Process for preparing triazole glycolate oxidase inhibitors

Abstract

The present disclosure provides a method for preparing 1,2,3-triazole-4-carboxylic acid related compounds of formula (I) and formula (II) by Suzuki coupling reaction, which is accomplished by combining a boron-containing derivative of 1,2,3-triazole-4-carboxylic acid, a compound of formula (IV), with a cycloalkylphenyl halide or sulfonate of formula (V). JPEG2023510758000143.jpg58157

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 958,443, filed January 8, 2020, and U.S. Provisional Patent Application No. 62 / 958,445, filed January 8, 2020, the entire contents of each of which are incorporated herein by reference for all purposes. [Background technology]

[0002] The prevalence of kidney stone disease (KSD) is approximately 10% in developed countries, with a lifetime recurrence rate of up to 50% [Johri, et al. (2010) Nephron Clin Pract. 116: c159]. Patients with KSD present with hematuria and renal colic, and treatment is primarily supportive. Medications to facilitate stone passage are effective for small stones (<5 mm). For larger stones, extracorporeal shock waves or minimally invasive surgery are used to break them into smaller pieces that can more easily pass through the renal tubule [Coe et al. (2005) J. Clin. Invest. 115: 2598].

[0003] Approximately 75% of kidney stones contain primarily calcium oxalate, and elevated urinary oxalate levels are present 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) J Am Soc Nephrol. 19: 1197]. In mammals, calcium levels are tightly regulated because calcium plays vital physiological roles in so many processes. However, oxalate is a metabolic end product whose physiological role is unknown. Oxalate is a divalent anion that must be excreted in urine and is prone to precipitation as tissue-damaging, insoluble calcium oxalate crystals.

[0004] Primary hyperoxaluria (PH) is a group of rare metabolic disorders inherited in an autosomal recessive manner that affect the glyoxylate or hydroxyproline pathway. Oxalate overproduction is common to all of these disorders. Three types of primary hyperoxaluria have been identified to date: primary hyperoxaluria type 1, type 2, and type 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 ultimately leads to renal failure after several years. PH2 and PH3 have less severe disease progression. Approximately 80% of PH patients suffer from PH1, the most severe type of PH. Given its statistical significance, the majority of PH studies have primarily focused on PH1 [Salido et al. (2012) Biochim Biophys Acta. 1822: 1453].

[0005] Because calcium levels are so tightly regulated in living organisms, altering urinary calcium levels is extremely difficult, and altering urinary calcium levels may have undesirable effects on vital physiological processes. Small increases in urinary oxalate can have a significant effect on calcium oxalate crystal formation, and elevated urinary oxalate levels are a major risk factor for calcium oxalate kidney stone formation [Pak, et al. (2004) Kidney Int. 66: 2032]. Consequently, small decreases in oxalate concentrations may reduce calcium oxalate levels below saturation, thereby inhibiting calcium oxalate stone formation. Regardless of urinary oxalate (UOx) levels in individuals with kidney stone disease, primary hyperoxaluria, or secondary hyperoxaluria, lowering UOx levels reduces the contribution of oxalate to calcium oxalate formation, thereby reducing the likelihood of stone formation and / or the severity of symptoms associated with excess calcium oxalate deposition [Marengo et al. (2008) Nat Clin Pract Nephrol. 4: 368].

[0006] The development of effective drugs to reduce urinary oxalate levels could be a valuable therapeutic option in the prevention and treatment of calcium oxalate-related conditions. Common approaches for the treatment of calcium oxalate-related urolithiasis include surgical removal of stones, dietary changes to increase fluid intake and limit oxalate intake, urinary alkalinization, diuretics, and crystallization inhibitors such as citrate, bicarbonate, and magnesium [Moe, supra]. However, none of these therapeutic approaches address the origin of these conditions. No drugs that specifically inhibit the endogenous biosynthesis of oxalate are commercially available for the prevention and treatment of calcium oxalate deposition-related conditions.

[0007] In humans, dietary oxalate contributes only 10%–50% of urinary oxalate excretion [Holmes, et al. (2001) Kidney Int. 59: 270]. Most urinary oxalate is derived from endogenous metabolism, primarily in the liver. In humans, the primary precursor of oxalate is glyoxylate. Therefore, approaches to reducing oxalate production require inhibiting the conversion of glyoxylate to oxalate or its production from precursors. In humans, the primary precursor of glyoxylate is glycolate in a reaction catalyzed by glycolate oxidase (GO), also known as hydroxyacid oxidase 1, a hepatic peroxisomal enzyme. Pharmacological inhibition of GO activity with small molecules reduces endogenous oxalate production and lowers urinary calcium oxalate levels, thus providing a specific approach for the prevention and treatment of calcium oxalate deposition and related conditions. Evidence exists that GO is a safe therapeutic target in humans. It has been reported that splicing-defective variants of human GO in individuals only cause sporadic asymptomatic glycolic aciduria without any obvious pathological effects [Frishberg, et al. (2014) J Med Genet. 51: 526].

[0008] Recently, 1,2,3-triazole-4-carboxylic acids have been described in relation to the treatment of GO-related diseases. Initial methods for preparing such compounds have also been described, but these methods remain in need of improvement to enable large-scale operation and increased yields.

[0009] As described in International Application PCT / US2019 / 040690 (herein referred to as No. 690), a compound of formula (Ia-1), i.e. [ka] was synthesized according to the scheme shown in Figure 1. The compound of formula (IIIa-1a-1) was obtained by Suzuki coupling reaction, which required 3.36 equivalents of compound (33) (2-(4-(3,3-difluorocyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) relative to compound of formula (VI-1a-1). Compound (33) was prepared from 1-bromo-4-(3,3-difluorocyclobutyl)benzene in about 59% yield and required further purification. From this Suzuki coupling reaction, the compound of formula (IIIa-1a-1) was isolated in about 51% yield. The overall yield of the compound of formula (IIIa-1a-1) isolated in two steps from the compound of formula (VI-1a-1) using this Suzuki reaction described in the '690 specification was only about 30%.

[0010] Despite the above methods, there remains a need to develop more efficient and improved methods for preparing 1,2,3-triazole-4-carboxylic acid related compounds, particularly cycloalkyldiphenyl 1,2,3-triazole-4-carboxylic acid compounds. Summary of the Invention

[0011] In one aspect, the present disclosure provides a compound represented by formula (II): [ka] A method for preparing the tautomer, or a salt thereof, is provided, which method comprises: (a) a compound of formula (IV), i.e. [ka] or a salt thereof to form a compound of formula (V), i.e. [ka] a first transition metal catalyst, and a first base in a first solvent to form a compound of formula (III): [ka] or a salt thereof, and (b) removing the PG group of said compound of formula (III) or said salt thereof to provide said compound of formula (II), said tautomer thereof, or said salt thereof; During the ceremony, the subscripts m and n are each independently 1 or 2; R 1 is C 1-6 is alkyl, R 2 and R 3 are each independently H or halogen; X 1 is a boron-containing group, X 2 is a halogen or a sulfonate, and In formula (IV) or formula (III), [ka] is expressed as follows: [ka] or a mixture thereof, and PG is an amine protecting group.

[0012] In another aspect, the present disclosure provides a compound represented by formula (Ia-1): [ka] A method for preparing the tautomer, or a salt thereof, is provided, which method comprises: (a1) A compound of formula (VI-1a-1), i.e. [ka] or its salt is reacted with bis(pinacolato)diboron, Pd(dppf)Cl2·CH2Cl2, and potassium acetate in 1,4-dioxane to give a compound of formula (IV-1a-2), i.e., [ka] or converting it into a salt thereof; (a) contacting the compound of formula (IV-1a-2) or the 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 produce a compound of formula (IIIa-1a-1), i.e., [ka] or forming a salt thereof; (b) treating the compound of formula (IIIa-1a-1) or the salt thereof with trifluoroacetic acid and anisole in dichloromethane to give a compound of formula (IIa-1), i.e. [ka] providing a tautomer thereof, or a salt thereof; (c) saponifying the compound of formula (IIa-1), the tautomer thereof, or the salt thereof with aqueous sodium hydroxide in tetrahydrofuran; and (d) acidifying with aqueous HCl to provide the compound of formula (Ia-1), the tautomer thereof, or the salt thereof. Includes:

[0013] In a related embodiment, a compound represented by formula (X), i.e. [ka] and R 1 is H or C 1-6 alkyl, and R 2 and R 3 are each independently H or halogen, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0014] 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.

[0015] In yet another aspect, provided herein are methods for inhibiting glycolate oxidase in a subject by administering a compound of formula (X) for the treatment of primary hyperoxaluria type 1 (PH1) and kidney and / or bladder stones. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows a synthetic scheme for preparing the compound of formula (Ia-1) described in International Application PCT / US2019 / 040690. [Figure 2] FIG. 2 shows a synthetic scheme for preparing compounds of formula (I). [Figure 3] FIG. 3 shows a synthetic scheme for preparing compounds of formula (Ia-1). [Figure 4] FIG. 4 shows a synthetic scheme for preparing compounds of formula (VI-1a-1). [Figure 5] FIG. 5 shows a synthetic scheme for preparing 1-bromo-4-(3,3-difluorocyclobutyl)benzene. [Figure 6] FIG. 6 shows a synthetic scheme for preparing compounds of formula (Ib-1) and formula (IIb-1). [Figure 7] FIG. 7 shows a synthetic scheme for preparing compounds of formula (Ic-1) and formula (IIc-1). [Figure 8] FIG. 8 shows synthetic schemes for preparing intermediates used in the preparation of compounds of Formula (Ib-1), Formula (IIb-1), Formula (Ic-1), and Formula (IIc-1). [Figure 9] FIG. 9 shows the catalytic reaction used to assay glycolate oxidase activity. DETAILED DESCRIPTION OF THE INVENTION

[0017] Detailed Description of the Invention I. Overview The present disclosure provides a method for preparing 1,2,3-triazole-4-carboxylic acid related compounds of formula (I) and formula (II) via Suzuki coupling reaction. The Suzuki coupling reaction is accomplished by combining a boron-containing derivative of 1,2,3-triazole-4-carboxylic acid, compound of formula (IV), with a cycloalkylphenyl halide or sulfonate salt of formula (V). The Suzuki coupling reaction achieves an excellent yield of approximately 61% in two steps, starting from the amine-protected 5-(4-halo-phenoxy)-1H-1,2,3-triazole-4-carboxylic acid, compound of formula (VI).

[0018] The present disclosure further provides effective therapeutic approaches suitable for inhibiting oxalate biosynthesis and treating primary hyperoxaluria type 1 (PH1) and other conditions associated with calcium oxalate deposition. Novel cycloalkyltriazole compounds useful as glycolate oxidase inhibitors, as well as methods for making and using these cycloalkyltriazole compounds, are provided.

[0019] II. Definition "Alkyl" has the indicated number of carbon atoms (i.e., C 1-6 refers to a straight or branched chain saturated aliphatic radical (meaning 1 to 6 carbons). Alkyl refers to any number of carbons, e.g., 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 1-6Alkyl 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.

[0020] "Alkylene" has the indicated number of carbon atoms (i.e., C 1-6 (meaning 1 to 6 carbons) refers to a straight-chain or branched-chain saturated aliphatic radical, i.e., a divalent hydrocarbon radical, that links at least two other groups. The two moieties linked to the alkylene may be attached to the same atom or different atoms in the alkylene group. For example, a straight-chain alkylene is —(CH2) where n is 1, 2, 3, 4, 5, or 6. n Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0021] "Alkoxy" refers to an alkyl group having an oxygen atom connecting it to its point of attachment, i.e., alkyl-O-. The alkoxy group can have any suitable number of carbon atoms, e.g., C1-C6. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0022] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain 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 groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups, such as phenyl, naphthyl, or biphenyl, have 6 to 12 ring members. Other aryl groups, such as phenyl or naphthyl, have 6 to 10 ring members. Some other aryl groups, such as phenyl, have 6 ring members.

[0023] "Aryloxy" refers to an aryl group having an oxygen atom connecting the aryl group to the point of attachment, i.e., aryl-O-. Aryloxy groups useful in the present disclosure include C aryl groups in which the aryl group has 6 to 10 ring members. 6-10 Examples include aryloxy.

[0024] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0025] "Carboxylic acid" refers to a compound of the formula RC(O)O, where the R groups can be alkyl, aryl, or arylalkyl. - or a dicarboxylic acid group R(C(O)O) where the R groups can be alkylene, alkylene-O-alkylene, alkylene-NH-alkylene, or alkylene-N(alkyl)-alkylene. - )2. Carboxylic acids useful in the present disclosure include, but are not limited to, acetic acid, malonic acid, 2,2'-oxydiacetic acid, iminodiacetic acid, and 2,2'-(methylazanediyl)acetic acid.

[0026] "Sulfonic acid" refers to the -SO3R group, where the R group can be halo (e.g., -F), alkyl (e.g., methyl or ethyl), haloalkyl (e.g., trifluoromethyl), aryl (e.g., phenyl, tosyl, p-fluorophenyl, or p-nitrophenyl), or heteroaryl (e.g., imidazolyl). Exemplary sulfonic acid groups include, but are not limited to, fluorosulfonic acid, methanesulfonic acid (OMs), trifluoromethanesulfonic acid (OTf), p-toluenesulfonic acid (OTs), p-fluorobenzenesulfonic acid, p-nitrophenylsulfonic acid (nosylate), and imidazole-1-sulfonic acid (imidazolate).

[0027] "OMs" refers to methanesulfonic acid, "-OTs" refers to p-toluenesulfonic acid, and "-OTf" refers to trifluoromethanesulfonic acid.

[0028] "Bidentate" refers to an alkoxy, aryloxy, or carboxylic acid group having at least two oxygen atoms (-O-) that can both form bonds to the same third atom, such as boron (B), provided that the two oxygen atoms are not part of a carbonyl group (-C=O). Useful bidentate groups in the present disclosure include bidentate C 2-8 Alkoxy group, bidentate C 6-10 Examples include aryloxy groups and bidentate carboxylic acid groups.

[0029] "Tridentate" refers to an alkoxy group having at least three carbon atoms and three oxygen atoms (-O-), where three of the oxygen atoms can form bonds to the same fourth atom, such as boron (B). Tridentate groups useful in the present disclosure include tridentate C 3-10 Examples include alkoxy groups.

[0030] A "catalyst" refers to a substance that increases the rate of a chemical reaction by lowering the activation energy, but remains unchanged by the reaction.

[0031] "Metal" refers to a periodic table element that is in the metal family and can be neutral, or can be positively charged as a result of having more or fewer electrons in its valence shell than a neutral metal element. Metals useful in this disclosure include alkali metals and transition metals. Alkali metals in this disclosure include alkali metal cations. Alkali metal cations useful in this disclosure include Li + , Na + , K. + , and Cs + Transition metals useful in the present disclosure 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.

[0032] "Transition metal catalyst" refers to a compound composed of a transition metal, as defined above, which may be neutral or positively charged.

[0033] Bases useful in the present disclosure include organic bases and inorganic bases. Exemplary organic bases include amines, alkali carboxylic acids, and alkali alkoxides, as defined herein. Exemplary inorganic bases include alkali bicarbonates, alkali carbonates, alkali tribasic phosphates, and alkali hydroxides, as defined herein. Amines useful as bases in the present disclosure include tertiary amines and aromatic amine bases, as defined herein.

[0034] "Amine" refers to a compound having the formula N(R)3, where the R groups can be, among others, hydrogen, alkyl, aryl, or heteroalkyl. These R groups can be the same or different. For example, the amine can be a primary amine (where each of the two R groups is hydrogen), a secondary amine (where one R is hydrogen), or a tertiary amine (where each R is other than hydrogen). In some embodiments, the secondary amine is a cyclic amine in which two R groups are bonded to the nitrogen atom to form a 5- to 6-membered heterocycle. Non-limiting examples of cyclic amines include pyrrolidine, piperidine, and morpholine.

[0035] "Tertiary amine" refers to a compound having the formula N(R)3, where the R group can be, among others, alkyl, aryl, heteroalkyl, heteroaryl, or two R groups taken together form an N-linked heterocycloalkyl. The R groups can 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).

[0036] "Aromatic amine base" refers to an N-containing 5- to 10-membered heteroaryl compound or a tertiary amine having the formula N(R)3, where at least one R group is aryl or heteroaryl. Aromatic amine bases useful herein include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), 4-dimethylaminopyridine, imidazole, 1-methylimidazole, dimethylaniline, and diethylaniline.

[0037] "Alkali carboxylic acid" is a compound consisting of an alkali metal cation and a carboxylic acid anion (RC(O)O -), where the R group can be alkyl or aryl. Alkali carboxylic acids useful in the present disclosure include, but are not limited to, lithium acetate (LiOC(O)CH3), sodium acetate (NaOC(O)CH3), potassium acetate (KOC(O)CH3), cesium acetate (CsOC(O)CH3), and potassium trimethylacetate (KOC(O)C(CH3)3).

[0038] "Alkali alkoxide" refers to the combination of an alkali metal cation and an alkoxide anion (RO - ) and R is C 1-4 Alkyl alkoxides refer to a class of compounds in which the alkyl group is an alkyl. Alkali alkoxides useful in the present disclosure include, but are not limited to, sodium methoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium isopropoxide.

[0039] "Alkali bicarbonate" is a compound of an alkali metal cation and a carbonate anion (HCO3 - Alkali carbonates useful in the present disclosure include lithium bicarbonate (LiHCO), sodium bicarbonate (NaHCO), potassium bicarbonate (KHCO), and cesium bicarbonate (CsHCO).

[0040] "Alkali carbonate" is a compound of alkali metal cation and carbonate anion (CO3 2- Alkali carbonates useful in the present disclosure include lithium carbonate (Li2CO3), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), and cesium carbonate (Cs2CO3).

[0041] "Alkali tribasic phosphate" is a compound consisting of an alkali metal cation and a phosphate anion (PO4 3- Alkaline tribasic phosphates useful in the present disclosure include trisodium phosphate (NaPO) and tripotassium phosphate (KPO).

[0042] "Alkali hydroxide" refers to a compound of an alkali metal cation and a hydroxide anion (OH - Alkali hydroxides useful in the present disclosure include LiOH, NaOH, KOH, and CsOH.

[0043] An "acid" is defined as a compound that contains a proton (H + ) or compounds that are electron pair acceptors under the Lewis definition. Acids useful in this disclosure include, but are not limited to, fluorine-substituted 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, among others.

[0044] A "protecting group" refers to a compound that renders a functional group unreactive to certain reaction conditions, but which can be subsequently removed in a later synthetic step to restore the functional group to its original state. Such protecting groups are well known to those skilled in the art and include those disclosed in "Protective Groups in Organic Synthesis," 4th Edition, by T.W. Greene and P.G.M. Wuts, John Wiley & Sons, Inc., New York, 2006, which is incorporated herein by reference in its entirety.

[0045] "Amine protecting group" refers to a protecting group used to protect one of the nitrogen atoms in a 1,2,3-triazole group. These amine protecting groups useful in the present disclosure include, but are not limited to, benzyl (Bn), 2-(trimethylsilyl)ethoxymethyl, p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 1-(2,4-dimethoxyphenyl)ethyl, 3,4-dimethoxybenzyl (DMPB), p-methoxyphenyl (PMP), tosyl (Ts), and other sulfonamide (nosyl and Nps) groups.

[0046] "Deprotection" refers to the use of one or more chemicals or agents to remove a protecting group, as defined above, returning said functional group to its original state.

[0047] "Transfer agent" refers to a chemical agent added to the reaction mixture during the deprotection step to effectively remove an amine protecting group, such as p-methoxybenzyl (PMB), 2,4-dimethoxybenzyl (DMB), 1-(2,4-dimethoxyphenyl)ethyl, or 3,4-dimethoxybenzyl (DMPB). Transfer agents useful in the present disclosure include, but are not limited to, anisole or the like. Anisole is believed to act as a transfer reagent to transfer the PMB protecting group or the like from the amine to the para position of the anisole.

[0048] "Contacting" refers to the process of bringing at least two distinct species into contact so that they can react. However, it is understood that the resulting reaction product may be made directly from the reaction between the added reagents or from intermediate products that may arise in the reaction mixture from one or more of the added reagents.

[0049] A "solvent" refers to a substance, e.g., a liquid, capable of dissolving a solute. Solvents can be polar or nonpolar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, while nonpolar solvents have a dielectric constant less than about 5 or a dipole moment less than about 1.0. Protic solvents are characterized by having a proton available for removal, e.g., a hydroxyl or carboxyl group. Aprotic solvents lack such groups. Representative polar protic solvents include alcohols (e.g., methanol, ethanol, propanol, isopropanol), acids (e.g., formic acid, acetic acid), and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, methyltetrahydrofuran, diethyl 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 are also useful in the present disclosure.

[0050] Solvents can also be classified based on their chemical structure, for example, 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 (e.g., 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.).

[0051] "Solvate" refers to a compound provided herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0052] "Hydrate" refers to a compound that is complexed with water molecules. The compounds of the present disclosure may be complexed with one-half the amount of water molecules or one to ten times the amount of water molecules.

[0053] "Tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0054] "Salt" refers to an acid or base salt of the compound used in the method of the present disclosure. Pharmaceutically acceptable salts include salts of the compound prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compound described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. These pharmaceutically acceptable salts are considered non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing, Easton, PA, 1985, incorporated herein by reference.

[0055] "About" refers to a range of values ​​that includes the specified value, and one of ordinary skill in the art would reasonably consider those values ​​similar to the specified value. In some embodiments, the term "about" refers to within the standard deviation using measurements generally accepted in the art. In some embodiments, "about" refers to a range of up to ±10% of the specified value. In some embodiments, "about" refers to the specified value.

[0056] "Composition," as used herein, is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining 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.

[0057] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and the absorption of the active agent by the subject. Pharmaceutical excipients useful in the present disclosure include, but are not limited to, binders, fillers, disintegrants, lubricants, coating materials, sweeteners, flavorings, and coloring agents. Other pharmaceutical excipients may also be useful in the present disclosure.

[0058] "Inhibition," "inhibit," and "inhibitor" refer to a compound or method that prevents a particular action or function. Inhibition can be partial or complete. Inhibition can be prophylactic or preventative.

[0059] "Administering" refers to administration to said subject orally, by suppository, topical contact, parenterally, intravenously, intraperitoneally, intramuscularly, intralesionally, intranasally, subcutaneously, intrathecally, by implantation of a sustained release device, e.g., a mini-osmotic pump, or via any other useful mechanism.

[0060] "Treate," "treating," and "treatment" refer to any indication of successful treatment or amelioration of an injury, condition, or symptom, including any objective or subjective parameter such as remission, palliation, reduction of symptoms or making the injury, condition, or symptom more tolerable to the patient, slowing the rate of degeneration or decline, making the end point of degeneration less debilitating, improving the patient's physical well-being, or improving the patient's mental well-being. Treatment or amelioration of symptoms may be based on objective or subjective parameters, including physical examination, neuropsychiatric function testing, and / or psychiatric evaluation.

[0061] "Patient" or "subject" refers to an organism suffering from or prone to a disease or condition treatable by administration of a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammals. In some embodiments, the patient is human. In some embodiments, the patient has been diagnosed with a disorder or condition, such as nephrolithiasis and / or primary hyperoxaluria. In some embodiments, the patient is suspected of having a disorder or condition, such as nephrolithiasis and / or primary hyperoxaluria. In some embodiments, the patient has previously been treated for a disorder or condition, such as nephrolithiasis and / or primary hyperoxaluria. In some embodiments, the patient is undergoing treatment or evaluation for a disorder or condition, such as nephrolithiasis and / or primary hyperoxaluria.

[0062] A "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition useful for treating or ameliorating a disease or condition, or for producing a detectable therapeutic or inhibitory effect. The appropriate amount will depend on the therapeutic purpose, and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Vols. 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 ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins).

[0063] "Primary hyperoxaluria type 1" and "PH1" are used interchangeably to refer to a condition caused by a deficiency of the liver enzyme alanine:glyoxylate aminotransferase (AGT). This deficiency leads to impaired glyoxylate metabolism in the liver, ultimately increasing oxalate synthesis and contributing to the formation of calcium oxalate kidney stones.

[0064] "Kidney stones" and / or "bladder stones" refer to small solid particles that occur within the kidney, renal pelvis, ureter, bladder, and / or urethra. Kidney stones and / or bladder stones typically contain or consist of particles of calcium salts, including, but not limited to, calcium oxalate particles and calcium phosphate particles (e.g., apatite or brushite particles). Kidney stones and / or bladder stones may also contain or consist of uric acid, struvite (i.e., NH4MgPO4·6H2O particles), and cystine (i.e., particles containing oxidized cysteine ​​disulfide dimers). Kidney stones and / or bladder stones typically range in size from less than a millimeter in their greatest dimension to 5 centimeters or more in their greatest dimension. Kidney stones often form in the kidney or renal pelvis, and when they are small enough (e.g., less than 5 mm), they pass through the ureters, bladder, and urethra and are expelled from the body through urination. Kidney and / or bladder stones often cause severe pain in the armpits and back under the ribs, as well as severe pain in the lower abdomen and groin. Other symptoms of kidney and / or bladder stones include, but are not limited to, painful urination, abnormally colored (e.g., pink, red, or brown) urine, cloudy urine, foul-smelling urine, nausea and vomiting, frequent urination or a feeling of incomplete urination, low urine output, fever, and chills. The presence of kidney and / or bladder stones in the urinary system can be confirmed using imaging techniques such as abdominal x-rays, CT scans, and ultrasound.

[0065] "Glycolate oxidase" and "GO" are used interchangeably to refer to the hepatic peroxisomal enzyme glycolate oxidase 1 (GO1), also known as hydroxyacid oxidase 1 (HAO1). The human enzyme is cataloged under NCBI accession number NP_060015.1 and UniProtKB reference number Q9UJM8. The mouse enzyme is cataloged under GenBank accession number EDL28373.1 and UniProtKB reference number Q9WU19. This enzyme catalyzes the conversion of glycolate to glyoxylate, a precursor to oxalate.

[0066] III. Methods for Preparing Compounds In one aspect, the present disclosure provides a compound represented by formula (II): [ka] A method for preparing the tautomer, or a salt thereof, is provided, which method comprises: (a) a compound of formula (IV), i.e. [ka] or a salt thereof to form a compound of formula (V), i.e. [ka] a first transition metal catalyst, and a first base in a first solvent to form a compound of formula (III): [ka] or a salt thereof, and (b) removing the PG group of said compound of formula (III) or said salt thereof to provide said compound of formula (II), said tautomer thereof, or said salt thereof; During the ceremony, the subscripts m and n are each independently 1 or 2; R 1 is C 1-6 is alkyl, R 2 and R 3 are each independently H or halogen; X 1 is a boron-containing group, X 2 is a halogen or a sulfonate, and In formula (IV) or formula (III), [ka] is expressed as follows: [ka] or a mixture thereof, and PG is an amine protecting group.

[0067] With respect to Formula (IV) or Formula (III), the 1,2,3-triazole moiety is protected with an amine protecting group (PG). Suitable amine protecting groups include, but are not limited to, benzyl (Bn), 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-nitrophenylsulfonyl (nosyl). 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).

[0068] 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) has formula (IV-1), i.e., [ka] and the compound of formula (III) is represented by formula (III-1), i.e. [ka] where m and n are subscripts, R 1 , R 2 , R 3 , and X 1 is as defined and explained herein.

[0069] In some embodiments, when the amine protecting group is p-methoxybenzyl (PMB), the compound of formula (IV) has formula (IV-1a), i.e. [ka] and the compound of formula (III) is represented by formula (III-1a), i.e. [ka] where m and n are subscripts, R 1 , R 2 , R 3 , and X 1 is as defined and explained herein.

[0070] In some embodiments, when the amine protecting group is other than 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 of formula (IV-1) or formula (IV-2), i.e. [ka] or a mixture thereof, and the compound of formula (III) is represented by formula (III-1) or formula (III-2), i.e. [ka] or a mixture thereof, with the subscripts m and n, R 1 , R 2 , R 3 , and X 1 is as defined and explained herein.

[0071] In some embodiments, when the amine protecting group is 2-(trimethylsilyl)ethoxymethyl (SEM), the compound of formula (IV) has formula (IV-1b) or formula (IV-2b), i.e. [ka] or a mixture thereof, and the compound of formula (III) is represented by formula (III-1b) or formula (III-2b), i.e. [ka] or a mixture thereof, with the subscripts m and n, R 1 , R 2 , R 3 , and X 1 is as defined and explained herein.

[0072] In some embodiments, X 1 is expressed as follows: (1) Y is an -OH group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-10 -BY2, which is an aryloxy group or a carboxylic acid group; (2) Y is bidentate C 2-8 Alkoxy group, bidentate C 6-10 -BY, which is an aryloxy group or a bidentate carboxylic acid group; (3) 9-borabicyclo[3,3,1]nonane (9-BBN) group, (4) Y is F or C 1-6 alkoxy, and M is an alkali metal ion, an ammonium ion, or a phosphonium ion; or (5) Y is tridentate C 3-10 -BYM is an alkoxy group, and M is an alkali metal ion, an ammonium ion, or a phosphonium ion. is.

[0073] In some embodiments, X 1 is -BY2, Y is -OH, C 1-6 Alkyl, C 1-6 Alkoxy group, C 6-10In some embodiments, X is an aryloxy group or a carboxylic acid group. 1 is -B(OH)2, -B(OEt)2, or -B(OiPr)2.

[0074] In some embodiments, X 1 is -BY and Y is a bidentate C 2-8 Alkoxy group, bidentate C 6-10 In some embodiments, X is an aryloxy group or a bidentate carboxylic acid group. 1 teeth, [ka] is selected from the group consisting of:

[0075] In some embodiments, X 1 is a 9-borabicyclo[3,3,1]nonane (9-BBN) group represented by the following formula: [ka]

[0076] In some embodiments, X 1 is -BY3M, and Y is F or C 1-6 alkoxy, and M is an alkali metal ion, an ammonium ion, or a phosphonium ion. In some embodiments, X 1 is -BF3M, -B(OiPr)3M, or -B(OiPr)3M, where M is Li + , Na + , or K + In some embodiments, X 1 is -BF3K, -B(OiPr)3K, or -B(OiPr)3Li.

[0077] In some embodiments, X 1 is -BYM and Y is a tridentate C 3-10 is an alkoxy group, and M is an alkali metal ion, an ammonium ion, or a phosphonium ion. In some embodiments, X 1 is expressed as follows: [ka] where M is Li + , Na + , or K + In some embodiments, M is K + is.

[0078] In some embodiments, X 1 is expressed by the following formula: [ka]

[0079] In some embodiments, the compound of formula (IV) has formula (IVa-1a), i.e. [ka] and R 1 is as defined and explained herein.

[0080] With respect to formula (V), in some embodiments, X 2 is a halogen. In some embodiments, X 2 is Cl, Br, or I. In some embodiments, X 2 is Br. In some embodiments, X 2 is a sulfonic acid. In some embodiments, X 2 is fluorosulfonic acid, methanesulfonic acid (OMs), p-toluenesulfonic acid (OTs), trifluoromethanesulfonic acid (OTf), p-fluorobenzenesulfonic acid, p-nitrophenylsulfonic acid (nosylate), or imidazole-1-sulfonic acid (imidazolate). In some embodiments, X 2 is methanesulfonic acid (OMs), p-toluenesulfonic acid (OTs), or trifluoromethanesulfonic acid (OTf).

[0081] In some embodiments, the compound of formula (V) has formula (V-1), i.e. [ka] where m and n are subscripts, R 2 , and R 3 is as defined and explained herein.

[0082] Regarding step (a), the first transition metal catalyst can be a compound containing 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.

[0083] In some embodiments, 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(amphos)Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2·CH2Cl2, Pd(dtbpf)Cl2, Pd(CH3CN)4(BF4)2, PdCl2, XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd-PEPPSI™-SIPr, or Pd-PEPPSI™-IPent. In some embodiments, the first palladium catalyst is [Pd(OAc)2]3, Na2PdCl4, Pd(CH3CN)4(CF3SO3)2, bis(benzonitrile)palladium(II) dichloride, palladium(II) (π-cinnamyl)chloride dimer, [di-tert-butyl(chloro)-phosphine]-palladium(II) dichloride dimer, di-μ-chlorotetrakis(di-tert-butylphosphinite)dihydrogendipalladate, di-μ-chlorobis(2'-amino-1,1'-biphenyl-2-yl-C,N)-dipalladium(II), chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]-palladium(II), Najera catalyst I, Najera catalyst II, di-μ-chlorobis[2-[(dimethylamino)-methyl]-phenyl-C,N]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)-methyl]-4,6-dimethoxyphenyl-C,N]-dipalladium(II), 1,2-bis(diphenylphosphino)-ethane]palladium(II) dichloride, [1,3-bis(diphenylphosphino)-propane]palladium(II) dichloride, [1,4-bis(diphenylphosphino)-butane]palladium(II) dichloride, bis(methyldiphenylphosphine)palladium(II) dichloride, benzylbis(triphenylphosphine)palladium(II) chloride, bis(triphenylphosphine)-palladium(II) diacetate, dichloro(1,5-cyclooctadiene)palladium(II), dichloro[9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene]-palladium(II), SingaCycle™-A1, SingaCycle™-A2, SingaCycle™-A3, SingaCycle™-A4, bis(tri-tert-butylphosphine)palladium(0), bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]-palladium(0), bis[1,2-bis(diphenylphosphino)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]palladium(II) dichloride (acrylamide:phosphine ratio = 20:2). In some embodiments, the first palladium catalyst is Pd(dppf)Cl, Pd(dppf)Cl·CHCl, or Pd(dtbpf)Cl. In some embodiments, the first palladium catalyst is Pd(dppf)Cl·CHCl.

[0084] In some embodiments, the first transition metal catalyst is present in a sub-stoichiometric amount. In some embodiments, the first palladium catalyst is present in a sub-stoichiometric amount. In some embodiments, Pd(dppf)Cl2·CH2Cl2 is present in a sub-stoichiometric amount. In some embodiments, the first transition metal catalyst is present in an amount of 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 one of its related formulae. In some embodiments, the first palladium catalyst is present in an amount of 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 one of its related formulae. In some embodiments, the first palladium catalyst is present in an amount of 0.05 to 0.1 equivalents relative to the compound of Formula (IV) or any one of its related formulae. In some embodiments, Pd(dppf)Cl2·CH2Cl2 is present in an amount of 0.05 to 0.1 equivalents relative to the compound of formula (IV) or any one of its related formulas.

[0085] Regarding step (a), the first base can be an alkali carbonate, alkali bicarbonate, alkali tribasic phosphate, alkali hydroxide, alkali carboxylic acid, amine, alkali alkoxide, or a combination thereof. Suitable alkali carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable alkali bicarbonates include lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate. Suitable alkali tribasic phosphates include trisodium phosphate and tripotassium phosphate. Suitable alkali hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. Suitable alkali carboxylic acids include lithium acetate, sodium acetate, potassium acetate, cesium acetate, and potassium trimethylacetate. Suitable amines include primary amines, secondary amines, tertiary amines, and aromatic amine bases. Suitable alkali alkoxides include sodium methoxide or sodium ethoxide. In some embodiments, the first base is sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, trisodium phosphate, tripotassium phosphate, cesium tribasic 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 base 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 base is potassium carbonate, tripotassium phosphate, or potassium acetate. In some embodiments, the first base comprises potassium carbonate. In some embodiments, the first base is potassium carbonate.

[0086] In some embodiments, the first base is present in an amount of 10 to 1 equivalent, 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 one of its related formulas. In some embodiments, the first base is present in an amount of 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 one of its related formulas. In some embodiments, the first base is present in an amount of 3 to 4 equivalents or about 3.5 equivalents relative to the compound of Formula (IV) or any one of its related formulas. In some embodiments, potassium carbonate is present in an amount of 3 to 4 equivalents or about 3.5 equivalents relative to the compound of Formula (IV) or any one of its related formulas.

[0087] With respect to step (a), in some embodiments, the compound of Formula (V) is present in an amount of 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 one of its related formulas. In some embodiments, the compound of Formula (V) is present in an amount of about 1.2 equivalents relative to the compound of Formula (IV) or any one of its related formulas. In some embodiments, the compound of Formula (V-1) is present in an amount of about 1.2 equivalents relative to the compound of Formula (IV-1a-1).

[0088] The first solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the first solvent is water, C 1-4The first solvent may be 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. 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 volumetric ratio of 1,4-dioxane:water 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 volumetric ratio of 1,4-dioxane:water of about 10:1.

[0089] Generally, the Suzuki reaction of step (a) can be carried out at ambient temperature to elevated temperatures. 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.

[0090] Regarding step (b), the compound of formula (III) can be deprotected by various methods to provide the compound of formula (II). When PG is p-methoxybenzyl (PMB), the compound of any one of formulas (III), (III-1), and (III-1a) can be deprotected by various methods to provide the compound of formula (II), for example, under acidic conditions, reductive (hydrogenolysis) conditions, or oxidative conditions.

[0091] In some embodiments, the PG group is removed by treatment with a first acid in a second solvent. In some embodiments, the p-methoxybenzyl (PMB) group is removed by treatment 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 comprises trifluoroacetic acid. In some embodiments, the first acid is trifluoroacetic acid.

[0092] 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 The second solvent is 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 comprises dichloromethane. In some embodiments, the second solvent is dichloromethane.

[0093] When the PG group is removed under acidic conditions, in some embodiments, the deprotection reaction mixture further comprises a transfer agent. When PG is p-methoxybenzyl (PMB), in some embodiments, the transfer agent is anisole.

[0094] In some embodiments, the p-methoxybenzyl (PMB) group is removed by treatment with trifluoroacetic acid and anisole in dichloromethane.

[0095] Generally, 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.

[0096] 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).

[0097] In some embodiments, the method further comprises: (c) contacting the compound of Formula (II), the tautomer thereof, or the salt thereof with a second base in a third solvent; and (d) acidifying with a second acid to give a compound of formula (I), i.e. [ka] To provide a tautomer thereof or a salt thereof Further includes:

[0098] Regarding step (c), the second base can be an alkali carbonate, an alkali hydroxide, an alkali alkoxide, or a combination thereof. Suitable alkali carbonates include lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Suitable alkali hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, and cesium hydroxide. Suitable alkali 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 aqueous sodium hydroxide.

[0099] The third solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the first solvent is water, C 1-4 The third solvent may be an alcohol, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), acetonitrile (ACN), N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), dimethoxyethane (DME), or a combination thereof. In some embodiments, the third solvent comprises tetrahydrofuran (THF) and water.

[0100] Generally, step (c) can be carried out at ambient to elevated temperatures. For example, the reaction mixture of step (c) may be at a temperature of 30°C to 100°C, or may be 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.

[0101] With respect to 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.

[0102] In some embodiments, step (d) is carried out in an aqueous solution. In some embodiments, step (d) is carried out by treating the aqueous extract of step (c) with an aqueous solution of hydrochloric acid. In some embodiments, step (d) is carried out by treating the aqueous extract of step (c) with an aqueous solution of hydrochloric acid to obtain a mixture having a pH value of 2 to 3.

[0103] Generally, step (d) can be carried out at ambient to elevated temperatures. For example, the reaction mixture of step (d) can be 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.

[0104] With respect to any one of Formula (I), Formula (II), Formula (III), Formula (V), and related formulae thereof, in some embodiments, the subscripts m and n are each 1. In some embodiments, one of the subscripts m and n is 2 and the other is 1. In some embodiments, the subscripts m and n are each 2.

[0105] In some embodiments, the compounds of formula (I) are represented by formula (Ia), formula (Ib), and formula (Ic), i.e. [ka] and R 2 and R 3 is as defined and explained herein.

[0106] In some embodiments, the compounds of formula (II) are represented by formulas (IIa), (IIb), and (IIc), i.e. [ka] and R 1 , R 2 , and R 3 is as defined and explained herein.

[0107] In some embodiments, the compounds of formula (III) are represented by formulas (IIIa-1a), (IIIb-1a), and (IIIc-1a), i.e. [ka] and R 1 , R 2 , and R 3 is as defined and explained herein.

[0108] In some embodiments, the compounds of formula (V) are represented by formulas (Va-1), (Vb-1), and (Vc-1), i.e. [ka] and R 2 and R 3 is as defined and explained herein.

[0109] With respect to any one of formulas (II), (III), (IV), and related formulas, 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 is methyl.

[0110] With respect to any one of formulas (I), (II), (III), (V), and related formulas thereof, in some embodiments, R 2 and R 3 are each independently a halogen. In some embodiments, R 2 and R 3 are F respectively.

[0111] In some embodiments, the compounds of formula (I) are represented by formulas (Ia-1), (Ib-1), and (Ic-1), i.e. [ka] It is represented by one of the following:

[0112] In some embodiments, the compounds of formula (II) are represented by formulas (IIa-1), (IIb-1), and (IIc-1), i.e. [ka] It is represented by one of the following:

[0113] In some embodiments, the compounds of formula (III) are represented by formulas (IIIa-1a-1), (IIIb-1a-1), and (IIIc-1a-1), i.e. [ka] It is represented by one of the following:

[0114] In some embodiments, the compound of any one of formula (IV), formula (IV-1), formula (IV-1a), and formula (IV-1a-1) has formula (IVa-1a-2), i.e. [ka] is expressed by

[0115] In some embodiments, the compounds of formula (V) are represented by formulas (Va-1-1), (Vb-1-1), and (Vc-1-1), i.e. [ka] It is represented by one of the following:

[0116] In some embodiments, the method further comprises, prior to step (a), (a1) A compound of formula (VI), i.e. [ka] or a salt thereof with a boron reagent, a second palladium catalyst, and a third base in a fourth solvent to form the compound of formula (IV) or the salt thereof, wherein X is Cl, Br, or I. Further includes:

[0117] Regarding step (a1), the boron reagent converts the compound of formula (VI) to the corresponding compound of formula (IV), i.e. [ka] X can be any drug that can be converted to 1represents a boron-containing group, which boron-containing groups are defined and explained herein. In some embodiments, the boron reagent is tetrahydroxydiboron, bis(catecholato)diboron, bis(hexyleneglycolato)diboron, bis(neopentylglycolato)diboron, or bis(pinacolato)diboron. In some embodiments, the boron reagent is bis(pinacolato)diboron.

[0118] The second palladium catalyst can 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)Cl2, Pd(dppf)Cl2·CH2Cl2, or Pd(dtbpf)Cl2. In some embodiments, the second palladium catalyst is Pd(dppf)Cl2·CH2Cl2.

[0119] In some embodiments, the second palladium catalyst is present in a sub-stoichiometric amount. In some embodiments, Pd(dppf)Cl2·CH2Cl2 is present in a sub-stoichiometric amount. In some embodiments, the second palladium catalyst is present in an amount of 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 second palladium catalyst is present in an amount of 0.03 to 0.05 equivalents relative to the compound of Formula (VI). In some embodiments, Pd(dppf)Cl2·CH2Cl2 is present in an amount of 0.03 to 0.05 equivalents relative to the compound of Formula (VI).

[0120] With respect to step (a1), the third base may be an alkali carbonate, alkali bicarbonate, alkali tribasic phosphate, alkali hydroxide, alkali carboxylic acid, amine, alkali alkoxide, or a combination thereof, 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, cesium tribasic 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 third base 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 third base is potassium carbonate, tripotassium phosphate, or potassium acetate. In some embodiments, the third base comprises potassium acetate. In some embodiments, the third base is potassium acetate.

[0121] In some embodiments, the third base is present in an amount of 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 third base is present in an amount of 2 to 5 equivalents, 2 to 4 equivalents, or about 3.0 equivalents relative to the compound of Formula (VI). In some embodiments, the third base is present in an amount of about 3.0 equivalents relative to the compound of Formula (VI). In some embodiments, potassium acetate is present in an amount of about 3.0 equivalents relative to the compound of Formula (VI).

[0122] The fourth solvent may be any suitable polar or non-polar, protic or aprotic solvent. In some embodiments, the fourth solvent is water, C 1-4The fourth solvent may be an 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. 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.

[0123] In some embodiments, when the amine protecting group (i.e., PG) is p-methoxybenzyl (PMB), the compound of formula (VI) has formula (VI-1a), i.e., [ka] and R 1 and X are as defined and explained herein.

[0124] In some embodiments of Formula (VI) or Formula (VI-1a), X is Br.

[0125] In some embodiments of Formula (VI) or Formula (VI-1a), R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. 1 is methyl.

[0126] In some embodiments, the compound of formula (VI) or formula (VI-1a) has the formula (VI-1a-1), i.e. [ka] is expressed by

[0127] In some embodiments, the compound of formula (VI) or formula (VI-1a) has the formula (VI-1a-1), i.e. [ka] and the compound of formula (IV) is represented by formula (IV-1a-2), i.e. [ka] is expressed by

[0128] Generally, step (a1) can be carried out at ambient temperature to elevated temperatures. 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.

[0129] In some embodiments, the compound of formula (IV) produced by step (a1) is used directly in the next step (ie, step (a)) without further purification.

[0130] In some embodiments, the present disclosure provides a compound represented by formula (I), i.e. [ka] A method for preparing the tautomer, or a salt thereof, is provided, which method comprises: (a1) A compound of formula (VI-1a), i.e. [ka] or a salt thereof is reacted with bis(pinacolato)diboron, a second palladium catalyst, and a third base in a fourth solvent to give a compound of formula (IV-1a-1), i.e., [ka] or converting it into a salt thereof; (a) reacting the compound of formula (IV-1a-1) or the salt thereof with a compound of formula (V-1), i.e. [ka] a first palladium catalyst and a first base in a first solvent to produce a compound of formula (III-1a), [ka] or forming a salt thereof; (b) treating the compound of formula (III-1a) or the salt thereof with trifluoroacetic acid and anisole in dichloromethane to give a compound of formula (II), i.e. [ka] providing a tautomer thereof, or a salt thereof; (c) saponifying the compound of formula (II), the tautomer thereof, or the salt thereof with a second base in a third solvent; and (d) acidifying with a second acid to provide said compound of formula (I), said tautomer thereof, or said salt thereof. wherein X is Cl, Br, or I; the subscripts m and n are each independently 1 or 2; R 1 is C 1-3 is alkyl, and R 2 and R 3 are F respectively.

[0131] In some embodiments, the method further comprises: (e) reacting said compound of formula (I), said tautomer, or said salt thereof with a compound of the following formula: [ka] the monosodium salt of said compound of formula (I) represented by the following formula: [ka] or a mixture thereof, or a tautomer thereof, wherein the subscripts m and n are each independently 1 or 2; and R 2 and R 3 are F respectively.

[0132] In some embodiments of formula (VI-1a), X is Br.

[0133] In some embodiments, the second palladium catalyst in step (a1) and the first palladium in step (a) are each independently Pd(dppf)Cl, Pd(dppf)Cl·CHCl, or Pd(dtbpf)Cl. In some embodiments, the second palladium catalyst in step (a1) and the first palladium in step (a) are each independently Pd(dppf)Cl·CHCl.

[0134] In some embodiments, the third base in step (a1) and the first base in 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 in step (a1) and the first base in step (a) are each independently potassium carbonate or potassium acetate. In some embodiments, the third base in step (a1) is potassium acetate and the first base in step (a) is potassium carbonate.

[0135] In some embodiments, the fourth solvent in step (a1) and the first solvent in step (a) are each independently water, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), or a combination thereof. In some embodiments, the fourth solvent in step (a1) and the first solvent in step (a) are each independently water, 1,4-dioxane, or a combination thereof. In some embodiments, the fourth solvent in step (a1) is 1,4-dioxane, and the first solvent in step (a) is a mixture of 1,4-dioxane and water.

[0136] In some embodiments, the second base in step (c) is lithium hydroxide, sodium hydroxide, or potassium hydroxide. In some embodiments, the second base in step (c) is sodium hydroxide. In some embodiments, the second base in step (c) is aqueous sodium hydroxide.

[0137] In some embodiments, the third solvent in step (c) is water, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), or a combination thereof. In some embodiments, the third solvent in step (c) is a mixture of water and tetrahydrofuran (THF).

[0138] In some embodiments, the second acid is hydrochloric acid. In some embodiments, the second acid is an aqueous solution of hydrochloric acid.

[0139] With respect to any one of Formula (I), Formula (II), Formula (III-1a), and Formula (V-1), in some embodiments, the subscripts m and n are each 1. In some embodiments, one of the subscripts m and n is 2 and the other is 1. In some embodiments, the subscripts m and n are each 2.

[0140] With respect to any one of Formula (II), Formula (III-1a), Formula (IV-1a-1), and Formula (VI-1a), in some embodiments, R 1 is methyl or ethyl. In some embodiments, R 1 is methyl.

[0141] All other reaction conditions for step (a1) and steps (a) to (d) are described above.

[0142] In some embodiments, step (e) is carried out by treating the compound of Formula (I) or its tautomer with aqueous sodium hydroxide. In some embodiments, the sodium hydroxide is present in an amount less than 1.0 equivalent, based on the compound of Formula (I), on an anhydrous and salt-free basis. In some embodiments, the sodium hydroxide is present in an amount of 0.80 to 0.95 equivalents, or 0.85 to 0.95 equivalents, based on the compound of Formula (I), on an anhydrous and salt-free basis. In some embodiments, the sodium hydroxide is present in an amount of about 0.88 equivalents, based on the compound of Formula (I), on an anhydrous and salt-free basis. In some embodiments, the reaction mixture of step (e) has a pH of about 9.5.

[0143] In some embodiments, step (e) comprises: (i) treating the compound of formula (I) or a tautomer thereof with aqueous sodium hydroxide; (ii) forming a slurry having a pH value of about 9.5; and (iii) freeze-drying the slurry to obtain a crystalline solid having the following formula: [ka] or a tautomer thereof of the compound of formula (I) represented by wherein sodium hydroxide is present in an amount of less than 1.0 equivalent based on the compound of formula (I) on a salt-free and anhydrous basis; the subscripts m and n are each independently 1 or 2; and R 2 and R 3 and each are F. In some embodiments, sodium hydroxide is present in an amount of about 0.88 equivalents on a salt-free and anhydrous basis relative to said compound of Formula (I).

[0144] In another aspect, the present disclosure provides a compound represented by formula (Ia-1): [ka] A method for preparing the tautomer, or a salt thereof, is provided, which method comprises: (a1) A compound of formula (VI-1a-1), i.e. [ka] or its salt is reacted with bis(pinacolato)diboron, Pd(dppf)Cl2·CH2Cl2, and potassium acetate in 1,4-dioxane to give a compound of formula (IV-1a-2), i.e., [ka] or converting it into a salt thereof; (a) contacting the compound of formula (IV-1a-2) or the 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 produce a compound of formula (IIIa-1a-1), i.e., [ka] or forming a salt thereof; (b) treating the compound of formula (IIIa-1a-1) or the salt thereof with trifluoroacetic acid and anisole in dichloromethane to give a compound of formula (IIa-1), i.e. [ka] providing a tautomer thereof, or a salt thereof; (c) saponifying the compound of formula (IIa-1), the tautomer thereof, or the salt thereof with aqueous sodium hydroxide in tetrahydrofuran; and (d) acidifying with aqueous HCl to provide the compound of formula (Ia-1), the tautomer thereof, or the salt thereof. Includes:

[0145] In some embodiments, step (a1) is carried out at a temperature of about 80°C, step (a) is carried out at a temperature of about 80°C, step (b) is carried out at a temperature of about 50°C, step (c) is carried out at a temperature of about 55°C, and step (d) is carried out at a temperature of about 20-25°C.

[0146] In some embodiments of Step (a1), Pd(dppf)Cl·CHCl is present in an amount of 0.02 to 0.5 equivalents relative to the compound of Formula (VI-1a-1). In some embodiments of Step (a1), Pd(dppf)Cl·CHCl is present in an amount of about 0.04 equivalents relative to the compound of Formula (VI-1a-1). In some embodiments of Step (a1), bis(pinacolato)diboron is present in an amount of about 1.5 equivalents relative to the compound of Formula (VI-1a-1). In some embodiments of Step (a1), potassium acetate is present in an amount of about 3.0 equivalents relative to the compound of Formula (VI-1a-1).

[0147] In some embodiments of 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 of 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 of Step (a), the amount of Pd(dppf)Cl·CHCl is 0.05 to 0.1 equivalents relative to the compound of Formula (IV-1a-2). In some embodiments of Step (a), the amount of Pd(dppf)Cl·CHCl is about 0.07 equivalents relative to the compound of Formula (IV-1a-2). In some embodiments of 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 of step (a), the amount of potassium carbonate is about 3.5 equivalents relative to said compound of formula (IV-1a-2).

[0148] In some embodiments, the compound of formula (IV-1a-2) prepared by step (a1) is used directly in the next step (ie, step (a)) without further purification.

[0149] In some embodiments, the compound of Formula (IIIa-1a-1) is isolated in an overall yield of at least 50% from both step (a1) and step (a). In some embodiments, the compound of Formula (IIIa-1a-1) is isolated in an overall yield of 50% to 80% or 60% to 70% from both step (a1) and step (a). In some embodiments, the compound of Formula (IIIa-1a-1) is isolated in an overall yield of about 60% from both step (a1) and step (a).

[0150] In some embodiments, the compound of formula (IIa-1) produced by step (b) is used directly in the next step (ie, step (c)) without further purification.

[0151] In some embodiments, step (d) is carried out by acidifying an aqueous extract of the reaction mixture of step (c).

[0152] In some embodiments, the method further comprises: (e) reacting the compound of formula (Ia-1), the tautomer thereof, or the salt thereof with a compound of the following formula: [ka] the monosodium salt of the compound of formula (Ia-1) represented by the following formula: [ka] or a mixture thereof, or a tautomer thereof.

[0153] In some embodiments, step (e) is carried out by treating the compound of Formula (Ia-1) or its tautomer with aqueous sodium hydroxide. In some embodiments, the sodium hydroxide is present in an amount of less than 1.0 equivalent, based on the compound of Formula (Ia-1), on an anhydrous and salt-free basis. In some embodiments, the sodium hydroxide is present in an amount of 0.80 to 0.95 equivalents, or 0.85 to 0.95 equivalents, based on the compound of Formula (Ia-1), on an anhydrous and salt-free basis. In some embodiments, the sodium hydroxide is present in an amount of about 0.88 equivalents, based on the compound of Formula (Ia-1), on an anhydrous and salt-free basis. In some embodiments, the reaction mixture of step (e) has a pH of about 9.5.

[0154] In some embodiments, step (e) comprises: (i) treating the compound of formula (Ia-1) or a tautomer thereof with aqueous sodium hydroxide; (ii) forming a slurry having a pH value of about 9.5; and (iii) freeze-drying the slurry to obtain a crystalline solid having the following formula: [ka] or a tautomer thereof of the compound of formula (Ia-1) wherein sodium hydroxide is present in an amount of less than 1.0 equivalent based on the compound of formula (Ia-1) on a salt-free and anhydrous basis; the subscripts m and n are each independently 1 or 2; and R 2 and R 3 and each are F. In some embodiments, sodium hydroxide is present in an amount of about 0.88 equivalents on a salt-free and anhydrous basis relative to said compound of Formula (Ia-1).

[0155] Certain compounds of the present disclosure can exist in solvated, including hydrated, and unsolvated forms. Generally, these solvated forms are equivalent to the unsolvated forms and are intended to be encompassed within the scope of the present disclosure.

[0156] Certain compounds of the present disclosure may exist as tautomers, and all such tautomers of the compounds are within the scope of the present disclosure.Tautomers refer to one of two or more structural isomers that exist in equilibrium and easily convert from one isomer to another.For example, 1,2,3-triazole of the following formula may exist in equilibrium. [ka]

[0157] In some embodiments of formula (I), compounds of the following formula may exist in equilibrium: [ka]

[0158] In some embodiments of formula (II), compounds of the following formula may exist in equilibrium: [ka]

[0159] In some embodiments, the compounds of the present disclosure may exist as monobasic addition salts, where the carboxylic acid moiety or the 1,2,3-triazole moiety is deprotonated to form a salt with a base. In some embodiments, the compounds of the present disclosure may exist as dibasic addition salts, where both the carboxylic acid moiety and the 1,2,3-triazole moiety are deprotonated to form a dibasic salt with a base. In some embodiments, the compound of formula (I) as a sodium salt has the following formula: [ka] the monosodium salt having the following formula: [ka] or mixtures thereof, wherein the subscripts m and n, R 2 , and R 3is as defined and explained herein. In some embodiments, the compound of formula (II) as a sodium salt has the following formula: [ka] and may have subscripts m and n, R 1 , R 2 , and R 3 is as defined and explained herein.

[0160] IV.Compound In one aspect, the present disclosure provides a compound represented by formula (X): [ka] and R 1 is H or C 1-6 alkyl, and R 2 and R 3 are each independently H or halogen, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0161] In some embodiments, the compound of formula (X) has formula (Xa): [ka] is expressed by

[0162] In some embodiments, the compound of formula (X) has formula (Xb), i.e. [ka] is expressed by

[0163] With respect to any one of formulas (X), (Xa), and (Xb), in some embodiments, R 1 is H. In some embodiments, R 1 is C 1-6 In some embodiments, R 1is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, or hexyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl.

[0164] With respect to any one of formulas (X), (Xa), and (Xb), in some embodiments, R 2 and R 3 are each independently a halogen. In some embodiments, R 2 and R 3 are each independently F, Cl, Br, or I. In some embodiments, R 2 and R 3 are F respectively.

[0165] Exemplary compounds of formula (X) are listed in Table 1. [Table 1]

[0166] In some embodiments, the compound of formula (X) has formula (Ib-1), i.e. [ka] is expressed by

[0167] In some embodiments, the compound of formula (X) has formula (Ic-1), i.e. [ka] is expressed by

[0168] The compounds of the present disclosure may exist as salts. The present disclosure includes such salts. When the compounds of the present disclosure contain a relatively acidic functional group (e.g., 1,2,3-triazole-4-carboxylic acid or 1,2,3-triazole), the present disclosure includes base addition salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts, or similar salts. R 1 C 1-6 When alkyl, the present disclosure may include acid addition salts, such as salts of mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), and salts of organic acids (acetic acid, propionic acid, glutamic acid, citric acid, etc.).

[0169] Pharmaceutically acceptable salts include salts of the active compounds prepared using relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein. When compounds of the present disclosure 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, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. These pharmaceutically acceptable salts are considered non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing, Easton, PA, 1985, incorporated herein by reference.

[0170] In some embodiments, the compounds of the present disclosure may exist as monobasic addition salts, where the carboxylic acid moiety or the 1,2,3-triazole moiety is deprotonated to form a salt with a base. In some embodiments, the compounds of the present disclosure may exist as dibasic addition salts, where the carboxylic acid moiety and the 1,2,3-triazole moiety are both deprotonated to form a dibasic salt with a base. In some embodiments, the compound of formula (X) as a sodium salt has the following formula: [ka] and R 1 , R 2 , and R 3 is as defined and explained herein.

[0171] The neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound, which differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0172] Certain compounds of the present disclosure may exist as solvates, including hydrates, or non-solvates. Generally, these solvates are equivalent to non-solvates and are included within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0173] Certain compounds of the present disclosure have asymmetric carbon atoms (optical centers), enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that may be defined with respect to absolute stereochemistry as (R)- or (S)-, and individual isomers encompassed within the scope of the present disclosure. The compounds of the present disclosure do not include compounds known in the art to be too unstable to be synthesized and / or isolated. The present disclosure is intended to include racemic and optically pure compounds. Optically active (R)- and (S)-isomers can be prepared using chiral synthetic equivalents or chiral reagents, or separated using various techniques.

[0174] Isomers include compounds that have the same number and kind of atoms, and therefore the same molecular weight, but differ with regard to the structural or configuration of those atoms.

[0175] Certain compounds of the present disclosure may exist as tautomers, and all such tautomers of the compounds are within the scope of the present disclosure. A tautomer refers to one of two or more structural isomers that exist in equilibrium and readily convert from one isomer to another. For example, 1,2,3-triazole of the following formula may exist in equilibrium: [ka] In some embodiments of formula (X), compounds of the following formula may exist in equilibrium: [ka]

[0176] Unless otherwise indicated, structures depicted herein are also intended to include all stereochemical forms of said structure, i.e., the R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0177] Unless otherwise indicated, the compounds of the present disclosure may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds of the present disclosure may contain unnatural proportions of isotopes of atoms, 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 disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0178] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure. Prodrugs can also be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be converted to the compounds of the present disclosure over time when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0179] V. Composition The compositions of the present disclosure can be prepared in a variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, sugar-coated tablets, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and other preparations suitable for oral ingestion by the patient. The compositions of the present disclosure can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compositions described herein can also be administered by inhalation, for example, intranasally. The compositions of the present disclosure can also be administered transdermally. The compositions of the present disclosure can also be administered via ocular, vaginal, and rectal routes, including suppositories, insufflations, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Thus, the present disclosure also provides pharmaceutical compositions comprising one or more pharmaceutically acceptable carriers and / or excipients and either 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)).

[0180] For preparing pharmaceutical compositions from the compounds of the present disclosure, pharmaceutically acceptable carriers can be either solid or liquid. Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details of formulation and administration techniques are well-documented in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing, Easton, Pennsylvania ("Remington's").

[0181] In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient, while in tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted into tablets of the particular shape and size.

[0182] The powders, capsules, and tablets preferably contain about 5% to about 70% of the active compound, for example, about 10% to about 70% of the active compound. Suitable carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting waxes, cocoa butter, and the like. The term "preparation" is intended to include formulating the active ingredient using an encapsulating material as a carrier, providing a capsule in which the active compound is surrounded by a carrier, with or without other excipients, thus uniting the other excipients. Cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0183] Suitable solid excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, pectin, dextrin, starch, tragacanth, low-melting waxes, cocoa butter, carbohydrates, sugars including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starches derived from corn, wheat, rice, potato, or other plants, celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose, gums including gum arabic and gum tragacanth, and proteins including, but not limited to, gelatin and collagen. Disintegrating or solubilizing agents, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate, may also be added.

[0184] Dragee cores are provided with a suitable coating, such as a concentrated sugar solution, which may include gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablet or dragee coating for product identification or to indicate the quantity of active compound (i.e., dosage). The pharmaceutical preparations of the present disclosure can also be administered orally using push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating material such as glycerol or sorbitol. Push-fit capsules can contain a compound provided herein (e.g., a compound of Formula (X)) mixed with a filler or binder, such as lactose or starch, a lubricant, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the 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.

[0185] For preparing suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and a compound provided herein (e.g., a compound of Formula (X)) is stirred to disperse homogeneously therein. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0186] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

[0187] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds provided herein (e.g., compounds of Formula (X)) in water and adding any suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a dispersing or wetting agent such as a viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, as well as natural phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (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 suspensions 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 preparations may be adjusted for osmotic pressure.

[0188] Also included are solid preparations that are intended to be converted, shortly before use, into liquid-type preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0189] Oily suspensions can be formulated by suspending the compounds provided herein (e.g., compounds of Formula (X)) in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. The oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as glycerol, sorbitol, or sucrose, can be added to provide a palatable oral preparation. These formulations can be preserved by the addition of an antioxidant, such as ascorbic acid. For examples of injectable oily vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present disclosure can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, as described above, or a mixture thereof. Suitable emulsifying agents include natural gums such as acacia and tragacanth, natural phospholipids such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweeteners and flavoring agents, as in the case of syrup and elixir formulations. Such formulations may also contain soothing agents, preservatives, or coloring agents.

[0190] The compositions of the present disclosure can be delivered by any suitable means, including oral, parenteral, and topical. Topical transdermal administration methods can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0191] The compositions of the present disclosure can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be formulated for administration via intradermal injection of drug-containing microspheres (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995), or as oral microspheres (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes allow for metered delivery over weeks or months.

[0192] In another embodiment, the compositions of the present disclosure can be formulated for parenteral administration, e.g., intravenous (IV) administration or administration into a body cavity or lumen of an organ. These formulations typically comprise a solution of the compositions of the present disclosure dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used include water and Ringer's solution, an isotonic sodium chloride solution. Sterile, fixed oils can also be used as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid, can also be used in the preparation of injectables. These solutions are sterile and generally free of undesirable substances. These formulations can be sterilized by various sterilization techniques. These formulations may contain pharmaceutically acceptable auxiliary substances necessary to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the compositions of the present disclosure in these formulations can vary widely and is selected primarily based on the volume, viscosity, weight, etc. of the liquid according to the particular mode of administration selected and the patient's needs. For IV administration, the formulation may be a sterile injectable preparation, such as an aqueous sterile injectable suspension or an oleaginous sterile injectable suspension. This suspension may be formulated using suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.

[0193] In another embodiment, the formulation of the composition of the present disclosure can be delivered using liposomes. Without wishing to be bound by theory, such liposomes may fuse with the cell membrane or be endocytosed. That is, they may fuse with the cell membrane by binding to a surface membrane protein receptor of the cell, by using a liposome-bound ligand, or by directly binding to an oligonucleotide to induce endocytosis. Liposomes can be used to target the delivery of the composition of the present disclosure to target cells in vivo, particularly if the liposome surface carries a ligand specific to the target cell or otherwise has preferential targeting for a particular organ (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0194] 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). Specifically, SEDDS and SMEDDS are isotropic mixtures of lipids, surfactants, and co-surfactants that can spontaneously disperse in aqueous media to form fine emulsions (SEDDS) or microemulsions (SMEDDS). Lipids useful in the formulations of the present disclosure include any natural or synthetic lipid, including, but not limited to, sesame oil, olive oil, castor oil, peanut oil, fatty acid esters, glycerol esters, Labrafil®, Labrasol®, Cremophor®, Solutol®, Tween®, Capryol®, Capmul®, Captex®, and Peceol®.

[0195] The pharmaceutical formulations of the compounds of formula (X) of the present disclosure can be provided as salts, which can be formed with a number of acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base form. In other cases, the preparations can be lyophilized powders in 1 mM to 50 mM histidine, 0.1% to 2% sucrose, 2% to 7% mannitol, at a pH range of 4.5 to 5.5, which is mixed with a buffer solution prior to use.

[0196] The pharmaceutical formulations of the compounds of formula (X) of the present disclosure can be provided as salts, which can be formed using bases, i.e., alkali metal salts and alkaline earth metal salts, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and ammonium salts, such as ammonium salts, trimethylammonium salts, diethylammonium salts, and tris(hydroxymethyl)methylammonium salts.

[0197] VI. Method Compounds of Formula (I), Formula (II), or Formula (X) and the compounds described in Table 1 are useful as glycolate oxidase inhibitors, and methods for inhibiting glycolate oxidase are also provided herein. The methods include contacting glycolate oxidase in a subject (e.g., a patient) in need thereof with a compound of any one of Formulas (I), (II), (X), (Xa), and (Xb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or salt, as described above. Inhibiting glycolate oxidase generally involves contacting the glycolate oxidase with the compound in an amount 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 any one of the compounds of Formula (I), Formula (II), Formula (X), Formula (Xa), and Formula (Xb) can result in about 1% to about 99% inhibition of glycolate oxidase (i.e., the activity of the inhibited glycolate oxidase is in the range of 99% to 1% of the activity of the glycolate oxidase in the absence of the compound). The level of glycolate oxidase inhibition can range 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 range 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, complete (i.e., 100%) glycolate oxidase inhibition occurs by contacting glycolate oxidase with a compound as described herein. In some embodiments, the compound of Formula (I), Formula (II), or Formula (X) reduces glyoxylic acid levels. In some embodiments, the compound of Formula (X) reduces glyoxylic acid levels.

[0198] In some embodiments of the method for inhibiting glycolate oxidase, the method comprises treating glycolate oxidase with a compound represented by the formula: [ka] This includes contacting the compound with its tautomer, or a pharmaceutically acceptable salt thereof.

[0199] In some embodiments of the method for inhibiting glycolate oxidase, the method comprises treating glycolate oxidase with a compound represented by the formula: [ka] This includes contacting the compound with its tautomer, or a pharmaceutically acceptable salt thereof.

[0200] In primary hyperoxaluria type 1 (PH1), the glyoxylate detoxification pathway is disrupted due to mutations in alanine-glyoxylate aminotransferase (AGT). AGT mutations prevent AGT from converting glyoxylate to pyruvate, resulting in elevated levels of oxalate and oxalate-containing kidney stones. Glycolate oxidase (GO) is a hepatic peroxisomal enzyme that catalyzes the oxidation of glycolate to glyoxylate, the substrate for AGT. Thus, GO plays a key role in glyoxylate production, while AGT plays a key role in glyoxylate detoxification. The present disclosure provides compounds and methods for treating PH1 by targeting GO, the source of AGT substrates. GO inhibitors, such as those described herein, can reduce glyoxylate levels in PH1 patients, thereby compensating for the inability of AGT mutants, which are downstream of GO in the glyoxylate detoxification pathway, to metabolize glyoxylate and preventing the buildup of harmful oxalate. In some embodiments, the compounds of formula (I) reduce glyoxylic acid levels in a PH1 patient or subject with PH1.

[0201] Methods for treating primary hyperoxaluria (PH1) are also provided. In Europe, the prevalence of PH1 is 1-3 per million, with an incidence of 1-9 per 100,000 births per year [Salido, supra]. PH1 is caused by mutations in the gene encoding the peroxisomal enzyme AGT, which results in a failure to detoxify glyoxylate, leading to a marked increase in oxalate synthesis by the liver. In PH1, increased urinary oxalate (UOx) excretion leads to the production of insoluble calcium oxalate (CaOx) crystals, which are prone to precipitation, primarily in the kidney, resulting in the formation of kidney stones and widespread nephrocalcinosis [Kaufman, supra]. This impairs renal function and progresses to end-stage renal disease (ESRD). Renal function, even at a rate of 30 ml / min / 1.73 m, is often associated with urinary ... 2 When the glomerular filtration rate (GFR) drops below 80%, the kidneys can no longer remove the amount of oxalate produced by the liver, leading to systemic deposition of CaOx (oxalosis). In people with PH1, the accumulated oxalate is deposited in the kidneys and renal tubules. Oxalate combines with calcium to form kidney and bladder stones, the primary component of these stones. Early symptoms of PH1 include hematuria, abdominal pain, stone passage, or recurrent renal tubular infections. This initial diagnosis is based on clinical and ultrasound findings and UOx assessment. AGT activity assessment in a liver biopsy and / or DNA analysis is required to confirm the diagnosis of PH1 and to initiate conservative treatment (high fluid intake, pyridoxine, CaOx crystallization inhibitors) aimed at maintaining kidney function. The most effective treatment for PH1 is (preemptive) liver transplantation (LTx) alone or in combination with kidney transplantation [Cochat, et al. (2012) Nephrol Dial Transplant. 27: 1729].

[0202] In some embodiments, the method for treating PH1 comprises administering to a subject in need thereof a compound of any one of Formula (I), Formula (II), Formula (X), Formula (Xa), and Formula (Xb), as described above, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or said salt. In some embodiments, the subject has kidney stones and / or bladder stones. In some embodiments, the compound of Formula (X) reduces glyoxylic acid levels in the subject. In some embodiments, the compound of Formula (X) reduces oxalate accumulation in the kidney and / or renal tubules.

[0203] In some embodiments of the methods for treating PH1, the methods include administering to a subject a compound represented by the formula: [ka] This includes administering the tautomer, or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments of the methods for treating PH1, the methods include administering to a subject a compound represented by the formula: [ka] This includes administering the tautomer, or a pharmaceutically acceptable salt thereof.

[0205] Also provided herein are methods for treating kidney stones and / or bladder stones. The methods include administering to a subject in need thereof a compound of any one of Formula (I), Formula (II), Formula (X), Formula (Xa), and Formula (Xb), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound or said salt, as described above. In some embodiments, the compound of Formula (X) reduces oxalate accumulation in the kidney and / or renal tubules.

[0206] In some embodiments of the methods for treating kidney stones and / or bladder stones, the methods include administering to a subject a compound represented by the formula: [ka] This includes administering the tautomer, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments of the methods for treating kidney stones and / or bladder stones, the methods include administering to a subject a compound represented by the formula: [ka] This includes administering the tautomer, or a pharmaceutically acceptable salt thereof.

[0208] Unless otherwise indicated, structures depicted herein are also intended to include all stereochemical forms of said structure, i.e., the R and S configurations for each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. [Example]

[0209] The following abbreviations are used in the examples below: [Table 2]

[0210] The compounds of formula (I) and formula (II) can be synthesized via Suzuki reaction of the compounds of formula (IV-1a-1) and formula (V-1) according to Scheme 1 shown in FIG. 2, in which the subscripts m and n, R 1 , R 2 , R 3 and X are defined and described herein, and the first and second palladium catalysts, the first and third bases, and the first and fourth solvents are defined and described herein.

[0211] Specifically, the compound of formula (Ia-1) was prepared according to Scheme 2 shown in Figure 3. The intermediate compound of formula (VI-1a-1) was prepared according to Scheme 3 shown in Figure 4. 1-Bromo-4-(3,3-difluorocyclobutyl)benzene was prepared according to Scheme 4 shown in Figure 5.

[0212] Example 1: Methyl 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (VI-1a-1) Step-1: 1-(chloromethyl)-4-methoxybenzene (02) [ka] PCl3 (2.73 kg, 19.9 mol, 1.1 eq) was added to a stirred solution of p-methoxybenzyl alcohol (2.5 kg, 18.09 mol, 1.0 eq) in DCM (12.5 L, 5.0 vol) at 0 °C. The reaction mixture was stirred at room temperature for 3.0 h. The reaction was monitored by TLC (mobile phase: 60% EtOAc in n-heptane). The reaction mixture was poured into cold aqueous ammonia (10.0 L, 4.0 vol). The organic layer was collected, and the aqueous layer was further extracted with DCM (2 × 6.0 L). The combined organic extracts were washed with brine (100 L, 4.0 vol) and dried over sodium sulfate. After filtration, the filtrate was concentrated under vacuum at 40 °C to give crude p-methoxybenzyl chloride (02) (2.45 kg, 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).

[0213] Step 2: 1-(azidomethyl)-4-methoxybenzene (03) [ka] 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.) at room temperature. The reaction mixture was stirred at 50°C for 18.0 h. 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 (2 x 20.0 L). The combined organic extracts were washed with water (2 x 20.0 L) and brine (3 x 20.0 L). After drying over sodium sulfate and filtration, the solvent was evaporated under vacuum at 50°C to give crude 1-(azidomethyl)-4-methoxybenzene 03 (2.12 kg) as a brown oil. This 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).

[0214] Step 3: Methyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (04) [ka] Dimethyl malonate (2.32 kg, 17.55 mol, 1.37 eq) and K2CO3 (7.11 kg, 51.44 mol, 4.0 eq) were added to a stirred solution of azide 03 (2.1 kg, 12.87 mol, 1.0 eq) in DMSO (13.65 L, 6.5 vol) at room temperature. The reaction mixture was stirred at 50 °C for 48.0 h. The reaction progress 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 (2 × 10.0 L). The MTBE extract was discarded. The aqueous layer was quenched with 4 N HCl (21.0 L, 10.0 vol) at <10 °C and extracted with EtOAc (2 × 20.0 L). The combined ethyl acetate extracts were washed with brine (3 x 20.0 L) and dried over sodium sulfate. After filtration, the filtrate was concentrated under vacuum at 50 °C to give crude methyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (04) as a yellow oil (1.6 kg), which was used directly in the next step.

[0215] Step 4: methyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (05) [ka] PCl5 (1.51 kg, 7.25 mol, 1.2 equiv.) was added to a stirred solution of O4 (1.6 kg, 6.08 mol, 1.0 equiv.) in toluene (10.0 L, 6.25 vol.) at room temperature. The reaction mixture was stirred at 60 °C for 2.0 h. The progress of the reaction was monitored by TLC (mobile phase: 40% ethyl acetate in n-heptane). The reaction mixture was then poured into cold aqueous 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 over sodium sulfate and filtration, the solvent was evaporated under vacuum at 50° C. to give crude methyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (05) as a brown semi-solid (1.32 kg), which was used directly in Step 5 without further purification. 1 H 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).

[0216] Step 5: methyl 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (VI-1a-1) [ka] 4-Bromophenol (0.798 kg, 4.615 mol, 1.0 equiv.) and KCO (2.551 kg, 18.44 mol, 4.0 equiv.) were added to a stirred solution of crude 05 (1.3 kg, 4.615 mol, 1.0 equiv.) in DMF (7.8 L, 6.0 vol.) at room temperature. The reaction mixture was stirred at 90 °C for 20 h. The progress of the reaction was monitored by TLC (mobile phase: 30% ethyl acetate in n-heptane). The reaction mixture was cooled to room temperature and quenched with water (20.0 L, 15.3 vol.) followed by extraction with EtOAc (2 × 15.0 L). The combined organic extracts were washed with water (2 × 10.0 L) and brine (3 × 10.0 L). After drying over sodium sulfate, the mixture was concentrated under vacuum at 50 °C to give 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 the pure compound of formula (VI-Ia-1) (650 g, 33.67%) as a pale yellow solid. 1 H NMR (300 MHz, chloroform-d) δ 7.35 (d, J = 9.0 Hz, 2H), 7.21 - 7.13 (m, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 9.0 Hz, 2H), 5.36 (s, 2H), 3.76 (s, 3H), 3.75 (s, 3H).

[0217] Example 2: 1-Bromo-4-(3,3-difluorocyclobutyl)benzene Step A: 4-Bromostyrene [ka] Methyltriphenylphosphonium bromide (7.53 kg, 21.07 mol, 1.3 equiv.) and K2CO3 (13.44 kg, 97.27 mol, 6.0 equiv.) were added to a stirred solution of p-bromobenzaldehyde (3.0 kg, 16.2 mol, 1.0 equiv.) in THF (45.0 L, 15.0 vol.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 60 °C for 18 h. The progress of the reaction was monitored by TLC (mobile phase: 25% EtOAc in n-hexane). The reaction mixture was cooled to room temperature, quenched with water (40.0 L, 13.33 vol.), and extracted with MTBE (2 × 25.0 L). The organic layer was washed with 0.5 N HCl solution (10 vol.). The organic layer was collected, dried over sodium sulfate, filtered, and the filtrate was evaporated to give 4-bromostyrene (2.33 kg, 78.57%) as a pale yellow liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.29 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.49 (dd, J = 17.6, 10.9 Hz, 1H), 5.58 (dd, J = 17.6, 0.8 Hz, 1H), 5.12 (dd, J = 10.9, 0.8 Hz, 1H).

[0218] Step B: 3-(4-bromophenyl)cyclobutan-1-one [ka] A solution of TfO (2.42 L, 14.42 mol, 1.1 eq) in 1,2-dichloroethane (0.72 L, 0.3 vol) was added 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) at −15° C. and stirred for 30 minutes at −15° C. A solution of 4-bromostyrene (2.4 kg, 13.11 mol, 1.0 eq) in 1,2-dichloroethane (1.68 L, 0.7 vol) was added, followed by the slow addition of a solution of 2,4,6-collidine (1.75 kg, 14.45 mol, 1.1 eq) in 1,2-dichloroethane (2.4 L, 1.0 vol). 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 n-hexane). The reaction mixture was quenched with water (24.0 L, 10.0 vol), and the product was extracted with DCM (3 x 15.0 L). The combined organic extracts were washed with brine (3 x 15.0 L) and concentrated. The crude product was purified by column chromatography on silica gel (7.0 kg, mesh size 230-400) eluting with 0-5% ethyl acetate in n-heptane. The oily product was triturated with n-hexane at room temperature to give a solid product. The solid was collected by filtration to give 3-(4-bromophenyl)cyclobutan-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).

[0219] Step C: 1-Bromo-4-(3,3-difluorocyclobutyl)benzene [ka] Diethylaminosulfur 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-28 °C) for 24 h. The progress of the reaction was monitored by TLC (mobile phase: 20% EtOAc in n-heptane). The reaction mixture was poured into 10% NaHCO3 solution (12.0 L, 20.0 vol.) and ice (5.0 kg) and extracted with DCM (2 × 6.0 L). The organic layer was collected and the solvent was evaporated to give the crude product, which was purified by column chromatography on silica gel (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).

[0220] Example 3: Methyl 1-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (IV-1a-2) [ka] Pd(dppf)Cl CHCl (65.85 g, 76.5 mmol, 0.04 equiv.), potassium acetate (563.14 g, 5.738 mol, 3.0 equiv.), and bis(pinacolato)diboron (728.58 g, 2.869 mol, 1.5 equiv.) were added to a stirred solution of the compound of formula (VI-1a-1) (800.0 g, 1.912 mol, 1.0 equiv.) in 1,4-dioxane (12.0 L, 15.0 vol.) at room temperature. The reaction mixture was degassed and stirred at 80 °C for 4.0 h. 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 and then filtered through Celite (1.0 kg), and the Celite was washed with ethyl acetate (2.4 L, 3.0 vol). The filtrate was diluted with water (8.0 L, 10.0 vol) and extracted with EtOAc (2 × 6.0 L). 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 triturated with n-heptane (4 × 3.0 L) to remove excess bis(pinacolato)diboron, and the n-heptane was decanted. The remaining heptane was removed under vacuum to give the compound of formula (IV-1a-2) (952.0 g) as a reddish oily syrup. The crude material of formula (IV-1a-2) was used directly in the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 7.66 - 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).

[0221] Example 4: Methyl 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (IIIa-1a-1) [ka] Pd(dppf)Cl·CHCl (123.02 g, 142.91 mmol, 0.07 equiv.), KCO (987.54 g, 7145.74 mmol, 3.5 equiv.) in water (950.0 mL) were added to a stirred solution of the compound of formula (IV-1a-2) (950.0 g, 2041.64 mmol, 1.0 equiv.) and 1-bromo-4-(3,3-difluorocyclobutyl)benzene (605.34 g, 2449.97 mmol, 1.2 equiv.) in 1,4-dioxane (9.5 L) at room temperature. The reaction mixture was degassed and stirred at 80 °C for 1 h. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to room temperature and then filtered through a Celite bed (1.0 kg), and the Celite was washed with ethyl acetate (2.4 L, 3.0 vol). The filtrate was concentrated to give the crude product of formula (IIIa-1a-1). The crude product was then purified by column chromatography on silica gel (mobile phase: 0-10% ethyl acetate in DCM). The product-containing fractions were combined, and the solvent was evaporated to give the compound of formula (IIIa-1a-1) (600.0 g, 61.16% for both steps described in Examples 3-4) as a light brown solid. 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).

[0222] Example 5: Methyl 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylate (IIa-1) [ka] Anisole (385.01 g, 3.560 mol, 3.0 eq) and TFA (6.0 L, 10.0 vol) were added to a stirred solution of the compound of formula (IIIa-1a-1) (600.0 g, 1.186 mol, 1.0 eq) in DCM (6.0 L, 10.0 vol) at room temperature. The reaction mixture was stirred at 50° C. for 15.0 hours. The progress of the reaction was monitored by TLC (mobile phase: 50% ethyl acetate in n-heptane). The solution was concentrated, and the residue was treated with n-heptane (10.0 vol). The resulting solid was filtered, and the wet solid was suspended in toluene (1.8 L, 3.0 vol). The resulting solid was collected by filtration to give the crude product of formula (IIa-1) (362.2 g, 79.18%) as a pale gray solid, 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).

[0223] Example 6: 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (Ia-1) [ka] A solution of 1.0 M NaOH (115.83 g, 2.895.75 mmol, 3.1 equiv.) in water (2.9 L) was added to a stirred solution of crude compound of formula (IIa-1) (360.0 g, 934.16 mmol, 1.0 equiv.) in THF (1.8 L) at room temperature. The reaction mixture was stirred at 55 °C for 4.0 h. The progress of the reaction was monitored by TLC (mobile phase: 80% ethyl acetate in n-heptane). The reaction mixture was cooled to room temperature and washed with DCM (2 × 3.0 L). The DCM layer was discarded, and the aqueous layer was acidified (pH 2-3) at room temperature using 1 N HCl (3.0 L). The precipitated solid was collected by filtration, and the wet cake was washed with water (3.6 L). The wet material (650.0 g) was dried at 45° C. for 40 hours to give the acid of formula (Ia-1) as an off-white solid (320.0 g). 1 H NMR (300 MHz, DMSO-d6) δ 7.72 - 7.56 (m, 4H), 7.39 (d, J = 8.1 Hz, 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 moisture content: 4.85%.

[0224] Example 7: Sodium salt of 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] A solution of 1.0 M NaOH (1.12 g, 28.14 mmol, 0.95 equiv) in water (30.0 mL, 2.7 vol) was added to a stirred solution of the wet compound of formula (Ia-1) (11.0 g, 29.62 mmol, 1.0 equiv) in water (55.0 mL) at room temperature. The reaction mixture was stirred for 1.0 hour (until the pH reached 9.5). The reaction mixture was filtered to remove undissolved solids (2.5 g). The filtrate was lyophilized for 42.0 hours to give the sodium salt (5.8 g) as an off-white solid.

[0225] Example 8: Monosodium salt of 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] 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 equivalents, 746 mmol) in water (870 mL) at room temperature (4.5% water content; water content was adjusted according to calculation) was added 1 N NaOH (609 mL) over 10 minutes (pH = 9.69). The suspension was stirred for 2.5 hours, after which the pH was measured to be 9.04. An additional 50 mL of 1 N NaOH was added, after which the pH was 9.65. After stirring for an additional 30 minutes, the pH was 9.54 (0.883 equivalents of 1 NaOH in total). The slurry was lyophilized to dryness to give sodium 5-((4'-(3,3-difluorocyclobutyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (283.5 g, 96.6%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.59 (dd, J = 8.6, 3.1 Hz, 4H), 7.38 (d, J = 8.1 Hz, 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%.

[0226] Elemental analysis of the product: Carbon (C) measured: 57.26%, Hydrogen (H) measured: 3.82%, Nitrogen (N) measured: 10.87%, and Sodium (Na) measured: 5.04%. The elemental analysis results correspond to the following formula: [ka] The monosodium salt of the compound of formula (Ia-1) was found to be identical to that of the monosodium salt of the compound of formula (Ia-1)

[0227] Example 9: 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (Ib-1) [ka] The compound of formula (Ib-1) was synthesized according to the synthetic scheme shown in Figure 6. In Figure 6, the compound of formula (Ib-1) and the compound of formula (IIb-1) may exist as tautomers as described herein. Compound 5 was prepared according to the scheme shown in Figure 8. The structure of compound 5 was determined according to J. Chem. Soc., Perkin Trans. 1, 1982, 627-630 and Humphrey J. Heterocyclic Chem 1991 301-304.

[0228] Step 1: 4-(3,3-difluorocyclopentyl)phenol (2) [ka] DAST was added to a solution of 3-(4-hydroxyphenyl)cyclopentanone (1) (2.00 g, 11.3 mmol) in DCE (20 mL). After 4 days, the reaction mixture was diluted with DCM (20 mL) and added to a saturated solution of sodium bicarbonate. The organic phase was collected, dried over sodium sulfate, filtered, and evaporated. The mixture was purified on a Combiflash column using 0% to 25% ethyl acetate-hexane and a silica gel (40 g) column to give the title compound (2) (1.20 g) (54%). 1 H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.5 Hz, 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).

[0229] Step 2: 4-(3,3-difluorocyclopentyl)phenyl trifluoromethanesulfonate (3) [ka] 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 equiv). The reaction mixture was cooled to 0 °C, followed by the addition of trifluoromethanesulfonic anhydride (TfO) (0.255 mL, 1.51 mmol, 1.50 equiv). The reaction mixture was allowed to warm slowly to room temperature. After 2 h, the mixture was diluted with EtO and quenched with 1.0 M aqueous HCl. The organic layer was washed with saturated NaHCO, brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified on a silica gel (24 g) cartridge using 0% to 15% EtOAc-hexane to give the title compound (0.240 g, 0.727 mmol) (72.0%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.43 - 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).

[0230] Step 3: 2-(4-(3,3-difluorocyclopentyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4) [ka] To a solution of 4-(3,3-difluorocyclopentyl)phenyl trifluoromethanesulfonate (3) (0.231 g, 0.70 mmol), bis(pinacolato)diboron (0.266 g, 1.05 mmol, 1.50 equiv.) in 1,4-dioxane (3.2 mL) was added potassium acetate (0.206 g, 2.10 mmol, 3.00 equiv.). The mixture was purged with argon gas for 5 minutes, and Pd(dppf)Cl.CHCl (0.042 g, 0.049 mmol, 0.07 equiv.) was added. 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) cartridge using 0% to 30% EtOAc-hexanes to afford the title compound (0.240 g, 0.475 mmol) (67.8%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H), 7.27 (t, J = 8.0 Hz, 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).

[0231] Step 4: methyl 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (IIIb-1a-1) [ka] To a solution of methyl 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (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 equiv.) in 1,4-dioxane (2.8 mL) was added potassium carbonate (0.312 g, 2.26 mmol, 3.50 equiv.) and water. The mixture was degassed using nitrogen, and then Pd(dppf)Cl.CHCl (0.033 g, 0.039 mmol, 0.060 equiv.) was added. The reaction mixture was heated at 85 °C for 4 h. 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 on a silica gel (24 g) column using 0% to 100% EtOAc-hexane to give the title compound (0.240 g, 0.462 mmol) (68%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.55 - 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).

[0232] Step 5: Methyl 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylate (IIb-1) [ka] To a suspension of methyl 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (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 equiv.) and TFA (5.0 mL, 65 mmol, 158 equiv.). The reaction mixture was stirred at 50°C for 4 h. The reaction mixture was then evaporated to dryness under reduced pressure to give a solid. Hexane was added to the solid and triturated. The hexane was decanted and stirred with EtOAc-hexane overnight to give the title compound (0.106 g, 0.265 mmol) (64.6%) as a beige solid after filtration. 1 H NMR (300 MHz, CDCl3) δ 7.57 (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).

[0233] Step 6: 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (Ib-1) To a solution of methyl 5-((4'-(3,3-difluorocyclopentyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylate (IIb-1) (0.106 g, 0.265 mmol, 1.00 equiv.) in THF (1.0 mL) was added a solution of 1 M NaOH (0.796 mL, 0.796 mmol, 3.00 equiv.). The reaction mixture was stirred at 50°C for 6 h. The reaction mixture was acidified using 1 M HCl solution, and the resulting solid was filtered and washed. The solid was transferred to a flask and dissolved in 10% water-EtOH (20 mL) with heating to completely dissolve, after which 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 (300 MHz, CD4OD) δ 7.60 (m, 4H), 7.36 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 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: t R = 6.911, 97.7% purity).

[0234] Example 10: 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (Ic-1) [ka] The compound of formula (Ic-1) was synthesized according to the synthetic scheme shown in Figure 7. In Figure 7, the compound of formula (Ic-1) and the compound of formula (IIc-1) may exist as tautomers as described herein. Compound 5 was prepared according to the scheme shown in Figure 8. The structure of compound 5 was determined according to J. Chem. Soc., Perkin Trans. 1, 1982, 627-630 and Humphrey J. Heterocyclic Chem 1991 301-304.

[0235] Step 1: 1-Bromo-4-(4,4-difluorocyclohexyl)benzene (Vc-1-1) [ka] To a solution of triethylamine trihydrofluoride (1.30 mL, 7.90 mmol, 2.00 equiv.) and trimethylamine (0.549 mL, 3.95 mmol, 1.00 equiv.) in DCM (6.0 mL) at 0 °C was added XtalFluor-E (N,N-diethyl-S,S-difluorosulfiriminium tetrafluoroborate) (1.35 g, 5.92 mmol, 1.50 equiv.) and 4-(4-bromophenyl)cyclohexan-1-one (7) (1.00 g, 3.95 mmol, 1.00 equiv.) in DCM (3.0 mL). The mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with DCM (20 mL), then added to saturated aqueous sodium bicarbonate (50 mL), and the resulting mixture was extracted with DCM (2 × 20 mL). The organic phases were combined and dried over NaSO, filtered, and the solvent was evaporated to give a crude mixture that was purified by silica gel column chromatography (40 g) using EtOAc / hexanes (0-10%) to give 1-bromo-4-(4,4-difluorocyclohexyl)benzene (1.03 g, 3.74 mmol) (94.8%) as a colorless oil (clear solid), which became a white solid on standing. 1H NMR (300 MHz, CDCl3) δ 7.48 - 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).

[0236] Step 2: 2-(4-(4,4-difluorocyclohexyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9) [ka] To a solution of 1-bromo-4-(4,4-difluorocyclohexyl)benzene (Vc-1-1) (1.12 g, 4.07 mmol), bis(pinacolato)diboron (1.54 g, 6.10 mmol, 1.50 equiv.) in 1,4-dioxane (19.0 mL) was added potassium acetate (1.20 g, 12.20 mmol, 3.00 equiv.). The mixture was purged with argon gas for 5 minutes, and Pd(dppf)Cl.CHCl (0.245 g, 0.285 mmol, 0.070 equiv.) was added. The reaction mixture was heated at 90 °C for 4 hours. The mixture was cooled to room temperature, filtered through Celite, and washed with DCM. Water (50 mL) was added to the filtrate and extracted with DCM (2 × 25 mL). The combined organic layers were dried and concentrated to give a crude residue, which was purified by silica gel column chromatography (40 g) using EtOAc in hexanes (0-10%) to give the title product (0.600 g, 1.86 mmol) (45.8%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 2.67 - 2.55 (m, 1H), 2.28 - 2.16 (m, 2H), 2.00 - 1.74 (m, 6H), 1.34 (s, 12H).

[0237] Step 3: Methyl 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (IIIc-1a-1) [ka] To a solution of methyl 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (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 equiv.) in p-dioxane (6.3 mL) was added potassium carbonate (0.693 g, 5.02 mmol, 3.50 equiv.) and water (0.629 mL). The reaction mixture was degassed for 5 min, and then Pd(dppf)Cl.CHCl (0.074 g, 0.086 mmol, 0.060 equiv.) was added. The mixture was stirred at 90 °C for 6 h. The reaction mixture was cooled to room temperature and filtered through Celite, washing with DCM. Water (50 mL) was added to the mixture and extracted with DCM (2 × 25 mL). The combined organic layers were dried and concentrated under reduced pressure to give a crude residue, which was purified by silica gel column chromatography (40 g) using 0-10% EtOAc in DCM as the eluent to give the title compound (0.620 g, 1.16 mmol) (81%) as a solid. 1 H NMR (300 MHz, CDCl3) δ 7.51 - 7.45 (m, 4H), 7.30 (d, J = 8.2 Hz, 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).

[0238] Step 4: Methyl 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylate (IIc-1) [ka] To a room temperature suspension of methyl 5-{[4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl]oxy}-1-[(4-methoxyphenyl)methyl]-1H-1,2,3-triazole-4-carboxylate (IIIc-1a-1) (0.675 g, 1.26 mmol) in DCM (2.2 mL) was added anisole (0.138 mL, 1.266 mmol, 1.000 equiv.) and TFA (7.6 mL, 99.33 mmol, 78.5 equiv.). After 4 h at 50 °C, the reaction mixture was evaporated to dryness under reduced pressure to give a solid. Hexane (25 mL) was added to the solid, and the hexane was removed by decantation. The resulting solid was triturated with EtOAc (100 mL) (stirring overnight), filtered, and triturated with EtOH (10 mL) (stirring for 30 min) to give the title compound (0.260 g, 0.629 mmol) (49.7%). 1 H NMR (300 MHz, CDCl3) δ 7.61 - 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).

[0239] Step 5: 5-((4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid (Ic-1) To a solution of methyl 5-{[4'-(4,4-difluorocyclohexyl)-[1,1'-biphenyl]-4-yl]oxy}-1H-1,2,3-triazole-4-carboxylic acid (IIc-1) (0.260 g, 0.553 mmol) in THF (1.0 mL) was added a solution of NaOH (1 M) (1.7 mL, 1.72 mmol, 3.10 equiv). The reaction mixture was stirred at 50 °C for 6 h. The reaction mixture was acidified (pH = 3) using 1.0 M HCl, and the suspension was stirred for 10 min. The solid was filtered, rinsed with water, and dried. The product was dissolved in a hot mixture of 10% water in EtOH to give the title compound as a white solid (0.099 g, 0.248 mmol) (44.8%) after standing. 1 H NMR (300 MHz, DMSO-d6) δ 7.18 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.88 (d, J = 7.7 Hz, 2H), 6.67 (d, J = 8.4 Hz, 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.

[0240] Example 11: Inhibition of glycolate oxidase A schematic of the catalytic reactions used to assay glycolate oxidase activity in the presence of compounds according to the present disclosure is shown in Figure 9. The glycolate oxidase (GO)-catalyzed conversion of glycolate to glyoxylic acid (top reaction) uses molecular oxygen (O2) to restore its oxidized state with the concomitant reduction of the cofactor flavin mononucleotide (FMN) and releases hydrogen peroxide (HO2). In the Trinder reaction (bottom reaction), horseradish peroxidase (HRP) uses hydrogen peroxide, 4-aminoantipyrine, and a phenol derivative (sulfonated DCIP) to produce a quinoneimine dye that is measured spectrophotometrically.

[0241] Human glycolate oxidase (hGO) expression BL21(DE3) E. coli cells transformed with the recombinant pET-15b expression vector containing an N-terminal His-tagged human Hao1 cDNA were grown in LB medium containing 0.1 mg / ml ampicillin. For purification of recombinant human glycolate oxidase (hGO) expressed in BL21 E. coli, bacterial pellets were thawed and resuspended in 2 ml of lysis buffer (50 mM NaH2PO4, 300 mM NaCl, 10 mM imidazole, 50 μM FMN, pH 7.5), followed by treatment with 1 mM PMSF for 30 min to inhibit proteases and 0.1% Triton X-100 and 0.2 mg / ml lysozyme to disrupt cell membranes. After sonication, the cells were centrifuged, and the supernatant containing the whole-cell extract (pre-column fraction) was loaded onto a Ni-NTA agarose column and incubated at 4°C for 30 min to allow the hexa-histidine tail of the recombinant GO protein to bind to the nickel ions. The column was washed with two bed volumes of lysis buffer containing 20 mM imidazole to remove unbound protein (wash fraction). GO was eluted using the same buffer containing 300 mM imidazole. The fraction containing purified GO was dialyzed overnight against 300 ml of dialysis buffer (50 mM NaH2PO4, 300 mM NaCl, pH 7.5) at 4°C with stirring and then stored in the dark at 4°C. Protein was quantified by bicinchoninic acid (BCA) assay.

[0242] Enzyme assay The enzymatic activity of hGO was determined in the presence of glycolic acid (40 mM glycolic acid) as a substrate and phosphate buffer (50 mM KPO, 0.1 mM EDTA, pH 7). Glyoxylic acid production was measured indirectly by quantitating the hydrogen peroxide formed during the first oxidation reaction. This hydrogen peroxide reacted with 4.9 mM 4-aminoantipyrine and 0.1 mM sulfonated 2,4-dichlorophenolindophenol in a conjugated horseradish peroxidase (HRP) reaction (Trinder reaction) to produce a quinone imine dye measured at 515 nm (Figure 3). Enzyme activity was calculated at 1 minute after the initiation of the Trinder reaction. The results of the enzymatic assay of the compounds of this disclosure are shown in Table 2. [Table 3]

[0243] Although the foregoing disclosure has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and a reference provided herein, the present application shall control.

Claims

1. A compound represented by formula (II), i.e. 【Chemical 1】 A process for preparing a tautomer thereof, or a salt thereof, comprising: (a) a compound of formula (IV), i.e. 【Chemistry 2】 or a salt thereof to form a compound of formula (V), i.e. 【Chemistry 3】 a first transition metal catalyst, and a first base are contacted in a first solvent to produce a compound of formula (III): 【Chemistry 4】 or a salt thereof, and (b) removing the PG group of said compound of formula (III) or said salt thereof to provide said compound of formula (II), said tautomer thereof, or said salt thereof; During the ceremony, the subscripts m and n are each independently 1 or 2; R 1 is C 1-6 is alkyl, R 2 and R 3 are each independently H or halogen; X 1 is a boron-containing group, X 2 is a halogen or a sulfonate, and In formula (IV) or formula (III), 【Chemistry 5】 is expressed as follows: 【Chemistry 6】 or a mixture thereof, and PG is an amine protecting group; The method.

2. 2. The method of claim 1, wherein the amine protecting group is [2-(trimethylsilyl)ethoxy]methyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl.

3. The method of claim 2, wherein the amine protecting group is 4-methoxybenzyl.

4. X 1 is expressed as follows: (1) Y is an —OH group, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 6-10 -BY is an aryloxy group or a carboxylic acid group 2 , (2) Y is bidentate C 2-8 Alkoxy group, bidentate C 6-10 -BY, which is an aryloxy group or a bidentate carboxylic acid group; (3) 9-borabicyclo[3,3,1]nonane (9-BBN) group, (4) Y is F or C 1-6 -BY is an alkoxy group, and M is an alkali metal ion, an ammonium ion, or a phosphonium ion. 3 M, or (5) Y is a tridentate C 3-10 -BYM is an alkoxy group, and M is an alkali metal ion, an ammonium ion, or a phosphonium ion. The method according to any one of claims 1 to 3, wherein

5. ︸ 1 が(()) 2 、() 2 、(()) 2 、BF 3 *、B(!P) 3 *、B(!P) 3 *、 【Chemistry 7】 and M is Li + , Na + , or K + The method of claim 4, wherein

6. X 1 is expressed as follows: 【Chemistry 8】 The method of claim 5, wherein

7. X 2 The method of any one of claims 1 to 6, wherein is Cl, Br, I, OMs, OTs, or OTf.

8. X 2 The method of claim 7 , wherein is Br.

9. 9. The method of any one of claims 1 to 8, wherein 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.

10. 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™-IPr, Pd-PEPPSI™-SIPr, or Pd-PEPPSI™-IPent.

11. The first palladium catalyst is Pd(dppf)Cl 2 , Pd(dppf)Cl 2 ・CH 2 Cl 2 , or Pd(dtbpf)Cl 2 The method of claim 10, wherein

12. 12. The method of any one of claims 1 to 11, wherein the first transition metal catalyst is present in a sub-stoichiometric amount.

13. 13. The method of any one of claims 1 to 12, wherein the first base is sodium carbonate, potassium carbonate, cesium carbonate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium acetate, cesium acetate, or a combination thereof.

14. 14. The method of claim 13, wherein the first base is potassium carbonate.

15. 15. The method of any one of claims 1 to 14, wherein said compound of formula (V) is present in an amount of 1.0 to 2.0 equivalents relative to said compound of formula (IV).

16. 16. The method of claim 15, wherein said compound of formula (V) is present in an amount of 1.2 equivalents relative to said compound of formula (IV).

17. The first solvent is water, C 1-4 17. The method of any one of claims 1 to 16, wherein the solvent is an 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.

18. 18. The method of claim 17, wherein the first solvent comprises dioxane and water.

19. 19. The method of any one of claims 1 to 18, wherein step (a) is carried out at a temperature of from 60°C to 110°C.

20. 20. The method of claim 19, wherein step (a) is carried out at a temperature of 80°C.

21. 21. The method of any one of claims 1 to 20, wherein in step (b) the PG group is removed by treatment with a first acid in a second solvent.

22. 22. The method of claim 21, wherein the first acid is trifluoroacetic acid.

23. 23. The method of claim 21 or 22, wherein the second solvent is dichloromethane or 1,2-dichloroethane.

24. The method of any one of claims 21 to 23, wherein the reaction mixture of step (b) further comprises a transfer agent.

25. 25. The method of claim 24, wherein the transfer agent is anisole.

26. (c) contacting the compound of formula (II), the tautomer thereof, or the salt thereof with a second base in a third solvent; and (d) acidifying with a second acid to give a compound of formula (I), i.e. 【Chemistry 9】 To provide a tautomer thereof or a salt thereof The method of any one of claims 1 to 25, further comprising:

27. 27. The method of claim 26, wherein the second base is lithium hydroxide, sodium hydroxide, or potassium hydroxide.

28. 28. The method of claim 27, wherein the second base is sodium hydroxide.

29. The third solvent is water, C 1-4 The method of any one of claims 26 to 28, wherein the solvent is an alcohol, dioxane, tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (MeTHF), acetonitrile (ACN), dimethoxyethane (DME), or a combination thereof.

30. 30. The method of claim 29, wherein the third solvent comprises tetrahydrofuran and water.

31. 31. The method of any one of claims 26 to 30, wherein the second acid is HCl.

32. 32. The method of any one of claims 26 to 31, wherein step (d) is carried out in an aqueous solution.

33. wherein said compound of formula (II) 【Chemistry 10】 The method of any one of claims 1 to 32, wherein the compound is represented by a formula selected from the group consisting of:

34. R 1 The method of any one of claims 1 to 33, wherein is methyl.

35. wherein said compound of formula (I) 【Chemistry 11】 The method of any one of claims 26 to 34, wherein the compound is represented by a formula selected from the group consisting of:

36. R 2 and R 3 The method of any one of claims 1 to 35, wherein each is independently halogen.

37. R 2 and R 3 37. The method of claim 36, wherein each is F.

38. Before step (a) (a1) A compound of formula (VI), namely 【Chemistry 12】 or a salt thereof with a boron reagent, a second palladium catalyst, and a third base in a fourth solvent to form the compound of formula (IV) or the salt thereof, wherein X is Cl, Br, or I. The method of any one of claims 1 to 37, further comprising:

39. 39. The method of claim 38, wherein the boron reagent is tetrahydroxydiboron, bis(catecholato)diboron, bis(hexyleneglycolato)diboron, bis(neopentylglycolato)diboron, or bis(pinacolato)diboron.

40. 40. The method of claim 39, wherein the boron reagent is bis(pinacolato)diboron.

41. The second palladium catalyst is Pd(dppf)Cl 2 , Pd(dppf)Cl 2 ・CH 2 Cl 2 , or Pd(dtbpf)Cl 2 The method according to any one of claims 38 to 40, wherein

42. 42. The method of any one of claims 38 to 41, wherein the third base is potassium acetate.

43. 43. The method of any one of claims 38 to 42, wherein the fourth solvent is 1,4-dioxane.

44. The compound of formula (VI) has the following formula: 【Chemistry 13】 The method according to any one of claims 38 to 43, wherein

45. A compound represented by formula (Ia-1), namely 【Chemistry 14】 A process for preparing a tautomer thereof, or a salt thereof, comprising: (a1) A compound of formula (VI-1a-1), namely 【Chemistry 15】 or its salts in 1,4-dioxane with bis(pinacolato)diboron, Pd(dppf)Cl 2 ・CH 2 Cl 2 and potassium acetate to give a compound of formula (IV-1a-2), i.e. 【Chemistry 16】 or converting it into a salt thereof; (a) The compound of formula (IV-1a-2) or the salt thereof is dissolved in a mixture of 1,4-dioxane and water with 1-bromo-4-(3,3-difluorocyclobutyl)benzene, Pd(dppf)Cl 2 ・CH 2 Cl 2 and potassium carbonate to produce a compound of formula (IIIa-1a-1), i.e. 【Chemistry 17】 or forming a salt thereof; (b) treating the compound of formula (IIIa-1a-1) or the salt thereof with trifluoroacetic acid and anisole in dichloromethane to give a compound of formula (IIa-1), i.e. 【Chemistry 18】 providing a tautomer thereof, or a salt thereof; (c) saponifying the compound of formula (IIa-1), the tautomer thereof, or the salt thereof with aqueous sodium hydroxide in tetrahydrofuran; and (d) acidifying with aqueous HCl to provide the compound of formula (Ia-1), the tautomer thereof, or the salt thereof. The method comprising:

46. 46. ​​The method of claim 45, 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, and step (c) is carried out at a temperature of 55°C, and step (d) is carried out at a temperature of 20 to 25°C.

47. The method according to claim 45 or 46, wherein in step (a), 1-bromo-4-(3,3-difluorocyclobutyl)benzene is present in an amount of 1.0 to 1.5 equivalents relative to the compound of formula (IV-1a-2).

48. In step (a), Pd(dppf)Cl 2 ・CH 2 Cl 2 The method of any one of claims 45 to 47, wherein is present in an amount of 0.05 to 0.1 equivalents relative to the compound of formula (IV-1a-2).

49. 49. The method according to any one of claims 45 to 48, wherein in step (a), potassium carbonate is present in an amount of 2.0 to 4.0 equivalents relative to the compound of formula (IV-1a-2).

50. 50. The method according to any one of claims 45 to 49, wherein the compound of formula (IV-1a-2) prepared by step (a1) is used directly in the next step without further purification.

51. 51. The method of any one of claims 45 to 50, wherein the compound of formula (IIIa-1) is isolated from both step (a1) and step (a) in an overall yield of at least 50%.

52. 52. The method of any one of claims 45 to 51, wherein the compound of formula (IIa-1) made by step (b) is used directly in the next step without further purification.

53. 53. The process of any one of claims 45 to 52, wherein step (d) is carried out by acidifying an aqueous extract of the reaction mixture of step (c).

54. (e) The compound of formula (Ia-1), the tautomer thereof, or the salt thereof is converted into a monosodium salt of the compound of formula (Ia-1) represented by the following formula: 【Chemistry 19】 The disodium salt of the compound of formula (Ia-1) represented by the following formula: 【Chemistry 20】 54. The method of any one of claims 45 to 53, further comprising converting the methyl group to methyl, ...

55. Step (e) (i) treating the compound of formula (Ia-1) or a tautomer thereof with aqueous sodium hydroxide; (ii) forming a slurry having a pH value of 9.5; and (iii) freeze-drying the slurry to obtain the monosodium salt of the compound of formula (Ia-1), represented by the formula: 【Chemical 21】 or its tautomers. and sodium hydroxide is present in an amount of less than 1.0 equivalent on a salt-free and anhydrous basis relative to the compound of formula (Ia-1).

56. 56. The method of claim 55, wherein sodium hydroxide is present in an amount of 0.88 equivalents on a salt-free and anhydrous basis relative to the compound of formula (Ia-1).

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