Triazole derivative and application thereof in medicine

Abstract

The invention relates to a triazole derivative and an application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate and a preparation method thereof, and an application of the triazole derivative in preparation of medicines for treating kidney stone, recurrent kidney stone, renal calculus and the like. The invention also relates to application of the pharmaceutical composition in drugs for treating type I primary hyperoxaluria (PH). # imgabs0 #

Description

A triazole derivative and its application in medicine Technical Field

[0001] The present invention relates to a compound described by general formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compound in preparing drugs for treating kidney stones, recurrent kidney stones, and type I primary hyperoxaluria (PH). Background Art

[0002] Kidney stones (renal calculi) are caused by the abnormal accumulation of crystalline substances (such as calcium, oxalate, uric acid, and cystine) in the kidneys. They are a common and frequently occurring disease of the urinary system. Their formation occurs when certain factors increase the concentration of crystalline substances in the urine or decrease their solubility, resulting in a supersaturated state. Crystals precipitate, grow, and accumulate locally, ultimately forming stones. Stones are primarily categorized by their composition into calcium oxalate stones, calcium phosphate stones, urate stones, magnesium ammonium phosphate stones, and cystine stones. Calcium oxalate stones are the most common, accounting for approximately 71% to 84% of cases.

[0003] Currently, the global incidence and prevalence of urolithiasis remain high and are on the rise, affecting approximately 12% of the world's population. Common treatments for urinary stones include surgery, but the recurrence rate is high, approximately 30-50% within 10 years after surgery (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.); dietary changes, such as drinking plenty of water, avoiding a high-oxalate diet, limiting calcium intake, reducing salt and purine intake, and supplementing with citric acid; and medications, primarily through antispasmodics and analgesia, infection control (for urinary tract obstruction), vitamin B6 (for hyperoxaluria), and thiazide diuretics (for hypercalciuria). However, these treatments do not address the root cause of the disease, and there are no commercially available drugs that specifically inhibit oxalate formation for the prevention and treatment of oxalate deposition-related conditions.

[0004] HAOX1 (Hydroxyacid Oxidase 1, also known as glycolate oxidase, GO) is a key enzyme involved in the oxalate metabolic pathway and is encoded by the HAO1 gene. 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, and type I primary hyperoxaluria (PH).

[0005] Summary of the Invention

[0006] The present invention provides a class of triazole compounds, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals thereof, for use as glycolate oxidase inhibitors. The compounds of the present invention effectively inhibit glycolate oxidase and are useful for preventing and treating conditions associated with oxalate deposition, such as kidney stones, recurrent kidney stones, and type I primary hyperoxaluria (PH).

[0007] The compound of the present invention has good pharmacokinetic properties and bioavailability, oral performance and good safety.

[0008] 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:

[0009] In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (II-1),

[0010] In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (II-2),

[0011] In some embodiments, the compound represented by general formula (I) is selected from the compound represented by general formula (II-3),

[0012] In some embodiments, R1 is selected from -COOH or tetrazolyl;

[0013] In some embodiments, R1 is selected from -COOH;

[0014] In some embodiments, R1 is selected from tetrazolyl;

[0015] In some embodiments, L is selected from -XC 0-4 Alkylene- or -C 0-4 Alkylene-X-, the alkylene group is optionally substituted by 1 to 4 R k replace;

[0016] In some embodiments, L is selected from -X-, -X-CH2-, or -CH2-X-;

[0017] In some embodiments, L is selected from a bond, -O-, -S-, -NH-, -CH2-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2NH-, -NHCH2-;

[0018] In some embodiments, L is selected from a bond, -O-, -CH2-, -CH2O-, -OCH2-, -CH2NH-, -NHCH2-;

[0019] In some embodiments, L is selected from a bond;

[0020] In some embodiments, L is selected from -O-;

[0021] In some embodiments, L is selected from -CH2-, -CH2O-, -CH2NH-;

[0022] In some embodiments, X is selected from a bond, -O-, -S-, -NH-;

[0023] In some embodiments, X is selected from a bond, -O-, -NH-;

[0024] In some embodiments, X is selected from a bond;

[0025] In some embodiments, Ring A, B, or C is each independently selected from a 3-20 membered carbocyclyl or a 3-20 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k replace;

[0026] In some embodiments, Ring A is optionally substituted with 1 to 4 R ka replace;

[0027] In some embodiments, Ring B is optionally substituted with 1 to 4 R kb replace;

[0028] In some embodiments, Ring C is optionally substituted with 1 to 4 R kc replace;

[0029] In some embodiments, R ka 、R kb 、R kc Each independently selected from Rk ;

[0030] In some embodiments, Ring A is selected from C 3-8 benzo; 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; the 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; optionally substituted by 1 to 4 R k replace;

[0031] In some embodiments, Ring A is selected from C 3-6 cycloalkyl, benzyl ring group, benzo 4-membered carbocyclic group, the cycloalkyl, benzyl ring group, benzo 4-membered carbocyclic group is optionally substituted by 1 to 4 R k replace;

[0032] In some embodiments, ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, When substituted, optionally substituted with 1 to 4 R k replace;

[0033] In some embodiments, Ring A is selected from

[0034] In some embodiments, Ring A is selected from

[0035] In some embodiments, Ring A is selected from

[0036] In some embodiments, Ring A is selected from Ring A1;

[0037] In some embodiments, Ring A1 is selected from

[0038] In some embodiments, when Ring A1 is selected from When ring B is selected from

[0039] In some embodiments, when Ring A1 is selected from Ring B is selected from When ring C is selected from

[0040] In some embodiments, when Ring A1 is selected from Ring B is selected from When ring C is selected from

[0041] In some embodiments, 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 replace;

[0042] In some embodiments, 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 by 1 to 4 R k replace;

[0043] In some embodiments, Ring B is selected from substituted or unsubstituted phenyl, pyridyl, When substituted, optionally substituted with 1 to 4 R k replace;

[0044] In some embodiments, Ring B is selected from

[0045] In some embodiments, Ring B is selected from

[0046] In some embodiments, Ring C is selected from a 3- to 12-membered carbocyclyl or a 4- to 12-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k replace;

[0047] In some embodiments, 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 by 1 to 4 R k replace;

[0048] In some embodiments, 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, optionally substituted with 1 to 4 R k replace;

[0049] In some embodiments, Ring C is selected from

[0050] In some embodiments, Ring C is selected from Ring C1;

[0051] In some embodiments, Ring C1 is selected from

[0052] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0053] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0054] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0055] In some embodiments, R k Each is independently selected from deuterium, F, Cl, Br, I, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0056] In some embodiments, R k Each independently selected from deuterium, F, Cl, Br, I, CF3, methyl, ethyl, methoxy, ethoxy, cyclopropyl;

[0057] In some embodiments, a and b are each independently selected from 0, 1, 2, 3, or 4.

[0058] Optionally, when L is selected from -O- or -S-, 1) R1 is selected from tetrazolyl;

[0059] or 2) R1 is selected from -COOH, and ring A is selected from benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl, The 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 are optionally substituted by 1 to 4 R k replace;

[0060] or 3) when R1 is selected from -COOH, 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 replace;

[0061] or 4) when R1 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, 4-12 membered paracarbocyclic group, and the spirocarbocyclic group and paracarbocyclic group are optionally substituted by 1 to 4 R k replace;

[0062] or 5) when R1 is selected from -COOH, ring A is selected from unsubstituted phenyl, ring B is selected from unsubstituted phenyl, and ring C is selected from triazolyl, 5- to 12-membered spirocarbocyclyl, 4- to 12-membered paracarbocyclyl, and the triazolyl, spirocarbocyclyl, and paracarbocyclyl are optionally substituted by 1 to 4 R k replace;

[0063] When L is selected from a bond, Ring A and Ring B are selected from substituted or unsubstituted phenyl, R1 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 replace.

[0064] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0065] R1 is selected from -COOH or tetrazolyl;

[0066] L selected from -XC 0-4 Alkylene- or -C 0-4 Alkylene-X-, the alkylene group is optionally substituted by 1 to 4 R k replace;

[0067] X is selected from a bond, -O-, -S-, -NH-;

[0068] Ring A is selected from C 3-8 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, the cycloalkyl, ... are optionally substituted by 1 to 4 R k replace;

[0069] 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 replace;

[0070] Ring C is selected from 3 to 12 membered carbocyclic groups or 4 to 12 membered heterocyclic groups, wherein the carbocyclic groups or heterocyclic groups are optionally substituted by 1 to 4 R k replace;

[0071] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0072] Provided that, when L is selected from -O- or -S-, 1) R1 is selected from tetrazolyl;

[0073] or 2) R1 is selected from -COOH, and ring A is selected from benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl, The 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 are optionally substituted by 1 to 4 R k replace;

[0074] or 3) when R1 is selected from -COOH, 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 replace;

[0075] or 4) when R1 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, 4-12 membered paracarbocyclic group, and the spirocarbocyclic group and paracarbocyclic group are optionally substituted by 1 to 4 R k replace;

[0076] or 5) when R1 is selected from -COOH, ring A is selected from unsubstituted phenyl, ring B is selected from unsubstituted phenyl, and ring C is selected from triazolyl, 5- to 12-membered spirocarbocyclyl, 4- to 12-membered paracarbocyclyl, and the triazolyl, spirocarbocyclyl, and paracarbocyclyl are optionally substituted by 1 to 4 R k replace;

[0077] When L is selected from a bond, Ring A and Ring B are selected from substituted or unsubstituted phenyl, R1 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 replace.

[0078] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0079] L is selected from -X-, -X-CH2- or -CH2-X-;

[0080] Ring A is selected from C 3-6 cycloalkyl, benzyl ring group, benzo 4-membered carbocyclic group, the cycloalkyl, benzyl ring group, benzo 4-membered carbocyclic group is optionally substituted by 1 to 4 R k replace;

[0081] 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 by 1 to 4 R k replace;

[0082] 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 by 1 to 4 R k replace;

[0083] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0084] The remaining definitions are the same as those of the first embodiment of the present invention.

[0085] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0086] L is selected from a bond, -O-, -S-, -NH-, -CH2-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2NH-, -NHCH2-;

[0087] Ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, When substituted, optionally substituted with 1 to 4 R k replace;

[0088] Ring B is selected from substituted or unsubstituted phenyl, pyridyl, When substituted, optionally substituted with 1 to 4 R k replace;

[0089] 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, optionally substituted with 1 to 4 R k replace;

[0090] R keach independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0091] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0092] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals,

[0093] L is selected from a bond, -O-, -CH2-, -CH2O-, -OCH2-, -CH2NH-, -NHCH2-;

[0094] Ring A is selected from

[0095] R k Each is independently selected from deuterium, F, Cl, Br, I, CF3, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl;

[0096] Ring B is selected from

[0097] Ring C is selected from

[0098] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0099] As a fifth embodiment of the present invention, the compound represented by the following general formula (II-1) or (II-2) or (II-3) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0100] X is selected from a bond, -O-, -NH-;

[0101] Ring A1 is selected from

[0102] or when ring A1 is selected from When ring B is selected from

[0103] or when ring A1 is selected from Ring B is selected from When ring C is selected from

[0104] or when ring A1 is selected from Ring B is selected from When ring C is selected from

[0105] R k Each independently selected from deuterium, F, Cl, Br, I, CF3, methyl, ethyl, methoxy, ethoxy, cyclopropyl;

[0106] Ring C1 is selected from

[0107] a and b are each independently selected from 0, 1, 2, 3 or 4;

[0108] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0109] As a sixth embodiment of the present invention, the compound represented by the following general formula (III-1) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0110] Ring A1 is selected from

[0111] R k Each independently selected from deuterium, F, Cl, Br, I, CF3, methyl, ethyl, methoxy, ethoxy, cyclopropyl;

[0112] b is selected from 0, 1, 2, 3 or 4.

[0113] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1 below:

[0114] Table E-1

[0115] The present invention relates to a pharmaceutical composition comprising the above compound or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0116] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions in preparing drugs for inhibiting glycolate oxidase (HAOX1).

[0117] The present invention relates to the use of the above-mentioned compound or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals or the above-mentioned pharmaceutical compositions for preparing drugs for treating kidney stones, recurrent kidney stones and type I primary hyperoxaluria.

[0118] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").

[0119] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0120] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., kidney stones, recurrent kidney stones, type I primary hyperoxaluria). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of 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, 25 0-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 7 5-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200 mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;.

[0121] In some embodiments, 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.

[0122] 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 form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably renal disease.

[0123] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, wherein 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, 100-400 mg / day, 200-400 mg / day, and 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, and 800 mg / day.

[0124] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein 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 the amount in the above-mentioned pharmaceutical composition.

[0125] 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.

[0126] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0127] Unless otherwise stated, the terms used in this specification and claims have the following meanings.

[0128] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon 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 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0129] "Halogen" refers to F, Cl, Br or I.

[0130] "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, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0131] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched 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; alkyl groups appearing herein have the same definition as this one. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0132] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0133] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Cycloalkyl groups as used herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0134] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group 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. The N and S optionally substituted in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom, can be attached to an aromatic ring or a non-aromatic ring, can be connected to a bridged ring or a spirocycle, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0135] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups 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. Examples of 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, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene; alkenyl groups appearing herein have the same definition as this one. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

[0136] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0137] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0138] "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 optionally 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, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0139] "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 one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0140] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 1 to 5 atoms selected from N, O or S (=O) n of heteroatoms.

[0141] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0142] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0143] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0144] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0145] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists solely of carbon atoms. As used herein, "carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" have the same definition as for spirocycle.

[0146] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting solely of carbon atoms. As used herein, "carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" has the same definition as for cyclyl.

[0147] "Carbon bridged ring," "bridged ring carbocyclic group," "bridged carbocyclic group," or "carbon bridged cyclic group" refers to a "bridged ring" in which the ring system consists only of carbon atoms. As used herein, "carbon bridged ring," "bridged ring carbocyclic group," "bridged carbocyclic group," or "carbon bridged cyclic group" has the same definition as for a bridged ring.

[0148] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system. The heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclyl" appearing in this document has the same definition as heterocycle.

[0149] "Heterocyclic ring", "heterocyclic ring group", "heterocyclic ring heterocyclyl" or "heterocyclic ring group" refers to a "cyclic ring" containing a heteroatom. The heterocyclic ring, "heterocyclic ring group", "heterocyclic ring heterocyclyl" or "heterocyclic ring group" appearing in this article have the same definition as the cyclic ring.

[0150] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom. Heterospirocycle, "heterospirocyclyl", "spiroheterocyclyl" or "heterospirocyclyl" appearing herein have the same definition as spirocycle.

[0151] "Heterobridged ring", "heterobridged cyclic group", "bridged heterocyclic group" or "heterobridged cyclic group" refers to a "bridged ring" containing a heteroatom. The heterobridged ring, "heterobridged cyclic group", "bridged heterocyclic group" or "heterobridged cyclic group" appearing herein have the same definition as that of the bridged ring.

[0152] "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.

[0153] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring is but not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, 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 When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the heteroaryl ring.

[0154] "5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring, 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 pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.

[0155] "5-membered and 6-membered heteroaromatic ring" refers to a 5-membered and 6-membered fused heteroaromatic ring, 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.

[0156] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged ring, spiro ring, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , ORd or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group. a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0157] “Containing 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.

[0158] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents, where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted with 1 to 5 substituents selected from..." means substituted with 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted with 1 to 4 substituents selected from D or F" means that the heterobridged ring is optionally substituted with 1, 2, 3, or 4 substituents selected from D or F.

[0159] An XY-membered ring (3≤X<Y, Y is any integer between 4 and 12) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0160] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0161] "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, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0162] "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.

[0163] "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.

[0164] "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.

[0165] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0166] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0167] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0168] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers, diastereomers and conformational isomers.

[0169] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0170] “IC 50 "It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0171] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0172] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0173] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0174] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0175] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254 Silica gel plates, the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm;

[0176] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0177] Boc: tert-butoxycarbonyl;

[0178] Ts: p-toluenesulfonyl;

[0179] Cbz: benzyloxycarbonyl;

[0180] TMS: trimethylsilyl.

[0181] Example 1: Preparation of Compound 1

[0182] Step 1: Preparation of 1b

[0183] Under an ice-water bath, diethylaminosulfur trifluoride (387 mg, 2.40 mmol) was slowly added dropwise to a solution of 1a (200 mg, 0.80 mmol, synthesized according to patent WO2018054365A1) in dichloromethane (10 mL). After the addition was complete, the mixture was slowly allowed to return to room temperature and react for 16 hours. After the reaction, saturated aqueous sodium bicarbonate was slowly added dropwise under an ice-water bath until the system became weakly alkaline. Water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 97:3) to afford 1b (90 mg, 21%).

[0184] 1 H 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).

[0185] Step 2: Preparation of 1c

[0186] At room temperature, 1b (1.00 g, 3.66 mmol), pinacol diboronate (1.86 g, 7.32 mmol), and potassium acetate (1.08 g, 11.02 mmol) were added sequentially to 1,4-dioxane (20 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (300 mg, 0.37 mmol) was also added. After nitrogen displacement, the temperature was raised to 80°C and the reaction was allowed to react for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 95:5) to afford 1c (1.10 g, 94%).

[0187] 1 H 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).

[0188] Step 3: Preparation of 1d

[0189] 1c (150 mg, 0.47 mmol) was dissolved in a mixture of methanol (15 mL) and ethyl acetate (3 mL) at room temperature. Palladium on carbon (150 mg, 10% wt) was added, and the atmosphere was replaced with hydrogen. The mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to afford 1d (140 mg, 93%).

[0190] 1 H 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).

[0191] Step 4: Preparation of 1e

[0192] At room temperature, 1d (150 mg, 0.47 mmol), p-bromoiodobenzene (200 mg, 0.70 mmol), and potassium carbonate (230 mg, 1.65 mmol) were added sequentially to 1,4-dioxane (10 mL) and water (10 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (38 mg, 0.05 mmol) was then added. After nitrogen substitution, the temperature was raised to 90°C and the reaction was allowed to proceed for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (100% petroleum ether) to afford 1e (100 mg, 61%).

[0193] 1 H 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).

[0194] Step 5: Preparation of 1f

[0195] At room temperature, 1e (100 mg, 0.28 mmol), pinacol diboronate (107 mg, 0.42 mmol), and potassium acetate (97 mg, 0.99 mmol) were added sequentially to 1,4-dioxane (5 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (25 mg, 0.03 mmol) was then added. After nitrogen substitution, the temperature was raised to 80°C and the reaction was allowed to react for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 95:5) to afford 1f (50 mg, 45%).

[0196] 1 H 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).

[0197] Step 6: Preparation of 1g

[0198] At room temperature, 1f (70 mg, 0.18 mmol), methyl 5-iodo-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (81 mg, 0.22 mmol, synthesized according to patent WO2019133770A2), and potassium carbonate (75 mg, 0.54 mmol) were added sequentially to 1,4-dioxane (5 mL) and water (0.5 mL). 1,1'-Bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (15 mg, 0.02 mmol) was then added. After nitrogen purge, the temperature was raised to 80°C and the reaction was allowed to react for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 95:5) to yield 1g (39 mg, 42%).

[0199] LCMS m / z=518.2[M+1] +

[0200] Step 7: 1h preparation

[0201] At room temperature, anisole (31 mg, 0.29 mmol) and trifluoroacetic acid (3 mL) were added to a solution of 1 g (50 mg, 0.10 mmol) in dichloromethane (5 mL). The temperature was raised to 50°C and the reaction was allowed to proceed for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 1h (50 mg, crude product), which was directly used in the next step without purification.

[0202] LCMS m / z=398.4[M+1] +

[0203] Step 8: Preparation of Compound 1

[0204] At room temperature, 1h (50 mg, crude) was dissolved in a mixture of tetrahydrofuran (3 mL) and methanol (1 mL). Aqueous sodium hydroxide (1.0 M, 4 mL, 4.00 mmol) was added, and the mixture was heated to 50°C for 16 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure. Under an ice-water bath, 1N dilute hydrochloric acid was slowly added dropwise to adjust the pH to approximately 3-4. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, XBridge@Prep C18 column, inner diameter x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was 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 lyophilization.

[0205] LCMS m / z=384.2[M+1] +

[0206] 1 H 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).

[0207] Example 2: Preparation of Compound 2

[0208] Step 1: Preparation of 2b

[0209] 2a (100 mg, 0.29 mmol, synthesized according to patent WO2019133770A2) and 4-bromo-2,5-difluorophenol (73 mg, 0.35 mmol) were dissolved in N-methylpyrrolidone (3 mL) at room temperature. Potassium carbonate (60 mg, 0.43 mmol) was added and the mixture was heated to 90°C for 16 h. After completion of the reaction, the mixture was cooled to room temperature, saturated brine (10 mL) was added, and extraction was performed with ethyl acetate (15 mL x 2). The organic phases were combined, washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 85:15) to afford 2b (52 mg, 38%).

[0210] 1 H 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).

[0211] Step 2: Preparation of 2c

[0212] At room temperature, 2b (70 mg, 0.15 mmol), 1d (56 mg, 0.17 mmol), and potassium carbonate (75 mg, 0.54 mmol) were added sequentially to 1,4-dioxane (10 mL) and water (1 mL). Under nitrogen protection, 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (13 mg, 0.02 mmol) was added, and the temperature was raised to 90°C for 4 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20) to obtain 2c (56 mg, 64%).

[0213] LCMS m / z=584.7[M+1] +

[0214] Step 3: 2D preparation

[0215] Anisole (45 mg, 0.42 mmol) and trifluoroacetic acid (5 mL) were added to a solution of 2c (80 mg, 0.14 mmol) in dichloromethane (5 mL) at room temperature and heated to 50°C for 16 h. After completion, the reaction was concentrated under reduced pressure, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 70:30) to obtain 2d (64 mg, 100%).

[0216] LCMS m / z=464.2[M+1] +

[0217] Step 4: Preparation of compound 2

[0218] 2d (64 mg, 0.14 mmol) was dissolved in a mixture of tetrahydrofuran (12 mL) and ethanol (4 mL) at room temperature. Aqueous sodium hydroxide (2.0 N, 3 mL, 6.00 mmol) was then added and the mixture was heated to 50°C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the pH was adjusted to approximately 3-4 by slowly adding 2N dilute hydrochloric acid solution dropwise under an ice-water bath. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x length = 19 mm x 250 mm). Preparation method: The crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was 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 2 (10 mg, 17%) was obtained after lyophilization.

[0219] LCMS m / z=436.1[M+1] +

[0220] 1 H 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).

[0221] Example 3: Preparation of Compound 3

[0222] Step 1: Preparation of 3b

[0223] Benzyltrimethylammonium tribromide (226 mg, 0.58 mmol) was added to a solution of 3a (70 mg, 0.58 mmol, synthesized according to patent WO2020227549A1) in acetonitrile (10 mL) and allowed to react at room temperature for 1 h. After completion of the reaction, silica gel was added, the mixture was concentrated under reduced pressure, and then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 94:6) to afford 3b (60 mg, 52%).

[0224] LCMS m / z=200.3[M+1] +

[0225] Step 2: Preparation of 3c

[0226] 2a (80 mg, 0.24 mmol, synthesized according to patent WO2019133770A2) and 3b (43 mg, 0.22 mmol) were dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (66 mg, 0.48 mmol) was added and the mixture was heated to 90°C for 16 h. After cooling to room temperature, the reaction mixture was added to water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined. The organic phases were washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 3c (91 mg, 92%).

[0227] LCMS m / z=458.5[M+1] +

[0228] Step 3: 3D preparation

[0229] 3c (116 mg, 0.25 mmol), 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (74 mg, 0.25 mmol, synthesized according to patent WO2020010309A1), potassium carbonate (104 mg, 0.75 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (20 mg, 0.03 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL) in sequence. The mixture was reacted at 90°C under a nitrogen atmosphere for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 80:20) to obtain 3d (98 mg, 71%).

[0230] LCMS m / z=546.3[M+1] +

[0231] Step 4: Preparation of 3e

[0232] Anisole (20 mg, 0.18 mmol) and trifluoroacetic acid (3 mL) were added to a solution of 3d (98 mg, 0.18 mmol) in dichloromethane (5 mL) and reacted at 50°C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to afford 3e (77 mg, crude product).

[0233] LCMS m / z=426.1[M+1] +

[0234] Step 5: Preparation of 3

[0235] 3e (77 mg, crude) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL). Aqueous sodium hydroxide (1.0 N, 5 mL, 5.00 mmol) was added and the mixture was allowed to react at 50°C for 16 h. The solvent was removed by concentration under reduced pressure, and the pH of the system was adjusted to 3-4 by dropwise addition of 1 N dilute hydrochloric acid in an ice-water bath. The crude product was filtered and purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x L = 19 mm x 250 mm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was 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 lyophilization.

[0236] LCMS m / z=398.1[M+1] +

[0237] 1 H 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).

[0238] Example 4: Preparation of Compound 4

[0239] Step 1: Preparation of 4a

[0240] 2a (200 mg, 0.59 mmol, synthesized according to patent WO2019133770A2) and 4-bromo-2,6-difluorophenol (148 mg, 0.71 mmol) were dissolved in N,N-dimethylformamide (5 mL). Potassium carbonate (122 mg, 0.89 mmol) was added and the mixture was heated to 90°C for 16 h. After completion of the reaction, the mixture was cooled to room temperature and added to water (30 mL). The mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined. The organic phases were washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 4a (194 mg, 70%).

[0241] LCMS m / z=468.4[M+1] +

[0242] Step 2: Preparation of 4b

[0243] 4a (100 mg, 0.21 mmol), 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (62 mg, 0.21 mmol, synthesized according to patent WO2020010309A1), potassium carbonate (87 mg, 0.63 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (17 mg, 0.02 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL) in sequence. The mixture was reacted at 90°C under a nitrogen atmosphere for 16 h. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 4b (109 mg, 92%).

[0244] LCMS m / z=556.2[M+1] +

[0245] Step 3: Preparation of 4c

[0246] Anisole (22 mg, 0.20 mmol) and trifluoroacetic acid (3 mL) were added to a solution of 4b (109 mg, 0.20 mmol) in dichloromethane (5 mL) and reacted at 50°C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to afford 4c (87 mg, crude product).

[0247] LCMS m / z=436.1[M+1] +

[0248] Step 4: Preparation of compound 4

[0249] 4c (87 mg, crude) was dissolved in tetrahydrofuran (5 mL) and methanol (3 mL). Aqueous sodium hydroxide (1.0 N, 5 mL, 5.00 mmol) was added and the mixture was allowed to react at 50°C for 16 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure. Under an ice-water bath, 1N dilute hydrochloric acid was slowly added dropwise to adjust the pH to approximately 3-4. The crude product was filtered and purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x L = 19 mm x 250 mm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was 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 4 (15 mg, two-step yield: 19%) was obtained by lyophilization.

[0250] LCMS m / z=408.1[M+1] +

[0251] 1 H 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).

[0252] Example 5: Preparation of Compound 5

[0253] Step 1: Preparation of 5a

[0254] 2a (300 mg, 0.88 mmol) and 4-bromo-3,5-difluorophenol (224 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (184 mg, 1.33 mmol) was added and the mixture was allowed to react at 90°C for 16 h. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 5a (100 mg, 24%).

[0255] 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).

[0256] Step 2: Preparation of 5b

[0257] 5a (100 mg, 0.21 mmol), 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (62 mg, 0.21 mmol, synthesized according to patent WO2020010309A1), potassium carbonate (87 mg, 0.63 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (17 mg, 0.02 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL) in sequence. The mixture was reacted at 90°C under a nitrogen atmosphere for 16 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 5b (60 mg, 51%).

[0258] Step 3: Preparation of 5c

[0259] Anisole (36 mg, 0.33 mmol) and trifluoroacetic acid (3 mL) were added to a solution of 5b (60 mg, 0.11 mmol) in dichloromethane (5 mL) and reacted at 50°C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 5c (50 mg, crude product).

[0260] LCMS m / z=436.1[M+1] +

[0261] Step 4: Preparation of compound 5

[0262] 5c (50 mg, crude) was dissolved in tetrahydrofuran (4 mL) and methanol (2 mL). Aqueous sodium hydroxide (1.0 N, 2 mL, 5.00 mmol) was added and the mixture was allowed to react at 50°C for 16 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure. Under an ice-water bath, 1N dilute hydrochloric acid was slowly added dropwise to adjust the pH to approximately 3-4. The crude product was filtered and purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x L = 19 mm x 250 mm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was 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 lyophilized to obtain compound 5 (10 mg, two-step yield: 23%).

[0263] LCMS m / z=408.1[M+1] +

[0264] 1 H 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).

[0265] Example 6: Preparation of Compound 6

[0266] Step 1: Preparation of 6a

[0267] 2a (300 mg, 0.88 mmol) and 4-bromo-2,3,5,6-tetrafluorophenol (263 mg, 1.07 mmol) were dissolved in N,N-dimethylformamide (6 mL). Potassium carbonate (184 mg, 1.33 mmol) was added and the mixture was allowed to react at 90°C for 16 h. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 6a (300 mg, 67%).

[0268] 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).

[0269] Step 2: Preparation of 6b

[0270] 6a (100 mg, 0.20 mmol), 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (59 mg, 0.20 mmol, synthesized according to patent WO2020010309A1), potassium carbonate (83 mg, 0.60 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (16 mg, 0.02 mmol) were added to 1,4-dioxane (5 mL) and water (0.5 mL) in sequence. The mixture was reacted at 90°C under a nitrogen atmosphere for 16 h. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 6b (70 mg, 60%).

[0271] LCMS m / z=592.2[M+1] +

[0272] Step 3: Preparation of 6c

[0273] Anisole (39 mg, 0.36 mmol) and trifluoroacetic acid (3 mL) were added to a solution of 6b (70 mg, 0.12 mmol) in dichloromethane (5 mL) and reacted at 50°C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain 6c (60 mg, crude product).

[0274] LCMS m / z=472.7[M+1] +

[0275] Step 4: Preparation of compound 6

[0276] 6c (60 mg, crude) was dissolved in tetrahydrofuran (4 mL) and methanol (2 mL). Aqueous sodium hydroxide (1.0 N, 2 mL, 5.00 mmol) was added and the mixture was allowed to react at 50°C for 16 h. After completion of the reaction, the solvent was removed by concentration under reduced pressure. Under an ice-water bath, 1N dilute hydrochloric acid was slowly added dropwise to adjust the pH to approximately 3-4. The crude product was filtered and purified by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x L = 19 mm x 250 mm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was 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 lyophilized to obtain compound 6 (10 mg, two-step yield: 19%).

[0277] LCMS m / z=444.4[M+1] +

[0278] 1 H 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).

[0279] Example 7: Preparation of Compound 7

[0280] Step 1: Preparation of 7a

[0281] Dissolve 2,3-dihydro-1H-4-indanol (550 mg, 4.11 mmol) in acetonitrile (11 mL) and add benzyltrimethylammonium tribromide (1.60 g, 4.11 mmol). The mixture is allowed to react at room temperature for 1 h. Concentrate under reduced pressure to obtain a crude product, which is then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 94:6) to afford 7a (836 mg, 96%).

[0282] LCMS m / z=211.0[M-1] -

[0283] Step 2: Preparation of 7b

[0284] 2a (150 mg, 0.44 mmol) and 7a (94 mg, 0.44 mmol) were dissolved in N,N-dimethylformamide (2 mL). Potassium carbonate (120 mg, 0.88 mmol) was added and the mixture was allowed to react at 90°C for 16 h. After cooling to room temperature, the reaction mixture was added to water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (15 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:tetrahydrofuran (v / v) = 85:15) to afford 7b (120 mg, 58%).

[0285] LCMS m / z=472.1[M+1] +

[0286] Step 3: Preparation of 7c

[0287] 7b (120 mg, 0.25 mmol), 2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborinane (81 mg, 0.28 mmol, synthesized according to patent WO2020010309A1), potassium carbonate (103 mg, 0.75 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride-dichloromethane complex (20 mg, 0.025 mmol) were added to 1,4-dioxane (3 mL) and water (0.3 mL) in sequence. The mixture was reacted at 90°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v / v) = 80:20) to afford 7c (140 mg, 98%).

[0288] LCMS m / z=560.5[M+1] +

[0289] Step 4: Preparation of compound 7d

[0290] Anisole (27 mg, 0.25 mmol) and trifluoroacetic acid (3 mL) were added to a solution of 7c (140 mg, 0.25 mmol) in dichloromethane (5 mL) and reacted at 50°C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to afford 7d (110 mg, crude product).

[0291] LCMS m / z=440.1[M+1] +

[0292] Step 5: Preparation of compound 7

[0293] Dissolve 7d (110 mg, crude) in tetrahydrofuran (5 mL) and methanol (3 mL). Add aqueous sodium hydroxide (1.0 N, 5 mL, 5.00 mmol) and allow to react at 50°C for 16 h. After completion of the reaction, concentrate under reduced pressure to remove the solvent. Adjust the pH to approximately 3-4 by slowly adding 1 N dilute hydrochloric acid solution under an ice-water bath. Filter the crude product and purify it by Pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, XBridge@Prep C18 column, ID x length = 19 mm x 250 mm). Preparation: Dissolve the crude product in dimethyl sulfoxide and filter through a 0.45 μm filter to prepare the sample solution. The mobile phase system is 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 7 (40 mg, two-step yield: 39%) was obtained by lyophilization.

[0294] LCMS m / z=412.2[M+1] +

[0295] 1 H 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).

[0296] Example 8: Preparation of Compound 8

[0297] Compound 8 was obtained using 8a as the starting material by referring to the synthetic method of Example 7.

[0298] LCMS m / z=426.4[M+1] +

[0299] 1 H 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).

[0300] Biological test examples:

[0301] 1. hHAO1 enzyme activity test

[0302] Experimental procedures

[0303] 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 μL / well, followed by the addition of 2.5 μL / well compound. After reacting at room temperature for 15 minutes, 5 μL of substrate mixed solution (glycolic acid, Amplex Red dye, HRP, 50 mM HEPES, pH 8.0) is added. The 384-well plate is then immediately placed in a BMG microplate reader and the fluorescence signal (Em540 nm / EX590 nm) is read. The mean and standard error (Mean ± SEM) are calculated and analyzed using Graphpad Prism software to calculate the IC 50 value.

[0304] Table 1. Inhibitory activity of compounds against hHAO1 enzyme

[0305] Conclusion: The compounds of the present invention, such as the example compounds, have good inhibitory activity against hHAO1, especially compounds 4, 6, 7, and 8 with IC 50 Less than 50 nM, it has better hHAO1 inhibitory activity than the control compound 1.

[0306] The structure of reference compound 1 is as follows:

[0307] 2. Pharmacokinetic Testing in Mice

[0308] 2.1 Experimental Animals: Male Balb / c mice, approximately 22 g, 6 to 8 weeks old, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0309] 2.2 Experimental Design: 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 before administration and fed 4 hours after administration.

[0310] Table 2. Dosing Information

[0311] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0312] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0313] Before and after drug administration, 0.03 ml of blood was collected from the eye sockets under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, 1, 2, 4, 7, and 24 hours. All samples were stored at -80°C prior to analysis.

[0314] Table 3. Pharmacokinetic parameters of test compounds in mouse plasma

[0315] -:not applicable.

[0316] Conclusion: 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.

[0317] 3. Pharmacokinetic Test in Rat

[0318] 3.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0319] 3.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0320] Table 4. Dosing Information

[0321] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0322] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose)

[0323] Before and after drug administration, 0.15 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0324] Table 5. Pharmacokinetic parameters of test compounds in rat plasma

[0325] -:not applicable.

[0326] Conclusion: The compounds of the present invention, such as the example compounds, have higher exposure and good bioavailability in rats, especially compound 6, which has better bioavailability than the control compound 1.

[0327] 4. Pharmacokinetic Testing in Beagle Dogs

[0328] 4.1 Experimental Animals: Male beagle dogs, weighing approximately 8-11 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0329] 4.2 Experimental Methods: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 14–18 hours prior to dosing. Food was resumed 4 hours after dosing. Dosing was performed according to Table 6.

[0330] Table 6. Dosing Information

[0331] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC

[0332] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose solution;)

[0333] *Dosage is based on the free base.

[0334] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0335] Table 7. Pharmacokinetic parameters of test compounds in beagle dog plasma

[0336] -:not applicable.

[0337] Conclusion: The compounds of the present invention, such as the example compounds, especially compounds 4 and 6, have higher exposure and good bioavailability in dogs.

[0338] 5. Monkey Pharmacokinetic Test

[0339] 5.1 Experimental Animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0340] 5.2 Experimental Methods: On the day of the experiment, cynomolgus monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before dosing and fed 4 hours after dosing.

[0341] Table 8. Dosing Information

[0342] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 0.5% MC (containing 0.5% Tween 80);

[0343] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; MC: methylcellulose solution;)

[0344] *Dosage is based on the free base.

[0345] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. For both the intravenous and oral gavage groups, blood was collected at the following time points: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0346] Table 9. Pharmacokinetic parameters of test compounds in monkey plasma

[0347] Conclusion: The compounds of the present invention, such as the example compounds, especially compounds 4 and 6, have higher exposure and good bioavailability in monkeys.

Claims

1. A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein: R1 is selected from -COOH or tetrazolyl; L selected from -XC 0-4 Alkylene- or -C 0-4 Alkylene-X-, the alkylene group is optionally substituted by 1 to 4 R k replace; X is selected from a bond, -O-, -S-, -NH-; Ring A is selected from C 3-8 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, the cycloalkyl, ... are optionally substituted by 1 to 4 R k replace; 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 replace; Ring C is selected from 3 to 12 membered carbocyclic groups or 4 to 12 membered heterocyclic groups, wherein the carbocyclic groups or heterocyclic groups are optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Provided that, when L is selected from -O- or -S-, 1) R1 is selected from tetrazolyl; or 2) R1 is selected from -COOH, and ring A is selected from benzo 4-membered carbocyclyl, benzo 5-membered carbocyclyl, benzo 6-membered carbocyclyl, benzo 5-membered heterocyclyl, benzo 6-membered heterocyclyl, The 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 are optionally substituted by 1 to 4 R k replace; or 3) when R1 is selected from -COOH, 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 replace; or 4) when R1 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, 4-12 membered paracarbocyclic group, and the spirocarbocyclic group and paracarbocyclic group are optionally substituted by 1 to 4 R k replace; or 5) when R1 is selected from -COOH, ring A is selected from unsubstituted phenyl, ring B is selected from unsubstituted phenyl, and ring C is selected from triazolyl, 5- to 12-membered spirocarbocyclyl, 4- to 12-membered paracarbocyclyl, and the triazolyl, spirocarbocyclyl, and paracarbocyclyl are optionally substituted by 1 to 4 R k replace; When L is selected from a bond, Ring A and Ring B are selected from substituted or unsubstituted phenyl, R1 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 replace.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from -X-, -X-CH2- or -CH2-X-; Ring A is selected from C 3-6 cycloalkyl, benzyl ring group, benzo 4-membered carbocyclic group, the cycloalkyl, benzyl ring group, benzo 4-membered carbocyclic group is optionally substituted by 1 to 4 R k replace; 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 replace; 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 by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, CONH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein L is selected from a bond, -O-, -S-, -NH-, -CH2-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -CH2NH-, -NHCH2-; Ring A is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, When substituted, optionally substituted with 1 to 4 R k replace; Ring B is selected from substituted or unsubstituted phenyl, pyridyl, When substituted, optionally substituted with 1 to 4 R k replace; 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, optionally substituted with 1 to 4 R k replace; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein L is selected from a bond, -O-, -CH2-, -CH2O-, -OCH2-, -CH2NH-, -NHCH2-; Ring A is selected from R k Each is independently selected from deuterium, F, Cl, Br, I, CF3, 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 5. The compound according to claim 4, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the group consisting of: X is selected from a bond, -O-, -NH-; Ring A1 is selected from or when ring A1 is selected from When ring B is selected from or when ring A1 is selected from Ring B is selected from When ring C is selected from or when ring A1 is selected from Ring B is selected from When ring C is selected from R k Each independently selected from deuterium, F, Cl, Br, I, CF3, methyl, ethyl, methoxy, ethoxy, cyclopropyl; Ring C1 is selected from a and b are each independently selected from 0, 1, 2, 3 or 4.

6. The compound of claim 1 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures in Table E-1.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

8. Use of the compound according to any one of claims 1 to 6, or its stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, or the pharmaceutical composition according to claim 7, in the preparation of a medicament for treating kidney stones, recurrent kidney stones, or type I primary hyperoxaluria.

9. A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, preferably 1-1500 mg, wherein the disease is preferably kidney stones, recurrent kidney stones, or primary hyperoxaluria type I.

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