 4.33(s, 4H), 1.54(s, 6H). LCMS: calcd for C ₂₃ H ₂₁ FN ₂ O ₅ S ₂ ([M+H]), found 489.1.

Example 24 Preparation of Compound 23

Compound 23 was obtained by replacing cyclopropanesulfonamide in the step of preparing compound 19 in Example 20 with 2-thiophenesulfonamide in the same molar amount.

Synthesis of compound 23: Add compound D2 (0.85g, 2.57mmol) to a round-bottomed flask, then add 50ml of dichloromethane, cool to 0 degrees Celsius, add 1-ethyl-(3-dimethylamino) to the reaction system Propyl)carbodiimide hydrochloride EDC (0.74 g, 3.85 mmol), 4-dimethylaminopyridine DMAP (0.47 g, 3.85 mmol) and 2-thiophenesulfonamide (0.63 g, 3.85 mmol), slowly rise The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to obtain the product (0.33 g, 0.69 mmol) with a yield of 27%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.40(s, 1H), 8.05(d, 1H), 7.85(d, 1H), 7.76(d, 1H), 7.16(m, 1H), 6.91(d, 1H), 6.85(d, 1H), 6.77(d, 1H), 6.55(d, 1H), 4.28(s, 4H), 1.56(s, 6H). LCMS: calcd for C ₂₁ H ₂₀ N ₂ O ₅ S ₃ ([M+H]),found477.1.

Example 25 Preparation of Compound 24

The cyclopropanesulfonamide in the step of preparing compound 19 in Example 20 was replaced with the same molar amount of methylsulfonamide, and compound 24 was obtained.

Synthesis of compound 24: Compound D2 (1.6 g, 4.83 mmol) and 100 ml of dichloromethane were added to the reaction flask, the system was cooled to 0 degrees Celsius, and 1-ethyl-(3-dimethylaminopropyl) was added to the reaction solution base) carbodiimide hydrochloride EDC (0.93 g, 4.83 mmol), 4-dimethylaminopyridine DMAP (0.59 g, 4.83 mmol) and methylsulfonamide MsNH2 (0.5 g, 5.26 mmol), slowly rise to The reaction was carried out at room temperature and detected by TLC until the raw materials disappeared, the reaction was stopped, the reaction solution was concentrated, and separated and purified to obtain 1.16 g of crude product, which was further separated by Biotage column to obtain 0.46 g of product with a yield of 23%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(m, 2H), 7.15(d, 1H), 6.91(d, 1H), 6.85(d, 1H), 6.80(d, 1H), 4.34(s, 4H), 3.12(s, 3H), 1.53(s, 6H). LCMS: calcd for C ₁₈ H ₂₀ N ₂ O ₅ S ₂ ([M+H]), found 409.1.

Example 26 Preparation of Compound 25

Synthesis of Compound E1: Compound int2 (5.0 g, 16.4 mmol), Compound 4-cyanonaphthalen-1-yl)boronic acid (Compound E, 4.86 g, 24.6 mmol), Pd(dppf)Cl ₂ were added to a round-bottomed flask (0.73g, 1mmol), potassium fluoride (3.72g, 64.0mmol), 90ml of dioxane and 10ml of water, the reaction mixture was refluxed under nitrogen protection, after 16 hours of reaction, the stirring was stopped, and after cooling, water and dichloride were added Methane, the organic phase was washed with 5% NaCl aqueous solution, then dried with anhydrous sodium sulfate, filtered to remove the desiccant, the organic phase was taken, the product obtained by rotary evaporation was passed through a silica gel column, and ethyl acetate: petroleum ether (1:5) After elution, the eluate was concentrated to remove the solvent, and after drying, 4.4 g of a white solid of compound E1 was obtained with a yield of 71.08%.

Synthesis of compound E2: Compound E1 (4.0 g, 10.6 mmol) was added to a round-bottomed flask, 50 ml of methanol was added to dissolve, and then 30% NaOH (2.83 g, 0.85 g of sodium hydroxide, 21.2 mmol) solution was added, and refluxed and stirred for 1 h. After the reaction was detected by TLC, the heating was stopped, cooled to room temperature, 50 ml of cold water was added, the pH value was adjusted to 6-7 with concentrated hydrochloric acid, the system was extracted twice with 100 ml of ethyl acetate, the organic phases were combined, and the organic phase was washed with 5% NaCl aqueous solution Washed, dried over anhydrous Na ₂ SO ₄ for 15 minutes, filtered to remove the desiccant, concentrated the filtrate, and the concentrate was separated by a Biotage column machine. %.

Synthesis of compound 25: Compound E2 (2.5 g, 6.64 mmol) was added to a round-bottomed flask, followed by 50 ml of dichloromethane, cooled to 0 degrees Celsius, and 1-ethyl-(3-dimethylamino) was added to the reaction system propyl)carbodiimide hydrochloride EDC (1.13 g, 5.90 mmol), 4-dimethylaminopyridine DMAP (0.72 g, 5.90 mmol) and methylsulfonamide _MsNH2 (0.61 g, 6.42 mmol), slowly The reaction was raised to room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to obtain the product (0.57 g, 1.33 mmol) with a yield of 20.1%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.75(d,1H), 8.58(s,1H), 8.43(d,1H), 8.08(d,1H), 7.85(t,1H), 7.82(t, 1H), 7.53(m, 2H), 7.40(d, 1H), 3.36(s, 3H), 1.63(s, 6H). LCMS: calcd for C ₂₁ H ₁₉ N ₃ O ₃ S ₂ ([M+H ]), found 426.1.

Example 27 Preparation of Compound 26

Synthesis of compound F1: Compound int2 (5.0 g, 16.4 mmol), compound pyridine-3-boronic acid (compound F, 2.95 g, 24 mmol), Pd(dppf)Cl ₂ (0.73 g, 1 mmol), and fluorine were added to a round-bottomed flask. Potassium chloride (3.72g, 64mmol), 90ml of dioxane, 10ml of water, the reaction mixture was protected with nitrogen, heated and refluxed for reaction under nitrogen protection, after 16h of reaction, TLC detected the reaction progress, after reaching the end of the reaction, stopped heating, Stir, after the reaction system is cooled, add 50 ml of water and 100 ml of dichloromethane to it, separate the organic phase, extract the aqueous phase with 100 ml of dichloromethane, combine the organic phases, wash the organic phase with 5% NaCl aqueous solution, and then Dry with anhydrous sodium sulfate for 15 minutes, remove the desiccant by filtration, concentrate the filtrate, pass through a silica gel column by rotary evaporation, and elute with ethyl acetate:petroleum ether (1:5) to obtain compound F1 as a brown-yellow oily substance 2.82 g, yield 58%.

Synthesis of compound F2: Compound F1 (2.5 g, 8 mmol) was added to the round-bottomed flask, 50 ml of methanol was added to dissolve, then 30% NaOH (2 ml, 15 mmol) solution was added, and the heating was refluxed and stirred for 1 h. After the reaction was monitored by TLC, the heating was stopped. After cooling, add 50 ml of cold water, adjust the pH of the system to 6-7 with concentrated hydrochloric acid, extract with 100 ml of ethyl acetate, wash the organic phase with 5% NaCl aqueous solution, then dry with anhydrous Na ₂ SO ₄ , filter to remove the desiccant, The filtrate was concentrated, and the concentrated substance was separated by a Biotage column machine to obtain 1.86 g of pure product with a yield of 84.7%.

Synthesis of compound 26: Add compound F2 (1.4 g, 5.1 mmol) and 100 ml of dichloromethane to the reaction flask, cool the system to 0 degrees Celsius, add 1-ethyl-(3-dimethylaminopropane to the reaction solution) base) carbodiimide hydrochloride EDC (1.13 g, 5.90 mmol), 4-dimethylaminopyridine DMAP (0.72 g, 5.90 mmol) and methylsulfonamide _MsNH2 (0.61 g, 6.42 mmol), slowly liter The reaction was carried out at room temperature and detected by TLC until the raw material disappeared, the reaction was stopped, the reaction solution was concentrated, and the product was separated and purified to obtain 0.32 g of the product with a yield of 18%.

¹ H NMR (CDCl ₃ , 400MHz)δ: 8.45(m, 2H), 8.31(d, 1H), 8.15(s, 1H), 7.92(d, 1H), 7.46(m, 1H), 7.36(d, 1H), 2.86(s, 3H), 1.53(s, 6H). LCMS: calcd for C ₁₅ H ₁₇ N ₃ O ₃ S ₂ ([M+H]), found 351.7.

Comparative Example 1

The compound of formula III is commercially available, that is, the currently marketed gout drug Recinade.

Test case I

The compounds of the present invention 1 to 26 prepared above and the compounds of the formula III and IV of the comparative examples were respectively tested for their URAT1 inhibitory activities. The specific test method is as follows:

(1) Experimental materials:

HEK-293T cell line stably expressing hURAT: independently constructed and owned by Ruizhi Chemical Research Co., Ltd.

The following materials were purchased from Wisdom Chemical Research Co., Ltd.:

Fetal bovine serum (Invitrogen, Cat. No. 10099141)

DMEM medium (Invitrogen, Cat. No. 10564)

Trypsin (Invitrogen, Cat. No. 25200056)

G418 (invivogen, item number: ant-gn-5)

Phosphate buffer (Invitrogen, Cat. No. 14190250)

¹⁴ C-uric acid (ARC, product number: ARC0513-250UCI)

Dimethyl sulfoxide DMSO (Sigma, catalog number: D2650)

15 ml centrifuge tubes (Greiner, Cat. No. 07030115)

50 ml centrifuge tubes (BD Falcon, Cat. No. 352098)

Penicillin-streptomycin (Invitrogen, Cat. No. 15070-063)

Benzbromarone (Benzbromarone, Bailingwei Technology, Cat.No.3562-84-3)

D-Sodium Gluconate (Aladdin, Cat.No.527-07-1)

Potassium D-gluconate (Aladdin, Cat.No.299-27-4)

Calcium D-gluconate (Aladdin, Cat.No.299-28-5)

(2) Experimental method

1. Preparation of experimental reagents

Cl-free HBSS buffer including: 125mM sodium D-gluconate, 4.8mM potassium D-gluconate, 1.3mM calcium D-gluconate, 1.2mM _KH2PO4 , 1.2mM _MgSO4 , _5.6mM glucose, 25mM HEPES (pH 7.4);

Lysis buffer: 100mM NaOH.

2. Cell Culture and Inoculation

1) Culture the HEK-293T cell line stably expressing hURAT1, the medium composition is: DMEM medium + 10% fetal bovine serum + 500 μg/ml G418 + 1% P/S;

2) When the cells grow to 80% full, discard the medium, add PBS to wash the cells once, then add trypsin-EDTA for digestion, add medium when the cells are detached, blow off the cells, and collect the cells by centrifugation. Add the medium and pipet to form a cell suspension;

3) Adjust the cell density to 7×105/ml, then inoculate 100 microliters/well into a 96-well white-bottom transparent cell culture plate, and culture for 12-24 hours.

3. Compound Preparation

1) Compounds were made into 20mM stock solution with DMSO, then diluted with DMSO to 1mM concentration and added to 96 wells;

2) On the 96-well plate, another quality control compound is set separately, this is a 100x compound plate;

3) 50-fold dilution of the corresponding wells with Cl-free HBSS buffer on another 96-well plate, this is a 2× compound plate;

4) Then add 30 microliters/well of buffer containing 0.1 μCi/ml 14C-uric acid and 30 microliters/well of 2× diluted compound to a new 96-well plate, and configure this into 1× The compound plate is ready for use.

4. Uptake of ¹⁴ C-uric acid in cells stably expressing hURAT1

1) The absorption test can be carried out after the cells in the 96-well plate adhere to the wall;

2) Wash cells once with 200 μl/well of pre-warmed buffer;

3) Blot each well, then immediately add 50 μl/well containing the corresponding compound and 0.1 μCi/ml 14C-uric acid solution;

4) Incubate the compound-added plate in a 37°C incubator for 5 minutes;

5) Immediately add 150 microliters of ice-cold buffer to each well to stop absorption. Wash each well three times with buffer;

6) During the cleaning process, try to avoid cell shedding;

7) Add 50 microliters/well of lysate to all wells, place on a shaker and shake at 900 rpm for 5 minutes;

8) Add 150 microliters/well of scintillation fluid Microsint40 to all wells, and shake at 900 rpm for 5 minutes;

9) Finally, the microplate was sent to the MicroBeta2 (produced by PerkinElmer) instrument to measure the radioactivity;

10) Analyze the data and calculate the IC50 (nM) of each compound with GraphPad Prism 5 software.

(3) Experimental results

The test results of IC50 (nM) are shown in Table 3.

table 3

It can be seen from Table 3 that the compounds of the examples of the present invention have good URAT1 inhibitory activity and can be used for the treatment of gout and hyperuricemia. The new compound disclosed in the present invention shows good URAT1 inhibitory activity, and the effect is significantly better than that of the gout drug Lesinurad that has been used on the market, and it can be judged that the compound of the present invention has low liver toxicity through preliminary tests (data not shown). ), so the present invention provides a new and better medicinal possibility for clinical treatment of diseases related to abnormal URAT1 activity.

Test Case II

The rat model of hyperuricemia caused by uric acid combined with potassium oxonate was selected, and compound 1 was used as an example to test the uric acid excretion-promoting effect of the compounds of the present invention. as comparison. The test compounds were divided into high and low dose groups. After 0.5 hours of administration, uric acid (1 g/kg, ig) and potassium oxazinate (200 mg/kg, ip) were simultaneously administered to make models. After modeling, the urine was collected continuously for 5 hours in a metabolic cage, and the urine volume, the concentration of uric acid in the urine and the total excretion of uric acid within 5 hours were measured respectively.

1. Test materials

1. Test drug

Compound 1 of the present invention and Recinade (batch number: 2020-10-20001) are both white powders, provided by Jiangsu Zhengda Qingjiang Pharmaceutical Co., Ltd. Before use, they were ground with 0.5% CMC-Na to prepare a suspension of corresponding concentration for gavage.

2. Animals and rearing

2.1 Animal species and sources

SD rats, SPF grade, 80, male, weighing 180-220g, purchased from the Laboratory Animal Management Department of Shanghai Institute of Family Planning Science, production license number: SCXK (Shanghai) 2018-0006, animal quality certificate number 20180006021263 80 rats were used for the formal test, divided into 10 groups of 8 rats each.

SD rats, SPF grade, 10, male, weighing 180-220g, were purchased from Speifu (Beijing) Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2019-0010, animal quality certificate number 110324201103715563. 10 rats were used for supplementary experiments and divided into 5 groups of 2 rats each.

2.2 Feeding conditions

The rats were kept in the Animal Center of China Pharmaceutical University (animal use license number: SYXK (Su) 2016-0011), the laboratory temperature was 24 ± 2 °C; the relative humidity was 60% to 80%; the number of air exchanges per hour: 10 -15 times/hour; light cycle: 12 (day)/12 (night) hours, no more than 5 per cage.

Feed: full-price pellet feed for mice, purchased from Yizheng Anlimao Biotechnology Co., Ltd., and its quality complies with GB14924.1-2010 "General Quality Standards for Compound Feeds for Laboratory Animals".

Litter: corncob particle litter, purchased from Yizheng Anlimao Biotechnology Co., Ltd.

Drinking water: drinking purified water.

3. Main instruments and equipment

BS210S Precision Electronic Balance (0.1mg～10g), Sartorius, Germany; FEJ-200 Electronic Balance (0.1～200g), Fuzhou Furi Hengzhibao Electronics Co., Ltd.; Rat Metabolic Cage, Suzhou Feng's Laboratory Animal Equipment Co., Ltd.; Varioskan LUX multi-function microplate reader, Thermo, USA.

4. Main reagents

Uric acid detection kit (phosphotungstic acid reduction method), Nanjing Jiancheng Bioengineering Institute, batch number: 20200916; potassium oxycyanate (A601239), batch number: F420BA0543, Sangon Bioengineering (Shanghai) Co., Ltd.; uric acid (A600978) , batch number: G703BA0017, Sangon Bioengineering (Shanghai) Co., Ltd.

2. Methods

1. Dose setting and grouping

The daily dose of Recinade in clinical trials is 400mg, the human body weight is 60kg, the maximum daily dose is 6.7mg/kg, and the rat dose is 41.6mg/kg converted from body surface area. Therefore, in this experiment, the high and low doses of Lesinuard and the test drug were set at 40.0 mg/kg and 80.0 mg/kg, which were about 1 and 2 times the clinically converted dose.

The daily dose of Verinuard clinical trial is 5-15mg, the human body weight is calculated as 60kg, the maximum daily dose is 0.25mg/kg, and the dose converted into rats is 1.56mg/kg based on body surface area. Therefore, the test compounds in this experiment refer to the Verinuard dose, and the high and low doses are set at 2.0 mg/kg and 4.0 mg/kg, which are approximately 1 and 2 times the clinically converted dose.

80 rats were formally tested and randomly divided into 10 groups with 8 rats in each group; after the formal experiment, another 10 rats were taken and divided into 5 groups with 2 rats in each group, so that the total number of animals in this group reached 10 rats. The groups are listed in Table 4.

Table 4

序号serial number	组别group	动物数(只)Number of animals (only)
11	正常组(0.5％CMC-Na)Normal group (0.5%CMC-Na)	88
22	模型组(0.5％CMC-Na)Model group (0.5%CMC-Na)	8+28+2
33	雷西钠德40.0mg/kgResinad 40.0mg/kg	8+28+2
44	雷西钠德80.0mg/kgResinad 80.0mg/kg	8+28+2
77	化合物1 2.0mg/kgCompound 1 2.0mg/kg	88
88	化合物1 4.0mg/kgCompound 1 4.0mg/kg	8+28+2

The medicines in each group were made into suspensions of corresponding concentrations with 0.5% CMC-Na, and the administration volume was 10 ml/kg.

2. Model establishment and detection indicators

The rats in each group were purchased and acclimated to the feeding, fasted for 12 h, and had free access to water during the period. After fasting, each group was given the test drug by gavage at the above dose, and 0.5 h after administration, uric acid (1 g/kg, ig) and potassium oxonate (200 mg/kg, ip) were simultaneously administered to make a model.

After modeling, the rats were placed in metabolic cages, and the urine was collected continuously for 5 h, and water was freely drank during the collection period. After the urine was collected, the urine volume (ml) was determined by weighing method, the concentration of uric acid in the urine was determined by the kit, and the total excretion of uric acid within 5 hours was calculated at the same time [urine volume (ml) × uric acid concentration in urine (μmol/ ml)].

3. Data processing and statistical methods

The measurement data of each test are

(Mean)±s (standard deviation) means, after the comparison between groups, after the F test, the student-t test was used to examine the significance, and P<0.05 was used as the significant indicator.

3. Results

Effects of test substances on uric acid excretion in uric acid (1g/kg, ig) and potassium oxonate (200mg/kg, ip) model rats

The test results are shown in Table 5.

table 5

*P<0.05, **P<0.01, compared with the normal group.

It can be seen from Table 5 that Compound 1 of the present invention has the effect of promoting uric acid excretion, and has a certain dose-effect correlation. The compounds of the present invention were able to achieve comparable or even better effects than 20 times their dose of lesinard. The pharmacodynamic intensity of the compound 1 of the present invention at 2 mg/kg is better than that of 40 mg/kg of Recinade, and the pharmacodynamic intensity of the compound 1 of the present invention at 4 mg/kg is better than that of 80 mg/kg of Resinad potency strength.

Test Case III

1. Pharmacokinetic studies

Taking compound 1 as an example, the pharmacokinetic study of the compound of the present invention in rats was carried out, and lecinade was used as a control.

(1) The male SD rats were divided into two groups, one group was intravenously injected with 10 mg/kg resinard, and the other group was given 40 mg/kg resinard by gavage, and the blood drug concentrations (units) at each time point were measured respectively. ng/mL), the results are recorded in Table 6.

Table 6

ND: The analyte concentration is below the lower limit of quantitation.

Pharmacokinetic parameters were calculated according to Table 6, and the results are shown in Table 7.

Table 7

It can be seen from Table 7 that the half-lives of lesinard in male SD rats were 2.1±0.1h and 3.1±0.2h respectively by intravenous injection and gavage; _Cmax was 57800.0±3903.8ng/ mL and 49200.0±12343.8ng/mL; AUC _(0-24h) were 88320±9194.5h*ng/mL and 356052.8±13655.0h*ng/mL, respectively; absolute bioavailability was 100.8%.

(2) In addition, male SD rats were divided into two groups, one group was intravenously injected with 1 mg/kg of compound 1 of the present invention, and the other group was given 4 mg/kg of compound 1 of the present invention by gavage, and the blood drugs at each time point were measured respectively. Concentration (unit ng/mL), the results are recorded in Table 8.

Table 8

Pharmacokinetic parameters were calculated according to the results in Table 8, and the results are shown in Table 9.

Table 9

It can be seen from Table 9 that the half-lives of compound 1 in male SD rats were 18.7±10.6h and 25.8±19.8h, respectively; the _Cmax was 1536.0±195.2ng/mL and 1536.0±195.2ng/mL, respectively. 641.3±147.8ng/mL; AUC _(0-24h) were 1573.9±358.1h*ng/mL and 6599.2±2969.6h*ng/mL; absolute bioavailability was 104.8%.

2. Tissue distribution studies

After intragastric administration of 40 mg/kg Recinade and 4 mg/kg Compound 1 of the present invention, the distribution of Recinade and Compound 1 in rat kidney and plasma at 1 hour, 4 hours and 24 hours was investigated.

Table 10 shows the distribution of resinard in the kidneys of rats after intragastric administration of 40 mg/kg resinad.

Table 10

It can be seen from Table 10 that after intragastric administration, lesinard is rapidly and widely distributed in the kidney, and the drug concentration in the kidney is close at 1h and 4h after administration, and is basically cleared at 24h.

Table 11 shows the distribution of compound 1 in rat kidneys after intragastric administration of compound 1 at 4 mg/kg.

Table 11

It can be seen from Table 11 that compound 1 can be rapidly distributed in the kidney tissue, and the drug concentration in the kidney is similar at 1h and 4h of administration, but the concentration is lower, which is significantly lower than that of lesinad; and the elimination is rapid, 24h Basically clear.

3. Excretion study in rat urine

After intragastric administration of 40 mg/kg Recinade and 4 mg/kg of compound 1 to be tested, the collected urine samples were measured. The cumulative excretion amount and cumulative excretion fraction of lesinad in rat urine are shown in Table 12, and the cumulative excretion amount and cumulative excretion fraction of Compound 1 of the present invention in rat urine are shown in Table 13.

Table 12

Table 13

As can be seen from Table 12 and Table 13, the compound 1 of the present invention has low urinary excretion and cumulative excretion fraction in male SD rats, which are lower than those of Recinade.

From the above results, it can be seen that the compound of the present invention has good URAT1 inhibitory activity, and the effect is significantly better than that of the gout drug Lesinurad (Lesinurad) that has been used in the market. When the dose of the compound of the present invention is only 1/20 of the dose of Recinad, it can show better efficacy in promoting uric acid excretion than Recinad. The compounds of the present invention can be rapidly distributed in renal tissue and can be rapidly cleared within 24 hours. The compounds of the present invention are capable of very low urinary excretion and fractional cumulative excretion. Therefore, the compound of the present invention exhibits excellent performance, can be used for the treatment of gout and hyperuricemia, and provides a new and better possibility for clinical treatment of diseases related to abnormal URAT1 activity.

The preferred embodiments of the present invention have been described above in detail, however, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, a variety of simple modifications can be made to the technical solutions of the present invention, including combining various technical features in any other suitable manner. These simple modifications and combinations should also be regarded as the content disclosed in the present invention. All belong to the protection scope of the present invention.

Claims

A kind of pyridinethioacetic acid compounds with structure shown in formula I,

in,

Ar is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted phenyl, and substituted or unsubstituted pyridine, wherein the substituent is selected from halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxy one or more of alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl;

R 1 and R 2 are each independently selected from a hydrogen atom, a C1-C6 alkyl group or a cycloalkyl group; or, R 1 and R 2 form a C3-C6 ring;

R 3 is selected from substituted or unsubstituted C1-C6 straight-chain alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl, substituted or unsubstituted C3-C7 heterocycloalkyl C4-C12 heterocyclic aryl and substituted or unsubstituted -NR 4 R 5 groups, wherein the heteroatom is selected from one or more of oxygen, sulfur and nitrogen, and the substituent is selected from halogen, cyano, nitro one or more of oxo, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heterocyclic aryl;

R 4 and R 5 are each independently selected from hydrogen atoms, C1-C4 alkyl groups, and R 4 and R 5 are not both hydrogen atoms.
The compound according to claim 1, wherein, in the structure shown in formula I:

Ar is selected from pyridine, substituted pyridine, phenyl, substituted phenyl, naphthyl and substituted naphthyl; wherein the substituent is selected from halogen, cyano, oxo, C1-C3 alkyl chain, C2-C4 One or more of the alkyl group that forms a ring with the substituted group, the heteroalkyl chain of C1-C3 and the heteroalkyl group that forms a ring with the substituted group of C2-C4; wherein the heteroalkyl chain and The heteroatom in the ring-forming heteroalkyl group is selected from one or more of oxygen, sulfur and nitrogen; and/or,

R 1 and R 2 are each independently selected from a hydrogen atom, a C1-C3 alkyl group or a cycloalkyl group; alternatively, R 1 and R 2 form a C2-C4 ring; and/or,

R 3 is selected from C1-C3 straight-chain alkyl, C1-C4 branched alkyl, C3-C6 cycloalkyl, C3-C4 substituted cycloalkyl, phenyl, substituted phenyl, -NR 4 R 5 group, thiophene, C5-C6 heterocyclic aryl group; wherein R 4 and R 5 are each independently selected from hydrogen atoms, methyl groups, ethyl groups, and R 4 and R 5 are not simultaneously hydrogen atoms; wherein Substituents are selected from halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl; the heteroatom in the heterocycloalkyl is selected from oxygen, sulfur and nitrogen one or more.
The compound according to claim 1 or 2, wherein Ar is selected from pyridine, substituted phenyl and substituted naphthyl; wherein the substituent is selected from halogen, cyano, methyl, ethyl, C2-C4 and A substituted group forms an alkyl group, a C2-C4 heteroalkyl group forms a ring with a substituted group and the heteroatom is an oxygen atom; and/or,

R 1 and R 2 are each independently selected from a hydrogen atom, a methyl group, an ethyl group; and/or,

R 3 is selected from C1-C3 straight-chain alkyl, C1-C4 branched-chain alkyl, C3-C6 cycloalkyl, C3-C4 substituted cycloalkyl, phenyl, substituted phenyl, -NR 4 R 5 group, a C5-C6 heterocyclic aryl group; wherein R 4 and R 5 are each independently selected from hydrogen atoms, methyl groups, ethyl groups, and R 4 and R 5 are not simultaneously hydrogen atoms; wherein substituents is selected from halogen and methyl; the heteroatom in the heterocycloalkyl is S.
The compound of any one of claims 1-3, wherein Ar is selected from the group consisting of pyridine, phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, cycloalkyl-substituted phenyl, heterocycloalkyl Substituted phenyl, alkyl substituted cyclic phenyl, heteroalkyl substituted cyclic phenyl, naphthyl, halogen substituted naphthyl, and cyano substituted naphthyl; and/or,

R 1 is a methyl group, R 2 is a methyl group; or one of R 1 and R 2 is a methyl group and the other is a hydrogen atom; and/or,

R 3 is selected from a hydrogen atom, a C1-C4 straight-chain alkyl group, a C3-C5 cycloalkyl group, a dimethylamino group, a diethylamino group, a halogenated phenyl group and an aromatic heterocycle.
The compound according to any one of claims 1-4, wherein Ar is selected from the group consisting of pyridine, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, alkyl-substituted cyclic phenyl, heteroalkyl-substituted phenyl Ring-forming phenyl and cyano-substituted naphthyl; and/or,

R 1 is a methyl group, R 2 is a methyl group; or one of R 1 and R 2 is a methyl group and the other is a hydrogen atom; and/or,

R3 is selected from hydrogen atom, methyl group, cyclopropyl group, dimethylamino group, halophenyl group and aromatic heterocycle containing one S atom.
The compound according to any one of claims 1-5, wherein the compound of the structure represented by the formula I is a compound encoded as IM 2 M 3 M 4 M 5 , wherein M 2 is taken from a to t Any one, M 3 is taken from any one of a to e, M 4 is taken from any one of a to e, M 5 is taken from any one of a to l; the corresponding compound structure of the code is as follows:
The compound according to claim 6, wherein, the compound of the structure shown in the formula I is a compound in which Ar, R 1 , R 2 and R 3 are respectively selected from the following groups:
The compound according to any one of claims 1-7, wherein the compound of the structure shown in the formula I comprises the following specific compounds:
A method for preparing the compound described in any one of claims 1-8, the method comprising: carrying out the sulfonamidation reaction of the compound shown in formula II,

The compound of formula II is the structure of formula II-1, formula II-2 or formula II-3, wherein,

In formula II-1, Y 1 is halogen, and Y 2 is methyl or ethyl;

In formula II-2, Y 1 is an Ar group in formula I, and Y 2 is methyl or ethyl;

In formula II-3, Y 1 is an Ar group in formula I, and Y 2 is H;

R 1 and R 2 are R 1 and R 2 in formula I.
The method according to claim 9, wherein the compound represented by the formula I is obtained from the compound represented by the formula II-3 through a sulfonamidation reaction.
The method according to claim 9, wherein the compound represented by the formula I is obtained from the compound represented by the formula II-2 through a hydrolysis reaction and a sulfonamidation reaction in sequence.
The method according to claim 9, wherein the compound represented by the formula I is obtained from the compound represented by the formula II-1 through a Suzuki coupling reaction, a hydrolysis reaction and a sulfonamidation reaction in sequence.
The method of any one of claims 9-12, wherein the method comprises the following reactions:
A pharmaceutical derivative or a preparation of the compound prepared by the structural compound shown in the formula I described in any one of claims 1-8 and/or the method described in any one of claims 9-13, the Pharmaceutical derivatives or formulations include pharmaceutically acceptable salts, compositions, solvates, hydrates and pharmaceutically acceptable prodrugs.
The compound of the structure shown in the formula I described in any one of claims 1-8, the compound prepared by the method described in any one of claims 9-13 and the structure compound shown in the formula I described in claim 14. Use of a combination of one or more of pharmaceutical derivatives or formulations in the preparation of a medicament for regulating uric acid levels and/or treating gout-related indications.