WO2018090921A1 - Urat1 inhibitor and use thereof - Google Patents

Abstract

Disclosed are a class of URAT1 inhibitor compounds and the use of such compounds. These compounds are compounds represented by the structure of formula (I) or pharmaceutically acceptable salts thereof. Experiments show that the compounds provided by the present invention have a very good inhibitory effect on hURAT1-transported uric acid in HEK293 transfected cells, and show that such compounds have a good potential for application in the treatment of hyperuricemia or gout.

Description

URAT1 inhibitor and its application Technical field

The invention belongs to the field of medicinal chemistry, and in particular relates to a class of URAT1 inhibitor compounds and the use of such compounds.

Background technique

Uric acid is the end product of sputum metabolism in the human body. Due to the lack of uric acid degrading enzymes in the human body, blood uric acid cannot be further decomposed, and excess uric acid needs to be excreted through the kidneys and intestines. The kidney is the main organ for uric acid excretion, accounting for about 70% of human uric acid excretion. Therefore, the ability of uric acid to transport in the kidney can directly regulate the level of blood uric acid. When the body is metabolically disordered, the amount of uric acid is increased, or excessive intake of sorghum food, and the kidneys are poorly excreted in uric acid, uric acid will accumulate in the blood, resulting in hyperuricemia. It is generally believed that uric acid content in male serum exceeds 7 mg/dL, and hyperuricemia is high in female serum when uric acid content exceeds 6 mg/dL. About 80-85% of patients with hyperuricemia are caused by poor uric acid excretion in the kidneys, which makes the uric acid accumulate in the blood (Cheeseman C. Solute carrier family 2, member 9 and uric acid homeostasis. Current Opinion in Nephrology and Hypertension, 2009, 18(5): 428-432). When the blood uric acid concentration in the human body is saturated, urate crystals are formed and deposited in joints, tendons, kidneys, etc., and gout is formed (Richette P, Bardin T. Gout. Lancet. 2010, 375 (9711): 318-328) . Gout can cause urate nephropathy and urinary acid urinary calculi, and lead to renal insufficiency; gout and hyperuricemia are also significantly positively associated with hyperlipidemia, hypertension, diabetes, atherosclerosis and other diseases (Rho YH, Woo JH, Choi SJ, et al. Association between serum uric acid and the adult treatment panel III-defined metabolic syndrome: results from a single hospital database. Metabolism. 2008, 57: (1) 71-76). Gout and hyperuricemia seriously affect people's health and quality of life.

Gout is the second largest metabolic disease after diabetes, and has been listed by the United Nations as one of the top 20 chronic diseases in the 21st century. With the improvement of human living standards and the prolongation of human life expectancy, the incidence of hyperuricemia and gouty disease is increasing. The incidence of gout in the general population is about 1-2%, and the incidence rate in developed countries is higher. A 2007-2008 survey reported that the number of gout patients in the United States has reached 8.3 million. The incidence of gout in the UK and Germany between 2000 and 2005 has reached 1.4% (Annemans L, Spaepen E, Gaskin M, et al. Gout in the UK and Germany: prevalence, comorbidities, and management in general practice 2000-2005.Annals Of the Rheumatic Diseases, 2008, 67(7): 960-966). The incidence of gout in China has risen sharply in the past decade or so, according to reports The number of patients with gout in China has exceeded 50 million, and the probability of male gout is much higher than that of women. An epidemiological study of 3978 people aged 40-74 in Shanghai City in 2010 showed that about 25% of men suffer from hyperuricemia (Raquel Villegas, Xiang YB, Cai QY, et al. Prevalence and determinants). Of hyperuricemia in middle-aged, urban Chinese men. Metabolic Syndrome and Related Disorders, 2010, 8(3): 263-270). About 5-12% of patients with hyperuricemia will eventually develop into gout (Peng Jianjun, Sun Feiyang. Cycloalkyl formic acid derivatives, preparation methods thereof and their application in medicine. Shanghai Hengrui Pharmaceutical Co., Ltd. WO2014183555A1) .

The drugs for treating acute episodes of gout mainly include colchicine, non-steroidal anti-inflammatory drugs, adrenocorticotropic hormone, glucocorticoids and other analgesic and anti-inflammatory drugs. Colchicine has a good effect on the acute attack of gout, but it has very serious adverse reactions such as diarrhea, vomiting, abdominal pain and phlegm; many non-steroidal anti-inflammatory drugs have serious gastrointestinal reactions. These drugs only temporarily relieve the patient's pain, can not reduce the blood uric acid concentration in the body and remove the urate deposited in the body.

To fundamentally treat gout, blood uric acid must be controlled to normal levels by taking a uric acid-lowering drug. Reducing uric acid levels in the body is a long-term treatment, mainly by inhibiting uric acid production and uric acid excretion.

Xanthine oxidase is a catabolic enzyme of nucleotides in the body and a key enzyme for the production of uric acid. The uric acid production inhibitor is targeted by xanthine oxidase, which reduces the production of uric acid by inhibiting its action, thereby effectively reducing blood uric acid. Level. The main drugs are: allopurinol and febuxostat. Allopurinol is used in large doses and can cause severe allergic rash. This allergic rash is sometimes fatal, and the drug also has serious side effects such as liver damage. In 2009, the non-Bustains listed in Europe and the United States also have very serious cardiovascular and gastrointestinal side effects, which can also cause headaches and certain liver damage, making gout patients unable to take febuxostat for a long time to achieve normal uric acid concentration in the body. Level.

Another major route to treating gout is to promote uric acid excretion. Its mechanism of action is to inhibit the transport of uric acid by human urate anion transporter 1 (hURAT1) in renal proximal tubular epithelial cells, and reduce the reabsorption of uric acid in the proximal convoluted tubules of the kidney, thereby promoting the kidney to uric acid. Excretion. hURAT1 is specifically expressed on the brush border membrane of human renal proximal tubular epithelial cells, and is the most important uric acid reabsorption protein in human body, controlling the reabsorption of uric acid after glomerular filtration by more than 90% (Wempe MF, Jutabha P, Quade B, et al. Developing potent human uric acid transporter 1 (hURAT1) inhibitors. Journal of Medicinal Chemistry. 2011, 54: 2701-2713). hURAT1 is encoded by the SLC22A12 gene and has multiple mutations that cause uric acid metabolism abnormalities. A meta-analysis indicates that the SLC22A12 gene contributes 0.13% to the blood uric acid level. (So A, Thorens B. Uric acid transport and disease. Journal of Clinical Investigation, 2010, 120(6): 1791-1799).

Clinically, the uric acid excretion drug URAT1 inhibitor, which is mainly used for the treatment of gout, includes benzbromarone. (Benzbromarone), Zurampic, probenecid and sulfinazolidone. AstraZeneca's Zurampic was approved in the United States and Europe in December 2015 and February 2016 at a dose of 200 mg/day in combination with allopurinol, which is far less effective than benzbromarone; and the US FDA requires a black frame for Zurampic It is indicated in the instructions for its severe renal toxicity, which also has very serious cardiovascular and other side effects. The effects of probenecid and sulfinpyrazone are very poor, and the dosage is large and the side effects are large.

Benzolamonone is still one of the most effective uric acid excretion drugs in the world, and its chemical name is 3,5-dibromo-4-hydroxyphenyl-2-ethyl-3-benzofuranyl-ketone. It was developed by the French company Snaofi-Synthelabo and was launched in 1976. However, due to the severe liver toxicity of benzbromarone, it failed to enter the US market. In 2003, it also withdrew from some European countries (Jansen TL, Reinders MK, van Roon EN, et al. Benzbromarone with drawn from the European market: another case of "absence of evidence is evidence of absence". Clinical Experimental Rheumatology, 2004, 22(5): 651). Another disadvantage of this drug is its strong inhibitory effect on CYP2C9 in the liver P450 enzyme system. In addition to causing liver toxicity, it also causes drug-drug interaction. However, due to the lack of good anti-gout drugs in the market, there are still more than 20 countries in China, Germany, Japan, Brazil, and New Zealand.

Studies have shown that benzbromarone liver toxicity is mainly caused by human liver metabolism. The drug is easily metabolized by CYP2C9 in the liver to 6-hydroxy benzbromarone, which is further metabolized by the P450s enzyme into two ortho-benzodiazepines. These substances are chemically active and can be passed through half with proteins or peptides. The conjugated addition of a thiol group on a cystine residue inactivates protein denaturation, resulting in hepatotoxicity. (Matthew G. McDonald MG, Rettie AE. Sequential metabolism and bioactivation of the hepatotoxin benzbromarone: formation of glutathione adducts from a catechol intermediate. Chemical Research in Toxicology. 2007, 20(12): 1833-1842). Benzolamone also has side effects such as diarrhea, stomach upset, nausea, macules, flushing, and itching.

Currently, the clinical trials for the treatment of gout drugs include AstraZeneca's Phase II clinical URAT1 inhibitor REDA-3170, Pfizer, BioCryst Pharmaceuticals, Korea LG life Sciences, Cymabay Therapeutics, JW Pharmaceuticals, Chugai Pharmaceuticals, Fuji Yakuhin and Sanwa Kagaku's products are also clinically stage I or II. The URAT1 inhibitor of Jiangsu Hengrui Pharmaceutical has entered Phase I clinical practice in China, and its structure has certain similarities with the two drugs of AstraZeneca. However, most clinical trial drugs still face the problem of poor efficacy and toxicity.

At present, there are few anti-gout drugs at home and abroad, and these drugs generally have shortcomings such as poor curative effect and large side effects. It is still a top priority to develop high-efficiency, low-toxic anti-gout new drugs on a global scale.

Summary of the invention

The object of the present invention is to provide a series of new compounds based on the prior art, aiming to obtain a UHT1 inhibitor with low toxicity and good efficacy for the treatment of hyperuricemia or gout disease. Experiments show that the compounds provided by the present invention The product has a very good inhibitory effect on hURAT1 transport uric acid in HEK293 transfected cells, indicating that this compound has a good application prospect in the treatment of hyperuricemia or gout.

The object of the invention can be achieved by the following measures:

a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

among them,

Ring A is a five-membered aromatic ring or a six-membered aromatic ring containing a hetero atom;

Ring B is a five-membered aromatic ring or a furan ring containing two N atoms;

D is a C or N atom;

E is a C or N atom;

G is an N or O atom, and G is an O atom when both D and E are C atoms;

Y is a carbonyl group, a sulfur group, a sulfone group, a sulfoxide group, an optionally substituted methylene group or an imino group; and when D or E in the ring A is an N atom such that the ring A forms a pyridine ring, or when the ring A is a benzene ring , Y is not a carbonyl group;

R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-3 substituted amino, C _1-3 alkoxy or C _{1 to 3} substituted alkoxy groups;

R ² is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-3 substituted amino, C _1-3 alkoxy or C _{1 to 3} substituted alkoxy groups;

R ³ is C _1-4 alkyl, C _1-4 substituted alkyl or halogen;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

The hetero atom in the ring of the group A is selected from one or two of N, S or O, and the substituent in the group Y is selected from a hydroxyl group, an amino group, a cyano group, a carboxyl group, a C _1-3 alkoxy group or C _{A 1-3} alkyl group, and the substituent in the group R ¹ , R ² or R ³ is selected from a hydroxyl group, a halogen, a nitro group, an amino group or a cyano group.

In one embodiment, the A ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridine ring, a triazole ring, an imidazole ring, a thiazole ring, an oxazole ring, an oxadiazole ring or a thiadiazole ring. Ring B is an imidazole ring, a pyrazole ring or a furan ring; and when the ring A is D Or when E is an N atom such that the A ring forms a pyridine ring, or when the A ring is a benzene ring, Y is not a carbonyl group.

In another embodiment, the invention is selected from a compound of formula (II), formula (III), formula (IV) or formula (V), or a pharmaceutically acceptable salt thereof,

Wherein Z ₁ , Z ₂ , Z ₃ or Z ₄ are each independently CH or N; X is S, O or NR ⁴ ; R ⁴ is H, -CH ₃ or -CH ₂ CH ₃ ; in formula (II) In (III) and (V), when Z ₁ , Z ₂ , Z ₃ and Z ₄ are both CH, Y is not a carbonyl group.

In a preferred embodiment, the invention is selected from the compounds shown by the structures described below, or a pharmaceutically acceptable salt thereof,

And in the formula (II-D) and the formula (III-A), Y is not a carbonyl group.

In a preferred embodiment, Y in the above formula is CH-OH, CH-NH ₂ , CH-CN, NH (imino), N-CH ₃ or C=O (carbonyl) groups, and R ³ is C _2-3 alkyl; and when D or E in the ring A is an N atom such that the ring A forms a pyridine ring, or when the ring A is a benzene ring, Y is not a carbonyl group or in formula (II-D) and formula (III) In -A), Y is not a carbonyl group.

In one preferred embodiment, R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, C _{1 ~ 3} alkyl group, C _{1 ~ 3} haloalkyl, C _{1 ~ 3} alkoxy groups or C _{1 ～3} haloalkoxy, m is 0, 1 or 2.

In a preferred embodiment, R ² is hydrogen, halogen, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, and n is 1 or 2.

In a more preferred embodiment, the compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

(3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone,

(3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[2,1-b]thiazol-5-yl)methanone,

(3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyrazin-3-yl)methanone,

3-bromo-5-[(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-2-hydroxybenzonitrile,

5-[(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-2-hydroxybenzonitrile,

2,6-dibromo-4-[(6-ethylimidazo[2,1-b]thiazol-5-yl)hydroxymethyl]phenol,

2,6-dibromo-4-[(2-ethylimidazo[1,2-a]pyrazin-3-yl)hydroxymethyl]phenol,

2-bromo-4-[(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-6-fluorophenol,

2,6-dibromo-4-[(2-ethylpyrazolo[1,5-a]pyridin-3-yl)hydroxymethyl]phenol,

2,6-dibromo-4-[(6-bromo-2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]phenol,

2,6-dibromo-4-{[2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]hydroxymethyl}phenol,

2,6-dibromo-4-[(2-ethylbenzofuran-3-yl)hydroxymethyl]phenol,

2,6-dibromo-4-[(2-ethylimidazo[1,2-a]pyridin-3-yl)methyl]phenol,

(3,5-dibromo-4-hydroxyphenyl)(6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methanone,

2-bromo-4-(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl-6-methylphenol,

2,6-dibromo-4-[(2-ethylbenzofuran-3-yl)(methoxy)methyl]phenol,

2,6-dibromo-4-{(2-ethyl-7-methoxyimidazo[1,2-a]pyridin-3-yl)hydroxymethyl}phenol,

(3,5-Dibromo-4-hydroxyphenyl)(2-propylfuro[2,3-b]pyridin-3-yl)methanone.

The preparation method of the compound of the present invention is as follows:

Formula one:

In the formula, an amino A ring (pyridine, pyrimidine, thiazole, pyrazine, etc.) compound is formed into an amide (or hydrazine) compound and then reacted with a substituted bromoacetophenone to obtain a corresponding imidazolium ring (pyridine, a pyrimidine, thiazole, pyrazine or the like compound which undergoes a demethylation, halogenation reaction, and/or reduction reaction or other reaction to obtain a corresponding target product.

Formula 2:

In the formula, the amino A ring (pyridine, pyrimidine, pyrazine, etc.) salt is subjected to ring-closing reaction with an alkyne to obtain a corresponding pyrazolo ring A (pyridine, pyrimidine, pyrazine, etc.) compound, followed by hydrolysis and decarboxylation. The obtained compound and the acyl group The chlorine is catalyzed by a Lewis acid to obtain a diaryl ketone compound, which is subjected to demethylation, halogenation, and/or reduction or other reaction to obtain the corresponding target product.

The definition of each group in the synthesis method is as described above.

Unless otherwise stated, the following terms used in the claims and the specification have the following meanings:

The "five-membered aromatic ring" refers to a fused, planar ring-structured fused ring group composed of five ring atoms, which has aromaticity and the ring atom may be an atom other than a carbon atom, that is, a hetero atom. When the five-membered aromatic ring contains a hetero atom, the hetero atom may be N, S or O, and the number of hetero atoms is not limited to one, and may be two, three or the like. The five-membered aromatic ring containing a hetero atom in the present invention includes, but is not limited to, a triazole ring, an imidazole ring, a thiazole ring, an oxazole ring, an oxadiazole ring or a thiadiazole ring.

"Six-membered aromatic ring" refers to a conjugated planar ring structure fused ring group composed of six ring atoms, which has aromaticity and the ring atom may be an atom other than a carbon atom, ie, a hetero atom. . When the six-membered aromatic ring contains a hetero atom, the hetero atom may be N, S or O, and the number of hetero atoms is not limited to one, and may be two, three or the like. The six-membered aromatic ring containing a hetero atom in the present invention includes, but is not limited to, a pyridine ring, a pyrimidine ring, a pyrazine ring and the like.

"Hydrogen" means hydrazine (1H), which is the main stable isotope of hydrogen.

"氘" refers to a stable morphological isotope of hydrogen, also known as heavy hydrogen, whose elemental symbol is D.

"Halogen" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"Alkyl" means a saturated aliphatic hydrocarbon radical of 1 to 20 carbon atoms, including both straight-chain and branched-chain groups (the numerical ranges referred to in this application, such as "1-20", mean the radical, In this case, it is an alkyl group which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms or the like up to and including 20 carbon atoms). An alkyl group having 1 to 4 carbon atoms is referred to as a lower alkyl group. When the lower alkyl group has no substituent, it is referred to as an unsubstituted lower alkyl group. More preferably, the alkyl group is a medium size alkyl group having from 2 to 5 carbon atoms. The alkyl group in the present invention is, for example, a methyl group, an ethyl group, a propyl group, a 2-propyl group, a n-butyl group, an isobutyl group, a t-butyl group or a pentyl group. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups. The alkyl group can be substituted or unsubstituted.

"Alkoxy" means an -O-(unsubstituted alkyl) group and an -O-(unsubstituted cycloalkyl) group, which further denotes -O-(unsubstituted alkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

"Carbonyl" means a C=O group.

"sulfone group" means a -S(O) ₂ - group.

"Thionylene group" means a -S(O)- group.

"Methylene" means a -CH ₂ - group.

"Imino" means a -NH- group.

"Hydroxy" means an -OH group.

"Nitro" means a -NO ₂ group.

"Amino" means a -NH ₂ group.

"Carboxy" means a -COOH group.

"Cyano" means a -CN group.

A "pharmaceutically acceptable salt" is a salt comprising a compound of formula (I) with an organic or inorganic acid, meaning those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:

(1) a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid And perchloric acid, etc., organic acids such as, but not limited to, acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, γ-hydroxybutyric acid , methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, Mandelic acid, succinic acid or malonic acid.

(2) a salt formed by replacing an acidic proton in a parent compound with a metal ion or by complexing with an organic base, such as an alkali metal ion, an alkaline earth metal ion or an aluminum ion, an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.

"Pharmaceutical composition" means a mixture of one or more of the compounds described herein or their pharmaceutically acceptable salts and prodrugs with other chemical ingredients, such as pharmaceutically acceptable carriers and excipients. . The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

In the following, the compounds of the formula (I) as active ingredients of the therapeutic agents, including all pharmaceutically acceptable salts thereof, are to be understood as falling within the scope of the invention, unless otherwise specified. In the present specification, they are simply referred to as "compounds of the formula (I)" for convenience only.

The present invention includes a pharmaceutical composition comprising, as an active ingredient, a compound of any one of the present invention, a pharmaceutically acceptable salt thereof, or a readily hydrolyzable prodrug thereof, supplemented with a pharmaceutically acceptable adjuvant.

Each compound of the present invention or a pharmaceutically acceptable salt thereof has low toxicity and good medicinal effect, and can be applied to preparation of a uric acid excretion drug, particularly for preparing a medicament for treating or preventing hyperuricemia or gout. Experiments show that the compounds provided by the present invention have a very good inhibitory effect on hURAT1 transport uric acid in HEK293 transfected cells, indicating that the compounds have a good application prospect in the treatment of hyperuricemia or gout.

detailed description

The invention will be further illustrated by the following examples, but the scope of the invention is not limited to the following examples.

Example 1: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone (4)

Step A: 2-aminopyrimidine (570 mg, 6.0 mmol), phosphorus oxychloride (4.6 g, 30.0 mmol), N,N-dimethylpropanoyl (910 mg, 9.0 mmol) and toluene (15 mL) The mixture was stirred at 110 ° C for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice water (60 mL) and then pH was adjusted to 8-9 with 2M aqueous sodium hydroxide. It was extracted with ethyl acetate (40 mL × 5) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:1 to 20:1) to give N,N-dimethyl-N'- ( Pyrimidin-2-yl)propanoid (1) (250 mg). The yield was 23.4%.

Step B: A mixture containing compound 1 (240 mg, 1.35 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (308 mg, 1.35 mmol) and DMF (10 mL) Then, the temperature was raised to 60 ° C and stirring was continued for 1.5 hours. After cooling to room temperature, water (40 mL) was added, and the pH was adjusted to 7-8 with a saturated aqueous sodium carbonate aqueous solution, and then extracted with ethyl acetate (40 mL × 3), and the combined organic phases were sequentially water (20 mL) and brine (20 mL) Washed and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:4 to 2:5) to give (2-ethylimidazo[1,2- a]pyrimidin-3-yl)(4-methoxyphenyl)methanone (2) (190 mg). The yield was 50.0%. ¹ H NMR (DMSO-d6, 400 MHz) δ 9.45-9.43 (m, 1H), 8.77-8.75 (m, 1H), 7.74 (dd, J = 2.0, 6.8 Hz, 2H), 7.31-7.29 (m, 1H), 7.12 (dd, J = 2.0, 6.8 Hz, 2H), 3.88 (s, 3H), 2.52-2.51 (m, 2H), 1.15 (t, J = 7.6 Hz, 3H).

Step C: To a solution of Compound 2 (120 mg, 0.427 mmol) in anhydrous dichloromethane (10 mL) overnight. The reaction mixture was poured into ice water (20 mL). It was extracted with ethyl acetate (30 mL × 3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether: THF = 1:5:1 to 5:5:1) to give (2-ethylimidazole) And [1,2-a]pyrimidin-3-yl)(4-hydroxyphenyl)methanone (3) (101 mg). The yield was 88.5%.

Step D: A solution of bromine (66 mg, 0.413 mmol) in EtOAc (2 mL)EtOAc. Stir for 0.5 hours. A saturated aqueous solution of sodium hydrogensulfite was added dropwise to the reaction mixture until the color faded. The solvent was evaporated under reduced pressure, then water (30 mL) was evaporated, and then,, It was extracted with ethyl acetate (40 mL × 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained product was crystallised from ethyl acetate / petroleum ether to give (3,5-dibromo-4-hydroxyphenyl) (2-ethylimidazo[1,2-a]pyrimidine-3 -yl)methanone (4). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.42 (dd, J = 2.0, 6.8 Hz, 1H), 8.78 (dd, J = 2.0, 7.6 Hz, 1H), 7.91 (s, 2H), 7.34-7.31 (m, 1H), 2.51-2.48 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 426.0 [M+H] ⁺ .

Example 2: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[2,1-b]thiazol-5-yl)methanone (8)

Step A: 2-aminothiazole (600 mg, 6.0 mmol), phosphorus oxychloride (4.6 g, 30.0 mmol), N,N-dimethylpropanoyl (910 mg, 9.0 mmol) and toluene (15 mL) The mixture was stirred at 110 ° C for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice water (60 mL) and then pH was adjusted to 8-9 with 2M aqueous sodium hydroxide. The organic layer was washed with water (20 mL) and brine (20 mL). The solvent was evaporated under reduced pressure to give N,N-dimethyl-N--(thiazol-2-yl)propanone (5) (890 mg). The yield was 80.9%.

Step B: A mixture containing compound 5 (439 mg, 2.40 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (604 mg, 2.64 mmol) and DMF (10 mL) Then, the temperature was raised to 60 ° C and stirring was continued for 2 hours, and the temperature was further raised to 130 ° C and stirred overnight. After cooling to room temperature, water (40 mL) was added, and the pH was adjusted to 7-8 with a saturated aqueous sodium carbonate aqueous solution, and then extracted with ethyl acetate (40 mL × 3), and the combined organic phases were sequentially water (20 mL) and brine (20 mL) Washed and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:30 to 1:20) to give (6-ethylimidazo[2,1- b]thiazol-5-yl)(4-methoxyphenyl)methanone (6) (311 mg). The yield was 45.3%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.14 (d, J = 4.4 Hz, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.45 (d, J = 4.4 Hz, 1H), 7.09 ( d, J = 8.8 Hz, 2H), 3.87 (s, 3H), 2.45 (q, J = 7.6 Hz, 2H), 1.10 (t, J = 7.6 Hz, 3H).

Step C: A 1.0 M solution of boron tribromide in toluene (1.6 mL) was added dropwise to a solution of compound 6 (113 mg, 0.395 mmol) in anhydrous dichloromethane (10 mL), and the mixture was stirred at room temperature. overnight. The reaction mixture was poured into ice water (20 mL). It was extracted with ethyl acetate (30 mL × 3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate:dichloromethane = 1:2) to give (2-ethylimidazo[1,2-a]pyrimidine. 3-yl)(4-hydroxyphenyl)methanone (7) (39 mg). The yield was 36.3%.

Step D: To a solution of compound 7 (37 mg, EtOAc. Water (20 mL) was added, and the mixture was filtered, and the filtered cake was washed with a large amount of water, and the obtained solid was dissolved in THF/ethyl acetate mixture and dried over anhydrous sodium sulfate. Then, it was filtered through a silica gel pad to give (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[2,1-b]thiazol-5-yl)methanone (8) (40 mg). The yield was 68.4%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.14 (d, J = 4.4 Hz, 1H), 7.86 (s, 2H), 7.46 (d, J = 4.4 Hz, 1H), 2.43 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 430.9 [M+H] ⁺ .

Example 3: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyrazin-3-yl)methanone (12)

Step A: Under an ice water bath, 2-aminopyrazine (2.0 g, 21.0 mmol), phosphorus oxychloride (4.84 g, 31.6 mmol), N,N-dimethylpropionyl group (2.34 g, 23.1) Triethylamine (4.68 g, 46.2 mmol) was added dropwise to a mixture of EtOAc and EtOAc. The reaction mixture was poured into ice water (60 mL) and then pH was adjusted to 8 to 9 with 2M aqueous sodium hydroxide. The organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. Then pass the short silica gel column Filtration and evaporation of the solvent under reduced pressure gave N,N-dimethyl-N--(pyrazin-2-yl)propanthene (9) (1.82 g). This compound was used in the next reaction without purification.

Step B: A mixture of crude product (900 mg), 2-bromo-1-(4-methoxyphenyl)ethanone (1.27 g, 5.54 mmol) and THF (25 mL) was stirred at room temperature overnight. After adding water (50 mL), the pH was adjusted to 7-8 with a saturated aqueous sodium carbonate solution, and then extracted with ethyl acetate (50 mL×3), and the combined organic phases were washed with water (20 mL) and brine (20 mL) Dry with sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:4 to 2:5) to give (2-ethylimidazo[1,2- a] pyrazin-3-yl)(4-methoxyphenyl)methanone (10) (160 mg). The total yield of the two steps of steps A and B was 5.5%. ¹ H NMR (DMSO-d6, 400 MHz) δ 9.23 (d, J = 1.2 Hz, 1H), 8.93 - 8.91 (m, 1H), 8.14 (d, J = 4.8 Hz, 1H), 7.76 (dd, J =2.0, 6.8 Hz, 2H), 7.12 (dd, J = 2.0, 6.8 Hz, 2H), 3.89 (s, 3H), 2.57 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz) , 3H).

For the experimental procedures of steps C and D, see steps C and D in Example 1, to obtain (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyrazine- 3-yl)methanone (12). ¹ H NMR (DMSO-d6, 400 MHz) 9.11 (d, J = 1.6 Hz, 1H), 8.59-8.58 (m, 1H), 7.78-7.97 (m, 1H), 7.72 (s, 2H), 2.71 (q) , J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 426.0 [M+H] ⁺ .

Example 4: Synthesis of 3-bromo-5-[(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-2-hydroxybenzonitrile (20)

Step A: 2-Aminopyridine (2.0 g, 21.3 mmol) and triethylamine (2.58 g, 25.5 mmol) were dissolved in dichloromethane (20 mL), then propionyl chloride (2.07 g, 22.4 mmol) was added dropwise in an ice water bath. The resulting mixture was naturally warmed to room temperature and stirring was continued overnight. Water (40 mL) was added, and the mixture was evaporated. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:15 to 1:10) to give N-(pyridin-2-yl)propanamide ( 13) (2.74g). The yield was 85.6%.

Step B: 4-methoxyacetophenone (44 g, 293 mmol) was added to 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane under ice-water bath. A mixture of bis(tetrafluoroborate) salt (104 g, 294 mmol), iodine (38.6 g, 152 mmol) and acetonitrile (440 mL). After the addition was completed, the resulting mixture was stirred at room temperature overnight. Water (1350 mL) was added to the reaction mixture, and a large amount of solid precipitated. Filtration and drying gave 3-iodo-4-methoxyacetophenone (14) (70 g). The yield was 86.5%.

Step C: A mixture containing compound 14 (70.0 g, 254 mmol), EtOAc (34.0 g, 380 mmol) and DMF (400 mL) was stirred at 130 ° C overnight. After cooling to room temperature, the mixture was filtered over EtOAc EtOAc (EtOAc) (EtOAc (EtOAc) Dry over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-acetyl-2-methoxybenzonitrile (15) (50.0g). This compound was used in the next reaction without further workup.

Step D: A solution of bromo (49.0 g, 307 mmol) in MeOH (50 mL). Water (900 mL) was added, filtered and dried to give 5-(2-bromo-acetyl)-2-hydroxy-3-methylbenzonitrile (16) (41.0 g). The total yield of the two-step reaction of steps B and C was 70.6%.

Step E: A mixture containing compound 16 (41.0 g, 161 mmol), Compound 13 (24.0 g, 161 mmol) and toluene (600 mL) was stirred under reflux for 48 hours. After cooling to room temperature, water (400 mL) was added and the pH was adjusted to 7-8 with saturated sodium bicarbonate. It was extracted with ethyl acetate (600 mL × 3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:30 to 2:1) to give 5-(2-ethylimidazo[1, 2-a]pyridine-3-carbonyl)-2-methoxybenzonitrile (17) (25.7 g). The yield was 52.3%.

Step F: To a solution of ethanethiol (8.4 mL) in THF (30 mL) The filter cake was further added to a mixture containing compound 17 (9.0 g, 29.5 mmol) and DMF (25 mL), and the mixture was stirred at 60 ° C for 2 hours. After cooling to room temperature and filtering through celite, water (100 mL) was added and the pH was adjusted to 5-6 with 2M aqueous citric acid. Filtration and recrystallization of the filter cake from acetonitrile gave 5-(2-ethylimidazo[1,2-a]pyridin-3-carbonyl)-2-hydroxybenzonitrile (18) (7.2 g). The yield was 83.8%.

Step G: NBS (5.28 g, 29.7 mmol) was added in EtOAc EtOAc EtOAc. Water (210 mL) was added, filtered, and the filter cake was washed with water (100mL×3) and then recrystallized from acetonitrile to give 3-bromo-5-(2-ethylimidazo[1,2-a]pyridine-3-carbonyl 2-hydroxybenzonitrile (19) (7.0 g). The yield was 76.8%. ¹ H NMR (DMSO-d6, 300 MHz) δ 9.01 (d, J = 6.9 Hz, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.78-7.75 (m, 1H), 7.65-7.59 (m, 1H), 7.22-7.17 (m, 1H), 2.58-2.50 (m, 2H), 1.19 (t, J = 7.2 Hz, 3H). MS (EI, m/z): 368.0 [MH] ^- .

Step H: To a solution of compound 19 (50 mg, 0.135 mmol) in MeOH (5 <RTI ID=0.0></RTI></RTI><RTIgt; ). After stirring for 0.5 hours, water (20 mL) was added, and the pH was adjusted to 5-6 with 2M aqueous citric acid, and then extracted with ethyl acetate/THF (7V/1V, 30mL×3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether: THF=10:30:1 to 20:10:1) to give 3-bromo-5- [(2-Ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-2-hydroxybenzonitrile (20). ¹ H NMR (DMSO-d6, 400 MHz) δ 8.18 (d, J = 7.2 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.52-7.50 (m, 2H), 7.24-7.20 (m) , 1H), 6.84-6.82 (m, 1H), 6.33 (s, 1H), 6.23 (s, 1H), 2.71 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H) . MS (EI, m/z): 3721. [M+H] ⁺ .

Example 5: Synthesis of 5-[(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-2-hydroxybenzonitrile (21)

The compound 18 is used as a raw material, and the preparation method of the compound 21 is as shown in the step H in the fourth embodiment. ^{1 H NMR (DMSO-d6,400MHz)} δ8.14 (d, J = 6.8Hz, 1H), 7.48-7.45 (m, 2H), 7.25-7.22 (m, 1H), 7.18-7.14 (m, 1H) , 6.85-6.83 (m, 1H), 6.78-6.74 (m, 1H), 6.16 (s, 1H), 2.71 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 294.1 [M+H] ⁺ .

Example 6: Synthesis of 2,6-dibromo-4-[(6-ethylimidazo[2,1-b]thiazol-5-yl)hydroxymethyl]phenol (22)

The compound 8 is used as a raw material, and the preparation method of the compound 22 is as shown in the step H in the fourth embodiment. ^{1 H NMR (DMSO-d6,400MHz)} δ9.93 (s, 1H), 7.52 (d, J = 4.8Hz, 1H), 7.46 (s, 2H), 7.12 (d, J = 4.4Hz, 1H), 6.24 (s, 1H), 6.02 (s, 1H), 2.59 (q, J = 7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 432.9 [M+H] ⁺ .

Example 7: Synthesis of 2,6-dibromo-4-[(2-ethylimidazo[1,2-a]pyrazin-3-yl)hydroxymethyl]phenol (23)

The compound 12 is used as a raw material, and the preparation method of the compound 23 is as shown in the step H in the fourth embodiment. ¹ H NMR (DMSO-d6, 400 MHz) 9.98 (s, 1H), 8.97 (d, J = 1.2 Hz, 1H), 8.27-8.26 (m, 1H), 7.81 (d, J = 4.4 Hz, 1H), 7.47(s, 2H), 6.46 (d, J = 4.4 Hz, 1H), 6.30 (d, J = 4.0 Hz, 1H), 2.75 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6) Hz, 3H). MS (EI, m/z): 425.9 [MH] ^- .

Example 8: Synthesis of 2-bromo-4-[(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-6-fluorophenol (28)

Step A: 2-Amino-5-fluoropyridine (2.5 g, 22.3 mmol) and triethylamine (2.71 g, 26.8 mmol) were dissolved in dichloromethane (25 mL), then propionyl chloride (2.17) was added dropwise in an ice water bath. g, 23.5 mmol), the mixture was warmed to room temperature and stirring was continued overnight. Water (40 mL) was added, and the mixture was evaporated. The solvent was evaporated under reduced pressure, and the product was purified (jjjjjjjjjjj ) (3.04g). The yield was 81.1%.

Step B: NBS (977 mg, 5.49 mmol) was added in EtOAc EtOAc EtOAc. After the addition of water (50 mL), EtOAc (EtOAc m. The solvent was evaporated under reduced pressure and the obtained product was crystallised from petroleum ether / ethyl acetate to give 3-bromo-5-fluoro 4-Hydroxyacetophenone (25) (1.0 g). The yield was 82.0%.

A solution of bromo (824 mg, 5.16 mmol) in MeOH (5 mL) Water (60 mL) was added, and the mixture was evaporated. The solvent was evaporated under reduced pressure, and the product was purified (jjjjjjjjjjjj -Hydroxyphenyl)ethanone (26) (940 mg). The yield was 70.2%.

Step D: A mixture containing compound 24 (210 mg, 1.25 mmol), compound 26 (300 mg, 0.962 mmol) and N-methylpyrrolidone (10 mL) was stirred at 150 ° C overnight. After cooling to room temperature, water (50 mL) was added, the pH was adjusted to 7-8 with a saturated aqueous sodium hydrogen carbonate solution, and then adjusted to pH 5-6 with 2M aqueous citric acid. It was extracted with ethyl acetate (50 mL × 3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:25 to 1:5) to give (3-bromo-5-fluoro-4-hydroxyl) Phenyl)(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)methanone (27). ¹ H NMR (DMSO-d6, 500 MHz) δ 11.44 (s, 1H), 9.24-9.22 (m, 1H), 7.78-7.85 (m, 1H), 7.75-7.71 (m, 2H), 7.63-7. m, 1H), 2.47 (q, J = 7.5 Hz, 2H), 1.18 (t, J = 7.5 Hz, 3H). MS (EI, m/z): 379.0 [MH] ^- .

Step E: To a solution of EtOAc (EtOAc) (EtOAc,EtOAc. After adding water (20 mL), the pH was adjusted to 5-6 with 2M EtOAc EtOAc. After filtration through a short pad of silica gel, the solvent was evaporated, evaporated, mjjjjjjjjjjjjjjjj Pyridin-3-yl)hydroxymethyl]-6-fluorophenol (28). ^{1 H NMR (DMSO-d6,400MHz)} δ10.43 (s, 1H), 8.27-8.25 (m, 1H), 7.59-7.56 (m, 1H), 7.31-7.25 (m, 2H), 7.15-7.12 ( m, 1H), 6.33 (d, J = 4.0 Hz, 1H), 6.21 (d, J = 4.0 Hz, 1H), 2.66 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 383.0 [M+H] ⁺ .

Example 9: Synthesis of 2,6-dibromo-4-[(2-ethylpyrazolo[1,5-a]pyridin-3-yl)hydroxymethyl]phenol (35)

Step A: A mixture containing 1-aminoiodide pyridine (15.54 g, 70.0 mmol), ethyl 2-pentynoate (9.72 g, 77.1 mmol), potassium carbonate (21.26 g, 154 mmol) and DMF (150 mL) Stir at room temperature for 4.5 hours. Water (450 mL) was added, filtered, and then filtered and washed with water (100mL) to give ethyl 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylate (29) (12.25 g). This compound was used in the next reaction without drying.

Step B: A mixture containing Compound 29 wet product (12.25 g), ethanol (30 mL), THF (30 mL) and 2M aqueous sodium hydroxide (70 mL) was stirred at 60 ° C overnight. About half of the solvent was distilled off under reduced pressure, water (150 mL) was added, and pH was adjusted to 5-6 with 2M hydrochloric acid. Filtration gave 2-ethylpyrazolo[1,5-a]pyridine-3-carboxylic acid (30) (10.0 g). This compound was used in the next reaction without drying.

Step C: The wet product containing Compound 30 (5.6 g) was suspended in water (100 mL), concentrated sulfuric acid (4 mL) was added, and the mixture was stirred at 80 ° C for 3 hours. Cool to room temperature and adjust the pH to 8-9 with 2M aqueous sodium hydroxide. The organic layer was washed with water (30 mL) and brine (20 mL) The solvent was evaporated under reduced pressure to give 2-ethylpyrazolo[1,5-a]pyridine (31) (3.18 g). The total yield of the three-step reaction of steps A, B and C was 47.7%.

Step D: A mixture containing compound 31 (584 mg, 3.99 mmol), 4-methoxybenzoyl chloride (680 mg, 3.99 mmol) and aluminum trichloride (800 mg, 6.0 mmol) was stirred at 100 ° C overnight. After slightly cooling, ethyl acetate (30 mL) and water (30 mL) were added and the pH was adjusted to 9-10 using 2M aqueous sodium hydroxide. Layered and collected organic layers. The aqueous layer was extracted with EtOAc (EtOAc)EtOAc. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:30 to 1:10) to give (2-ethylpyrazolo[1,5 -a]pyridin-3-yl)(4-methoxyphenyl)methanone (32) (305 mg). The yield was 27.3%. ¹ H NMR (DMSO-d6, 300 MHz) δ 8.79 (d, J = 6.9 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.44 - 7.39 (m, 1H), 7.33 - 7.30 (m) , 1H), 7.08-7.03 (m, 3H), 3.86 (s, 3H), 2.84 (q, J = 7.5 Hz, 2H), 1.21. (t, J = 7.5 Hz, 3H).

Step E: 60% sodium hydride (218 mg, 5.45 mmol) was added portionwise to a solution of ethyl thiol (338 mg, 5.44 mmol) in DMF (3 mL). A DMF (3 mL) solution was added to the above reaction mixture, and the resulting mixture was stirred at 120 ° C for 2 hours. After cooling to room temperature, water (30 mL) was added and the pH was adjusted to 7-8 with dilute hydrochloric acid. After extraction with ethyl acetate (30 mL × 3), the combined organic phases were washed with water (20 mL, 3) and brine (20 mL). The solvent was evaporated under reduced pressure to give (2-ethylpyrazolo[1,5-a]pyridin-3-yl)(4-hydroxyphenyl)methanone (33) (420 mg). This compound was used in the next reaction without purification. ^{1 H NMR (DMSO-d6,300MHz)} δ10.22 (s, 1H), 8.76 (d, J = 6.6Hz, 1H), 7.56 (d, J = 8.4Hz, 2H), 7.42-7.31 (m, 2H ), 7.05-7.01 (m, 1H), 6.87 (d, J = 8.4 Hz, 2H), 2.84 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H). MS (EI, m/z): 265.1 [MH] ^- .

Step F: A solution of bromine (67 mg, 0.419 mmol) in acetic acid (1 mL) was added dropwise to a solution of compound 33 (73 mg) and anhydrous sodium acetate (46.3 mg, 0.564 mmol) in acetic acid (5 mL). Stir overnight. A dilute aqueous solution of sodium hydrogen sulfite was added dropwise to the reaction mixture until the color faded. The solvent was evaporated under reduced pressure, an appropriate amount of water was added, and the pH was adjusted to 7-8 with a saturated aqueous sodium hydrogen carbonate solution. It was extracted with ethyl acetate (40 mL × 2) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:20 to 1:1) to give (3,5-dibromo-4-hydroxybenzene) (2-Ethylpyrazolo[1,5-a]pyridin-3-yl)methanone (34) (60 mg). The total yield of the two steps of steps A and B was 75.4%. ^{1 H NMR (DMSO-d6,300MHz)} δ10.77 (s, 1H), 8.81 (d, J = 6.9Hz, 1H), 7.80 (s, 2H), 7.50-7.40 (m, 2H), 7.12-7.07 (m, 1H), 2.82 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H). MS (EI, m / z) : 420.9 [MH] -.

Step G: To a mixture of compound 34 (160 mg, 0.377 mmol) After the mixture was stirred at reflux for 0.5 hr, sodium borohydride (143 mg, 3.78 <RTI ID=0.0></RTI></RTI><RTIgt; After cooling to room temperature, water (20 mL) was added, and the pH was adjusted to 5-6 with 2M aqueous citric acid, and then extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with brine (20 mL) Dry over sodium sulfate. The solvent is evaporated under reduced pressure and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:5) to give 2,6-dibromo-4-[(2-ethylpyr Zizo[1,5-a]pyridin-3-yl)hydroxymethyl]phenol (35). ¹ H NMR (DMSO-d6, 400 MHz) 9.84 (s, 1H), 8.55-8.54 (m, 1H), 7.46-7.43 (m, 3H), 7.14-7.10 (m, 1H), 6.79-6.76 (m, 1H), 5.98 (d, J = 4.0 Hz, 1H), 5.88 (d, J = 4.0 Hz, 1H), 2.72 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H) . MS (EI, m / z) : 425.0 [MH] -.

Example 10: Synthesis of 2,6-dibromo-4-[(6-bromo-2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]phenol (40)

Step A: To a solution of p-methoxyacetophenone (3.0 g, 20.0 mmol) in DMF (15 mL) After the addition was completed, stirring was continued at this temperature for 40 minutes, and then ethyl propionate (2.04 g, 20 mmol) was added dropwise. After the addition, the mixture was naturally warmed to room temperature and stirred overnight. After the addition of water (60 mL), EtOAc (EtOAc m. The solvent was evaporated under reduced pressure, and the product was purified (jjjjjjjjjjj Diketone (36) (3.16 g). The yield was 76.6%.

Step B: 2-Amino-5-bromopyridine (1.3 g, 7.51 mmol) and compound 36 (1.86 g, 9.02 mmol) were dissolved in THF (26 mL), then iophthalic acid (2.9 g). , 9.00 mmol) and boron trifluoride etherate (220 mg, 1.55 mmol). After adding water (30 mL), the pH was adjusted to 7-8 with a saturated sodium hydrogen carbonate solution, and then extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated brine (20 mL) . The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:30) to give (6-bromo-2-ethylimidazo[1,2- a] Pyridin-3-yl)(4-methoxyphenyl)methanone (37) (575 mg). The yield was 21.3%.

For the experimental procedures of steps C and D, see steps C and D in Example 1.

For the experimental procedure of Step E, see Step H in Example 4 to obtain 2,6-dibromo-4-[(6-bromo-2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxyl Methyl] phenol (40). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.98 (s, 1H), 8.40 (d, J = 1.2 Hz, 1H), 7.55-7.48 (m, 1H), 7.45 (s, 2H), 7.35-7.32 (m, 1H), 6.38 (d, J = 4.0 Hz, 1H), 6.26 (d, J = 4.0 Hz, 1H), 2.60 (q, J = 7.6 Hz, 2H), 1.18 (t, J = 7.6 Hz) , 3H). MS (EI, m/z): 502.9 [MH] ^- .

Example 11: 2,6-Dibromo-4-{[2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]hydroxymethyl}phenol (41 )Synthesis

For the preparation of compound 41, see Example 10, wherein the 2-amino-5-bromopyridine of Example 10, Step B, was replaced with 2-amino-4-trifluoromethylpyridine. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.39 (d, J = 7.2 Hz, 1H), 8.00 (s, 1H), 7.44 (s, 2H), 7.12-7.10 (m, 1H), 6.54 (s) , 1H), 6.46 (s, 1H), 6.30 (s, 1H), 2.76 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 494.9 [M+H] ⁺ .

Example 12: Synthesis of 2,6-dibromo-4-[(2-ethylbenzofuran-3-yl)hydroxymethyl]phenol (42)

Taking (3,5-dibromo-4-hydroxyphenyl)(2-ethylbenzofuran-3-yl)methanone as a starting material, the preparation method of the compound 42 is shown in the step H in Example 4. ¹ H NMR (DMSO-d6, 400 MHz) δ 9.87 (s, 1H), 7.53 (s, 2H), 7.48-7.46 (m, 1H), 7.40-7.38 (m, 1H), 7.22 to 7.18 (m, 1H), 7.14-7.11 (m, 1H), 6.03 (d, J = 4.0 Hz, 1H), 5.92 (d, J = 4.0 Hz, 1H), 2.90 (q, J = 7.6 Hz, 2H), 1.25 ( t, J = 7.6 Hz, 3H). MS (EI, m / z) : 425.0 [MH] -.

Example 13: Synthesis of 2,6-dibromo-4-[(2-ethylimidazo[1,2-a]pyridin-3-yl)methyl]phenol (47)

Step A: A mixture containing compound 13 (300 mg, 2.0 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (460 mg, 2.0 mmol) and toluene (10 mL) . After cooling to room temperature, water (30 mL) was added and the pH was adjusted to 8-9 with a saturated aqueous solution of potassium carbonate. It was extracted with dichloromethane (40 mL × 3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:30 to 1:1) to give (2-ethylimidazo[1,2- a] Pyridin-3-yl)(4-methoxyphenyl)methanone (43) (254 mg). The yield was 45.3%. ¹ H NMR (DMSO-d6, 500 MHz) δ 9.18 (d, J = 7.0 Hz, 1H), 7.74-7.69 (m, 3H), 7.58-7.55 (m, 1H), 7.17-7.14 (m, 1H), 7.09 (d, J = 8.5 Hz, 2H), 3.87 (s, 3H), 2.45 (q, J = 7.5 Hz, 2H), 1.11 (t, J = 7.5 Hz, 3H). MS (EI, m/z): 281.1 [M+H] ⁺ .

Step B: Sodium borohydride (267 mg, 7.06 mmol) was added in portions to a solution of compound 43 ( 1.32 g, 4. After the addition was completed, stirring was continued for 20 minutes. Water (100 mL) was added and a large amount of solid precipitated. After filtration, the cake was dissolved with EtOAc (EtOAc) (EtOAc) The solvent was evaporated to give (2-ethylimidazo[1,2-a]pyridin-3-yl)(4-methoxyphenyl)methanone (44) (1.29 g). The yield was 97.0%. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.14 - 8.12 (m, 1H), 7.48-7.45 (m, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.16-7.12 (m, 1H) , 6.90-6.88 (m, 2H), 6.74-6.72 (m, 1H), 6.23 (s, 1H), 6.07 (s, 1H), 3.72 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H) ), 1.26 (t, J = 7.6 Hz, 3H).

Step C: To a solution of compound 44 (1.06 g, 3. <RTI ID=0.0></RTI> </RTI> <RTIgt; The mixture was stirred at room temperature for 3 hours. Water (40 mL) was added and the pH was adjusted to 7-8 with saturated sodium bicarbonate. The layers were separated, and the aqueous layer was washed with methylene chloride (40 mL×2). dry. The solvent was evaporated under reduced pressure and the obtained crystals crystals crystals crystals crystalsssssssssssssssssssssss ). The yield was 89.7%.

For the experimental procedures of steps D and E, see steps C and D in Example 1, to obtain 2,6-dibromo-4-[(2-ethylimidazo[1,2-a]pyridin-3-yl). Phenyl]phenol (47). ¹ H NMR (DMSO-d6, 400 MHz) 9.84 (s, 1H), 8.15 (d, J = 6.8 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.29 (s, 2H), 7.20- 7.16 (m, 1H), 6.86-6.83 (m, 1H), 4.25 (s, 2H), 2.75 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 409.0 [MH] ^- .

Example 14: (3,5-Dibromo-4-hydroxyphenyl)(6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methanone ( 49) Synthesis

For the preparation of the compound 49, see steps A and B in Example 2, wherein the 2-aminothiazole in the step A of Example 2 was replaced with 2-amino-1,3,4-thiadiazole, in Example 2, Step B. 2-Bromo-1-(4-methoxyphenyl)ethanone was replaced with 2-bromo-1-(3,5-dibromo-4-hydroxyphenyl)ethanone. ^{1 H NMR (DMSO-d6,400MHz)} 9.23 (s, 1H), 7.84 (s, 2H), 2.69 (q, J = 7.6Hz, 2H), 1.22 (t, J = 7.6Hz, 3H). MS (EI, m/z): 429.8 [MH] ^- .

Example 15: Synthesis of 2-bromo-4-(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl-6-methylphenol (54)

Step A: A solution of bromoacetyl bromide (9.9 g, 49.0 mmol) in dichloromethane (10 mL) was added dropwise to 2-methylanisole (5.0 g, 40.9 mmol) over -20 min. And aluminum trichloride (6.0g, 45.0mmol) In a solution of dichloromethane (40 mL). After the addition was completed, the resulting mixture was further stirred at this temperature for 2.0 hours. The reaction solution was poured into an appropriate amount of ice water, and extracted with dichloromethane (60 mL×3). The combined organic phases were sequentially water (30mL), saturated aqueous sodium hydrogen carbonate (30mL×2), water (30mL) and saturated salt Wash with water (30 mL) and dry over anhydrous sodium sulfate. The organic phase was filtered through a short silica gel column. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:100 to 1:30) to give 2-bromo-1-(3-methyl- 4-methoxyphenyl)ethanone (50) (3.0 g). The yield was 30.2%.

Step B: A mixture containing compound 13 (1.85 g, 12.3 mmol), compound 50 (3.0 g, 12.3 mmol) and toluene (30 mL) was stirred under reflux overnight. After cooling to room temperature, water (50 mL) was added and the pH was adjusted to 8-9 using 2M aqueous potassium carbonate. It was extracted with dichloromethane (60 mL × 3) and dried over anhydrous sodium sulfate. The product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:10 to 1:5) to give (3-methyl-4-methoxyphenyl) (2-B) Imidazo[1,2-a]pyridin-3-yl)methanone (51) (1.7 g). The yield was 47.0%.

Step C: 1.0 M boron tribromide toluene solution (6.8 mL) was added dropwise to a solution of compound 51 (800 mg, 2.72 mmol) in anhydrous dichloromethane (20 mL). Stir for 6 hours. The reaction was poured into an appropriate amount of ice water, and the pH was adjusted to 7 to 8 with a saturated aqueous sodium hydrogen carbonate solution. It was extracted with ethyl acetate (40 mL × 2) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:5 to 2:1) to give (3-methyl-4-hydroxyphenyl) (2-Ethylimidazo[1,2-a]pyridin-3-yl)methanone (52) (630 mg). The yield was 82.6%.

Step D: NBS (440 mg, 2.47 mmol) was added in EtOAc. Water (40 mL) was added, and ethyl acetate (30 mL × 3) was evaporated. The solvent is distilled off under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:3 to 1:1) to give (3-bromo-4-hydroxy-5- (Phenylphenyl)(2-ethylimidazo[1,2-a]pyridin-3-yl)methanone (53) (625 mg). The yield was 77.3%.

For the experimental procedure of Step E, see Step H in Example 4 to give 2-bromo-4-(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl-6-methylphenol. (54). ¹ H NMR (DMSO-d6, 400 MHz) 9.07 (s, 1H), 8.04 (d, J = 6.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.26-7.17 (m, 2H), 6.97 (s, 1H), 6.80-6.77 (m, 1H), 5.86 (s, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.16 (s, 3H), 1.25 (t, J = 7.6 Hz) , 3H). MS (EI, m/z): 360.0 [MH] ^- .

Example 16: Synthesis of 2,6-dibromo-4-[(2-ethylbenzofuran-3-yl)(methoxy)methyl]phenol (58)

Step A: a mixture containing benzbromarone (100 mg, 0.236 mmol), diisopropylethylamine (46 mg, 0.356 mmol), chloromethyl methyl ether (28 mg, 0.348 mmol) and dichloromethane (6 mL) Stir at room temperature overnight. After the addition of water (20 mL), EtOAc (EtOAc m. The solvent was evaporated under reduced pressure to give [3,5-dibromo-4-(methoxymethoxy)phenyl](2-ethylbenzofuran-3-yl)methanone (55) (108 mg). The yield was 97.8%.

Step B: Sodium borohydride (87 mg, 2.30 mmol) was added to a solution of compound 55 (108 mg, 0.230 mmol After the addition was completed, the resulting mixture was stirred at 40 ° C for 1.5 hours. Most of the solvent was evaporated under reduced pressure. Water (EtOAc) (EtOAc) The solvent was evaporated under reduced pressure to give [3,5-dibromo-4-(methoxymethoxy)phenyl](2-ethylbenzofuran-3-yl)methanol (5) (105 mg). The yield was 97.0%.

Step C: 60% sodium hydride (13 mg, 0.325 mmol) was added to a solution of compound 56 (100 mg, 0.213 mmol) in DMF (5 mL). Stirring was continued for 30 minutes, then iodomethane (60 mg, 0.422 mmol) was added and the mixture was stirred at room temperature overnight. After the addition of water (15 mL), EtOAc (EtOAc m. The solvent was evaporated under reduced pressure to give 3-{[3,5-dibromo-4-(methoxymethoxy)phenyl](methoxy)methyl}-2-ethylbenzofuran (57) (102 mg). The yield was 98.9%.

Step D: Concentrated hydrochloric acid (3 mL) was added to EtOAc (3 mL). After adding water (20 mL), EtOAc (EtOAc m. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:60) to give 2,6-dibromo-4-[(2-ethylbenzene) And furan-3-yl)(methoxy)methyl]phenol (58). ¹ H NMR (DMSO-d6, 400 MHz) δ 9.93 (s, 1H), 7.51-7.49 (m, 3H), 7.40-7.38 (m, 1H), 7.24-7.20 (m, 1H), 7.16-7. m, 1H), 5.60 (s, 1H), 3.28 (s, 3H), 2.92 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 439.0 [MH] ^- .

Example 17: Synthesis of 2,6-dibromo-4-{(2-ethyl-7-methoxyimidazo[1,2-a]pyridin-3-yl)hydroxymethyl}phenol (64)

Step A: 2-Amino-4-methoxypyridine (4.9 g, 39.5 mmol) and triethylamine (4.4 g, 43.5 mmol) were dissolved in tetrahydrofuran (30 mL), then propionyl chloride was added dropwise in an ice water bath (4.0 g, 43.5 mmol), the resulting mixture was stirred at room temperature overnight. Water (100 mL) was added, and the mixture was evaporated. Potassium carbonate (4.1 g, 29.7 mmol), methanol (50 mL) and water (12 mL) were added to the product, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc. The solvent was evaporated under reduced pressure to give N-(4-methoxypyridin-2-yl)propanamide (59) (4.85 g). The yield was 68.2%.

Step B: A mixture containing compound 59 (4.85 g, 26.9 mmol), 2-bromo-1-(4-methoxyphenyl)ethanone (6.14 g, 26.9 mmol) and toluene (50 mL) was stirred under reflux. overnight. After cooling to room temperature, water (50 mL) was added and the pH was adjusted to 8-9 using 2M aqueous potassium carbonate. It was extracted with dichloromethane (70 mL × 3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:5 to 2:3) to give (2-ethyl-7-methoxyimidazole) And [1,2-a]pyridin-3-yl)(4-methoxyphenyl)methanone (60) (900 mg). The yield was 10.8%. ¹ H NMR (DMSO-d6, 400 MHz) δ 9.08 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.17 (s, 1H), 7.08 (d, J = 8.4) Hz, 2H), 6.88-6.86 (m, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 2.38 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H) ).

Step C: A 1.0 M solution of boron tribromide in toluene (9 mL) was added dropwise to a solution of compound 60 (900 mg, 2.9 mmol) in anhydrous dichloromethane (25 mL). . The reaction solution was poured into ice water (50 mL) and the pH was adjusted to 7-8 with saturated aqueous sodium hydrogen carbonate. It was extracted with ethyl acetate (40 mL × 3) and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, methanol: dichloromethane = 1:50 to 1:20) to give (2-ethyl-7-hydroxyimidazo[1] , 2-a]pyridin-3-yl)(4-hydroxyphenyl)methanone (61) (477 mg) and (2-ethyl-7-methoxyimidazo[1,2-a]pyridine-3 -yl)(4-hydroxyphenyl)methanone (62) (277 mg). The yields were 58.3% and 32.2%, respectively. Compound ^{61: 1 H NMR (DMSO-} d6,400MHz) δ10.83 (s, 1H), 10.22 (s, 1H), 9.06 (d, J = 7.6Hz, 1H), 7.54 (d, J = 8.4Hz, 2H), 6.89-6.84 (m, 3H), 6.77-6.75 (m, 1H), 2.37 (q, J = 7.6 Hz, 2H), 1.08 (t, J = 7.6 Hz, 3H). Compound ^{62: 1 H NMR (DMSO-} d6,400MHz) δ10.25 (s, 1H), 9.03 (d, J = 7.6Hz, 1H), 7.57 (dd, J = 2.0,6.8Hz, 2H), 7.15 ( d, J = 2.4 Hz, 1H), 6.91-6.83 (m, 3H), 3.91 (s, 3H), 2.45 (q, J = 7.6 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H).

Experimental Procedures for Steps D and E Referring to Steps F and G of Example 9, respectively, 2,6-dibromo-4-{(2-ethyl-7-methoxyimidazo[1,2-a] was obtained. Pyridin-3-yl)hydroxymethyl}phenol (64). ^{1 H NMR (DMSO-d6,400MHz)} 7.95 (d, J = 7.6Hz, 1H), 7.40 (s, 2H), 6.87 (s, 1H), 6.52 (d, J = 7.6Hz, 1H), 6.25 ( d, J = 3.6 Hz, 1H), 6.14 (d, J = 3.6 Hz, 1H), 3.79 (s, 3H), 2.63 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H). MS (EI, m/z): 453.0 [MH] ^- .

Example 18: Synthesis of (3,5-dibromo-4-hydroxyphenyl)(2-propylfuro[2,3-b]pyridin-3-yl)methanone (69)

Step A: A mixture containing 5-bromo-2-hydroxypyridine (2.5 g, 14.4 mmol), iodosuccinimide (4.7 g, 20.9 mmol) and acetonitrile (40 mL) was stirred at 82 ° C for 20 min. After cooling to room temperature, filtration, the cake was recrystallized from ethyl acetate to give 5-bromo-2-hydroxy-3-iodopyridine (65) (4.0 g). The yield was 92.6%.

Step B: Compounds 65 (4.0 g, 13.3 mmol), cuprous iodide (254 mg, 1.33 mmol), bis(triphenylphosphine)palladium dichloride (468 mg, 0.667 mmol) and triethylamine (50 mL) 1-pentyne (1.09 g, 16.0 mmol) was added to the mixture, and the mixture was stirred at 50 ° C overnight. The solvent was evaporated under reduced pressure. EtOAc (EtOAc)EtOAc. The solvent was distilled off under reduced pressure. The product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:200 to 1:100) to give 5-bromo-2-propylfuro[2,3-b]pyridine (66) (1.72g). The yield was 53.9%. ^{1 H NMR (DMSO-d6,400MHz)} 8.29-8.25 (m, 2H), 6.67 (s, 1H), 2.80-2.78 (m, 2H), 1.73-1.71 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).

Step C: Compound 66 (1.0 g, 4.16 mmol) was dissolved in methanol (20 mL), and 10% palladium carbon (100 mg) was added, and the mixture was hydrogenated in hydrogen at 40 ° C under normal pressure overnight. The mixture was filtered through celite, and evaporated to drynessield. The yield was 92.5%. ^{1 H NMR (DMSO-d6,400MHz)} 8.20-8.18 (m, 1H), 8.00-7.98 (m, 1H), 7.30-7.27 (m, 1H), 6.67 (s, 1H), 2.80-2.76 (m, 2H), 1.76-1.70 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H).

Step D: A mixture containing compound 67 (50 mg, 0.31 mmol), 3,5-dibromo-4-methoxybenzoyl chloride (280 mg, 0.853 mmol) and diisopropylethylamine (5 mL) Stir at °C overnight. The solvent was evaporated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated. The product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:50 to 1:8) to give (3,5-dibromo-4-methoxyphenyl) (2) - propylfuro[2,3-b]pyridin-3-yl)methanone (68) (54 mg). The yield was 38.4%. ^{1 H NMR (DMSO-d6,400MHz)} 8.16 (s, 2H), 7.84-7.81 (m, 1H), 7.70 (s, 1H), 6.13-6.10 (m, 1H), 3.84 (s, 3H), 2.95 - 2.90 (m, 2H), 2.01-1.95 (m, 2H), 1.23-1.20 (m, 3H).

The experimental procedure of Step E was carried out by referring to Step B in Example 15 to obtain (3,5-dibromo-4-hydroxyphenyl)(2-propylfuro[2,3-b]pyridin-3-yl). Methyl ketone (69). MS (EI, m/z): 440.1 [M+H] ⁺ .

Example 19: Inhibition of uric acid transport in HEK293-hURAT1 transfected cell lines by compound

First, cell strain, reagent name and source:

HEK293 cell line was purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; plasmid pCMV6-hURAT1 was purchased from Origene Technologies, Inc; geneticin (G418) was purchased from Bioengineering Co., Ltd.; polylysine was purchased from Sigma -Aldrich Co.LLC; ¹⁴ C-uric acid was purchased from American Radiolabeled Chemicals, Inc.; sodium gluconate, potassium gluconate, calcium gluconate, KH ₂ PO ₄ , MgSO ₄ , glucose and HEPES were purchased from Sinopharm Chemical Reagent Co., Ltd. ; DMEM medium, fetal bovine serum was purchased from Thermo Fisher Scientific Inc; benzbromarone was purchased from Sigma-Aldrich Co. LLC;

Second, the test method:

The HEK293 cell line was used to construct a stable transgenic cell line with high expression of hURAT1: plasmid pCMV6-hURAT1 was transfected into HEK293 cells, and stably transfected with G418 (final concentration 500 μg/mL) to obtain stable transgenic cell lines with high expression. hURAT1 transport membrane protein, which can be used for in vitro inhibition of hURAT1 transport uric acid (Weaver YM, Ehresman DJ, Butenhoff JL, et al. Roles of rat renal organic anion transporters in transporting perfluorinated carboxylates with different chain lengths. Toxicological Sciences, 2009, 113 ( 2): 305-314). HEK293 cells are human embryonic kidney cells with high transfection efficiency and are a very common engineering cell line for expressing foreign genes.

2. Coating a 24-well plate: A polylysine solution having a concentration of 0.1 mg/mL was added at 200 μl/well in a 24-well plate and allowed to stand overnight. Remove the polylysine solution, rinse with sterile water and dry thoroughly before use.

3. Cell culture: The HEK293-hURAT1 stable cell line was inserted into the coated 24-well plate at 2×10 ⁵ cells/well, and placed in a CO ₂ cell incubator at 37 ° C, 5% CO ₂ . Incubate for 3 days under the conditions.

4. Formulation of HBSS buffer: Weigh each reagent at a final concentration of 125 mM sodium gluconate, 4.8 mM potassium gluconate, 1.3 mM calcium gluconate, 1.2 mM KH ₂ PO ₄ , 1.2 mM MgSO ₄ , 5.6 mM glucose, 25 mM HEPES. Then add deionized water to the corresponding volume, and mix well, that is, the pH 7.4 HBSS buffer (without chloride ion), stored in the refrigerator at -20 ° C.

5. On the day of the experiment, the HBSS buffer was removed from -20 ° C and heated to 37 ° C in a water bath. The 24-well plate in which the HEK293-hURAT1 stable cell line was cultured was taken out, the medium was carefully washed, and the cells were gently washed with HBSS buffer. Further, 160 μl/well was added to the HBSS buffer, and a test compound having a final concentration of 500 nM was added at 20 μl/well as a test compound well; or HBSS was added at 180 μl/well without adding a test compound as a blank control well. Leave at room temperature for 10 min.

6. Add ¹⁴ C-uric acid at a final concentration of 50 μM at 20 μl/well and let stand for 20 min at room temperature.

7. Aspirate each well and gently wash the cells with pre-chilled HBSS buffer and blot. Finally, 0.2 mol/L NaOH was added to dissolve the cells, and the cell debris was collected and the appropriate amount of scintillation fluid was added. After thorough mixing, the radioactivity (CPM value) of the isotope ¹⁴ C-uric acid was detected on a PerkinElmer MicroBeta Trilux 1450 liquid scintillation analyzer.

8. In the HEK293-hURAT1 stable cell line, the formula for calculating the inhibition rate of hURAT1 transport uric acid was as follows. The CPM value of the _{test compound was} expressed as CPM _{(test compound)} ; the CPM value of the _{blank control} was CPM _{(blank control).} Said. The test compounds were each set in triplicate, the test results were averaged, and the standard deviation SD was calculated. The test results are shown in Table 1.

Third, the test results

Compared with benzbromarone, the compounds 8, 12, 20, 23, 40 had a very good inhibitory effect on hURAT1 transport uric acid in HEK293 transfected cells at a concentration of 500 nM.

Table 1. Inhibition rate of hURAT1 transport uric acid in HEK293 transfected cell lines by test compound and benzbromarone

Claims (10)

1. a compound of the formula (I) or a pharmaceutically acceptable salt thereof,

   

   among them,

   Ring A is a five-membered aromatic ring or a six-membered aromatic ring containing a hetero atom;

   Ring B is a five-membered aromatic ring or a furan ring containing two N atoms;

   D is a C or N atom;

   E is a C or N atom;

   G is an N or O atom, and G is an O atom when both D and E are C atoms;

   Y is a carbonyl group, a sulfur group, a sulfone group, a sulfoxide group, an optionally substituted methylene group or an imino group; and when D or E in the ring A is an N atom such that the ring A forms a pyridine ring, or when the ring A is a benzene ring , Y is not a carbonyl group;

   R ¹ is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-3 substituted amino, C _1-3 alkoxy or C _{1 to 3} substituted alkoxy groups;

   R ² is hydrogen, deuterium, hydroxy, halogen, nitro, amino, cyano, C _1-3 alkyl, C _1-3 substituted alkyl, C _1-3 substituted amino, C _1-3 alkoxy or C _{1 to 3} substituted alkoxy groups;

   R ³ is C _1-4 alkyl, C _1-4 substituted alkyl or halogen;

   m is an integer from 0 to 3;

   n is an integer from 1 to 3;

   The hetero atom in the ring of the group A is selected from one or two of N, S or O, and the substituent in the group Y is selected from a hydroxyl group, an amino group, a cyano group, a carboxyl group, a C _1-3 alkoxy group or C _{A 1-3} alkyl group, and the substituent in the group R ¹ , R ² or R ³ is selected from a hydroxyl group, a halogen, a nitro group, an amino group or a cyano group.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a triazole ring, an imidazole ring, a thiazole ring, an oxazole ring, or an evil. An oxadiazole ring or a thiadiazole ring, the B ring is an imidazole ring, a pyrazole ring or a furan ring; and when D or E in the ring A is an N atom such that the ring A forms a pyridine ring, or the ring A is benzene In the ring, Y is not a carbonyl group.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds represented by the structures of formula (II), formula (III), formula (IV) or formula (V),

   

   Wherein Z ₁ , Z ₂ , Z ₃ or Z ₄ are each independently CH or N; X is S, O or NR ⁴ ; R ⁴ is H, -CH ₃ or -CH ₂ CH ₃ ; in formula (II) In (III) and (V), when Z ₁ , Z ₂ , Z ₃ and Z ₄ are both CH, Y is not a carbonyl group.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the compounds shown by the following structures,

   

   

   And in the formula (II-D) and the formula (III-A), Y is not a carbonyl group.
5. The compound according to any one of claims 1 to 4, wherein Y is a CH-OH, CH-NH ₂ , CH-CN, NH, NCH ₃ or CO group, R ³ , or a pharmaceutically acceptable salt thereof Is C _2-3 alkyl; in formula (II-D) and formula (III-A), Y is not a carbonyl group.
6. The compound according to any one of claims 1 to 4, wherein R ¹ is hydrogen, hydrazine, hydroxy, halogen, nitro, amino, cyano, C _1-3 alkyl, or a pharmaceutically acceptable salt thereof. C _1-3 haloalkyl, C _1-3 alkoxy or C _1-3 haloalkoxy, m is 0, 1 or 2.
7. The compound according to any one of claims 1 to 4, wherein R ² is hydrogen, halogen, nitro, cyano, C _1-3 alkyl, C _1-3 haloalkyl, or a pharmaceutically acceptable salt thereof , n is 1 or 2.
8. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

   (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyrimidin-3-yl)methanone,

   (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[2,1-b]thiazol-5-yl)methanone,

   (3,5-dibromo-4-hydroxyphenyl)(2-ethylimidazo[1,2-a]pyrazin-3-yl)methanone,

   3-bromo-5-[(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-2-hydroxybenzonitrile,

   5-[(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-2-hydroxybenzonitrile,

   2,6-dibromo-4-[(6-ethylimidazo[2,1-b]thiazol-5-yl)hydroxymethyl]phenol,

   2,6-dibromo-4-[(2-ethylimidazo[1,2-a]pyrazin-3-yl)hydroxymethyl]phenol,

   2-bromo-4-[(2-ethyl-6-fluoroimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]-6-fluorophenol,

   2,6-dibromo-4-[(2-ethylpyrazolo[1,5-a]pyridin-3-yl)hydroxymethyl]phenol,

   2,6-dibromo-4-[(6-bromo-2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl]phenol,

   2,6-dibromo-4-{[2-ethyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]hydroxymethyl}phenol,

   2,6-dibromo-4-[(2-ethylbenzofuran-3-yl)hydroxymethyl]phenol,

   2,6-dibromo-4-[(2-ethylimidazo[1,2-a]pyridin-3-yl)methyl]phenol,

   (3,5-dibromo-4-hydroxyphenyl)(6-ethylimidazo[2,1-b][1,3,4]thiadiazol-5-yl)methanone,

   2-bromo-4-(2-ethylimidazo[1,2-a]pyridin-3-yl)hydroxymethyl-6-methylphenol,

   2,6-dibromo-4-[(2-ethylbenzofuran-3-yl)(methoxy)methyl]phenol,

   2,6-dibromo-4-{(2-ethyl-7-methoxyimidazo[1,2-a]pyridin-3-yl)hydroxymethyl}phenol,

   (3,5-Dibromo-4-hydroxyphenyl)(2-propylfuro[2,3-b]pyridin-3-yl)methanone.
9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, as an active ingredient or a main active ingredient, supplemented with a pharmaceutically acceptable adjuvant.
10. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, for the manufacture of a urinary excretion drug, in particular for the preparation or treatment of a hyperuricemia or gout drug.