WO2017173965A1 - Novel urat1 inhibitor and pharmaceutical application thereof - Google Patents

Abstract

A novel URAT1 inhibitor and a pharmaceutical application thereof. The inhibitor is a compound represented by formula (I) and a pharmaceutically acceptable salt of the compound, wherein a radical group of the compound is defined by the specification. The compound represented by formula (I) can be used to prepare a pharmaceutical product promoting uric acid excretion, specifically for preparing a pharmaceutical product for treating or preventing hyperuricemia or gout.

Description

Novel URAT1 inhibitors and their application in medicine Technical field

The present invention relates to novel compounds for the treatment of disorders associated with abnormal levels of uric acid and pharmaceutically acceptable salts thereof, processes for their preparation and pharmaceutical compositions containing the same, and their use as URAT1 inhibitors for the treatment of gout, for the treatment of hyperuricemia and Reduce serum uric acid and other uses.

Background technique

Gout is a group of heterogeneous and metabolic diseases caused by long-term metabolic disorders and/or decreased uric acid excretion in the human body. It is divided into primary and secondary. Clinical manifestations of hyperuricemia and urate crystal deposition, leading to recurrent arthritis, gouty nephropathy, gout condensate deposition, urinary acid urinary system coagulation production, etc. (Pharmaceutical Herald. 2006, 25 (8 ): 803-806). Hyperuricemia is a serum uric acid content exceeding normal, generally more than 417 μmol / L (7.0 mg / dL) for men and 357 μmol / L (6.0 mg / dL) for women. When the blood uric acid concentration is supersaturated, there is crystallization of monosodium urate, which is deposited in the synovial fluid, the cartilage of the peripheral joint, the auricle of the ear and the olecranon of the elbow (The Cecil Textbook of Medicine. 23rd ed. 2008: 2069-2075.; Lancet. 2010, 375 (9711): 318-328.; Conn's Current Therapy 2010, 1st ed. 2008: 588-591.), such symptoms can be diagnosed as gout.

The occurrence of gout and hyperuricemia is not only affected by age, gender, region, ethnicity, heredity, environment, etc., but also with other metabolic syndromes such as obesity, hypertension, hyperlipidemia, coronary heart disease, insulin resistance and Diabetes is closely related (Circ J 2005, 69(8): 928-933.; Metabolism. 2008, 57(1) 71-76.; Curr Opin Rheumatol. 2005, 17(3): 341-345.). Studies have shown that hyperuricemia and hypertension are the main causes of metabolic syndrome, and there are mechanisms of interaction that can exacerbate the risk factor for cardiovascular disease (Korean J Gastroenterol, 2008, 49(3): 173-176.). At the same time, there are also reports in the literature that the level of serum uric acid in patients with type 2 diabetes is significantly higher than that in the normal population. Hyperuricemia accelerates the development and progression of diabetic nephropathy in patients with type 2 diabetes (Eur J Clin Invest, 2001, 31 (4) ): 318-321.). In recent years, multiple risk factor intervention trials have also shown that hyperuricemia is an independent risk factor for myocardial infarction (BMC Public Health, 2011, 11: 832.). Therefore, gout and hyperuricemia, like diabetes, are a serious metabolic disease that endangers human health.

With the development of social economy and lifestyle changes in China in the past 30 years, the incidence of gout in China has risen linearly. In 2009, the prevalence of hyperuricemia in Shanghai was 10.0%; the prevalence of hyperuricemia in 1120 subjects in Beijing was 17.86%; the prevalence rate in Guangzhou was the highest in the country, 27.9% for men and 12.4% for women. The overall prevalence rate is as high as 21.81%. The prevalence of gout in the western developed countries is also high, with approximately 6.1 million people suffering from gout in the United States (Part II. Arthritis Rheum. 2008, 58(1): 26-35.).

The transport of uric acid in the kidney can directly regulate the level of blood uric acid, and about 85% of gout is caused by reduced uric acid excretion (Curr Opin Nephrol Hypertens, 2009, 18(5): 428-432.). Physiological and pharmacological studies define the classic mode of renal uric acid transport: glomerular filtration, renal tubular reabsorption, renal tubular secretion, post-secretion reabsorption, especially tubular reabsorption, which affects uric acid excretion. The most important factor. Proteins involved in uric acid reabsorption have been shown to be: urate unidirectional transporters (UAT), organic anion transporters OAT1 and OAT3, and urate anion transporter 1, URAT1. URAT1 is responsible for the transport of uric acid into the epithelial cells through the brushy edge of the proximal convoluted tubule. It is the main uric acid reabsorption transport protein in the human body, and is specifically expressed in the proximal convoluted epithelial cells, independent of membrane voltage and intracellular and extracellular pH. The effect of the value is an electrically neutral urate exchanger, which is time-dependent and saturated (Nature. 2002, 417 (6887): 447-452.). The reabsorption of uric acid in the proximal tubules is largely accomplished by URAT1 (Arthritis And Rheumatism, 1975, 18(6): 805-809.). URAT1 is a member of the organic anion transporter (OAT) superfamily. It is encoded by the SLC22A12 gene and consists of 9 exons with 9 exons. It has 12 transmembrane domains with a full-length cDNA of 2642 bp and a coding region of 1659 bp. There are a variety of mutations that are prone to abnormal uric acid metabolism. A meta-analysis indicates that the SLC22A12 gene contributes 0.13% to the blood uric acid level. (J Clin Invest, 2010, 120(6): 1791-1799.). It has also been found that the SLC22A12 gene in patients with renal hypouricemia is mutated and loses the ability to encode the mature protein of URAT1, suggesting that URAT1 is important for the uric acid reabsorption function of the kidney. Taniguchi et al. found that the G774A mutation of the SCL22A12 gene is an inhibitor of goutogenesis, and the serum uric acid level of the heterozygous G774A mutation is significantly lower than that of healthy people (Arthritis Rheum. 2005; 52(8): 2576-2577.). Guan et al studied the polymorphism of the gene sequence sr893006 in SLC22A12 in 124 patients with primary gout and 168 healthy Chinese male subjects, suggesting that the polymorphism of the gene sequence may be in Chinese men with hyperuricemia. Genetic risk factors (Scand J Rheumatol. 2009; 38(4): 276-81.). Therefore, URAT1 will remain one of the main targets for the development of drugs for the treatment of gout and hyperuricemia in the future.

The uric acid excretion drugs currently used in the market for the treatment of gout are Benzbromarone, Probenecid, Sulfinpyrazone, Lesinurad and the like. Benzobromarone is currently the most commonly used drug for the treatment of hyperuricemia and gout. It mainly acts as a uric acid excretion by inhibiting the reabsorption of uric acid by URAT1. Compared with benzbromarone, probenecid and sulfinpyrazone have a poor effect on uric acid excretion in the treatment of gout. Benzobromarone is a benzofuran derivative developed in the 1960s by the French company Snaofi-Synthelabo, in 1976 Listed in Germany in the past, it has been widely used in the treatment of gout and hyperuricemia. However, benzbromarone has serious side effects such as liver damage. After the international report that the drug may cause the risk of fulminant hepatitis in 2003, it has been withdrawn from the market in some countries (Pharmaceutical Herald, 2006, 25(8): 803).

In December 2015, the US FDA approved Zurampic (Lesinurad) developed by AstraZeneca for the treatment of gout, which is currently the latest clinically used URAT1 inhibitor. AstraZeneca has also developed a combination of Lesinurad and allopurinol, which has also entered Phase III clinical studies. Lesinurad is an oral solid preparation that can be combined with xanthine oxidase inhibitors for the treatment of gout-related hyperuricemia. However, there are many adverse reactions in Lesinurad: when it is combined with xanthine oxidase inhibitors, headache, flu, increased serum creatinine and gastroesophageal reflux disease; when there is often a renal function-related adverse reaction at a dose of 400 mg, it can also cause serious Cardiovascular adverse reactions. At the same time, Lesinurad is a moderate inhibitor of the P450 enzyme CYP2C9 and a sensitive CYP3A substrate, which is not recommended for patients with severe liver injury.

RDEA-3170, currently developed by AstraZeneca, has been in clinical phase II, and some of the disclosed URAT1 inhibitor patents include WO2005121112, WO2011159839, WO2007086504, WO2008062740, WO2009070740, WO2011085009, WO2014017643, WO2014183555, WO2014077285, and the like.

In order to better meet market demand, we hope to develop new high-efficiency, low-toxic URAT1 inhibitors. The present invention provides a novel structural URAT1 inhibitor and finds that such compounds have good URAT1 inhibitory activity, and it is expected that the novel URAT1 inhibitor can be used for the treatment of gout, hyperuricemia and related renal diseases, and lowering blood uric acid concentration.

Summary of the invention

It is an object of the present invention to provide a novel class of URAT1 inhibitors based on the prior art.

Another object of the present invention is to provide a pharmaceutical use of the above URAT1 inhibitor.

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

a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer and a mixture thereof, and a pharmaceutically acceptable compound thereof Accepted salt,

among them,

Y or Z are independently N or CH,

R ¹ or R ² are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C _1-4 alkyl, substituted C _1-4 alkyl, C _3-4 cycloalkyl, C _{1- 4} alkoxy, substituted C _1-4 alkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted heteroaryl are one or more of which substituents The group is selected from the group consisting of halogen, cyano, hydroxy, amino, C _1-2 alkyl, C _1-2 haloalkyl, C _1-2 alkoxy or C _1-2 haloalkoxy,

R ³ or R ⁴ are each independently selected from H or C _1-3 alkyl, or R ³ and R ⁴ together form a 3-6 membered cycloalkyl group,

R ⁵ is H, C _1-4 alkyl or substituted C _1-4 alkyl, the substituent of which is selected from C _1-2 alkoxy, hydroxy or amino.

In another preferred embodiment, the compound is selected from the group consisting of a compound of formula (II), formula (III) or formula (IV),

In one embodiment, in each of the compounds of the present invention, R ¹ or R ² are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C _1-3 alkyl, substituted C _1-3 alkane. , C _3-4 cycloalkyl, C _1-3 alkoxy, substituted C _1-3 alkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl, substituted thiophene One or more of a group, a furyl group, a substituted furyl group, a thiazolyl group or a substituted thiazolyl group, the substituents being independently selected from the group consisting of halogen, cyano, amino, hydroxy, trifluoromethyl, Oxy, ethoxy, difluoromethoxy or trifluoromethoxy.

In another embodiment, in each of the compounds of the present invention, R ¹ or R ² are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C _1-3 alkyl, C _1-3 alkoxy , C _1-3 fluoroalkyl, C _1-3 fluoroalkoxy, phenyl, halophenyl, cyanophenyl, methylphenyl, ethylphenyl, methoxyphenyl, One or more of an ethoxyphenyl group, a naphthyl group, and a cyanophenyl group.

In another embodiment, in each of the compounds of the present invention, R ³ or R ⁴ are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, or R ³ and R ^{4 are taken} together to form 3- 5-membered cycloalkyl.

In another embodiment, in each of the compounds of the invention, R ⁵ is H or C _1-3 alkyl.

In another aspect, each compound of the invention may be selected from:

2-methyl-2-{[5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid,

2-methyl-2-{[5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid methyl ester,

2-[(6-fluoroimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

2-[(6-fluoroimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

2-(imidazo[1,2-a]pyridin-8-yl)indol-2-methylpropanoic acid,

2-(imidazo[1,2-a]pyridin-8-yl)indol-2-methylpropanoate,

2-[(5-Cyanoimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid,

2-[(5-Cyanoimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoate,

2-[(5-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

2-[(5-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

2-methyl-2-[(2-methylimidazo[1,2-a]pyridin-5-yl)indolyl]propionic acid,

2-methyl-2-[(2-methylimidazo[1,2-a]pyridin-5-yl)indolyl]propionic acid methyl ester,

7-[(2-carboxypropan-2-yl)indolyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid,

Methyl 7-[(2-carboxypropan-2-yl)indolyl]pyrazolo[1,5-a]pyridine-3-carboxylate,

2-methyl-2-{[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]indenyl}propionic acid,

2-methyl-2-{[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]indenyl}methyl propionate,

2-([1,2,4]triazolo[1,5-a]pyridin-5-ylindenyl)-2-methylpropanoic acid,

2-([1,2,4]triazolo[1,5-a]pyridin-5-ylindenyl)-2-methylpropanoate,

1-{[5-(Trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}cyclobutanecarboxylic acid,

1-{[5-(Trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}cyclobutanecarboxylate,

2-[(6-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

2-[(6-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

2-methyl-2-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid,

2-methyl-2-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid methyl ester,

2-methyl-2-[(6-phenylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid,

2-methyl-2-[(6-phenylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid methyl ester,

2-{[6-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

Methyl 2-{[6-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoate,

2-{[3-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

Methyl 2-{[3-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoate,

2-{[5-(4-cyanophenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

2-{[5-(4-Cyanophenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid methyl ester,

2-{[5-(4-cyanophenyl)imidazo[1,2-a]pyridin-6-yl]indenyl}-2-methylpropanoic acid,

Methyl 2-{[5-(4-cyanophenyl)imidazo[1,2-a]pyridin-6-yl]indolyl}-2-methylpropanoate,

2-{[8-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

Methyl 2-{[8-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

2-{[6-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indenyl}-2-methylpropanoic acid,

Methyl 2-{[6-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

2-{[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

Methyl 2-{[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

2-{[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

Methyl 2-{[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

2-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

Methyl 2-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

2-methyl-2-[(5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid,

2-methyl-2-[(5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid methyl ester,

2-[(3-bromo-5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

2-[(3-Bromo-5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

2-{[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

Methyl 2-{[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoate,

2-[(3-bromo-5-cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

2-[(3-Bromo-5-cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

2-[(3-bromo-7-methoxyimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid,

Methyl 2-[(3-bromo-7-methoxyimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoate.

The present invention also provides a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer and a mixture thereof. And methods of pharmaceutically acceptable salts thereof, the method comprising:

The compound of the formula (IA) is subjected to a substitution reaction with a compound of the formula (IB), optionally further subjected to a hydrolysis reaction under basic conditions to obtain a compound of the formula (I); wherein: X ¹ is a leaving group or SH, The leaving group is halogen, OMs (methanesulfonyloxy), OTs (p-toluenesulfonyloxy) or OTf (trifluoromethanesulfonyloxy), preferably halogen; X ² is halogen, OMs, OTs or SH; when X ¹ is a leaving group, X ² is SH; when X ¹ is SH, X ² is halogen, OMs, OTs. Other groups are defined as defined in the claims and the general formula (I).

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

"Alkyl" is used to mean a saturated hydrocarbon group, and C _1-4 alkyl means a saturated hydrocarbon group having 1 to 4 carbon atoms, which includes methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl and neobutyl. In the present invention, alkyl is preferably C _1-4 alkyl, more preferably C _1-3 alkyl. The substituted alkyl group means an alkyl group having one or more substituents. When the number of the substituents is two or more (including two), the respective substituents may be the same or different. The substituted C _1-4 alkyl group means a saturated hydrocarbon group having 1 to 4 carbon atoms having one or more (2 or more) substituents; for example, "fluoromethyl" means having one or two The methyl group of one or three fluorine substituents, "fluoroethyl" means an ethyl group having 1 to 5 fluorine substituents.

"Cycloalkyl" means a monocyclic or fused ring that is all carbon (a "fused" ring means that each ring in the system shares an adjacent pair of carbon atoms with other rings in the system), one of which Or a plurality of rings do not have a fully connected π-electron system, examples of cycloalkyl groups (not limited to) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene , cycloheptane and cycloheptatriene. Cycloalkyl groups can be substituted and unsubstituted. When substituted, the substituent is preferably one or more groups each selected from the group consisting of alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, fluorenyl, Alkyl, aryl, cyano, halogen, carbonyl, thiocarbonyl, C-carboxy, O-carboxy, O-carbamoyl, N-carbamoyl, C-amido, N-amido, nitro, Amino and -NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ^{11 are} as defined above.

"Heteroaryl" means a monocyclic or fused ring radical of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining ring atoms being C In addition, it has a fully conjugated π-electron system. Non-limiting examples of unsubstituted heteroaryl sites are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, indole, tetrazole, triazine and carbazole. Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two, independently selected from the group consisting of lower alkyl, three Haloalkyl, halogen, hydroxy, lower alkoxy, fluorenyl, (lower alkyl)thio, cyano, acyl, thioacyl, O-carbamoyl, N-carbamoyl, O-thiocarba Acyl, N-thiocarbamoyl, C-amido, N-amido, nitro, N-sulfonylamino, S-sulfonylamino, R ¹⁰ S(O)-, R ¹⁰ S(O) ₂ ‐, ‐C(O)OR ¹⁰ , R ¹⁰ C(O)O‐ and ‐NR ¹⁰ R ¹¹ , wherein R ¹⁰ and R ^{11 are} as defined above. Preferred heteroaryl groups are optionally substituted by one or two substituents independently selected from halo, lower alkyl, trihaloalkyl, hydroxy, decyl, cyano, N-amido, mono or dioxane Amino group, carboxyl group or N-sulfonylamino group.

"Halo C _1-4 alkyl" means a saturated hydrocarbon group having from 1 to 4 carbon atoms having one or more (ie two or more) halogen substituents, wherein each halogen substituent may be the same, Can be different. The "fluoro C _1-3 alkoxy group" means a saturated hydrocarbon group having 1 to 3 carbon atoms having one or more (ie, 2 or more) fluorine substituents. The halogenated C _1-4 alkyl group in the present invention includes, but is not limited to, a halogenated methyl group, a halogenated ethyl group, a halogenated n-propyl group, a halogenated isopropyl group, a halogenated n-butyl group, a halogenated isobutyl group, Halogenated neobutyl, etc., more specific groups include, but are not limited to, trifluoromethyl, difluoromethyl, monofluoromethyl, trichloromethyl, dichloromethyl, monochloromethyl, tetrafluoroethyl , trifluoroethyl, difluoroethyl, monofluoroethyl, trichloroethyl, dichloroethyl, monochloroethyl, and the like.

"Halogen" includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

"Alkoxy" means an "-O-alkyl" group having from 1 to 10 carbon atoms. The C _1-4 alkoxy group means that the alkoxy group has 1 to 4 carbon atoms. The alkoxy group in the invention is preferably a C _1-4 alkoxy group, more preferably a C _1-3 alkoxy group. The substituted alkoxy group means an alkoxy group having one or more substituents. When the number of the substituents is two or more (including two), the respective substituents may be the same or different. The substituted C _1-4 alkoxy group means an alkoxy group having 1 to 4 carbon atoms having one or more (ie, 2 or more) substituents. Alkoxy groups in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and neobutoxy.

"Hydroxy" refers to a "-OH" group.

"D" refers to the similar position of hydrogen.

"Cyano" refers to the -CN group.

"Carboxy" refers to a -COOH group.

"Pharmaceutically acceptable salt" means 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 For example (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, neighbors 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 propylene An acid or the like is preferably hydrochloric acid or (L) malic 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.

The present invention discloses a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, supplemented with a pharmaceutically acceptable adjuvant.

Each compound of the present invention or a pharmaceutically acceptable salt thereof can be used for the preparation of a uric acid excretion drug, particularly for the preparation of a medicament for treating or preventing hyperuricemia or gout.

DRAWINGS

Figure 1 is a graph showing the growth inhibitory effect of Compound 6 and Lesinurad on human hepatoma cell HepG2.

detailed description

The following preparation examples and biological examples are given to enable those skilled in the art to understand and practice the invention more clearly. They are not to be construed as limiting the scope of the invention, but are merely illustrative and representative.

Example 1: Synthesis of 2-methyl-2-{[5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}propionic acid (6)

Step A: Methyl bromoisobutyrate (7.0 g, 38.7 mmol) and potassium thioacetate (4.83 g, 42.3 mmol) The mixture was stirred under reflux for 2 hours in acetone (36 mL). After cooling, the solvent was evaporated under reduced pressure. The solvent was evaporated under reduced pressure to give ethyl <RTI ID=0.0>#</RTI> </RTI> <RTIgt; </RTI> <RTIgt;

Step B: Potassium hydroxide (8.98 g, 160 mmol) was dissolved in methanol (90 mL), and then the crude compound (7.3 g) of Compound 1 was added under ice-water bath, and the mixture was stirred at 0 to 10 ° C overnight. Add an appropriate amount of water and adjust the pH to 3 to 4 with 2M hydrochloric acid. The organic layer was washed with water (50 mL×3) and brine (30 mL) The solvent was evaporated under reduced pressure at room temperature, and the product was purified by column chromatography (200-300 mesh silica gel, methylene chloride: petroleum ether = 1 : 50) to afford methyl mercaptoisobutyrate (2) (3.12 g). The total yield of the two steps of steps A and B was 60.0%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 3.74 (s, 3H), 1.60 (s, 6H). MS (EI, m/z): 133.0 [MH] ^- .

Step C: A solution of bromine (4.31 g, 27.0 mmol) in dichloromethane (10 mL) was added dropwise to 2-amino-6-(trifluoromethyl)pyridine (4.37 g, 27.0 mmol). In a solution of methyl chloride (70 mL), the mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate (40 mL) was added and the mixture was evaporated. 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 = 1:50 to 1:30) to give 3-bromo-6-(trifluoromethyl) Pyridin-2-amine (3) (2.79 g). The yield was 42.9%. ¹ H NMR (CDCl ₃ , 300 MHz) δ 7.79 (d, J = 9.0 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 5.22 (s, 2H).

Step D: A mixture containing Compound 3 (2.77 g, 11.5 mmol), 40% aqueous chloroacetaldehyde (6.77 g, 34.5 mmol), sodium bicarbonate (966 mg, 11.5 mmol) and ethanol (25 mL) was sealed at 110 ° C The tube was stirred overnight. After slightly cooling, a 40% aqueous solution of chloroacetaldehyde (6.77 g, 34.5 mmol) and sodium hydrogencarbonate (966 mg, 11.5 mmol) were added, and stirring was continued at 110 ° C overnight. After cooling, most of the solvent was evaporated under reduced pressure. 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 = 1:50 to 1:30) to give 8-bromo-5-(trifluoromethyl) Imidazo[1,2-a]pyridine (4) (2.0 g). The yield was 65.6%. ¹ H NMR (DMSO-d ₆ , 500 MHz) δ 8.21 (d, J = 1.0 Hz, 1H), 7.91 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H). MS (EI, m/z): 265.0 [M+H] ⁺ .

Step E: Dioxane (6 mL), Compound 4 (100 mg, 0.377 mmol), Pd ₂ (dba) ₃ (17.3 mg, 0.019 mmol) and 4,5-bisdiphenylphosphine were sequentially added to a three-necked flask A. -9,9-Dimethoxyxanthracene (xantphos) (22 mg, 0.0380 mmol), and the mixture was stirred under nitrogen for 40 min. To another three-necked flask B was added dioxane (4 mL), compound 2 (100 mg, 0.745 mmol) and diisopropylethylamine (98 mg, 0.758 mmol), and the mixture was stirred under nitrogen for 20 min. The mixture in the three-necked flask A was transferred to the above-mentioned three-necked flask B by a syringe. The resulting mixture was stirred at reflux overnight. After cooling to room temperature, water (30 mL) was added, and ethyl acetate (30 mL × 3) 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 = 1:50 to 1:25) to give 2-methyl-2-{[5-( Methyl trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propanoate (5) (54 mg). The yield was 45.0%. MS (EI, m/z): 341.0 [M+Na] ⁺ .

Step F: A mixture containing compound 5 (54 mg, 0.170 mmol), THF (1 mL), methanol (2mL), water (2mL) and sodium hydroxide (21mg, 0.525mmol) was stirred overnight at room temperature. Water (10 mL) was added, washed with methyl t-butyl ether (MTBE) (10 mL×2), and the aqueous phase was collected. The aqueous phase was adjusted to pH 3-4 with dilute aqueous HCl, and then extracted with ethyl acetate (15 mL, The solvent was evaporated under reduced pressure and the obtained crystals crystals crystals crystals crystals crystalssssssssssssssssssss ] mercapto}propionic acid (6) (18 mg). The yield was 34.8%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 12.96 (s, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 1.62 (s, 6H). MS (EI, m/z): 305.1 [M+H] ⁺ .

Example 2: Synthesis of 2-[(6-fluoroimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropionic acid (10)

The experimental procedure for preparing compound 10 using 2-amino-5-fluoropyridine as a starting material is shown in steps C, D, E and F of Example 1, respectively.

Compound 8: ¹ H NMR (CDCl ₃ , 500 MHz) δ 8.10-8.09 (m, 1H), 7.74 (s, 1H), 7.69 (s, 1H), 7.45-7.43 (m, 1H).

Compound ^{10: 1 H NMR (DMSO-} d 6, 300MHz) δ9.22 (s, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 1.52 (s, 6H) . MS (EI, m/z): 255.0.0 [M+H] ⁺ .

Example 3: Synthesis of 2-(imidazo[1,2-a]pyridin-8-yl)indol-2-methylpropanoic acid (14)

Step A: A solution of bromine (5.25 g, 32.9 mmol) in dichloromethane (10 mL) was added dropwise to a solution of methyl 6-aminopicolinate (5.0 g, 32.9 mmol) in dichloromethane (70 mL). The resulting mixture was stirred at room temperature overnight. A saturated aqueous solution of sodium hydrogencarbonate (40 mL) was added and the mixture was evaporated. 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 = 1:20 to 1:5) to give methyl 6-amino-5-bromopyridinecarboxylate ( 11) (1.83g). The yield was 24.1%. ¹ H NMR (CDCl ₃ , 500 MHz) δ 7.78 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H).

Step B: Compound 11 (1.83 g, 7.92 mmol), 40% aqueous chloroacetaldehyde (4.76 g, 23.7 mmol), dioxane (16 mL), sodium bicarbonate (670 mg, 7.98 mmol) and water (4 mL) The mixture was stirred at 90 ° C overnight. After slightly cooling, a 40% aqueous solution of chloroacetaldehyde (2.38 g, 12.1 mmol) was added, and then the mixture was stirred at 90 ° C and stirring was continued overnight. After cooling, most of the solvent was evaporated under reduced pressure. Water (20 mL) was added and the pH was adjusted to 7-8 with saturated sodium hydrogen carbonate. 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 = 1:20 to 1:15) to give 8-bromoimidazo[1,2-a] Pyridine-5-carboxylic acid methyl ester (12) (1.24 g). The yield was 61.4%. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 8.85 (s, 1H), 7.84 (s, 1H), 7.77-7.68 (m, 2H), 3.97 (s, 3H).

Step C: A mixture containing compound 12 (100 mg, 0.392 mmol), sodium sulphate sulphate (122 mg, 0.508 mmol) and DMF (4 mL) was stirred at 70 ° C for 1 hour, and after cooling slightly, methyl bromoisobutyrate was added ( 284 mg, 1.57 mmol) and potassium carbonate (81 mg, 0.587 mmol), and the mixture was stirred at 60 ° C overnight. After the addition of 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 = 1:20 to 1:10) to give 8-[(1-methoxy-2-) Methyl-1-propion-2-yl)indenyl]imidazo[1,2-a]pyridine-5-carboxylic acid methyl ester (13) (34 mg). The yield was 28.1%. ¹ H NMR (CDCl ₃ , 500 MHz) δ 8.84 (s, 1H), 7.78 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 4.01 (s, 3H), 3.71 (s, 3H), 1.69 (s, 6H).

Step D: Compound 13 (32 mg, 0.14 mmol) was dissolved in THF (1 mL) and methanol (2mL), and 2M sodium hydroxide solution (3mL) was added, and the mixture was stirred at 40 ° C for 1 hour. About half of the solvent was distilled off under reduced pressure at 40 ° C, water (20 mL) was added, and washed with MTBE (10 mL × 2), and the aqueous phase was collected. The aqueous phase was adjusted to pH 5 to 6 with dilute aqueous hydrochloric acid, and the solvent was evaporated under reduced pressure. The obtained product was extracted with methylene chloride/methanol = 5/1 (15mL × 4), and the combined solution was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 2-(imidazo[1,2-a]pyridin-8-ylindenyl)-2-methylpropanoic acid (14). _{^{1 H NMR (DMSO-d 6}} , 500MHz) δ9.08 (s, 1H), 7.52-7.50 (m, 1H), 7.39-7.38 (m, 2H), 7.27 (d, J = 7.5Hz, 1H), 1.43 (s, 6H). MS (EI, m/z): 235.1 [MH] ^- .

Example 4: 2-[(5-Cyanoimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid (19) and 2-[(5-cyanoimidazolium) Synthesis of [1,2-a]pyridin-8-yl)indenyl]-2-methylpropionic acid (22)

The experimental procedures for preparing compounds 19 and 22 using 2-amino-6-cyanopyridine as a starting material are described in detail in steps C, D, E and F of Example 1.

Compound ^{17: 1 H NMR (DMSO-} d 6, 300MHz) δ8.20 (s, 1H), 7.96 (d, J = 5.7Hz, 1H), 7.85 (d, J = 0.6Hz, 1H), 7.60 (d , J = 5.7 Hz, 1H).

Compound ^{19: 1 H NMR (DMSO-} d 6, 400MHz) δ8.20 (s, 1H), 8.01-7.98 (m, 1H), 7.89 (d, J = 1.5Hz, 1H), 7.41 (d, J = 7.5 Hz, 1H), 1.51 (s, 6H). MS (EI, m/z): 260.1 [MH] ^- .

Compound 20: ¹ H NMR (DMSO-d ₆ , 500 MHz) δ 8.32 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 1.5 Hz, 1H), 7.79-7.76 (m, 2H).

Compound 22: MS (EI, m / z): 260.1 [MH] -.

Example 5: Synthesis of 2-methyl-2-[(2-methylimidazo[1,2-a]pyridin-5-yl)indenyl]propionic acid (25)

Step A: A mixture containing 2-amino-6-fluoropyridine (500 mg, 4.46 mmol), bromoacetone (1.83 g, 13.4 mmol), ethanol (10 mL) and sodium bicarbonate (375 mg, 4.46 mmol) was sealed at 90 ° C The tube was stirred overnight. After cooling, most of the solvent was distilled off under reduced pressure, and an appropriate amount of water was added, and the pH was adjusted to 7 to 8 with a saturated sodium hydrogen carbonate solution. It was extracted with ethyl acetate (20 mL × 3) and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the product is purified by column chromatography (200-300) Silica gel, ethyl acetate: petroleum ether = 1:20 to 1:3 eluted to give 5-fluoro-2-methylimidazo[1,2-a]pyridine (23) (108 mg). The yield was 16.1%.

Step B: A mixture containing compound 23 (108 mg, 0.719 mmol), triethylamine (182 mg, 1.80 mmol), Compound 2 (193 mg, 1.44 mmol) and DMF (5 mL) was stirred at 70 ° C for 60 hours. After the addition of 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 = 1:8 to 1:1) to give 2-methyl-2-[(2- Methyl imidazo[1,2-a]pyridin-5-yl)indolyl]propanoate (24) (35 mg). The yield was 18.4%.

Step C: Compound 24 is hydrolyzed according to the procedure of Example D in Example 3, and acidified to give 2-methyl-2-[(2-methylimidazo[1,2-a]pyridin-5-yl)indenyl] Propionic acid (25). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.34 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.88-7.84 (m, 1H), 7.65 (d, J = 7.2 Hz, 1H), 2.51 (s, 3H), 1.52 (s, 6H). MS (EI, m/z): 251.1 [M+H]+.

Example 6: Synthesis of 7-[(2-carboxypropan-2-yl)indolyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid (29)

Step A: A mixture of 1-aminoiodide pyridine (6.17 g, 27.8 mmol), ethyl propiolate (3.0 g, 30.6 mmol), potassium carbonate (8.44 g, 61.2 mmol) and DMF (40 mL) at room temperature Stir under overnight. Water (200 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 = 1:30 to 1:10) to give pyrazolo[1,5-a]pyridine- Ethyl 3-carboxylate (26) (3.46 g). The yield was 65.4%.

Step B: 2.0 M bistrimethylsilylamino sodium THF solution (16 mL, 32 mmol) was added dropwise to a solution of compound 26 (3.4 g, 17.9 mmol) in THF (15 mL) at -30 to -40 °C. Stirring was continued for 1 hour after the addition. Then, a solution of iodine (5.4 g, 21.3 mmol) in THF (10 mL) was added dropwise at this temperature, and stirring was continued for 40 minutes. Saturated brine (40 mL) was added, then a saturated sodium thiosulfate solution was added dropwise until the color was removed, and extracted with ethyl acetate (40 mL×3), and the combined organic phases were washed with saturated brine (25 mL×2). Sodium is dry. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:15) to give 7-iodopyrazolo[1,5-a]pyridine-3 Ethyl formate (27) (1.96 g). The yield was 34.6%. _{^{1 H NMR (DMSO-d 6}} , 300MHz) δ8.53 (s, 1H), 8.11 (dd, J = 1.2,8.7Hz, 1H), 7.75-7.72 (m, 1H), 7.33 (dd, J = 1.2 , 8.7 Hz, 1H), 4.31 (q, J = 6.9 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H).

For the experimental procedures of steps C and D, see steps E and F in Example 1, to give 7-[(2-carboxypropan-2-yl)indolyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid ( 29). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.42 (s, 1H), 8.03 (dd, J = 0.8, 8.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.17 (d, J = 6.4 Hz, 1H), 1.58 (s, 6H). MS (EI, m/z): 279.1 [MH] ^- .

Example 7: 2-Methyl-2-{[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]indenyl}propionic acid Synthesis of (33)

Step A: A mixture containing compound 3 (300 mg, 1.24 mmol), isopropanol (4 mL) and N,N-dimethylformamide dimethyl acetal (DMFDMA) (195 mg, 1.64 mmol) was refluxed under nitrogen. Stir for 3 hours. After cooling to 50 ° C, hydroxylamine hydrochloride (114 mg, 1.64 mmol) was added, and the resulting mixture was stirred at this temperature for 6 hours. The solvent was evaporated under reduced pressure. EtOAc (EtOAc) The solvent was evaporated under reduced pressure and the product was purified mjjjjjjjjjjjjj 2-yl]-N'-hydroxyformamidine (30) (300 mg). The yield was 84.9%.

Step B: The compound 30 (290 mg, 1.02 mmol), THF (10 mL) and polyphosphoric acid (700 mg, 2.07 mmol) was stirred at 100 ° C overnight, and most of the solvent was evaporated under reduced pressure. After adding an appropriate amount of water, the pH was adjusted to 8 to 9 with a 2M sodium hydroxide solution, and then extracted with ethyl acetate (15 mL × 2) 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 give 8-bromo-5-(trifluoromethyl)-[1,2,4]triazole Zoxao[1,5-a]pyridine (31) (190 mg). The yield was 55.8%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.79 (s, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H).

For the experimental procedures of steps C and D, see steps E and F in Example 1 to give 2-methyl-2-{[5-(trifluoromethyl)-[1,2,4]triazolo[1 , 5-a]pyridin-8-yl]fluorenyl}propionic acid (33). _{^{1 H NMR (DMSO-d 6}} , 400MHz) δ13.19 (s, 1H), 8.71 (s, 1H), 7.85 (d, J = 7.6Hz, 1H), 7.69 (d, J = 7.6Hz, 1H) , 1.62 (s, 6H). MS (EI, m / z) : 304.0 [MH] -.

Example 8: Synthesis of 2-([1,2,4]triazolo[1,5-a]pyridin-5-ylindenyl)-2-methylpropanoic acid (37)

For the preparation of the compound 5-bromo-[1,2,4]triazolo[1,5-a]pyridine (35), see steps A and B in Example 7. Wherein compound 3 in step A was replaced with 2-amino-6-bromopyridine. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.62 (s, 1H), 7.91 (dd, J = 2.8, 7.2 Hz, 1H), 7.66 - 7.62 (m, 2H).

For the preparation of the compound 2-([1,2,4]triazolo[1,5-a]pyridin-5-ylindenyl)-2-methylpropanoic acid (37), see step E in Example 1. And F, wherein compound 4 in step E of Example 1 is replaced with compound 35. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.55 (s, 1H), 7.88-7.85 (m, 1H), 7.71-7.67 (m, 1H), 7.30-7.28 (m, 1H), 1.57 (s) , 6H). MS (EI, m/z): 236.1 [MH] ^- .

Example 9: Synthesis of 1-{[5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}cyclobutanecarboxylic acid (40)

Experimental procedure Referring to steps A and B in Example 1, ethyl 1-bromocyclobutanecarboxylate was reacted with potassium thioacetate, and the obtained compound was subjected to alcoholysis with potassium hydroxide to give ethyl 1-nonylcyclobutanecarboxylate ( 38). Experimental procedure Referring to steps E and F in Example 1, compound 38 was reacted with compound 4, and the obtained compound was hydrolyzed and acidified to obtain 1-{[5-(trifluoromethyl)imidazo[1,2-a. Pyridine-8-yl]fluorenyl}cyclobutanecarboxylic acid (40). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 13.19 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 2.94 - 2.91 (m, 2H), 2.37 - 2.21 (m, 4H). MS (EI, m/z): 315.0 [MH] ^- .

Example 10: Synthesis of 2-[(6-cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid (41)

For the preparation method of compound 41 using 2-amino-5-cyanopyridine as a starting material, see steps C, D, E and F in Example 1. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.34 (d, J = 1.2 Hz, 1H), 8.10 (s, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.40 (s, 1H) , 1.54 (s, 6H). MS (EI, m/z): 260.1 [MH] ^- .

Example 11: Synthesis of 2-methyl-2-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}propionic acid (42)

For the preparation method of compound 42 using 2-amino-5-(trifluoromethyl)pyridine as a starting material, see steps C, D, E and F in Example 1. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 9.22-9.21 (m, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 1.56 (s, 6H). MS (EI, m/z): 305.1 [M+H] ⁺ .

Example 12: Synthesis of 2-methyl-2-[(6-phenylimidazo[1,2-a]pyridin-8-yl)indenyl]propionic acid (43)

Starting from 2-amino-5-phenylpyridine, the preparation method of compound 43 is as shown in Steps C, D, E and F of Example 1. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.92 (d, J = 1.2 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.70 - 7.68 (m, 2H), 7.62 - 7.60 ( m, 2H), 7.55-7.51 (m, 2H), 7.45-7.43 (m, 1H), 1.55 (s, 6H). MS (EI, m/z): 311.1 [MH] ^- .

Example 13: Synthesis of 2-{[6-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}-2-methylpropanoic acid (48)

Step A: Add NCS (2.6 g, 19.5) to a mixture containing 2-amino-6-(trifluoromethyl)pyridine (3.0 g, 18.5 mmol), perchloric acid (0.5 mL) and DMF (30 mL). (mmol), the resulting mixture was stirred at room temperature for 48 hours. Water (120 mL) was added, and the mixture 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 = 1:50 to 1:10) to give 2-amino-4-chloro-6-(3) Fluoromethyl)pyridine (44) (1.6 g). The yield was 44.0%.

The experimental procedures of steps B, C, D and E are sequentially followed by steps C, D, E and F in Example 1, to give 2-{[chloro-5-(trifluoromethyl)imidazo[1,2 -a] Pyridin-8-yl]fluorenyl}-2-methylpropionic acid (48). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.15 - 8.14 (m, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.22 (s, 1H), 1.66 (s, 6H). MS (EI, m / z) : 337.0 [MH] -.

Example 14: Synthesis of 2-{[3-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}-2-methylpropionic acid (51)

Step A: To a mixture containing compound 4 (500 mg, 1.89 mmol), lithium chloride (80 mg, 1.89 mmol), NCS (265 mg, 1.98 mmol) and DMF (10 mL) was added perchloric acid (5 drops). Stir at room temperature for 3 hours. Water (40 mL) was added, and the mixture was evaporated. The solvent was evaporated under reduced pressure and the product was purified mjjjjjjjjjjjjj Imidazo[1,2-a]pyridine (49) (280 mg). The yield was 49.5%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.00 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H).

The experimental procedures of Steps B and C are sequentially followed by the steps E and F in Example 1, to obtain 2-{[3-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl. ] mercapto}-2-methylpropionic acid (51). _{^{1 H NMR (DMSO-d 6}} , 400MHz) δ7.88 (s, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.31 (d, J = 8.0Hz, 1H), 1.64 (s, 6H) . MS (EI, m / z) : 337.0 [MH] -.

Example 15: 2-{[5-(4-Cyanophenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropionic acid (57) and 2-{[ Synthesis of 5-(4-cyanophenyl)imidazo[1,2-a]pyridin-6-yl]fluorenyl}-2-methylpropionic acid (60)

Step A: To a solution containing 2-amino-6-bromopyridine (3.46 g, 20 mmol), 4-cyanobenzeneboronic acid (3.7 g, 25.2 mmol), potassium phosphate trihydrate (16.6 g, 62.3 mmol), water (20 mL) Tricyclohexylphosphine (560 mg, 2.0 mmol) and palladium acetate (224 mg, 1.0 mmol) were added to a mixture of toluene (80 mL). After cooling to room temperature, water (100 mL) was added, and ethyl acetate The solvent is evaporated under reduced pressure, and the product is purified by column chromatography (200-300 mesh silica gel, ethyl acetate: petroleum ether = 1:40 to 1:5) to give 4-(6-aminopyridin-2-yl) Benzoonitrile (52) (1.78 g). The yield was 45.6%.

The experimental operations of steps B, C(C1), D(D1), and E(D1) are sequentially referred to steps C, D, and E in Example 1. F, 2-{[5-(4-cyanophenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid (57) and 2-{[5 -(4-Cyanophenyl)imidazo[1,2-a]pyridin-6-yl]indolyl}-2-methylpropanoic acid (60).

Compound 53: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.19 (dd, J = 1.6, 8.0 Hz, 2H), 7.93 (dd, J = 1.6, 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.43 (s, 2H).

Compound 57: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.08 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 1.2 Hz, 1H) ), 7.64 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 1.57 (s, 6H). MS (EI, m/z): 336.1 [MH] ^- .

Compound 60: ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.06 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 9.6 Hz, 1H) ), 7.59 (s, 1H), 7.44 (d, J = 9.6 Hz, 1H), 7.21 (s, 1H), 1.27 (s, 6H). MS (EI, m/z): 336.1 [MH] ^- .

Example 16: 2-{[8-(4-Cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropionic acid (66) and 2 Synthesis of -{[6-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]fluorenyl}-2-methylpropionic acid (69)

Experimental Procedures for Steps A and B, respectively, refer to Steps E and C in Example 1 to give methyl 2-[(2-amino-5-bromopyridin-4-yl)indolyl]-2-methylpropanoate (62 And methyl 2-[(2-amino-3-bromopyridin-4-yl)indolyl]-2-methylpropanoate (63).

Compound ^{63: 1 H NMR (DMSO-} d 6, 400MHz) δ8.00 (s, 1H), 6.41 (s, 1H), 6.29 (s, 2H), 3.69 (s, 3H), 1.57 (s, 6H) .

Step C: Compound 62 (200 mg, 0.655 mmol), (4-cyanonaphthalen-1-yl)boronic acid (142 mg, 0.721 mmol), n-butanol (15 mL), sodium carbonate (138 mg, 1.30 mmol) and A mixture of (triphenylphosphine)palladium (40 mg, 0.0346 mmol) was stirred under reflux overnight under nitrogen. The solvent was evaporated under reduced pressure. 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 = 1:20 to 1:2) to give 2-{[2-amino-3-(4) Methyl cyanonaphthalen-1-yl)pyridin-4-yl]fluorenyl}-2-methylpropanoate (64) (85 mg). The yield was 34.4%. _{^{1 H NMR (DMSO-d 6}} , 400MHz) δ8.25 (d, J = 7.2Hz, 1H), 8.20 (d, J = 8.4Hz, 1H), 8.01 (d, J = 5.6Hz, 1H), 7.85 -7.81 (m, 1H), 7.69-7.63 (m, 1H), 7.48-7.42 (m, 2H), 6.54 (d, J = 5.6 Hz, 1H), 5.44 (s, 2H), 3.66 (s, 3H) ), 1.35 (s, 6H).

Step D: A mixture containing compound 64 (80 mg, 0.212 mmol), 40% aqueous chloroacetaldehyde (125 mg, 0.637 mmol) and ethanol (10 mL) was stirred at 100 ° C overnight. The solvent was evaporated under reduced pressure, and ethyl acetate 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 = 1:5 to 20:1) to give 2-{[8-(4-cyanophthalene) Methyl-1-imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate (65) (77 mg). The yield was 90.5%.

Step E: A mixture containing compound 65 (70 mg, 0.170 mmol), THF (1.5 mL) and methanol (l. Water (10 mL) was added, extracted with MTBE (10 mL×2), and the aqueous phase was collected. The aqueous phase was adjusted to pH 3-4 with 2M hydrochloric acid, then extracted with ethyl acetate (15 mL×2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained product was crystallised from THF/ petroleum ether to give 2-{[8-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl] fluorenyl }-2-Methylpropionic acid (66). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.81 (s, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H) , 7.86-7.82 (m, 1H), 7.65-7.60 (m, 3H), 7.41 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 1.34 (s, 3H), 1.30 (s, 3H) ). MS (EI, m/z): 386.1 [MH] ^- .

The operations of steps C1, D1 and E1 are respectively referred to steps C, D and E in this example to obtain 2-{[6-cyanophthalen-1-yl)imidazo[1,2-a]pyridine. -7-yl]decyl}-2-methylpropionic acid (69). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.66 (s, 1H), 8.27 (d, J = 7.2 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H) , 7.86-7.81 (m, 2H), 7.73 (d, J = 0.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.58-7.56 (m, 1H), 1.25 (s, 3H), 1.19 (s , 3H). MS (EI, m/z): 386.1 [MH] ^- .

Example 17: Synthesis of 2-{[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]fluorenyl}-2-methylpropionic acid (70)

For the experimental procedure for the preparation of compound 70 using compound 62 as a starting material, see steps C, D and E in Example 16. _{^{1 H NMR (DMSO-d 6}} , 400MHz) δ8.58 (d, J = 7.2Hz, 1H), 8.07 (s, 1H), 7.91 (d, J = 8.4Hz, 2H), 7.61-7.59 (m, 3H), 7.06 (d, J = 7.2 Hz, 1H), 1.29 (s, 6H). MS (EI, m/z): 338.1 [M+H] ⁺ .

Example 18: Synthesis of 2-{[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]fluorenyl}-2-methylpropionic acid (71)

For the experimental procedure for the preparation of compound 71 using compound 63 as a starting material, see steps C, D and E in Example 16. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.81 (s, 1H), 8.14 (s, 1H), 8.01-7.99 (m, 3H), 7.81 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 1.43 (s, 6H). MS (EI, m/z): 338.1 [M+H] ⁺ .

Example 19: Synthesis of 2-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]fluorenyl}-2-methylpropionic acid (72)

For the experimental procedure for preparing compound 72 using compound 63 as a starting material, see steps C, D and E in Example 16, wherein 4-fluorobenzene of (4-cyanonaphthalen-1-yl)boronic acid in step 16 of Example 16 is used. Boric acid replacement. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.67 (s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 7.73 (s, 1H), 7.50-7.46 (m, 2H), 7.36-7.31 (m, 2H), 1.40 (s, 6H). MS (EI, m/z): 331.1 [M+H] ⁺ .

Example 20: Synthesis of 2-methyl-2-[(5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid (75)

For the preparation method of the compound 75, 3-bromo-6-methylpyridin-2-amine is used as the starting material, and the steps D, E and F in the embodiment 1 are referred to. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.92 (s, 1H), 7.68 (s, 1H), 7.35 (d, J = 6.8 Hz, 1H), 6.83 (d, J = 6.8 Hz, 1H) , 2.62 (s, 3H), 1.44 (s, 6H). MS (EI, m/z): 251.0 [M+H] ⁺ .

Example 21: Synthesis of 2-[(3-bromo-5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid (77)

Step A: Perchloric acid (4 drops) was added to a mixture containing compound 74 (128 mg, 0.484 mmol), NBS (95 mg, 0.534 mmol) and DMF (7 mL), and the mixture was stirred at room temperature overnight. After adding water (25 mL), the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with brine (30 mL) . The solvent was evaporated under reduced pressure, and the product was purifiedjjjjjjjjjjjjjj , 2-a]pyridin-8-yl)indenyl]-2-methylpropanoic acid methyl ester (76) (95 mg). The yield was 57.2%.

For the experimental procedure of Step B, see Step F in Example 1, to obtain 2-[(3-bromo-5-methylimidazo[1,2-a]pyridin-8-yl)indenyl]-2-methylpropane Acid (77). ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.62 (s, 1H), 7.26 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 3.00 (s, 3H) , 1.44 (s, 6H). MS (EI, m/z): 329.0 [M+H] ⁺ .

Example 22: Synthesis of 2-{[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}-2-methylpropanoic acid (78)

Starting from 2-amino-3-bromopyridine and alpha-bromo-4-methoxyacetophenone, the preparation method of compound 78 is shown in steps D, E and F of Example 1. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.53 (d, J = 6.4 Hz, 1H), 8.36 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 7.2 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 6.94-6.91 (m, 1H), 3.81 (s, 3H), 1.53 (s, 6H). MS (EI, m/z): 343.1 [M+H] ⁺ .

Example 23: Synthesis of 2-[(3-bromo-5-cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid (80)

For the preparation method of the compound 80, the compound 21 is used as the starting material. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.87-7.85 (m, 2H), 7.22 (d, J = 7.6 Hz, 1H), 1.64 (s, 6H). MS (EI, m / z) : 338.0 [MH] -.

Example 24: Synthesis of 2-[(3-bromo-7-methoxyimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid (84)

The 5-bromo-4-methylpyridin-2-amine is subjected to a ring-closing reaction with chloroacetaldehyde, and then subjected to a coupling reaction with methyl 2-acetylindol-2-methylpropionate, and the obtained product is hydrolyzed and hydrolyzed. And acidification, to give 2-[(3-bromo-7-methoxyimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid (84), the specific experimental operation see implementation Steps D, E, and F in Example 1 and Step A in Example 21. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.18 (s, 1H), 7.59 (s, 1H), 7.09 (s, 1H), 3.87 (s, 3H), 1.39 (s, 6H). MS (EI, m/z): 345.0 [M+H] ⁺ .

Example 25: Biological evaluation of compounds

In vitro inhibition assays for hURAT1 transport uric acid can be used to screen for potentially active compounds with reduced blood uric acid. The present invention pre-establishes a stable cell line highly expressing hURAT1, and blocks the ability of the stable cell line to take up radioisotope-labeled uric acid by detecting the compound. In this example, Lesinurad was used as a positive control (purchased from Chengdu Yichao Medical Technology Co., Ltd.) to evaluate the inhibitory activity of the compound on hURAT1 transport uric acid.

Construction of a highly expressed hURAT1 stable cell line:

HEK293 cell line (human embryonic kidney cells, purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) was transfected with plasmid pCMV6-hURAT1 (purchased from Origene Technologies, Inc.) and G418 was purchased at a concentration of 500 μg/ml. Engineering Bioengineering (Shanghai) Co., Ltd.) carried out resistance screening and obtained stable plants. The membrane surface of this cell strain highly expresses the hURAT1 transporter, and can be used as a model cell for screening a hURAT1 transport uric acid inhibitor in vitro according to the present invention (Toxicological Sciences, 2009, 113(2): 305-314.).

In vitro inhibition test of hURAT1 transport uric acid:

1. Coating of cell plates: 0.1 mg/ml poly-D-Lysin (purchased from Sigma-Aldrich Co. LLC) was added at 200 μl/well and allowed to stand at room temperature overnight. Wash with sterile water and let it dry.

2. Culture of cells: hURAT1 stably transfected cells were inserted into the coated cell plates at 2 × 10 ⁵ /well, and cultured for 3 days at 37 ° C in a 5% CO ₂ incubator.

3. Preparation of buffer HBSS: 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 (all purchased from Shanghai Sinopharm) Group Chemical Reagent Co., Ltd.) Prepare HBSS buffer and adjust the pH to 7.4. Place a 37 °C medium temperature bath before the experiment.

4. Gently wash the cells in the cell plate with HBSS, then add HBSS at 160 μl/well, and add the test compound at a final concentration of 500 nM at 20 μl/well as the test compound well; add HBSS at 180 μl/well but not Test compounds were used as blank control wells. Place at room temperature for 10 min. ¹⁴ C uric acid (purchased from American Radiolabeled Chemicals, Inc.) at a final concentration of 50 μM was added at 20 μl/well and allowed to stand at room temperature for 20 min.

5. Aspirate each well solution and wash the cells with HBSS and blot. Finally, 0.2 M NaOH was added to dissolve the cells, and the cell debris was collected and an appropriate amount of scintillation fluid was added to the PerkinElmer MicroBeta Trilux 1450 liquid scintillation analyzer to measure the isotope ¹⁴ C radiation intensity (CPM value). Three replicate wells were set for each test group, and the test results were averaged and the SD values were calculated.

In the hURAT1 stable cell line, the inhibition rate of the compound for hURAT1 transport uric acid is as follows:

Experimental results:

Compared with the positive drug Lesinurad, the compound had a 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 stably transfected cell lines by test compound and Lesinurad

Example 26: Cytotoxicity test of compound 6 against human hepatoma cells HepG2, human normal liver cells L-02 and WRL-68

In this example, the cytotoxic effect of the compound 6 provided by the present invention on human hepatoma cells HepG2, human normal liver cells L-02 and WRL-68 was tested using Lesinurad as a positive control.

experimental method:

1. Human hepatoma cell HepG2 (purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences), human normal liver cell L-02 (purchased from Wuhan Punosi Biotechnology Co., Ltd.) and human normal liver cell WRL-68 (by Nanjing University of Life Sciences Huihui) were cultured in DMEM medium (containing 10% fetal bovine serum, 100 U/mL penicillin, 0.1 mg/mL streptomycin, purchased from Thermo Fisher Scientific Inc), and incubated at 37 ° C, 5% CO ₂ The tank is cultured to a cell density of about 90%.

2. Inoculate the cells in a 96-well plate at a number of 2 × 10 ³ /well cells, and incubate at 37 ° C, 5% CO ₂ incubator for 24 h.

3. DMEM medium was used to prepare test compound 6 with different concentration gradient or control drug Lesinurad (purchased from Chengdu Yichao Medical Technology Co., Ltd.), and added as 100 μL/well as test compound well or control drug well; according to 100 μL/ The wells were added to the DMEM medium as a negative control well. Incubate for 96 h at 37 ° C in a 5% CO ₂ incubator.

4. Resazurin (15 mg/50 mL, 200×, purchased from Sigma-Aldrich Co. LLC), methylene blue (25 mg/10 mL, 1000×, purchased from Sigma-Aldrich Co. LLC), potassium ferricyanide (0.329 g/100 mL) , 100×, purchased from Aladdin Reagent Co., Ltd.) and potassium ferrocyanide (0.422 g/100 mL, 100×, purchased from Aladdin Reagent Co., Ltd.) diluted with PBS (0.1 M, pH=7.4). It was formulated into a 10 x Alamar Blue solution, and diluted with a phenol red free DMEM (purchased from Thermo Fisher Scientific Inc) medium into a 1 x Alamar Blue solution, which was prepared immediately before use.

5. The cells were washed twice with PBS (0.1 M, pH = 7.4), and Alamar Blue solution was added at 100 μL/well; 100 μL/well of Alamar Blue solution was added to the well-free wells as a blank control well. The plate 96 is set 37 ℃, 5% CO ₂ incubator 3h.

6. Cell fluorescence values were measured at Ex 530/Em 590 nm using a microplate reader Victor X4 (Perkin Elmer). The fluorescence value of the test compound wells is represented by F _{(test compound)} ; the fluorescence value of the blank control well is represented by F _{(blank control)} ; and the fluorescence value of the negative control well is represented by F _{(negative control)} . The cell viability at different drug concentrations was calculated according to the following formula, and each concentration was repeatedly measured 3 times to obtain an average value and a standard deviation.

7. using Prism Graph software test compounds were calculated half 6 cells HepG2, L-02, and of WRL-68 inhibitory concentration (IC _50).

Experimental results:

After 96 hours of the action of compound 6 on human hepatoma cell line HepG2, the half-inhibitory concentration (IC ₅₀ ) was greater than 1000 μM, and the IC ₅₀ of Lesinurad to HepG2 cells was 135.0 μM. Compound 6 and L-02 on human WRL-68 cells in normal liver IC ₅₀ greater than 800μM, Lesinurad for the L-02 and IC ₅₀ of WRL-68 were 118.7 and 133.0μM. Therefore, Compound 6 is much less toxic to human hepatoma cells HepG2, human normal liver cells L-02 and WRL-68 than Lesinurad.

Claims (10)

1. a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and a pharmaceutically acceptable compound thereof salt,

   

   among them:

   Y or Z are independently selected from N or CH, respectively.

   R ¹ or R ² are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C _1-4 alkyl, substituted C _1-4 alkyl, C _3-4 cycloalkyl, C _{1- 4} alkoxy, substituted C _1-4 alkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, substituted heteroaryl are one or more of which substituents The group is selected from the group consisting of halogen, cyano, hydroxy, amino, C _1-2 alkyl, C _1-2 haloalkyl, C _1-2 alkoxy or C _1-2 haloalkoxy,

   R ³ or R ⁴ are each independently selected from H or C _1-3 alkyl, or R ³ and R ⁴ together form a 3-6 membered cycloalkyl group,

   R ⁵ is H, C _1-4 alkyl or substituted C _1-4 alkyl, the substituent of which is selected from C _1-2 alkoxy, hydroxy or amino.
2. A compound according to claim 1 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, and mixtures thereof, and a pharmaceutically acceptable compound thereof a salt, wherein the compound is selected from the group consisting of a compound of formula (II), formula (III) or formula (IV),

   
3. The compound according to claim 1 or 2, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and a pharmaceutically acceptable compound thereof Accepted salts wherein R ¹ or R ² are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C _1-3 alkyl, substituted C _1-3 alkyl, C _3-4 naphthenic , C _1-3 alkoxy, substituted C _1-3 alkoxy, phenyl, substituted phenyl, naphthyl, substituted naphthyl, thienyl, substituted thienyl, furyl, substituted furan One or more of a thiol group or a substituted thiazolyl group, the substituents being independently selected from the group consisting of halogen, cyano, amino, hydroxy, trifluoromethyl, methoxy, ethoxy, and Fluoromethoxy or trifluoromethoxy.
4. A compound according to claim 3 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof and mixtures thereof, and pharmaceutically acceptable thereof a salt, wherein R ¹ or R ² are each independently selected from the group consisting of H, D, halogen, cyano, hydroxy, carboxy, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 fluoroalkyl, C _1-3 fluoroalkoxy, phenyl, halophenyl, cyanophenyl, methylphenyl, ethylphenyl, methoxyphenyl, ethoxyphenyl, naphthyl, cyano One or more of the phenyl groups.
5. The compound according to claim 1 or 2, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and a pharmaceutically acceptable compound thereof Accepted salts wherein R ³ or R ⁴ are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, or R ³ and R ⁴ together form a 3-5 membered cycloalkyl.
6. The compound according to claim 1 or 2, or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof and a mixture thereof, and a pharmaceutically acceptable compound thereof Accepted salts wherein R ⁵ is H or C _1-3 alkyl.
7. A compound according to claim 1 or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof, and mixtures thereof, and a pharmaceutically acceptable compound thereof a salt wherein the compound is selected from the group consisting of:

   2-methyl-2-{[5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid,

   2-methyl-2-{[5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid methyl ester,

   2-[(6-fluoroimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

   2-[(6-fluoroimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

   2-(imidazo[1,2-a]pyridin-8-yl)indol-2-methylpropanoic acid,

   2-(imidazo[1,2-a]pyridin-8-yl)indol-2-methylpropanoate,

   2-[(5-Cyanoimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid,

   2-[(5-Cyanoimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoate,

   2-[(5-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

   2-[(5-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

   2-methyl-2-[(2-methylimidazo[1,2-a]pyridin-5-yl)indolyl]propionic acid,

   2-methyl-2-[(2-methylimidazo[1,2-a]pyridin-5-yl)indolyl]propionic acid methyl ester,

   7-[(2-carboxypropan-2-yl)indolyl]pyrazolo[1,5-a]pyridine-3-carboxylic acid,

   Methyl 7-[(2-carboxypropan-2-yl)indolyl]pyrazolo[1,5-a]pyridine-3-carboxylate,

   2-methyl-2-{[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]indenyl}propionic acid,

   2-methyl-2-{[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]indenyl}methyl propionate,

   2-([1,2,4]triazolo[1,5-a]pyridin-5-ylindenyl)-2-methylpropanoic acid,

   2-([1,2,4]triazolo[1,5-a]pyridin-5-ylindenyl)-2-methylpropanoate,

   1-{[5-(Trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}cyclobutanecarboxylic acid,

   1-{[5-(Trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]fluorenyl}cyclobutanecarboxylate,

   2-[(6-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

   2-[(6-Cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

   2-methyl-2-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid,

   2-methyl-2-{[6-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indenyl}propionic acid methyl ester,

   2-methyl-2-[(6-phenylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid,

   2-methyl-2-[(6-phenylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid methyl ester,

   2-{[6-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

   Methyl 2-{[6-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoate,

   2-{[3-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

   Methyl 2-{[3-chloro-5-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoate,

   2-{[5-(4-cyanophenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

   2-{[5-(4-Cyanophenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid methyl ester,

   2-{[5-(4-cyanophenyl)imidazo[1,2-a]pyridin-6-yl]indenyl}-2-methylpropanoic acid,

   Methyl 2-{[5-(4-cyanophenyl)imidazo[1,2-a]pyridin-6-yl]indolyl}-2-methylpropanoate,

   2-{[8-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

   Methyl 2-{[8-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

   2-{[6-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indenyl}-2-methylpropanoic acid,

   Methyl 2-{[6-(4-cyanophthalen-1-yl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

   2-{[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

   Methyl 2-{[8-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

   2-{[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

   Methyl 2-{[6-(4-cyanophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

   2-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoic acid,

   Methyl 2-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-7-yl]indolyl}-2-methylpropanoate,

   2-methyl-2-[(5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid,

   2-methyl-2-[(5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]propionic acid methyl ester,

   2-[(3-bromo-5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

   2-[(3-Bromo-5-methylimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

   2-{[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoic acid,

   Methyl 2-{[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-8-yl]indolyl}-2-methylpropanoate,

   2-[(3-bromo-5-cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoic acid,

   2-[(3-Bromo-5-cyanoimidazo[1,2-a]pyridin-8-yl)indolyl]-2-methylpropanoate,

   2-[(3-bromo-7-methoxyimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoic acid,

   Methyl 2-[(3-bromo-7-methoxyimidazo[1,2-a]pyridin-6-yl)indolyl]-2-methylpropanoate.
8. A pharmaceutical composition according to any one of claims 1 to 7 or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof And mixtures thereof, and pharmaceutically acceptable salts thereof, are active ingredients or active ingredients, supplemented by pharmaceutically acceptable excipients
9. The compound according to any one of claims 1 to 7, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and The use of a pharmaceutically acceptable salt for the preparation of a urinary excretion drug.
10. The compound according to any one of claims 1 to 7, or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture thereof, and The use of a pharmaceutically acceptable salt for the preparation of a medicament for the treatment or prevention of hyperuricemia or gout.

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