Preparation method of triazole glycolate oxidase inhibitor

Abstract

The present invention provides a method for preparing 1,2,3-triazole-4-carboxylic acid related compounds of formula (I) and (II) by Suzuki coupling reaction. The Suzuki coupling reaction is achieved by coupling a compound of formula (IV) (boron-containing derivative of 1,2,3-triazole-4-carboxylate) with a cycloalkylphenyl halide or sulfonate of formula (V):

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 958,443, filed on January 8, 2020, and U.S. Provisional Application No. 62 / 958,445, filed on January 8, 2020, each of which is incorporated herein by reference in its entirety for all purposes. Background Art

[0003] The prevalence of kidney stone disease (KSD) in developed countries is approximately 10%, with a lifetime recurrence rate of up to 50% [Johri, et al. (2010) Nephrology Clin Pract. 116: c159]. Patients with KSD present with hematuria and renal colic, and drug treatment is largely symptomatic. Administering drugs to promote stone passage is effective for small stones (<5 mm). For larger stones, extracorporeal sound waves or minimally invasive surgery are used to break the stones into smaller pieces that are more easily passed through the urinary tract [Coe et al. (2005) J Clin Invest. 115: 2598].

[0004] Approximately 75% of kidney stones contain primarily calcium oxalate, and elevated urinary oxalate levels are found in up to 50% of patients with KSD. Furthermore, elevated urinary oxalate levels increase the risk of kidney stone formation [Moe (2006) Lancet 367:333; Sakhaee (2009) Kidney Int. 75:585; Kaufman et al. (2008) Am J Soc Nephrol. 19:1197]. In mammals, calcium has important physiological roles in many processes and its levels are tightly regulated. However, oxalate is a metabolic end product with no known physiological role. Oxalate is a divalent anion that must be excreted in the urine and tends to precipitate as insoluble calcium oxalate crystals that are harmful to tissues.

[0005] Primary hyperoxaluria (PH) is a group of rare metabolic diseases with autosomal recessive inheritance that affect the glyoxylate or hydroxyproline pathways. They all have one thing in common, which is the overproduction of oxalate. So far, three forms of primary hyperoxaluria have been identified. They are called primary hyperoxaluria types 1, 2, and 3. Primary hyperoxaluria type 1 (PH1) is caused by mutations in the liver-specific enzyme alanine-glyoxylate aminotransferase (AGT). Primary hyperoxaluria type 2 (PH2) is caused by mutations in glyoxylate reductase-hydroxypyruvate reductase (GRHPR). Primary hyperoxaluria type 3 (PH3) is caused by mutations in 4-hydroxy-2-oxoglutarate aldolase (HOGA1). PH1 eventually leads to kidney failure after several years. PH2 and PH3 have a milder course. About 80% of PH patients have PH1, which is the most severe type of PH. Given its statistical dominance, most studies on PH refer essentially to PH1 [Salido et al. (2012) Biochem. Biophys. 1822:1453].

[0006] Because calcium levels are so tightly regulated in the body, altering them in the urine is difficult and may have undesirable effects on important physiological processes. Slight increases in urine oxalate can have a large effect on calcium oxalate crystal formation, and elevated urine oxalate levels are a major risk factor for calcium oxalate kidney stone formation [Pak, et al. (2004) Kidney Int. 66:2032]. Therefore, a small decrease in oxalate concentration can reduce calcium oxalate levels below saturation, thereby preventing calcium oxalate stone formation. Regardless of urine oxalate (UOx) levels in patients with kidney stones, primary hyperoxaluria, or secondary hyperoxaluria, lowering UOx levels will reduce the contribution of oxalate to calcium oxalate formation, thereby reducing the probability of stone formation and / or reducing the severity of conditions associated with excessive calcium oxalate deposition [Marengo et al. (2008) Nat Clin Pract Nephrol. 4:368].

[0007] The development of an effective drug to reduce urinary oxalate levels would be a valuable therapeutic option for the prevention and treatment of diseases associated with calcium oxalate. Common approaches to treating urolithiasis caused by calcium oxalate include surgical removal of the stones, dietary changes to increase fluid intake and limit oxalate intake, urine alkalinization, diuretics, and crystallization inhibitors such as citrate, bicarbonate, and magnesium [Moe, Supramolecular Chemistry]. However, none of these treatments address the origin of the disease. There are no commercially available drugs that specifically inhibit the endogenous biosynthetic formation of oxalate for the prevention and treatment of conditions associated with calcium oxalate deposition.

[0008] In humans, dietary oxalate accounts for only 10-50% of the amount of urinary oxalate excreted [Holmes, et al. (2001) Kidney Int. 59:270]. Most urinary oxalate is derived from endogenous metabolism, primarily in the liver. In humans, the major precursor of oxalate is glyoxylate. Therefore, methods to reduce oxalate production must prevent the conversion of glyoxylate to oxalate, or prevent the generation of glyoxylate from its precursors. In humans, the major precursor of glyoxylate is glycolic acid in a reaction catalyzed by the peroxisomal liver enzyme glycolate oxidase (GO), also known as hydroxyacid oxidase 1. Pharmacological inhibition of GO activity by small molecules would reduce endogenous oxalate production and result in reduced levels of calcium oxalate in the urine, thus providing a specific approach for the prevention and treatment of calcium oxalate deposition and related conditions. There is evidence that GO is a safe therapeutic target in humans. One report describes the finding that, in one individual, a defective splice variant of human GO caused only isolated asymptomatic glycolic aciduria with no apparent adverse effects [Frishberg, et al. (2014) J Med Genet. 51:526].

[0009] Recently, a series of 1,2,3-triazole-4-carboxylic acids have been described for use in treating GO-related diseases. Although initial methods for preparing such compounds have also been described, there remains a need for improved methods that can be run on a large scale and increase yields in these processes.

[0010] As described in PCT / US2019 / 040690 (herein referred to as the '690 application), the compound of formula (Ia-1):

[0011]

[0012] according to Figure 1 The compound of formula (IIIa-1a-1) was synthesized by the scheme shown. The compound of formula (IIIa-1a-1) was obtained by Suzuki coupling reaction, and 3.36 equivalents of compound (33) (2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) were required for the reaction relative to the compound of formula (VI-1a-1). Compound (33) was prepared from 1-bromo-4-(3,3-difluorocyclobutyl)benzene in a yield of about 59% and required further purification. For the Suzuki coupling reaction, the compound of formula (IIIa-1a-1) was isolated in a yield of about 51%. By using the Suzuki reaction as described in the '690 application, starting from the compound of formula (VI-1a-1), the compound of formula (IIIa-1a-1) was isolated in a two-step total yield of only about 30%.

[0013] Despite the above methods, there is still a need to develop more efficient and improved methods for preparing 1,2,3-triazole-4-carboxylic acid related compounds, especially cycloalkyldiphenyl 1,2,3-triazole-4-carboxylic acid compounds.

[0014] Brief description

[0015] In one aspect, the present invention provides a method for preparing a compound as represented by formula (II), its tautomer or a salt thereof:

[0016]

[0017] The method comprises:

[0018] a) a compound of formula (IV) or a salt thereof:

[0019]

[0020] With a compound of formula (V):

[0021]

[0022] The first transition metal catalyst and the first base are contacted in a first solvent to form a compound of formula (III) or a salt thereof:

[0023]

[0024] and

[0025] b) removing the PG group of the compound of formula (III) or a salt thereof to obtain a compound of formula (II), a tautomer thereof or a salt thereof,

[0026] in:

[0027] The subscripts m and n are each independently 1 or 2;

[0028] R 1 It is C 1-6 alkyl;

[0029] R 2 and R 3 are each independently H or halogen;

[0030] X 1 represents a boron-containing group;

[0031] X 2 is a halogen or a sulfonate group; and

[0032] In formula (IV) or (III) It is expressed by the following formula:

[0033] or mixtures thereof; and

[0034] PG is an amine protecting group.

[0035] In another aspect, the present invention provides a method for preparing a compound represented by formula (Ia-1), a tautomer thereof or a salt thereof:

[0036]

[0037] The method comprises:

[0038] a1) the compound of formula (VI-1a-1) or a salt thereof:

[0039]

[0040] With bis-pinacol diboron, Pd(dppf)Cl 2 ·CH 2 Cl 2 and potassium acetate in 1,4-dioxane to form a compound of formula (IV-1a-2) or a salt thereof:

[0041]

[0042] a) a compound of formula (IV-1a-2) or a salt thereof is reacted with 1-bromo-4-(3,3-difluorocyclobutyl)benzene, Pd(dppf)Cl in a mixture of 1,4-dioxane and water; 2 ·CH 2 Cl 2 and potassium carbonate to form a compound of formula (IIIa-1a-1) or a salt thereof:

[0043]

[0044] b) treating the compound of formula (IIIa-1a-1) or a salt thereof with trifluoroacetic acid and anisole in dichloromethane to obtain the compound of formula (IIa-1), its tautomer or a salt thereof:

[0045]

[0046] c) saponifying the compound of formula (IIa-1), its tautomer or a salt thereof with an aqueous solution of sodium hydroxide in tetrahydrofuran; and

[0047] d) acidifying with aqueous HCl to obtain the compound of formula (Ia-1), its tautomer or a salt thereof.

[0048] In a related aspect, provided herein is a compound represented by formula (X), a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0049]

[0050] Among them, R 1 H or C 1-6 Alkyl; R 2and R 3 Each is independently H or halogen.

[0051] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (X), a tautomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0052] In yet another aspect, provided herein are methods of inhibiting glycolate oxidase in a subject using a compound of formula (X) to treat primary hyperoxaluria, type I (PH1), and kidney and / or bladder stones. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 This is a synthetic scheme for preparing compounds of formula (Ia-1) as described in PCT / US2019 / 040690.

[0055] Figure 2 The following is a synthetic scheme for preparing compounds of formula (I).

[0056] Figure 3 This is a synthetic scheme for preparing compounds of formula (Ia-1).

[0057] Figure 4 This is a synthetic scheme for preparing the compound of formula (VI-1a-1).

[0058] Figure 5 The invention is a synthetic scheme for preparing 1-bromo-4-(3,3-difluorocyclobutyl)benzene.

[0059] Figure 6 This is a synthetic scheme for preparing compounds of formula (Ib-1) and formula (IIb-1).

[0060] Figure 7 This is a synthetic scheme for preparing compounds of formula (Ic-1) and formula (IIc-1).

[0061] Figure 8 The present invention is a synthetic scheme for preparing intermediates used to prepare compounds of formula (Ib-1), formula (IIb-1), formula (Ic-1) and formula (IIc-1).

[0062] Fig. 9 The catalytic reaction used to measure glycolate oxidase activity is shown.

[0063] Details

[0064] I. Overview

[0065] The present disclosure provides a method for preparing 1,2,3-triazole-4-carboxylic acid related compounds shown in formula (I) and (II) by Suzuki coupling reaction. The Suzuki coupling reaction is achieved by coupling a boron-containing derivative of a compound of formula (IV), 1,2,3-triazole-4-carboxylate, with a cycloalkylphenyl halide or sulfonate shown in formula (V). Starting from a compound of formula (VI), which is an amine-protected 5-(4-halophenoxy)-1H-1,2,3-triazole-4-carboxylate, the Suzuki coupling reaction provides an excellent yield of about 61% in two steps.

[0066] The present disclosure also provides effective treatment methods for inhibiting the formation of biosynthetic oxalate and for treating primary hyperoxaluria, type I (PH1), and other conditions associated with calcium oxalate deposition. Provided are novel cycloalkyltriazole compounds useful as glycolate oxidase inhibitors, and methods for preparing and using the cycloalkyltriazole compounds.

[0067] II. Definitions

[0068] Alkyl refers to a straight or branched chain saturated aliphatic group (i.e., C 1-6 represents one to six carbons). Alkyl groups may include any number of carbons, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc.

[0069] Alkylene refers to a straight or branched chain saturated aliphatic group (i.e., C 1-6 , which represents one to six carbon atoms) and connects at least two other groups, i.e., a divalent hydrocarbon group. The two groups connected to the alkylene group can be connected to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene group can be -(CH 2 )n -, wherein n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene.

[0070] "Alkoxy" refers to an alkyl group with an oxygen atom attached to the point of attachment: alkyl-O-. The alkoxy group can have any suitable number of carbon atoms, such as C 1 -C 6 The alkoxy group includes, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.

[0071] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl can include any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl can be monocyclic, fused to form a bicyclic or tricyclic group, or connected by chemical bonds to form a biaryl. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, with a methylene linker. Some aryl groups are 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups are 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups are 6 ring members, such as phenyl.

[0072] "Aryloxy" refers to an aryl group having an oxygen atom attached to the point of attachment: aryl-O-. Aryloxy groups useful in the present invention include C 6-10 Aryloxy, wherein the aryl group is a 6- to 10-membered ring.

[0073] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0074] Carboxylates are salts of the formula RC(O)O - wherein the R group may be an alkyl, aryl or aralkyl group; or a dicarboxylate group R(C(O)O - ) 2 , wherein the R group can be alkylene, alkylene-O-alkylene, alkylene-NH-alkylene or alkylene-N(alkyl)-alkylene. Carboxylates useful in the present invention include, but are not limited to, acetates, malonates, 2,2'-oxydiacetates, iminodiacetates and 2,2'-(methylazadiyl)acetates.

[0075] Sulfonate refers to -SO 3R groups, wherein the R groups can be halogen (e.g., -F), alkyl (e.g., methyl or ethyl), haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl, tosyl, p-fluorophenyl or p-nitrophenyl), heteroaryl (e.g., imidazolyl). Exemplary sulfonate groups include, but are not limited to, fluorosulfonate, methanesulfonate (OMs), trifluoromethanesulfonate (OTf), p-toluenesulfonate (OTs), p-fluorobenzenesulfonate, p-nitrobenzenesulfonate (nosylate), and imidazylate-1-sulfonate (imidazylate).

[0076] "OMs" refers to methanesulfonate; "-OTs" refers to p-toluenesulfonate; and "-OTf" refers to triflate.

[0077] "Bidentate" refers to an alkoxy, aryloxy or carboxylate group having at least two oxygen atoms (-O-) that can form two bonds with the same third atom, such as boron (B), provided that the two oxygen atoms are not part of a carbonyl group (-C=O). Bidentate groups useful in the present invention include bidentate C 2-8 Alkoxy, bidentate C 6-10 Aryloxy and bidentate carboxylate groups.

[0078] "Tridentate" refers to an alkoxy group having at least three carbon atoms and three oxygen atoms (-O-), wherein the three oxygen atoms can form a bond with the same fourth atom, such as boron (B). Tridentate groups useful in the present invention include tridentate C 3-10 Alkoxy.

[0079] A "catalyst" is a substance that increases the rate of a chemical reaction by lowering the activation energy without changing the products of the reaction.

[0080] "Metal" refers to a metallic element in the periodic table, which can be neutral or positively charged due to having more or fewer electrons in the valence shell than a neutral metallic element. Metals useful in the present invention include alkali metals and transition metals. Alkali metals in the present invention include alkali metal cations. Alkali metal cations useful in the present invention include Li + 、Na + , K + and Cs + Transition metals that can be used in the present invention include Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, and Ac.

[0081] "Transition metal catalyst" refers to a compound composed of a transition metal as defined above, which may be neutral or positively charged.

[0082] Bases useful in the present invention include organic bases and inorganic bases. Exemplary organic bases include amines, alkali metal carboxylates, and alkali metal alkoxides as defined herein. Exemplary inorganic bases include alkali metal bicarbonates, alkali metal carbonates, alkali metal triphosphates, and alkali metal hydroxides as defined herein. Amines useful as bases in the present invention include tertiary amines and aromatic amine bases as defined herein.

[0083] Amines are compounds having the formula N(R) 3 Compounds, wherein the R groups can be hydrogen, alkyl, aryl or heteroalkyl etc. The R groups can be the same or different. For example, amines can be primary amines (two R are each hydrogen), secondary amines (one R is hydrogen) and tertiary amines (each R is not hydrogen). In some embodiments, secondary amines are cyclic amines, wherein the two R groups connected to the nitrogen atom form a 5-6 membered heterocycle. Non-limiting examples of cyclic amines include pyrrolidine, piperidine and morpholine.

[0084] A tertiary amine is a tertiary amine having the formula N(R) 3 Compounds wherein the R groups may be alkyl, aryl, heteroalkyl, heteroaryl, etc., or two R groups together form a heterocycloalkyl connected by N. The R groups may be the same or different. Non-limiting examples of tertiary amines include triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, dimethylaniline, diethylaniline, 1,8-bis(dimethylamino)naphthalene, quinuclidine, and 1,4-diazabicyclo[2.2.2]-octane (DABCO).

[0085] Aromatic amine base refers to a 5- to 10-membered heteroaryl compound containing N or having the formula N(R) 3 A tertiary amine, wherein at least one R group is an aryl or heteroaryl group. Aromatic amine bases that can be used in the present application include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine and 2,3-lutidine), tris-methylpyridine (e.g., 2,3,4-tris-methylpyridine, 2,3,5-tris-methylpyridine, 2,3,6-tris-methylpyridine, 2,4,5-tris-methylpyridine, 2,4,6-tris-methylpyridine and 3,4,5-tris-methylpyridine), 4-dimethylaminopyridine, imidazole, 1-methylimidazole, dimethylaniline and diethylaniline.

[0086] Alkali metal carboxylates are salts of alkali metals composed of alkali metal cations and carboxylate anions (RC(O)O - ) wherein the R group may be an alkyl group or an aryl group. The alkali metal carboxylates that can be used in the present invention include, but are not limited to, lithium acetate (LiOC(O)CH 3 ), sodium acetate (NaOC(O)CH 3 ), potassium acetate (KOC(O)CH 3 ), cesium acetate (CsOC(O)CH3 ) and potassium trimethylacetate (KOC(O)C(CH 3 ) 3 ).

[0087] Alkali metal alkoxides are composed of alkali metal cations and alkoxide anions (RO - ) composed of a class of compounds, wherein R is C 1-4 Alkoxides useful in the present invention include, but are not limited to, sodium methoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium isopropoxide.

[0088] Alkali metal bicarbonate refers to an alkali metal cation and a carbonate anion (HCO 3 - ) is a class of compounds composed of. The alkali metal carbonates that can be used in the present invention include lithium bicarbonate (LiHCO 3 ), sodium bicarbonate (NaHCO 3 ), potassium bicarbonate (KHCO 3 ) and cesium bicarbonate (CsHCO 3 ).

[0089] Alkali metal carbonates are composed of alkali metal cations and carbonate anions (CO 3 2- ) is a class of compounds composed of. The alkali metal carbonates that can be used in the present invention include lithium carbonate (Li 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ) and cesium carbonate (Cs 2 CO 3 ).

[0090] Alkali metal triphosphate refers to an alkali metal cation and a phosphate anion (PO 4 3- ) is a class of compounds composed of. The alkali metal triphosphates that can be used in the present invention include trisodium phosphate (Na 3 PO 4 ) and tripotassium phosphate (K 3 PO 4 ).

[0091] Alkali metal hydroxides are compounds composed of alkali metal cations and hydroxide anions (OH - The alkali metal hydroxides that can be used in the present invention include LiOH, NaOH, KOH and CsOH.

[0092] An acid is an acid that can donate a proton (H +) or a compound that is an electron pair acceptor under the Lewis definition. Acids that can be used in the present invention include, but are not limited to, fluorinated carboxylic acids (trifluoroacetic acid), sulfonic acids, and mineral acids as defined herein. Mineral acids are inorganic acids such as hydrogen halides (hydrofluoric acid, hydrochloric acid, hydrobromic acid, etc.), as well as sulfuric acid, nitric acid, and phosphoric acid. Sulfonic acids include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.

[0093] A protecting group refers to a compound that renders a functional group unreactive to a particular set of reaction conditions, but which can then be removed in a subsequent synthetic step to restore the functional group to its original state. Such protecting groups are well known to those of ordinary skill in the art, and compounds comprising them are disclosed in Protective Groups in Organic Synthesis, 4th edition, TW Greene and PGM Wuts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.

[0094] "Amine protecting group" refers to a protecting group used to protect a nitrogen atom in a 1,2,3-triazolyl group. Amine protecting groups that can be used in the present invention include, but are not limited to, benzyl (Bn) groups, 2-(trimethylsilyl)ethoxymethyl, p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 1-(2,4-dimethoxyphenyl)ethyl, 3,4-dimethoxybenzyl (DMPB), p-methoxyphenyl (PMP), toluenesulfonyl (Ts) and other sulfonamide (Nosyl & Nps) groups.

[0095] "Deprotection" refers to the removal of a protecting group as defined above using one or more chemicals or reagents, thereby restoring the functional group to its original state.

[0096] Transfer agents refer to chemical reagents added to the reaction mixture during the deprotection step to effectively remove the amine protecting group, such as p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 1-(2,4-dimethoxyphenyl)ethyl or 3,4-dimethoxybenzyl (DMPB). Transfer agents that can be used in the present invention include, but are not limited to, anisole and the like. It is believed that anisole reacts as a transfer agent, wherein a protecting group such as PMB is transferred from the amine to the para position of anisole.

[0097] "Contacting" refers to the process of bringing at least two different substances into contact so that they can react. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents, or through an intermediate that reacts with one or more added reagents and can be formed in the reaction mixture.

[0098] "Solvent" refers to a substance that can dissolve a solute, such as a liquid. A solvent can be polar or non-polar, protic or non-protic. Polar solvents generally have a dielectric constant greater than about 5 or a dipole moment higher than about 1.0, and non-polar solvents have a dielectric constant lower than about 5 or a dipole moment lower than about 1.0. Protic solvents are characterized by having a proton that can be used to remove, such as having a hydroxyl or carboxyl group. Aprotic solvents lack such a group. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.) and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, ether, 1,4-dioxane, acetone, ethyl acetate, dimethylformamide, acetonitrile, dimethyl sulfoxide and N-methylpyrrolidone. Representative non-polar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene and toluene. Other solvents may be used in the present invention.

[0099] Solvents can also be grouped according to their chemical structure, such as ethers (e.g., diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, etc.), ketones (e.g., acetone, methyl isobutyl ketone, etc.), esters (ethyl acetate, butyl acetate, isobutyl acetate, etc.), aromatic solvents (e.g., benzene, toluene, xylene, etc.), chlorinated solvents (e.g., dichloromethane, 1,2-dichloroethane, etc.), hydrocarbons (n-heptane, hexane, cyclohexane, methylcyclohexane, etc.), alcohols (methanol, ethanol, propanol, isopropanol, etc.), or acids (e.g., formic acid, acetic acid, etc.).

[0100] "Solvate" refers to a compound provided herein or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. In the case where the solvent is water, the solvate is a hydrate.

[0101] "Hydrate" refers to a compound complexed with water molecules. The compounds of the present invention may be complexed with 1 / 2 water molecules or 1 to 10 water molecules.

[0102] "Tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another.

[0103] "Salt" refers to an acidic or basic salt of a compound used in the methods of the present invention. Pharmaceutically acceptable salts include salts of compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (pure alkali or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amine salts or magnesium salts, or similar salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mark Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0104] "Approximately" refers to a range of values ​​including the specified value that one of ordinary skill in the art would consider to be reasonably similar to the specified value. In some embodiments, the term "about" means within the standard deviation of the measurement value generally accepted in the art. In some embodiments, "about" means a range extending to + / -10% of the specified value. In some embodiments, "about" refers to the specified value.

[0105] As used herein, "composition" is intended to include a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0106] "Pharmaceutically acceptable excipient" refers to a substance that helps the active agent to be administered to a subject and absorbed by the subject. Pharmaceutical excipients that can be used in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavors, and pigments. Other pharmaceutical excipients can be used in the present invention.

[0107] "Inhibitor," "inhibit," and "inhibitor" refer to a compound that inhibits a specific action or function or a method of inhibiting a specific action or function. Inhibition may be partial or complete. Inhibition may be protective or preventative.

[0108] "Administering" means administering to a subject orally, as a suppository, by topical contact, parenterally, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally, subcutaneously, intrathecally, by implantation of a sustained release device, e.g., an osmotic mini-pump, or by any other useful mechanism.

[0109] "Treatment" means any marker of success in treating or ameliorating an injury, pathology or condition, including any objective or subjective parameter, such as relief; remission; lessening of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing the rate of degeneration or decline; making the final point of degeneration less debilitating; improving the patient's physical or mental well-being. Treatment or amelioration of symptoms may be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0110] "Patient" or "subject" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition provided herein. Non-limiting examples include humans, other mammals, buffaloes, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is a human. In some embodiments, the patient has been diagnosed with a disease or condition such as nephrolithiasis and / or primary hyperoxaluria. In some embodiments, the patient is suspected of having a disease or condition such as nephrolithiasis and / or primary hyperoxaluria. In some embodiments, the patient has previously been treated for a disease or condition such as nephrolithiasis and / or primary hyperoxaluria. In some embodiments, the patient is being treated or evaluated for a disease or condition such as nephrolithiasis and / or primary hyperoxaluria.

[0111] "Therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition that can be used to treat or improve an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The exact amount will depend on the purpose of the treatment, and can be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th edition, 2003, Gennaro, Ed., Lippincott Williams Wilkins Publishing Company).

[0112] "Primary hyperoxaluria, type I" and "PH1" are interchangeable and refer to a disorder caused by a deficiency in alanine:glyoxylate aminotransferase (AGT), a liver enzyme. This deficiency results in impaired glyoxylate metabolism in the liver, ultimately leading to increased oxalate synthesis, which can lead to the formation of calcium oxalate kidney stones.

[0113] "Kidney stones" and / or "bladder stones" refer to small solid particles that occur in the kidneys, renal pelvis, ureters, bladder and / or urethra. Typically, kidney stones and / or bladder stones contain or consist of calcium salt particles, including but not limited to calcium oxalate particles and calcium phosphate particles (e.g., apatite particles or brushite particles). Kidney stones and / or bladder stones may also contain or consist of uric acid, struvite (i.e., NH 4 MgPO 4 6H 2 O particles) and cystine (i.e., particles containing oxidized cysteine ​​disulfide dimers). Kidney and / or bladder stones typically range in size from less than 1 mm in their largest dimension to 5 cm or more in their largest dimension. Kidney stones typically form in the kidneys or renal pelvis, and when they are small enough (e.g., less than 5 mm), they can pass through the ureters, bladder, and urethra and out of the body through urination. Kidney and / or bladder stones typically cause severe pain in the sides and back, below the ribs, and in the lower abdomen and groin. Other symptoms of kidney and / or bladder stones include, but are not limited to, painful urination, abnormal urine color (e.g., pink, red, or brown), cloudy urine, foul-smelling urine, nausea and vomiting, a constant need to urinate, low urine output, fever, and chills. Imaging techniques such as abdominal X-rays, CT scans, and ultrasound can be used to confirm the presence of kidney and / or bladder stones in the urinary system.

[0114] "Glycolate oxidase" and "GO" are used interchangeably and refer to the liver peroxisomal enzyme glycolate oxidase 1 (GO1), also known as hydroxy acid oxidase 1 (HAO1). The human enzyme is catalogued under NCBI accession number NP_060015.1 and UniProtKB, reference number Q9UJM8. The mouse enzyme is catalogued under GenBank accession number EDL28373.1 and UniProtKB, reference number Q9WU19. The enzyme catalyzes the conversion of glycolate to glyoxylate, which is an oxalate precursor.

[0115] Compound Preparation Method

[0116] In one aspect, the present invention provides a method for preparing a compound as represented by formula (II), its tautomer or a salt thereof:

[0117]

[0118] The method comprises:

[0119] a) a compound of formula (IV) or a salt thereof:

[0120]

[0121] With a compound of formula (V):

[0122]

[0123] The first transition metal catalyst and the first base are contacted in a first solvent to form a compound of formula (III) or a salt thereof:

[0124]

[0125] and

[0126] b) removing the PG group of the compound of formula (III) or a salt thereof to obtain a compound of formula (II), a tautomer thereof or a salt thereof,

[0127] in:

[0128] The subscripts m and n are each independently 1 or 2;

[0129] R 1 It is C 1-6 alkyl;

[0130] R 2 and R 3 are each independently H or halogen;

[0131] X 1 represents a boron-containing group;

[0132] X 2 is a halogen or a sulfonate group; and

[0133] In formula (IV) or (III) It is expressed by the following formula:

[0134]

[0135] or mixtures thereof; and

[0136] PG is an amine protecting group.

[0137] With respect to formula (IV) or (III), the 1,2,3-triazole group is protected with an amine protecting group (PG). Suitable amine protecting groups include, but are not limited to, benzyl (Bn) groups, 2-(trimethylsilyl)ethoxymethyl (SEM), p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 3,4-dimethoxybenzyl (DMPM), 1-(2,4-dimethoxyphenyl)ethyl, p-methoxyphenyl (PMP), p-toluenesulfonyl (Ts) and p-nitrobenzenesulfonyl (Nosyl group). In some embodiments, the amine protecting group is 2-(trimethylsilyl)ethoxymethyl (SEM), p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 3,4-dimethoxybenzyl (DMPM) or 1-(2,4-dimethoxyphenyl)ethyl. In some embodiments, the amine protecting group is p-methoxybenzyl (PMB).

[0138] In some embodiments, when the amine protecting group is benzyl (Bn), p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 3,4-dimethoxybenzyl (DMPM) or 1-(2,4-dimethoxyphenyl)ethyl, the compound of formula (IV) is represented by formula (IV-1):

[0139] and

[0140] The compound of formula (III) is represented by formula (III-1):

[0141]

[0142] Among them, the subscripts m and n, R 1 , R 2 , R 3 and X 1 As defined and described herein.

[0143] In some embodiments, when the amine protecting group is p-methoxybenzyl (PMB), the compound of formula (IV) is represented by formula (IV-1a):

[0144] and

[0145] The compound of formula (III) is represented by formula (III-1a):

[0146]

[0147] Among them, the subscripts m and n, R 1 , R 2 , R 3 and X 1 As defined and described herein.

[0148] In some embodiments, when the amine protecting group is not benzyl (Bn), p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 3,4-dimethoxybenzyl (DMPM) or 1-(2,4-dimethoxyphenyl)ethyl, the compound of formula (IV) is represented by formula (IV-1) or (IV-2):

[0149]

[0150] or a mixture thereof; the compound of formula (III) is represented by formula (III-1) or (III-2):

[0151]

[0152] or a mixture thereof, wherein the subscripts m and n, R 1 , R 2 , R 3 and X 1 As defined and described herein.

[0153] In some embodiments, when the amine protecting group is 2-(trimethylsilyl)ethoxymethyl (SEM), the compound of formula (IV) is represented by formula (IV-1b) or (IV-2b):

[0154]

[0155] or a mixture thereof; the compound of formula (III) is represented by formula (III-1b) or (III-2b):

[0156]

[0157] or a mixture thereof, wherein the subscripts m and n, R 1 , R 2 , R 3 and X 1 As defined and described herein.

[0158] With respect to any of Formula (IV), (IV-1), (IV-2), (IV-1a), (IV-1b), and (IVb-2b), in some embodiments, X 1 It is expressed by the following formula:

[0159] 1)-BY 2 , where Y is -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 an aryloxy or carboxylate group;

[0160] 2) -BY, where Y is a bidentate C 2-8Alkoxy, bidentate C 6-10 an aryloxy group or a bidentate carboxylate group;

[0161] 3) 9-boranobicyclo[3,3,1]nonane (9-BBN) group;

[0162] 4)-BY 3 M, where Y is F or C 1-6 Alkoxy, M is an alkali metal ion, ammonium ion or phosphonium ion; or

[0163] 5)-BYM, where Y is a three-tooth C 3-10 Alkoxy group, M is an alkali metal ion, ammonium ion or phosphonium ion.

[0164] In some embodiments, X 1 Yes-BY 2 , wherein Y is -OH, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-10 In some embodiments, X 1 Yes -B(OH) 2 、-B(OEt) 2 or -B(OiPr) 2 .

[0165] In some embodiments, X 1 Y-BY, where Y is a bidentate C 2-8 Alkoxy, bidentate C 6-10 In some embodiments, X 1 Select from the following group:

[0166]

[0167] In some embodiments, X 1 is a 9-boranobicyclo[3,3,1]nonane (9-BBN) group represented by the formula:

[0168]

[0169] In some embodiments, X 1 Yes-BY 3 M, where Y is F or C 1-6 Alkoxy; M is an alkali metal ion, an ammonium ion or a phosphonium ion. In some embodiments, X 1 Yes-BF 3 M, -B(OiPr) 3 M or -B (OiPr) 3 M, where M is Li + 、Na + or K+ In some embodiments, X 1 Yes-BF 3 K, -B(OiPr) 3 K or -B (OiPr) 3 Li.

[0170] In some embodiments, X 1 Y-BYM, where Y is a three-tooth C 3-10 Alkoxy; M is an alkali metal ion, an ammonium ion or a phosphonium ion. In some embodiments, X 1 It is expressed by the following formula:

[0171]

[0172] Where M is Li + 、Na + or K + In some embodiments, M is K + .

[0173] In some embodiments, X 1 It is expressed by the following formula:

[0174]

[0175] In some embodiments, the compound of formula (IV) is represented by formula (IVa-1a):

[0176]

[0177] Among them, R 1 As defined and described herein.

[0178] With respect to Formula (V), in some embodiments, X 2 In some embodiments, X 2 is Cl, Br or I. In some embodiments, X 2 is Br. In some embodiments, X 2 is a sulfonate. In some embodiments, X 2 is fluorosulfonate, methanesulfonate (OM), p-toluenesulfonate (OTs), trifluoromethanesulfonate (OTf), p-fluorobenzenesulfonate, p-nitrobenzenesulfonate (nosylate) or imidazylate. 2 It is the methanesulfonate (OM), p-toluenesulfonate (OTs) or trifluoromethanesulfonate (OTf).

[0179] In some embodiments, the compound of formula (V) is represented by formula (V-1):

[0180]

[0181] Among them, the subscripts m and n, R 2 and R 3 As defined and described herein.

[0182] With respect to step a), the first transition metal catalyst may be a compound comprising one or more transition metals or transition metal cations. Suitable transition metals include, but are not limited to, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y, Zr, Nb, Mo, Tc, Ru, Rh, Pd, Ag, Cd, La, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, and Ac. Suitable transition metal cations include, but are not limited to, Cd 2+ 、Co 2+ 、Co + Cr 2+ Cr + , Cu + (i.e., Cu(I)), Cu 2+ (i.e. Cu(II)), Fe 2+ , Fe + , Mn 2+ , Mn + 、Ni 2 + 、Ni + , Pd 2+ (i.e. Pd(II)) and Zn 2+ In some embodiments, the first transition metal catalyst is a first palladium catalyst, a ruthenium catalyst, a rhodium catalyst, a cobalt catalyst, a nickel catalyst, an iron catalyst, a copper catalyst, or a combination thereof. In some embodiments, the first transition metal catalyst is a first palladium catalyst.

[0183] In some embodiments, the first palladium catalyst is Pd(acac) 2 、[Pd(allyl)Cl] 2 、Pd(CH 3 CN) 2 Cl 2 、Pd(dba) 2 、Pd(CH 3 COO 2 , Pd 2 (dba) 3 , Pd 2 (dba) 3 ·CHCl 3 、Pd(PPh 3 ) 4 、Pd(OAc) 2、Pd(PCy 3 ) 2 Cl 2 、Pd(PPh 3 ) 2 Cl 2 、Pd[P(o-tol) 3 ] 2 Cl 2 、Pd(amphos)Cl 2 、Pd(dppf)Cl 2 、Pd(dppf)Cl 2 ·CH 2 Cl 2 、Pd(dtbpf)Cl 2 、Pd(CH 3 CN) 4 (BF 4 ) 2 , PdCl 2 、XPhos-Pd-G3、Pd-PEPPSI TM -IPr、Pd-PEPPSI TM -SIPr or Pd-PEPPSI TM -IPent. In some embodiments, the first palladium catalyst is [Pd(OAc) 2 ] 3 、Na 2 PdCl 4 、Pd(CH 3 CN) 4 (CF 3 SO 3 ) 2, bis(cyanobenzene)palladium(II) chloride, palladium(II) chloride (π-cinnamyl) dimer, [di-tert-butyl(chloro)phosphine]palladium(II) chloride dimer, dihydrogen di-μ-chlorotetrakis(di-tert-butylphosphinito)-dipalladate, bis-μ-chlorobis(2'-amino-1,1'-diphenyl-2-yl-C,N)dipalladium(II), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II), Najera's catalyst I, Najera's catalyst II, di-μ-chlorobis[2-[(dimethylamino)methyl]-phenyl-C,N]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]-4,6-dimethyl Oxyphenyl-C,N]-dipalladium(II), 1,2-bis(diphenylphosphino)-ethane] dichloropalladium(II), [1,3-bis(diphenylphosphino)-propane] dichloropalladium(II), [1,4-bis(diphenylphosphino)-butane] dichloropalladium(II), bis(methyldiphenylphosphine) dichloropalladium(II), benzylbis(triphenylphosphine) chloridepalladium(II), bis(triphenylphosphine) diacetatepalladium(II), dichloro(1,5-cyclooctadiene)palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]-palladium(II), SingaCycle TM -A1, SingaCycle TM -A2, SingaCycle TM -A3, SingaCycle TM -A4, bis(tri-tert-butylphosphine)palladium(0), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]-palladium(0), bis[1,2-bis(diphenylphosphine)ethane]-palladium(0), poly(methylphenyl)silane-supported palladium / alumina hybrid catalyst, polydimethylsilane-supported palladium / alumina hybrid catalyst, or poly[N-isopropylacrylamide-co-4-(diphenylphosphino)-styrene]dichloropalladium(II) (ratio, acrylamide:phosphine=20:2). In some embodiments, the first palladium catalyst is Pd(dppf)Cl 2 、Pd(dppf)Cl 2 ·CH 2 Cl 2 or Pd(dtbpf)Cl 2 In some embodiments, the first palladium catalyst is Pd(dppf)Cl 2 ·CH 2 Cl 2 .

[0184] In some embodiments, the first transition metal catalyst is present in a substoichiometric amount. In some embodiments, the first palladium catalyst is present in a substoichiometric amount. In some embodiments, Pd(dppf)Cl 2 ·CH 2 Cl 2 It is a substoichiometric amount. In some embodiments, the amount of the first transition metal catalyst is 0.01 to 0.5 equivalents, 0.02 to 0.2 equivalents, or 0.05 to 0.1 equivalents, relative to the compound of formula (IV) or any structure related thereto. In some embodiments, the amount of the first palladium catalyst is 0.01 to 0.5 equivalents, 0.02 to 0.2 equivalents, or 0.05 to 0.1 equivalents, relative to the compound of formula (IV) or any structure related thereto. In some embodiments, the amount of the first palladium catalyst is 0.05 to 0.1 equivalents, relative to the compound of formula (IV) or any structure related thereto. In some embodiments, Pd(dppf)Cl 2 ·CH 2 Cl 2 The amount is 0.05 to 0.1 equivalents.

[0185] Regarding step a), the first base can be an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal triphosphate, an alkali metal hydroxide, an alkali metal carboxylate, an amine, an alkali metal alkoxide, or a combination thereof. Suitable alkali metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable alkali metal bicarbonates include lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate. Suitable alkali metal triphosphates include trisodium phosphate and tripotassium phosphate. Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. Suitable alkali metal carboxylates include lithium acetate, sodium acetate, potassium acetate, cesium acetate, and trimethyl potassium acetate. Suitable amines include primary amines, secondary amines, tertiary amines, and aromatic amine bases. Suitable alkali metal alkoxides include sodium methoxide or sodium ethoxide. In some embodiments, the first alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, trisodium phosphate, tripotassium phosphate, tricesium phosphate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium acetate, potassium acetate, cesium acetate, 1,8-bis(dimethylamino)-naphthalene, tert-butylamine, diisopropylamine, N,N-diisopropylethylamine, 1-methylimidazole, sodium methoxide or a combination thereof. In some embodiments, the first alkali is sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium acetate, cesium acetate or a combination thereof. In some embodiments, the first alkali is potassium carbonate, tripotassium phosphate or potassium acetate. In some embodiments, the first alkali includes potassium carbonate. In some embodiments, the first alkali is potassium carbonate.

[0186] In some embodiments, the amount of the first base is 10 to 1 equivalents, 1 to 5 equivalents, 2 to 5 equivalents, 2 to 4 equivalents, 3 to 4 equivalents, or about 3.5 equivalents relative to the compound of formula (IV) or any structure related thereto. In some embodiments, the amount of the first base is 2 to 5 equivalents, 2 to 4 equivalents, 3 to 4 equivalents, or about 3.5 equivalents relative to the compound of formula (IV) or any structure related thereto. In some embodiments, the amount of the first base is 3 to 4 equivalents, or about 3.5 equivalents relative to the compound of formula (IV) or any structure related thereto. In some embodiments, the amount of potassium carbonate is 3 to 4 equivalents, or about 3.5 equivalents relative to the compound of formula (IV) or any structure related thereto.

[0187] Regarding step a), in some embodiments, the amount of the compound of formula (V) is 1.0 to 2.0 equivalents, 1.1 to 2.0 equivalents, 1.1 to 1.5 equivalents, or about 1.2 equivalents relative to the compound of formula (IV) or any structure related thereto. In some embodiments, the amount of the compound of formula (V) is about 1.2 equivalents relative to the compound of formula (IV) or any structure related thereto. In some embodiments, the amount of the compound of formula (V-1) is about 1.2 equivalents relative to the compound of formula (IV-1a-1).

[0188] The first solvent can be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the first solvent is water, C 1-4 In some embodiments, the first solvent comprises dioxane and water. In some embodiments, the first solvent comprises 1,4-dioxane and water. In some embodiments, the first solvent has a 1,4-dioxane: water volume ratio of 20: 1 to 1: 1, 20: 1 to 5: 1, 15: 1 to 5: 1, or about 10: 1. In some embodiments, the first solvent has a 1,4-dioxane: water volume ratio of about 10: 1.

[0189] Typically, the Suzuki reaction of step (a) can be carried out at ambient temperature to an elevated temperature. For example, the reaction mixture of step a) can be at a temperature of 30°C to 110°C or heated to reflux. In some embodiments, step a) is carried out at a temperature of 60°C to 110°C, 70°C to 110°C, 70°C to 100°C, 70°C to 90°C, or about 80°C. In some embodiments, step a) is carried out at a temperature of 70°C to 90°C. In some embodiments, step a) is carried out at a temperature of about 80°C.

[0190] For step b), the compound of formula (III) can be deprotected by various methods to provide the compound of formula (II). When the PG group is p-methoxybenzyl (PMB), any of the compounds of formula (III), (III-1) and (III-1a) can be deprotected by various methods, for example, under acidic, reductive (hydrogenolysis) or oxidative conditions to obtain the compound of formula (II).

[0191] In some embodiments, the PG group is removed by treating with a first acid in a second solvent. In some embodiments, the p-methoxybenzyl (PMB) group is removed by treating with a first acid in a second solvent. In some embodiments, the first acid is trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, or a combination thereof. In some embodiments, the first acid includes trifluoroacetic acid. In some embodiments, the first acid is trifluoroacetic acid.

[0192] The second solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the second solvent is water, C 1-4 In some embodiments, the second solvent is selected from the group consisting of ethyl alcohol, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, benzene, toluene, xylene, chlorobenzene, dichloromethane, 1,2-dichloroethane, or a combination thereof. In some embodiments, the second solvent is dichloromethane or 1,2-dichloroethane. In some embodiments, the second solvent includes dichloromethane. In some embodiments, the second solvent is dichloromethane.

[0193] When the PG group is removed under acidic conditions, in some embodiments, the deprotection reaction mixture further comprises a transfer agent. When the protecting group is p-methoxybenzyl (PMB), in some embodiments, the transfer agent is anisole.

[0194] In some embodiments, the p-methoxybenzyl (PMB) group is removed by treatment with trifluoroacetic acid and anisole in dichloromethane.

[0195] Typically, step b) under acidic conditions can be carried out at ambient to elevated temperatures. For example, the reaction mixture of step b) can be at a temperature of 30°C to 60°C or heated to reflux. In some embodiments, step b) is carried out at a temperature of about 50°C.

[0196] In some embodiments, the p-methoxybenzyl (PMB) group is removed by hydrogenolysis. In some embodiments, the p-methoxybenzyl (PMB) group is removed under oxidative conditions by treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0197] In some embodiments, the method further comprises:

[0198] c) contacting the compound of formula (II), its tautomer or a salt thereof with a second base in a third solvent; and

[0199] d) acidifying with a second acid to obtain a compound of formula (I), a tautomer thereof or a salt thereof:

[0200]

[0201] About step c), the second base can be an alkali metal carbonate, an alkali metal hydroxide, an alkali metal alkoxide or a combination thereof. Suitable alkali metal carbonates include lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate. Suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide. Suitable alkali metal alkoxides include sodium methoxide, sodium tert-butoxide and potassium tert-butoxide. In some embodiments, the second base is lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof. In some embodiments, the second base is lithium hydroxide, sodium hydroxide or potassium hydroxide. In some embodiments, the second base is sodium hydroxide. In some embodiments, the second base is an aqueous sodium hydroxide solution.

[0202] The third solvent can be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the first solvent is water, C 1-4 In some embodiments, the third solvent comprises tetrahydrofuran (THF) and water.

[0203] Typically, step c) can be carried out at ambient temperature to elevated temperature. For example, the reaction mixture of step c) can be at a temperature of 30°C to 100°C or heated to reflux. In some embodiments, step c) is carried out at a temperature of 30°C to 80°C, 40°C to 70°C, 40°C to 60°C, or 50°C to 60°C. In some embodiments, step c) is carried out at a temperature of 50°C to 60°C. In some embodiments, step c) is carried out at a temperature of about 55°C.

[0204] Regarding step d), in some embodiments, the second acid is hydrochloric acid, sulfuric acid, phosphoric acid or a combination thereof. In some embodiments, the second acid is hydrochloric acid. In some embodiments, the second acid is an aqueous solution of hydrochloric acid.

[0205] In some embodiments, step d) is performed in aqueous solution. In some embodiments, step d) is performed by treating the aqueous extract of step c) with aqueous hydrochloric acid. In some embodiments, step d) is performed by treating the aqueous extract of step c) with aqueous hydrochloric acid to obtain a mixture with a pH value of 2 to 3.

[0206] Typically, step d) can be carried out at ambient temperature to elevated temperature. For example, the reaction mixture of step d) can be reacted at a temperature of 20°C to 50°C. In some embodiments, step d) is carried out at a temperature of 20°C to 30°C or at room temperature. In some embodiments, step d) is carried out at room temperature.

[0207] With respect to any of Formulas (I), (II), (III), (V) and related structures thereof, in some embodiments, subscripts m and n are each 1. In some embodiments, one of subscripts m and n is 2 and the other is 1. In some embodiments, subscripts m and n are each 2.

[0208] In some embodiments, the compound of formula (I) is represented by any one of formula (Ia), (Ib), and (Ic):

[0209]

[0210] Among them, R 2 and R 3 As defined and described herein.

[0211] In some embodiments, the compound of formula (II) is represented by any one of formula (IIa), (IIb), and (IIc):

[0212]

[0213] Among them, R 1 , R 2 and R3 As defined and described herein.

[0214] In some embodiments, the compound of formula (III) is represented by any one of formula (IIIa-1a), (IIIb-1a), and (IIIc-1a):

[0215]

[0216]

[0217] Among them, R 1 , R 2 and R 3 As defined and described herein.

[0218] In some embodiments, the compound of formula (V) is represented by any one of formula (Va-1), (Vb-1), and (Vc-1):

[0219]

[0220] Among them, R 2 and R 3 As defined and described herein.

[0221] With respect to any of Formula (II), (III), (IV) and their related structures, in some embodiments, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl. 1 It's methyl.

[0222] With respect to any of Formula (I), (II), (III), (V) and related structures thereof, in some embodiments, R 2 and R 3 Each is independently halogen. In some embodiments, R 2 and R 3 Each is F.

[0223] In some embodiments, the compound of formula (I) is represented by any one of formula (Ia-1), (Ib-1), and (Ic-1):

[0224]

[0225] In some embodiments, the compound of formula (II) is represented by any one of formula (IIa-1), (IIb-1), and (IIc-1):

[0226]

[0227]

[0228] In some embodiments, the compound of formula (III) is represented by any one of formula (IIIa-1a-1), (IIIb-1a-1), and (IIIc-1a-1):

[0229]

[0230] In some embodiments, the compound of any one of Formula (IV), (IV-1), (IV-1a) and (IV-1a-1) is represented by Formula (IVa-1a-2):

[0231]

[0232] In some embodiments, the compound of formula (V) is represented by any one of formula (Va-1-1), (Vb-1-1), and (Vc-1-1):

[0233]

[0234] In some embodiments, the method further comprises, before step a):

[0235] a1) a compound of formula (VI) or a salt thereof:

[0236]

[0237] The method further comprises contacting with a boron reagent, a second palladium catalyst and a third base in a fourth solvent to form a compound of formula (IV) or a salt thereof, wherein X is Cl, Br or I.

[0238] For step a1), the boron reagent may be any reagent capable of converting a compound of formula (VI) into the corresponding compound of formula (IV):

[0239]

[0240] Among them, X 1 Represents a boron-containing group, which is defined and described herein. In some embodiments, the boron reagent is tetrahydroxydiboron, bis-catechol borate, bis(hexenyl glycolate)diboron, biboric acid neopentyl glycol ester or bis-pinacolyl diboron. In some embodiments, the boron reagent is bis-pinacolyl diboron.

[0241] The second palladium catalyst may be the same as the first palladium catalyst as described above. In some embodiments, the second palladium catalyst is the same as the first palladium catalyst. In some embodiments, the second palladium catalyst is Pd(dppf)Cl 2 、Pd(dppf)Cl 2 ·CH2 Cl 2 or Pd(dtbpf)Cl 2 In some embodiments, the second palladium catalyst is Pd(dppf)Cl 2 ·CH 2 Cl 2 .

[0242] In some embodiments, the second palladium catalyst is in a substoichiometric amount. In some embodiments, Pd(dppf)Cl 2 ·CH 2 Cl 2 is a substoichiometric amount. In some embodiments, the amount of the second palladium catalyst is 0.01 to 0.5 equivalents, 0.02 to 0.2 equivalents, 0.02 to 0.1 equivalents, or 0.03 to 0.05 equivalents relative to the compound of formula (VI). In some embodiments, the amount of the second palladium catalyst is 0.03 to 0.05 equivalents relative to the compound of formula (VI). In some embodiments, Pd(dppf)Cl 2 ·CH 2 Cl 2 The amount is 0.03 to 0.05 equivalents.

[0243] About step a1), the third base can be alkali carbonate, alkali bicarbonate, alkali triphosphate, alkali hydroxide, alkali carboxylate, amine, alkali alcohol salt, or its combination, each of which is defined and described above. In some embodiments, the third base is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, trisodium phosphate, tripotassium phosphate, tricesium phosphate, sodium hydroxide, potassium hydroxide, cesium hydroxide, sodium acetate, potassium acetate, cesium acetate, 1,8-bis (dimethylamino)-naphthalene, tert-butylamine, diisopropylamine, N, N-diisopropylethylamine, 1-methylimidazole, sodium methoxide or its combination. In some embodiments, the third base is sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium acetate, cesium acetate or its combination. In some embodiments, the third base is potassium carbonate, tripotassium phosphate or potassium acetate. In some embodiments, the third base includes potassium acetate. In some embodiments, the third base is potassium acetate.

[0244] In some embodiments, the amount of the third base is 1 to 10 equivalents, 1 to 5 equivalents, 2 to 5 equivalents, 2 to 4 equivalents, or about 3.0 equivalents relative to the compound of formula (VI). In some embodiments, the amount of the third base is 2 to 5 equivalents, 2 to 4 equivalents, or about 3.0 equivalents relative to the compound of formula (VI). In some embodiments, the amount of the third base is about 3.0 equivalents relative to the compound of formula (VI). In some embodiments, the amount of potassium acetate is about 3.0 equivalents relative to the compound of formula (VI).

[0245] The fourth solvent can be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the fourth solvent is water, C 1-4 In some embodiments, the fourth solvent comprises dioxane. In some embodiments, the fourth solvent comprises 1,4-dioxane. In some embodiments, the fourth solvent is 1,4-dioxane.

[0246] In some embodiments, when the amine protecting group (ie, PG) is p-methoxybenzyl (PMB), the compound of formula (VI) is represented by formula (VI-1a):

[0247]

[0248] Among them, R 1 and X are as defined and described herein.

[0249] In some embodiments, X of formula (VI) or (VI-1a) is Br.

[0250] In some embodiments, R of formula (VI) or (VI-1a) 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl or n-hexyl. 1 It's methyl.

[0251] In some embodiments, the compound of formula (VI) or (VI-1a) is represented by formula (VI-1a-1):

[0252]

[0253] In some embodiments, the compound of formula (VI) or (VI-1a) is represented by formula (VI-1a-1):

[0254] and

[0255] The compound of formula (IV) is represented by formula (IV-1a-2):

[0256]

[0257] Typically, step a1) can be carried out at ambient temperature to an elevated temperature. For example, the reaction mixture of step a1) can be at a temperature of 30°C to 110°C or heated to reflux. In some embodiments, step a1) is carried out at a temperature of 60°C to 110°C, 70°C to 110°C, 70°C to 100°C, 70°C to 90°C, or about 80°C. In some embodiments, step a1) is carried out at a temperature of 70°C to 90°C. In some embodiments, step a1) is carried out at a temperature of about 80°C.

[0258] In some embodiments, the compound of formula (IV) produced by step a1) is directly used in the next step reaction (ie, step a)) without further purification.

[0259] In some embodiments, the present invention provides a method for preparing a compound represented by formula (I), a tautomer thereof or a salt thereof:

[0260]

[0261] The method comprises:

[0262] a1) the compound of formula (VI-1a) or a salt thereof:

[0263]

[0264] and contacting with bis-pinacol diboron, a second palladium catalyst and a third base in a fourth solvent to obtain a compound of formula (IV-1a-1) or a salt thereof:

[0265]

[0266] a) reacting a compound of formula (IV-1a-1) or a salt thereof with a compound of formula (V-1):

[0267]

[0268] The first palladium catalyst and the first base are contacted in a first solvent to form a compound of formula (III-1a) or a salt thereof:

[0269]

[0270] b) treating the compound of formula (III-1a) or a salt thereof with trifluoroacetic acid and anisole in dichloromethane to obtain a compound of formula (II), a tautomer thereof or a salt thereof:

[0271]

[0272] c) saponifying the compound of formula (II), its tautomer or a salt thereof with a second base in a third solvent; and

[0273] d) acidifying with a second acid to obtain a compound of formula (I), a tautomer thereof or a salt thereof,

[0274] wherein X is Cl, Br or I;

[0275] The subscripts m and n are each independently 1 or 2;

[0276] R 1 It is C 1-3 Alkyl; and

[0277] R 2 and R 3 Each is F.

[0278] In some embodiments, the method further comprises:

[0279] e) converting the compound of formula (I), its tautomer or a salt thereof into a monosodium salt of the compound of formula (I) represented by the following formula:

[0280]

[0281] The disodium salt of the compound of formula (I) represented by the following formula:

[0282]

[0283] or a mixture thereof, or a tautomer thereof, wherein the subscripts m and n are each independently 1 or 2; R 2 and R 3 Each is F.

[0284] In some embodiments, X of formula (VI-1a) is Br.

[0285] In some embodiments, the second palladium catalyst of step a1) and the first palladium catalyst of step a) are each independently Pd(dppf)Cl 2 、Pd(dppf)Cl 2 ·CH 2 Cl 2 , or Pd(dtbpf)Cl 2In some embodiments, the second palladium catalyst of step a1) and the first palladium catalyst of step a) are each Pd(dppf)Cl 2 ·CH 2 Cl 2 .

[0286] In some embodiments, the third base of step a1) and the first base of step a) are each independently sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium acetate or cesium acetate. In some embodiments, the third base of step a1) and the first base of step a) are each independently potassium carbonate or potassium acetate. In some embodiments, the third base of step a1) is potassium acetate; the first base of step a) is potassium carbonate.

[0287] In some embodiments, the fourth solvent of step a1) and the first solvent of step a) are each independently water, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF) or a combination thereof. In some embodiments, the fourth solvent of step a1) and the first solvent of step a) are each independently water, 1,4-dioxane or a combination thereof. In some embodiments, the fourth solvent of step a1) is 1,4-dioxane; the first solvent of step a) is a mixture of 1,4-dioxane and water.

[0288] In some embodiments, the second base of step c) is lithium hydroxide, sodium hydroxide or potassium hydroxide. In some embodiments, the second base of step c) is sodium hydroxide. In some embodiments, the second base of step c) is aqueous sodium hydroxide.

[0289] In some embodiments, the third solvent of step c) is water, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF) or a combination thereof. In some embodiments, the third solvent of step c) is a mixture of water and tetrahydrofuran (THF).

[0290] In some embodiments, the second acid is hydrochloric acid. In some embodiments, the second acid is an aqueous solution of hydrochloric acid.

[0291] With respect to any of Formulas (I), (II), (III-1a), (V-1), in some embodiments, subscripts m and n are each 1. In some embodiments, one of subscripts m and n is 2 and the other is 1. In some embodiments, subscripts m and n are each 2.

[0292] With respect to any of Formula (II), (III-1a), (IV-1a-1), and (VI-1a), in some embodiments, R 1is methyl or ethyl. In some embodiments, R 1 It's methyl.

[0293] All other reaction conditions of steps a1) and a) to d) are as described above.

[0294] In some embodiments, step e) is carried out by treating the compound of formula (I) or its tautomer with aqueous sodium hydroxide solution. In some embodiments, the amount of sodium hydroxide is less than 1.0 equivalents, based on salt-free and anhydrous, relative to the compound of formula (I). In some embodiments, the amount of sodium hydroxide is 0.80 to 0.95 or 0.85 to 0.95 equivalents, based on salt-free and anhydrous, relative to the compound of formula (I). In some embodiments, the amount of sodium hydroxide is about 0.88 equivalents, based on salt-free and anhydrous, relative to the compound of formula (I). In some embodiments, the pH value of the reaction mixture of step e) is about 9.5.

[0295] In some embodiments, step e) is performed by:

[0296] i) treating a compound of formula (I) or a tautomer thereof with aqueous sodium hydroxide in water;

[0297] ii) forming a slurry having a pH of about 9.5; and

[0298] iii) freeze-drying the slurry to obtain the monosodium salt of the compound of formula (I) represented by the following formula:

[0299]

[0300] or a tautomer thereof,

[0301] wherein the amount of sodium hydroxide is less than 1.0 equivalent relative to the compound of formula (I), calculated on a salt-free and anhydrous basis; subscripts m and n are each independently 1 or 2; R 2 and R 3 Each is F. In some embodiments, the amount of sodium hydroxide relative to the compound of formula (I) is about 0.88 equivalents on a salt-free and anhydrous basis.

[0302] In another aspect, the present invention provides a method for preparing a compound represented by formula (Ia-1), a tautomer thereof or a salt thereof:

[0303]

[0304] The method comprises:

[0305] a1) the compound of formula (VI-1a-1) or a salt thereof:

[0306]

[0307] With bis-pinacol diboron, Pd(dppf)Cl 2 ·CH 2 Cl 2 and potassium acetate in 1,4-dioxane to form a compound of formula (IV-1a-2) or a salt thereof:

[0308]

[0309] a) a compound of formula (IV-1a-2) or a salt thereof is reacted with 1-bromo-4-(3,3-difluorocyclobutyl)benzene, Pd(dppf)Cl in a mixture of 1,4-dioxane and water; 2 ·CH 2 Cl 2 , and contact with potassium carbonate to form a compound of formula (IIIa-1a-1) or a salt thereof:

[0310]

[0311] b) treating the compound of formula (IIIa-1a-1) or a salt thereof with trifluoroacetic acid and anisole in dichloromethane to obtain the compound of formula (IIa-1), its tautomer or a salt thereof:

[0312]

[0313] c) saponifying the compound of formula (IIa-1), its tautomer or a salt thereof with an aqueous solution of sodium hydroxide in tetrahydrofuran; and

[0314] d) acidifying with aqueous HCl to obtain the compound of formula (Ia-1), its tautomer or a salt thereof.

[0315] In some embodiments, step a1) is performed at a temperature of about 80°C; step a) is performed at a temperature of about 80°C; step b) is performed at a temperature of about 50°C; step c) is performed at a temperature of about 55°C; step d) is performed at a temperature of about 20-25°C.

[0316] In some embodiments, in step a1), relative to the compound of formula (VI-1a-1), Pd(dppf)Cl 2 ·CH 2 Cl 2 The amount of Pd(dppf)Cl is 0.02 to 0.5 equivalents. In some embodiments, in step a1), relative to the compound of formula (VI-1a-1), Pd(dppf)Cl 2 ·CH 2 Cl 2The amount of is about 0.04 equivalents. In some embodiments, in step a1), the amount of bis-pinacolyl diboron is about 1.5 equivalents relative to the compound of formula (VI-1a-1). In some embodiments, in step a1), the amount of potassium acetate is about 3.0 equivalents relative to the compound of formula (VI-1a-1).

[0317] In some embodiments, in step a), the amount of 1-bromo-4-(3,3-difluorocyclobutyl)benzene is 1.0 to 1.5 equivalents relative to the compound of formula (IV-1a-2). In some embodiments, in step a), the amount of 1-bromo-4-(3,3-difluorocyclobutyl)benzene is about 1.2 equivalents relative to the compound of formula (IV-1a-2). In some embodiments, in step a), the amount of Pd(dppf)Cl is about 1.2 equivalents relative to the compound of formula (IV-1a-2). 2 ·CH 2 Cl 2 The amount of Pd(dppf)Cl is 0.05 to 0.1 equivalents. In some embodiments, in step a), relative to the compound of formula (IV-1a-2), Pd(dppf)Cl 2 ·CH 2 Cl 2 The amount is about 0.07 equivalents. In some embodiments, in step a), the amount of potassium carbonate is 2.0 to 4.0 equivalents relative to the compound of formula (IV-1a-2). In some embodiments, in step a), the amount of potassium carbonate is about 3.5 equivalents relative to the compound of formula (IV-1a-2).

[0318] In some embodiments, the compound of formula (IV-1a-2) produced by step a1) is directly used in the next step (ie, step a)) without further purification.

[0319] In some embodiments, the compound of formula (IIIa-1a-1) is isolated from steps a1) and a) with a combined yield of at least 50%. In some embodiments, the compound of formula (IIIa-1a-1) is isolated from steps a1) and a) with a combined yield of 50% to 80% or 60% to 70%. In some embodiments, the compound of formula (IIIa-1a-1) is isolated from steps a1) and a) with a combined yield of about 60%.

[0320] In some embodiments, the compound of formula (IIa-1) produced by step b) is directly used in the next step (ie, step c)) without further purification.

[0321] In some embodiments, step d) is performed by acidifying an aqueous extract of the reaction mixture of step c).

[0322] In some embodiments, the method further comprises:

[0323] e) converting the compound of formula (Ia-1), its tautomer or a salt thereof into a monosodium salt of the compound of formula (Ia-1) represented by the following formula:

[0324]

[0325] The disodium salt of the compound of formula (Ia-1) represented by the following formula:

[0326]

[0327] or a mixture thereof, or a tautomer thereof.

[0328] In some embodiments, step e) is carried out by treating a compound of formula (Ia-1) or a tautomer thereof with an aqueous sodium hydroxide solution in water. In some embodiments, the amount of sodium hydroxide is less than 1.0 equivalents, in terms of salt-free and anhydrous, relative to the compound of formula (Ia-1). In some embodiments, the amount of sodium hydroxide is 0.80 to 0.95 or 0.85 to 0.95 equivalents, in terms of salt-free and anhydrous, relative to the compound of formula (Ia-1). In some embodiments, the amount of sodium hydroxide is about 0.88 equivalents, in terms of salt-free and anhydrous, relative to the compound of formula (Ia-1). In some embodiments, the pH value of the reaction mixture of step e) is about 9.5.

[0329] In some embodiments, step e) is performed by:

[0330] i) treating the compound of formula (Ia-1) or its tautomer with aqueous sodium hydroxide in water;

[0331] ii) forming a slurry having a pH of about 9.5; and

[0332] iii) freeze-drying the slurry to obtain the monosodium salt of the compound of formula (Ia-1) represented by the following formula:

[0333]

[0334] or a tautomer thereof,

[0335] wherein the amount of sodium hydroxide is less than 1.0 equivalent, calculated on a salt-free and anhydrous basis, relative to the compound of formula (Ia-1); the subscripts m and n are each independently 1 or 2; and R 2 and R 3 Each is F. In some embodiments, the amount of sodium hydroxide is about 0.88 equivalents, based on salt-free and anhydrous, relative to the compound of formula (Ia-1).

[0336] Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.

[0337] Certain compounds of the present invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present invention. Tautomer refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. For example, the 1,2,3-triazole of the following formula may exist in equilibrium:

[0338]

[0339] In some embodiments, in formula (I), the following compounds may exist in equilibrium:

[0340]

[0341] In some embodiments, in formula (II), the following compounds may exist in equilibrium:

[0342]

[0343] In some embodiments, the compounds of the present invention may exist as monobasic base addition salts, wherein the carboxylic acid or 1,2,3-triazole group is deprotonated and forms a salt with a base. In some embodiments, the compounds of the present invention may exist as dibasic base addition salts, wherein both the carboxylic acid and the 1,2,3-triazole group are deprotonated and form a dibasic base salt with a base. In some embodiments, the sodium salt form of the compound of formula (I) is a monosodium salt as shown below:

[0344]

[0345] The disodium salt is shown as follows:

[0346] or

[0347] mixtures thereof, wherein the subscripts m and n, R 2 and R 3 As defined and described herein. In some embodiments, the sodium salt of the compound of formula (II) may have the following formula:

[0348]

[0349] Among them, the subscripts m and n, R 1 , R 2 and R 3 As defined and described herein.

[0350] Compound

[0351] In one aspect, the present invention provides a compound represented by formula (X), a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0352]

[0353] Among them, R 1 H or C 1-6 Alkyl; R 2 and R 3 Each is independently H or halogen.

[0354] In some embodiments, the compound of formula (X) is represented by formula (Xa):

[0355]

[0356] In some embodiments, the compound of formula (X) is represented by formula (Xb):

[0357]

[0358] With respect to any of Formulas (X), (Xa), and (Xb), in some embodiments, R 1 is H. In some embodiments, R 1 It is C 1-6 In some embodiments, R 1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl or hexyl. 1 In some embodiments, R 1 It is ethyl.

[0359] With respect to any of Formulas (X), (Xa), and (Xb), in some embodiments, R 2 and R 3 Each is independently halogen. In some embodiments, R 2 and R 3 Each is independently F, Cl, Br or I. In some embodiments, R 2 and R 3 Each is F.

[0360] Examples of compounds of formula (X) are listed in Table 1.

[0361] Table 1: Compounds

[0362]

[0363]

[0364] In some embodiments, the compound of formula (X) is represented by formula (Ib-1):

[0365]

[0366] In some embodiments, the compound of formula (X) is represented by formula (Ic-1):

[0367]

[0368] The compounds of the present invention may exist in the form of salts. The present invention includes such salts. When the compounds of the present invention contain relatively acidic functional groups (e.g., 1,2,3-triazole-4-carboxylic acid or 1,2,3-triazole), the present invention includes base addition salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts or magnesium salts, or similar salts. When R 1 C 1-6 When the group is alkyl, the present invention may include acid addition salts such as inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts and organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts.

[0369] Pharmaceutically acceptable salts include salts of active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds described in the present invention contain relatively acidic functional groups, base addition salts can be obtained by reacting the neutral form of such compounds with a sufficient amount of the desired base (pure alkali or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts or magnesium salts, or similar salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mark Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0370] In some embodiments, the compounds of the present invention may exist as monobasic base addition salts, wherein the carboxylic acid or 1,2,3-triazole group is deprotonated and forms a salt with a base. In some embodiments, the compounds of the present invention may exist as dibasic base addition salts, wherein both the carboxylic acid and the 1,2,3-triazole group are deprotonated and form a dibasic base salt with a base. In some embodiments, the sodium salt form of the compound of formula (X) may have any of the following formulas:

[0371]

[0372] Among them, R 1 , R 2 and R 3 As defined and described herein.

[0373] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound.The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0374] Some compounds of the present invention may exist in non-solvated form and solvated form, including hydrated form. Typically, solvated form is equivalent to non-solvated form and is included within the scope of the present invention. Some compounds of the present invention may exist in multiple crystals or amorphous forms. Generally speaking, for the intended use of the present invention, all physical forms are equivalent and are intended to fall within the scope of the present invention.

[0375] Certain compounds of the invention possess asymmetric carbon atoms (optical centers); enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomeric forms that can be defined in terms of absolute stereochemistry as (R)- or (S)-, as well as individual isomers are included within the scope of the invention. The compounds of the invention do not include those that are known in the art to be too unstable to synthesize and / or separate. The invention is intended to include compounds in racemic and optically pure forms. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using a variety of techniques.

[0376] Isomers include compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

[0377] Certain compounds of the present invention may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of the present invention. Tautomer refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. For example, the 1,2,3-triazole of the following formula may exist in equilibrium:

[0378]

[0379] In some embodiments, in formula (X), the following compounds may exist in equilibrium:

[0380]

[0381] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, both the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention.

[0382] Unless otherwise indicated, the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present invention may be labeled with radioactive or stable isotopes, such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), fluorine-18( 18 F), nitrogen-15 ( 15 N), oxygen-17 ( 17 O), oxygen-18 ( 18 O), carbon-13 ( 13 C) or carbon-14 ( 14 C) All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0383] In addition to salt forms, the present invention also provides compounds in the form of prodrugs. Prodrugs of compounds described herein are those compounds that are prone to chemical changes under physiological conditions to provide compounds of the present invention. In addition, prodrugs can be converted into compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch groove with a suitable enzyme or chemical reagent, prodrugs can be slowly converted into compounds of the present invention.

[0384] Composition

[0385] The compositions of the present invention can be prepared into a variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for ingestion by patients. The compositions of the present invention can also be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal or intraperitoneal administration. In addition, the compositions described herein can be administered by inhalation, such as intranasal administration. In addition, the compositions of the present disclosure can be administered transdermally. The compositions of the present invention can also be administered by intraocular, intravaginal and intrarectal routes, including suppositories, insufflations, powders and aerosol formulations (e.g., steroid inhalers, see Rohatagi, Journal of Clinical Pharmacology. 35: 1187-1193, 1995; Tjwa, Annals of Allergy, Asthma and Immunology. 75: 107-111, 1995). Therefore, the present invention also provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and / or excipients and a compound provided herein (e.g., a compound of formula (X)) or a pharmaceutically acceptable salt of a compound provided herein (e.g., a compound of formula (X)).

[0386] In order to prepare pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Solid carriers may be one or more substances, which may also be used as diluents, flavoring agents, adhesives, preservatives, tablet disintegrants, or encapsulating materials. The details of formulation and administration techniques are described in detail in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mark Publishing Company, Easton, Pennsylvania ("Remington's").

[0387] In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in a specified shape and size.

[0388] Powders, capsules and tablets preferably contain from about 5% to about 70% of the active compound, for example from about 10% to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier, the encapsulating material providing a capsule in which the active ingredient, with or without other excipients, is surrounded by a carrier and thereby combined with it. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0389] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low melting wax; cocoa butter; carbohydrates; sugars, including but not limited to lactose, sucrose, mannitol or sorbitol, starch from corn, wheat, rice, potato or other plants; celluloses, such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; and gums, including gum arabic and tragacanth; and proteins, including but not limited to gelatin and collagen. Disintegrators or solubilizers may be added, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.

[0390] The dragee core has a suitable coating, such as a concentrated sugar solution, which may also include gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to tablets or dragee coatings for product identification or characterization of the amount (i.e., dosage) of the active compound. The pharmaceutical preparation of the present invention may also be used orally, for example, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and coatings such as glycerol or sorbitol. Push-fit capsules may include compounds provided herein (e.g., compounds of formula (X)) mixed with fillers or adhesives such as lactose or starch, lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, compounds provided herein (e.g., compounds of formula (X)) may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycol, with or without stabilizers.

[0391] To prepare suppositories, a low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the compound provided herein (e.g., compound of formula (X)) is then dispersed uniformly therein by stirring. The molten homogeneous mixture is then poured into a mold of suitable size, allowed to cool, and thereby solidified.

[0392] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations may be formulated in solution in aqueous polyethylene glycol.

[0393] Aqueous solutions suitable for oral use can be prepared by dissolving a compound provided herein (e.g., a compound of formula (X)) in water and adding optional suitable colorants, flavorings, stabilizers and thickeners. Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active ingredients in water containing a viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth and gum arabic, dispersants or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g., 17ethyleneoxyhexadecyl alcohol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose, aspartame or saccharin. The formulation may be adjusted according to osmotic pressure.

[0394] Also included are preparations in solid form that are converted into liquid form shortly before use for oral administration. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these preparations may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0395] Oil suspensions can be prepared by suspending the compounds provided herein (e.g., compounds of formula (X)) in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil or mineral oils such as liquid paraffin; or mixtures of these. The oil suspension may contain a thickener, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners may be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations may be preserved by adding antioxidants such as ascorbic acid. For an example of an injectable oil carrier, see Minto, Journal of Pharmacology and Experimental Therapeutics. 281: 93-102, 1997. The pharmaceutical preparations of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil, as described above, or a mixture thereof. Suitable emulsifiers include naturally occurring gums, such as gum arabic and tragacanth, naturally occurring phospholipids, such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitol monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitol monooleate. Emulsions may also contain sweeteners and flavoring agents, such as syrups and elixirs in the formulation. Such preparations may also include a demulcent, a preservative, or a coloring agent.

[0396] The compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical methods. Transdermal administration methods by topical routes can be formulated into applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, coatings, powders and aerosols.

[0397] The compositions of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be formulated to be administered by intradermal injection of drug-containing microspheres, which are slowly released subcutaneously (see Rao, Journal of Biomaterials Science-Polymer Edition. 7: 623-645, 1995); as a biodegradable and injectable gel formulation (see, for example, Gao Pharmaceutical Research. 12: 857-863, 1995); or, as microspheres for oral administration (see, for example, Eyles, Journal of Pharmacy and Pharmacology. 49: 669-674, 1997). Both transdermal and intradermal routes can provide sustained delivery for weeks or months.

[0398] In another embodiment, the composition of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or organ lumen. The preparation for administration generally comprises a solution in which the composition of the present invention is dissolved in a pharmaceutically acceptable carrier. Acceptable carriers and solvents that can be used include water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils can be used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections. These solutions are sterile and generally do not contain unwanted substances. These preparations can be sterilized by various sterilization techniques. As needed, the preparation can include pharmaceutically acceptable auxiliary substances to approach physiological conditions, such as pH regulators and buffers, toxicity regulators, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the composition of the present invention in these preparations can vary widely, and will be selected mainly based on fluid volume, viscosity, body weight, etc., and selected according to the selected specific mode of administration and the needs of the patient. For intravenous administration, the preparation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. Such suspensions can be prepared using those suitable dispersants or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as 1,3-butanediol solution.

[0399] In another embodiment, the preparation of the composition of the present invention can be delivered by using liposomes. Without wishing to be bound by theory, such liposomes may fuse with the cell membrane; or be endocytosed, that is, by using a ligand connected to the liposome or directly connected to the oligonucleotide, which binds to the surface membrane protein receptor of the cell, resulting in endocytosis. By using liposomes, especially when the liposome surface carries a ligand specific to the target cell or otherwise preferentially targets a specific organ, the composition of the present invention can be delivered to the target cell in vivo. (See, e.g., Al-Muhammed, Journal of Microencapsulation. 13: 293-306, 1996; Chonn, Current Views in Biotechnology. 6: 698-708, 1995; Ostro, Journal of Hospital Pharmacy. 6: 1576-1587, 1989).

[0400] Lipid-based drug delivery systems include lipid solutions, lipid emulsions, lipid dispersions, self-emulsifying drug delivery systems (SEDDS) and self-microemulsifying drug delivery systems (SMEDDS). In particular, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants and co-surfactants that can spontaneously disperse in aqueous media and form miniemulsions (SEDDS) or microemulsions (SMEDDS). The lipids that can be used for the formulations of the present invention include any natural or synthetic lipids, including but not limited to sesame oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerides, oleic acid macrogol glycerides, and the like. Caprylic / capric macrogol glycerides Polyoxyethylene castor oil PEG-15 Hydroxystearate Twain Propylene glycol caprylate Glyceryl Monooleate Mixed caprylic and capric glycerides and monoolein

[0401] The pharmaceutical preparation of the compound of formula (X) of the present invention can be in salt form and can be formed by reaction with many acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be more soluble in water or other protic solvents in the form of the corresponding free alkali. In other cases, the preparation can be a lyophilized powder in 1mM-50mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, with a pH range of 4.5 to 5.5, mixed with buffer before use.

[0402] The pharmaceutical preparations of the compounds of formula (X) according to the present invention may be in the form of salts and may be formed with bases, i.e. cationic salts such as alkali metal salts and alkaline earth metal salts, e.g. sodium, lithium, potassium, calcium, magnesium, and ammonium salts, e.g. ammonium salts, trimethylammonium salts, diethylammonium salts and tris(hydroxymethyl)methylammonium salts.

[0403] method

[0404] Compounds of formula (I), (II) or (X) and compounds listed in Table 1 can be used as inhibitors of glycolate oxidase, and methods of inhibiting glycolate oxidase are also provided herein. The method comprises providing glycolate oxidase and a compound according to any one of the above formulas (I), (II), (X), (Xa) and (Xb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or salt to a subject (e.g., a patient) in need thereof. Inhibiting glycolate oxidase generally comprises contacting glycolate oxidase with an amount of the compound sufficient to reduce the activity of the glycolate oxidase compared to the activity of the glycolate oxidase in the absence of the compound. For example, contacting glycolate oxidase with a compound according to any one of formulas (I), (II), (X), (Xa) and (Xb) can result in about 1% to about 99% inhibition of glycolate oxidase (i.e., the activity of the inhibited glycolate oxidase is 99% to 1% of the activity of the glycolate oxidase in the absence of the compound). The level of glycolate oxidase inhibition can be from about 1% to about 10%, or from about 10% to about 20%, or from about 20% to about 30%, or from about 30% to about 40%, or from about 40% to about 50%, or from about 50% to about 60%, or from about 60% to about 70%, or from about 70% to about 80%, or from about 80% to about 90%, or from about 90% to about 99%. The level of glycolate oxidase inhibition can be from about 5% to about 95%, or from about 10% to about 90%, or from about 20% to about 80%, or from about 30% to about 70%, or from about 40% to about 60%. In some embodiments, contacting glycolate oxidase with a compound described herein will result in complete (i.e., 100%) glycolate oxidase inhibition. In some embodiments, compounds of formula (I), (II) or (X) reduce glyoxylate levels. In some embodiments, compounds of formula (X) reduce glyoxylate levels.

[0405] In some embodiments, in a method for inhibiting glycolate oxidase, the method comprises contacting glycolate oxidase with a compound represented by the following formula, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0406] or

[0407] In some embodiments, in a method for inhibiting glycolate oxidase, the method comprises contacting glycolate oxidase with a compound represented by the following formula, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0408] or

[0409] In primary hyperoxaluria type I (PH1), mutations in alanine-glyoxylate transamination (AGT) disrupt the glyoxylate detoxification pathway. Mutations in AGT prevent AGT from converting glyoxylate into pyruvate, and the resulting accumulation of glyoxylate leads to higher levels of oxalate and oxalate-containing kidney stones. Glycolate oxidase (GO) is a peroxisomal liver enzyme that catalyzes the oxidation of glycolate to glyoxylate, a substrate for AGT. Therefore, GO plays a key role in glyoxylate production, while AGT plays a key role in glyoxylate detoxification. The present invention provides compounds and methods for treating PH1 by targeting GO, a source of AGT substrates. The GO inhibitors described herein can reduce glyoxylate levels in PH1 patients, thereby compensating for the ability of mutant AGT (located downstream of GO in the glyoxylate detoxification pathway) to metabolize glyoxylate and preventing the harmful accumulation of oxalate. In some embodiments, compounds of formula (I) reduce glyoxylate levels in PH1 patients or subjects suffering from PH1.

[0410] Also provided herein are methods for treating primary hyperoxaluria (PH1). In Europe, the prevalence of PH1 is 1-3 per million people, with an incidence of 1-9 per 100,000 live births per year [Salido, Supramolecular Chemistry]. PH1 is caused by mutations in the gene encoding the peroxisomal enzyme AGT, which is unable to detoxify glyoxylate and results in a marked increase in the synthesis of oxalate by the liver. In PH1, elevated excretion of urinary oxalate (UOx) leads to the production of insoluble calcium oxalate (CaOx) crystals that tend to precipitate primarily in the kidneys, forming kidney stones and diffuse nephrocalcinosis [Kaufman, Supramolecular Chemistry]. This impairs renal function and progresses to end-stage renal disease (ESRD). Once renal function declines to a glomerular filtration rate (GFR) below 30 ml / min / 1.73 m 2 , oxalate produced by the liver can no longer be cleared by the kidneys, resulting in systemic deposition of CaOx (oxalic acidosis). In people with PH1, the accumulated oxalate is deposited in the kidneys and urinary tract. It combines with calcium to form the main component of kidney and bladder stones. The first symptoms of PH1 include hematuria, abdominal pain, stone passage, or recurrent urinary tract infections. The initial diagnosis is based on clinical and ultrasonographic findings and UOx evaluation. AGT activity assessment in liver biopsy and / or DNA analysis is required to confirm the PH1 diagnosis and to initiate conservative treatment (high fluid intake, pyridoxine, CaOx crystallization inhibitors) with the goal of maintaining renal function. The most effective treatment for PH1 is liver transplantation (LTx), alone (upfront) or in combination with renal transplantation [Cochat, et al. (2012) Nephrol Dialysis Transplant. 27:1729].

[0411] In some embodiments, the method for treating PH1 comprises administering to a subject in need thereof a compound according to any one of the above formulas (I), (II), (X), (Xa) and (Xb), a pharmaceutically acceptable salt thereof; or a pharmaceutical composition containing the compound or salt. In some embodiments, the subject suffers from kidney stones and / or bladder stones. In some embodiments, the compound of formula (X) reduces glyoxylate levels in the subject. In some embodiments, the compound of formula (X) reduces the accumulation of oxalate in the kidney and / or urinary tract.

[0412] In some embodiments of the method of treating PH1, the method comprises administering a compound of the following formula, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0413] or

[0414] In some embodiments of the method of treating PH1, the method comprises administering a compound of the following formula, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0415] or

[0416] Also provided herein is a method for treating kidney stones and / or bladder stones. The method comprises administering to a subject in need thereof a compound according to any one of the above formulas (I), (II), (X), (Xa) and (Xb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the compound or salt. In some embodiments, the compound of formula (X) reduces the accumulation of oxalate in the kidney and / or urinary tract.

[0417] In some embodiments of the method of treating kidney stones and / or bladder stones, the method comprises administering a compound represented by the following formula, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0418] or

[0419] In some embodiments of the method of treating kidney stones and / or bladder stones, the method comprises administering a compound represented by the following formula, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

[0420] or

[0421] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, both the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Example

[0422] The following abbreviations are used in the following examples:

[0423] aq water-based

[0424] bs wide single peak

[0425] CD 3 OD methanol-d 4

[0426] CDCl 3 Chloroform-d

[0427] conc. Concentration

[0428] DAST Diethylaminosulfur trifluoride

[0429] DCE 1,2-Dichloroethane

[0430] DCM Dichloromethane

[0431] DIPEA Diisopropylethylamine

[0432] DMA Dimethylacetamide

[0433] DMF Dimethylformamide

[0434] DMSO Dimethyl sulfoxide

[0435] Eq. Equivalent

[0436] E 2 O Diethyl ether

[0437] EtOAc Ethyl acetate

[0438] h hour

[0439] Hex

[0440] HPLC High Performance Liquid Chromatography

[0441] LRMS Low Resolution Mass Spectrometry

[0442] M Moore

[0443] MeOH Methanol

[0444] MTBE Methyl tert-butyl ether

[0445] min

[0446] NaCl Sodium chloride

[0447] Na 2 SO 4 Sodium sulfate

[0448] PMB p-Methoxybenzyl

[0449] RBF Round Bottom Flask

[0450] rt room temperature

[0451] t R Retention time

[0452] satd. saturated

[0453] SiO 2 Silicone

[0454] TFA Trifluoroacetic acid

[0455] Tf 2 O Trifluoromethanesulfonic anhydride

[0456] THF Tetrahydrofuran

[0457] TLC Thin Layer Chromatography

[0458] XtalFluor-E N,N-diethyl-S,S-difluorothiaminium tetrafluoroborate.

[0459] According to Figure 2 Scheme 1 shown in the figure, synthesizes compounds of formula (I) and (II) by Suzuki reaction of compound of formula (IV-1a-1) and compound of formula (V-1), wherein subscripts m and n, R 1 , R 2 , R 3 and X are as defined and described herein; the first palladium catalyst and the second palladium catalyst, the first base and the third base, and the first solvent and the fourth solvent are as defined and described herein.

[0460] In particular, the compound of formula (Ia-1) is according to Figure 3 The intermediate compound of formula (VI-1a-1) is prepared according to Figure 4 1-Bromo-4-(3,3-difluorocyclobutyl)benzene was prepared as shown in Scheme 3. Figure 5 Prepared as shown in Scheme 4.

[0461] Example 1: 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (VI-1a-1)

[0462] Step 1: 1-(Chloromethyl)-4-methoxybenzene (02)

[0463]

[0464] At 0°C, PCl 3 (2.73kg, 19.9mol, 1.1 equivalents) was added to a stirred solution of p-methoxybenzyl alcohol (2.5kg, 18.09mol, 1.0 equivalents) in DCM (12.5L, 5.0Vol). The reaction mixture was stirred at room temperature for 3.0 hours. The reaction was monitored by TLC (mobile phase: 60% ethyl acetate in n-heptane). The reaction mixture was poured into cold ammonia (10.0L, 4.0vol). The organic layer was collected and the aqueous layer was further extracted with DCM (2X6.0L). The organic extracts were combined, washed with brine (100L, 4.0vol) and dried over sodium sulfate. After filtration, the filtrate was concentrated under vacuum at 40°C to obtain a crude p-methoxybenzyl chloride product (02) (2.45kg, 86.48%) as a yellow oil, which was used in step 2 without further purification. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.17 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 8.7 Hz, 2H), 4.42 (s, 2H), 3.65 (s, 3H).

[0465] Step 2: 1-(Azidomethyl)-4-methoxybenzene (03)

[0466]

[0467] At room temperature, sodium azide (1.19 kg, 18.3 mol, 1.2 equiv.) was added to a stirred solution of p-methoxybenzyl chloride (02) (2.4 kg, 15.32 mol, 1.0 equiv.) in DMF (9.6 L, 4.0 Vol.). The reaction mixture was stirred at 50 ° C for 18.0 hours. The progress of the reaction was monitored by TLC (mobile phase: 100% n-heptane). The reaction mixture was quenched with water (24.0 L, 10.0 Vol) and extracted with EtOAc (2x20.0 L). The combined organic extracts were washed with water (2x20.0 L) and brine (3x20.0 L). After drying with sodium sulfate, the solvent was filtered and evaporated at 50 ° C under vacuum to obtain a crude product of 1-(azidomethyl)-4-methoxybenzene (03) (2.12 kg) as a brown oil. The crude product was used in step 3 without further purification. 1 H NMR (300 Mhz, chloroform-d) δ 7.27 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 4.29 (s, 2H), 3.84 (s, 3H).

[0468] Step 3: 5-Hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (04)

[0469]

[0470] At room temperature, dimethyl malonate (2.32 kg, 17.55 mol, 1.37 equivalents) and K 2 CO 3 (7.11 kg, 51.44 mol, 4.0 equiv) was added to a stirred solution of azide 03 (2.1 kg, 12.87 mol, 1.0 equiv) dissolved in DMSO (13.65 L, 6.5 vol). The reaction mixture was stirred at 50 °C for 48.0 hours. The progress of the reaction was monitored by TLC (mobile phase: 40% ethyl acetate in n-heptane). The reaction mixture was cooled to room temperature, diluted with water (21.0 L, 10 vol), and then washed with MTBE (2X10.0 L). The MTBE extract was discarded. The aqueous layer was quenched with 4N HCl (21.0 L, 10.0 Vol) below 10 °C and extracted with EtOAc (2x20.0 L). The combined ethyl acetate extracts were washed with brine (3x20.0 L) and dried over sodium sulfate. After filtration, the filtrate was concentrated under vacuum at 50°C to give a crude product (1.6 kg) of methyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (04) as a yellow oil, which was used in the next step.

[0471] Step 4: 5-Chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (05)

[0472]

[0473] At room temperature, PCl 5 (1.51 kg, 7.25 mol, 1.2 eq) was added to a stirred solution of 04 (1.6 kg, 6.08 mol, 1.0 eq) in toluene (10.0 L, 6.25 vol). The reaction mixture was stirred at 60 ° C for 2.0 hours. The progress of the reaction was monitored by TLC (mobile phase was 40% ethyl acetate in n-heptane). The reaction mixture was then poured into cooled ammonia (16.0 L, 10.0 vol) and ice (10.0 kg). The reaction mixture was extracted with ethyl acetate (2×20.0 L). The combined organic extracts were washed with brine (16.0 L, 10.0 vol). After drying with sodium sulfate and filtering, the solvent was evaporated under vacuum at 50 ° C to obtain a brown semi-solid 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester crude product (05) (1.32 kg). The crude product 05 was used directly in step 5 without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ 7.2-7.5 (m, 2H), 6.9-7.1 (m, 2H), 5.45 (s, 2H), 3.9 (s, 3H), 3.8 (s, 3H).

[0474] Step 5: 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (VI-1a- 1)

[0475]

[0476] At room temperature, 4-bromophenol (0.798 kg, 4.615 mol, 1.0 equivalent) and K 2 CO 3 (2.551kg, 18.44mol, 4.0 equivalents) was added to a stirred solution of crude 05 (1.3kg, 4.615) in DMF (7.8L, 6.0vol). The reaction mixture was stirred at 90°C for 20 hours. The reaction progress was monitored by TLC (the mobile phase was 30% ethyl acetate in n-heptane). The reaction mixture was cooled to room temperature, quenched with water (20.0L, 15.3vol), and then extracted with EtOAc (2X15.0L). The combined organic extracts were washed with water (2x10.0L) and brine (3X10.0L). After drying with sodium sulfate, it was then concentrated under vacuum at 50°C to obtain the crude product of formula (VI-Ia-1). The crude product of formula (VI-Ia-1) was purified by column chromatography on silica gel (5.0 kg, mesh size 230-400) eluting with 0-30% EtOAc in n-heptane to give pure compound of formula (VI-Ia-1) (650 g, 33.67%) as a light yellow solid. 1 H NMR (300MHz, chloroform-d) δ7.35(d,J=9.0Hz,2H),7.21–7.13(m,2H),6.77(d,J=8.6Hz,2H),6.61(d,J=9.0Hz,2H),5.36(s,2H),3.76(s,3H),3.75(s,3H).

[0477] Example 2: 1-Bromo-4-(3,3-difluorocyclobutyl)benzene

[0478] Step A: 4-Bromostyrene

[0479]

[0480] At room temperature, in a nitrogen atmosphere, methyltriphenylphosphonium bromide (7.53 kg, 21.07 mol, 1.3 equivalents) and K 2 CO 3(13.44kg, 97.27mol, 6.0 equivalents) was added to a stirred solution of p-bromobenzaldehyde (3.0kg, 16.2mol, 1.0 equivalents) dissolved in THF (45.0L, 15.0vol). The reaction mixture was stirred at 60°C for 18 hours. The progress of the reaction was monitored by TLC (mobile phase was 25% EtOAc in n-hexane). The reaction mixture was cooled to room temperature, quenched with water (40.0L, 13.33vol) and extracted with MTBE (2X25.0L). The organic layer was washed with 0.5N HCl solution (10vol). The organic layer was collected, dried over sodium sulfate, filtered, and the filtrate was evaporated to give 4-bromostyrene (2.33kg, 78.57%) as a light yellow liquid. 1 H NMR (300MHz, chloroform-d) δ7.29 (d, J=8.5Hz, 2H), 7.09 (d, J=8.5Hz, 2H), 6.49 (dd, J= 17.6, 10.9Hz, 1H), 5.58 (dd, J = 17.6, 0.8Hz, 1H), 5.12 (dd, J = 10.9, 0.8Hz, 1H).

[0481] Step B: 3-(4-bromophenyl)cyclobutan-1-one

[0482]

[0483] To a solution of dimethylacetamide (DMAc) (1.34 L, 14.45 mol, 1.1 eq.) in 1,2-dichloroethane (4.8 L, 2.0 vol) was added Tf 2A solution of 1,2-dichloroethane (0.72 L, 0.3 vol) was added to 4-bromostyrene (2.4 kg, 13.11 mol, 1.0 equiv) in 1,2-dichloroethane (1.68 L, 0.7 vol) and stirred at -15 °C for 30 minutes. A solution of 2,4,6-trimethylpyridine (1.75 kg, 14.45 mol, 1.1 equiv) in 1,2-dichloroethane (2.4 L, 1.0 vol) was added slowly. The reaction mixture was heated at 90 °C for 16.0 hours and then cooled to room temperature. The progress of the reaction was monitored by TLC (mobile phase 30% EtOAc in hexane). The reaction mixture was quenched with water (24.0 L, 10.0 vol) and the product was extracted with DCM (3x15.0 L). The combined organic extracts were washed with brine (3x15.0 L) and concentrated. The crude product was purified by column chromatography on silica gel (7.0 kg, mesh size 230-400) eluted with 0-5% ethyl acetate in n-heptane. The oily product was ground with n-hexane at room temperature to give a solid product. The solid was collected by filtration to give 3-(4-bromophenyl)cyclobutane-1-one (0.750 kg, 25.42%) as an off-white solid. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.41 (d, J = 8.5 Hz, 2H), 7.16–7.07 (m, 2H), 3.64–3.51 (m, 1H), 3.50–3.38 (m, 2H), 3.22–3.07 (m, 2H).

[0484] Step C: 1-Bromo-4-(3,3-difluorocyclobutyl)benzene

[0485]

[0486] (Diethylamino)sulfur trifluoride (DAST) (1.074 kg, 6.66 mol, 2.5 equiv) was added to a stirred solution of 3-(4-bromophenyl)cyclobutan-1-one (0.6 kg, 2.666 mol, 1.0 equiv) in DCM (12.0 L, 20.0 vol) at -30 °C. The reaction mixture was stirred at room temperature (26 °C to 28 °C) for 24 hours. The progress of the reaction was monitored by TLC (mobile phase 20% EtOAc in n-heptane). The reaction mixture was poured into 10% NaHCO 3Solution (12.0 L, 20.0 vol) and ice (5.0 kg) and extracted with DCM (2 x 6.0 L). The organic layer was collected and the solvent was evaporated to give a crude product, which was purified by silica gel column chromatography (4.5 kg, mesh size 230-400) (mobile phase 0-5% ethyl acetate and n-heptane) to give pure 1-bromo-4-(3,3-difluorocyclobutyl)benzene (362.0 g, 54.95%) as a yellow liquid. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.36–7.28 (m, 2H), 7.02–6.95 (m, 2H), 3.29–3.14 (m, 1H), 2.97–2.78 (m, 2H), 2.62–2.40 (m, 2H).

[0487] Example 3: 1-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (IV-1a-2)

[0488]

[0489] At room temperature, Pd(dppf)Cl 2 .CH 2 Cl 2 (65.85g, 76.5mmol, 0.04 equivalents), potassium acetate (563.14g, 5.738mol, 3.0 equivalents), bis-pinacolato diboron (728.58g, 2.869mol, 1.5 equivalents) were added to a stirred solution of the compound of formula (VI-1a-1) (800.0g, 1.912mol, 1.0 equivalents) in 1,4-dioxane (12.0L, 15.0vol.). The reaction mixture was degassed and stirred at 80°C for 4.0 hours. The progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in n-heptane). The reaction mixture was cooled to room temperature, then filtered through diatomaceous earth (1.0kg) and washed with ethyl acetate (2.4L, 3.0vol). The filtrate was diluted with water (8.0L, 10.0vol) and extracted with EtOAc (2x6.0L). The organic layer was washed with brine (8.0 L, 10.0 vol), dried over sodium sulfate, and the solvent was evaporated under reduced pressure at 50 ° C. The residue was ground with n-heptane (4x3.0 L) to remove excess bis-pinacolato diboron and the n-heptane was poured out. The residual heptane was removed in vacuo to obtain a compound of formula (IV-1a-2) (952.0 g) as a reddish oily slurry. The crude product of formula (IV-1a-2) was used directly in the next step without further purification. 1 H NMR (300 MHz, DMSO-d 6)δ7.66–7.58(m,2H),7.22–7.11(m,2H),6.94–6.79(m,4H),5.42(s,2H),3.70(s,3H),3.60(s,3H),1.29(s,12H).

[0490] Example 4: 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIIa-1a-1)

[0491]

[0492] At room temperature, Pd(dppf)Cl 2 ·CH 2 Cl 2 (123.02g, 142.91mmol, 0.07eq.), K 2 CO 3 (987.54g, 7145.74mmol, 3.5eq.) was dissolved in water (950.0mL) and added to a stirred solution of the compound of formula (IV-1a-2) (950.0g, 2041.64mmol, 1.0eq.) and 1-bromo-4-(3,3-difluorocyclobutyl)benzene (605.34g, 2449.97mmol, 1.2eq.) in 1,4-dioxane (9.5L). The reaction mixture was degassed and stirred at 80°C for 1 hour. The reaction progress was monitored by HPLC. The reaction mixture was cooled to room temperature and then filtered through a diatomaceous earth bed (1.0kg), and the diatomaceous earth was washed with ethyl acetate (2.4L, 3.0vol). The filtrate was concentrated to obtain a crude product of formula (IIIa-1a-1). The crude product was then purified by silica gel column chromatography (mobile phase 0-10% ethyl acetate in DCM). The fractions containing the product were combined and the solvent was evaporated to give the compound of formula (IIIa-1a-1) as a light brown solid (600.0 g, 61.16% yield for two steps as described in Example 3-4). 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.57–7.41 (m, 4H), 7.37–7.18 (m, 4H), 6.88–6.76 (m, 4H), 5.39 (s, 2H), 3.77 (s, 3H), 3.75 (s, 3H), 3.56–3.35 (m, 1H), 3.16–2.95 (m, 2H), 2.86–2.58 (m, 2H).

[0493] Example 5: 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIa-1)

[0494]

[0495] At room temperature, anisole (385.01 g, 3.560 mol, 3.0 equivalents) and TFA (6.0 L, 10.0 vol) were added to a stirred solution of (6.0 L, 10.0 vol.) of the compound of formula (IIIa-1a-1) (600.0 g, 1.186 mol, 1.0 equivalents) in DCM. The reaction mixture was stirred at 50 ° C for 15.0 hours. The reaction progress was monitored by TLC (the mobile phase was 50% ethyl acetate in n-heptane). The solution was concentrated and the residue was treated with n-heptane (10.0 vol). The obtained solid was filtered and the wet solid was suspended in toluene (1.8 L, 3.0 vol). The obtained solid was collected by filtration to obtain the crude product of formula (IIa-1), which was a light gray solid (362.2 g, 79.18%), which was used in the next step without further purification. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.63–7.49 (m, 4H), 7.33–7.27 (m, 4H), 3.96 (s, 3H), 3.51–3.34 (m, 1H), 3.15–2.93 (m, 2H), 2.84–2.56 (m, 2H).

[0496] Example 6: 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (Ia-1)

[0497]

[0498] At room temperature, a solution of 1.0M NaOH (115.83g, 2.895.75mmol, 3.1eq.) in water (2.9L) was added to a stirred solution of the crude compound of formula (IIa-1) (360.0g, 934.16mmol, 1.0eq.) in THF (1.8L). The reaction mixture was stirred at 55°C for 4.0 hours. The reaction progress was monitored by TLC (mobile phase was 80% ethyl acetate in n-heptane). The reaction mixture was cooled to room temperature and washed with DCM (2x3.0L). The DCM layer was discarded and the water layer was acidified with 1N HCl (3.0L) at room temperature (to a pH of 2 to 3). The precipitated solid was collected by filtration and the wet cake was washed with water (3.6L). The wet material (650.0g) was dried at 45°C for 40h to obtain the acid of formula (Ia-1) as an off-white solid (320.0g).1 H NMR (300 MHz, DMSO-d 6 )δ7.72–7.56(m,4H),7.39(d,J=8.1Hz,2H),7.23–7.08(m,2H),3.53–3.38(m,1H),3.11–2.92(m,2H),2.85–2.57(m,2H); MS(ES) - ):370.4(M-1); HPLC(area purity):97.67%; and water content:4.85%.

[0499] Example 7: 5-((4'-(3,3-difluorocyclobutyl)-[1,1-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid sodium salt

[0500]

[0501] At room temperature, a solution of 1.0M NaOH (1.12 g, 28.14 mmol, 0.95 eq.) in water (30.0 mL, 2.7 Vol.) was added to a stirred solution of wet compound (11.0 g, 29.62 mmol, 1.0 eq.) of formula (Ia-1) in water. The reaction mixture was stirred for 1.0 hour (to a pH of 9.5). The reaction mixture was filtered to remove undissolved solids (2.5 g). The filtrate was freeze-dried for 42.0 hours to obtain the sodium salt (5.8 g) of an off-white solid.

[0502] Example 8: 5-((4'-(3,3-difluorocyclobutyl)-[1,1-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid monosodium salt

[0503]

[0504] To a mechanically stirred (798 rpm) suspension of 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (290.0 g, 1.00 eq, 746 mmol) (water content 4.5%, adjusted accordingly in calculation) in water (870 mL) was added 1 N NaOH (609 mL) over 10 minutes at room temperature (pH = 9.69). The suspension was stirred for 2.5 hours and then the pH was measured to be 9.04. An additional 50 mL of 1 N NaOH was added and then the pH became 9.65. After stirring for an additional 30 minutes, the pH was 9.54 (a total of 0.883 eq. of 1 N NaOH was added). The slurry was lyophilized to dryness to afford sodium 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylate (283.5 g, 96.6%) as an off-white solid. 1 H NMR (300 MHz, DMSO-d 6 )δ7.59(dd,J=8.6,3.1Hz,4H),7.38(d,J=8.1Hz,2H),7.06–6.95(m,2H),3.50–3.36(m,1H),3.12–2.93(m,2H),2.82–2.59(m,2H); MS(ES) - ):370.2(M-1); HPLC(area purity):96.56%.

[0505] Product elemental analysis: carbon (C) contains 57.26%; hydrogen (H) contains 3.82%; nitrogen (N) contains 10.87%; and sodium (Na) contains 5.04%. The elemental analysis results are consistent with the monosodium salt of the compound of formula (Ia-1) shown below:

[0506]

[0507] Example 9: 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole- 4-Carboxylic acid (Ib-1)

[0508]

[0509] The compound of formula (Ib-1) is as follows Figure 6 The synthesis scheme shown is shown. Figure 6 In the present invention, as described herein, the compounds of formula (Ib-1) and (IIb-1) can exist in tautomeric forms. Figure 8The structure of compound 5 was determined according to J. Chem. Soc., Perkin Trans. 1, 1982, 627-630 and Humphrey J. Heterocyclic Chemistry 1991, 301-304.

[0510] Step 1: 4-(3,3-difluorocyclopentyl)phenol (2)

[0511]

[0512] To a solution of 3-(4-hydroxyphenyl)cyclopentanone (1) (2.00 g, 11.3 mmol) in DCE (20 mL) was added DAST. After four days, the reaction mixture was diluted with DCM (20 mL) and added to saturated sodium bicarbonate solution. The organic phase was collected, dried over sodium sulfate, filtered and evaporated. The mixture was purified on a combiflash chromatograph using a silica gel (40 g) column with 0% to 25% ethyl acetate-hexane to give the title compound (2) (1.20 g) (54%). 1 H NMR (400 MHz, CDCl 3 )δ7.10(d,J=8.6Hz,2H),6.79(d,J=8.5Hz,2H),4.71(s,1H),3.35–3.14(m,1H),2.52(m,1H),2.30(m,1H),2.14(m,3H),1.84(m,1H).

[0513] Step 2: 4-(3,3-difluorocyclopentyl)phenyl trifluoromethanesulfonate (3)

[0514]

[0515] To a solution of 4-(3,3-difluorocyclopentyl)phenol (2) (0.200 g, 1.01 mmol) in DCM (4.0 mL) under nitrogen was added pyridine (0.097 mL, 1.21 mmol, 1.20 eq). The reaction mixture was cooled to 0°C and trifluoromethanesulfonic anhydride (Tf 2 O) (0.255 mL, 1.51 mmol, 1.50 eq). The reaction mixture was slowly warmed to room temperature. After two hours, the mixture was washed with Et 2 O and quenched with 1.0 M aqueous HCl. The organic layer was washed with saturated NaHCO 3 , brine, dried over sodium sulfate, filtered and evaporated. The residue was purified on a silica gel (24 g) column using 0% to 15% EtOAc-hexanes to give the title compound (0.240 g, 0.727 mmol) (72.0%) as a colorless oil. 1 H NMR (300 MHz, CDCl3 )δ7.43–7.14(m,4H),3.60–3.23(m,1H),2.83–2.47(m,1H),2.42–2.00(m,4H),2.01–1.75(m,1H).

[0516] Step 3: 2-(4-(3,3-difluorocyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4)

[0517]

[0518] To a solution of 4-(3,3-difluorocyclopentyl)phenyl trifluoromethanesulfonate (3) (0.231 g, 0.70 mmol) and bis-pinacolatodiboron (0.266 g, 1.05 mmol, 1.50 eq) in 1,4-dioxane was added potassium acetate (0.206 g, 2.10 mmol, 3.00 eq). The mixture was purged with argon for 5 minutes and Pd(dppf)Cl was added 2 .CH 2 Cl 2 (0.042 g, 0.049 mmol, 0.07 eq). The reaction mixture was heated at 90 °C for 18 hours. The mixture was cooled to room temperature, diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The combined organics were washed with water (200 mL), brine, dried and evaporated. The residue was purified on a silica gel (24 g) column using 0% to 30% EtOAc-hexanes to give the title compound (0.240 g, 0.475 mmol) (67.8%) as a white solid. 1 H NMR (300 MHz, CDCl 3 )δ7.79(d,J=8.0Hz,2H),7.27(t,J=8.0Hz,2H),3.42–3.25(m,1H),2.75–2.46(m,1H),2.49–2.09(m,4H),2.02–1.76(m,1H),1.36(s,12H).

[0519] Step 4: 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl) 1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIIb-1a-1)

[0520]

[0521] To a solution of 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (VI-1a-1) (0.270 g, 0.646 mmol) and 2-(4-(3,3-difluorocyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) (0.238 g, 0.775 mmol, 1.20 eq) in 1,4-dioxane (2.8 mL) were added potassium carbonate (0.312 g, 2.26 mmol, 3.50 eq) and water. After the mixture was degassed with nitrogen, Pd(dppf)Cl was added. 2 .CH 2 Cl 2 To the filtrate was added 4-nitro-2-nitropropene (0.033 g, 0.039 mmol, 0.060 eq). The reaction mixture was heated at 85 ° C for 4 hours. The mixture was filtered through a celite pad and washed with DCM. Water was added to the filtrate and the two layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified using 0% to 100% EtOAc-hexane on a silica gel (24 g) column to give the title compound (0.240 g, 0.462 mmol) (68%) as a white solid. 1 H NMR (300 MHz, CDCl 3 )δ7.55–7.44(m,4H),7.39–7.24(m,2H),7.28–7.13(m,2H),6.94–6.69(m,4H),5.39(s,2H),3.77 (s,3H),3.76(s,3H),3.43–3.24(m,1H),2.84–2.50(m,1H),2.53–2.11(m,4H),2.01–1.80(m,1H).

[0522] Step 5: 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-yl Methyl carboxylate (IIb-1)

[0523]

[0524] To a suspension of 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIIb-1a-1) (0.213 g, 0.411 mmol) in DCM (2.0 mL) was added anisole (0.223 mL, 2.05 mmol, 5.00 eq) and TFA (5.0 mL, 65 mmol, 158 eq). The reaction mixture was stirred at 50 °C for 4 hours. The reaction mixture was then evaporated to dryness under reduced pressure to give a solid. Hexane was added to the solid and ground. The hexane was decanted and then stirred overnight with EtOAc-hexane to give the title compound (0.106 g, 0.265 mmol) (64.6%) as a beige solid after filtration. 1 H NMR (300 MHz, CDCl 3 )δ7.57(m,4H),7.37–7.23(m,4H),3.98(s,3H),3.50-3.24(m,1H),2.75–2.49(m,1H),2.50–2.10(m,4H),2.02-1.82(m,1H).

[0525] Step 6: 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-yl Carboxylic acid (Ib-1)

[0526] To a solution of 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIb-1) (0.106 g, 0.265 mmol, 1.00 eq) in THF (1.0 mL) was added 1 M NaOH solution (0.796 mL, 0.796 mmol, 3.00 eq). The reaction mixture was stirred at 50 °C for 6 hours. The reaction mixture was acidified with 1 M HCl solution, the resulting solid was filtered and washed with . The solid was transferred to a flask and dissolved in 10% water-EtOH (20 mL), heated to complete dissolution, and then water was slowly added until a white solid precipitated. The solid was filtered and dried to give the title compound (0.050 g, 0.130 mmol) (48.9%) as an off-white solid. 1 H NMR (300MHz, CD 4 OD)δ7.60(m,4H),7.36(d,J=8.1Hz,2H),7.20(d,J=8.1Hz,2H),3.59–3.36(m,1H) ,2.70–2.44(m,1H),2.42–2.08(m,4H),2.03–1.77(m,1H); LRMS(ES-):384.43(MH) - ;and HPLC:tR =6.911, 97.7% purity).

[0527] Example 10: 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-trifluoromethane Oxazole-4-carboxylic acid (Ic-1)

[0528]

[0529] The compound of formula (Ic-1) is as follows Figure 7 The synthesis scheme shown is shown. Figure 7 In the present invention, as described herein, the compounds of formula (Ic-1) and (IIc-1) can exist in tautomeric forms. Figure 8 The structure of compound 5 was determined according to J. Chem. Soc., Perkin Trans. 1, 1982, 627-630 and Humphrey J. Heterocyclic Chemistry 1991, 301-304.

[0530] Step 1: 1-Bromo-4-(4,4-difluorocyclohexyl)benzene (Vc-1-1)

[0531]

[0532] To a solution of triethylamine trihydrofluoride (1.30 mL, 7.90 mmol, 2.00 eq) and trimethylamine (0.549 mL, 3.95 mmol, 1.00 eq) in DCM (6.0 mL) at 0°C was added a solution of XtalFluor-E (N,N-diethyl-S,S-difluoroammonium sulfinium tetrafluoroborate) (1.35 g, 5.92 mmol, 1.50 eq) and 4-(4-bromophenyl)cyclohexanone (7) (1.00 g, 3.95 mmol, 1.00 eq) in DCM (3.0 mL). The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with DCM (20 mL), which was then added to a saturated aqueous sodium bicarbonate solution (50 mL) and the resulting mixture was extracted with DCM (2×20 mL). The organic phases were combined and washed with Na 2 SO 4 Dried and filtered, the solvent was evaporated and the resulting crude mixture was purified by silica gel column chromatography (40 g) using EtOAc / hexane (0 to 10%) to give 1-bromo-4-(4,4-difluorocyclohexyl)benzene (1.03 g, 3.74 mmol) (94.8%) as a colorless oil (clear solid) which turned into a white solid upon standing. 1 H NMR (300 MHz, CDCl 3)δ7.48–7.39(m,2H),7.14–7.06(m,2H),2.64–2.50(m,1H),2.30–2.14(m,2H),2.02–1.68(m,6H).

[0533] Step 2: 2-(4-(4,4-difluorocyclohexyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9)

[0534]

[0535] To a solution of 1-bromo-4-(4,4-difluorocyclohexyl)benzene (Vc-1-1) (1.12 g, 4.07 mmol) and bis-pinacolato diboron (1.54 g, 6.10 mmol, 1.50 eq) in 1,4-dioxane (19.0 mL) was added potassium acetate (1.20 g, 12.20 mmol, 3.00 eq). The mixture was purged with argon for 5 minutes, and Pd(dppf)Cl was added. 2 .CH 2 Cl 2 To the filtrate was added 4-(4-(2-nitro-1-yl)-2-nitropropene (0.245 g, 0.285 mmol, 0.070 eq). The reaction mixture was heated at 90 ° C for 4 hours. The mixture was cooled to room temperature, filtered through diatomaceous earth and washed with DCM. Water (50 mL) was added to the filtrate and extracted with DCM (2x25 mL). The combined organic layer was dried and concentrated to give a crude residue, which was purified by EtOAc / hexane (0-10%) on silica gel column chromatography (40 g) to give the title product (0.600 g, 1.86 mmol) (45.8%) as a white solid. 1 H NMR (300 MHz, CDCl 3 )δ7.76(d,J=8.0Hz,2H),7.23(d,J=8.2Hz,2H),2.67–2.55(m,1H),2.28–2.16(m,2H),2.00–1.74(m,6H),1.34(s,12H).

[0536] Step 3: 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl) 1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIIc-1a-1)

[0537]

[0538] To a solution of 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (VI-1a-1) (0.600 g, 1.43 mmol) and 2-(4-(4,4-difluorocyclohexyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9) (0.655 g, 1.75 mmol, 1.22 eq) in 1,4-dioxane (6.3 mL) was added potassium carbonate (0.693 g, 5.02 mmol, 3.50 eq) and water (0.629 mL). The reaction mixture was degassed for 5 minutes and Pd(dppf)Cl was added. 2 .CH 2 Cl 2 The mixture was stirred at 90 ° C for 6 hours. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth and washed with DCM. Water (50mL) was added to the mixture and extracted with DCM (2x25mL). The combined organic layer was dried and concentrated under reduced pressure to give a crude residue, which was purified on silica gel column chromatography (40g) using EtOAc in DCM (0-10%) as eluent to give the title compound (0.620g, 1.16mmol) (81%) in solid form. 1 H NMR (300MHz, CDCl3) δ7.51–7.45(m,4H),7.30(d,J=8.2Hz,2H),7.25–7.21(m,2H),6.86–6.78(m,4H ),5.39(s,2H),3.77(s,3H),3.76(s,3H),2.77–2.57(m,1H),2.36–2.16(m,2H),2.06–1.72(m,6H).

[0539] Step 4: 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-yl Methyl carboxylate (IIc-1)

[0540]

[0541] To a suspension of 5-{[4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl]oxy}-1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIIc-1a-1) (0.675 g, 1.26 mmol) in DCM (2.2 mL) at room temperature, anisole (0.138 mL, 1.266 mmol, 1.000 eq) and TFA (7.6 mL, 99.33 mmol, 78.5 eq) were added. After reacting at 50°C for 4 hours, the reaction mixture was evaporated to dryness under reduced pressure to obtain a solid. Hexane (25 mL) was added to the solid and decanted. The resulting solid was triturated with EtOAc (100 mL) (stirred overnight), filtered and triturated with EtOH (10 mL) (stirred for 30 min) to afford the title compound (0.260 g, 0.629 mmol) (49.7%). 1 H NMR (300 MHz, CDCl 3 )δ7.61–7.56(m,2H),7.54–7.49(m,2H),7.31–7.24(m,4H),3.96(s,3H),2.73–2.59(m,1H),2.31–2.15(m,2H),2.04–1.74(m,6H).

[0542] Step 5: 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-yl Carboxylic acid (Ic-1)

[0543] To a solution of 5-{[4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl]oxy}-1H-1,2,3-triazole-4-carboxylic acid methyl ester (IIc-1) (0.260 g, 0.553 mmol) in THF (1.0 mL) was added NaOH (1 M) solution (1.7 mL, 1.72 mmol, 3.10 eq). The reaction mixture was stirred at 50 °C for 6 hours. The reaction mixture was acidified with 1.0 M HCl (pH = 3) and the suspension was stirred for 10 minutes. The solid was filtered, rinsed with water and dried. The product was dissolved in a hot mixture of 10% water in EtOH and the title compound was obtained after standing as a white solid (0.099 g, 0.248 mmol) (44.8%). 1 H NMR (300 MHz, DMSO-d 6)δ7.18(d,J=8.2Hz,2H),7.12(d,J=7.9Hz,2H),6.88(d,J=7.7Hz,2H),6.67(d,J=8.4Hz,2H),2. 30–2.26(m,1H),1.71–1.55(m,3H),1.55–1.37(m,3H),1.35–1.15(m,2H); MS:ESI+[M+]399.89.

[0544] Example 11: Inhibition of glycolate oxidase

[0545] The catalytic reaction used to determine glycolate oxidase activity in the presence of the compounds of the invention is summarized in Fig. 9 Glycolate oxidase (GO) catalyzes the conversion of glycolate to glyoxylate (top reaction), accompanied by the reduction of the cofactor flavin mononucleotide (FMN), using molecular oxygen (O 2 ) restores its oxidized state, releasing hydrogen peroxide (H 2 O 2 ). In a coupled endpoint colorimetric (Trinder) reaction (bottom reaction), horseradish peroxidase (HRP) uses hydrogen peroxide, 4-aminoantipyrine, and a phenol derivative (sulfonated DCIP) to generate a quinoneimine dye that is measured spectrophotometrically.

[0546] Human glycolate oxidase (hGO) expression: BL21 (DE3) E. coli transformed with the recombinant pET-15b expression vector of human Hao1 cDNA with N-terminal His tag were grown in LB medium in the presence of 0.1 mg / ml ampicillin. To purify the recombinant human glycolate oxidase (hGO) expressed in BL21 E. coli, the bacterial pellet was thawed and resuspended in 2 mL of lysis buffer (50 mM NaH 2 PO 4, 300mM NaCl, 10mM imidazole, 50μM FMN, pH 7.5), and then treated with 1mM PMSF (for protease inhibition), 0.1% Triton X-100 and 0.2mg / mL lysozyme for 30 minutes to destroy the cell membrane. After ultrasonic treatment, the cells were centrifuged and the supernatant containing the total cell extract (pre-column portion) was loaded into a Ni-NTA agarose column and incubated at 4°C for 30 minutes to allow the 6 histidine tails of the recombinant GO protein to bind to nickel ions. The column was washed with two bed volumes of lysis buffer containing 20mM imidazole to remove unbound proteins (washing portion). GO was eluted using the same buffer containing 300mM imidazole. The portion containing purified GO was dialyzed overnight at 4°C with stirring using 300ml dialysis buffer (50mM NaH2PO4, 300mM NaCl, pH7.5) and then kept at 4°C in the dark. Protein was quantified by bicinchoninic acid (BCA) assay.

[0547] Enzyme assay: In the presence of glycolate as substrate (40 mM glycolic acid) and phosphate buffer (50 mM KPO 4 The enzymatic activity of hGO was determined in the presence of 4% paraformaldehyde (0.1 mM EDTA, pH 7). The production of glyoxylate was measured indirectly by quantifying the hydrogen peroxide formed during the first oxidation reaction. This hydrogen peroxide was reacted with 4.9 mM 4-aminoantipyrine and 0.1 mM sulfonated 2,4-dichlorophenol indophenol in a coupled horseradish peroxidase (HRP) reaction to produce a quinoneimine dye ( Figure 3 ), detected at 515 nm (Trinder reaction). The enzyme activity was calculated 1 minute after the start of the Trinder reaction. The enzyme analysis results of the compounds of the present invention are shown in Table 2.

[0548] Table 2: In vitro inhibition of human glycolate oxidase by the compounds of the present invention

[0549]

[0550] Although the foregoing disclosure has been described in some detail by way of illustration and example for the purpose of clarity of understanding, those skilled in the art will appreciate that certain changes and modifications may be implemented within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were incorporated by reference individually. In the event of a conflict between the present application and the references provided herein, the present application shall prevail.

Claims

1. A method for preparing a compound represented by formula (II), its tautomer or its salt: include: a) a compound of formula (IV) or a salt thereof: With a compound of formula (V): The first transition metal catalyst and the first base are contacted in a first solvent to form a compound of formula (III) or a salt thereof: and b) removing the PG group of the compound of formula (III) or a salt thereof to obtain a compound of formula (II), a tautomer thereof or a salt thereof, in: The subscripts m and n are each independently 1 or 2; R 1 It is C 1-6 alkyl; R 2 and R 3 are each independently a halogen; X 1 Selected from the group consisting of -B(OH)2, -B(OEt)2, -B(OiPr)2, -BF3M, -B(OiPr)3M, Where M is Li + 、Na + or K + ; X 2 is a halogen or a sulfonate group; and In formula (IV) or (III) It is expressed by the following formula: or mixtures thereof; and PG is [2-(trimethylsilyl)ethoxy]methyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl.

2. The method according to claim 1, characterized in that The PG is 4-methoxybenzyl.

3. The method according to claim 1, characterized in that in, X 1 As shown in the following formula:

4. The method according to any one of claims 1 to 3, characterized in that in, X 2 is Cl, Br, I, OMs, OTs or OTf.

5. The method according to claim 4, characterized in that in, X 2 It's Br.

6. The method according to any one of claims 1 to 3, characterized in that in, The first transition metal catalyst is a first palladium catalyst, a ruthenium catalyst, a rhodium catalyst, a cobalt catalyst, a nickel catalyst, an iron catalyst, a copper catalyst or a combination thereof.

7. The method according to claim 6, characterized in that in, The first palladium catalyst is Pd(acac)2, [Pd(allyl)Cl]2, Pd(CH3CN)2Cl2, Pd(dba)2, Pd(CH3COO)2, Pd2(dba)3, Pd2(dba)3·CHCl3, Pd(PPh3)4, Pd(OAc)2, Pd(PCy3)2Cl2, Pd(PPh3)2Cl2, Pd[P(o-tol)3]2Cl2, Pd(ampphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(CH3CN)4(BF4)2, PdCl2, XPhos-Pd-G3, Pd-PEPPSI TM -IPr、Pd-PEPPSI TM -SIPr, or Pd-PEPPSI TM -IPent.

8. The method according to claim 7, characterized in that in, The first palladium catalyst is Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2 or Pd(dtbpf)Cl2.

9. The method according to any one of claims 1 to 3, characterized in that in, The first transition metal catalyst is present in an amount of 0.01 to 0.5 equivalents relative to the compound of formula (IV).

10. The method according to any one of claims 1 to 3, characterized in that in, The first base is sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium acetate, cesium acetate or a combination thereof.

11. The method according to claim 10, characterized in that in, The first base is potassium carbonate.

12. The method according to any one of claims 1 to 3, characterized in that in, The amount of the compound of formula (V) relative to the compound of formula (IV) is 1.0 to 2.0 equivalents, 1.1 to 2.0 equivalents, 1.1 to 1.5 equivalents or 1.2 equivalents.

13. The method according to claim 12, characterized in that in, The amount of the compound of formula (V) was 1.2 equivalents relative to the compound of formula (IV).

14. The method according to any one of claims 1 to 3, characterized in that in, The first solvent is water, C 1-4 alcohol, benzene, toluene, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), acetonitrile (ACN), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), dimethoxyethane (DME), ethylene glycol, or a combination thereof.

15. The method according to claim 14, characterized in that The first solvent includes dioxane and water.

16. The method according to any one of claims 1 to 3, characterized in that Step a) is carried out at a temperature of 60°C to 110°C, 70°C to 110°C, 70°C to 100°C, 70°C to 90°C or 80°C.

17. The method according to claim 16, characterized in that Step a) is carried out at a temperature of 80°C.

18. The method according to any one of claims 1 to 3, characterized in that In step b), the PG group is removed by treatment with a first acid in a second solvent.

19. The method according to claim 18, characterized in that The first acid is trifluoroacetic acid.

20. The method of claim 18, wherein: The second solvent is dichloromethane or 1,2-dichloroethane.

21. The method of claim 18, wherein: The reaction mixture of step b) further comprises a transfer agent.

22. The method according to claim 21, characterized in that The transfer agent is anisole.

23. A method for preparing a compound represented by the following formula (I), or a tautomer thereof or a salt thereof, comprising: a) a compound of formula (IV) or a salt thereof: With a compound of formula (V): The first transition metal catalyst and the first base are contacted in a first solvent to form a compound of formula (III) or a salt thereof: and b) removing the PG group of the compound of formula (III) or a salt thereof to obtain a compound of formula (II), a tautomer thereof or a salt thereof, c) contacting the compound of formula (II), its tautomer or a salt thereof with a second base in a third solvent; and d) acidifying with a second acid to obtain a compound of formula (I), a tautomer thereof or a salt thereof: in: The subscripts m and n are each independently 1 or 2; R 1 It is C 1-6 alkyl; R 2 and R 3 are each independently a halogen; X 1 Selected from the group consisting of -B(OH)2, -B(OEt)2, -B(OiPr)2, -BF3M, -B(OiPr)3M, -B(OiPr)3M, Where M is Li + 、Na + or K + ; X 2 is a halogen or a sulfonate group; and In formula (IV) or (III) It is expressed by the following formula: or mixtures thereof; and PG is [2-(trimethylsilyl)ethoxy]methyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl.

24. The method of claim 23, wherein: The second base is lithium hydroxide, sodium hydroxide or potassium hydroxide.

25. The method of claim 24, wherein: The second base is sodium hydroxide.

26. The method according to any one of claims 23 to 25, characterized in that The third solvent is water, C 1-4 alcohol, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), acetonitrile (ACN), dimethoxyethane (DME), or a combination thereof.

27. The method of claim 26, wherein: The third solvent includes tetrahydrofuran and water.

28. The method according to any one of claims 23 to 25, characterized in that The second acid is HCl.

29. The method according to any one of claims 23 to 25, characterized in that The step d) is carried out in an aqueous solution.

30. The method according to any one of claims 1 to 3, characterized in that The compound of formula (II) is represented by a structural formula selected from the group consisting of:

31. The method according to any one of claims 1 to 3, characterized in that R 1 It's methyl.

32. The method according to any one of claims 23 to 25, characterized in that The compound of formula (I) is represented by a structural formula selected from the group consisting of:

33. The method of claim 1, wherein: R 2 and R 3 Each is F.

34. The method of claim 1, wherein: Before step a), the method further comprises: a1) a compound of formula (VI) or a salt thereof: The method further comprises contacting with a boron reagent, a second palladium catalyst and a third base in a fourth solvent to form a compound of formula (IV) or a salt thereof, wherein X is Cl, Br or I.

35. The method of claim 34, wherein: The boron reagent is tetrahydroxydiboron, bis-catechol borate, bis-(2-methyl-2,4-pentanediol) borate, bis-(neopentyl glycol) diboron or bis-pinacol diboron.

36. The method of claim 35, wherein: The boron reagent is bis-pinacolyl diboron.

37. The method according to any one of claims 34 to 36, characterized in that The second palladium catalyst is Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2 or Pd(dtbpf)Cl2.

38. The method according to any one of claims 34 to 36, characterized in that The third base is potassium acetate.

39. The method according to any one of claims 34 to 36, characterized in that The fourth solvent is 1,4-dioxane.

40. The method according to any one of claims 34 to 36, characterized in that The compound of formula (VI) is represented by the following formula:

41. A method for preparing a compound represented by formula (Ia-1), its tautomer or a salt thereof: include: a1) the compound of formula (VI-1a-1) or a salt thereof: With bis-pinacol diboron, Pd(dppf)Cl2·CH2Cl2 and potassium acetate in 1,4-dioxane to convert into a compound of formula (IV-1a-2) or a salt thereof: a) contacting a compound of formula (IV-1a-2) or a salt thereof with 1-bromo-4-(3,3-difluorocyclobutyl)benzene, Pd(dppf)Cl2.CH2Cl2, and potassium carbonate in a mixture of 1,4-dioxane and water to form a compound of formula (IIIa-1a-1) or a salt thereof: b) treating the compound of formula (IIIa-1a-1) or a salt thereof with trifluoroacetic acid and anisole in dichloromethane to obtain the compound of formula (IIa-1), its tautomer or a salt thereof: c) saponifying the compound of formula (IIa-1), its tautomer or a salt thereof with an aqueous solution of sodium hydroxide in tetrahydrofuran; and d) acidifying with aqueous HCl to obtain the compound of formula (Ia-1), its tautomer or a salt thereof.

42. The method of claim 41, wherein: Step a1) is carried out at a temperature of 80°C; step a) is carried out at a temperature of 80°C; step b) is carried out at a temperature of 50°C; step c) is carried out at a temperature of 55°C; step d) is carried out at a temperature of 20-25°C.

43. The method according to claim 41 or 42, characterized in that In step a), the amount of 1-bromo-4-(3,3-difluorocyclobutyl)benzene used is 1.0 to 1.5 equivalents relative to the compound of formula (IV-1a-2).

44. The method according to claim 41 or 42, characterized in that In step a), the amount of Pd(dppf)Cl2.CH2Cl2 used is 0.05 to 0.1 equivalent relative to the compound of formula (IV-1a-2).

45. The method according to claim 41 or 42, characterized in that In step a), potassium carbonate is used in an amount of 2.0 to 4.0 equivalents relative to the compound of formula (IV-1a-2).

46. ​​The method according to claim 41 or 42, characterized in that The compound of formula (IV-1a-2) prepared in step a1) is directly used in the next step without further purification.

47. The method of claim 41 or 42, wherein: The compound of formula (IIIa-1) is isolated from step a1) and step a) with an overall yield of at least 50%.

48. The method of claim 41 or 42, wherein: The compound of formula (IIa-1) prepared in step b) is directly used in the next step without further purification.

49. The method according to claim 41 or 42, characterized in that Step d) is carried out by acidifying the aqueous extract of the reaction mixture of step c).

50. The method of claim 41 or 42, further comprising: e) converting the compound of formula (Ia-1), its tautomer or a salt thereof into a monosodium salt of the compound of formula (Ia-1) represented by the following formula: The disodium salt of the compound of formula (Ia-1) represented by the following formula: or a mixture thereof, or a tautomer thereof.

51. The method of claim 50, wherein: in, Step e) is carried out in the following manner: i) treating the compound of formula (Ia-1) or its tautomer with aqueous sodium hydroxide in water; ii) forming a slurry having a pH of 9.5; and iii) freeze-drying the slurry to obtain the monosodium salt of the compound of formula (Ia-1) or its tautomer represented by the following formula: Wherein, relative to the compound of formula (Ia-1), the amount of sodium hydroxide used is less than 1.0 equivalent, calculated on a salt-free and anhydrous basis.

52. The method of claim 51, wherein: The amount of sodium hydroxide used is 0.88 equivalents relative to the compound of formula (Ia-1), calculated on a salt-free and anhydrous basis.

53. A compound represented by formula (X), its tautomer or a pharmaceutically acceptable salt thereof: It is characterized in that R 1 H or C 1-6 Alkyl; R 2 and R 3 are each independently halogen.

54. The compound of claim 53, represented by formula (Xa):

55. The compound of claim 53, represented by formula (Xb):

56. A compound according to any one of claims 53 to 55, characterized in that R 1 It's H.

57. A compound according to any one of claims 53 to 55, characterized in that R 1 It is C 1-6 alkyl.

58. The compound of claim 57, wherein R 1 It's methyl.

59. A compound according to any one of claims 53 to 55, characterized in that R 2 and R 3 Each is -F.

60. The compound of claim 53, its tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

61. The compound of claim 53, its tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is:

62. A pharmaceutical composition comprising the compound of claim 61 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

63. Use of a compound as claimed in claim 61 or a pharmaceutical composition as claimed in claim 62 for the preparation of a pharmaceutical composition for the treatment of primary hyperoxaluria, type I (PH1).

64. Use of the compound according to claim 61 or the pharmaceutical composition according to claim 62 for preparing a pharmaceutical composition for treating kidney stones and / or bladder stones.

65. Use of the compound of claim 61 for preparing a pharmaceutical composition for inhibiting glycolate oxidase.

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