WO2024109917A1 - 一种三唑衍生物及其在医药上的应用 - Google Patents

一种三唑衍生物及其在医药上的应用 Download PDF

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WO2024109917A1
WO2024109917A1 PCT/CN2023/133910 CN2023133910W WO2024109917A1 WO 2024109917 A1 WO2024109917 A1 WO 2024109917A1 CN 2023133910 W CN2023133910 W CN 2023133910W WO 2024109917 A1 WO2024109917 A1 WO 2024109917A1
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membered
ring
benzo
carbocyclyl
optionally substituted
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PCT/CN2023/133910
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English (en)
French (fr)
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张晨
赵明亮
邓华
唐平明
袁洪媛
余彦
李瑶
严庞科
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西藏海思科制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a compound described by general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as use of the compounds in the preparation of drugs for treating kidney stones, recurrent kidney stones and type I primary hyperoxaluria (PH).
  • general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as use of the compounds in the preparation of drugs for treating kidney stones, recurrent kidney stones and type I primary hyperoxaluria (PH).
  • Kidney stones are caused by abnormal accumulation of crystal substances (such as calcium, oxalic acid, uric acid, cystine, etc.) in the kidneys. They are common and frequently occurring diseases of the urinary system. The formation process is that certain factors cause the concentration of crystal substances in urine to increase or the solubility to decrease, resulting in an oversaturated state, precipitation of crystals, local growth, accumulation, and eventually formation of stones. According to the composition of the stones, they are mainly divided into calcium oxalate stones, calcium phosphate stones, urate stones, magnesium ammonium phosphate stones, and cystine stones. Among them, calcium oxalate stones are the most common, accounting for about 71% to 84%.
  • HAOX1 Hydroacid Oxidase 1, also known as glycolate oxidase, GO
  • This enzyme is located upstream of glyoxylate aminotransferase (AGT, encoded by the AGXT gene), and its main function is to oxidize glycolate from internal metabolism and food into glyoxylate. Due to the high activity of glycolate oxidase, excessive accumulation of glyoxylate is converted into oxalic acid, and oxalate accumulates in the kidneys, leading to oxalate deposition-related diseases. Therefore, drugs that inhibit glycolate oxidase are needed for the prevention and treatment of oxalate deposition-related diseases, such as kidney stones, recurrent kidney stones, type I primary hyperoxaluria (PH), etc.
  • PH primary hyperoxaluria
  • the present invention aims to provide a triazole compound or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, which is applied to glycolate oxidase inhibitors.
  • the compounds of the present invention can effectively inhibit glycolate oxidase and can be used to prevent and treat oxalate deposition-related diseases, such as kidney stones, recurrent kidney stones, and type I primary hyperoxaluria (PH).
  • the compound of the present invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.
  • the present invention provides a class of compounds or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, wherein the compound is selected from the compounds represented by general formula (I), wherein:
  • the compound represented by general formula (I) is selected from the compound represented by general formula (II-1),
  • the compound represented by general formula (I) is selected from the compound represented by general formula (II-2),
  • the compound represented by general formula (I) is selected from the compound represented by general formula (II-3),
  • R 1 is selected from -COOH or tetrazolyl
  • R 1 is selected from -COOH
  • R 1 is selected from tetrazolyl
  • L is selected from -XC 0-4 alkylene- or -C 0-4 alkylene-X-, said alkylene being optionally substituted with 1 to 4 R k ;
  • L is selected from -X-, -X-CH 2 -, or -CH 2 -X-;
  • L is selected from a bond, -O-, -S-, -NH-, -CH 2 -, -CH 2 O- , -OCH 2 -, -CH 2 S-, -SCH 2 -, -CH 2 NH-, -NHCH 2 -;
  • L is selected from a bond, -O-, -CH 2 -, -CH 2 O-, -OCH 2 -, -CH 2 NH-, -NHCH 2 -;
  • L is selected from a bond
  • L is selected from -O-;
  • L is selected from -CH 2 -, -CH 2 O-, -CH 2 NH-;
  • X is selected from a bond, -O-, -S-, -NH-;
  • X is selected from a bond, -O-, -NH-;
  • X is selected from a bond
  • Ring A, B or C is each independently selected from a 3-20 membered carbocyclyl or a 3-20 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k ;
  • Ring A is optionally substituted with 1 to 4 R ka ;
  • Ring B is optionally substituted with 1 to 4 R kb ;
  • Ring C is optionally substituted with 1 to 4 R kc ;
  • R ka , R kb , and R kc are each independently selected from R k ;
  • ring A is selected from C 3-8 membered cycloalkyl, benzene, 5-6 membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl, the cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl are optionally substituted by 1 to 4 R k ;
  • ring A is selected from C 3-6 membered cycloalkyl, phenyl ring group, benzo 4-membered carbocyclyl, and the cycloalkyl, phenyl ring group, benzo 4-membered carbocyclyl are optionally substituted by 1 to 4 R k ;
  • ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, When substituted, it is optionally substituted with 1 to 4 R k ;
  • Ring A is selected from
  • Ring A is selected from
  • Ring A is selected from
  • Ring A is selected from Ring A1;
  • Ring A1 is selected from
  • Ring A1 when Ring A1 is selected from When Ring B is selected from
  • Ring A1 when Ring A1 is selected from Ring B is selected from When Ring C is selected from
  • Ring A1 when Ring A1 is selected from Ring B is selected from When Ring C is selected from
  • ring B is selected from phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl, wherein the phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl are optionally substituted with 1 to 4 R k ;
  • ring B is selected from phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 5-membered heterocyclyl, wherein the phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 5-membered heterocyclyl is optionally substituted with 1 to 4 R k ;
  • Ring B is selected from substituted or unsubstituted phenyl, pyridinyl, When substituted, it is optionally substituted with 1 to 4 R k ;
  • Ring B is selected from
  • Ring B is selected from
  • Ring C is selected from 3 to 12 membered carbocyclyl or 4 to 12 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k ;
  • ring C is selected from 3 to 6 membered carbocyclyl, 5 to 12 membered spirocarbocyclyl, 4 to 12 membered and carbocyclyl, 4 to 6 membered heterocyclyl, 5 to 12 membered spiroheterocyclyl, 4 to 12 membered and heterocyclyl, wherein the carbocyclyl, spirocarbocyclyl, and carbocyclyl, heterocyclyl, spiroheterocyclyl, and heterocyclyl are optionally substituted with 1 to 4 R k ;
  • ring C is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, pyridinyl, pyrazinyl, pyridazinyl, triazinyl, When substituted, it is optionally substituted with 1 to 4 R k ;
  • Ring C is selected from
  • Ring C is selected from Ring C1;
  • Ring C1 is selected from
  • each R k is independently selected from deuterium, F, Cl, Br, I, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;
  • each R k is independently selected from deuterium, F, Cl, Br, I, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl;
  • a and b are each independently selected from 0, 1, 2, 3 or 4.
  • R 1 is selected from tetrazolyl
  • R 1 is selected from -COOH
  • Ring A is selected from benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group,
  • the benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 5-membered heterocyclic group, and benzo 6-membered heterocyclic group are optionally substituted by 1 to 4 R k ;
  • Ring A is selected from unsubstituted phenyl, cyclohexyl or cyclobutyl
  • Ring B is selected from benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 5-membered heterocyclic group, and the benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 5-membered heterocyclic group are optionally substituted by 1 to 4 R k ;
  • R 1 when R 1 is selected from -COOH, ring A is selected from unsubstituted cyclohexyl, ring B is selected from unsubstituted phenyl, and ring C is selected from 5-12 membered spirocarbocyclic group and 4-12 membered paracarbocyclic group, and the spirocarbocyclic group and paracarbocyclic group are optionally substituted by 1 to 4 R k ;
  • R 1 is selected from -COOH
  • ring A is selected from unsubstituted phenyl
  • ring B is selected from unsubstituted phenyl
  • ring C is selected from triazolyl, 5- to 12-membered spirocarbocyclyl, 4- to 12-membered carbocyclyl, and the triazolyl, spirocarbocyclyl, and carbocyclyl are optionally substituted by 1 to 4 R k ;
  • Ring A and Ring B are selected from substituted or unsubstituted phenyl
  • R 1 is selected from -COOH
  • Ring C is selected from a 3- to 12-membered carbocyclic group and Ring C is not selected from a phenyl ring group
  • the 3- to 12-membered carbocyclic group is optionally substituted by 1 to 4 R k .
  • R1 is selected from -COOH or tetrazolyl
  • L is selected from -XC 0-4 alkylene- or -C 0-4 alkylene-X-, wherein the alkylene is optionally substituted with 1 to 4 R k ;
  • X is selected from a bond, -O-, -S-, -NH-;
  • Ring A is selected from C 3-8 membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl, said cycloalkyl, phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl are optionally substituted by 1 to 4 R k ;
  • Ring B is selected from phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl, wherein the phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl are optionally substituted by 1 to 4 R k ;
  • Ring C is selected from 3 to 12-membered carbocyclyl or 4 to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 1 is selected from tetrazolyl
  • R 1 is selected from -COOH
  • Ring A is selected from benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 5-membered heterocyclic group, benzo 6-membered heterocyclic group,
  • the benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 6-membered carbocyclic group, benzo 5-membered heterocyclic group, and benzo 6-membered heterocyclic group are optionally substituted by 1 to 4 R k ;
  • Ring A is selected from unsubstituted phenyl, cyclohexyl or cyclobutyl
  • Ring B is selected from benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 5-membered heterocyclic group, and the benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 5-membered heterocyclic group are optionally substituted by 1 to 4 R k ;
  • R 1 when R 1 is selected from -COOH, ring A is selected from unsubstituted cyclohexyl, ring B is selected from unsubstituted phenyl, ring C is selected from 5-12 membered spirocarbocyclic group, 4-12 membered paracarbocyclic group, and the spirocarbocyclic group and paracarbocyclic group are optionally substituted by 1 to 4 R k ;
  • R 1 is selected from -COOH
  • ring A is selected from unsubstituted phenyl
  • ring B is selected from unsubstituted phenyl
  • ring C is selected from triazolyl, 5- to 12-membered spirocarbocyclyl, 4- to 12-membered carbocyclyl, and the triazolyl, spirocarbocyclyl, and carbocyclyl are optionally substituted by 1 to 4 R k ;
  • Ring A and Ring B are selected from substituted or unsubstituted phenyl
  • R 1 is selected from -COOH
  • Ring C is selected from a 3- to 12-membered carbocyclic group and Ring C is not selected from a phenyl ring group
  • the 3- to 12-membered carbocyclic group is optionally substituted by 1 to 4 R k .
  • L is selected from -X-, -X-CH 2 - or -CH 2 -X-;
  • Ring A is selected from C 3-6 membered cycloalkyl, benzyl, benzo 4-membered carbocyclic group, wherein the cycloalkyl, benzyl, benzo 4-membered carbocyclic group is optionally substituted by 1 to 4 R k ;
  • Ring B is selected from phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 5-membered heterocyclic group, wherein the phenyl, 5- to 6-membered heteroaryl, benzo 4-membered carbocyclic group, benzo 5-membered carbocyclic group, benzo 5-membered heterocyclic group is optionally substituted by 1 to 4 R k replacement;
  • Ring C is selected from 3- to 6-membered carbocyclyl, 5- to 12-membered spirocarbocyclyl, 4- to 12-membered and heterocyclyl, 4- to 6-membered heterocyclyl, 5- to 12-membered spiroheterocyclyl, and 4- to 12-membered and heterocyclyl, wherein the carbocyclyl, spirocarbocyclyl, and heterocyclyl, heterocyclyl, and heterocyclyl are optionally substituted by 1 to 4 R k ;
  • L is selected from a bond, -O-, -S-, -NH-, -CH 2 -, -CH 2 O- , -OCH 2 -, -CH 2 S-, -SCH 2 -, -CH 2 NH-, -NHCH 2 -;
  • Ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl ring, pyridyl, When substituted, it is optionally substituted with 1 to 4 R k ;
  • Ring B is selected from substituted or unsubstituted phenyl, pyridyl, When substituted, it is optionally substituted with 1 to 4 R k ;
  • Ring C is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, When substituted, it is optionally substituted with 1 to 4 R k ;
  • L is selected from a bond, -O-, -CH 2 -, -CH 2 O-, -OCH 2 - , -CH 2 NH-, -NHCH 2 -;
  • Ring A is selected from
  • R k is independently selected from deuterium, F, Cl, Br, I, CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;
  • Ring B is selected from
  • Ring C is selected from
  • X is selected from a bond, -O-, -NH-;
  • Ring A1 is selected from
  • R k is independently selected from deuterium, F, Cl, Br, I, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl;
  • Ring C1 is selected from
  • a, b are each independently selected from 0, 1, 2, 3 or 4;
  • Ring A1 is selected from
  • R k is independently selected from deuterium, F, Cl, Br, I, CF 3 , methyl, ethyl, methoxy, ethoxy, cyclopropyl;
  • b is selected from 0, 1, 2, 3 or 4.
  • the present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1 below:
  • the present invention relates to a pharmaceutical composition, comprising the above compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the present invention relates to the use of the above-mentioned compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in preparing drugs for inhibiting glycolate oxidase (HAOX1).
  • the present invention relates to the use of the above-mentioned compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in preparing drugs for treating kidney stones, recurrent kidney stones and type I primary hyperoxaluria.
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • the present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition.
  • the mammal of the present invention includes a human.
  • an "effective amount” or “therapeutically effective amount” as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate to some extent one or more symptoms of the disease or condition being treated (e.g., kidney stones, recurrent kidney stones, primary hyperoxaluria type I). In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms or causes of a disease, or any effect of a biological system. Other desired changes. For example, an "effective amount” for therapeutic use is the amount of the compound disclosed herein that provides a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg.
  • g 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg , 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300
  • the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg g, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being kidney disease.
  • a method for treating a disease in a mammal comprising administering to a subject a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, In some embodiments, the daily dose includes but is not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day.
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.
  • the amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include prot
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; the alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v -(v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring.
  • Heterocycloalkyl can be connected to a bridge ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to a substituted or unsubstituted straight chain and branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl,
  • Alkynyl refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, and examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-propynyl, 2-but ...
  • alkynyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be a monocyclic ring, a bridged ring, or a spirocyclic ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S.
  • the N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group may be connected to a heteroatom or a carbon atom, may be connected to an aromatic ring or a non-aromatic ring, may be connected to a bridged ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofur
  • Spirocycle or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:
  • Bicyclic or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • the "carbospirocycle”, “spirocarbocyclyl”, “spirocarbocyclyl” or “carbospirocyclyl” appearing in this document have the same definition as spirocycle.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic
  • Carbobridge ring “bridged ring carbocyclic group”, “bridged carbocyclic group” or “carbon bridged cyclic group” refers to a “bridged ring” whose ring system consists of only carbon atoms. "Carbobridge ring”, “bridged ring carbocyclic group”, “bridged carbocyclic group” or “carbon bridged cyclic group” appearing in this article have the same definition as the bridged ring.
  • Heteromonocycle refers to a “heterocyclic group” or “heterocycle” of a monocyclic ring system.
  • the heterocyclic group, “monocyclic heterocyclyl” or “heteromonocyclic group” appearing in this document has the same definition as heterocycle.
  • Heterocyclic ring refers to a "cyclic ring” containing a heteroatom.
  • the heterocyclic ring, “heterocyclic ring group”, “cyclic heterocyclic group” or “heterocyclic ring group” appearing in this article have the same definition as cyclic ring.
  • Heterospirocycle refers to a "spirocycle” containing a heteroatom. Heterospirocycle, “heterospirocyclyl”, “spiro heterocyclyl” or “heterospirocyclyl” appearing herein have the same definition as spirocycle.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • the heterobridged ring, “heterobridged ring group”, “bridged heterocyclic group” or “heterobridged ring group” appearing herein have the same definition as the bridged ring.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include
  • the heteroaryl groups appearing in this article have the same definition as this definition.
  • the heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the heteroaryl ring.
  • 5-membered ring and 5-membered heteroaromatic ring refers to a 5-membered fused heteroaromatic ring, at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the whole group is aromatic.
  • Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.
  • 5- and 6-membered heteroaromatic ring refers to a 5- and 6-membered fused heteroaromatic ring, where at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic.
  • Non-limiting examples include benzo 5-membered heteroaromatic group, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.
  • Ra and Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged, spiro or paracyclic groups.
  • Consing 1 to 5 heteroatoms selected from O, S, and N means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, and N.
  • “Replaced by 1 to X substituents selected from" means substituted by 1, 2, 3 ....X substituents, X is selected from any integer between 1 and 10.
  • “replaced by 1 to 4 R k” means substituted by 1, 2, 3 or 4 R k .
  • “replaced by 1 to 5 substituents selected from" means substituted by 1, 2, 3, 4 or 5 substituents selected from"
  • “the heterobridged ring is optionally substituted by 1 to 4 substituents selected from D or F” means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from D or F.
  • X-Y membered rings (3 ⁇ X ⁇ Y, Y is any integer from 4 to 12) include X, X+1, X+2, X+3, X+4...Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • “4-7 membered heteromonocyclic rings” refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • “5-10 membered heterocyclic rings” refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers, diastereomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Boc tert-butoxycarbonyl
  • Ts p-toluenesulfonyl
  • diethylaminosulfur trifluoride (387 mg, 2.40 mmol) was slowly added dropwise to a dichloromethane (10 mL) solution of 1a (200 mg, 0.80 mmol, synthesized according to patent WO2018054365A1). After the addition was complete, the mixture was slowly returned to room temperature for 16 h. After the reaction was completed, a saturated aqueous sodium bicarbonate solution was slowly added dropwise under an ice-water bath until the system became weakly alkaline. Water (10 mL) was added, and dichloromethane (20 mL x 2) was extracted. The organic phases were combined, washed with saturated brine (20 mL), and then precipitated with anhydrous sulfuric acid.
  • Preparation method The crude product was dissolved in methanol and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Gradient elution method acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL/min; elution time 15 min), and compound 1 (10 mg, two-step yield: 27%) was obtained after freeze-drying.
  • Preparation method The crude product was dissolved in methanol and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Gradient elution method acetonitrile was eluted from 30% to 80% (flow rate: 12 mL/min; elution time 15 min), and compound 2 (10 mg, 17%) was obtained after freeze-drying.
  • Preparation method The crude product was dissolved in dimethyl sulfoxide and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Gradient elution method acetonitrile was gradient eluted from 30% to 80% (flow rate: 12 mL/min; elution time 15 min), and compound 3 (15 mg, two-step yield: 21%) was obtained by freeze-drying.
  • Preparation method The crude product was dissolved in dimethyl sulfoxide and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Preparation method The crude product was dissolved in dimethyl sulfoxide and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Preparation method The crude product was dissolved in dimethyl sulfoxide and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Preparation method The crude product is dissolved in dimethyl sulfoxide and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Gradient elution method Acetonitrile is gradient eluted from 30% to 80% (flow rate: 12mL/min; elution time 15min), and lyophilized to obtain compound 7 (40mg, two-step yield: 39%).
  • the in vitro hHAO1 activity assay uses glycolic acid as a substrate and is detected by the Amplex Red method.
  • a certain concentration of hHAO1 protein is added to a 384-well plate at 2.5 ⁇ L/well, followed by the addition of 2.5 ⁇ L/well compound. After reacting at room temperature for 15 minutes, 5 ⁇ L of substrate mixed solution (glycolic acid, Amplex Red dye, HRP, 50 mM HEPES, pH 8.0) is added.
  • substrate mixed solution glycolic acid, Amplex Red dye, HRP, 50 mM HEPES, pH 8.0
  • the 384-well plate is then immediately placed in a BMG microplate reader to read the fluorescence signal (Em540nm/EX590nm).
  • the mean and standard error (Mean ⁇ SEM) are statistically analyzed and analyzed using Graphpad Prism software to calculate the IC 50 value.
  • the compounds of the present invention have good inhibitory activity against hHAO1, especially compounds 4, 6, 7, and 8, whose IC50 is less than 50 nM, have better hHAO1 inhibitory activity than the control compound 1.
  • reference compound 1 The structure of reference compound 1 is as follows:
  • mice Male Balb/c mice, about 22 g, 6 to 8 weeks old, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, Balb/c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
  • the compounds of the present invention such as the example compounds, have higher exposure and good bioavailability in mice, especially compounds 6 and 8, which have better bioavailability than the control compound 1.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
  • the compounds of the present invention have higher exposure and good bioavailability in rats, especially compound 6, which has better bioavailability than the control compound 1.
  • beagle dogs On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours one day before administration and fed 4 hours after administration. The administration was performed according to Table 6.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC
  • the compounds of the present invention such as the example compounds, especially compounds 4 and 6, have higher exposure and good bioavailability in dogs.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 0.5% MC (containing 0.5% Tween80);
  • 1.0 mL of blood was collected from the limb veins and placed in EDTAK2 centrifuge tubes. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48h. Before analysis, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
  • the compounds of the present invention such as the example compounds, especially compounds 4 and 6, have higher exposure and good bioavailability in monkeys.

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Abstract

本发明涉及三唑衍生物及其在医药上的应用，具体涉及一种通式（I）所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗肾结石、复发性肾结石，I型原发性高草酸尿症（PH）的药物中的应用。

Description

一种三唑衍生物及其在医药上的应用 技术领域
本发明涉及一种通式(I)所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗肾结石、复发性肾结石，I型原发性高草酸尿症(PH)的药物中的应用。
背景技术
肾结石(renal calculi)是晶体物质(如钙、草酸、尿酸、胱氨酸等)在肾脏的异常聚积所致，为泌尿系统的常见病、多发病。其形成过程是某些因素造成尿中晶体物质浓度升高或溶解度降低，呈过饱和状态，析出结晶并在局部生长、聚积，最终形成结石。根据结石的成分，主要分为草酸钙结石、磷酸钙结石、尿酸盐结石、磷酸铵镁结石、胱氨酸结石。其中草酸钙结石最为常见，约占71％～84％。
目前，全球尿石症的发病率和患病率居高不下且呈上升趋势，大约12％的世界人口受到不同形式的尿石症影响。治疗尿路结石的常见方法包括手术治疗，但术后10年内复发率高，约为30～50％(Rule AD,Lieske JC,Li X,et al.The ROKS Nomogram for predicting a second symptomatic stone episode.J Amer Soc Nephrol 2014；25:2685-7.)；膳食改变，通过大量饮水、避免高草酸饮食、限制钙摄入、低盐、低嘌呤、补充柠檬酸等；药物治疗，主要通过解痉止痛、控制感染(尿路梗阻时)、维生素B6(高草酸尿)、噻嗪类利尿剂(高钙尿)等。但是，这些治疗方法均不能解决疾病的根源，商业上没有专门抑制草酸形成的药物以用于预防和治疗草酸盐沉积相关病症。
HAOX1(Hydroxyacid Oxidase 1，也称为glycolate oxidase，GO)，是参与草酸代谢途径的关键酶，由HAO1基因编码。该酶位于乙醛酸氨基转移酶(AGT，由AGXT基因编码)的上游，主要功能是将来自内部代谢和食物的乙醇酸氧化为乙醛酸。由于乙醇酸氧化酶的高活性，过度积累的乙醛酸转化为草酸，草酸盐累积于肾脏，从而导致草酸盐沉积相关病症。因此，需要抑制乙醇酸氧化酶的药物用于预防和治疗草酸盐沉积相关病症，如肾结石、复发性肾结石，I型原发性高草酸尿症(PH)等。
发明内容
本发明的目的在于提供一类三唑类化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，将其应用于乙醇酸氧化酶抑制剂。本发明中的化合物能有效抑制乙醇酸氧化酶并可用于预防和治疗草酸盐沉积相关病症，例如肾结石、复发性肾结石，I型原发性高草酸尿症(PH)。
本发明化合物其具有良好的药代性能和生物利用度、具有口服性能和良好的安全性。
本发明提供一种类化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(I)所示的化合物，其中，
在一些实施方案中，通式(I)所示的化合物选自通式(II-1)所示化合物，
在一些实施方案中，通式(I)所示的化合物选自通式(II-2)所示化合物，
在一些实施方案中，通式(I)所示的化合物选自通式(II-3)所示化合物，
在一些实施方案中，R1选自-COOH或四氮唑基；
在一些实施方案中，R1选自-COOH；
在一些实施方案中，R1选自四氮唑基；
在一些实施方案中，L选自-X-C0-4亚烷基-或-C0-4亚烷基-X-，所述亚烷基任选被1至4个Rk取代；
在一些实施方案中，L选自-X-、-X-CH2-或-CH2-X-；
在一些实施方案中，L选自键、-O-、-S-、-NH-、-CH2-、-CH2O-、-OCH2-、-CH2S-、-SCH2-、-CH2NH-、-NHCH2-；
在一些实施方案中，L选自键、-O-、-CH2-、-CH2O-、-OCH2-、-CH2NH-、-NHCH2-；
在一些实施方案中，L选自键；
在一些实施方案中，L选自-O-；
在一些实施方案中，L选自-CH2-、-CH2O-、-CH2NH-；
在一些实施方案中，X选自键、-O-、-S-、-NH-；
在一些实施方案中，X选自键、-O-、-NH-；
在一些实施方案中，X选自键；
在一些实施方案中，环A、B或C各自独立地选自3-20元碳环基或3-20元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，环A任选被1至4个Rka取代；
在一些实施方案中，环B任选被1至4个Rkb取代；
在一些实施方案中，环C任选被1至4个Rkc取代；
在一些实施方案中，Rka、Rkb、Rkc各自独立的选自Rk；
在一些实施方案中，环A选自C3-8元环烷基、苯、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基，所述环烷基、苯基、5至6 元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
在一些实施方案中，环A选自C3-6元环烷基、苯环基、苯并4元碳环基，所述环烷基、苯环基、苯并4元碳环基任选被1至4个Rk取代；
在一些实施方案中，环A选自取代或未取代的环丙基、环丁基、环戊基、环己基、苯环基、吡啶基、当被取代时，任选被1至4个Rk取代；
在一些实施方案中，环A选自
在一些实施方案中，环A选自
在一些实施方案中，环A选自
在一些实施方案中，环A选自环A1；
在一些实施方案中，环A1选自
在一些实施方案中，当环A1选自时，环B选自
在一些实施方案中，当环A1选自环B选自时，环C选自
在一些实施方案中，当环A1选自环B选自时，环C选自
在一些实施方案中，环B选自苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基，所述的苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
在一些实施方案中，环B选自苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并5元杂环基，所述的苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并5元杂环基任选被1至4个Rk取代；
在一些实施方案中，环B选自取代或未取代的苯基、吡啶基、 当被取代时，任选被1至4个Rk取代；
在一些实施方案中，环B选自
在一些实施方案中，环B选自
在一些实施方案中，环C选自3至12元碳环基或4至12元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
在一些实施方案中，环C选自3至6元碳环基、5至12元螺碳环基、4至12元并碳环基、4至6元杂环基、5至12元螺杂环基、4至12元并杂环基，所述碳环基、螺碳环基、并碳环基、杂环基、螺杂环基、并杂环基任选被1至4个Rk取代；
在一些实施方案中，环C选自取代或未取代的环丙基、环丁基、环戊基、环己基、氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、三氮唑基、四氮唑基、吡唑基、吡咯基、吡啶基、吡嗪基、哒嗪基、三嗪基、 当被取代时，任选被1至4个Rk取代；
在一些实施方案中，环C选自
在一些实施方案中，环C选自环C1；
在一些实施方案中，环C1选自选自
在一些实施方案中，Rk各自独立的选自氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C0-4亚烷基-C3-6碳环、-C0-4亚烷基-3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；
在一些实施方案中，Rk各自独立的选自氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C0-4亚烷基-C3-6碳环、-C0-4亚烷基-3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
在一些实施方案中，Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗 啉基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
在一些实施方案中，Rk各自独立的选自氘、F、Cl、Br、I、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基；
在一些实施方案中，Rk各自独立的选自氘、F、Cl、Br、I、CF3、甲基、乙基、甲氧基、乙氧基、环丙基；
在一些实施方案中，a、b各自独立地选自0、1、2、3或4。
任选地，当L选自-O-或-S-时，1)R1选自四氮唑基；
或2)R1选自-COOH，环A选自苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基、 所述苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
或3)R1选自-COOH，环A选自未取代的苯基、环己基或环丁基时，环B选自苯并4元碳环基、苯并5元碳环基、苯并5元杂环基，所述的苯并4元碳环基、苯并5元碳环基、苯并5元杂环基任选被1至4个Rk取代；
或4)R1选自-COOH，环A选自未取代的环己基、环B选自未取代的苯基时，环C选自5至12元螺碳环基、4-12元并碳环基，所述的螺碳环基、并碳环基任选被1至4个Rk取代；
或5)R1选自-COOH，环A选自未取代的苯基、环B选自未取代的苯基时，环C选自三氮唑基、5至12元螺碳环基、4-12元并碳环基，所述的三氮唑基、螺碳环基、并碳环基任选被1至4个Rk取代；
当L选自键，环A、环B选自取代或未取代的苯基，R1选自-COOH，环C选自3至12元碳环基且环C不选自苯环基，所述的3至12元碳环基任选被1至4个Rk取代。
作为本发明的第一种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
R1选自-COOH或四氮唑基；
L选自-X-C0-4亚烷基-或-C0-4亚烷基-X-，所述亚烷基任选被1至4个Rk取代；
X选自键、-O-、-S-、-NH-；
环A选自C3-8元环烷基、苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基，所述环烷基、苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
环B选自苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基，所述的苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
环C选自3至12元碳环基或4至12元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
Rk各自独立的选自氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C0-4亚烷基-C3-6碳环、-C0-4亚烷基-3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；
条件是，当L选自-O-或-S-时，1)R1选自四氮唑基；
或2)R1选自-COOH，环A选自苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基、 所述苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
或3)R1选自-COOH，环A选自未取代的苯基、环己基或环丁基时，环B选自苯并4元碳环基、苯并5元碳环基、苯并5元杂环基，所述的苯并4元碳环基、苯并5元碳环基、苯并5元杂环基任选被1至4个Rk取代；
或4)R1选自-COOH，环A选自未取代的环己基、环B选自未取代的苯基时，环C选自5至12元螺碳环基、4-12元并碳环基，所述的螺碳环基、并碳环基任选被1至4个Rk取代；
或5)R1选自-COOH，环A选自未取代的苯基、环B选自未取代的苯基时，环C选自三氮唑基、5至12元螺碳环基、4-12元并碳环基，所述的三氮唑基、螺碳环基、并碳环基任选被1至4个Rk取代；
当L选自键，环A、环B选自取代或未取代的苯基，R1选自-COOH，环C选自3至12元碳环基且环C不选自苯环基，所述的3至12元碳环基任选被1至4个Rk取代。
作为本发明的第二种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
L选自-X-、-X-CH2-或-CH2-X-；
环A选自C3-6元环烷基、苯环基、苯并4元碳环基，所述环烷基、苯环基、苯并4元碳环基任选被1至4个Rk取代；
环B选自苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并5元杂环基，所述的苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并5元杂环基任选被1至4 个Rk取代；
环C选自3至6元碳环基、5至12元螺碳环基、4至12元并碳环基、4至6元杂环基、5至12元螺杂环基、4至12元并杂环基，所述碳环基、螺碳环基、并碳环基、杂环基、螺杂环基、并杂环基任选被1至4个Rk取代；
Rk各自独立的选自氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C0-4亚烷基-C3-6碳环、-C0-4亚烷基-3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
其余定义与本发明第一种实施方案相同。
作为本发明的第三种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
L选自键、-O-、-S-、-NH-、-CH2-、-CH2O-、-OCH2-、-CH2S-、-SCH2-、-CH2NH-、-NHCH2-；
环A选自取代或未取代的环丙基、环丁基、环戊基、环己基、苯环基、吡啶基、 当被取代时，任选被1至4个Rk取代；
环B选自取代或未取代的苯基、吡啶基、 当被取代时，任选被1至4个Rk取代；
环C选自取代或未取代的环丙基、环丁基、环戊基、环己基、氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、三氮唑基、四氮唑基、吡唑基、吡咯基、吡啶基、吡嗪基、哒嗪基、三嗪基、 当被取代时，任选被1至4个Rk取代；
Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环 丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代；
其余定义与本发明第一种或第二种实施方案相同。
作为本发明的第四种实施方案，前述通式(I)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
L选自键、-O-、-CH2-、-CH2O-、-OCH2-、-CH2NH-、-NHCH2-；
环A选自
Rk各自独立的选自氘、F、Cl、Br、I、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基；
环B选自
环C选自
其余定义与本发明第一种、第二种或第三种实施方案相同。
作为本发明的第五种实施方案，下述通式(II-1)或(II-2)或(II-3)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
X选自键、-O-、-NH-；
环A1选自
或者当环A1选自时，环B选自
或者当环A1选自环B选自时，环C选自
或者当环A1选自环B选自时，环C选自
Rk各自独立的选自氘、F、Cl、Br、I、CF3、甲基、乙基、甲氧基、乙氧基、环丙基；
环C1选自选自
a、b各自独立地选自0、1、2、3或4；
其余定义与本发明第一种、第二种、第三种或第四种实施方案相同。
作为本发明的第六种实施方案，下述通式(III-1)所示的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
环A1选自
Rk各自独立的选自氘、F、Cl、Br、I、CF3、甲基、乙基、甲氧基、乙氧基、环丙基；
b选自0、1、2、3或4。
本发明涉及一种下述化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自如下表E-1所示结构之一：
表E-1


本发明涉及一种药物组合物，包括上述化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体。
本发明涉及上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者上述药物组合物用于制备抑制乙醇酸氧化酶(HAOX1)药物中的应用。
本发明涉及上述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或者上述药物组合物用于制备治疗肾结石、复发性肾结石，I型原发性高草酸尿症药物中的应用。
本发明涉及一种药物组合物或药物制剂，所述的药物组合物或药物制剂包含治疗有效量的本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和药用赋型剂。该药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。
本发明还提供一种用于治疗哺乳动物的疾病的方法，其包括向所述哺乳动物给予治疗有效量的本发明所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或药物组合物。一些实施方案中，本发明中所述哺乳动物包括人。
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如肾结石、复发性肾结石，I型原发性高草酸尿症)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何 其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1000mg、1-800mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg；
在一些实施方案中，该药物组合物包括但不限于1-1500mg、1-1000mg、1-800mg、1-600mg、20-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选肾脏疾病。
一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以1-1500mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、100mg/天、125mg/天、150mg/天、200mg/天、400mg/天、600mg/天、800mg/天。
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量与上述药物组合物中其量相同。
本发明中本发明化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量在每种情况下以游离碱的形式换算。
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。
除非有相反的陈述，在本申请说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括17F和19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“卤素”是指F、Cl、Br或I。
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，为1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH2)v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价。
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；本文中出现的烯基，其定义与本定义一致。烯基可以是一价、二价、三价或四价。
“炔基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，主链包括2至10个碳原子，包括但不限于在主链上有2至6个碳原子，主链上有2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔 基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、 “碳环基”或“碳环”可以是一价、二价、三价或四价。
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)个选自N、O或S的杂原子，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、 “杂环基”或“杂环”可以是一价、二价、三价或四价。
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有1至5个选自N、O或S(＝O)n的杂原子。
“螺环”或“螺环基”可以是一价、二价、三价或四价。
“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O)n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括：
“并环”或“并环基”可以是一价、二价、三价或四价。
“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，桥环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O)n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括 立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。 本文中出现的“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”，其定义与螺环一致。
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。本文中出现的“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”，其定义与并环一致。
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。本文中出现的“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”，其定义与桥环一致。
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，本文中出现的杂环基、“单环杂环基”或“杂单环基”，其定义与杂环一致。
“杂并环”、“杂并环基”“并环杂环基”或“杂并环基”是指含有杂原子的“并环”。本文中出现的杂并环、“杂并环基”“并环杂环基”或“杂并环基”，其定义与并环一致。
“杂螺环”、“杂螺环基”、“螺环杂环基”或“杂螺环基”是指含有杂原子的“螺环”。本文中出现的杂螺环、“杂螺环基”、“螺环杂环基”或“杂螺环基”，其定义与螺环一致。
“杂桥环”、“杂桥环基”、“桥环杂环基”或“杂桥环基”是指含有杂原子的“桥环”。本文中出现的杂桥环、“杂桥环基”、“桥环杂环基”或“杂桥环基”，其定义与桥环一致。
“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。
“5元环并5元杂芳环”是指5并5元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了吡咯并吡咯环、吡唑并吡咯环、吡唑并吡唑环、吡咯并呋喃环、吡唑并呋喃环、吡咯并噻吩环、吡唑并噻吩环。
“5并6元杂芳环”是指5并6元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了苯并5元杂芳基、6元杂芳环并5元杂芳环。
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、 氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。
“1至X个选自…的取代基所取代”是指被1、2、3….X个取代基所取代，X选自1至10之间的任意整数。如“1至4个Rk取代”是指被1、2、3或4个Rk取代。如“1至5个选自…的取代基所取代”是指被1、2、3、4或5个选自…的取代基所取代。如“杂桥环任选被1至4个选自D或F的取代基所取代”是指杂桥环任选被1、2、3或4个选自D或F的取代基所取代。
X-Y元的环(3≤X＜Y，Y选自4至12之间的任意整数)包括了X、X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、光学异构体、对映异构体、非对映异构体和构象异构体。
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。
具体实施方式
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)；
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；
Boc：叔丁氧基羰基；
Ts：对甲苯磺酰基；
Cbz：苄氧羰基；
TMS：三甲基硅基。
实施例1：化合物1的制备
第一步：1b的制备
冰水浴下，将三氟化二乙氨基硫(387mg,2.40mmol)缓慢滴加到1a(200mg,0.80mmol，参照专利WO2018054365A1合成)的二氯甲烷(10mL)溶液中，滴加完毕后，缓慢回到室温反应16h。反应结束后，在冰水浴下，缓慢滴加饱和碳酸氢钠水溶液至体系成弱碱性。加入水(10mL)，二氯甲烷(20mL x 2)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤后，经无水硫酸 钠干燥，抽滤，滤液减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝97:3)得1b(90mg,21％)。
1H NMR(400MHz,CDCl3)δ7.47-7.42(m,2H),7.25-7.20(m,2H),5.93-5.87(m,1H),2.76-2.61(m,4H),2.24-2.10(m,2H).
第二步：1c的制备
室温下，依次将1b(1.00g,3.66mmol)、联硼酸频那醇酯(1.86g,7.32mmol)、醋酸钾(1.08g,11.02mmol)加入到1,4-二氧六环(20mL)中，加入1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(300mg,0.37mmol)，氮气置换后，升温至80℃反应16h。反应完毕后，冷却至室温，垫硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝95:5)得1c(1.10g,94％)。
1H NMR(400MHz,CDCl3)δ7.77(d,2H),7.37(d,2H),5.99-5.92(m,1H),2.82-2.58(m,4H),2.26-2.10(m,2H),1.34(s,12H).
第三步：1d的制备
室温下将得到1c(150mg,0.47mmol)溶于甲醇(15mL)和乙酸乙酯(3mL)的混合溶剂中，加入钯碳(150mg,10％Wt)，氢气置换后，氢气氛围下室温下搅拌16h。反应结束后，硅藻土过滤，滤液经减压浓缩得1d(140mg,93％)。
1H NMR(400MHz,CDCl3)δ7.76(d,2H),7.23(d,2H),2.67-2.55(m,1H),2.26-2.16(m,2H),1.97-1.78(m,6H),1.33(s,12H).
第四步：1e的制备
室温下，依次将1d(150mg,0.47mmol)、对溴碘苯(200mg,0.70mmol)、碳酸钾(230mg,1.65mmol)加入到1,4-二氧六环(10mL)和水(10mL)中。再加入1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(38mg,0.05mmol)，氮气置换后，升温至90℃反应16h。反应完毕后，冷却至室温，硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(100％石油醚)得1e(100mg,61％)。
1H NMR(400MHz,CDCl3)δ7.57-7.52(m,2H),7.52-7.48(m,2H),7.46-7.41(m,2H),7.32-7.27(m,2H),2.72-2.58(m,1H),2.31-2.14(m,2H),2.04-1.76(m,6H).
第五步：1f的制备
室温下，依次将1e(100mg,0.28mmol)、联硼酸频那醇酯(107mg,0.42mmol)、醋酸钾(97mg,0.99mmol)加入到1,4-二氧六环(5mL)中，再加入1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(25mg,0.03mmol)，氮气置换后，升温至80℃反应16h。反应完毕后，冷却至室温，硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝95:5)得1f(50mg,45％)。
1H NMR(400MHz,CDCl3)δ7.87(d,2H),7.62-7.53(m,4H),7.29(d,2H),2.72-2.58(m,1H),2.29-2.15(m,2H),2.04-1.78(m,6H),1.36(s,12H).
第六步：1g的制备
室温下，依次将1f(70mg,0.18mmol)、5-碘-1-(4-甲氧基苄基)-1H-1,2,3-三唑-4-羧酸甲酯(81mg,0.22mmol，参照专利WO2019133770A2合成)、碳酸钾(75mg,0.54mmol)加入到1,4-二氧六环(5mL)和水(0.5mL)中。再加入1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络 合物(15mg,0.02mmol)，氮气置换后，升温至80℃反应16h。反应完毕后，冷却至室温，硅藻土过滤、滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝95:5)得1g(39mg,42％)。
LCMS m/z＝518.2[M+1]+
第七步：1h的制备
室温下，将苯甲醚(31mg,0.29mmol)和三氟乙酸(3mL)分别加入到1g(50mg,0.10mmol)的二氯甲烷(5mL)溶液中，升温至50℃反应16h。反应完毕后，减压浓缩，加入水(10mL)，二氯甲烷(20mL x 2)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤后，经无水硫酸钠干燥，抽滤，滤液经减压浓缩得1h(50mg，粗品)无需纯化，直接做下一步。
LCMS m/z＝398.4[M+1]+
第八步：化合物1的制备
室温下，将1h(50mg，粗品)溶于四氢呋喃(3mL)和甲醇(1mL)的混合溶液中，加入氢氧化钠水溶液(1.0M,4mL,4.00mmol)，升温至50℃反应16h。反应完毕后，减压浓缩除去溶剂，冰水浴下，缓慢滴加1N稀盐酸溶液将体系pH值调至3～4左右。该溶液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C18，内径x长度＝19mm x250mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的三氟乙酸)。梯度洗脱方法：乙腈由30％梯度洗脱至80％(流速：12mL/min；洗脱时间15min)，冻干后得到化合物1(10mg,两步收率：27％)。
LCMS m/z＝384.2[M+1]+
1H NMR(400MHz,DMSO-d6)δ15.77(s,1H),13.15(s,1H),8.01-7.81(m,2H),7.76(d,2H),7.68(d,2H),7.37(d,2H),2.84-2.70(m,1H),2.20-1.87(m,6H),1.80-1.63(m,2H).
实施例2：化合物2的制备
第一步：2b的制备
室温下，将2a(100mg,0.29mmol，参照专利WO2019133770A2合成)和4-溴-2,5-二氟苯酚(73mg,0.35mmol)溶于N-甲基吡咯烷酮(3mL)溶液中，再加入碳酸钾(60mg,0.43mmol)，升温至90℃反应16h。反应完毕后，冷却至室温，加入饱和食盐水(10mL)，乙酸乙酯(15mL x 2)萃取。合并有机相，有机相用饱和食盐水(15mL x 2)洗涤后，经无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝85:15)得2b(52mg,38％)。
1H NMR(400MHz,CDCl3)δ7.35(dd,1H),7.25-7.18(m,2H),6.82-6.75(m,2H),6.28-6.21(m,1H),5.43(s,2H),4.28-4.20(m,2H),3.76(s,3H),1.21(t,3H).
第二步：2c的制备
室温下，依次将2b(70mg,0.15mmol)、1d(56mg,0.17mmol)、碳酸钾(75mg,0.54mmol)加入到1,4-二氧六环(10mL)和水(1mL)中。氮气保护下，加入1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(13mg,0.02mmol)，升温至90℃反应4h。反应完毕后，冷却至室温，硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝80:20)得2c(56mg,64％)
LCMS m/z＝584.7[M+1]+
第三步：2d的制备
室温下，将苯甲醚(45mg,0.42mmol)和三氟乙酸(5mL)分别加入到2c(80mg,0.14mmol)的二氯甲烷(5mL)溶液中，升温至50℃反应16h。反应完毕后，减压浓缩，加入水(10mL)，二氯甲烷(20mL x 2)萃取，合并有机相，用饱和食盐水(20mL)洗涤后，经无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝70:30)得2d(64mg,100％)。
LCMS m/z＝464.2[M+1]+
第四步：化合物2的制备
室温下，将2d(64mg，0.14mmol)溶于四氢呋喃(12mL)和乙醇(4mL)的混合溶液中，再加入氢氧化钠水溶液(2.0N,3mL,6.00mmol)，升温至50℃反应16h。反应完毕后，减压浓缩除去反应液，冰水浴下，缓慢滴加2N稀盐酸溶液将体系pH值调至3-4左右。滤液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C18，内径x长度＝19mm x250mm)。制备方法：粗品用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的三氟乙酸)。梯度洗脱方法：乙腈由30％梯度洗脱至80％(流速：12mL/min；洗脱时间15min)，冻干后得到化合物2(10mg,17％)。
LCMS m/z＝436.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ7.65-7.56(m,1H),7.55-7.47(m,2H),7.41-7.35(m,2H),7.35-7.27(m,1H),2.82-2.72(m,1H),2.19-1.86(m,6H),1.79-1.63(m,2H).
实施例3：化合物3的制备
第一步：3b的制备
将三溴苄基三甲基铵(226mg,0.58mmol)加入到3a(70mg,0.58mmol,参照专利WO2020227549A1合成)的乙腈(10mL)溶液中，室温反应1h。反应结束后，加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝94:6)得3b(60mg,52％)。
LCMS m/z＝200.3[M+1]+
第二步：3c的制备
将2a(80mg,0.24mmol,参照专利WO2019133770A2合成)和3b(43mg,0.22mmol)溶于N,N-二甲基甲酰胺(2mL)溶液中，加入碳酸钾(66mg,0.48mmol)，升温至90℃反应16h。冷却至室温，将反应液加入到水(30mL)中，乙酸乙酯(15mL x 3)萃取，合并有机相。有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得3c(91mg,92％)。
LCMS m/z＝458.5[M+1]+
第三步：3d的制备
依次将3c(116mg,0.25mmol)、2-(4-(3,3-二氟环丁基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环己烷(74mg,0.25mmol,参照专利WO2020010309A1合成)、碳酸钾(104mg,0.75mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(20mg,0.03mmol)加入到1,4-二氧六环(5mL)和水(0.5mL)中，氮气氛围下90℃反应16h。反应完毕后，冷却至室温，硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝80:20)得3d(98mg,71％)
LCMS m/z＝546.3[M+1]+
第四步：3e的制备
将苯甲醚(20mg,0.18mmol)、三氟乙酸(3mL)加入到3d(98mg,0.18mmol)的二氯甲烷(5mL)溶液中，50℃反应16h。反应完毕后，减压浓缩得3e(77mg,粗品)。
LCMS m/z＝426.1[M+1]+
第五步：3的制备
将3e(77mg,粗品)溶于四氢呋喃(5mL)和甲醇(3mL)的中，加入氢氧化钠水溶液(1.0N,5mL,5.00mmol)，50℃反应16h。减压浓缩除去溶剂，冰水浴下，滴加1N稀盐酸溶液将体系pH值调至3～4。过滤得粗品，粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C18，内径x长度＝19mm x250mm)。制备方法：粗品用二甲基亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的三氟乙酸)。梯度洗脱方法：乙腈由30％梯度洗脱至80％(流速：12mL/min；洗脱时间15min)，冻干得化合物3(15mg,两步收率：21％)。
LCMS m/z＝398.1[M+1]+
1H NMR(400MHz,CD3OD)δ7.59(d,2H),7.49(d,1H),7.33(d,2H),7.01(d,1H),3.46-3.36(m,1H),3.36-3.32(m,2H),3.08-2.92(m,2H),2.90-2.83(m,2H),2.77-2.59(m,2H).
实施例4：化合物4的制备
第一步：4a的制备
将2a(200mg,0.59mmol，参照专利WO2019133770A2合成)和4-溴-2,6-二氟苯酚(148mg,0.71mmol)溶于N,N-二甲基甲酰胺(5mL)溶液中，加入碳酸钾(122mg,0.89mmol)，升温至90℃反应16h。反应完毕后，冷却至室温，将反应液加入到水(30mL)中，乙酸乙酯(15mL x 3)萃取，合并有机相。有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得4a(194mg,70％)。
LCMS m/z＝468.4[M+1]+
第二步：4b的制备
依次将4a(100mg,0.21mmol)、2-(4-(3,3-二氟环丁基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环己烷(62mg,0.21mmol,参照专利WO2020010309A1合成)、碳酸钾(87mg,0.63mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(17mg,0.02mmol)加入到1,4-二氧六环(5mL)和水(0.5mL)中，氮气氛围下90℃反应16h。反应完毕后，冷却至室温，硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得4b(109mg,92％)
LCMS m/z＝556.2[M+1]+
第三步：4c的制备
将苯甲醚(22mg,0.20mmol)、三氟乙酸(3mL)加入到4b(109mg,0.20mmol)的二氯甲烷(5mL)溶液中，50℃反应16h。反应完毕后，减压浓缩得4c(87mg,粗品)。
LCMS m/z＝436.1[M+1]+
第四步：化合物4的制备
将4c(87mg,粗品)溶于四氢呋喃(5mL)和甲醇(3mL)溶液中，加入氢氧化钠水溶液(1.0N,5mL,5.00mmol)，50℃反应16h。反应完毕后，减压浓缩除去溶剂，冰水浴下，缓慢滴加1N稀盐酸溶液将体系pH值调至3～4左右。过滤得粗品，粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C18，内径x长度＝19mm x250mm)。制备方法：粗品用二甲基亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的三氟乙酸)。梯度洗脱方法：乙腈由30％梯度洗脱至80％(流速：12mL/min；洗脱时间15min)，冻干得化合物4(15mg,两步收率：19％)。
LCMS m/z＝408.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ7.75(d,2H),7.65(d,2H),7.43(d,2H),3.54-3.43(m,1H),3.10-2.96(m,2H),2.82-2.64(m,2H).
实施例5：化合物5的制备
第一步：5a的制备
将2a(300mg,0.88mmol)和4-溴-3,5-二氟苯酚(224mg,1.07mmol)溶于N,N-二甲基甲酰胺(6mL)溶液中，加入碳酸钾(184mg,1.33mmol)，90℃反应16h。将反应液加入到水(30mL)中，乙酸乙酯(15mL x 3)萃取，合并有机相。有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得5a(100mg,24％)。
1H NMR(400MHz,CDCl3)δ7.18-7.13(m,2H),6.81-6.73(m,2H),6.35-6.28(m,2H),5.38(s,2H),4.26(q,2H),3.75(s,3H),1.21(t,3H).
第二步：5b的制备
依次将5a(100mg,0.21mmol)、2-(4-(3,3-二氟环丁基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环己烷(62mg,0.21mmol,参照专利WO2020010309A1合成)、碳酸钾(87mg,0.63mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(17mg,0.02mmol)加入到1,4-二氧六环(5mL)和水(0.5mL)中，氮气氛围下90℃反应16h。硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得5b(60mg,51％)
第三步：5c的制备
将苯甲醚(36mg,0.33mmol)、三氟乙酸(3mL)加入到5b(60mg,0.11mmol)的二氯甲烷(5mL)溶液中，50℃反应16h。反应完毕后，减压浓缩得5c(50mg,粗品)。
LCMS m/z＝436.1[M+1]+
第四步：化合物5的制备
将5c(50mg,粗品)溶于四氢呋喃(4mL)和甲醇(2mL)溶液中，加入氢氧化钠水溶液(1.0N,2mL,5.00mmol)，50℃反应16h。反应完毕后，减压浓缩除去溶剂，冰水浴下，缓慢滴加1N稀盐酸溶液将体系pH值调至3～4左右。过滤得粗品，粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C18，内径x长度＝19mm x250mm)。制备方法：粗品用二甲基亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的三氟乙酸)。梯度洗脱方法：乙腈由30％梯度洗脱至80％(流速：12mL/min；洗脱时间15min)，冻干得化合物5(10mg,两步收率：23％)。
LCMS m/z＝408.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ7.48-7.36(m,4H),7.07-6.95(m,2H),3.54-3.42(m 1H),3.10-2.96(m,2H),2.83-2.65(m,2H).
实施例6：化合物6的制备
第一步：6a的制备
将2a(300mg,0.88mmol)和4-溴-2,3,5,6-四氟苯酚(263mg,1.07mmol)溶于N,N-二甲基甲酰胺(6mL)溶液中，加入碳酸钾(184mg,1.33mmol)，90℃反应16h。将反应液加入到水(30mL)中，乙酸乙酯(15mL x 3)萃取，合并有机相。有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得6a(300mg,67％)。
1H NMR(400MHz,DMSO-d6)δ7.30(d,2H),6.92(d,2H),5.63(s,2H),4.12(t,2H),3.73(s,3H),1.08(t,3H).
第二步：6b的制备
依次将6a(100mg,0.20mmol)、2-(4-(3,3-二氟环丁基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环己烷(59mg,0.20mmol,参照专利WO2020010309A1合成)、碳酸钾(83mg,0.60mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(16mg,0.02mmol)加入到1,4-二氧六环(5mL)和水(0.5mL)中，氮气氛围下90℃反应16h。硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得6b(70mg,60％)
LCMS m/z＝592.2[M+1]+
第三步：6c的制备
将苯甲醚(39mg,0.36mmol)、三氟乙酸(3mL)加入到6b(70mg,0.12mmol)的二氯甲烷(5mL)溶液中，50℃反应16h。反应完毕后，减压浓缩得6c(60mg,粗品)。
LCMS m/z＝472.7[M+1]+
第四步：化合物6的制备
将6c(60mg,粗品)溶于四氢呋喃(4mL)和甲醇(2mL)溶液中，加入氢氧化钠水溶液(1.0N,2mL,5.00mmol)，50℃反应16h。反应完毕后，减压浓缩除去溶剂，冰水浴下，缓慢滴加1N稀盐酸溶液将体系pH值调至3～4左右。过滤得粗品，粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C18，内径x长度＝19mm x250mm)。制备方法：粗品用二甲基亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的三氟乙酸)。梯度洗脱方法：乙腈由30％梯度洗脱至80％(流速：12mL/min；洗脱时间15min)，冻干得化合物6(10mg,两步收率：19％)。
LCMS m/z＝444.4[M+1]+
1H NMR(400MHz,DMSO-d6)δ7.59-7.46(m,4H),3.57-3.45(m,1H),3.10-2.97(m,2H),2.85-2.69(m,2H).
实施例7：化合物7的制备
第一步：7a的制备
将2,3-二氢-1H-4-茚醇(550mg,4.11mmol)溶于乙腈(11mL)中，加入苄基三甲基三溴化铵(1.60g,4.11mmol)，室温反应1h。减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝94:6)得7a(836mg,96％)。
LCMS m/z＝211.0[M-1]-
第二步：7b的制备
将2a(150mg,0.44mmol)和7a(94mg,0.44mmol)溶于N,N-二甲基甲酰胺(2mL)溶液中，加入碳酸钾(120mg,0.88mmol)，90℃反应16h。冷却至室温，将反应液加入到水(10mL)中，乙酸乙酯(15mL x 3)萃取，合并有机相。有机相用饱和食盐水(15mL x 2)洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得7b(120mg,58％)。
LCMS m/z＝472.1[M+1]+
第三步：7c的制备
依次将7b(120mg,0.25mmol)、2-(4-(3,3-二氟环丁基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼杂环己烷(81mg,0.28mmol,参照专利WO2020010309A1合成)、碳酸钾(103mg,0.75mmol)、1,1'-二(二苯膦基)二茂铁二氯化钯-二氯甲烷络合物(20mg,0.025mmol)加入到1,4-二氧六环(3mL)和水(0.3mL)中，氮气氛围下90℃反应16h。冷却至室温，硅藻土过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝80:20)得7c(140mg,98％)。
LCMS m/z＝560.5[M+1]+
第四步：化合物7d的制备
将苯甲醚(27mg,0.25mmol)、三氟乙酸(3mL)加入到7c(140mg,0.25mmol)的二氯甲烷(5mL)溶液中，50℃反应16h。反应完毕后，减压浓缩得7d(110mg,粗品)。
LCMS m/z＝440.1[M+1]+
第五步：化合物7的制备
将7d(110mg,粗品)溶于四氢呋喃(5mL)和甲醇(3mL)溶液中，加入氢氧化钠水溶液(1.0N,5mL,5.00mmol)，50℃反应16h。反应完毕后，减压浓缩除去溶剂，冰水浴下，缓慢滴加1N稀盐 酸溶液将体系pH值调至3～4左右。过滤得粗品，粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C18，内径x长度＝19mm x250mm)。制备方法：粗品用二甲基亚砜溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的三氟乙酸)。梯度洗脱方法：乙腈由30％梯度洗脱至80％(流速：12mL/min；洗脱时间15min)，冻干得化合物7(40mg,两步收率：39％)。
LCMS m/z＝412.2[M+1]+
1H NMR(400MHz,DMSO-d6)δ15.13(s,1H),13.17(s,1H),7.48-7.34(m,4H),7.16(d,1H),6.87(d,1H),3.51-3.41(m,1H),3.09-2.93(m,4H),2.87-2.64(m,4H),2.08-1.94(m,2H).
实施例8：化合物8的制备
化合物8以8a为起始物料，参考实施例7的合成方法得到。
LCMS m/z＝426.4[M+1]+
1H NMR(400MHz,DMSO-d6)δ15.22(s,1H),13.41(s,1H),7.64-7.53(m,3H),7.48(d,2H),3.57-3.43(m,1H),3.12-2.96(m,2H),2.83-2.65(m,2H).
生物测试例：
1.hHAO1酶活测试
实验步骤
体外hHAO1活性测定采用以乙醇酸作为底物，通过Amplex Red法进行检测。将一定浓度的hHAO1蛋白按照2.5μL/孔加至384孔板中，随后加入2.5μL/孔化合物。室温反应15分钟后，加入5μL的底物混合溶液(乙醇酸，Amplex Red dye,HRP,50mM HEPES,pH 8.0)。随后立即将384孔板放入BMG酶标仪中，读取荧光信号(Em540nm/EX590nm)。统计平均数和标准误差(Mean±SEM)，并使用Graphpad Prism软件进行分析，计算IC50值。
表1.化合物对hHAO1酶的抑制活性

结论：本发明的化合物，例如实施例化合物，对hHAO1有良好的抑制活性，特别是化合物4、6、7、8的IC50小于50nM，相比于对照化合物1具有更优的hHAO1抑制活性。
对照化合物1结构如下：
2.小鼠药代动力学测试
2.1试验动物：雄性Balb/c小鼠，22g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。
2.2试验设计：试验当天，Balb/c小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表2.给药信息
注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MC
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；MC：甲基纤维素)
于给药前及给药后异氟烷麻醉经眼眶取血0.03ml，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点：0,5,15,30min,1,2,4,7h，24h；分析检测前，所有样品存于-80℃。
表3.测试化合物在小鼠血浆中的药代动力学参数
-：不适用。
结论：本发明的化合物，例如实施例化合物，在小鼠上具有较高的暴露量，良好的生物利用度，特别是化合物6和8，相比于对照化合物1，具有更优的生物利用度。
3.大鼠药代动力学测试
3.1试验动物：雄性SD大鼠，220g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。
3.2试验设计：试验当天，SD大鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。
表4.给药信息
注：静脉给药溶媒:5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MC
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；MC：甲基纤维素)
于给药前及给药后异氟烷麻醉经眼眶取血0.15ml，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为：0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表5.测试化合物在大鼠血浆中的药代动力学参数
-：不适用。
结论：本发明的化合物，例如实施例化合物，在大鼠上具有较高的暴露量，良好的生物利用度，特别是化合物6，相比于对照化合物1，具有更优的生物利用度。
4.比格犬药代动力学测试
4.1试验动物：雄性比格犬，8～11kg左右，6只/化合物，购于北京玛斯生物技术有限公司。
4.2试验方法：试验当天，比格犬按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。按照表6给药。
表6.给药信息
注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MC
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；MC：甲基纤维素溶液；)
*剂量以游离碱计。
于给药前及给药后通过颈静脉或四肢静脉取血1ml，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5,15,30min,1,2,4,6,8,10,12,24,48h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表7.测试化合物在比格犬血浆中的药代动力学参数
-：不适用。
结论：本发明的化合物，例如实施例化合物，特别是化合物4、6，在犬上具有较高的暴露量，良好的生物利用度。
5.猴药代动力学测试
5.1试验动物：雄性食蟹猴，3～5kg，3～6年龄，6只/化合物。购于苏州西山生物技术有限公司。
5.2试验方法：试验当天，食蟹猴按体重随机分组。给药前1天禁食不禁水14～18h，给药后4h给食。
表8.给药信息
注：静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MC(含0.5％Tween80)；
(DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯；Saline：生理盐水；MC：甲基纤维素溶液；)
*剂量以游离碱计。
于给药前及给药后通过四肢静脉取血1.0mL，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点均为:0,5min,15min,30min,1,2,4,6,8,10,12, 24，48h。分析检测前，所有样品存于-80℃，用LC-MS/MS对样品进行定量分析。
表9.测试化合物在猴血浆中药代动力学参数
结论：本发明的化合物，例如实施例化合物，特别是化合物4、6，在猴上具有较高的暴露量，良好的生物利用度。

Claims (9)

  1. 一种化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(I)所示的化合物，其中，
    R1选自-COOH或四氮唑基；
    L选自-X-C0-4亚烷基-或-C0-4亚烷基-X-，所述亚烷基任选被1至4个Rk取代；
    X选自键、-O-、-S-、-NH-；
    环A选自C3-8元环烷基、苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基，所述环烷基、苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
    环B选自苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基，所述的苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
    环C选自3至12元碳环基或4至12元杂环基，所述碳环基或杂环基任选被1至4个Rk取代；
    Rk各自独立的选自氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-6烷基、OC1-6烷基、SC1-6烷基、C2-6烯基、C2-6炔基、NHC1-6烷基、N(C1-6烷基)2、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C0-4亚烷基-C3-6碳环、-C0-4亚烷基-3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-6烷基、C1-6烷氧基的取代基所取代；
    条件是，当L选自-O-或-S-时，1)R1选自四氮唑基；
    或2)R1选自-COOH，环A选自苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基、 所述苯并4元碳环基、苯并5元碳环基、苯并6元碳环基、苯并5元杂环基、苯并6元杂环基任选被1至4个Rk取代；
    或3)R1选自-COOH，环A选自未取代的苯基、环己基或环丁基时，环B选自苯并4元碳环基、苯并5元碳环基、苯并5元杂环基，所述的苯并4元碳环基、苯并5元碳环基、苯并5元杂环基任选被1至4个Rk取代；
    或4)R1选自-COOH，环A选自未取代的环己基、环B选自未取代的苯基时，环C选自5至12元螺碳环基、4-12元并碳环基，所述的螺碳环基、并碳环基任选被1至4个Rk取代；
    或5)R1选自-COOH，环A选自未取代的苯基、环B选自未取代的苯基时，环C选自三氮唑基、5至12元螺碳环基、4-12元并碳环基，所述的三氮唑基、螺碳环基、并碳环基任选被1至4个Rk取代；
    当L选自键，环A、环B选自取代或未取代的苯基，R1选自-COOH，环C选自3至12元碳环基且环C不选自苯环基，所述的3至12元碳环基任选被1至4个Rk取代。
  2. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，
    L选自-X-、-X-CH2-或-CH2-X-；
    环A选自C3-6元环烷基、苯环基、苯并4元碳环基，所述环烷基、苯环基、苯并4元碳环基任选被1至4个Rk取代；
    环B选自苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并5元杂环基，所述的苯基、5至6元杂芳基、苯并4元碳环基、苯并5元碳环基、苯并5元杂环基任选被1至4个Rk取代；
    环C选自3至6元碳环基、5至12元螺碳环基、4至12元并碳环基、4至6元杂环基、5至12元螺杂环基、4至12元并杂环基，所述碳环基、螺碳环基、并碳环基、杂环基、螺杂环基、并杂环基任选被1至4个Rk取代；
    Rk各自独立的选自氘、卤素、OH、＝O、CN、NH2、COOH、CONH2、C1-4烷基、OC1-4烷基、SC1-4烷基、C2-4烯基、C2-4炔基、NHC1-4烷基、N(C1-4烷基)2、-O-C3-6碳环、-O-3至7元杂环、-NH-C3-6碳环、-NH-3至7元杂环、-C0-4亚烷基-C3-6碳环、-C0-4亚烷基-3至7元杂环，所述的烷基、亚烷基、烯基、炔基、碳环或杂环任选被1至4个选自氘、卤素、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。
  3. 根据权利要求2所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中
    L选自键、-O-、-S-、-NH-、-CH2-、-CH2O-、-OCH2-、-CH2S-、-SCH2-、-CH2NH-、-NHCH2-；
    环A选自取代或未取代的环丙基、环丁基、环戊基、环己基、苯环基、吡啶基、 当被取代时，任选被1至4个Rk取代；
    环B选自取代或未取代的苯基、吡啶基、 当被取代时，任选被1至4个Rk取代；
    环C选自取代或未取代的环丙基、环丁基、环戊基、环己基、氧杂环丁基、四氢呋喃基、四氢吡喃基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、吗啉基、三氮唑基、四氮唑基、吡唑基、吡咯基、吡啶基、吡嗪基、哒嗪基、三嗪基、 当被取代时，任选被1至4个Rk取代；
    Rk各自独立的选自氘、F、Cl、Br、I、OH、＝O、CN、NH2、COOH、CONH2、NHCH3、N(CH3)2、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基，所述的甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基任选被1至4个选自氘、F、Cl、Br、I、＝O、CN、OH、NH2、C1-4烷基、C1-4烷氧基的取代基所取代。
  4. 根据权利要求3所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中
    L选自键、-O-、-CH2-、-CH2O-、-OCH2-、-CH2NH-、-NHCH2-；
    环A选自
    Rk各自独立的选自氘、F、Cl、Br、I、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、甲硫基、乙烯基、乙炔基、丙炔基、环丙基、环丁基、氮杂环丁基、氧杂环丁基、吡咯烷基、哌啶基、吡唑基、吡咯基、吗啉基；
    环B选自
    环C选自
  5. 根据权利要求4所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，化合物选自通式(II-1)、(II-2)、(II-3)所示，
    X选自键、-O-、-NH-；
    环A1选自
    或者当环A1选自时，环B选自
    或者当环A1选自环B选自时，环C选自
    或者当环A1选自环B选自时，环C选自
    Rk各自独立的选自氘、F、Cl、Br、I、CF3、甲基、乙基、甲氧基、乙氧基、环丙基；
    环C1选自选自
    a、b各自独立地选自0、1、2、3或4。
  6. 根据权利要求1所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中化合物选自表E-1结构之一。
  7. 一种药物组合物，包括权利要求1-6任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，优选地，药物组合物中含有1-1500mg的权利要求1-6任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶。
  8. 根据权利要求1-6任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶或权利要求7所述的药物组合物在用于制备治疗肾结石、复发性肾结石，I型原发性高草酸尿症药物中的应用。
  9. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-6任意一项所述的化合物或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，治疗有效量优选1-1500mg，所述的疾病优选肾结石、复发性肾结石，I型原发性高草酸尿症。
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