CN107089955B

CN107089955B - Sulfonamide derivative and preparation method and application thereof

Info

Publication number: CN107089955B
Application number: CN201710077574.2A
Authority: CN
Inventors: 黄常伟; 王晓军; 杨新业; 马发城; 李峥; 黄伟明; 顾峥; 吴族平; 张英俊
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Guangdong HEC Pharmaceutical
Priority date: 2016-02-18
Filing date: 2017-02-14
Publication date: 2020-10-23
Anticipated expiration: 2037-02-14
Also published as: CN107089955A

Abstract

The invention relates to a sulfonamide derivative and a pharmaceutical composition containing the same. The compounds or pharmaceutical compositions are useful for inhibiting urate anion transporters. The invention also relates to methods for preparing such compounds and pharmaceutical compositions, and their use in the treatment or prevention of diseases associated with elevated blood uric acid levels in mammals, particularly humans.

Description

Sulfonamide derivative and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a sulfonamide compound or a composition thereof, and a preparation method and application thereof, wherein the compound or the composition has the application of inhibiting the activity of a urate anion transporter, and can be used for preventing or treating diseases related to high uric acid level in blood.

Background

Uric acid is the terminal metabolite of human purine compounds. In humans, uric acid is excreted mainly by the kidneys, with the excretion accounting for nearly two-thirds of the total excretion. When uric acid is produced excessively or excretion is obstructed, uric acid accumulation causes the rise of uric acid concentration in blood of a human body, and hyperuricemia is caused. Under the normal purine diet state, the fasting blood uric acid level of the male is higher than 420 mu mol/L and the fasting blood uric acid level of the female is higher than 360 mu mol/L, namely the hyperuricemia is obtained. Hyperuricemia can be classified into (1) hyperuricemia type, (2) uric acid excretion type, and (3) mixed type, and such a classification diagnosis helps to find the cause of hyperuricemia and to give a targeted treatment.

With the supersaturated concentration of uric acid in blood, sodium urate salt begins to form crystals and deposit in joint synovium, bursa, cartilage and other tissues, causing recurrent inflammatory reactions when the uric acid level in vivo changes rapidly, local trauma causes the release of tiny crystals or the change of urate crystal protein coating, and then inducing gout. Gout is particularly characterized by acute characteristic arthritis and chronic tophus diseases, mainly comprising acute paroxysmal arthritis, tophus formation, tophus chronic arthritis, urate nephropathy and uric acid lithangiuria, and joint disability and renal insufficiency of serious patients can occur. Gout is also associated with a variety of conditions including hypertension, metabolic syndrome, hyperlipidemia, diabetes and insulin resistance (Terkellaub RA. clinical practice. Gout [ J ]. N Engl J Med.2003,349: 1647-.

Hyperuricemia and gout are serious metabolic diseases that endanger human health; there are data indicating that about 5-12% of patients with hyperuricemia eventually develop gout. Uric acid is the material basis for the development of hyperuricemia and gout, and therefore, reducing the concentration of uric acid in blood can be used for preventing or treating hyperuricemia and gout and reducing the risk of suffering from other hyperuricemia and ventilation complications.

Studies have shown that about 90% of hyperuricemia is caused by a decrease in uric acid excretion in the kidney, which mainly involves 4 processes: glomerular filtration, tubular and collecting reabsorption, tubular and collecting secretion and reabsorption after secretion, all of which are completed by the participation of corresponding proteins, only 8% -12% of uric acid is finally excreted out of the body (Liu Ruo Xia, Yu Lu Ping, Wu Xin Rong, Shandong medicine [ J]Vol 52, 28 th year 2012). Urate anion transporter 1(URAT1) is a transmembrane transporter found by Enomoto et al to be located on the brush border side of renal proximal tubular epithelial cells and involved in the reabsorption of uric acid in the renal proximal tubular. The hURAT1 is encoded by SLC22A12 gene on chromosome 11q13, contains 10 exons and 9 introns, and consists of 555 amino acid residues, 12 transmembrane structures and-NH located inside the cell₂and-COOH terminal. It was found that the SLC22A12 gene carried by renal hypouricemia patients is mutated to lose the ability to encode the mature protein of URAT1, thereby confirming that URAT1 is the causative gene of renal hypouricemia (Enomoto, Kimura H, Chairongdua A, et al]Nature,2002,417(6887):447-452), which has important significance on the uric acid reabsorption function of the kidney and is closely related to the regulation of the uric acid level in the blood.

Therefore, the substance having URAT1 inhibitory activity can promote the excretion of uric acid in blood, and is useful for the treatment and prevention of diseases associated with a high blood uric acid level, including hyperuricemia, gout, tophus, gouty arthritis, renal disorder associated with hyperuricemia, urinary calculi, and the like.

Such drugs have become a hot point for the development of drugs for treating hyperuricemia, gout and diseases related to hyperuricemia.

Summary of The Invention

The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.

The invention provides a compound with URAT1 inhibitory activity, which is used for preparing medicines for preventing or treating diseases related to hyperuricemia in blood, such as hyperuricemia, tophus, gouty arthritis, kidney disorder related to hyperuricemia, urolithiasis and the like; the compound of the invention can well inhibit URAT1, and has excellent physicochemical property and pharmacokinetic property.

The invention also provides processes for the preparation of these compounds, pharmaceutical compositions containing these compounds and methods of using these compounds or compositions in the treatment of the above-mentioned diseases in mammals, especially humans.

Specifically, the method comprises the following steps:

in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),

wherein the content of the first and second substances,

ring A is C_6-10Aryl or C_1-9A heteroaryl group;

ring B is C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-6A heteroaryl group;

l is a bond, -O-or-NH-;

L⁰is a bond or-CH₂-；

R is hydrogen, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl or C_6-10aryl-C_1-6An alkyl group; said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl and C_6-10aryl-C_1-6Alkyl may be further independently optionally substituted with one or more substituents selected from deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro and cyano;

each R¹Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -OR⁴、-NR⁵R⁶、-L¹-C(＝O)-L²-R⁷、-L³-S(＝O)_t-L⁴-R⁸、C_3-8Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-10aryl-C_1-6Alkyl or C_1-9heteroaryl-C_1-6Alkyl radical, wherein R¹May be further optionally substituted with one or more groups selected from hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy and C_3-6Cycloalkyl, substituted with a substituent;

R⁴、R⁵、R⁶、R⁷and R⁸Each independently of the others is hydrogen, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, C_3-8Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

L¹and L³Each independently being a bond, -O-, -NH-or C_1-6An alkylene group;

L²and L⁴Each independently a bond, -O-, -NR⁹-or C_1-6An alkylene group;

R⁹is hydrogen, deuterium, C_1-3Alkyl radical, C_1-3Haloalkyl, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-6A heteroaryl group;

t is 0, 1 or 2;

R²is hydrogen, deuterium, C_1-3Alkyl radical, C_1-3Haloalkyl or C_3-6A cycloalkyl group;

each R³Independently hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano or C_1-3An alkyl group;

m is 0, 1,2,3,4 or 5;

n is 0, 1,2 or 3;

provided that, when the B ring is phenyl, R¹Is methyl and m is 1, L is-O-or-NH-.

In some embodiments, ring A is

Wherein the content of the first and second substances,

X¹is-O-, -S-or-NH-;

each X²、X³、X⁴And X⁵Independently CH or N;

X⁶and X⁷Each independently is-O-, -S-, -NH-or-CH₂-。

In other embodiments, ring a is phenyl, naphthyl, 2, 3-dihydro-1H-indene, 1,2,3, 4-tetrahydronaphthyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, 1H-benzimidazolyl, benzopyrazolyl, 1, 4-benzodioxanyl, or 1, 3-benzodioxolanyl.

In some embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, phenyl, or naphthyl.

In some embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methyloxymethyl, ethyloxymethyl, ethyloxyethyl, acetyl, acetoxyethyl, acetamidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, naphthyl, benzyl, furanyl, thienyl, pyridinyl, or pyrimidinyl;

each R¹Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, phenoxy, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, acetyl, methylsulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuryl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, phenyl, thienyl, pyridyl, indolyl, and the likeOr naphthyl, wherein R¹May be further optionally substituted with one or more groups selected from hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, C_1-4Haloalkoxy and C_3-6Cycloalkyl substituents.

In some embodiments, the invention relates to pharmaceutical compositions having a compound of formula (II), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, or prodrug of a compound of formula (II),

wherein, A, R, R¹Each R³M and n have the meanings as described in the invention.

In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or (II) of the present invention, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or combination thereof.

In some embodiments, the pharmaceutical composition of the present invention further comprises other agents for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis, wherein the agents are colchicine, non-steroidal anti-inflammatory drugs, glucocorticoids, uric acid production inhibiting drugs, uric acid excretion promoting drugs, urinary alkalinizing agents, or any combination thereof.

In another aspect, the present invention relates to the use of a compound of formula (I) or (II) or a pharmaceutical composition thereof for the preparation of a medicament for the prevention or treatment of hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis in a mammal, including a human.

In another aspect, the invention relates to the use of a compound of formula (I) or (II) or a pharmaceutical composition thereof for the manufacture of a medicament for reducing uric acid levels in blood.

In another aspect, the invention relates to the use of a compound of formula (I) or (II), or a pharmaceutical composition thereof, in the manufacture of a medicament for inhibiting a urate anion transporter in a subject.

In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound encompassed by formula (I) or formula (II).

Biological test results show that the compound provided by the invention can be used as a better urate anion transporter inhibitor.

Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.

The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.

Detailed description of the invention

Definitions and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; andEliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.

Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.

Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.

The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemases and solutions (Wiley Interscience, New York, 1981);Principles of AsymmetricSynthesis(2^ndEd.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.TablesofResolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of NotreDame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A PracticalApproach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。

the compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.

In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.

The term "unsubstituted" means that the specified group bears no substituents.

The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein. Substituents described herein include, but are not limited to, D, F, Cl, Br, I, N₃、CN、NO₂、OH、SH、NH₂Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Of tertiary importanceButyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)₂-, ethylene (-CH)₂CH₂-, isopropylidene (-CH (CH)₃)CH₂-) and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical having at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 12 carbon atoms; in another embodiment, the alkenyl group contains 3 to 12 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 3-12 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)₂C.ident.CH), 1-propynyl (-C.ident.C-CH)₃) And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited toWithout limitation, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "alkoxyalkyl" means that the alkoxy group is attached to the rest of the molecule through an alkyl group, wherein the alkoxy group and the alkyl group have the meaning as described herein. The alkoxyalkyl group may be optionally substituted with one or more substituents described herein. Examples of alkoxyalkyl groups include, but are not limited to, methyloxymethyl (-CH)₂OCH₃) Ethyl oxymethyl (-CH)₂OCH₂CH₃) Ethyl oxyethyl group (-CH)₂CH₂O CH₂CH₃) And so on.

The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups; the alkyl group has the meaning described in the present invention. In some of these embodiments, the alkylamino group is one or two C_1-6The alkyl group is attached to a lower alkylamino group formed on the nitrogen atom. In other embodiments, the alkylamino group is one or two C_1-4To the nitrogen atom to form an alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "alkylaminoalkyl" denotes an alkylamino group attached to the rest of the molecule through an alkyl group, wherein the alkylamino group and the alkyl group have the meaning as described herein. The alkylaminoalkyl group may be optionally substituted with one or more substituents described herein. Examples of alkylaminoalkyl groups include, but are not limited to, methylaminomethyl (-CH)₂NCH₃) Ethyl aminomethyl (-CH)₂NCH₂CH₃) Ethyl aminoethyl (-CH)₂CH₂NCH₂CH₃) And so on.

The terms "haloalkyl", "haloalkoxy" or "haloalkylamino" denote alkyl, alkoxy or alkylamino groups substituted with one or more halogen atoms, wherein alkyl, alkoxy or alkylamino groups have the meaning as described herein, examples of which include, but are not limited to, trifluoromethyl, 2,3, 3-tetrafluoropropyl, difluoromethoxy, trifluoromethoxy, trifluoromethylamino and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 all carbon atoms. In one embodiment, cycloalkyl groups contain 7 to 12 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein. Suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "carbocycle" or "carbocyclyl" refers to a monovalent or multivalent non-aromatic, saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 total carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In one embodiment, carbocyclyl contains 3 to 8 carbon atoms; in yet another embodiment, carbocyclyl contains 3 to 6 carbon atoms. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like. The carbocyclyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, monocyclic, bicyclic, or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise indicated, a heterocyclyl group may be attached to other groups in the molecule through a carbon atom, may be attached to other groups in the molecule through a nitrogen atom, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiepanyl, oxazepanyl, thiazepanyl, oxazepanyl, and pyrrolidinyl

Radical diaza

Radical, sulfur nitrogen hetero

Yl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.

The term "n-atomic" where n is an integer typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is n. For example, piperidinyl is a heterocycloalkyl group of 6 atoms, and decahydronaphthyl is a carbocyclyl group of 10 atoms.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The term "halogen" or "halogen atom" means a fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (I).

The term "aryl" denotes a monocyclic, bicyclic or tricyclic all carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". In one embodiment, aryl is a carbocyclic ring system consisting of 6 to 10 ring atoms and containing at least one aromatic ring therein. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.

The term "arylalkyl" means that the aryl group is attached to the rest of the molecule through an alkyl group, wherein the aryl group and the alkyl group have the meaning as described herein. The arylalkyl group can be optionally substituted with one or more substituents described herein. Examples of arylalkyl groups include, but are not limited to, phenylmethyl, phenylethyl, naphthyl-1-methyl, naphthyl-2-methyl, and the like.

The term "heteroaryl" denotes a monocyclic, bicyclic or tricyclic ring containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring is aromatic and at least one aromatic ring contains one or more heteroatoms and has one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, heteroaryl is a 5-12 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, heteroaryl is 5-6 atom consisting of 1,2,3, or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl), oxadiazolyl (e.g., 1,2,3, 4-oxadiazolyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, isothiazolyl, 2-thiadiazolyl (e.g., 1,3, 4-thiadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 5-thiadiazolyl) Thiatriazolyl (e.g., 1,2,3, 4-thiatriazolyl), tetrazolyl (e.g., 2H-1,2,3, 4-tetrazolyl, 1H-1,2,3, 4-tetrazolyl), triazolyl (e.g., 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl), 2-thienyl, 3-thienyl, 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), 2-pyrazinyl, triazinyl (e.g., 1,3, 5-triazine), tetrazinyl (e.g., 1,2,4, 5-tetrazine, 1,2,3, 5-tetrazine); the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,2,4] triazolo [1,5-a ] pyridyl, and the like.

The term "heteroarylalkyl" means that the heteroaryl group is attached to the rest of the molecule through an alkyl group, wherein the heteroaryl group and the alkyl group have the meaning as described herein. The heteroarylalkyl group may be optionally substituted with one or more substituents described herein.

As described herein, the ring system formed by a linker attached to the center of the ring (as shown in formula a) means that the linker can be attached to the rest of the molecule at any available position on the ring system. Formula a represents that any possible attachment position on the E ring can be attached to the rest of the molecule.

As described herein, a ring system formed on a ring wherein a substituent is bonded to the center (as shown in formula b) represents that the substituent may be substituted at any substitutable position on the ring. For example, the substituent R represented by the formula b may be mono-or polysubstituted at any possible substituted position on the G ring, as shown in formulae c1 to c 19.

The term "protecting group" or "PG" refers to a substituent that, when reacted with other functional groups, is generally used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH₂CH₂SO₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.

The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)₁-C₂₄) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the invention contains a hydroxyl group, i.e.It may be acylated to give the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel delivery systems, Vol.14of the A.C.S.Symphosium Series, Edward B.Roche, ed., Bioredeployers in Drug designs, American Pharmaceutical Association and PergammonPress, 1987, J.Rautio et al, Prodrug: Design and Clinical Applications, Nature review delivery, 2008,7,255 and 270, S.J.Hecker et al, Prodrugs of pharmaceuticals and phosphates, Journal of chemical Chemistry,2008,51,2328 and 2345.

"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.

As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, descriptive acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts includeAdipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valeric acid salts, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N⁺(C_1-4Alkyl radical)₄A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C_1-8Sulfonates and aromatic sulfonates.

"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.

When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.

The term "treating" any disease or condition, as used herein, means all that can slow, halt, arrest, control or halt the progression of the disease or condition, but does not necessarily mean that all the symptoms of the disease or condition have disappeared, and also includes prophylactic treatment of the symptoms, particularly in patients susceptible to such disease or disorder. In some of these embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.

The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a disorder, slowing or delaying the progression of a disease, or preventing a disease, etc.) in a subject. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a subject, is effective for: (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition or disease (i) mediated by a urate anion transporter (URAT1), or (ii) associated with urate anion transporter activity, or (iii) characterized by aberrant activity of urate anion transporter; or (2) reduces or inhibits the activity of a urate anion transporter; or (3) reducing or inhibiting the expression of a urate anion transporter. In another embodiment, the term "therapeutically effective amount" means an amount that, when administered to a cell, or organ, or non-cellular biological substance, or medium, at least partially reduces or inhibits urate anion transporter activity; or an amount of a compound of the invention effective to at least partially reduce or inhibit the expression of a urate anion transporter.

The terms "administration" and "administering" of a compound as used herein shall be understood as providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof. It will be appreciated that the effect on the blood uric acid concentration may be effected by one skilled in the art by treating a patient currently suffering from such a disorder, or prophylactically treating a patient suffering from such a disorder, with an effective amount of a compound of the present invention.

The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from mixing, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.

Description of the Compounds of the invention

The invention discloses a sulfonamide derivative, pharmaceutically acceptable salt thereof, a pharmaceutical preparation and a composition thereof, which can be used as a urate anion transporter inhibitor and have potential application in treating symptoms or diseases with higher uric acid value in human blood, such as hyperuricemia, tophus, gouty arthritis, kidney disorder related to hyperuricemia and urolithiasis.

In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,

wherein, A, B, R, L, L⁰Each R¹、R²Each R³M and n have the meanings as described in the invention.

In some embodiments, the a ring is aryl or heteroaryl.

In some embodiments, ring B is cycloalkyl, heterocyclyl, aryl, or heteroaryl.

In some embodiments, L is a bond, -O-, or-NH-.

In some embodiments, L⁰Is a bond or-CH₂-。

In some embodiments, R is hydrogen, deuterium, alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or arylalkyl; the alkyl, alkenyl, alkynyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and arylalkyl groups may be further independently optionally substituted with one or more substituents selected from deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, and cyano.

In some embodiments, each R¹Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, alkyl, alkenyl, alkynyl, haloalkyl, -OR⁴、-NR⁵R⁶、-L¹-C(＝O)-L²-R⁷、-L³-S(＝O)_t-L⁴-R⁸Cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein R is¹May be further optionally substituted with one or more substituents selected from hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, and cycloalkyl;

R⁴、R⁵、R⁶、R⁷and R⁸Each independently is hydrogen, deuterium, alkyl, alkenyl, alkynyl,Haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

L¹and L³Each independently is a bond, -O-, -NH-, or alkylene;

L²and L⁴Each independently a bond, -O-, -NR⁹-or an alkylene group;

R⁹is hydrogen, deuterium, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;

t is 0, 1 or 2.

In some embodiments, R²Is hydrogen, deuterium, alkyl, haloalkyl or cycloalkyl.

In some embodiments, each R³Independently hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano or alkyl.

In some embodiments, m is 0, 1,2,3,4, or 5.

In some embodiments, n is 0, 1,2, or 3.

In some embodiments, the compounds of the present invention, provided that when ring B is phenyl, R¹Is methyl and m is 1, L is-O-or-NH-.

In some embodiments, ring a is C_6-10Aryl or C_1-9A heteroaryl group.

In other embodiments, ring A is

Wherein the content of the first and second substances,

X¹is-O-, -S-or-NH-;

each X²、X³、X⁴And X⁵Independently CH or N;

X⁶and X⁷Each independently is-O-, -S-, -NH-or-CH₂-。

In still other embodiments, ring a is phenyl, naphthyl, 2, 3-dihydro-1H-indene, 1,2,3, 4-tetrahydronaphthyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, 1H-benzimidazolyl, benzopyrazolyl, 1, 4-benzodioxanyl, or 1, 3-benzodioxolyl.

In some embodiments, ring B is C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-6A heteroaryl group.

In other embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, phenyl, or naphthyl.

In some embodiments, R is hydrogen, deuterium, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl or C_6-10aryl-C_1-6An alkyl group; said C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6alkoxy-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl and C_6-10aryl-C_1-6Alkyl groups may be further independently optionally substituted with one or more substituents selected from deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro and cyano.

In other embodiments, R is hydrogen, deuterium, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4alkylamino-C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl radical, C_1-6Heteroaryl or C_6-10aryl-C_1-4An alkyl group; said C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4alkoxy-C_1-4Alkyl radical, C_1-4alkylamino-C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl radical, C_1-6Heteroaryl and C_6-10aryl-C_1-4Alkyl groups may be further independently optionally substituted with one or more substituents selected from deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro and cyano.

In some embodiments, R is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, allyl, ethynyl, propargyl, difluoromethyl, trifluoromethyl, 2-difluoroethyl, methyloxymethyl, ethyloxymethyl, ethyloxyethyl, acetyl, acetoxyethyl, acetamidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, phenyl, naphthyl, benzyl, furanyl, thienyl, pyridinyl, or pyrimidinyl.

In some embodiments, each R¹Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Haloalkyl, -OR⁴、-NR⁵R⁶、-L¹-C(＝O)-L²-R⁷、-L³-S(＝O)_t-L⁴-R⁸、C_3-8Cycloalkyl radical, C_2-9Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-10aryl-C_1-6Alkyl or C_1-9heteroaryl-C_1-6Alkyl radical, wherein R¹May be further optionally substituted with one or more groups selected from hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, C_1-6Haloalkoxy and C_3-6Cycloalkyl, substituted with a substituent;

L¹and L³Each independently being a bond, -O-, -NH-or C_1-6An alkylene group;

L²and L⁴Each independently a bond, -O-, -NR⁹-or C_1-6An alkylene group;

R⁹is hydrogen, deuterium, C_1-3Alkyl radical, C_1-3Haloalkyl, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-6A heteroaryl group.

In other embodiments, each R¹Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, -OR⁴、-NR⁵R⁶、-L¹-C(＝O)-L²-R⁷、-L³-S(＝O)_t-L⁴-R⁸、C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl radical, C_1-9Heteroaryl group, C_6-10aryl-C_1-3Alkyl or C_1-9heteroaryl-C_1-3Alkyl radical, wherein R¹May be further optionally substituted with one or more groups selected from hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, C_1-4Haloalkoxy and C_3-6Cycloalkyl, substituted with a substituent;

R⁴、R⁵、R⁶、R⁷and R⁸Each independently of the others is hydrogen, deuterium, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Haloalkyl, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-6A heteroaryl group;

L¹and L³Each independently being a bond, -O-, -NH-or C_1-4An alkylene group;

L²and L⁴Each independently a bond, -O-, -NR⁹-or C_1-4An alkylene group;

R⁹hydrogen, deuterium, methyl, isopropyl, trifluoromethyl, cyclopropyl or phenyl.

Also in some embodiments, each R¹Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, phenoxy, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, acetyl, methanesulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, phenyl, or naphthyl, wherein R.¹May be further optionally substituted with one or more groups selected from hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, C_1-4Haloalkoxy and C_3-6Cycloalkyl substituents.

In some embodiments, R²Is hydrogen, deuterium, C_1-3Alkyl radical, C_1-3Haloalkyl or C_3-6A cycloalkyl group.

In some embodiments, each R³Independently hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano or C_1-3An alkyl group.

In some embodiments, the present invention comprises a stereoisomer, geometric isomer, tautomer, nitrogen oxide, solvate, hydrate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof, of a compound of, but is in no way limited to, one of the following:

stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I) are included within the scope of the present invention unless otherwise indicated.

The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I) or formula (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.

In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.

The compounds of formula (I) or formula (II) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.

The compounds of formula (I) or formula (II) may be present in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) or formula (II) and/or in the isolation of an enantiomer of a compound of formula (I) or formula (II).

Pharmaceutically acceptable acid addition salts may be formed from the disclosed compounds of the invention by the action of an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts may be formed from the disclosed compounds by reaction with an inorganic or organic base.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of pharmaceutical salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable salts.

In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms of the disclosed compounds.

Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、¹⁸F、³¹P、³²P、³⁵S、³⁶Cl and¹²⁵I。

in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present³H、¹⁴C and¹⁸those compounds of F, or in which a non-radioactive isotope is present, e.g.²H and¹³those of C. The isotopically enriched compounds can be used for metabolic studies (use)¹⁴C) Reaction kinetics study (using, for example²H or³H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.¹⁸F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or formula (II) can be prepared by conventional techniques known to those skilled in the art or by the procedures and examples described in the present specification using a suitable isotopically labelled reagent in place of the original used unlabelled reagent.

In addition, heavier isotopes are, in particular, deuterium (i.e.,²substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I) or formula (II). Can use isotopic enrichment factorTo define the concentration of such heavier isotopes, in particular deuterium. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D₂O, acetone-d₆、DMSO-d₆Those solvates of (a).

Pharmaceutical compositions, formulations and administration of the compounds of the invention

The present invention provides a pharmaceutical composition comprising a compound disclosed herein, for example, as set forth in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof.

The present invention provides methods of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more other agents for the prevention or treatment of hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia and urolithiasis.

Other agents for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis include, but are not limited to: colchicine, non-steroidal anti-inflammatory drugs, glucocorticoids, uric acid production-inhibiting drugs, uricosuric drugs, urinary alkalizing agents or any combination thereof.

The other drug for treating hyperuricemia, tophus, gouty arthritis, kidney disorder related to hyperuricemia and urolithiasis is colchicine, indomethacin, etoricoxib, diclofenac, ibuprofen, rofecoxib, celecoxib, meloxicam, prednisone, hydrocortisone succinate, allopurinol, probenecid, fensultone, benzbromarone, oxypurinol, febuxostat, recombinant aspergillus flavus urate oxidase, pegylated recombinant urate oxidase, sodium bicarbonate tablets, potassium sodium citrate mixture or any combination thereof.

The amount of compound in the pharmaceutical compositions disclosed herein is that amount which is effective to detect inhibition of the urate anion transporter in the biological sample or patient. The dosage of the active ingredient in the composition of the present invention may vary, however, the amount of the active ingredient must be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of drugs, and other factors that will be recognized by those skilled in the art. The dosage range is generally about 0.5mg to 1.0g per patient per day and may be administered in a single dose or in multiple doses. In one embodiment, the dosage range is from about 0.5mg to 500mg per patient per day; from about 0.5mg to 200mg per patient per day in another embodiment; and in yet another embodiment from about 5mg to 50mg per patient per day.

It will also be appreciated that certain compounds of the invention may be present in free form and used in therapy, or if appropriate in the form of a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.

The medicaments or pharmaceutical compositions disclosed herein may be prepared and packaged in bulk (bulk) form, wherein a safe and effective amount of the compound of formula (I) may be extracted and then administered to a patient in the form of a powder or syrup. Typically, the administration to a patient is at a dosage level of between 0.0001 and 10mg/kg body weight per day to achieve effective antagonism of the urate anion transporter. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain, for example, from 0.5mg to 1g, or from 1mg to 700mg, or from 5mg to 100mg of the disclosed compounds.

When the pharmaceutical composition of the invention contains one or more other active ingredients in addition to the compound of the invention, the compound weight ratio of the compound of the invention to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when a compound of the present invention is mixed with another pharmaceutical agent, the weight ratio of the compound of the present invention to the other pharmaceutical agent typically ranges from about 1000: 1 to about 1: 1000, e.g., from about 200: 1 to about 1: 200. Mixtures of the compounds of the invention with other active ingredients are generally also within the above-mentioned ranges, but in each case an effective dose of each active ingredient should be used.

As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.

Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and those other excipients are present in the formulation.

The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).

Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. sup. 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.

The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack publishing company).

Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.

The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.

In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.

The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.

Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.

The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.

Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.

The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.

The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.

Coloring and flavoring agents may be used in all of the above dosage forms.

The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, poly-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers of hydrogels.

The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.

The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.

The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.

The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methylparaben, and parabenPropyl benzoate, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and glucose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin (f: (f))

CyDex,Lenexa,KS)。

The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile emulsion ready for use.

The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.

Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.

Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.

In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a fine powder formThe disclosed compounds are obtained together with one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns₅₀Values (e.g., measured by laser diffraction).

Aerosols can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art

The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.

Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).

Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.

Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.

Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.

Use of the Compounds and compositions of the invention

The compound or the pharmaceutical composition disclosed by the invention can be used for preparing medicines for treating, preventing, improving, controlling or relieving hyperuricemia, tophus, gouty arthritis, kidney disorders related to hyperuricemia and urolithiasis in mammals including human beings, and can also be used for preparing other medicines for inhibiting urate anion transporters.

In particular, the amount of the compound in the composition of the present invention is effective to detectably inhibit urate anion transporters, and the compound of the present invention is useful as a medicament for preventing or treating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis in humans.

The compounds or compositions of the present invention may be used, but are in no way limited to, in preventing, treating or alleviating hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urolithiasis in mammals, including humans, by administering to a patient an effective amount of the compounds or compositions of the present invention.

In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.

General synthetic procedure

To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.

In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.

Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.

The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.

The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.

The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.

The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.

NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC1₃、DMSO-d₆、CD₃OD or acetone-d₆TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).

The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-M (column model: Zorbax SB-C18,2.1X 30mm,3.5 micron, 6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (CH with 0.1% formic acid)₃CN) in (H containing 0.1% formic acid)₂O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.

The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by DAD detector, and finally calculated by area normalization to obtain the purity of the compound.

The following acronyms are used throughout the invention:

CDC1₃deuterated chloroform;

DMSO-d₆deuterated dimethyl sulfoxide;

g

h hours

min for

mmol millimole

DEG C

MeCN、CH₃CN acetonitrile

MeOH methanol

mL, mL

RT, RT, r.t. Room temperature

rpm rotation per minute

Rt Retention time

Typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. A, B, R, L, L unless otherwise stated⁰Each R¹、R²Each R³M and n have the definitions as described in the present invention.

Synthesis scheme 1

The compound (6) can be prepared by the following process:

the compound (1) is subjected to bromination reaction to obtain a compound (2), then the compound (2) and the compound (3) are subjected to reaction and cyclization to obtain a compound (4), and finally the compound (4) and the compound (5) are subjected to substitution reaction to obtain a compound (6).

Synthesis scheme 2

Compound (6a) can be prepared by the following procedure:

and carrying out substitution reaction on the compound (4a) and a compound (5a) substituted by different substituents to obtain a compound (6 a).

The following examples may further illustrate the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Examples

EXAMPLE 1 methyl 2- (5-chlorothiophene-2-sulfonylamino) -4-cyclopropylthiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 5-chlorothiophene-2-sulfonyl chloride (2.39g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 0.80g, 21%).

MS(ES-API,pos.ion)m/z:379.0[M+1]；

¹H NMR(400MHz,CDCl₃)7.47(s,1H),6.89(s,1H),3.88(s,3H),3.03–2.92(m,1H),1.22–1.20(m,2H),1.02–1.00(m,2H)。

Example 2- (3-Cyanobenzenesulfonylamino) -4-cyclopropylthiazole-5-carboxylic acid methyl ester

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL one-neck flask, 3-cyanobenzenesulfonyl chloride (2.22g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 0.55g, 15%).

MS(ES-API,pos.ion)m/z:364.0[M+1]；

¹H NMR(400MHz,CDCl₃)8.21–8.19(m,2H),7.84(d,J＝7.5Hz,1H),7.64(t,J＝7.7Hz,1H),3.89(s,3H),3.06–2.94(m,1H),1.24–1.22(m,2H),1.02–1.00(m,2H)。

Example 3 methyl 4-cyclopropyl-2- (4-fluorobenzenesulfonamido) thiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-fluorobenzenesulfonyl chloride (2.14g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 1.64g, 46%).

MS(ES-API,pos.ion)m/z:357.0[M+1]；

¹H NMR(400MHz,CDCl₃)9.42(s,1H),7.96–7.92(m,2H),7.14–7.10(m,2H),3.85(s,3H),2.97–2.90(m,1H),1.20–1.15(m,2H),0.98–0.94(m,2H)。

Example 4-Cyclopropylmethyl-2- (4-methylbenzenesulfonamido) thiazole-5-carboxylic acid methyl ester

First step methyl 2-bromo-4-cyclopropyl-3-oxobutanoate

Methyl 4-cyclopropyl-3-oxobutyrate (3.12g,20mmol), magnesium perchlorate (1.34g,6.0mmol) and ethyl acetate (50mL) were charged to a 100mL single vial, and after the reaction mixture was stirred at room temperature for 0.1h, N-bromosuccinimide (3.93g,22mmol) was added to the reaction vial in portions, and after completion of the addition, the reaction mixture was stirred at room temperature for 12 h. Ice water (100mL) was added to the reaction flask, the aqueous phase was extracted with ethyl acetate (60 mL. times.2), the organic phases were combined, and the organic phase was washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/10) to give the title compound (pale yellow oily liquid, 4.28g, 91%).

MS(ES-API,pos.ion)m/z:236.0[M+2]。

Second step 2-amino-4-cyclopropylmethylthiazole-5-carboxylic acid methyl ester

Methyl 2-bromo-4-cyclopropyl-3-oxobutanoate (2.35g,10mmol), thiourea (0.84g,11mmol), sodium bicarbonate (1.68g,20mmol) and ethanol (80mL) were added to a 250mL single neck flask and the reaction mixture was stirred at 80 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/4) to give the title compound (light yellow solid, 1.27g, 60%).

MS(ES-API,pos.ion)m/z:213.1[M+1]。

The third step is 4-cyclopropylmethyl-2- (4-methylbenzenesulfonamido) thiazole-5-carboxylic acid methyl ester

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (2.12g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-methylbenzenesulfonyl chloride (2.10g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 2.38g, 65%).

MS(ES-API,pos.ion)m/z:367.1[M+1]；

¹H NMR(400MHz,CDCl₃)7.84(d,J＝8.1Hz,2H),7.29(d,J＝3.2Hz,2H),3.85(s,3H),2.96(d,J＝7.2Hz,2H),2.43(s,3H),1.03–1.01(m,1H),0.61–0.59(m,2H),0.34–0.32(m,2H)。

Example 5 methyl 4-cyclopropyl-2- (4-fluorobenzamido) thiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 2-naphthalenesulfonyl chloride (2.49g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 2.06g, 53%).

MS(ES-API,pos.ion)m/z:389.1[M+1]；

¹H NMR(400MHz,DMSO-d₆)8.50(s,1H),8.20(d,J＝7.6Hz,1H),8.10(d,J＝8.7Hz,1H),8.02(d,J＝7.7Hz,1H),7.84–7.81(m,1H),7.73–7.61(m,2H),3.78(s,3H),2.96–2.77(m,1H),1.07–1.01(m,4H)。

Example 6 Ethyl 4-cyclopropyl-2- (4-fluorobenzamido) thiazole-5-carboxylate

Ethyl 2-amino-4-phenylthiazole-5-carboxylate (2.48g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-necked flask, 4-methylbenzenesulfonyl chloride (2.10g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 1.37g, 34%).

MS(ES-API,pos.ion)m/z:403.1[M+1]；

¹H NMR(400MHz,CDCl₃)9.40(s,1H),7.84(d,J＝8.3Hz,2H),7.58–7.37(m,5H),7.28(s,1H),4.22(q,J＝7.1Hz,2H),2.41(s,3H),1.25(t,J＝7.1Hz,3H)。

Example 7 Ethyl 4-cyclohexyl-2- (4-methylbenzenesulfonamido) thiazole-5-carboxylate

First step Ethyl 2-bromo-3-cyclohexyl-3-oxopropanoate

Ethyl 3-cyclohexyl-3-oxopropanoate (3.97g,20mmol), magnesium perchlorate (1.34g,6.0mmol) and ethyl acetate (50mL) were added to a 100mL single-necked flask, and after the reaction mixture was stirred at room temperature for 0.1h, N-bromosuccinimide (3.93g,22mmol) was added to the flask in portions and after completion of the addition, the reaction mixture was stirred at room temperature for 12 h. Ice water (100mL) was added to the reaction flask, the aqueous phase was extracted with ethyl acetate (60 mL. times.2), the organic phases were combined, and the organic phase was washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/50) to give the title compound (light yellow solid, 4.49g, 81%).

MS(ES-API,pos.ion)m/z:278.0[M+2]。

Second step 2-amino-4-cyclohexylthiazole-5-carboxylic acid ethyl ester

Ethyl 2-bromo-3-cyclohexyl-3-oxopropanoate (2.77g,10mmol), thiourea (0.84g,11mmol), sodium bicarbonate (1.68g,20mmol) and ethanol (80mL) were added to a 250mL single neck flask and the reaction mixture was stirred at 80 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/2) to give the title compound (light yellow solid, 0.53g, 21%).

MS(ES-API,pos.ion)m/z:255.1[M+1]。

The third step is 4-cyclohexyl-2- (4-methylbenzenesulfonamido) thiazole-5-carboxylic acid ethyl ester

Ethyl 2-amino-4-cyclohexylthiazole-5-carboxylate (2.54g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-methylbenzenesulfonyl chloride (2.10g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 1.80g, 44%).

MS(ES-API,pos.ion)m/z:409.1[M+1]；

¹H NMR(400MHz,CDCl₃)7.87(d,J＝8.2Hz,2H),7.26(d,J＝8.0Hz,2H),4.30(q,J＝7.1Hz,2H),3.67–3.63(m,1H),2.41(s,3H),1.80–1.76(m,5H),1.49–1.29(m,8H)。

Example 8 Ethyl 2- (4-methylphenylsulfonamido) -4- (thiophen-2-yl) thiazole-5-carboxylate

First step 2-amino-4- (thien-2-yl) thiazole-5-carboxylic acid ethyl ester

3-oxo-3- (thiophen-2-yl) -propionic acid ethyl ester (1.98g,10mmol), elemental iodine (2.79g,11mmol), copper oxide (0.875g,11mmol) and ethanol (40mL) were added to a 100mL single neck flask and the reaction mixture was stirred at 90 ℃ for 8.0 h. Thiourea (0.76g,10mmol) was then added to the reaction flask and the reaction stirred at 90 ℃ overnight. The reaction mixture was cooled to room temperature, the reaction solution was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution (100mL) was added to the residue, the aqueous phase was extracted with ethyl acetate (60mL × 2), the organic phases were combined, the organic phase was washed with a saturated saline solution (60mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/dichloromethane (v/v) ═ 1/50) to give the title compound (white solid, 0.31g, 12%).

MS(ES-API,pos.ion)m/z:255.0[M+1]。

Second step Ethyl 2- (4-methylphenylsulfonamido) -4- (thien-2-yl) thiazole-5-carboxylate

Ethyl 2-amino-4- (thiophen-2-yl) thiazole-5-carboxylate (2.54g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-methylbenzenesulfonyl chloride (2.10g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid 1.39g, 34%).

MS(ES-API,pos.ion)m/z:409.0[M+1]；

¹H NMR(400MHz,CDCl₃)7.85(d,J＝8.1Hz,2H),7.76(d,J＝3.4Hz,1H),7.50(d,J＝4.9Hz,1H),7.25(s,2H),7.13–7.05(m,1H),4.31(q,J＝7.1Hz,2H),2.40(s,3H),1.34(t,J＝7.1Hz,3H)。

Example 9 methyl 2- (4-Acetylphenylsulfonamido) -4-cyclopropylthiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL one-neck flask, 4-acetylbenzenesulfonyl chloride (2.41g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 1.98g, 52%).

MS(ES-API,pos.ion)m/z:381.0[M+1]；

¹H NMR(400MHz,DMSO-d₆)8.11(d,J＝8.5Hz,2H),7.95(d,J＝8.4Hz,2H),3.79(s,3H),2.97–2.90(m,1H),2.62(s,3H),1.20–1.15(m,2H),0.98–0.94(m,2H)。

Example 10 methyl 2- ([1,1' -biphenyl ] -4-ylsulfonamido) -4-cyclopropylthiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-phenylbenzenesulfonyl chloride (2.78g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 2.82g, 68%).

MS(ES-API,pos.ion)m/z:415.1[M+1]；

¹H NMR(400MHz,CDCl₃)8.01(d,J＝8.4Hz,2H),7.65(d,J＝8.4Hz,2H),7.59–7.51(m,2H),7.49–7.39(m,3H),3.87(s,3H),3.01–2.92(m,1H),1.21–1.16(m,2H),0.99–0.95(m,2H)。

Example 11 methyl 4-cyclopropyl-2- (4-phenoxyphenylsulfonamido) thiazole-5-carboxylate

First step methyl 4-cyclopropyl-2- (4-phenoxyphenylsulfonamido) thiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-phenoxybenzenesulfonyl chloride (2.96g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/2) to give the title compound (white solid, 3.23g, 75%).

MS(ES-API,pos.ion)m/z:431.1[M+1]；

¹H NMR(400MHz,CDCl₃) 7.93-7.84 (m,2H),7.41(t, J ═ 7.9Hz,2H),7.22(t, J ═ 7.4Hz,1H),7.07(d, J ═ 7.7Hz,2H),7.00(t, J ═ 5.8Hz,2H),3.87(s,3H), 3.01-2.92 (m,1H), 1.21-1.16 (m,2H), 0.99-0.95 (m, 2H). Example 12 methyl 4-cyclopropyl-2- (2-methoxy-4-methylphenylsulfonamido) thiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 2-methoxy-4-methylbenzenesulfonyl chloride (2.43g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/2) to give the title compound (white solid, 0.65g, 17%).

MS(ES-API,pos.ion)m/z:383.1[M+1]；

¹H NMR(400MHz,CDCl₃)7.87(d,J＝8.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.79(s,1H),3.86(s,3H),3.84(s,3H),3.01–2.92(m,1H),2.40(s,3H),1.21–1.16(m,2H),0.99–0.95(m,2H)。

Example 13 methyl 4-cyclopropyl-2- (2, 3-dihydro-1H-indene-5-sulfonylamino) thiazole-5-carboxylate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-necked flask, 2, 3-dihydro-1H-indene-5-sulfonyl chloride (2.38g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12H. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/2) to give the title compound (white solid, 1.44g, 38%).

MS(ES-API,pos.ion)m/z:379.1[M+1]；

¹H NMR(600MHz,DMSO-d₆)7.64(s,1H),7.60(d,J＝7.8Hz,1H),7.39(d,J＝7.9Hz,1H),3.78(s,3H),2.93–2.84(m,5H),2.10–2.00(m,2H),1.09–1.01(m,4H)。

Example 14 methyl 4-cyclopropyl-2- (4-methylbenzenesulfonamido) thiazole-5-carboxylate

First step methyl 2-bromo-3-cyclopropyl-3-oxopropanoate

Methyl 3-cyclopropyl-3-oxopropanoate (2.84g,20mmol), magnesium perchlorate (1.34g,6.0mmol) and ethyl acetate (50mL) were added to a 100mL single vial, and after the reaction mixture was stirred at room temperature for 0.1h, N-bromosuccinimide (3.93g,22mmol) was added portionwise to the vial, and after the addition, the reaction mixture was stirred at room temperature for 12 h. Ice water (100mL) was added to the reaction flask, the aqueous phase was extracted with ethyl acetate (60 mL. times.2), the organic phases were combined, and the organic phase was washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/10) to give the title compound (pale yellow oily liquid, 3.98g, 90%).

MS(ES-API,pos.ion)m/z:222.0[M+2]。

Second step 2-amino-4-cyclopropylthiazole-5-carboxylic acid methyl ester

Methyl 2-bromo-3-cyclopropyl-3-oxopropanoate (2.21g,10mmol), thiourea (0.84g,11mmol), sodium bicarbonate (1.68g,20mmol) and ethanol (80mL) were added to a 250mL single neck flask and the reaction mixture was stirred at 80 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/2), and purified to give the title compound (pale yellow oily liquid, 1.31g, 66%).

MS(ES-API,pos.ion)m/z:199.1[M+1]。

The third step is 4-cyclopropyl-2- (4-methyl benzene sulfonamide) thiazole-5-methyl formate

Methyl 2-amino-4-cyclopropylthiazole-5-carboxylate (1.98g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-methylbenzenesulfonyl chloride (2.10g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 2.29g, 65%).

MS(ES-API,pos.ion)m/z:353.1[M+1]；

¹H NMR(400MHz,CDCl₃)7.81(d,J＝8.2Hz,2H),7.24(d,J＝8.1Hz,2H),3.84(s,3H),2.99–2.87(m,1H),2.40(s,3H),1.19–1.11(m,2H),0.96–0.90(m,2H)。

Example 15 methyl 4-cyclobutyl-2- (4-methylphenylsulfonamido) thiazole-5-carboxylate

First step ethyl 2-bromo-3-cyclobutyl-3-oxopropanoate

Ethyl 3-cyclobutyl-3-oxopropanoate (3.40g,20mmol), magnesium perchlorate (1.34g,6.0mmol) and ethyl acetate (50mL) were charged to a 100mL single-neck flask, and after stirring the reaction mixture at room temperature for 0.1h, N-bromosuccinimide (3.93g,22mmol) was added portionwise to the flask, and after completion of the addition, the reaction mixture was stirred at room temperature for 12 h. Ice water (100mL) was added to the reaction flask, the aqueous phase was extracted with ethyl acetate (60 mL. times.2), the organic phases were combined, and the organic phase was washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/20) to give the title compound (light brown oily liquid, 4.88g, 98%). MS (ES-API, pos.ion) M/z:250.0[ M +2 ].

Second step 2-amino-4-cyclobutylthiazole-5-carboxylic acid ethyl ester

Methyl 2-bromo-3-cyclopropyl-3-oxopropanoate (2.49g,10mmol), thiourea (0.84g,11mmol), sodium bicarbonate (1.68g,20mmol) and ethanol (80mL) were added to a 250mL single neck flask and the reaction mixture was stirred at 80 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/2), and purified to give the title compound (pale yellow oily liquid, 2.10g, 93%).

MS(ES-API,pos.ion)m/z:227.1[M+1]。

The third step is 4-cyclobutyl-2- (4-methylphenylsulfonamido) thiazole-5-carboxylic acid ethyl ester

Ethyl 2-amino-4-cyclobutylthiazole-5-carboxylate (2.26g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-methylbenzenesulfonyl chloride (2.10g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 2.17g, 57%).

MS(ES-API,pos.ion)m/z:381.0[M+1]；

¹H NMR(600MHz,CDCl₃)7.85(d,J＝8.3Hz,2H),7.29(d,J＝8.2Hz,2H),4.38–4.31(m,1H),4.27(q,J＝7.1Hz,1H),2.40(s,2H),2.34–2.32(m,1H),2.19–2.10(m,1H),2.07–2.02(m,1H),1.94–1.84(m,1H),1.33(t,J＝7.1Hz,2H)。

Example 16 methyl 4- (1-methylcyclopropyl) -2- (4-methylphenylsulfonamido) thiazole-5-carboxylate

First step methyl 2-bromo-3- (1-methylcyclopropyl) -3-oxopropanoate

Methyl 3- (1-methylcyclopropyl) -3-oxopropanoate (3.12g,20mmol), magnesium perchlorate (1.34g,6.0mmol) and ethyl acetate (50mL) were added to a 100mL single vial, and after the reaction mixture was stirred at room temperature for 0.1h, N-bromosuccinimide (3.93g,22mmol) was added to the reaction vial in portions, and after completion of addition, the reaction mixture was stirred at room temperature for 12 h. Ice water (100mL) was added to the reaction flask, the aqueous phase was extracted with ethyl acetate (60 mL. times.2), the organic phases were combined, and the organic phase was washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/20) to give the title compound (pale yellow oily liquid, 4.33g, 92%).

MS(ES-API,pos.ion)m/z:236.0[M+2]。

Second step methyl 2-amino-4- (1-methylcyclopropyl) thiazole-5-carboxylate

Methyl 2-bromo-3- (1-methylcyclopropyl) -3-oxopropanoate (2.35g,10mmol), thiourea (0.84g,11mmol), sodium bicarbonate (1.68g,20mmol) and ethanol (80mL) were added to a 250mL single neck flask and the reaction mixture was stirred at 80 ℃ for 2.5 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/2) to give the title compound (light yellow solid, 1.34g, 65%).

MS(ES-API,pos.ion)m/z:213.1[M+1]。

The third step is 4- (1-methylcyclopropyl) -2- (4-methylphenylsulfonamido) thiazole-5-carboxylic acid methyl ester

Methyl 2-amino-4- (1-methylcyclopropyl) thiazole-5-carboxylate (2.12g,10mmol), pyridine (7.9g,100mmol) and dichloromethane (20mL) were added to a 100mL single-neck flask, 4-methylbenzenesulfonyl chloride (2.10g,11mmol) was added to the reaction flask, and the reaction mixture was stirred at room temperature for 12 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v) ═ 1/1) to give the title compound (white solid, 2.02g, 55%).

MS(ES-API,pos.ion)m/z:367.1[M+1]。

Biological activity assay

Test example URAT1 (uric acid anion transporter) inhibitory Activity measurement

1) Test method

Construction of hURAT1-stably expressing cell line

The human URAT1 plasmid was transfected into HEK-293T cells, and G418(Geneticin ) was used to obtain a human URAT1 stably expressing cell line.

b. Uric acid absorption inhibition

Inoculating human URAT1 expression cells into 96-well plates, incubating for at least 12h, removing culture medium,in combination with (Cl)^-) -free HBSS buffer wash cells; the compounds were diluted four-fold with buffer to give a series of compound solutions from 200. mu.M to 0.8nM concentration, 5. mu.L of the compound solution prepared above was mixed with 45. mu.L of [8-¹⁴C]Mixing buffer solution of uric acid, adding into 96-well plate containing stable transfected cells (final concentration of compound is 20 μ M-0.08 nM), and arranging buffer solution hole (transfected cells without drug) and negative hole (non-transfected cells without drug); after incubation at 37 ℃ for 5min, the buffer was removed and the cells were washed with buffer, 50. mu.L of lysis buffer (100mM NaOH solution) was added to each well, the cells were lysed and shaken at 600rpm for 10 min. Centrifuging at 1000rpm for 5min, transferring 45 μ L of the supernatant to an Isoplate-96 microwell plate, adding 150 μ L of Lultima Gold to each well^TMXR, and shake at 600rpm for 10 min. Read [8-¹⁴C]Residual amount of uric acid, and the inhibition of the compound [8-¹⁴C]IC was calculated by XLFit software after the inhibition of uric acid absorption₅₀Value, measured IC₅₀The values are shown in Table 2.

Inhibition rate (%) ([ 1- (drug well)¹⁴C uptake-negative well¹⁴C uptake)/(buffer wells¹⁴C uptake-negative well¹⁴C intake)]×100；

Wherein, the negative hole is a hole of non-inoculated transfected cells.

2) Test results

Table 2 test results for inhibitory activity of URAT1, a compound of the invention

Numbering	URAT1 IC₅₀(μM)
		Example 1	0.222
Example 2	0.138
		Example 4	0.135
Example 6	0.085
		Example 14	0.025
Example 15	0.288
		Example 16	0.108

And (4) conclusion: the compound of the invention has better inhibitory activity to URAT 1.

Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.

Claims

1. A compound which is a compound represented by formula (I) or a tautomer or a pharmaceutically acceptable salt of the compound represented by formula (I),

wherein:

ring A is C_6-10Aryl or C_1-9A heteroaryl group;

l is-O-;

L⁰is a bond or-CH₂-；

R is C_1-6Alkyl or C_1-6alkylamino-C_1-6An alkyl group; said C_1-6Alkyl and C_1-6alkylamino-C_1-6Alkyl may be further independently optionally substituted with one or more substituents selected from deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro and cyano;

L¹and L³Each independently being a bond, -O-, -NH-or C_1-6An alkylene group;

L²and L⁴Each independentlyIs a bond, -O-, -NR⁹-or C_1-6An alkylene group;

t is 0, 1 or 2;

m is 0, 1,2,3,4 or 5;

n is 0, 1,2 or 3;

provided that, when the B ring is phenyl, R¹Is methyl and m is 1, L is-O-.

2. The compound of claim 1, wherein ring a is

Wherein the content of the first and second substances,

X¹is-O-, -S-or-NH-;

each X²、X³、X⁴And X⁵Independently CH or N;

X⁶and X⁷Each independently is-O-, -S-, -NH-or-CH₂-。

3. The compound according to claim 1 or 2, wherein,

ring A is phenyl, naphthyl, 2, 3-dihydro-1H-indene, 1,2,3, 4-tetrahydronaphthyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, 1H-benzimidazolyl, benzopyrazolyl, 1, 4-benzodioxanyl or 1, 3-benzodioxolane.

4. The compound of claim 1, wherein,

ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxirane, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, phenyl, or naphthyl.

5. The compound of claim 1, wherein,

r is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or acetamidoethyl;

each R¹Independently hydrogen, deuterium, F, Cl, Br, I, hydroxyl, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, ethynyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, phenoxy, methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, acetyl, methanesulfonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, indolyl, quinolinyl, isoquinolinyl, phenyl, or naphthyl, wherein R.¹May be further optionally substituted with one or more groups selected from hydrogen, deuterium, oxo (═ O), F, Cl, Br, I, hydroxy, amino, nitro, cyano, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Haloalkyl, C_1-4Haloalkoxy and C_3-6Cycloalkyl substituents.

6. The compound of claim 1, which is a compound of formula (II), or a tautomer or a pharmaceutically acceptable salt of a compound of formula (II),

7. the compound of claim 1, which is a compound having one of the following structural formulae or a tautomer or pharmaceutically acceptable salt of a compound having one of the following structural formulae,

8. a pharmaceutical composition comprising a compound of any one of claims 1-7 and a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle, or combination thereof.

9. The pharmaceutical composition of claim 8, further comprising an additional agent for preventing or treating hyperuricemia, tophus, gouty arthritis, and renal disorders associated with hyperuricemia, said agent being colchicine, a non-steroidal anti-inflammatory agent, a glucocorticoid, an uric acid production-inhibiting agent, a uric acid excretion-promoting agent, a urinary alkalinizing agent, or any combination thereof.

10. Use of a compound according to any one of claims 1-7 or a pharmaceutical composition according to any one of claims 8-9 in the manufacture of a medicament for inhibiting a urate anion transporter in a subject.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 to 9 in the manufacture of a medicament for use in lowering uric acid levels in blood.

12. Use of a compound according to any one of claims 1 to 7 or a pharmaceutical composition according to any one of claims 8 to 9 for the manufacture of a medicament for the prevention or treatment of hyperuricemia, tophus, gouty arthritis and renal disorders associated with hyperuricemia in a mammal.

13. The use of claim 12, wherein the mammal is a human.