CN114621136B

CN114621136B - Pyridinothioic acid compound, preparation method, pharmaceutical derivative or formulation and application thereof

Info

Publication number: CN114621136B
Application number: CN202011433011.0A
Authority: CN
Inventors: 陈洁; 黄绿; 谢福佳
Original assignee: Jiangsu Chia Tai Qingjiang Pharmaceutical Co Ltd
Current assignee: Jiangsu Chia Tai Qingjiang Pharmaceutical Co Ltd
Priority date: 2020-12-09
Filing date: 2020-12-09
Publication date: 2023-11-07
Anticipated expiration: 2040-12-09
Also published as: WO2022121222A1; CN114621136A

Abstract

The invention relates to the field of medicines, in particular to a pyridine thioglycollic acid compound, a preparation method, a pharmaceutical derivative or a formulation and application thereof. The pyridine thioglycollic acid compound has a structure shown in a formula I, wherein Ar is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted phenyl and substituted or unsubstituted pyridine, and the substituent is selected from one or more of halogen, cyano, nitro, oxo, alkyl, halogenated alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl; r is R ₁ And R is ₂ Each independently selected from a hydrogen atom, a C1-C6 alkyl or cycloalkyl group; alternatively, R ₁ And R is ₂ Forming a C3-C6 ring. The compound provided by the invention has good URAT1 inhibition activity, and can be used for treating gout and hyperuricemia.

Description

Pyridinothioic acid compound, preparation method, pharmaceutical derivative or formulation and application thereof

Technical Field

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

Background

Gout is a disease that results in increased blood uric acid levels or decreased uric acid excretion due to disturbed purine metabolism, which in turn leads to deposition of urates in tissues. The clinical manifestation of the drug is acute and chronic arthritis and soft tissue injury caused by repeated attacks of hyperuricemia and urate deposition, gouty nephropathy caused by urine acid kidney stones, is a metabolic disease seriously endangering human health, and the attacks of the drug are closely related to obesity, hyperlipidemia, diabetes, hypertension, cardiovascular and cerebrovascular diseases and the like. Furthermore, gout onset is also related to sex, age, region and genetic factors.

In developed western countries, the incidence of gout is on the rise. One survey data showed that, in 1990-2015, the prevalence of adult human in the uk increased from 1.0% to 3.9% and that of adult male gout in the united states increased from 1.8% to 4.5%. With the development of socioeconomic and the change of life style of people, the prevalence of gout has increased year by year in developing countries, for example, gout cases are quite rare in China in 1980, but by 2015, the prevalence rate of gout in Chinese population is about 1.14%. According to the report of the incidence rate of hyperuricemia in various places in recent years, the conservation estimation is that about 1.2 hundred million hyperuricemia patients account for 9.0% of the population by 2020, and the gout patients are more than 1200 ten thousand.

The pathogenesis of gout includes two stages: 1. uric acid, an end product of purine metabolism in the body, exists in the form of urate under physiological environment, and can be precipitated to form monosodium urate (MSU) crystals which are deposited on joints and surrounding tissues when the concentration of uric acid in blood exceeds a dissolution threshold (408 mu mol/L or 6.8 mg/dl); 2. stimulation of joints and tissues by MSU crystallization elicits immune responses leading to spontaneous inflammation. Gout is said to be an inflammatory and immunological disorder caused by metabolic diseases. The clinical symptoms of gout people are mainly as follows: elevated serum uric acid concentrations (i.e., hyperuricemia); red and swollen joints; recurrent episodes of acute and chronic arthritis; MSU gathers and deposits joints for a long time and forms tophus (tophi) around the joints, and when severe, joint deformity and even disability of patients are caused; kidney function destruction, involving glomeruli, tubular lesions, interstitial dormitis, etc., even renal failure; urinary acid kidney stones; also has complicated hyperlipidemia, hypertension, diabetes, arteriosclerosis, and coronary heart disease.

The drug treatment method of gout mainly comprises the following steps:

1. reducing uric acid production in vivo, using Xanthine Oxidase Inhibitors (XOIS), which prevent xanthine and hypoxanthine from oxidizing to form urates and hydrogen peroxide by inhibiting xanthine oxidase, are the oldest anti-gout drugs, which are still used as first-line uric acid lowering drugs in many countries' guidelines for gout treatment, mainly including allopurinol, febuxostat and topiroxostat. The use of XOIs leads on the one hand to an increase in serum urine xanthine concentration leading to xanthine urine and on the other hand to an increase in serum mercaptopurine and detritus, which are toxic XO metabolites.

2. Uric acid excretion promoting medicine: increasing uric acid levels excreted with urine, which is a two-wire hypouricemic therapeutic agent, can selectively inhibit organic anion transporters (Organic anion transporters, OATs) expressed at proximal tubular cells, such as URAT1 and GLUT9, thereby increasing renal excretion of urate. The medicine is the main stream research and development direction of the current gout treatment medicine, and is mainly probenecid, benzbromarone, benzsulzolone, lesinurad which is newly marketed and the like in the market.

3. The use of recombinant uricase converts uric acid into readily soluble and excreted allantoin.

Lesinurad (RDEA 594) is a recently marketed oral drug for increasing uric acid excretion for the treatment of gout, which inhibits the renal proximal tubule uric acid transporter URAT1. Lesinurad (Lesinurad) is an orally potent URAT1 inhibitor. Clinical research results in the phase I and the phase II show that the combination of the Lesinurad and the xanthine oxidase inhibitor can effectively regulate uric acid level, has higher safety, and has the molecular structure as follows:

however, the compound has serious hepatotoxicity, so that the discovery of a novel anti-gout drug which can be replaced has great significance for clinical treatment.

Disclosure of Invention

The invention aims to overcome the problems existing in the prior art, and provides a novel pyridylthioacetic acid compound with a structure shown in a formula I, a method for preparing the compound with the structure shown in the formula I, a pharmaceutical derivative or a formulation of the compound with the structure shown in the formula I and application thereof. The compound provided by the invention has good URAT1 inhibition activity, and can be used for treating gout and hyperuricemia.

In order to achieve the above object, the first aspect of the present invention provides a pyrithione acid compound having 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;

R ₁ and R is ₂ Each independently selected from a hydrogen atom, a C1-C6 alkyl or cycloalkyl group; alternatively, R ₁ And R is ₂ A C3-C6 ring;

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

R ₄ and R is ₅ Each independently selected from hydrogen atom, C1-C4 alkyl, and R ₄ And R is ₅ Not both hydrogen atoms.

The inventors of the present invention have found that by using the compounds of the structure shown in formula I above, an even better effect than the existing gout drugs can be achieved. In order to further enhance the therapeutic effect, one or more of the following preferred embodiments may be selected.

Regarding Ar groups:

preferably, ar is selected from pyridine (in the present application, unless otherwise specified, when the group is not previously defined as "substituted", it is in an unsubstituted state), substituted phenyl and substituted naphthyl;

preferably, ar is selected from pyridine and substituted phenyl.

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

preferably, in the Ar group, the substituents are selected from one or more of halogen, cyano, oxo, C1-C3 alkyl chain, C2-C4 alkyl that is cyclic with the substituted group, C1-C3 heteroalkyl chain, and C2-C4 heteroalkyl that is cyclic with the substituted group; wherein the heteroatoms in the heteroalkyl chain and the cyclic heteroalkyl are selected from one or more of oxygen, sulfur, and nitrogen, most preferably oxygen atoms.

Preferably, in the Ar group, the substituents are selected from halogen, cyano, methyl, ethyl, C2-C4 alkyl groups which are cyclic with the substituted groups, C2-C4 heteroalkyl groups which are cyclic with the substituted groups and the heteroatoms are oxygen atoms.

Preferably, ar groups are 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 3-5 heteroatom in heterocycloalkyl), alkyl substituted cyclic phenyl, heteroalkyl substituted cyclic phenyl, naphthyl, halogen substituted naphthyl, and cyano substituted naphthyl.

Preferably, ar groups are selected from pyridine, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, alkyl-substituted cyclic phenyl (more preferably C3-C6 alkyl, both substitution sites are in the clinic), heteroalkyl-substituted cyclic phenyl (more preferably 3-6 heteroalkyl, one or two oxygen atoms in the heteroatom, both substitution sites are in the clinic), and cyano-substituted naphthyl.

With respect to R ₁ Radicals and R ₂ The group:

preferably, R ₁ And R is ₂ Each independently selected from a hydrogen atom, a C1-C3 alkyl or cycloalkyl group; alternatively, R ₁ And R is ₂ Forming a C2-C4 ring.

According to one embodiment, R ₁ And R is ₂ Each independently selected from the group consisting of hydrogen atoms, methyl groups, and ethyl groups.

According to one embodiment, R ₁ Is methyl, R ₂ Is methyl.

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

With respect to R ₃ The group:

preferably, R ₃ Selected from the group consisting of C1-C3 straight chain alkyl, C1-C4 branched chain alkyl, C3-C6 cycloalkyl, C3-C4 substituted cycloalkyl, phenyl, substituted phenyl, -NR ₄ R ₅ A group, thiophene, C5-C6 heteroaryl; wherein R is ₄ And R is ₅ Each independently selected from hydrogen atom, methyl, ethyl, and R ₄ And R is ₅ Not both hydrogen atoms.

Preferably, R ₃ The substituents in the group are selected from halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl.

According to one embodiment, R ₃ The substituents in the group are halogen.

Preferably, R ₃ The heteroaryl groups in the groups, the heteroatoms in the heterocycloalkyl groups are each independently selected from one or more of oxygen, sulfur and nitrogen, most preferably S.

Preferably, R ₃ Selected from the group consisting of a hydrogen atom, a C1-C4 linear alkyl group, a C3-C5 cycloalkyl group, a dimethylamino group, a diethylamino group, a halophenyl group, and an aromatic heterocycle.

Preferably, R ₃ Selected from the group consisting of hydrogen, methyl, cyclopropyl, dimethylamino, halophenyl (e.g., 4-fluorophenyl) and aromatic heterocycle (e.g., containing a heteroatom S).

Ar, R as described above in the present invention ₁ 、R ₂ 、R ₃ 、R ₄ And R is ₅ May be combined with each other. The invention is equivalent to that of Ar, R ₁ 、R ₂ 、R ₃ 、R ₄ And R is ₅ In various combinations of the various embodiments of (a) to save text,and are not described in detail.

The following examples of the present invention are not intended to limit the scope of the present invention.

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

ar is selected from pyridine, substituted pyridine, phenyl, substituted phenyl, naphthyl and substituted naphthyl; wherein the substituents are selected from one or more of halogen, cyano, oxo, C1-C3 alkyl chain, C2-C4 alkyl which is cyclic with the substituted group, C1-C3 heteroalkyl chain, and C2-C4 heteroalkyl which is cyclic with the substituted group; wherein the heteroatoms in the heteroalkyl chain and the cyclic heteroalkyl are selected from one or more of oxygen, sulfur, and nitrogen;

R ₁ And R is ₂ Each independently selected from a hydrogen atom, a C1-C3 alkyl or cycloalkyl group; alternatively, R ₁ And R is ₂ A C2-C4 ring;

R ₃ selected from the group consisting of C1-C3 straight chain alkyl, C1-C4 branched chain alkyl, C3-C6 cycloalkyl, C3-C4 substituted cycloalkyl, phenyl, substituted phenyl, -NR ₄ R ₅ A group, thiophene, C5-C6 heteroaryl; wherein R is ₄ And R is ₅ Each independently selected from hydrogen atom, methyl, ethyl, and R ₄ And R is ₅ Not both hydrogen atoms; wherein the substituents are selected from halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl; the heteroatom in the heterocycloalkyl group is selected from one or more of oxygen, sulfur and nitrogen.

According to a second embodiment, in the structure of formula I:

ar is selected from pyridine, substituted phenyl and substituted naphthyl; wherein the substituents are selected from halogen, cyano, methyl, ethyl, C2-C4 alkyl groups which form a ring with the substituted groups, C2-C4 heteroalkyl groups which form a ring with the substituted groups and the heteroatoms are oxygen atoms;

R ₁ and R is ₂ Each independently selected from the group consisting of hydrogen, methyl, ethyl;

R ₃ selected from the group consisting of C1-C3 straight chain alkyl, C1-C4 branched chain alkyl, C3-C6 cycloalkyl, C3-C4 substitutedCycloalkyl, phenyl, substituted phenyl, -NR ₄ R ₅ A group, a C5-C6 heteroaryl group; wherein R is ₄ And R is ₅ Each independently selected from hydrogen atom, methyl, ethyl, and R ₄ And R is ₅ Not both hydrogen atoms; wherein the substituents are selected from halogen and methyl; the heteroatom in the heterocycloalkyl group is S.

According to a third embodiment, in the structure of 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 3-5 heteroatom in heterocycloalkyl), alkyl-substituted cyclic phenyl, heteroalkyl-substituted cyclic phenyl, naphthyl, halogen-substituted naphthyl, and cyano-substituted naphthyl;

R ₁ is methyl, R ₂ Is methyl; or R is ₁ And R is ₂ One of which is methyl and the other is a hydrogen atom;

R ₃ selected from the group consisting of a hydrogen atom, a C1-C4 linear alkyl group, a C3-C5 cycloalkyl group, a dimethylamino group, a diethylamino group, a halophenyl group, and an aromatic heterocycle.

According to a fourth embodiment, in the structure of formula I:

ar is selected from pyridine, halogen substituted phenyl, trifluoromethyl substituted phenyl, alkyl substituted cyclic phenyl (more preferably C3-C6 alkyl, two substitution sites are in the clinic), heteroalkyl substituted cyclic phenyl (more preferably 3-6 heteroalkyl, one or two oxygen atoms in the heteroatom, two substitution sites are in the clinic) and cyano substituted naphthyl;

R ₃ selected from the group consisting of a hydrogen atom, a methyl group, a cyclopropyl group, a dimethylamino group, a halophenyl group, and an aromatic heterocycle having one S atom.

The following list of specific compounds is not intended to limit the scope of the invention. For theseThe compounds being encoded in five-letter form, encoded as M ₁ M ₂ M ₃ M ₄ M ₅ Wherein the first bit M ₁ Fixed as I, representing a compound of formula I; second bit M ₂ Corresponding to Ar group, M at position 3 ₃ Corresponding to R ₁ Group, M at position 4 ₄ Corresponding to R ₂ Group, M at position 5 ₅ Corresponding to R ₃ The codes corresponding to the specific functional groups in each group are shown in table 1. For example, the substance encoded as Iaaaa represents a structure of formula I wherein Ar is a benzene ring, R ₁ Is H, R ₂ Is H, R ₃ A substance which is H. Note that each code is not limited to represent only one compound, but may also represent a group of compounds, e.g., ibaaa represents a benzene ring in which Ar is substituted at any position with X (fluoro or chloro or bromo or iodo or methyl) in the structure of formula I, R ₁ Is H, R ₂ Is H, R ₃ A substance which is H; it is understood that when 1 code represents a group of compounds, the group of compounds have similar structures and properties.

In Table 1, the black dots ". Cndot" marked on a functional group only indicate the sites that are linked to the structure of formula I (without any longer yielding any meaning that the symbol is conventionally expressed in the chemical formula), and when a functional group is marked with a plurality of black dots, it means that all of the marked sites can be taken as sites linked to the structure of formula I; wherein X in the functional group represents fluorine, chlorine, bromine, iodine or methyl; when a substituent is directed to the interior of a ring, it means that the substitution site is not limited nor is the number of substitutions; r is R ₄ Represents H, methyl or ethyl, R ₅ Represents H, methyl or ethyl, and R ₄ And R is ₅ And not H at the same time.

TABLE 1

The present application has been embodied by Table 1At least 1200 encodings are disclosed as IM ₂ M ₃ M ₄ M ₅ Wherein M is a compound of formula (I) ₂ Taken from any one of a to t, M ₃ Taken from any one of a to e, M ₄ Taken from any one of a to e, M ₅ The specific structures of the compounds obtained from any one of a to l are shown in Table 1. The compounds represented by these codes may be a single compound or a group of compounds, but the structure is exact based on the description of table 1, limited by the spread of text, and not a list of specific codes, but all the coded compounds from table 1 are considered to be listed in the present application. The compounds with specific structures can solve the technical problems of the application and realize better effects.

Further, some of the compounds of the specific structure of formula I are listed in Table 2 below, with Table 2 mainly illustrating Ar and R ₃ Part of the optional groups R ₁ And R is ₂ Methyl is taken as an example only and is not limited to the preferred mode. The table 2 is not intended to limit the scope of the present application.

TABLE 2

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

In a second aspect, the present invention provides a process for the preparation of a compound of formula I according to the first aspect of the invention, which process comprises: carrying out a sulfonamide reaction on the compound shown in the formula II,

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

in formula II-1, Y ₁ Is halogen, Y ₂ Methyl or ethyl;

in formula II-2, Y ₁ Is an Ar group in formula I, Y ₂ Methyl or ethyl;

in formula II-3, Y ₁ Is an Ar group in formula I, Y ₂ Is H;

R ₁ and R is ₂ R in formula I ₁ And R is ₂ 。

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

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

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

according to one embodiment of the invention, the compound shown in the formula I is obtained by carrying out a sulfonamide reaction on the compound shown in the formula II-3.

According to one embodiment of the invention, the compound shown in the formula I is obtained by sequentially carrying out hydrolysis reaction (obtaining the compound shown in the formula II-3) and sulphonamide reaction on the compound shown in the formula II-2.

According to one specific embodiment of the invention, the compound shown in the formula I is obtained by sequentially carrying out Suzuki coupling reaction (to obtain a compound shown in the formula II-2), hydrolysis reaction (to obtain a compound shown in the formula II-3) and sulphonylamidation reaction on the compound shown in the formula II-1.

The sulfonamide reaction may be performed in a manner conventional in the art. Preferably, the process of the sulfonamide reaction comprises: the compound shown as II-3 is contacted with a sulfonamide compound in the presence of a solvent such as methylene chloride, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and 4-Dimethylaminopyridine (DMAP).

Preferably, in the sulfonamide reaction, the compound shown in II-3 is mixed with a solvent, and EDC, DMAP and a sulfonamide compound are added at a temperature of-2 ℃ to 5 ℃ to be heated to room temperature (20 ℃ to 30 ℃) in the reaction.

The hydrolysis reaction may be carried out in a manner conventional in the art. Preferably, the hydrolysis reaction comprises the following steps: the solution of the compound of formula II-2 is contacted with an aqueous alkaline solution and heated to reflux.

Preferably, in the hydrolysis reaction, the solvent of the solution of the compound of formula II-2 is an organic solvent, for example, 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 completed (as judged by TLC monitoring), it is cooled (preferably diluted simultaneously, for example by adding cold water) and the pH is adjusted to be weakly acidic or neutral (e.g. ph=6-7).

Preferably, in the hydrolysis reaction, the material with the pH value adjusted is subjected to extraction, washing, drying, concentration, separation and the like to obtain the compound with the structure shown in the formula II-3.

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

Preferably, in the Suzuki coupling reaction, the reflux reaction is performed under the protection of an inert gas (such as nitrogen).

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

Preferably, in the Suzuki coupling reaction, the material after the reaction is finished (judged by TLC monitoring) is subjected to extraction, washing, drying, concentration, separation and the like to obtain the compound with the structure shown in the formula II-2.

The compound shown in the formula II-1 can be prepared, and preferably, the preparation method of the compound shown in the formula II-1 comprises the following steps: (1) 3-bromo-4-chloropyridine and sodium sulfide are subjected to contact reaction in the presence of N, N-Dimethylformamide (DMF) to obtain an intermediate compound int1; (2) The intermediate compound int1 is reacted with ethyl 2-halogen-fatty acid in the presence of DMF and carbonate.

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

Preferably, in step (1), the temperature of the contact reaction is 90-105 ℃ for 1.5-2.5 hours.

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

Preferably, the material obtained by the contact reaction in the step (1) is cooled, extracted, the pH value is adjusted to 5-6, and solid-liquid separation is carried out, so as to obtain the intermediate compound int1.

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

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

According to one embodiment of the present invention, the compounds of formula I are prepared by the reaction scheme shown below.

In a third aspect, the present invention provides a pharmaceutical derivative or formulation of a compound of formula I according to the first aspect of the present invention, including pharmaceutically acceptable salts, compositions, solvates, hydrates and pharmaceutically acceptable prodrugs.

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

Such pharmaceutically acceptable salts include, for example, but are not limited to, na, K, li, mg, ca, zn salts.

Such pharmaceutically acceptable prodrugs include, for example, but are not limited to, esters, carbonates, enacamprosates, thiocarbonates, N-acyl derivatives, N-acyloxy derivatives, amino acid conjugates, and the like.

The pharmaceutical derivative or formulation may contain a carrier such as, but not limited to, mannitol, sorbitol, sodium metabisulfite, sodium bisulphite, sodium thiosulfate, cysteine hydrochloride, thioglycolic acid, methionine, disodium vitamin C, EDTA, calcium sodium EDTA, carbonates, acetates, phosphates of monovalent alkali metals or aqueous solutions thereof, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acids, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivatives, cellulose and derivatives thereof, alginates, gelatin, polyvinylpyrrolidone, glycerin, ground temperature 80, agar, calcium carbonate, calcium bicarbonate, surfactants, polyethylene glycol, cyclodextrin, beta-cyclodextrin, phospholipid materials, kaolin, talc, calcium stearate, magnesium stearate and the like. For example in solid oral formulations.

The pharmaceutical derivatives or formulations may contain excipients, including for example but not limited to binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavoring agents and wetting agents, and if desired, the tablets may be coated. For example in solid oral formulations.

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

The pharmaceutical derivatives or formulations may contain disintegrants, for example including but not limited to starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate. For example in solid oral formulations.

The pharmaceutical derivatives or formulations may contain a lubricant, for example including but not limited to magnesium stearate. For example in solid oral formulations.

The pharmaceutical derivatives or formulations may contain a wetting agent, for example including but not limited to sodium lauryl sulfate. For example in solid oral formulations.

The pharmaceutical derivatives or formulations may contain suspending agents, including for example but not limited to sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats. For example, in liquid, orally administered formulations (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.

The pharmaceutical derivatives or formulations may contain emulsifying agents, including, for example, but not limited to, lecithin, sorbitan monooleate, acacia. For example in liquid oral formulations or in dry products.

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

The pharmaceutical derivatives or formulations may contain a preservative, for example including but not limited to methylparaben, propylparaben, sorbic acid. For example in liquid oral formulations or in dry products.

The pharmaceutical derivatives or formulations may contain a sterile carrier, for example in an injectable preparation. Depending on the carrier and concentration, the compounds of the invention may be suspended or dissolved. Solutions are typically prepared by dissolving the compound in a carrier, sterilizing by filtration before filling it into a suitable vial or ampoule, and sealing. Adjuvants such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier. To improve its stability, the composition may be frozen after filling into vials 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 agents, granules, medicinal granules, pills, powders, pastes, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops and patches. The formulations of the present invention are preferably oral dosage forms, such as: capsules, tablets, oral liquid, granules, pills, powder, pills, paste and the like.

The route of administration of the present invention may be oral, parenteral or topical, preferably in oral and injectable form. Formulations suitable for oral administration for pharmaceutical use may be presented as tablets, capsules, granules or other liquid form formulations 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 for coating, enteric, sustained release or quantitative release. The solid oral compositions may be prepared by conventional methods of mixing, filling, tabletting, and the like. Repeated mixing can distribute the active throughout those compositions using large amounts of filler.

In a fourth aspect, the invention provides the use of a compound of formula I and a pharmaceutical derivative or formulation thereof in the manufacture of a medicament for modulating uric acid levels and/or treating associated indications for gout.

The related indications include, but are not limited to, hyperuricemia, gout, gouty arthritis, inflammatory arthritis, kidney disease, nephrolithiasis, joint inflammation, deposition of urate crystals in joints, urolithiasis, deposition of urate crystals in renal parenchyma, gout flares, tophaceous gout, or combinations thereof.

The compound shown in the formula I and the pharmaceutical derivative or the preparation thereof have good URAT1 inhibition activity, can be used for treating gout and hyperuricemia, and provide a new medicinal possibility for clinically treating diseases related to abnormal URAT1 activity.

The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.

Detailed Description

The present invention will be described in detail by examples. The described embodiments of the invention are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.

The starting materials used in the examples below were all commercially available analytical pure unless otherwise specified.

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

Synthesis of Compound int 1: to a 1000ml round bottom flask was added 3-bromo-4-chloropyridine (38.4 g,0.2 mol), na ₂ S·9H ₂ O (95.84 g,0.4 mol) and 500ml of N, N-Dimethylformamide (DMF), the reaction mixture was nitrogen-protected under nitrogenThe reaction was allowed to warm to 100deg.C under reduced pressure, stirring was continued, the reaction temperature was maintained at 100deg.C for 2h, the progress of the reaction was monitored by Thin Layer Chromatography (TLC) using ethyl acetate: petroleum ether (1:6) is taken as a developing agent, after TLC detects that the reaction reaches the end point, after the reaction mixture is cooled, the reaction mixture is poured into 1000ml of ice water and stirred, the system is extracted twice with 500ml of dichloromethane, the aqueous phase is reserved, then the aqueous phase is adjusted to pH value of 5-6 by using concentrated hydrochloric acid, stirring is continued for 1h at room temperature, suction filtration is carried out, the solid is collected, the obtained solid is dried in vacuum at 45 ℃ to obtain a compound int1, the compound int1 is a pale yellow solid, 24.5g of a product is obtained after drying, the yield is 64%, and the compound is directly used for the next reaction without purification.

Synthesis of Compound int 2: into a 1000ml round bottom flask was added compound int1 (19 g,0.1 mol), stirred at room temperature with 150ml of N, N-Dimethylformamide (DMF), dissolved and K added ₂ CO ₃ (27.6 g,0,2 mol), ethyl 2-bromo-2 methylpropionate (23.4 g,0.12 mol), the mixture was stirred at room temperature, monitored by TLC (ethyl acetate: petroleum ether=1:1 as developing agent), after the reaction was complete, the mixture was poured into 1000ml of ice water, stirred, extracted 3 times with 200ml of dichloromethane, the organic phases were combined, the organic phase was washed once with 5% aqueous nacl solution, and the organic phase was washed once with anhydrous Na ₂ SO ₄ Drying, filtering, collecting filtrate, concentrating the solvent to dryness, purifying with column chromatography, and purifying with ethyl acetate: petroleum ether=1:5 was eluted as a washing machine and the eluate was concentrated to give compound int2 as a colorless liquid, weighing 28.5g.

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

Example 2 preparation of compound 1:

synthesis of compound A1: into a round bottom flask was charged compound int2 (5.0 g,16.4 mmol), compound p-chlorobenzoic acid (compound A,3.75g,24 mmol), pd (dppf) Cl ₂ (0.73 g,1 mmol), potassium fluoride (3.72 g,64 mmol), dioxane 90ml, water 10The reaction mixture is protected by nitrogen, the temperature is increased for reflux reaction under the protection of nitrogen, after the reaction is carried out for 16 hours, TLC detects the reaction progress, after the reaction end point is reached, heating is stopped, stirring is carried out, after the reaction system is cooled, 50ml of water and 100ml of dichloromethane are added, an organic phase is separated, the water phase is extracted by 100ml of dichloromethane, the organic phase is combined, the organic phase is washed by 5% NaCl aqueous solution and is dried by anhydrous sodium sulfate for 15 minutes, a drying agent is removed by filtration, the filtrate is concentrated, and a substance obtained by rotary evaporation is subjected to a silica gel column and ethyl acetate: petroleum ether (1:5) elution gave 4.36g of Compound A1 as an oily liquid in 81.14% yield.

Synthesis of compound A2: adding compound A1 (4.0 g,12 mmol) into a round bottom flask, adding 50ml of methanol for dissolution, adding 30% NaOH (2 ml,15 mmol) solution, heating and refluxing for stirring for 1h, stopping heating after TLC monitoring the reaction, adding 50ml of cold water after cooling, regulating the pH value of the system to 6-7 with concentrated hydrochloric acid, extracting with 100ml of ethyl acetate, washing the organic phase with 5% NaCl aqueous solution, and using anhydrous Na ₂ SO ₄ Drying, filtering to remove the drying agent, concentrating the filtrate, and separating the concentrated substance by using a Biotage column chromatography to obtain 2.33g of pure product with the yield of 63%.

Synthesis of Compound 1: to a round bottom flask was added compound A2 (0.75 g,2.44 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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), and the reaction was allowed to slowly warm to room temperature, TLC was allowed to check, until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give product 1 (0.25 g,0.61 mmol) in 25% yield by column separation and purification.

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 preparation of Compound 2

The cyclopropanesulfonamide in the step of preparing compound 1 in example 2 was replaced with N, N-dimethyl sulfonamide in the same molar amount to obtain compound 2.

Synthesis of Compound 2: to a round bottom flask was added compound A2 (0.75 g,2.44 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.7 g,3.66 mmol), 4-dimethylaminopyridine DMAP (0.45 g,3.66 mmol) and N, N-dimethyl-sulfonamide (0.45 g,3.66 mmol), and the reaction was allowed to slowly warm to room temperature, and TLC was performed to check until the starting material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to give the product (0.27 g,0.65 mmol) in 27% yield.

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.

Example 4 preparation of Compound 3

The cyclopropanesulfonamide in the step of preparing compound 1 in example 2 was replaced with the same molar amount of ethylsulfonamide to obtain compound 3.

Synthesis of Compound 3: to a round bottom flask was added compound A2 (0.75 g,2.44 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.7 g,3.66 mmol), 4-dimethylaminopyridine DMAP (0.45 g,3.66 mmol) and ethyl sulfonamide (0.4 g,3.66 mmol), and the reaction was allowed to slowly warm to room temperature, TLC was allowed to check until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give a product (0.23 g,0.58 mmol) by column separation and purification in 23% yield.

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

The cyclopropane sulfonamide in the step of preparing the compound 1 in example 2 was replaced with 4-fluorobenzenesulfonamide in the same molar amount to obtain a compound 4.

Synthesis of Compound 4: to a round bottom flask was added compound A2 (0.75 g,2.44 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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) were added to the reaction system, followed by slow warming to room temperature for reaction, TLC detection was performed until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to obtain the product (0.3 g,0.65 mmol) in 30% yield by column separation and purification.

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

The cyclopropanesulfonamide in the step of preparing compound 1 in example 2 was replaced with the same molar amount of 2-thiophenesulfonamide, to obtain compound 5.

Synthesis of Compound 5: to a round bottom flask was added compound A2 (0.75 g,2.44 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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), and the reaction was allowed to proceed slowly to room temperature, TLC was allowed to check, until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give a product (0.29 g,0.64 mmol) by column separation and purification in 29% yield.

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.

EXAMPLE 7 preparation of Compound 6

The cyclopropanesulfonamide in the step of preparing compound 1 in example 2 was replaced with the same molar amount of methylsulfonamide to obtain compound 6.

Synthesis of Compound 6: into a reaction flask, compound A2 (1.8 g,5.86 mmol) and 100ml of dichloromethane were added, the system was cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (1.13 g,5.90 mmol), 4-dimethylaminopyridine DMAP (0.72 g,5.90 mmol) and methylsulfonamide MsNH were added to the reaction solution ₂ (0.613 g,6.42 mmol) was slowly warmed to room temperature for reaction, TLC detection was performed until the starting material disappeared, the reaction was stopped, the reaction solution was concentrated, and isolation and purification were performed to obtain 0.58g of a product, yield 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.

Example 8 preparation of Compound 7

Synthesis of compound B1: into a round bottom flask was charged compound int2 (5.0 g,16.4 mmol), compound 4-trifluoromethyl phenylboronic acid (compound B,4.56g,24 mmol), pd (dppf) Cl ₂ (0.73 g,1 mmol), potassium fluoride (3.72 g,64 mmol), dioxane 90ml, water 10ml, the reaction mixture is protected with nitrogen, the temperature is raised under nitrogen protection for reflux reaction, after 16h of reaction, TLC detects the progress of the reaction, after reaching the end point of the reaction, heating is stopped, stirring is carried out, 50ml of water and 100ml of dichloromethane are added to the reaction system after cooling, the organic phase is separated, the aqueous phase is extracted with 100ml of dichloromethane, the organic phases are combined, the organic phase is washed with 5% aqueous NaCl solution, dried for 15 minutes with anhydrous sodium sulfate, the drying agent is removed by filtration, the filtrate is concentrated, the material obtained by rotary evaporation is passed through a silica gel column, ethyl acetate: petroleum ether (1:5) elution gave 4.82g of Compound B1 as a pale yellow oil in 79.4% yield.

Synthesis of compound B2: adding compound B1 (4.0 g,11 mmol) into a round bottom flask, adding 50ml of methanol for dissolution, adding 30% NaOH (2.93 g, 0.88g,22mmol of sodium hydroxide) solution, heating and refluxing for stirring for 1h, stopping heating after TLC monitoring the reaction, cooling, adding 50ml of cold water, regulating the pH value of the system to 6-7 by using concentrated hydrochloric acid, extracting by using 100ml of ethyl acetate, washing the organic phase by using 5% NaCl aqueous solution, and using anhydrous Na ₂ SO ₄ Drying, filtering to remove the drying agent, concentrating the filtrate, and separating the concentrated substance by using a Biotage column chromatography to obtain 2.95g of pure product with the yield of 79.73%.

Synthesis of Compound 7: to a round bottom flask was added compound B2 (1.0 g,2.93 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.8 g,4.2 mmol), 4-dimethylaminopyridine DMAP (0.5 g,4.2 mmol) and cyclopropanesulfonamide (0.5 g,4.2 mmol), and the reaction was allowed to proceed slowly to room temperature, TLC was allowed to check until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to perform column separation and purification to give a product (0.36 g,0.81 mmol) in 28% yield.

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.

Example 9 preparation of Compound 8

The cyclopropanesulfonamide in the step of preparing compound 7 in example 8 was replaced with N, N-dimethyl sulfonamide in the same molar amount to obtain compound 8.

Synthesis of Compound 8: to a round bottom flask was added compound B2 (1 g,2.93 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.8 g,4.2 mmol), 4-dimethylaminopyridine DMAP (0.5 g,4.2 mmol) and N, N-dimethyl sulfonamide (0.5 g,4.2 mmol), and the reaction was slowly warmed to room temperature, TLC was performed to detect the disappearance of the starting material, the reaction was stopped, and the reaction mixture was concentrated to perform column separation and purification to give product 8 (0.42 g,0.94 mmol) in 32% yield.

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

The cyclopropanesulfonamide in the step of preparing compound 7 in example 8 was replaced with ethylsulfonamide to obtain compound 9.

Synthesis of compound 9: to a round bottom flask was added compound B2 (1 g,2.93 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.8 g,4.2 mmol), 4-dimethylaminopyridine DMAP (0.5 g,4.2 mmol) and ethyl sulfonamide (0.46 g,4.2 mmol), and the reaction was slowly warmed to room temperature, TLC was checked until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated and purified by column separation to give the product (0.32 g,0.74 mmol) in 25% yield.

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

The cyclopropane sulfonamide in the step of preparing compound 7 in example 8 was replaced with 4-fluorobenzenesulfonamide in the same molar amount to obtain compound 10.

Synthesis of Compound 10: to a round bottom flask was added compound B2 (1 g,2.93 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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) were added to the reaction system, followed by slow warming to room temperature for reaction, TLC detection was performed until the starting material disappeared, the reaction was stopped, and the reaction solution was concentrated to perform column separation and purification to give the product (0.4 g,0.8 mmol) in 27% yield.

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

The cyclopropanesulfonamide in the step of preparing compound 7 in example 8 was replaced with the same molar amount of 2-thiophenesulfonamide, to obtain compound 11.

Synthesis of Compound 11: to a round bottom flask was added compound B2 (1 g,2.93 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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), and the reaction was slowly warmed to room temperature, TLC was checked until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to perform column separation and purification to give a product (0.38 g,0.78 mmol) in 27% yield.

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 to obtain compound 6.

Synthesis of Compound 12: into a reaction flask, compound B2 (1.8 g,5.30 mmol) and 100ml of dichloromethane were added, the system was cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (1.01 g,5.30 mmol), 4-dimethylaminopyridine DMAP (0.64 g,5.30 mmol) and methylsulfonamide MsNH were added to the reaction solution ₂ (0.55 g,5.8 mmol), slowly heating to room temperature, detecting by TLC until the raw materials disappear, stopping the reaction, concentrating the reaction solution, and performing column separation and purification to obtainThe crude product was 0.9g, yielding 0.6g of product in 27% yield.

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: into a round bottom flask was charged compound int2 (5.0 g,16.4 mmol), compound 3,4- (methylenedioxy) phenylboronic acid (compound C,3.98g,24 mmol), pd (dppf) Cl ₂ (0.73 g,1 mmol), potassium fluoride (3.72 g,64 mmol), dioxane 90ml, water 10ml, the reaction mixture is protected with nitrogen, the temperature is raised under nitrogen protection for reflux reaction, after 16h of reaction, TLC detects the progress of the reaction, after reaching the end point of the reaction, heating is stopped, stirring is carried out, 50ml of water and 100ml of dichloromethane are added to the reaction system after cooling, the organic phase is separated, the aqueous phase is extracted with 100ml of dichloromethane, the organic phases are combined, the organic phase is washed with 5% aqueous NaCl solution, dried for 15 minutes with anhydrous sodium sulfate, the drying agent is removed by filtration, the filtrate is concentrated, the material obtained by rotary evaporation is passed through a silica gel column, ethyl acetate: petroleum ether (1:5) elution gave compound C1 as a pale yellow oil, 5.42g, 95.42% yield.

Synthesis of compound C2: adding compound C1 (5.0 g,14.5 mmol) into a round bottom flask, adding 50ml of methanol for dissolution, adding 30% NaOH (3.87 g, 1.16g,29mmol of sodium hydroxide) solution, heating and refluxing for stirring for 1h, stopping heating after TLC monitoring the reaction, cooling, adding 50ml of cold water, regulating the pH value of the system to 6-7 by using concentrated hydrochloric acid, extracting by using 100ml of ethyl acetate, washing the organic phase by using 5% NaCl aqueous solution, and using anhydrous Na ₂ SO ₄ Drying, filtering to remove the drying agent, concentrating the filtrate, and separating the concentrated substance by using a Biotage column chromatography to obtain 3.84g of pure product with the yield of 83.66%.

Synthesis of Compound 13: to a round bottom flask was added compound C2 (0.75 g,2.36 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.68 g,3.55 mmol), 4-dimethylaminopyridine DMAP (0.43 g,3.55 mmol) and cyclopropanesulfonamide (0.43 g,3.55 mmol), and the reaction was allowed to proceed slowly to room temperature, TLC was followed until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to conduct column separation and purification to give a product (0.28 g,0.67 mmol) in 28% yield.

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

The cyclopropanesulfonamide in the step of preparing compound 13 in example 14 was replaced with N, N-dimethyl sulfonamide in the same molar amount to obtain compound 14.

Synthesis of Compound 14: to a round bottom flask was added compound C2 (0.75 g,2.36 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.68 g,3.55 mmol), 4-dimethylaminopyridine DMAP (0.43 g,3.55 mmol) and N, N-dimethyl-sulfonamide (0.43 g,3.55 mmol), and the reaction was allowed to slowly warm to room temperature, and TLC was performed to examine until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give a product (0.3 g,0.71 mmol) in 30% yield by column separation and purification.

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

The cyclopropanesulfonamide in the step of preparing compound 13 in example 14 was replaced with the same molar amount of ethylsulfonamide to obtain compound 15.

Synthesis of Compound 14: to a round bottom flask was added compound C2 (0.75 g,2.36 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.68 g,3.55 mmol), 4-dimethylaminopyridine DMAP (0.43 g,3.55 mmol) and ethyl sulfonamide (0.39 g,3.55 mmol), and the reaction was allowed to slowly warm to room temperature, TLC was allowed to check until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give a product (0.26 g,0.64 mmol) by column separation and purification in 26% yield.

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

The cyclopropanesulfonamide in the step of preparing compound 13 in example 14 was replaced with the same molar amount of 4-fluorobenzenesulfonamide to obtain compound 16.

Synthesis of Compound 16: to a round bottom flask was added compound C2 (0.75 g,2.36 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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) were added, followed by reaction slowly warming to room temperature, TLC detection was performed until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give a product (0.36 g,0.76 mmol) in 32% yield by column separation and purification.

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

The cyclopropanesulfonamide in the step of preparing compound 13 in example 14 was replaced with the same molar amount of thiophenesulfonamide to obtain compound 17.

Synthesis of Compound 17: to a round bottom flask was added compound C2 (0.75 g,2.36 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.68 g,3.55 mmol), 4-dimethylaminopyridine DMAP (0.43 g,3.55 mmol) and thiophenesulfonamide (0.62 g,3.55 mmol) were added to the reaction system, followed by slow heating to room temperature, TLC detection was performed until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to obtain a product (0.36 g,0.76 mmol) in 32% yield by column separation and purification.

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

The cyclopropanesulfonamide in the step of preparing compound 13 in example 14 was replaced with the same molar amount of methylsulfonamide to obtain compound 18.

Synthesis of Compound 18: into a reaction flask, compound C2 (1.12 g,3.53 mmol) and 100ml of dichloromethane were added, the system was cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.68 g,3.53 mmol), 4-dimethylaminopyridine DMAP (0.43 g,3.53 mmol) and methylsulfonamide MsNH were added to the reaction solution ₂ (0.37 g,3.90 mmol) was slowly warmed to room temperature for reaction, TLC detection was performed until the starting material disappeared, the reaction was stopped, the reaction solution was concentrated, and separation and purification were performed to obtain 1.1g of the crude product, followed by Biotage column separation to obtain 0.35g of the product in 25% yield.

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: into a round bottom flask was charged compound int2 (5.0 g,16.4 mmol), compound benzo-1, 4-dioxane-6-boric acid (compound D,4.44g,24 mmol), pd (dppf) Cl ₂ (0.73 g,1 mmol), potassium fluoride (3.72 g,64 mmol), dioxane 90ml, water 10ml, the reaction mixture is protected with nitrogen, the temperature is raised under nitrogen protection for reflux reaction, after 16h of reaction, TLC detects the progress of the reaction, after reaching the end point of the reaction, heating is stopped, stirring is carried out, 50ml of water and 100ml of dichloromethane are added to the reaction system after cooling, the organic phase is separated, the aqueous phase is extracted with 100ml of dichloromethane, the organic phases are combined, the organic phase is washed with 5% aqueous NaCl solution, dried for 15 minutes with anhydrous sodium sulfate, the drying agent is removed by filtration, the filtrate is concentrated, the material obtained by rotary evaporation is passed through a silica gel column, ethyl acetate: petroleum ether (1:5) elution gave compound D1 as a pale yellow oily liquid 5.57g in 94.25% yield.

Synthesis of compound D2: in a round bottom flaskAdding compound D1 (5.0 g,13.9 mmol), dissolving in 50ml of methanol, adding 30% NaOH (3.70 g, 1.11g,28.9mmol of sodium hydroxide) solution, heating and refluxing while stirring for 1h, stopping heating after TLC monitoring the reaction, cooling, adding 50ml of cold water, adjusting pH of the system to 6-7 with concentrated hydrochloric acid, extracting with 100ml of ethyl acetate, washing the organic phase with 5% NaCl aqueous solution, and adding anhydrous Na ₂ SO ₄ Drying, filtering to remove the drying agent, concentrating the filtrate, and separating the concentrated substance by using a Biotage column chromatography to obtain 3.35g of pure product with the yield of 72.67%.

Synthesis of Compound 19: to a round bottom flask was added compound D2 (0.85 g,2.57 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.74 g,3.85 mmol), 4-dimethylaminopyridine DMAP (0.47 g,3.85 mmol) and cyclopropanesulfonamide (0.47 g,3.85 mmol), and the reaction was allowed to proceed slowly to room temperature, TLC was allowed to check until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to perform column separation and purification to give a product (0.27 g,0.66 mmol) in 24% yield.

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

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The cyclopropanesulfonamide in the step of preparing compound 19 in example 20 was replaced with N, N-dimethyl sulfonamide in the same molar amount to obtain compound 20.

Synthesis of Compound 20: to a round bottom flask was added compound D2 (0.85 g,2.57 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.74 g,3.85 mmol), 4-dimethylaminopyridine DMAP (0.47 g,3.85 mmol) and N, N-dimethyl-sulfonamide (0.47 g,3.85 mmol) were added, the reaction was slowly allowed to proceed to room temperature, TLC detection was performed until the starting material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation purification was performed to give the product (0.29 g,0.66 mmol) in 26% yield.

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

The cyclopropanesulfonamide in the step of preparing compound 19 in example 20 was replaced with the same molar amount of ethylsulfonamide to obtain compound 21.

Synthesis of Compound 21: to a round bottom flask was added compound D2 (0.85 g,2.57 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.74 g,3.85 mmol), 4-dimethylaminopyridine DMAP (0.47 g,3.85 mmol) and ethyl sulfonamide (0.42 g,3.85 mmol), and the reaction was allowed to slowly warm to room temperature, TLC was checked until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give a product (0.25 g,0.59 mmol) in 23% yield by column separation and purification.

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

The cyclopropanesulfonamide in the step of preparing compound 19 in example 20 was replaced with the same molar amount of 4-fluorobenzenesulfonamide to obtain compound 22.

Synthesis of Compound 22: to a round bottom flask was added compound D2 (0.85 g,2.57 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (0.74 g,3.85 mmol), 4-dimethylaminopyridine DMAP (0.47 g,3.85 mmol) and 4-fluorobenzenesulfonamide (0.67 g,3.85 mmol) were added to the reaction system, followed by reaction slowly warming to room temperature, TLC detection was performed until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to give a product (0.36 g,0.74 mmol) in 29% yield by column separation and purification.

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

The cyclopropanesulfonamide in the step of preparing compound 19 in example 20 was replaced with the same molar amount of 2-thiophenesulfonamide to obtain compound 23.

Synthesis of Compound 23: to a round bottom flask was added compound D2 (0.85 g,2.57 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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) were added to the reaction system, followed by slow warming to room temperature for reaction, TLC detection was performed until the starting material disappeared, the reaction was stopped, and the reaction mixture was concentrated to obtain the product (0.33 g,0.69 mmol) by column separation and purification in 27% yield.

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]),found 477.1.

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 to obtain compound 24.

Synthesis of Compound 24: to the reaction flask, compound D2 (1.6 g,4.83 mmol) and 100ml of dichloromethane were added, the system was cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) 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) were added to the reaction flask, the reaction was slowly allowed to proceed to room temperature, TLC detection was performed until the starting material disappeared, the reaction was stopped, the reaction solution was concentrated, and separation and purification were performed to give 1.16g of crude product, followed by Biotage column separation to give 0.46g of product, yield 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: into a round bottom flask was charged compound int2 (5.0 g,16.4 mmol), compound 4-cyanonaphthalen-1-yl) boronic acid (compound E,4.86g,24.6 mmol), pd (dppf) Cl ₂ (0.73 g,1 mmol), potassium fluoride (3.72 g,64.0 mmol), dioxane 90ml and water 10ml, and the reaction mixture was refluxed under nitrogen protection, and after 16 hours the stirring was stopped After cooling, water and methylene chloride are added, the organic phase is washed by 5% NaCl aqueous solution, then dried by anhydrous sodium sulfate, the desiccant is removed by filtration, the organic phase is taken out, and the product obtained by rotary evaporation is passed through a silica gel column and ethyl acetate: petroleum ether (1:5) is eluted, the eluent is concentrated to remove the solvent, and 4.4g of white solid of the compound E1 is obtained after drying, and the yield is 71.08%.

Synthesis of compound E2: adding compound E1 (4.0 g,10.6 mmol) into a round bottom flask, adding 50ml of methanol for dissolution, adding 30% NaOH (2.83 g,0.85g of sodium hydroxide, 21.2 mmol) solution, refluxing and stirring for 1h, stopping heating after TLC detection reaction is finished, cooling to room temperature, adding 50ml of cold water, adjusting pH value to 6-7 with concentrated hydrochloric acid, extracting the system with 100ml of ethyl acetate twice, combining organic phases, washing the organic phases with 5% NaCl aqueous solution, and using anhydrous Na ₂ SO ₄ Drying for 15 minutes, filtering to remove the drying agent, concentrating the filtrate, separating the concentrated solution by using a Biotage column machine, concentrating the eluent to obtain a compound E2, weighing 2.8g, and obtaining 75 percent of yield.

Synthesis of Compound 25: into a round bottom flask was charged compound E2 (2.5 g,6.64 mmol), followed by 50ml of dichloromethane, cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (1.13 g,5.90 mmol), 4-dimethylaminopyridine DMAP (0.72 g,5.90 mmol) and methylsulfonamide MsNH were added to the reaction system ₂ (0.61 g,6.42 mmol) was slowly warmed to room temperature for reaction, TLC detection was performed until the starting material disappeared, the reaction was stopped, the reaction solution was concentrated, and column separation and purification were performed to give the product (0.57 g,1.33 mmol) in 20.1% yield.

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: into a round bottom flask was charged compound int2 (5.0 g,16.4 mmol), compound pyridine-3-boronic acid (compound F,2.95g,24 mmol), pd (dppf) Cl ₂ (0.73 g,1 mmol), potassium fluoride (3.72 g,64 mmol), dioxane 90ml, water 10ml, the reaction mixture is protected with nitrogen, the temperature is raised under nitrogen protection for reflux reaction, after 16h of reaction, TLC detects the progress of the reaction, after reaching the end point of the reaction, heating is stopped, stirring is carried out, 50ml of water and 100ml of dichloromethane are added to the reaction system after cooling, the organic phase is separated, the aqueous phase is extracted with 100ml of dichloromethane, the organic phases are combined, the organic phase is washed with 5% aqueous NaCl solution, dried for 15 minutes with anhydrous sodium sulfate, the drying agent is removed by filtration, the filtrate is concentrated, the material obtained by rotary evaporation is passed through a silica gel column, ethyl acetate: petroleum ether (1:5) elution gave compound F1 as a tan oil in a yield of 58% 2.82 g.

Synthesis of compound F2: adding compound F1 (2.5 g,8 mmol) into a round bottom flask, adding 50ml of methanol for dissolution, adding 30% NaOH (2 ml,15 mmol) solution, heating and refluxing for stirring for 1h, stopping heating after TLC monitoring the reaction, adding 50ml of cold water after cooling, regulating the pH value of the system to 6-7 by using concentrated hydrochloric acid, extracting by using 100ml of ethyl acetate, washing the organic phase by using 5% NaCl aqueous solution, and using anhydrous Na ₂ SO ₄ Drying, filtering to remove the drying agent, concentrating the filtrate, and separating the concentrated substance by using a Biotage column chromatography to obtain 1.86g of pure product with the yield of 84.7%.

Synthesis of Compound 26: into a reaction flask, compound F2 (1.4 g,5.1 mmol) and 100ml of dichloromethane were added, the system was cooled to 0℃and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride EDC (1.13 g,5.90 mmol), 4-dimethylaminopyridine DMAP (0.72 g,5.90 mmol) and methylsulfonamide MsNH were added to the reaction solution ₂ (0.61 g,6.42 mmol) was slowly warmed to room temperature for reaction, TLC detection was performed until the starting material disappeared, the reaction was stopped, the reaction solution was concentrated, and isolation and purification were performed to obtain 0.32g of the product in 18% yield.

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 shown in formula III is commercially available, namely, the gout drug, namely, the Sinolide (Lesinurad) which is currently marketed.

Test case

The above-prepared compound 1-compound 26 of the present application and the compounds of comparative examples formula III and formula IV were each tested for URAT1 inhibitory activity. The specific test method is as follows:

(1) Experimental materials:

HEK-293T cell line stably expressing hURAT: the intelligent chemical research company is built and owned autonomously.

The following materials were purchased from the wise chemical research company, inc.:

Fetal bovine serum (Invitrogen, cat# 10099141)

DMEM medium (Invitrogen, cat# 10564)

Trypsin (Invitrogen, cat# 25200056)

G418 (invivogen, cat# ant-gn-5)

Phosphate buffer (Invitrogen, cat. No. 14190250)

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

Dimethyl sulfoxide DMSO (Sigma, cat# D2650)

15 ml centrifuge tube (Greiner, cat# 07030115)

50 ml centrifuge tube (BD Falcon, cat# 352098)

Penicillin-streptomycin (Invitrogen, cat# 15070-063)

Benzbromarone (Benzbromarone, carboline technology, cat. No. 3562-84-3)

D-sodium gluconate (Allatin, cat. No. 527-07-1)

D-Potassium gluconate (Allatin, cat. No. 299-27-4)

D-calcium gluconate (Allatin, cat. No. 299-28-5)

(2) Experimental method

1. Preparation of experimental reagent

Cl-free HBSS buffer comprising: 125mM sodium D-gluconate, 4.8mM potassium D-gluconate, 1.3mM calcium D-gluconate, 1.2mM KH ₂ PO ₄ ，1.2mM MgSO ₄ 5.6mM glucose, 25mM HEPES (pH 7.4);

lysate: 100mM NaOH.

2. Cell culture and seeding

1) Culturing HEK-293T cell strain stably expressing hURAT1, wherein the culture medium comprises the following components: DMEM medium+10% foetal calf serum+500. Mu.g/ml G418+1% P/S;

2) When the cells grow to 80% full, discarding the culture medium, adding PBS to wash the cells once, then adding pancreatin-EDTA to digest, adding the culture medium when the cells are wall-removed, blowing to remove the cells, centrifuging to collect the cells, and adding the culture medium to blow into a cell suspension;

3) The cell density was adjusted to 7X 105/ml and then inoculated into 96-well white-bottomed cell culture plates in an amount of 100. Mu.l/well for 12-24 hours.

3. Compound formulation

1) Preparing a mother solution with the concentration of 20mM by using DMSO, diluting the compound to the concentration of 1mM by using DMSO, and adding the compound into 96 wells;

2) A quality control compound is arranged on the 96-well plate, which is a 100x compound plate;

3) 50-fold dilutions of the corresponding wells were performed in a separate 96-well plate with Cl-free HBSS buffer, which is a 2X compound plate;

4) After that, 30. Mu.l/well of a buffer containing 0.1. Mu. Ci/ml of 14C-uric acid and 30. Mu.l/well of a 2X diluted compound were added to a new 96-well plate, and this was prepared as a 1X compound plate for use.

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

1) Performing an absorption test after cell culture in a 96-well plate is attached;

2) Washing the cells 1 time with 200 μl/well of pre-warmed buffer;

3) Each well was blotted dry immediately followed by 50 μl/well of the corresponding compound and 0.1 μCi/ml of 14C-uric acid solution;

4) Incubating the plates with the compounds in an incubator at 37 ℃ for 5 minutes;

5) Immediately, 150 μl ice-cold buffer was added to each well to terminate the absorption. Washing each well with buffer solution three times;

6) In the cleaning process, the cell falling off is avoided as much as possible;

7) 50 μl/well of lysate was added to all wells and placed on a shaker for 5 minutes at 900 rpm;

8) Add 150 μl/well of scintillant Microsint40 to all wells and shake at 900rpm for 5 minutes;

9) Finally, the microwell plate was sent to a MicroBeta2 (manufactured by PerkinElmer corporation) instrument to measure radioactivity;

10 Analytical data, compound IC50 (nM) was calculated using GraphPad Prism 5 software.

(3) Experimental results

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

TABLE 3 Table 3

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Experiments show that the compound provided by the embodiment of the invention has good URAT1 inhibition activity and can be used for treating gout and hyperuricemia. The novel compound disclosed by the invention shows good URAT1 inhibition activity, the effect is obviously better than that of a gout drug Lesinurad which is already used in the market, and preliminary tests prove that the compound disclosed by the invention has lower hepatotoxicity (data not shown), so that the novel compound disclosed by the invention provides a novel and better medicinal possibility for clinically treating diseases related to abnormal URAT1 activity.

The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.

Claims

1. A pyridine thioglycollic acid compound with a structure shown in a formula I,

wherein,

ar is selected from substituted or unsubstituted naphthyl, substituted or unsubstituted phenyl and substituted or unsubstituted pyridine, wherein the substituent is selected from one or more of halogen, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl and alkynyl;

R ₁ and R is ₂ Each independently selected from a hydrogen atom, a C1-C6 alkyl or cycloalkyl group;

2. A pyridine thioglycollic acid compound with a structure shown in a formula I,

wherein, in the structure shown in formula I:

ar is selected from pyridine, substituted pyridine, phenyl, substituted phenyl, naphthyl and substituted naphthyl; wherein the substituents are selected from one or more of halogen, oxo, C1-C3 alkyl chain, C2-C4 alkyl groups which are cyclic with the substituted groups, and C2-C4 heteroalkyl groups which are cyclic with the substituted groups; wherein the heteroatom in the cyclic heteroalkyl is selected from one or more of oxygen, sulfur, and nitrogen;

R ₁ And R is ₂ Each independently selected from a hydrogen atom, a C1-C3 alkyl or cycloalkyl group;

R ₃ selected from the group consisting of C1-C3 straight chain alkyl, C1-C4 branched chain alkyl, C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -NR ₄ R ₅ A group, thiophene, C5-C6 heteroaryl; wherein R is ₄ And R is ₅ Each independently selected from hydrogen atom, methyl, ethyl, and R ₄ And R is ₅ Not both hydrogen atoms; wherein the substituents are selected from halogen, cyano, methyl, ethyl, n-propyl, isopropyl, cyclopropyl and cyclobutyl; the heteroatoms in the heteroaryl group are selected from one or more of oxygen, sulfur and nitrogen.

3. The compound of claim 2, wherein Ar is selected from pyridine, substituted phenyl, and substituted naphthyl; wherein the substituents are selected from halogen, methyl, ethyl, C2-C4 alkyl groups which form a ring with the substituted groups, C2-C4 heteroalkyl groups which form a ring with the substituted groups and the heteroatoms are oxygen atoms;

R ₃ selected from the group consisting of C1-C3 straight chain alkyl, C1-C4 branched chain alkyl, C3-C6 cycloalkyl, substituted or unsubstituted phenyl, -NR ₄ R ₅ A group, a C5-C6 heteroaryl group; wherein R is ₄ And R is ₅ Each independently selected from hydrogen atom, methyl, ethyl, and R ₄ And R is ₅ Not both hydrogen atoms; wherein the substituents are selected from halogen and methyl; the heteroatom in the heterocyclic aryl is S.

4. A pyridine thioglycollic acid compound with a structure shown in a formula I,

wherein Ar is selected from pyridine, phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, cycloalkyl-substituted phenyl, heterocycloalkyl-substituted phenyl, alkyl-substituted cyclic phenyl, heteroalkyl-substituted cyclic phenyl, naphthyl, and halogen-substituted naphthyl;

R ₃ selected from the group consisting of C1-C4 straight chain alkyl, C3-C5 cycloalkyl, dimethylamino, diethylamino, halophenyl, and aromatic heterocycle.

5. A pyridine thioglycollic acid compound with a structure shown in a formula I,

wherein Ar is selected from pyridine, halogen substituted phenyl, trifluoromethyl substituted phenyl, alkyl substituted cyclic phenyl and heteroalkyl substituted cyclic phenyl;

R ₃ selected from methyl, cyclopropyl, dimethylamino, halophenyl, and aromatic heterocycles containing one S atom.

6. A pyridine thioglycollic acid compound with a structure shown in a formula I,

Wherein the compound with the structure shown in the formula I is coded as IM ₂ M ₃ M ₄ M ₅ Wherein M is a compound of formula (I) ₂ Taken from any one of b to o, s, t, M ₃ Taken from any one of b to e, M ₄ Taken from any one of b to e, M ₅ Taken from any one of b to l; the structure of the corresponding compound is encoded as follows:

x is fluorine, chlorine, bromine, iodine or methyl.

7. A compound, the compound being:

8. a process for preparing a compound according to any one of claims 1 to 7, the process comprising: carrying out a sulfonamide reaction on the compound shown in the formula II,

in formula II-1, Y ₁ Is halogen, Y ₂ Methyl or ethyl;

in formula II-2, Y ₁ Is an Ar group in formula I, Y ₂ Methyl or ethyl;

in formula II-3, Y ₁ Is an Ar group in formula I, Y ₂ Is H;

R ₁ and R is ₂ R in formula I ₁ And R is ₂ 。

9. The method of claim 8, wherein the compound of formula I is obtained from a compound of formula II-3 by a sulfonamide reaction;

or the compound shown in the formula I is obtained by sequentially carrying out hydrolysis reaction and sulphonamide reaction on the compound shown in the formula II-2;

or the compound shown in the formula I is obtained by sequentially carrying out Suzuki coupling reaction, hydrolysis reaction and sulfonamide reaction on the compound shown in the formula II-1.

10. A method according to claim 8 or 9, wherein the method comprises the following reaction:

11. a pharmaceutical derivative or formulation of a compound of formula I according to any one of claims 1 to 7, selected from pharmaceutically acceptable salts, compositions.

12. Use of a structural compound of formula I according to any one of claims 1 to 7 and/or a pharmaceutical derivative or formulation of a structural compound of formula I according to claim 11 for the manufacture of a medicament for modulating uric acid levels and/or for the treatment of a related indication of gout.