WO2018202039A1 - Heterocyclic compound and preparation method therefor - Google Patents

Abstract

Disclosed in the present invention is a compound as represented by formula (A), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The new compound as represented by formula (A) disclosed in the present invention exhibits good URAT1 inhibitory activities, providing a new medicinal possibility for the clinical treatment of diseases associated with abnormal URAT1 activities.

Description

Heterocyclic compound and preparation method thereof Technical field

This invention relates to heterocyclic compounds and processes for their preparation.

Background technique

Heterocyclic compounds are organic compounds containing a heterocyclic structure in a molecule. The atoms constituting the ring contain at least one hetero atom in addition to the carbon atom. It is the largest class of organic compounds. The most common heteroatoms are nitrogen, sulfur, and oxygen. Can be divided into two major categories of aliphatic heterocycles and aromatic heterocycles. Heterocyclic compounds are ubiquitous in the structure of drug molecules.

Gout is an inflammatory disease characterized by pain and swelling caused by deposition of monosodium urate (MSU) in joints and subcutaneous areas. It is one of the oldest diseases that plague humans. The premise of gout in the MSU deposition instrument is hyperuricemia, a pathological condition in which the level of serum uric acid (sUA) is higher than the solubility of uric acid in the blood. Hyperuricemia is usually caused by excessive uric acid production and/or reduced uric acid excretion, with the latter accounting for approximately 90% of patients with hyperuricemia.

At present, hyperuricemia and gout treatment drugs mainly include: 1 anti-inflammatory analgesic drugs for symptomatic control of joint pain, pain, etc., such as colchicine and non-steroidal anti-inflammatory drugs (NSAID); A drug that inhibits uric acid production. Such as allopurinol, oxynium and nonbuxostat and other xanthine oxidase (XO) inhibitors; 3 for uric acid excretion drugs, such as probenecid and benzbromarone; 4 for acute gout attacks A uric acid-decomposing drug that rapidly lowers blood uric acid, such as uricase and PEGylase. However, these drugs have more serious side effects, such as colchicine has diarrhea, vomiting, abdominal pain and other common side effects, the effective dose is similar to the dose that causes gastrointestinal symptoms; probenecid can cause renal colic And renal dysfunction; benzbromarone has the risk of causing fulminant hepatitis; allopurinol has adverse reactions such as liver and bone marrow toxicity and allergic reaction; uric acid enzyme preparation is administered by injection, the patient's compliance is not as good as oral preparation, only applicable Lowering blood uric acid during acute gout attacks is not suitable for long-term treatment.

The urate transporter 1 (URAT1) is located on the brush border of the epithelial cells of the proximal convoluted tubules of the kidney. It is an important uric acid transporter found in the kidney in recent years and is responsible for the reabsorption of uric acid in the kidney. It has been proven that inhibition of URAT1 inhibits the reabsorption of uric acid in the kidney and increases the excretion of uric acid in the urine, thereby achieving the goal of lowering blood uric acid and controlling the onset of gout. For example, Lesinurad developed a selective uric acid absorption inhibitor for AstraZeneca, which reduces uric acid secretion and lowers uric acid levels in serum by inhibiting the URAT1 transporter in the kidney. The drug was approved by the FDA in December 2015. High blood levels of uric acid (hyperuricemia) associated with gout in the blood, approved by the European Medicines Agency (EMA) on February 18, 2016, and associated with drugs that reduce uric acid production (such as allopurinol and non-Busso) Can be combined to increase the response rate of gout patients who have not responded well to the above drugs, but there are still kidney-related risks and poor efficacy in the treatment alone. How to maximize the efficacy of URAT1 inhibitors and overcome their side effects as much as possible Become a research hotspot.

Summary of the invention

It is an object of the present invention to provide a class of heterocyclic compounds useful in the preparation of URAT1 inhibitors and processes for their preparation.

The present invention first provides a compound represented by the formula (A), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

W ₁ , W ₂ , W ₃ are each independently selected from NR ^b , S, O or CR ^a ; W ₄ , W ₅ is C, N; Z is selected from O or -NH-;

R ₁ , R ₂ , R ₅ , R ₆ are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, cycloalkyl, substituted aryl, haloalkyl or alkyl containing one or more oxygen and Cycloalkyl;

When Z is selected from O, R _{7 is} selected from hydrogen or a C ₁ -C ₆ alkyl group; when Z is selected from -NH-, R _{7 is} selected from hydrogen, aryl, alkyl or alkyl-substituted sulfonyl;

Wherein R ^a , R ^b , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl Base, -OR ^d , -S(O) _m R ^d , -C(O)R ^d , C(O)OR ^d , -C(O)NR ^e R ^f , -NR ^e R ^f or NR ^e C( O) R ^f , or a combination of R ₃ and R ₄ is a cycloalkyl group and a substituted cycloalkyl group, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group Optionally, independently, further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aromatic Base, heteroaryl, -OR ^d , -S(O) _m R ^d , -C(O)R ^d , C(O)OR ^d , -C(O)NR ^e R ^f , -NR ^e R ^f or Substituted by a substituent of NR ^e C(O)R ^f ;

R ^{d is} selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted with a substituent of an aryl group, a carboxyl group, a carboxylate group, -C(O)NR ^e R ^f , -NR ^e R ^f or NR ^e C(O)R ^f ;

R ^e and R ^f are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Optionally, independently, further selected from one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxyl group, or a carboxylate group; and m is 0, 1 or 2;

When R ₃ and R _{4 are} combined to be a cyclobutyl group and W ₃ is S, and R ₁ is hydrogen, R _{2 is} not hydrogen or a bromine atom;

When R ₃ and R _{4 are} combined to be a cyclobutyl group and W ₁ is S, and R ₂ is hydrogen, R _{1 is} not a bromine atom;

When R ₃ and R _{4 are} both methyl and W ₁ is S and R ₂ is hydrogen, R _{1 is} not hydrogen or a bromine atom.

Further, the structure of the compound is as follows: (II):

Wherein R _{1 is} selected from the group consisting of hydrogen, alkyl, halogen, aryl or substituted aryl, and amide;

R _{2 is} selected from the group consisting of hydrogen, alkyl, halogen, and cyano;

R ₃ and R ₄ are each independently selected from hydrogen, an alkyl group, or a combination of R ₃ and R ₄ is a cycloalkyl group;

When R ₃ and R _{4 are} combined to be a cyclobutyl group and R ₁ is hydrogen, R _{2 is} not a hydrogen or a bromine atom.

Preferably, the R _{1 is} selected from one of a hydrogen atom, a chlorine atom, a bromine atom, a methyl group, a phenyl group, and an amide group.

Preferably, the R _{2 is} selected from one of a hydrogen atom, a chlorine atom, a bromine atom, and a cyano group.

Preferably, the R ₃ and R ₄ are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group, or a combination of R ₃ and R ₄ is a cyclobutyl group.

Further preferably, the compound is any one of the following compounds 1, 4-16, 58-84:

Further, the structure of the compound is as follows: (III):

Wherein R _{1 is} selected from the group consisting of alkyl, halogen, and hydrogen;

R _{2 is} selected from the group consisting of an alkyl group, a halogen, a substituted aryl group, and hydrogen;

R ₃ , R ₄ are each selected from alkyl, hydrogen, or R ₃ and R _{4 are} combined to form a cycloalkyl group;

When R ₃ and R _{4 are} combined to form a cyclobutyl group, R _{1 is} not a bromine atom;

When R ₃ and R _{4 are} both methyl and R ₂ is hydrogen, R _{1 is} not hydrogen or a bromine atom.

Preferably, the R _{1 is} selected from one of a hydrogen atom and a bromine atom.

Preferably, the R _{2 is} selected from one of a hydrogen atom, a bromine atom, a methyl group, a pyridine, a 3-chloropyridine, and a p-cyanophenyl group.

Preferably, the R ₃ and R ₄ are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group, or a combination of R ₃ and R ₄ is a cyclobutyl group.

Further preferably, the compound is any one of the following compounds 17-24, 85-89, 91-96, 98, 100-113:

Further, the structure of the compound is as follows: (IV):

Wherein R ₁ is an alkyl group or hydrogen;

R _{2 is} selected from the group consisting of alkyl, halogen or hydrogen;

R _{b is} selected from the group consisting of an alkyl group, a methoxyalkyl group, an aryl group, a heteroaryl group, and a substituted aryl group or a heteroaryl group;

R ₃ and R ₄ are each selected from alkyl or hydrogen, or R ₃ and R _{4 are} combined to form a cycloalkyl group.

Preferably, said R ₁ is a hydrogen atom.

Preferably, the R _{2 is} selected from one of a hydrogen atom and a bromine atom.

Preferably, the Rb is selected from the group consisting of methyl, 1-methoxymethyl, 1-methoxyethyl, 1-methoxypropyl, phenyl, 4-cyano-phenyl, (4-cyano -Phenyl)-methyl, 3-bromo-phenyl, 4-bromo-phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-methyl-4- , pyridyl-2-fluoro-4-yl, pyridin-2-methoxy-4-yl, pyridin-3-methyl-yl, pyridin-4-methyl-yl, 1-(1-(pyridine- a 4-ethyl)ethyl, pyrimidin-2-yl, pyrimidin-3-yl, quinolin-4-yl, (3-cyano-phenyl)methyl group;

And/or, R ₃ and R ₄ are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group, or a combination of R ₃ and R ₄ is a cyclobutyl group.

Further preferably, the compound is any one of the following compounds 25-49, 57:

Further, the structure of the compound is as follows: (V):

Wherein R ₁ is an alkyl group or hydrogen;

R _{2 is} selected from the group consisting of an alkyl group, an aryl group, a heteroaryl group or a hydrogen;

R _{b is} selected from the group consisting of an alkyl group, a methoxyalkyl group, an aryl group, a heteroaryl group, and a substituted aryl group or a heteroaryl group;

R ₃ and R ₄ are each selected from alkyl or hydrogen, or R ₃ and R _{4 are} combined to form a cycloalkyl group.

Preferably, said R ₁ is a hydrogen atom.

Preferably, the R _{2 is} selected from one of a hydrogen atom, a pyridin-4-yl group, and a 4-cyano-phenyl group.

Preferably, the Rb is selected from one of a methyl group, a pyridin-3-yl group, and a 2-fluoro-pyridin-4-yl group; and/or the R ₃ and R ₄ are each selected from a hydrogen atom and a methyl group. One of ethyl, propyl, isopropyl, or a combination of R ₃ and R ₄ is a cyclobutyl group.

Further preferably, the compound is any one of the following compounds 50-54:

Further, the structure of the compound is as follows: (VI):

Wherein R ₁ is an alkyl group;

R _{2 is} selected from the group consisting of an alkyl group and a halogen;

R ₃ and R _{4 are} combined to form a cyclobutyl group.

Preferably, said R ₁ is a hydrogen atom.

Preferably, the R ₁ is a hydrogen atom or a bromine atom.

Further preferably, the compound is the following compound 55 or compound 56:

The present invention also provides a process for the preparation of the aforementioned compound, characterized in that it comprises the steps carried out according to the following route:

Or follow the steps below:

Or follow the steps below:

Or follow the steps below:

Or follow the steps below:

The present invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a URAT1 inhibitor.

The drug is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai-naphthalene syndrome, Kay-Sei's syndrome Symptoms, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency The drug, preferably, is a drug for preventing and/or treating gout or hyperuricemia.

The present invention also provides a pharmaceutical composition comprising the aforementioned compound or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient, together with a pharmaceutically acceptable adjuvant Prepared preparation.

The experimental results show that the compound of the present invention is a URAT1 inhibitor, which has been proven to be useful for the treatment of gout and hyperuricemia, and can also be used for the treatment of recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, Coronary heart disease, Lai-naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, Sarcoidosis or hypoxanthine-guanine phosphoribosyltransferase deficiency.

Definitions of terms of use in connection with the present invention: Unless otherwise stated, the initial definitions provided herein by the group or term apply to the group or term of the entire specification; for terms not specifically defined herein, it should be based on the disclosure and context. Given the meanings that those skilled in the art can give to them.

"Substitution" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.

The minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C _a - C _b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms. Thus, for example, (C ₁ -C ₆ )alkyl means an alkyl group containing from 1 to 6 carbon atoms.

The C ₁ -C ₆ alkyl group means an alkyl group of C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , that is, a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl, and the like.

The cycloalkyl group means a cyclic alkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the like.

The halogen means a fluorine atom, a bromine atom, a chlorine atom, or an iodine atom.

The term "pharmaceutically acceptable" means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.

The terms "salt" and "pharmaceutically acceptable salt" refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount). These salts may be precipitated in a solution and collected by filtration, or recovered after evaporation of the solvent, or may be obtained by lyophilization after reaction in an aqueous medium.

It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention.

The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Any technique implemented based on the above description of the present invention is within the scope of the present invention.

detailed description

Example 1. Synthesis of the compound of the present invention

The reaction formula is as follows:

R _{1 is} selected from one of a hydrogen atom, a chlorine atom, a bromine atom, a methyl group, a phenyl group, and an amide group.

R _{2 is} selected from one of a hydrogen atom, a chlorine atom, a bromine atom, and a cyano group.

R ₃ and R ₄ are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group. It may be the same group or a different group; or R3 and R4 may be combined into a cyclobutyl group.

Specific example: synthesis of product 1

1) Synthesis of 2-(thienthio[3,2-b]pyridin-7-fluorenyl)-2-methylpropanoate (Int 1.2)

To a 100 mL reaction flask was added 7-chlorothiophene [3,2-b]pyridine (1.69 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), N-methylpyrrolidone (30 mL), and heated to 80 ° C to stir the reaction. After 3 hours, cesium carbonate (6.52 g, 20 mmol) and ethyl 2-bromoisobutyrate (2.15 g, 11 mmol) were added to the reaction flask, and the reaction was continued at 100 ° C for 2 hours. After the reaction was completed, water was added ( The mixture was extracted with EtOAc (3 mL, EtOAc) MS: 282.1 (M+H ⁺ ).

2) Synthesis of 2-(thiophene[3,2-b]pyridin-7-fluorenyl)-2-methylpropionic acid (1)

Intermediate 2 (281 mg, 1 mmol), methanol (5 mL), water (5 mL), lithium hydroxide (96 mg, 4 mmol) was added to a 100 mL reaction flask and allowed to react at room temperature for 16 hours. After completion of the reaction, it was neutralized with 2N hydrochloric acid under an ice water bath to a pH of about 5, and then filtered, and the filter cake was washed with 10 mL of water, and the cake was dried to obtain Compound 1 (177 mg) in a yield of 70%. Mass Spectrum: 254.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H).

Synthesis of 2-bromo-7-chlorothiophene [3,2-b]pyridine (int3)

To a 100 ml three-necked flask was added 7-chlorothiophene [3,2-b]pyridine (5 g, 0.029 mol), THF (20 ml), EtOAc (m.) After the completion of the dropwise addition, the reaction was carried out at -78 ° C for 30 min, then bromine (9.28 g, 0.058 mol) was added dropwise, and the addition was completed, and the temperature was naturally raised to - room temperature at -78 ° C. After the reaction was completely monitored by TLC, saturated sodium sulfite solution was added, and ethyl acetate was used. The organic layer was combined and dried over anhydrous sodium sulfate. The solvent was purified by silica gel column chromatography to afford intermediate int3 (5.825 g, yield 81%), mass spectrum: 248 (M+H ⁺ )

Synthesis of 3-bromo-7-chlorothiophene [3,2-b]pyridine (int4)

To a 100 ml three-necked flask was added 7-chlorothiophene [3,2-b]pyridine (5 g, 0.029 mol), acetic acid (20 ml), and bromine (9.28 g, 0.058 mol) was added dropwise at room temperature. After 18 h, the reaction mixture was stirred and evaporated to dryness eluted eluted eluted eluted eluted eluted eluted eluted eluted : 248 (M+H ⁺ ).

Synthesis of 2,3-dibromo-7-chlorothiophene [3,2-b]pyridine (int5)

To a 100 ml three-necked flask was added 2-bromo 7-chlorothiophene [3,2-b]pyridine (5 g, 0.029 mol), acetic acid (20 ml), and bromine (9.28 g, 0.058 mol) was added dropwise at room temperature. After the completion of the reaction, the mixture was reacted for 18 h, and the reaction mixture was evaporated. EtOAc EtOAc EtOAc EtOAc EtOAc ), mass spectrum: 328 (M+H ⁺ ).

Synthesis of 2-chloro-7chlorothiophene [3,2-b]pyridine

To a 100 ml three-necked flask was added 7-chlorothiophene [3,2-b]pyridine (5 g, 0.029 mol), THF (20 ml), EtOAc (m.) After the completion of the dropwise addition, the reaction was carried out at -78 ° C for 30 min, and 1,1-dichloroethane (9.28 g, 0.058 mol) was added dropwise. After the dropwise addition, the temperature was naturally raised from -78 ° C to room temperature, and the reaction was completely saturated by TLC. The sodium sulfite solution was extracted with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate. The solvent was purified by silica gel column to afford intermediate int6 (5.825 g, yield 81%), mass spectrum: 204 (M+H ⁺ )

Synthesis of 3-chloro-7chlorothiophene [3,2-b]pyridine

Add 7-chlorothiophene [3,2-b]pyridine (5 g, 0.029 mol), acetic acid (20 ml) to a 100 ml three-necked flask, and add NCS (9.28 g, 0.058 mol) at room temperature. After the addition, the reaction was carried out for 18 h, TLC After the reaction was completed, a saturated aqueous solution of sodium sulfite was added, and the mixture was combined with ethyl acetate. The organic layer was combined and dried over anhydrous sodium sulfate. The solvent was purified by silica gel to afford intermediate int7 (6.329 g, yield 88%). M+H ⁺ )

Description: Products 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 58, 59, 60, 61, 62, 63, 64, 65 , 66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84 in the same way, with the corresponding reagent synthesis.

The starting material of the product 1 was prepared by replacing ethyl 2-bromoisobutyrate with 2-bromo-2-cyclobutylacetic acid ethyl ester. According to the same preparation method as the product 1, the product 2 (2-(thiophene [3, 2-b]pyridine-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 266.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine as int3, and ethyl 2-bromoisobutyrate was replaced with 2-bromo-2-cyclobutylacetate as the product 1 The preparation method can be used to obtain the product 3 (2-(thiophene[3,2-b]pyridine-2-bromo-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 344.1, 346.1 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 6H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int3, and the product 4 (2-(thiophene[3,2-b]pyridine-2) was obtained by the same preparation method as the product 1. -Bromo-7-fluorenyl)-2-methylpropanoic acid), mass spectrum: 332.0, 334.0 (M+H ⁺ ). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 13.06 (s, 1H), 8.63 (d, J = 4.9 Hz, 1H), 7.86 (s, 1H), 7.39 (d, J = 4.9 Hz, 1H) , 1.54 (s, 6H).

Replace the raw material 7-chlorothiophene [3,2-b]pyridine of the product 1 with 2-phenyl-7-chlorothiophene [2,3-b]pyridine, and replace 2-ethyl 2-bromoisobutyrate with 2- The product 5 (2-(thiophene[3,2-b]pyridin-2-phenyl-7-fluorenyl)-2- can be obtained by the same preparation method as the product of bromo-2-cyclobutylacetate. Cyclobutylacetic acid): Mass Spectrum: 342.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.43 – 7.29 (m, 5H) 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine as int4, and ethyl 2-bromoisobutyrate was replaced with 2-bromo-2-cyclobutylacetate, as in product 1 The preparation method can be used to obtain the product 6 (2-(thiophene[3,2-b]pyridine-3-bromo-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 344.0, 346.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine to int5, and ethyl 2-bromoisobutyrate was replaced with 2-bromo-2-cyclobutylacetate, as in product 1 The preparation method can be used to obtain the product 7 (2-(thiophene[3,2-b]pyridine-2,3-dibromo-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 421.0, 423.0, 425.0 ( M+H+).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 ( m, 2H), 2.22–1.93 (m, 2H).

Replace the raw material 7-chlorothiophene [3,2-b]pyridine of the product 1 with 2-methyl-7-chlorothiophene [2,3-b]pyridine, and replace 2-ethyl 2-bromoisobutyrate with 2- The bromo-2-cyclobutylacetic acid ethyl ester can be obtained according to the same preparation method as the product 1 (2-(thiophen[3,2-b]pyridine-2-methyl-7-fluorenyl)-2- Cyclobutylacetic acid): Mass Spectrum: 380.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 3.39 (s, 3H) , 2.93–2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine as int6, and ethyl 2-bromoisobutyrate was replaced with 2-bromo-2-cyclobutylacetate as the product 1 The product was prepared as the product 9 (2-(thiophene[3,2-b]pyridine-2-chloro-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 300.1 (M+H+).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with intr6, and the product 10 (2-(thiophene[3,2-b]pyridine-2) was obtained by the same preparation method as the product 1. -Chloro-7-fluorenyl)-2-methylpropanoic acid): Mass Spectrum: 288.1 (M+H ⁺ ).

_{^{1 HNMR (DMSO-d 6,}} 400MHz): δ13.06 (s, 1H), 8.63 (d, J = 4.9Hz, 1H), 7.86 (s, 1H), 7.39 (d, J = 4.9Hz, 1H) , 1.54 (s, 6H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine to int6, and ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromo-2-ethylbutanoate, as in product 1 The preparation method gave the product 11 (2-(thiophene[3,2-b]pyridine-2-chloro-7-fluorenyl)-2-ethylbutyric acid): mass spectrum: 316.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 13.06 (s, 1H), 8.63 (d, J = 4.9 Hz, 1H), 7.86 (s, 1H), 7.39 (d, J = 4.9 Hz, 1H) , 1.94–1.75 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H)

Substituting 7-chlorothiophene [3,2-b]pyridine, which is the starting material for the preparation of product 1, with 2-methyl-3-bromo-7-chlorothiophene [2,3-b]pyridine, ethyl 2-bromoisobutyrate Substituting 2-bromo-2-cyclobutylacetic acid ethyl ester, product 12 (2-(thiophene[3,2-b]pyridine-2-methyl-3-bromo) can be obtained according to the same preparation procedure as product -7-fluorenyl)-2-cyclobutylacetic acid): Mass spectrum: 358.0, 360.0 (M+H ⁺ ). ¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 3.39 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Replace the raw material 7-chlorothiophene [3,2-b]pyridine of the product 1 with 2-methyl-3-chloro-7-chlorothiophene [2,3-b]pyridine, ethyl 2-bromoisobutyrate Substituting 2-bromo-2-cyclobutylacetic acid ethyl ester, the product 13 (2-(thiophene[3,2-b]pyridine-2-methyl-3-chloro) can be obtained by the same preparation method as the product -7-Mercapto)-2-cyclobutylacetic acid: mass spectrum: 314.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 3.39 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Replace the raw material 7-chlorothiophene [3,2-b]pyridine of the product 1 with 2-formamido-7-chlorothiophene [2,3-b]pyridine, and replace 2-ethyl 2-bromoisobutyrate with 2 -Bromo-2-cyclobutylacetate, product 14 (2-(thiophene[3,2-b]pyridine-2-carboxamide-7-fluorenyl)-2 can be obtained according to the same preparation procedure as product -cyclobutylacetic acid): Mass Spectrum: 309.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Replace the raw material 7-chlorothiophene [3,2-b]pyridine of the product 1 with 3-cyano-7-chlorothiophene [2,3-b]pyridine, and replace the ethyl 2-bromoisobutyrate with 2- The bromo-2-cyclobutylacetic acid ethyl ester can be obtained according to the same preparation method as the product 1 (2-(thiophen[3,2-b]pyridin-2-cyano-7-fluorenyl)-2- Cyclobutylacetic acid): Mass Spectrum: 291.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Substituting 7-chlorothiophene [3,2-b]pyridine, which is the starting material for the preparation of product 1, with 2-methyl-3-cyano-7-chlorothiophene [2,3-b]pyridine, 2-bromoisobutyric acid B The ester was replaced with 2-bromo-2-cyclobutylacetic acid ethyl ester. The product 16 (2-(thiophene[3,2-b]pyridine-2-methyl-3- Cyano-7-fluorenyl-2-cyclobutylacetic acid): Mass Spectrum: 305.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 3.39 (s, 3H) , 2.93–2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

The ethyl 2-bromoisobutyrate as the starting material for the preparation of the product 1 was replaced with ethyl 2-bromoacetate, and the product 58 (2-(thiophene[3,2-b]pyridine- 7-fluorenyl)-acetic acid): Mass spectrum: 226.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H).

The starting material of the product 1 was prepared by replacing ethyl 2-bromoisobutyrate with ethyl 2-bromopropionate, and the same preparation as in product 1 was used to obtain the product 59 (2-(thiophene[3,2-b]pyridine). -7-fluorenyl)-propionic acid): Mass spectrum: 240.1 (M+H+).

1H NMR (DMSO-d6, 400MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d) , J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material of the product 1 was prepared by replacing ethyl 2-bromoisobutyrate with ethyl 2-bromobutyrate, and the same preparation method as the product 1 was used to obtain the product 60 (2-(thiophene[3,2-b]pyridine). -7-fluorenyl)-butyric acid: mass spectrum: 254.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08 - 1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The ethyl 2-bromoisobutyrate as the starting material for the preparation of the product 1 was replaced with ethyl 2-bromopentanoate, and the product 61 (2-(thiophene[3,2-b]pyridine) was obtained by the same preparation method as the product. -7-fluorenyl)-pentanoic acid: mass spectrum: 268.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03 - 1.78 (m, 2H), 1.57 - 1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The ethyl 2-bromoisobutyrate as the starting material for the preparation of the product 1 was replaced with ethyl 2-bromoisovalerate, and the product 62 (2-(thiophene [3,2-b]] was obtained by the same preparation method as the product. Pyridine-7-fluorenyl)-3-methylbutyric acid): Mass Spectrum: 268.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H) ).

The ethyl 2-bromoisobutyrate as the starting material for the preparation of the product 1 was replaced with ethyl 2-bromo-2-ethylbutanoate, and the product 63 (2-(thiophene [3, 2-b]pyridin-7-mercapto)-2-ethylbutyric acid): mass spectrum: 282.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H) ).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int3, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoacetate, and the same preparation method as the product 1 was obtained. Product 64 (2-(2-Bromo-thiophene[3,2-b]pyridin-7-fluorenyl)-acetic acid): mp.: 304.0, 306.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H) .

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int3, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromopropionate, and the same preparation method as the product 1 was used. The product 65 (2-(2-bromo-thiophene[3,2-b]pyridin-7-mercapto)-propionic acid) was obtained: mass spectrum: 318.0, 320.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 is replaced by int3, and the ethyl 2-bromoisobutyrate is replaced with ethyl 2-bromobutyrate, and the same preparation method as the product 1 can be used. The product 66 (2-(2-bromo-thiophene[3,2-b]pyridin-7-mercapto)-butyric acid) was obtained: mass spectrum: 332.0, 334.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08–1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 is replaced by int3, and the ethyl 2-bromoisobutyrate is replaced with ethyl 2-bromopentanoate, and the same preparation method as the product 1 can be used. to give product 67 (2- (2-bromo - thieno [3,2-b] pyridin-7-mercapto-yl) - pentanoic acid): mass ^{Spectrum: 346.0,348.0 (M + H +)} .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03–1.78 (m, 2H), 1.57–1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int3, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoisovalerate, according to the same preparation method as the product 1. The product 68 is obtained (2- (2-bromo - thieno [3,2-b] pyridin-7-mercapto-yl) -3-methyl-butyric acid): mass ^{Spectrum: 346.0,348.0 (M + H +)} .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine as int3, and ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromo-2-ethylbutanoate, as in product 1 The preparation method can be used to obtain the product 69 (2-(2-bromo-thiophene[3,2-b]pyridin-7-fluorenyl)-2-ethylbutanoic acid): mass spectrum: 360.0, 362.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine as int3, and ethyl 2-bromoisobutyrate was replaced with 2-bromo-2-cyclobutylacetate as the product 1 The preparation method can be used to obtain the product 70 (2-(2-bromo-thiophene[3,2-b]pyridin-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 344.0, 346.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.54 (d, J = 5.1 Hz, 1H), 7.83 (s, 1H), 7.16 (d, J = 5.1 Hz, 1H), 2.83 (dt, J = 12.6, 9.0 Hz, 2H), 2.36–2.25 (m, 2H), 2.24–1.93 (m, 2H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int4, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoacetate, and the same preparation method as the product 1 was obtained. Product 71 (2-(3-Bromo-thiophene[3,2-b]pyridin-7-fluorenyl)-acetic acid): Mass Spectrum: 304.0, 306.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H) .

The raw material for preparing product 1 is replaced by 7-chlorothiophene [3,2-b]pyridine to int4, and ethyl 2-bromoisobutyrate is replaced with ethyl 2-bromopropionate, and the same preparation method as product 1 can be used. The product 72 (2-(3-bromo-thiophene[3,2-b]pyridin-7-mercapto)-propionic acid) was obtained: mass spectrum: 318.0, 320.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 is replaced by int4, and the ethyl 2-bromoisobutyrate is replaced with ethyl 2-bromobutyrate, and the same preparation method as the product 1 can be used. The product 73 (2-(3-bromo-thiophene[3,2-b]pyridin-7-mercapto)-butyric acid) was obtained: mass spectrum: 332.0, 334.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08–1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 is replaced by int4, and the ethyl 2-bromoisobutyrate is replaced with ethyl 2-bromopentanoate, and the same preparation method as the product 1 can be used. to give product 74 (2- (3-bromo - thieno [3,2-b] pyridin-7-mercapto-yl) - pentanoic acid): mass ^{Spectrum: 346.0,348.0 (M + H +)} .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03–1.78 (m, 2H), 1.57–1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int4, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoisovalerate, according to the same preparation method as the product 1. The product 75 is obtained (2- (3-bromo - thieno [3,2-b] pyridin-7-mercapto-yl) -3-methyl-butyric acid): mass ^{Spectrum: 346.0,348.0 (M + H +)} .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H)

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine as int4, and ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromo-2-ethylbutanoate, as in product 1 The preparation method can be used to obtain the product 76 (2-(3-bromo-thiophene[3,2-b]pyridin-7-fluorenyl)-2-ethylbutanoic acid): mass spectrum: 360.0, 362.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int4, and the same product as the product 1 was obtained to obtain the product 77 (2-(3-bromo-thiophene [3,2-b] Pyridine-7-mercapto)-2-methylpropanoic acid): mass spectrum: 332.0, 334.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H) .

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int5, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoacetate, and the same preparation method as the product 1 was obtained. The product 78 (2- (2,3-dibromo - thieno [3,2-b] pyridin-7-mercapto-yl) - acetic acid): mass ^{spectrum: 382.0,384.0,386.0 (M + H +)} .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int5, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromopropionate, and the same preparation method as the product 1 was used. to give product 79 (2- (2,3-dibromo - thieno [3,2-b] pyridin-7-mercapto-yl) - propionic acid): mass ^{spectrum: 396.0,398.0,400.0 (M + H +)} .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int5, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromobutyrate, and the same preparation method as the product 1 was used. The product 80 (2-(2,3-dibromo-thiophene[3,2-b]pyridin-7-mercapto)-butyric acid) was obtained: mass spectrum: 410.0, 412.0, 414.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08 –1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 is replaced by int5, and the ethyl 2-bromoisobutyrate is replaced with ethyl 2-bromopentanoate, and the same preparation method as the product 1 can be used. The product 81 (2-(2,3-dibromo-thiophene[3,2-b]pyridin-7-mercapto)-pentanoic acid) was obtained: mass spectrum: 424.0, 426.0, 428.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03 –1.78 (m, 2H), 1.57–1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int5, and the ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromoisovalerate, according to the same preparation method as the product 1. The product 82 (2-(2,3-dibromo-thiophene[3,2-b]pyridin-7-fluorenyl)-3-methylbutanoic acid) can be obtained: mass spectrum: 424.0, 426.0, 428.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H).

The starting material for the preparation of product 1 was replaced by 7-chlorothiophene [3,2-b]pyridine as int5, and ethyl 2-bromoisobutyrate was replaced with ethyl 2-bromo-2-ethylbutanoate, as in product 1 The preparation method can be used to obtain the product 83 (2-(2,3-dibromo-thiophene[3,2-b]pyridin-7-fluorenyl)-2-ethylbutanoic acid): mass spectrum: 438.0, 440.0, 442.0 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 4H), 0.93 (t, J=7.3Hz, 6H).

The starting material 7-chlorothiophene [3,2-b]pyridine of the product 1 was replaced with int5, and the product 84 (2-(2,3-dibromo-thiophene [3, 2-b]pyridin-7-mercapto)-2-methylpropanoic acid): mass spectrum: 410.0, 412.0, 414.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H).

Example 2 Synthesis of a Compound of the Invention

The reaction formula is as follows:

R _{1 is} selected from one of a hydrogen atom and a bromine atom.

R _{2 is} selected from the group consisting of a hydrogen atom, a bromine atom, a methyl group, a pyridine, a 3-chloropyridine, and a p-cyanophenyl group.

R ₃ and R ₄ are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group. It may be the same group or a different group; or R ₃ and R _{4 may be} combined into a cyclobutyl group.

Specific examples:

1) Synthesis of 2-(thiophene[2,3-b]pyridine-3-methyl-4-indenyl)-2-cyclobutylacetate (Int 17.2)

To a 100 mL reaction flask was added 3-methyl-4-chlorothiophene [2,3-b]pyridine (1.83 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), N-methylpyrrolidone (30 mL), and heated. The reaction was stirred at 80 ° C for 3 hours, then cesium carbonate (6.52 g, 20 mmol) and 2-bromo-2-cyclobutylacetate (2.15 g, 11 mmol) were added to the reaction flask, and the reaction was continued at 100 ° C for 2 After the completion of the reaction, water (150 mL) was added, and the mixture was extracted with EtOAc (3 mL). 1.84 g), yield 60%. MS: 308.1 (M+H ⁺ ).

2) Synthesis of 2-(thiophene[2,3-b]pyridine-3-methyl-4-indolyl)-2-cyclobutylacetic acid (17)

Intermediate 2 (308 mg, 1 mmol), methanol (5 mL), water (5 mL), and lithium hydroxide (96 mg, 4 mmol) were reacted in a 100 mL reaction flask for 16 hours at room temperature. After completion of the reaction, it was neutralized with 2N hydrochloric acid to a pH of about 5 in an ice water bath, and then filtered, and the filter cake was washed with 10 mL of water, and the cake was dried to obtain Compound 1 (195 mg) in a yield of 70%. Mass Spectrum: 280.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 3.39 (s, 3H) , 2.93–2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Synthesis of 2-bromo-4-chlorothiophene [2,3-b]pyridine (int8)

To a 100 ml three-necked flask was added 4-chlorothiophene [2,3-b]pyridine (5 g, 0.029 mol), THF (20 ml), EtOAc (m.). After the completion of the dropwise addition, the reaction was carried out at -78 ° C for 30 min, then bromine (9.28 g, 0.058 mol) was added dropwise, and the addition was completed, and the temperature was naturally raised to - room temperature at -78 ° C. After the reaction was completely monitored by TLC, saturated sodium sulfite solution was added, and ethyl acetate was used. acetate, the organic layers were combined, dried over anhydrous sodium sulfate, the solvent was concentrated through a silica gel column to give intermediate int8 (5.811g, 81% yield), mass ^{spectrum: 248 (M + H +)} .

Synthesis of 3-bromo-4-chlorothiophene [2,3-b]pyridine (int9)

To a 100 ml three-necked flask was added 4-chlorothiophene [2,3-b]pyridine (5 g, 0.029 mol), acetic acid (20 ml), and bromine (9.28 g, 0.058 mol) was added dropwise at room temperature. After 18 h, the reaction mixture was stirred and evaporated to dryness eluted eluted eluted eluted eluted eluted eluted eluted eluted : 248 (M+H ⁺ ).

Synthesis of 2,3-dibromo-4-chlorothiophene [2,3-b]pyridine (int10)

To a 100 ml three-necked flask was added 2-bromo-4-chlorothiophene [2,3-b]pyridine (5 g, 0.029 mol), acetic acid (20 ml), and bromine (9.28 g, 0.058 mol) was added dropwise at room temperature. After the completion of the reaction, the mixture was reacted for 18 h, and then the mixture was evaporated. EtOAc EtOAc EtOAc EtOAc. ), mass spectrum: 328 (M+H ⁺ ).

Description: The same method is used for the products 18, 19, 20, 21, 22, 23, 24, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113. , synthesized with the corresponding reagent.

The starting material of the product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, and the product was obtained according to the same preparation method as the product 17 18 (2-(Thienyl [2,3-b]pyridin-3-yl)-2-cyclobutylacetic acid): mass spectrum: 266.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

Substituting the starting material 3-methyl-4-chlorothiophene [2,3-b]pyridine to int9, the same preparation as in product 17 affords the product 19 (2-(thiophene [2,3- b] Pyridin-2-bromo-3-indolyl)-2-cyclobutylacetic acid): mass spectrum: 401.0, 403.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Substituting 3-methyl-4-chlorothiophene [2,3-b]pyridine, the starting material for the preparation of product 17, with 3-(4-pyridyl)-4-chlorothiophene [2,3-b]pyridine, according to the product The same preparation method can be used to obtain the product 20 (2-(thiophene[2,3-b]pyridine-2-(pyridin-4-yl)-3-indolyl)-2-cyclobutylacetic acid): mass spectrum: 343.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 - 7.69 (m, 5H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Substituting the starting material 3-methyl-4-chlorothiophene [2,3-b]pyridine to int10, the product 21 (2-(thiophene [2,3-] can be obtained according to the same preparation method as product 17 b] Pyridine-2,3-dibromo-3-indolyl)-2-cyclobutylacetic acid): mass spectrum: 423.0, 425.0, 427.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 ( m, 2H), 2.22–1.93 (m, 2H).

The starting material for the preparation of product 17 was replaced by 3-methyl-4-chlorothiophene [2,3-b]pyridine to 3-(3-chloro-4-pyridyl)-4-chlorothiophene [2,3-b]pyridine. The product 22 (2-(thiophene[2,3-b]pyridine-2-(3-chloro-pyridin-4-yl)-3-indenyl)-2-cyclobutane can be obtained by the same preparation method as the product 17 Glycine): Mass Spectrum: 377.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 - 7.69 (m, 4H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

Substituting 3-methyl-4-chlorothiophene [2,3-b]pyridine, which is the starting material for the preparation of product 17, with 3-(4-cyanophenyl)-4-chlorothiophene [2,3-b]pyridine, according to The same preparation as in product 17 gave the product 23 (2-(thiophene[2,3-b]pyridine-2-(4-cyano-phenyl)-3-indolyl)-2-cyclobutylacetic acid) : Mass Spectrum: 367.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 - 7.69 (m, 5H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

The starting material for the preparation of product 17 was replaced by 3-methyl-4-chlorothiophene [2,3-b]pyridine to 3-(3-fluoro-4-pyridyl)-4-chlorothiophene [2,3-b]pyridine. The product 24 (2-(thiophene[2,3-b]pyridine-2-(3-fluoro-pyridin-4-yl)-3-indenyl)-2-cyclobutane can be obtained according to the same preparation method as product 17 Glycine): Mass Spectrum: 361.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 - 7.69 (m, 4H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, 2-bromo-2-cyclobutylacetate Substituting for ethyl 2-bromoacetate, the product 85 (2-(thiophene[2,3-b]pyridin-4-indolyl)-acetic acid) was obtained by the same procedure as product 17: mass spectrum: 226.1 (M+ H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, 2-bromo-2-cyclobutylacetate Substituting to ethyl 2-bromopropionate, product 86 (2-(thiophene[2,3-b]pyridin-4-indolyl)-propionic acid) can be obtained by the same preparation as product 17: mass spectrum: 240.1 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, 2-bromo-2-cyclobutylacetate Substituting for ethyl 2-bromobutyrate, product 87 (2-(thiophene[2,3-b]pyridin-4-yl)-butyric acid) was obtained by the same preparation as product 17: mass spectrum: 254.1 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08 - 1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, 2-bromo-2-cyclobutylacetate Substitution with ethyl 2-bromopentanoate gave the product 88 (2-(thiophene[2,3-b]pyridin-4-indolyl)-pentanoic acid) by mass spectrometry: 268.1 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03 - 1.78 (m, 2H), 1.57 - 1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, 2-bromo-2-cyclobutylacetate Substituting to ethyl 2-bromoisovalerate, the product 89 (2-(thiophene[2,3-b]pyridin-4-indolyl)-3-methylbutanoic acid) can be obtained according to the same preparation procedure as product 17 : Mass Spectrum: 268.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H) ).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, 2-bromo-2-cyclobutylacetate Substitution with ethyl 2-bromoisobutyrate gave the product 90 (2-(thiophene[2,3-b]pyridin-4-indolyl)-2-methylpropanoic acid) according to the same preparation as product 17 : Mass Spectrum: 254.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with 4-chlorothiophene [2,3-b]pyridine, 2-bromo-2-cyclobutylacetate Substituting ethyl 2-bromo-2-ethylbutanoate, the product 91 (2-(thiophene[2,3-b]pyridin-4-yl)-2-ethyl) can be obtained according to the same preparation procedure as product 17 Butyric acid): Mass spectrum: 282.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int8, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoacetate. the product prepared in the same method to give product 17 92 (2- (2-bromo - thieno [2,3-b] pyridin-4-mercapto-yl) - acetic acid): mass ^{Spectrum: 304.0,306.0 (M + H +)} .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H)

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int8, 2-bromo-2-cyclobutylacetate with ethyl 2-bromopropionate, according to The same preparation as the product 17 gave the product 93 (2-(2-bromo-thiophene[2,3-b]pyridin-4-indolyl)-propionic acid): mass spectrum: 318.0, 320.0 (M+H+).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int8, 2-bromo-2-cyclobutylacetate with ethyl 2-bromobutyrate, according to The same preparation as the product 17 gave the product 94 (2-(2-bromo-thiophene[2,3-b]pyridin-4-indolyl)-butyric acid): mass spectrum: 332.0, 334.0 (M+H+).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08–1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int8, 2-bromo-2-cyclobutylacetate with ethyl 2-bromopentanoate, according to The same preparation as the product 17 gave the product 95 (2-(2-bromo-thiophene[2,3-b]pyridin-4-indolyl)-pentanoic acid): mass spectrum: 346.0, 348.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03–1.78 (m, 2H), 1.57–1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int8, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoisovalerate. The product 96 (2-(2-bromo-thiophene[2,3-b]pyridin-4-indolyl)-3-methylbutanoic acid) was obtained by the same procedure as the product 17: mass spectrum: 346.0, 348.0 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int8, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoisobutyrate. The product 97 (2-(2-bromo-thiophene[2,3-b]pyridin-4-indolyl)-2-methylpropanoic acid) was obtained by the same procedure as the product 17: mass spectrum: 332.0, 334.0 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H) .

Replace the starting material 3-methyl-4-chlorothiophene [2,3-b]pyridine with int8, 2-bromo-2-cyclobutylacetate with 2-bromo-2-ethylbutyl Ethyl acetate, product 98 (2-(2-bromo-thiophene[2,3-b]pyridin-4-indolyl)-2-ethylbutanoic acid) can be obtained according to the same procedure as product 17: mass spectrum: 360.0, 362.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H).

Substituting the starting material 3-methyl-4-chlorothiophene [2,3-b]pyridine to int8, the product 99 (2-(2-bromo-thiophene) can be obtained by the same preparation method as product 17 2,3-b]pyridin-4-indenyl)-2-cyclobutylacetic acid): mass spectrum: 344.0, 346.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.86 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39–2.29 (m, 2H), 2.22–1.93 (m, 2H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int9, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoacetate. The same preparation of product 17 gave the product 100 (2-(3-bromo-thiophene[2,3-b]pyridin-4-indolyl)-acetic acid): mass spectrum: 304.0, 306.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H) .

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int9, 2-bromo-2-cyclobutylacetic acid ethyl ester with ethyl 2-bromopropionate, according to The same preparation as the product 17 gave the product 101 (2-(3-bromo-thiophene[2,3-b]pyridin-4-indolyl)-propionic acid): mass spectrum: 318.0, 320.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int9, 2-bromo-2-cyclobutylacetate with ethyl 2-bromobutyrate, according to The same preparation as in product 17 gave the product 102 (2-(3-bromo-thiophene[2,3-b]pyridin-4-indolyl)-butyric acid): mass spectrum: 332.0, 334.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08–1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int9, 2-bromo-2-cyclobutylacetate with ethyl 2-bromopentanoate, The same preparation as the product 17 gave the product 103 (2-(3-bromo-thiophene[2,3-b]pyridin-4-indolyl)-pentanoic acid): mass spectrum: 346.0, 348.0 (M+H ⁺ ) .

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03–1.78 (m, 2H), 1.57–1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int9, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoisovalerate. The product 104 (2-(3-bromo-thiophene[2,3-b]pyridin-4-indolyl)-3-methylbutanoic acid) was obtained by the same procedure as the product 17: mass spectrum: 346.0, 348.0 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int9, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoisobutyrate. The product 105 (2-(3-bromo-thiophene[2,3-b]pyridin-4-indolyl)-2-methylpropanoic acid) was obtained by the same procedure as the product 17: mass spectrum: 332.0, 334.0 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H) .

Replace the starting material 3-methyl-4-chlorothiophene [2,3-b]pyridine with int9, 2-bromo-2-cyclobutylacetate with 2-bromo-2-ethylbutyl Ethyl acetate, product 106 (2-(3-bromo-thiophene[2,3-b]pyridin-4-indolyl)-2-ethylbutanoic acid) can be obtained by the same preparation as product 17: mass spectrum: 360.0, 362.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (s, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 4H), 0.93 (t, J = 7.3 Hz, 6H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int10, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoacetate. The same preparation of product 17 gave product 107 (2-(2,3-dibromo-thiophene[2,3-b]pyridin-4-yl)-acetic acid): mass spectrum: 382.0, 384.0, 386.0 (M+ H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.46 (s, 2H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int10, and 2-bromo-2-cyclobutylacetate was replaced with ethyl 2-bromopropionate. The same preparation as in product 17 gave the product 108 (2-(2,3-dibromo-thiophene[2,3-b]pyridin-4-indolyl)-propionic acid): mass spectrum: 396.0, 398.0, 400.0 ( M+H+).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 1.57 (d, J = 7.1 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int10, 2-bromo-2-cyclobutylacetate with ethyl 2-bromobutyrate, according to The same preparation as the product 17 gave the product 109 (2-(2,3-dibromo-thiophene[2,3-b]pyridin-4-indolyl)-butyric acid): mass spectrum: 410.0, 412.0, 414.0 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.30 (t, J = 7.0 Hz, 1H), 2.08 –1.77 (m, 2H), 1.06 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int10, 2-bromo-2-cyclobutylacetic acid ethyl ester with ethyl 2-bromopentanoate, according to The same preparation as in product 17 gave the product 110 (2-(2,3-dibromo-thiophene[2,3-b]pyridin-4-indolyl)-pentanoic acid): mass spectrum: 424.0, 426.0, 428.0 ( M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.29 (t, J = 7.2 Hz, 1H), 2.03 –1.78 (m, 2H), 1.57–1.39 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int10, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoisovalerate. The product 111 (2-(2,3-dibromo-thiophene[2,3-b]pyridin-4-indolyl)-3-methylbutanoic acid) was obtained according to the same preparation procedure as product 17: mass spectrum: 424.0 , 426.0, 428.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.14 (d, J = 7.4 Hz, 1H), 2.27 (dq, J = 13.6, 6, 7 Hz, 1H), 1.31 (dd, J = 15.2, 6.7 Hz, 6H).

The starting material for the preparation of product 17 was prepared by replacing 3-methyl-4-chlorothiophene [2,3-b]pyridine with int10, 2-bromo-2-cyclobutylacetate with ethyl 2-bromoisobutyrate. The product 112 (2-(2,3-dibromo-thiophene[2,3-b]pyridin-4-indolyl)-2-methylpropanoic acid) was obtained according to the same preparation procedure as product 17: mass spectrum: 410.0 , 412.0, 414.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.54 (s, 6H).

Replace the starting material 3-methyl-4-chlorothiophene [2,3-b]pyridine with int10, 2-bromo-2-cyclobutylacetate with 2-bromo-2-ethylbutyl Ethyl acetate, product 113 (2-(2,3-dibromo-thiophene[2,3-b]pyridin-4-ylyl)-2-ethylbutanoic acid) can be obtained according to the same preparation procedure as product 17 : Mass Spectrum: 438.0, 440.0, 442.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 1.94 - 1.75 (m, 4H), 0.93 (t, J=7.3Hz, 6H).

Example 3 Synthesis of a Compound of the Invention

The reaction formula is as follows:

R ₁ is a hydrogen atom.

R _{2 is} selected from one of a hydrogen atom and a bromine atom.

R _{3 is} selected from the group consisting of methyl, 1-methoxymethyl, 1-methoxyethyl, 1-methoxypropyl, phenyl, 4-cyano-phenyl, (4-cyano-phenyl) -methyl, 3-bromo-phenyl, 4-bromo-phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-methyl-4-yl, pyridine- 2-fluoro-4-yl, pyridin-2-methoxy-4-yl, pyridin-3-methyl-yl, pyridin-4-methyl-yl, 1-(1-(pyridin-4-yl) One of ethyl, pyrimidin-2-yl, pyrimidin-3-yl, quinolin-4-yl, (3-cyano-phenyl)methyl.

R ₄ and R _{5 are} combined in a cyclobutyl or cyclopentyl group.

Specific examples:

1) Synthesis of 7-chloro-1-phenyl-1H-pyrrole [3,2-b]pyridine (Int 25.2)

To a 100 mL reaction flask was added 7-chloro-1H-pyrrole [3,2-b]pyridine (1.52 g, 10 mmol), iodobenzene (3.06 g, 15 mmol), cuprous iodide (285 mg, 1.5 mmol), 8 -Hydroxyquinoline (218 mg, 1.5 mmol), potassium carbonate (4.14 g, 30 mmol), dimethyl sulfoxide (15 ml), and the mixture was heated to 120 ° C under nitrogen for 6 hours. After the reaction was completed, water was added ( 150 mL), extracted with EtOAc (3×100 mL), EtOAc (EtOAc) MS: 229.1 (M + H ⁺ ).

2) Synthesis of 2-(1-phenyl-1H-pyrrole[3,2-b]pyridin-7-fluorenyl)-2-cyclobutylacetate (Int 25.3)

To a 100 mL reaction flask was added 7-chloro-1-phenyl-1H-pyrrole [3,2-b]pyridine (2.28 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), N-methylpyrrolidone (30 mL) The reaction was stirred at 80 ° C for 3 hours, then cesium carbonate (6.52 g, 20 mmol) and ethyl 2-bromoisobutyrate (2.15 g, 11 mmol) were added to the reaction flask, and the reaction was continued at 100 ° C for 2 hours. After the reaction is completed, water (150 mL) is added, and the mixture is extracted with ethyl acetate (3×100 ml), and the organic layer is combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then evaporated. g), yield 60%. MS: 353.1 (M+H ⁺ ).

3) Synthesis of 2-(1-phenyl-1H-pyrrole[3,2-b]pyridin-7-fluorenyl)-2-cyclobutylacetic acid (25)

Intermediate 25.3 (308 mg, 1 mmol), methanol (5 mL), water (5 mL), and lithium hydroxide (96 mg, 4 mmol) were reacted in a 100 mL reaction flask for 16 hours at room temperature. After completion of the reaction, it was neutralized with 2N hydrochloric acid to a pH of about 5 in an ice water bath, and then filtered, and the filter cake was washed with 10 mL of water, and the filter cake was dried to obtain compound 25 (227 mg) in a yield of 70%. Mass Spectrum: 226.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 5H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

Description: The products 26, 28, 29, 30, 31, 32, 33, 34, 37, 38, 43, 44, 45, 47, 49 were synthesized in the same manner using the corresponding reagents.

Substituting the starting material iodobenzene of product 25 with 4-iodopyridine, the product 26 (2-(1-(pyridin-4-yl)-1H-pyrrole [3,2-] can be obtained according to the same preparation method as product 25 b] Pyridin-7-mercapto)-2-cyclobutylacetic acid): Mass spectrum: 326.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 4H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene for the preparation of product 25 is replaced by 3-iodopyridine, and the product 28 (2-(1-(pyridin-3-yl)-1H-pyrrole [3,2-b] can be obtained by the same preparation method as product 25 Pyridine-7-mercapto)-2-cyclobutylacetic acid: mass spectrum: 326.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 4H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene for the preparation of the product 25 is replaced by 4-iodopyrimidine, and the product 29 (2-(1-pyrimidin-2-yl)-1H-pyrrole [3,2-b] can be obtained by the same preparation method as the product 25 Pyridine-7-mercapto)-2-cyclobutylacetic acid: mass spectrum: 327.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene for the preparation of product 25 is replaced by 2-methyl 4-iodopyridine, and the product 30 (2-(1-(pyridin-2-methyl-4-yl)-) can be obtained by the same preparation method as product 25 1H-Pyrrol[3,2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid): mass spectrum: 340.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material iodobenzene of the product 25 was replaced with 2-fluoro-4-iodopyridine, and the product 31 (2-(1-(pyridine-2-fluoro-4-yl)-1H-) was obtained according to the same preparation method as the product 25 Pyrrole [3,2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid: mass spectrum: 344.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene of product 25 is replaced by 2-methoxy 4-iodopyridine, and the product 32 (2-(1-(pyridine-2-methoxy-4-yl) can be obtained by the same preparation method as product 25 -1H-pyrrole[3,2-b]pyridin-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 356.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 3.31 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material iodobenzene of the product 25 was replaced with 5-iodopyrimidine, and the product 33 (2-(1-pyrimidin-3-yl)-1H-pyrrole [3,2-b] was obtained according to the same preparation method as the product 25 Pyridine-7-mercapto)-2-cyclobutylacetic acid: mass spectrum: 327.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material for the preparation of product 25 is replaced by 4-iodopyridine, and 7-chloro-1H-pyrrole [3,2-b]pyridine is replaced by 3-bromo-7-chloro-1H-pyrrole [3,2-b]pyridine. The product 34 (2-(3-bromo-1-(pyrimidin-2-yl)-1H-pyrrole[3,2-b]pyridine-7-fluorenyl)-2 can be obtained according to the same preparation method as product 25. -cyclobutylacetic acid): mass spectrum: 404.0, 406.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene for the preparation of the product 25 is replaced by 2-iodopyridine, and the product 37 (2-(1-(pyridin-2-yl)-1H-pyrrole [3,2-b] can be obtained by the same preparation method as the product 25 Pyridine-7-mercapto)-2-cyclobutylacetic acid: mass spectrum: 326.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene for the preparation of product 25 is replaced by 4-iodopyridine, and the product 38 (2-(1-(pyridin-4-yl)-1H-pyrrole [3,2-b] can be obtained by the same preparation method as product 25 Pyridine-7-sulfinyl)-2-cyclobutylacetic acid: mass spectrum: 342.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 4H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene of the product 25 was replaced with 4-cyanoiodobenzene, and the product 43 (2-(1-cyano-phenyl)-1H-pyrrole [3] was obtained according to the same preparation method as the product 25 , 2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid): Mass Spectrum: 350.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene of the product 25 was replaced with 3-bromoiodobenzene, and the product 44 (2-(1-(3-bromo-phenyl)-1H-pyrrole [3, 2] was obtained by the same preparation method as the product 25 -b]pyridine-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 403.0, 405.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene for the preparation of product 25 is replaced by 4-bromoiodobenzene, and the product 45 (2-(1-(4-bromo-phenyl)-1H-pyrrole [3, 2] can be obtained by the same preparation method as product 25 -b]pyridine-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 403.0, 405.0 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene of the product 25 was replaced with 4-iodoquinoline, and the product 47 (2-(1-(quinolin-4-yl)-1H-pyrrole [3, 2] was obtained by the same preparation method as the product 25 -b]pyridine-7-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 376.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 6H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The starting material iodobenzene for the preparation of the product 25 is replaced by 4-iodopyridine, and the 2-bromo-2-cyclobutylacetic acid ethyl ester is replaced by ethyl 2-bromo-2-cyclopentylacetate, which is the same preparation method as the product 25 The product 49 (2-(1-(pyridin-4-yl)-1H-pyrrole[3,2-b]pyridin-7-fluorenyl)-2-cyclopentyl acetic acid) can be obtained: mass spectrum: 340.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 4H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 4H).

Example 4 Synthesis of Compounds 27, 35, 36, 39, 40, 41, 42, 46, 48, 57

1) Synthesis of the intermediate 7-chloro-1-methyl-1H-pyrrole [2,3-b]pyridine (int27-1)

The compound 7-chloro-1H-pyrrole[2,3-b]pyridine (1 g, 0.52 mmol) was dissolved in EtOAc (10 mL), EtOAc (EtOAc, EtOAc, Stir at room temperature. After TLC was monitored, the reaction was completed, and then 25 mL of water and EA (10 mL X 3 ) was added and dried over anhydrous sodium sulfate. After drying, the solid was beaten with EA hot and filtered to give 0.7 g of compound. The yield was 89%. MS: 167.1 (M+H+).

2) Synthesis of 2-(1-methyl-1H-pyrrole[3,2-b]pyridin-7-fluorenyl)-2-cyclobutylacetate (Int 27-2)

To a 100 mL reaction flask was added 7-chloro-1-methyl-1H-pyrrole [3,2-b]pyridine (2.28 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), N-methylpyrrolidone (30 mL) The reaction was stirred at 80 ° C for 3 hours, then cesium carbonate (6.52 g, 20 mmol) and ethyl 2-bromoisobutyrate (2.15 g, 11 mmol) were added to the reaction flask, and the reaction was continued at 100 ° C for 2 hours. After the reaction is completed, water (150 mL) is added, and the mixture is extracted with ethyl acetate (3×100 ml), and the organic layer is combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and then evaporated. (2.11 g), yield 60%. MS: 291.1 (M+H ⁺ ).

3) Synthesis of 2-(1-methyl-1H-pyrrole[3,2-b]pyridin-7-fluorenyl)-2-cyclobutylacetic acid (27)

Intermediate 27-2 (291 mg, 1 mmol), methanol (5 mL), water (5 mL), and lithium hydroxide (96 mg, 4 mmol) were reacted in a 100 mL reaction flask for 16 hours at room temperature. After the reaction is completed, it is neutralized with 2N hydrochloric acid to a pH of about 5 in an ice water bath, and then filtered, and the filter cake is washed with 10 mL of water, and the cake is dried to obtain a compound (2-(1-methyl-1H-pyrrole [3] , 2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid) 27 (227 mg), yield 70%: mass spectrum: 263.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

Description: The products 35, 36, 39, 40, 41, 42, 46, 48, 57 were synthesized in the same manner using the corresponding reagents.

The starting material methyl iodide of the product 27 was replaced with 3-(bromomethyl)pyridine, and the product 35 (2-(1-(pyridin-3-methyl-yl)-1H-) was obtained according to the same preparation procedure as the product. Pyrrole [3,2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid: mass spectrum: 340.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 4.23 (s, 2H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material methyl iodide of product 27 was replaced by 4-(bromomethyl)pyridine, and the same preparation as in product 27 gave product 36 (2-(1-(pyridin-4-methyl-yl)-1H-). Pyrrole [3,2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid: mass spectrum: 340.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 4.23 (s, 2H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material methyl iodide of the product 27 was replaced with 1-methoxymethyl chloride, and the product 39 (2-(1-methoxymethyl-1H-pyrrole [3, 2] was obtained by the same preparation method as the product 27 -b]pyridine-7-sulfinyl)-2-cyclobutylacetic acid): mass spectrum: 293.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.23 (s, 2H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H) ).

The starting material methyl iodide for the preparation of product 27 was replaced by 1-methoxyethyl chloride, and the product 40 (2-(1-methoxyethyl-1H-pyrrole [3, 2] was obtained by the same preparation method as product 27 -b]pyridine-7-sulfinyl)-2-cyclobutylacetic acid): mass spectrum: 307.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.23-4.53 (m, 4H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material methyl iodide for the preparation of product 27 was replaced by 1-methoxypropyl chloride, and the product 41 (2-(1-methoxypropyl-1H-pyrrole [3, 2] was obtained by the same preparation method as product 27 -b]pyridine-7-sulfinyl)-2-cyclobutylacetic acid: mass spectrum: 321.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 4.23-4.53 (m, 6H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material methyl iodide of product 27 was replaced by 4-cyanobenzyl bromide. The product 42 (2-(1-(4-cyano-phenyl)-methyl)- 1H-Pyrrol[3,2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid): Mass Spectrum: 364.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 4.23 (s, 2H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material methyl iodide of product 27 was replaced with 4-(2-bromoethyl)pyridine, and the product 46 (2-(1-(1-(pyridin-4-yl))) was obtained by the same preparation method as product 27 Base-2-)-1H-pyrrole[3,2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid): mass spectrum: 354.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 4H), 7.23 (d, J = 5.0 Hz, 1H), 4.23 (m, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 5H), 2.22 - 1.93 (m , 2H).

The starting material methyl iodide of the product 27 was replaced with 3-cyanobenzyl bromide, and the product 48 (2-(1-(3-cyano-phenyl)methyl)-1H) was obtained according to the same preparation procedure as the product - Pyrrole [3,2-b]pyridin-7-mercapto)-2-cyclobutylacetic acid): Mass Spectrum: 364.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 4H), 7.23 (d, J = 5.0 Hz, 1H), 4.23 (s, 2H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material methyl iodide of product 27 was replaced with 2-bromo-2-cyclobutylacetic acid ethyl ester. The product 57 (2-(1H-pyrrole[3,2-b]pyridine) was obtained by the same preparation method as product 27 -7-Chloro)-2-cyclobutylacetic acid): Mass Spectrum: 251.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

Example 5 Synthesis of a Compound of the Invention

The reaction formula is as follows:

R ₁ is a hydrogen atom.

R _{2 is} selected from one of a hydrogen atom, a pyridin-4-yl group, and a 4-cyano-phenyl group.

R _{3 is} selected from one of a methyl group, a pyridin-3-yl group, and a 2-fluoro-pyridin-4-yl group.

R ₄ and R _{5 are} combined to form a cyclobutyl group.

Specific examples:

1) Synthesis of 4-chloro-1-(pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine (Int 51.2)

To a 100 mL reaction vial was added 4-chloro-1H-pyrrole[2,3-b]pyridine (1.52 g, 10 mmol), 3-iodopyridine (3.08 g, 15 mmol), cuprous iodide (285 mg, 1.5 mmol) , 8-hydroxyquinoline (218mg, 1.5mmol), potassium carbonate (4.14g, 30mmol), dimethyl sulfoxide (15ml), under nitrogen protection, heated to 120 ° C, stirred for 6 hours, after the reaction is completed, added The mixture was extracted with EtOAc (3 mL, EtOAc (EtOAc) %. MS: 230.1 (M + H ⁺ ).

2) Synthesis of 2-(1-(pyridin-3-yl)-1H-pyrrole[2,3-b]pyridin-4-indenyl)-2-cyclobutylacetate (Int 51.3)

To a 100 mL reaction vial was added 4-chloro-1-(pyridin-3-yl)-1H-pyrrole[2,3-b]pyridine (2.29 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), N- Methylpyrrolidone (30 mL), heated to 80 ° C, stirred for 3 hours, then added cesium carbonate (6.52 g, 20 mmol) and ethyl 2-bromoisobutyrate (2.15 g, 11 mmol) to the reaction flask, continuing at 100 After reacting at °C for 2 hours, after completion of the reaction, water (150 mL) was added, and the mixture was extracted with ethyl acetate (3×100 ml). The organic layer was combined, washed with brine, dried over anhydrous sodium sulfate, filtered, Intermediate 51.3 (2.11 g), yield 60%. MS: 354.1 (M + H ⁺ ).

3) Synthesis of 2-(1-(pyridin-3-yl)-1H-pyrrole[2,3-b]pyridin-4-indolyl)-2-cyclobutylacetic acid (51)

Intermediate 51.3 (353 mg, 1 mmol), methanol (5 mL), water (5 mL), and lithium hydroxide (96 mg, 4 mmol) were reacted in a 100 mL reaction flask for 16 hours at room temperature. After completion of the reaction, it was neutralized with 2N hydrochloric acid to a pH of about 5 in an ice water bath, then filtered, and the filter cake was washed with 10 mL of water, and the cake was dried to give compound 51 (227 mg), yield 70%. Mass spectrum: 326.1 (M+H ⁺ ).

^{1 H NMR (400MHz, DMSO)} : δ (ppm) 13.09 (s, 1H), 8.89 (d, J = 4.0Hz, 1H), 8.51 (d, J = 4.0Hz, 1H), 7.96 (dt, J = 4.0 Hz, 2H), 7.64 (d, J = 4.0 Hz, 1H), 1.55 (s, 6H).

Description: Product 52 was synthesized in the same manner using the corresponding reagent.

The starting material 3-yodopyridine of the product 51 was replaced by 2-fluoro-4-iodopyridine, and the product 52 (2-(1-(2-fluoro-pyridin-4-yl)-) was obtained by the same preparation method as the product 51. 1H-Pyrrol[2,3-b]pyridin-4-indolyl)-2-cyclobutylacetic acid): Mass Spectrum: 344.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

Example 6, Synthesis of Compounds 50, 53, 54

1) Synthesis of 2-(1-methyl)-1H-pyrrole[2,3-b]pyridin-4-indenyl)-2-cyclobutylacetate (Int 51.3)

To a 100 mL reaction flask was added 4-chloro-1-methyl-1H-pyrrole [2,3-b]pyridine (2.29 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), N-methylpyrrolidone (30 mL) The reaction was stirred at 80 ° C for 3 hours, then cesium carbonate (6.52 g, 20 mmol) and 2-bromocyclobutylacetate (2.15 g, 11 mmol) were added to the reaction flask, and the reaction was continued at 100 ° C for 2 times. After the completion of the reaction, water (150 mL) was added, and the mixture was extracted with EtOAc EtOAc (EtOAc) 2.11 g), yield 60%. MS: 354.1 (M + H ⁺ ).

2) Synthesis of 2-(1-methyl)-1H-pyrrole[2,3-b]pyridin-4-indenyl)-2-cyclobutylacetic acid (51)

Intermediate 50.3 (353 mg, 1 mmol), methanol (5 mL), water (5 mL), and lithium hydroxide (96 mg, 4 mmol) were reacted in a 100 mL reaction flask for 16 hours at room temperature. After completion of the reaction, it was neutralized with 2N hydrochloric acid to a pH of about 5 in an ice water bath, then filtered, and the filter cake was washed with 10 mL of water, and the cake was dried to give compound 50 (227 mg), yield 70%. Mass Spectrum: 263.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

Description: The products 53, 54 were synthesized in the same manner using the corresponding reagents.

The starting material for the preparation of product 50 is 4-chloro-1-methyl-1H-pyrrole [2,3-b]pyridine substituted with 3-(4-pyridyl)-4-chloro-1-methyl-1H-pyrrole [2 , 3-b]pyridine, according to the same preparation method as product 50 to give the product 53 (2-(1-methyl-4-(pyridin-4-yl)-1H-pyrrole[2,3-b]pyridine 4-Mercapto)-2-cyclobutylacetic acid): Mass Spectrum: 340.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

The starting material for the preparation of product 50 is 4-chloro-1-methyl-1H-pyrrole[2,3-b]pyridine substituted with 3-(4-cyanophenyl)-4-chloro-1-methyl-1H-pyrrole [2,3-b]pyridine, product 54 (2-(1-cyano-4-(4-cyano-phenyl)-1H-pyrrole [2,3] can be obtained according to the same preparation as product 50 -b]pyridin-4-indenyl)-2-cyclobutylacetic acid): mass spectrum: 340.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.63 – 7.39 (m, 3H), 7.23 (d, J = 5.0 Hz, 1H), 3.23 (s, 3H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m , 2H).

Example 7. Synthesis of a compound of the invention

The reaction formula is as follows:

Specific examples:

1) Synthesis of 2-(3-bromo-imidazo[1,2-a]pyridin-5-fluorenyl)-2-cyclobutylacetate (Int 55.1)

To a 100 mL reaction flask was added 3-bromo-5-chloro-imidazole [1,2-a]pyridine (2.32 g, 10 mmol), sodium sulfide (1.17 g, 15 mmol), N-methylpyrrolidone (30 mL), and heated. The reaction was stirred at 80 ° C for 3 hours, then cesium carbonate (6.52 g, 20 mmol) and ethyl 2-bromoisobutyrate (2.15 g, 11 mmol) were added to the reaction flask, and the reaction was continued at 100 ° C for 2 hours. After that, water (150 mL) was added, and the mixture was extracted with EtOAc EtOAc EtOAc EtOAc. The yield was 60%. MS: 356.0, 358.0 (M + H ⁺ ).

2) Synthesis of 2-(3-bromo-imidazo[1,2-a]pyridin-5-fluorenyl)-2-cyclobutylacetic acid (55)

Intermediate 55.2 (356 mg, 1 mmol), methanol (5 mL), water (5 mL), and lithium hydroxide (96 mg, 4 mmol) were reacted in a 100 mL reaction flask for 16 hours at room temperature. After completion of the reaction, it was neutralized with 2N hydrochloric acid to a pH of about 5 in an ice water bath, and then filtered, and the filter cake was washed with 10 mL of water, and the filter cake was dried to obtain Compound 55 (227 mg) in a yield of 70%. Mass spectrum: 328.0, 330.0 (M+H ⁺ ).

^{1 H NMR (400MHz, DMSO)} : δ (ppm) 13.09 (s, 1H), 8.89 (d, J = 4.0Hz, 1H), 8.51 (d, J = 4.0Hz, 1H), 7.96 (dt, J = 4.0 Hz, 2H), 7.64 (d, J = 4.0 Hz, 1H), 1.55 (s, 6H).

Note: Product 56 was synthesized in the same manner using the corresponding reagent.

The starting material for the preparation of product 55, 3-bromo-5-chloro-imidazole [1,2-a]pyridine, was replaced with 5-chloroimidazo[1,2-a]pyrimidine, which was obtained according to the same preparation procedure as product 55. (2-(Imidazo[1,2-a]pyridin-5-fluorenyl)-2-cyclobutylacetic acid): mass spectrum: 250.1 (M+H ⁺ ).

¹ H NMR (DMSO-d ₆ , 400 MHz): δ 8.67 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 5.8 Hz, 1H), 7.23 (d, J = 5.0 Hz, 1H), 2.93 - 2.79 (m, 2H), 2.39 - 2.29 (m, 2H), 2.22 - 1.93 (m, 2H).

The advantageous effects of the present invention will be described below by way of test examples.

Test Example 1. Determination of biological activity of the compound of the present invention

Test Example: Determination of the inhibitory activity of the compound of the present invention on URAT1

1) Experimental materials:

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

Trypsin (Invitrogen, Cat. No. 25200056)

Phosphate buffer (Invitrogen, Cat. No. 14190250)

Durbuco Modified Eagle Medium (Invitrogen, Cat. No. 10564)

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

Transfer to IT-293 Transfection Reagent (MIRUS BIO, Cat. No. MIR2706)

Serum-free optimized and improved Eagle's medium (Invitrogen, Cat. No. 31985-070)

Urate Anion Transporter 1 Plasmid (Genecopoeia, Cat. No. EX-T4563-M03)

Uric acid [8-14C] (ARC, Cat. No. ARC0513-250UCI)

Ultimate ^TM XR gold scintillation fluid (PerkinElmer, Cat.No.6013111)

Benzobromarone (Belling Technology, Cat. No. 3562-84-3)

D-gluconate sodium salt (Aladdin, Cat. No. 527-07-1)

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

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

Dimethyl sulfoxide (Sigma, Cat. No. D2650)

Centrifuge tube, 15ml (Greiner, Cat.No.07030115)

Centrifuge tube, 50ml (BD Falcon, Cat. No. 352098)

Poly D-lysine 96 microplate (BD, Cat. No. 356461)

Isolation of 96 microplates (PERKIN ELMER, Cat. No. 6005040)

2) Experimental method:

i) Buffer preparation:

Ii) Cell culture:

1 HEK-293T cells stably expressing hURAT1 were cultured in 10% FBS and 1% P/S DMEM medium, and cultured overnight in a 37-degree incubator with 5% carbon dioxide.

2 The medium was removed, washed once with PBS, and then trypsinized for 2 minutes. After the cells were separated in the culture dish, 10 ml of the medium was added to terminate the digestion.

3 Place the cells in a centrifuge for 1000 minutes at 1000 rpm, add a new 10 ml medium to resuspend the cells, and count the number of cells. The number of cells was adjusted to ⁴ x 10 ⁵ cells per ml.

4 The above counted cells were seeded into 96-well plates at 100 μL per well.

5 The 96-well plates inoculated with the cells were placed in a 37-degree cell culture incubator overnight.

Iii) Isotope carbon 14 labeled uric acid absorption experiment:

1 Add 5 ml of Cl-free HBSS buffer to a 15 ml centrifuge tube, then add carbon 14-labeled uric acid to bring the concentration of uric acid to 2 uCi/ml.

2 The medium in the 96-well plate that had been cultured overnight was sucked up and washed three times with 100 ml of pre-warmed Cl-free HBSS buffer.

3 Soak the buffer in the cleaned 96-well plate.

On each of the cleaned 96-well plates, 50 μl of Cl-free HBSS buffer containing carbon 14-labeled uric acid was added to each well, followed by the addition of the DMSO solution of the compound to be tested.

5 After the above 96-well plate was allowed to stand at room temperature for 5 minutes, all the liquid inside was drained.

6 Wash three times with 100 ml of pre-cooled Cl-free HBSS buffer.

7 After sucking up the remaining liquid in the plate, add 50 μl of cell lysate to each well and shake at a speed of 600 rpm for 10 minutes on a mixer.

⑧ 50 l Ultima Gold ^TM XR scitillation cocktail after scintillation fluid, shaking continued for 10 minutes.

After the oscillating plate was pasted with a sealing film, it was read on a MicroBeta Trilux.

9 The test compound was dissolved in DMSO, and then the same concentration of DMSO was added to the HEK293/hURAT1 cell well containing no test compound. Uric acid uptake of cells at each test concentration was expressed as the average percent inhibition of the DMSO control. The radioactivity value obtained for the wells containing DMSO is considered to be 100% uptake of the cells. The IC50 value of a compound can be calculated from the inhibition rate at different concentrations.

The activity data of the above compounds of the present invention are as follows:

Tests have shown that the compounds of the examples of the present invention have good URAT1 inhibitory activity, can be used for the treatment of gout and hyperuricemia, and can also be used for recurrent gout attacks, gouty arthritis, hypertension, cardiovascular diseases, coronary heart disease. , Lai-naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, nodules Treatment of disease or secondary jaundice-guanine phosphoribosyltransferase deficiency and other diseases with abnormal URAT1 activity.

In summary, the novel compound represented by the formula (A) disclosed in the present invention exhibits a good URAT1 inhibitory activity, and provides a new medicinal possibility for clinical treatment of diseases associated with abnormal URAT1 activity.

Claims (29)

a compound represented by the formula (A), or an optical isomer thereof, or a solvate thereof, or a pharmaceutically acceptable salt thereof, or a prodrug thereof,

W ₁ , W ₂ , W ₃ are each independently selected from NR ^b , S, O or CR ^a ; W ₄ , W ₅ is C, N; Z is selected from O or -NH-; R ₁ , R ₂ , R ₅ , R ₆ are each independently selected from hydrogen, halogen, cyano, nitro, alkyl, cycloalkyl, substituted aryl, haloalkyl or alkyl containing one or more oxygen and Cycloalkyl; When Z is selected from O, R _{7 is} selected from hydrogen or a C ₁ -C ₆ alkyl group; when Z is selected from -NH-, R _{7 is} selected from hydrogen, aryl, alkyl or alkyl-substituted sulfonyl; R ^a , R ^b , R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ^d , -S(O) _m R ^d , -C(O)R ^d , C(O)OR ^d , -C(O)NR ^e R ^f , -NR ^e R ^f or NR ^e C(O) R ^f , or R ₃ , R _{4 are} combined to be a cycloalkyl group and a substituted cycloalkyl group, wherein the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are each independently Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, oxo, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, Heteroaryl, -OR ^d , -S(O) _m R ^d , -C(O)R ^d , C(O)OR ^d , -C(O)NR ^e R ^f , -NR ^e R ^f or NR ^e Substituted by a substituent of C(O)R ^f ; R ^{d is} selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are independently Optionally further one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, hetero Substituted with a substituent of an aryl group, a carboxyl group, a carboxylate group, -C(O)NR ^e R ^f , -NR ^e R ^f or NR ^e C(O)R ^f ; R ^e and R ^f are each independently selected from hydrogen, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Optionally, independently, further selected from one or more selected from the group consisting of halogen, cyano, nitro, hydroxy, oxo, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl Substituted by a substituent of a heteroaryl group, a carboxyl group, or a carboxylate group; and m is 0, 1 or 2; When R ₃ and R _{4 are} combined to be a cyclobutyl group and W ₃ is S, and R ₁ is hydrogen, R _{2 is} not hydrogen or a bromine atom; When R ₃ and R _{4 are} combined to be a cyclobutyl group and W ₁ is S, and R ₂ is hydrogen, R _{1 is} not a bromine atom; When R ₃ and R _{4 are} both methyl and W ₁ is S and R ₂ is hydrogen, R _{1 is} not hydrogen or a bromine atom. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound has the following formula (II):

Wherein R _{1 is} selected from the group consisting of hydrogen, alkyl, halogen, aryl or substituted aryl, and amide; R _{2 is} selected from the group consisting of hydrogen, alkyl, halogen, and cyano; R ₃ and R ₄ are each independently selected from hydrogen, an alkyl group, or a combination of R ₃ and R ₄ is a cycloalkyl group; When R ₃ and R _{4 are} combined to be a cyclobutyl group and R ₁ is hydrogen, R _{2 is} not a hydrogen or a bromine atom. The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R _{1 is} selected from a hydrogen atom, a chlorine atom, a bromine atom, One of a methyl group, a phenyl group, and an amide group. The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the R _{2 is} selected from a hydrogen atom, a chlorine atom, a bromine atom, One of the cyano groups. The compound according to claim 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ₃ and R ₄ are each independently selected from a hydrogen atom and a methyl group. One of ethyl, propyl, isopropyl, or a combination of R ₃ and R ₄ is a cyclobutyl group. The compound according to any one of items 2 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is the following compound 1, 4-16, Any of 58-84:

The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound has the following formula (III):

Wherein R _{1 is} selected from the group consisting of alkyl, halogen, and hydrogen; R _{2 is} selected from the group consisting of an alkyl group, a halogen, a substituted aryl group, and hydrogen; R ₃ , R ₄ are each selected from alkyl, hydrogen, or R ₃ and R _{4 are} combined to form a cycloalkyl group; When R ₃ and R _{4 are} combined to form a cyclobutyl group, R _{1 is} not a bromine atom; When R ₃ and R _{4 are} both methyl and R ₂ is hydrogen, R _{1 is} not hydrogen or a bromine atom. The compound according to claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R _{1 is} selected from one of a hydrogen atom and a bromine atom . The compound according to claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the R _{2 is} selected from the group consisting of a hydrogen atom, a bromine atom, and a methyl group. One of pyridine, 3-chloropyridine, and p-cyanophenyl. The compound according to claim 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ₃ and R ₄ are each independently selected from a hydrogen atom and a methyl group. One of ethyl, propyl, isopropyl, or a combination of R ₃ and R ₄ is a cyclobutyl group. The compound according to any one of items 7 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is the following compound 17-24, 85- 89, 91-96, 98, 100-113:

The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound has the following formula (IV):

Wherein R ₁ is an alkyl group or hydrogen; R _{2 is} selected from the group consisting of alkyl, halogen or hydrogen; R _{b is} selected from the group consisting of an alkyl group, a methoxyalkyl group, an aryl group, a heteroaryl group, and a substituted aryl group or a heteroaryl group; R ₃ and R ₄ are each selected from alkyl or hydrogen, or R ₃ and R _{4 are} combined to form a cycloalkyl group. The compound according to claim 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ₁ is a hydrogen atom. The compound according to claim 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R _{2 is} selected from one of a hydrogen atom and a bromine atom . The compound according to claim 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the R _{b is} selected from the group consisting of methyl and 1-methoxy , 1-methoxyethyl, 1-methoxypropyl, phenyl, 4-cyano-phenyl, (4-cyano-phenyl)-methyl, 3-bromo-phenyl, 4 -Bromo-phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridin-2-methyl-4-yl, pyridin-2-fluoro-4-yl, pyridin-2-yl Oxy-4-yl, pyridine-3-methyl-yl, pyridin-4-methyl-yl, 1-(1-(pyridin-4-yl)ethyl, pyrimidin-2-yl, pyrimidine-3- a group of a quinolin-4-yl group or a (3-cyano-phenyl)methyl group; And/or, R ₃ and R ₄ are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group, or a combination of R ₃ and R ₄ is a cyclobutyl group. The compound according to any one of 12 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is the following compound 25-49, 57 Any of the following:

The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound has the following formula (V):

Wherein R ₁ is an alkyl group or hydrogen; R _{2 is} selected from the group consisting of an alkyl group, an aryl group, a heteroaryl group or a hydrogen; R _{b is} selected from the group consisting of an alkyl group, a methoxyalkyl group, an aryl group, a heteroaryl group, and a substituted aryl group or a heteroaryl group; R ₃ and R ₄ are each selected from alkyl or hydrogen, or R ₃ and R _{4 are} combined to form a cycloalkyl group. The compound according to claim 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ₁ is a hydrogen atom. The compound according to claim 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the R _{2 is} selected from a hydrogen atom, a pyridin-4-yl group, One of 4-cyano-phenyl groups. The compound according to claim 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the Rb is selected from the group consisting of methyl, pyridin-3-yl, 2 a one of -fluoro-pyridin-4-yl; And/or, R ₃ and R ₄ are each selected from the group consisting of a hydrogen atom, a methyl group, an ethyl group, a propyl group, and an isopropyl group, or a combination of R ₃ and R ₄ is a cyclobutyl group. The compound according to any one of items 17 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is any one of the following compounds 50-54 One:

The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound has the following formula (VI):

Wherein R ₁ is an alkyl group; R _{2 is} selected from the group consisting of an alkyl group and a halogen; R ₃ and R _{4 are} combined to form a cyclobutyl group. The compound according to claim 22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ₁ is a hydrogen atom. The compound according to claim 22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein R ₁ is a hydrogen atom or a bromine atom. The compound according to any one of 22 to 24, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the compound is the following compound 55 or compound 56:

A process for the preparation of a compound according to claims 1 to 25, which comprises the steps of:

Or follow the steps below:

Or follow the steps below:

Or follow the steps below:

Or follow the steps below:

The use of the compound according to any one of claims 1 to 25, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a URAT1 inhibitor. The use according to claim 27, characterized in that the medicament is for preventing and/or treating gout, recurrent gout attack, gouty arthritis, hyperuricemia, hypertension, cardiovascular disease, coronary heart disease, Lai -naphthalene syndrome, Kay-Sei's syndrome, kidney disease, kidney stones, kidney failure, joint inflammation, arthritis, urolithiasis, lead poisoning, hyperparathyroidism, psoriasis, sarcoidosis or A drug of hypoxanthine-guanine phosphoribosyltransferase deficiency, preferably, the drug is a drug for preventing and/or treating gout or hyperuricemia. A pharmaceutical composition comprising the compound according to any one of claims 1 to 25, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as an active ingredient, Formulations prepared with pharmaceutically acceptable excipients.