WO2022066933A1 - Pentafluoro-sulfanyl -substituted triazolyl compounds and methods of use thereof - Google Patents

Abstract

Provided herein are compounds, compositions, and methods useful for inhibiting glycolate oxidase (GO) activity and for the treatment, prevention and amelioration of one or more symptoms of diseases or disorders related to GO enzymatic activity or the accumulation of glyoxylate.

Description

PENTAFLUORO-SULFANYL -SUBSTITUTED TRIAZOLYL COMPOUNDS AND METHODS OF USE THEREOF FIELD OF THE INVENTION [0001] Provided herein are compounds, compositions, and methods useful for inhibiting glycolate oxidase (GO) enzyme activity and for the treatment, prevention and amelioration of one or more symptoms of hyperoxaluria, including primary hyperoxaluria and stone formation in the kidney and urinary tract. BACKGROUND OF THE INVENTION [0002] Hyperoxaluria is characterized by an increased concentration of oxalate in an individual, normally manifesting as elevated urinary oxalate excretion. Oxalate is a dicarboxylic acid which can form a complex with cations such as calcium to generate highly insoluble calcium oxalate crystals. Deposition of calcium oxalate crystals can impact kidney function, resulting in the formation of stones throughout the urinary tract (urolithiasis), kidneys (nephrolithiasis) and progressively increased levels of calcium in the kidneys (nephrocalcinosis) (National Organization for Rare Disorders – PH disease database). The overall implications are kidney damage, kidney stones, urinary tract-infections, chronic kidney disease and in some cases, end-stage-renal disease (ESRD). Furthermore, hyperoxaluria, combined with reduction in glomerular function can lead to systemic oxalosis, whereby oxalate depositions occurs throughout the body, including bones, retina, central- nervous tissue and the vasculature lining (Bhasin, World J. Nephrol.2015, 42(2), 235-244). [0003] Hyperoxalxria is sub-divided into primary and secondary hyperoxaluria based on the clinical etiology. Primary hyperoxaluria (PH) is a genetic error of metabolism due to defective enzyme activity and is further divided into three subtypes (Harambat, Int. J. Nephrol.2011:864580). Primary hyperoxaluria type I (PH1) is an autosomal recessive disorder caused by a deficiency of the liver-specific, peroxisomal enzyme, alanine-glyoxylate aminotransferase (AGT, gene name is AGXT). This is the most severe form of PH, and accounts for approximately 80% of diagnosed PH cases. PH1 often develops during childhood or adolescence, and the disorder is characterized by recurrent kidney stones. Kidney failure is observed in approximately 20-50% of PH1 patients. The AGT enzyme is responsible for the detoxification of glyoxylate to glycine and competes with lactate dehydrogenase (LDH)-mediated conversion of glyoxylate to oxalate. Thus, loss of AGT function results in increased production of oxalate. The estimated prevalence of PH1 in Europe is 1–3 cases per million people and accounts for ∼1% of pediatric end-stage renal disease (ESRD) in registries from Europe, USA and Japan (Harambat 2011). Over 150 AGXT mutations have been identified in PH1, and this genetic diversity may explain the heterogeneous clinical manifestations and disease severity of PH1 patients. As such, there is a frequent delay in establishing the PH1 diagnosis, and the incidence rate may be underrepresented (van der Hoeven, Nephrol. Dial. Transplant 2012, 27(10), 3855-3862). Diagnosis of PH1 is made by either confirmed mutation in the AGXT gene or reduced AGT activity in a liver biopsy specimen (Williams, Hum. Mutat.2009, 30, 910-917). [0004] Primary hyperoxaluria type II (PH2) is caused by a deficiency in the glyoxylate reductase/hydroxypyruvate reductase (GRHPR) gene. The gene which encodes this enzyme is responsible for the conversion of glyoxylate to glycine, and mutations usually result in a loss of glyoxylate reductase (GR) function. PH2 is generally believed to have a milder clinical course than PH1 with a lower risk of ESRD, although nephrolithiasis and frequent kidney stones are common in these patients (Dhondup, Am. J. Transplant.2018, 18, 253- 257). Chronic as well as terminal renal insufficiency may occur in these patients (Kemper, Eur. J. Pediatr.1997, 156(7), 509-512). [0005] Primary hyperoxaluria type III (PH3) is caused by mutations in the HOGA1 gene which encodes for the liver-specific, mitochondrial enzyme 4-hydroxy-2-oxoglutarate aldolase (Belostotsky, Am. J. Hum. Genet.2010, 87(3), 392-399). The exact role this enzyme plays in the production of oxalate is not fully understood, but a current hypothesis is that the substrate of HOGA, 4-hydroxy-2-oxoglutarate (HOG), is capable of inhibiting GR (Reidel, Biochim. Biophys. Acta.2012, 1822(10), 1544-1552). While cases of ESRD in PH3 patients are significantly less common than in those of PH1 patients, incidents of kidney stones remain high in this diseased population and the patient and hospitalization burden is significant. For example, approximately 50-65% of individuals with PH3 present with a stone prior to five years of age (Monico, Clin. J. Am. Soc. Nephrol.2011, 6, 2289-2295), and while some individuals experience less kidney stone incidents during adolescence and their adult life, this is not true for all individuals. It has also been noted that the PH3 carrier frequency rate is 1:185, similar to that of PH1. The genetic prevalence is 1:136,000, making PH3 more common than originally thought based on clinical diagnosis (Hopp, J. Am. Soc. Nephrol. 2015, 26, 2559-2570). [0006] Increased urinary oxalate concentrations in PH patients correlate with increased disease severity and progression to end-stage renal disease (Zhao, CJASN, 2016, 11(1), 119- 126). Clinically, urinary oxalate concentrations below < 0.45 mmol/day are considered in the normal range. Patients with a urinary oxalate concentration of > 2.4 mmol/day have a significantly higher risk of developing ESRD (Hazard Ratio = 3.4). Higher urinary oxalate excretion at both diagnosis and follow-up are associated with poorer renal outcome in PH patients. On average, PH1 patients have higher urinary oxalate concentrations (average of 297 patients is 2.0 mmol/day) and not surprisingly renal survival was only 27% after 30 years of follow-up, as compared with 92% and 95% for PH2 and PH3 individuals, where the urinary oxalate concentrations are lower, but still well above the normal range. In addition, elevated 24-hour urinary oxalate excretion has also been associated with a higher risk of chronic kidney disease (CKD) progression and ESRD in individuals with CKD stages 2 to 4 (Waikar, JAMA Internal Medicine, 2019). These findings confirm the critical importance of urinary oxalate excretion as a predictor of renal survival and the potential therapeutic value of lowering urinary oxalate concentrations. [0007] There are currently no approved therapies which are generally effective for hyperoxaluria patients. Shortly after clinical evidence of increased oxalate excretion, patients are normally advised to increase their fluid intake (recommendation is >2 L per day). Modification of diet to reduce dietary sources of oxalate and increase calcium supplementation to complex free oxalate in the GI tract and reduce oxalate absorption are also common but have limited value in PH patients. Pyridoxine (Vitamin B6) is a co-factor for AGT and has been found to be beneficial in lowering urinary oxalate by approximately 30% in some PH1 patients but is ineffective for the majority of patients (Watts, Clin. Sci. Lond.1985, 69, 87-90). [0008] Dual liver and kidney transplantation is the only effective means of fully reversing hyperoxaluria in PH1 patients. The timing of the liver-kidney transplant is usually dictated by the stage of chronic kidney disease and time to ESRD of the patient (Cochat, Nephrol. Dial. Transplant.2012, 27, 1729-1736). Liver-kidney transplantation should be planned pre- emptively before significant systemic oxalosis occurs. Conventional dialysis is not effective for the removal of plasma oxalate concentrations from hyperoxaluria patients but is often utilized in patients with stage 5 CKD while awaiting transplantation. In these patients, high efficacy dialysis is recommended, which can modestly slow the disease progression, but does not prevent ESRD (Ellis, Nephrol. Dial. Transplant.2001, 16, 348-354). [0009] Efforts to reduce the endogenous synthesis of oxalate should be effective in the treatment of hyperoxaluria. Glycolate oxidase (GO) is a peroxisomal enzyme encoded by the HAO1 gene, that catalyzes the oxidation of glycolate to glyoxylate. As glyoxylate is converted to oxalate by lactate dehydrogenase (LDH), a substrate reduction approach which lowers the concentrations of glyoxylate, should be effective for hyperoxaluric diseases. Inhibition of glycolate oxidase would therefore reduce the oxidative conversion of glycolate to glyoxylate. Glycolate is highly soluble and can be readily excreted in urine, and humans with a loss-of-function mutation in GO do not exhibit any clinical manifestations (McGregor, BioRxiv, 2019, 524256). Thus, such an approach is expected to be both safe and effective. [00010] Validation of GO inhibition as an approach for hyperoxaluria comes from animal knock-out studies (Martin-Higueras, Mol. Ther.2016, 24(4), 719-725), siRNA- treatment in a PH1-mouse model (Dutta, Mol. Therap.2016, 24(4), 770-778 and Liebow, J. Am. Soc. Nephrol.2017, 28, 494-503), CRISPR-treatment in a rat model (Zabaleta, Nature Communications, 2018, 9:5454) and clinical data using an siRNA approach (Lumasiran Phase 3 Data). [00011] Small molecule inhibition of GO is an attractive alternative to the siRNA or gene therapy treatment approach. There remains a need for novel classes of compounds which can inhibit the GO protein and be utilized for treatment of hyperoxaluria including primary hyperoxaluria, and calcium oxalate stone formation. SUMMARY OF THE INVENTION [00012] Provided herein are compounds of Formula (I) or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, single stereoisomer, mixture of stereoisomers, racemic mixture of stereoisomers or isotopic variant thereof. In certain embodiments, the compounds are inhibitors of the glycolate oxidase enzyme. In yet other embodiments, the compounds are inhibitors of GO. In certain embodiments, the compounds as GO inhibitors will confer therapeutic benefits associated with reducing endogenous production of glyoxylate. [00013] In certain embodiments, provided herein are compound having the Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers or isotopic variant: I) wherein:

R¹ is hydrogen or a group converted to hydrogen in vivo, which is selected from alkyl, aryl, aralkyl ; L¹ is -O-;

Ring A is monocyclic cycloalkyl; Ring B is aryl or heteroaryl; each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; and k is 0, 1, 2, 3 or 4. [00014] Also provided are pharmaceutical compositions formulated for administration by an appropriate route and means containing therapeutically effective concentrations of one or more of the compounds provided herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, and optionally comprising at least one pharmaceutical carrier. In certain embodiments, the pharmaceutical compositions deliver amounts effective for lowering oxalate levels in a subject in need thereof. In certain embodiments, the pharmaceutical compositions deliver amounts effective for reducing kidney stone formation in a subject in need thereof. In another aspect, provided herein are methods of treating a disease or disorder associated with elevated oxalate levels, comprising administering to a subject having such disease or disorder, a therapeutically effective amount of one or more compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical compositions disclosed herein. In certain embodiments, the disease or disorder is hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease. In yet certain embodiments, the disease or disorder is primary hyperoxaluria, idiopathic hyperoxaluria or idiopathic oxalate kidney stone disease. In yet certain embodiments, the disease or disorder is associated with the AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof. [00015] Also provided herein are combination therapies using one or more compounds or compositions provided herein, in combination with other pharmaceutical agents for the treatment of the diseases and disorders described herein. [00016] These and other aspects of the subject matter described herein will become evident upon reference to the following detailed description and drawings. BRIEF DESCRIPTION OF THE DRAWING [00017] FIG.1 shows an overlay of the compound plasma concentration profile for the compound of Example 1 and glycolate concentration profile in plasma at various timepoints upon oral administration of 20 mg/kg of compound of Example 1 in rats. DETAILED DESCRIPTION OF THE INVENTION A. DEFINITIONS [00018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. The term “patient” refers to an animal which includes mammals such as mice, rats, cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans, including neonatal, infant, juvenile, adolescent, adult or geriatric patients. [00019] The term “halo”, “halogen” or “halide” as used herein and unless otherwise indicated, refers to any radical of fluorine, chlorine, bromine or iodine. [00020] The term “alkyl” as used herein and unless otherwise indicated, refers to a saturated hydrocarbon chain radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms or otherwise having from one to ten, one to eight, one to six or one to four carbon atoms, and which is attached to the rest of the molecule by a single bond. In certain embodiments, the hydrocarbon chain is optionally deuterated. For example, C₁-C₆ alkyl indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. In some embodiments, an alkyl is a C1-C6 alkyl which represents a straight-chain or branched saturated hydrocarbon radical having 1 to 6 carbon atoms. Examples of alkyl include without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. [00021] The term “alkylene” as used herein and unless otherwise indicated, refers to a divalent hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms or otherwise having from one to ten, one to eight, one to six or one to four carbon atoms. In certain embodiments, the hydrocarbon chain is optionally deuterated. Alkylene groups include but are not limited to methylene, ethylene, propylene and n-butylene. [00022] The term “cycloalkyl” as used herein and unless otherwise indicated, refers to a monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon radical having the indicated number of ring carbon atoms or otherwise having three to ten carbon atoms and which are fully saturated or partially unsaturated. Multicyclic cycloalkyl may be fused, bridged or spiro-ring systems. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, and partially unsaturated hydrocarbon rings such as cyclobutylene, cyclopentene and cyclohexene. In some embodiments, cycloalkyl is a monocyclic C₃-C₈ cycloalkyl. [00023] The term “haloalkyl” as used herein and unless otherwise indicated, refers to an alkyl radical in which at least one hydrogen atom is replaced by a halogen. In some embodiments, more than one hydrogen atom (e.g., 2, 3, 4, 5 or 6) are replaced by halogens. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluoro) or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluoro and chloro). “Haloalkyl” also includes alkyl moieties in which all hydrogens have been replaced by halogens (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl). [00024] The term “aralkyl” as used herein and unless otherwise indicated, refers to an alkyl radical in which an alkyl hydrogen atom is replaced by an aryl group. One of the carbons of the alkyl moiety serves as the point of attachment of the aralkyl group to another moiety. Non-limiting examples of “aralkyl” include benzyl, 2-phenylethyl, and 3-phenylpropyl groups. [00025] The term “aryl” as used herein and unless otherwise indicated, is intended to mean any stable monocyclic or bicyclic carbon ring radical of up to 6 members in each ring, wherein at least one ring is aromatic. Examples of aryl include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or biphenyl. [00026] The term “deuterium” as used herein and unless otherwise indicated, refers to the heavy isotope of hydrogen represented by the symbol D or ²H. As used herein, when a particular position in a compound is designated as “deuterated” or as having deuterium, it is understood that the compound is an isotopically enriched compound and the presence of deuterium at that position in the compound is substantially greater than its natural abundance of 0.0156%. [00027] The term “enantiomerically pure” or “pure enantiomer” as used herein denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of a single enantiomer to the exclusion of its corresponding non-superimposable mirror image. [00028] The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used herein and unless otherwise indicated, represents a stable 4-, 5-, 6- or 7-membered monocyclic- or a stable 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heterocyclic ring system which comprises at least one non-aromatic (i.e. saturated or partially unsaturated) ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms may optionally be oxidized as N-oxide, sulfoxide or sulfone, and wherein the nitrogen atom may optionally be quaternized. A heterocycle can be bonded via a ring carbon atom or, if available, via a ring nitrogen atom. Bicyclic heterocyclic ring systems may be fused, bridged, or spiro-bicyclic heterocyclic ring system(s). In some embodiments, heterocyclyl is monocyclic having 4 to 7 or 4 to 6, ring atoms, of which 1 or 2 are heteroatoms independently selected from the group consisting of N, O and S. In some embodiments, a heterocyclyl group is bicyclic, and in which case, the second ring may be an aromatic or a non-aromatic ring which consists of carbon atoms and from one to four, preferably up to three, heteroatoms independently selected from the group consisting of N, O and S, or the second ring may be a benzene ring, or a “cycloalkyl”, or a “cycloalkenyl”, as defined herein. Examples of such heterocyclic groups include, but are not limited to azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine, piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine, 1,3-thiazolidine, tetrahydrothiopyran, tetrahydrotriazine, 1,3-dioxane, 1,4-dioxane, hexahydrotriazine, tetrahydro-oxazine, tetrahydropyrimidine, perhydroazepine, perhydro-1,4-diazepine, perhydro-1,4-oxazepine, 7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane, 7- azabicyclo[4.1.0]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-oxa-6-azaspiro[3.3]heptane, dihydrobenzofuran, diydrobenzimidazolyl, dihydrobenzoxazole, and dihydrobenzothiazolyl, and N-oxides or sulfones or sulfoxides thereof. [00029] The term “heteroaryl”, as used herein and unless otherwise indicated, represents a stable an aromatic 5-, 6- or 7-membered monocyclic- or stable 9- or 10-membered fused bicyclic ring system, which consists of carbon atoms and from one to four, or from one to three, heteroatoms selected from the group consisting of N, O and S wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. In the case of a “heteroaryl” which is a bicyclic group, the second ring need not comprise a heteroatom and may be fused to a benzene ring. Accordingly, bicyclic “heteroaryl” includes, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and from one to four, or from one to three, heteroatoms, as defined immediately above, fused to a benzene ring, or a second monocyclic “heteroaryl”, or a “heterocyclyl”, a “cycloalkyl”, or a “cycloalkenyl”, as defined above. Examples of heteroaryl groups include, but are not limited to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole, benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, benzimidazole, benzothiadiazole, isoindole, pyrrolopyridines, imidazopyridines such as imidazo[1,2-a]pyridine, pyrazolopyridine, pyrrolopyrimidine and N-oxides thereof. [00030] The term “hydrate” as used herein and unless otherwise indicated, refers to a compound provided herein or a salt thereof, that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces. [00031] The term “in vivo” as used herein and unless otherwise indicated, refers to a process or event occurring in a living organism or living system. [00032] The term “calcium oxalate stones” as used herein and unless otherwise indicated, refers to crystalline material comprising calcium oxalate salt present as stones or plaques in the kidney, bladder or urinary tract. The term “hyperoxaluria” refers to a condition characterized by elevated levels of oxalate in the urine or plasma or by the presence of kidney stones. In certain embodiments, hyperoxaluria is characterized by urinary oxalate excretion rate of greater than about 0.5 mmol/1.73 m² per day, greater than about 0.7 mmol/1.73 m² per day, greater than about 0.8 mmol/1.73 m², greater than about 1.0 mmol/1.73 m² per day, greater than about 1.2 mmol/1.73 m² per day or greater than about 2 mmol/1.73 m² per day. In certain embodiments, elevated oxalate levels means having an oxalate excretion rate that is greater than normal urinary excretion, which is less than about 0.45 mmol/1.73 m² per day. In certain embodiments, the urinary oxalate excretion rate is about two-fold higher than normal. In certain embodiments, the urinary oxalate excretion rate is about four-fold higher than normal. In yet certain embodiments, hyperoxaluria is characterized by urinary oxalate/creatinine ratio greater than the reference range for age. In certain embodiments, hyperoxaluria is characterized by glycolate/creatinine ratio greater than the reference range for age. Hyperoxaluria includes both primary hyperoxaluria and secondary hyperoxaluria. [00033] The term “prodrug” is a compound which is converted to a therapeutically active compound after administration, and the term should be interpreted as broadly herein as is generally understood in the art. While not intending to limit the scope of the invention, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Generally, but not necessarily, a prodrug is inactive or less active than the therapeutically active compound to which it is converted. For example, an ester may be derived from a carboxylic acid functional group of the therapeutically active compound. While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester. [00034] “Primary hyperoxaluria” refers to a condition characterized by the overproduction of oxalate and/or defective production or function of one or more enzymes that regulate the levels of oxalate in the body. In certain embodiments, the primary hyperoxaluria is associated with deficiency in the expression of alanine:glyoxylate aminotransferase (AGT) or a mutation in AGXT, the gene encoding AGT, and may be classified as Type 1 primary hyperoxaluria, or PH1. In certain embodiments, the primary hyperoxaluria is associated with deficiency in the expression of glyoxylate reductase (GR) or a mutation in the gene encoding GR (GRPHR), and which may be classified as Type 2 primary hyperoxaluria, or PH2. In yet other embodiments, the primary hyperoxaluria is associated with the deficiency in the expression of 4-hydroxy-2-oxoglutarate aldolase (HOGA) or a mutation in the gene encoding HOGA (HOGA1), and which may be classified as Type 3 primary hyperoxaluria, or PH3. [00035] The term “solvate” as used herein and unless otherwise indicated, refers to a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term “solvate” includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, and the like). [00036] The term "treating", "treat", or "treatment" refers generally to administering one or more pharmaceutical substances, especially at least one compound of Formula (I) to a patient that has a disease, disorder or condition, or has a symptom or condition of a disease or disorder, or has a predisposition toward a disease or disorder, with the purpose to cure, heal, relieve, alter, alleviate, ameliorate, slow the progress of, improve or affect the disease, disorder or condition or the predisposition toward the disease, disorder or condition. In addition to its customary meaning, the term "preventing", “prevent”, or “prevention” also refers to delaying the onset of, or reducing the risk of developing a disease, disorder or condition or of a process that can lead to the disease, disorder or condition, or the recurrence of symptoms of the disease, disorder or condition. [00037] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state. [00038] Unless stated otherwise or specifically described, it is understood that substitutions where present can occur on any atom of the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups. [00039] Unless specifically stated otherwise, where a compound may assume alternative tautomeric or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, unless specifically stated otherwise, the compounds provided herein may be enantiomerically pure, or be enantiomeric mixtures. [00040] In the description herein, if there is any discrepancy between a chemical name and chemical structure, the chemical structure controls. [00041] B. COMPOUNDS [00042] In certain embodiments, provided herein are compounds having the Formula (I), or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers or isotopic variant: I) wherein:

R¹ is hydrogen or a group converted to hydrogen in vivo, which is selected from alkyl, aryl, aralkyl ; L¹ is -O- ;

Ring A is monocyclic cycloalkyl; Ring B is aryl or heteroaryl; each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; and k is 0, 1, 2, 3 or 4. [00043] In certain embodiments, provided herein are compounds of Formula (II): I) wherein:

R¹ is hydrogen or a group converted to hydrogen in vivo, which is selected from alkyl, aryl, aralkyl ; L¹ is -O-;

Ring B is aryl or heteroaryl; each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; k is 0, 1, 2, 3 or 4; m is 1, 2 or 3 and n is 1 or 2. [00044] In certain embodiments, provided herein are compounds of Formula (III)

I) wherein:

R¹ is hydrogen or a group converted to hydrogen in vivo, which is selected from alkyl, aryl, aralkyl ; L¹ is -O-;

Ring B is aryl or heteroaryl; each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; and k is 0, 1, 2, 3 or 4. [00045] In certain embodiments, provided herein are compounds of Formula (III) wherein L¹ and Ring B are trans-substitutions. In certain embodiments, provided herein are compounds of Formula (III) wherein L¹ and Ring B are cis-substitutions. In yet certain embodiments, provided herein are compounds of Formula (III) wherein L¹ and Ring B are cis-1,3- or cis-1,4- substitutions. In yet certain embodiments, provided herein are compounds of Formula (III) wherein L¹ and Ring B are trans-1,3- or trans-1,4- substitutions. [00046] In certain embodiments, provided herein are compounds of Formula (IIIa-1) or (IIIa-2):

[00047] 2) R¹ is

y g g p y g , ted from alkyl, aryl, aralkyl ; L¹ is -O-;

Ring B is aryl or heteroaryl; each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; and k is 0, 1, 2, 3 or 4. [00048] In certain embodiments, provided herein are compounds of Formula (IIIb-1) or (IIIb-2):

2) R¹ is hy

rogen or a group converte to y rogen n v vo, w c s se ecte from alkyl, aryl, aralkyl ; L¹ is -O- ;

Ring B is aryl or heteroaryl; each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; and k is 0, 1, 2, 3 or 4. [00049] In certain embodiments, provided herein are compounds of Formula (IIIa-1), (IIIa-2), (IIIb-1) or (IIIb-2) wherein Ring B is aryl. In certain embodiments, Ring B is phenyl. In certain embodiments, provided herein are compounds of Formula (IIIa-1), (IIIa-2), (IIIb-1) or (IIIb-2) wherein Ring B is heteroaryl. In certain embodiments, Ring B is pyridine or pyrimidine, pyridazine, pyrazine or triazine. In certain embodiments, Ring B is pyridine or pyrimidine. [00050] In certain embodiments, provided herein are compounds of Formula (IV):

V) wherein:

R¹ is hydrogen or a group converted to hydrogen in vivo, which is selected from alkyl, aryl, aralkyl ; L¹ is -O-;

each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; k is 0, 1, 2, 3 or 4; m is 1,2 or 3; n is 1 or 2 and each Y is C or N provided no more than two Ys are N. [00051] In certain embodiments, provided herein are compounds of Formula (V)

V)

wherein: R¹ is hydrogen or a group converted to hydrogen in vivo, which is selected from alkyl, aryl, aralkyl ; L¹ is -O- ;

each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; k is 0, 1, 2, 3 or 4; m is 1,2 or 3; n is 1 or 2 and each Y is C or N provided no more than two Ys are N. [00052] In certain embodiments, provided herein are compounds of Formula (I), (II), (III), (IIIa-1), (IIIa-2), (IIIb-1), (IIIb-2), (IV) or (V) wherein j is 0, 1 or 2 and k is 0, 1 or 2. In certain embodiments, provided herein are compounds of Formula (I), (II), (III), (IIIa-1), (IIIa-2), (IIIb-1) or (IIIb-2) wherein Ring B is aryl; j is 0, 1 or 2 and k is 0, 1 or 2. In certain embodiments, provided herein are compounds of Formula (I), (II), (III), (IIIa-1), (IIIa-2), (IIIb-1) or (IIIb-2) wherein B is heteroaryl; j is 0, 1 or 2 and k is 0, 1 or 2. In certain embodiments, provided herein are compounds of Formula (I), (II), (III), (IIIa-1), (IIIa-2), (IIIb-1) or (IIIb-2) wherein Ring B is aryl; j is 0 and k is 0. In certain embodiments, provided herein are compounds of Formula (I), (II), (III), (IIIa-1), (IIIa-2), (IIIb-1) or (IIIb-2) wherein Ring B is heteroaryl; j is 0 and k is 0. [00053] In certain embodiments, the compounds of Formula (I) is 5-((4-(4-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-4-carboxylic acid or 5-(((trans)-4-(4-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-4- carboxylic acid. [00054] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds. [00055] The compounds of this disclosure may contain one or more stereogenic centers and thus occur as racemates and racemic mixtures, enantiomerically enriched mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. The compounds of the present disclosure may, either by nature of stereogenic centers or by restricted rotation, be present in the form of isomers (e.g., enantiomers, diastereomers). [00056] It will also be appreciated that when two or more stereogenic centers are present in the compounds of the disclosure, several diastereomers and enantiomers of the exemplified structures will often be possible. It is intended that pure stereoisomers, pure diastereomers, pure enantiomers, and mixtures thereof, are within the scope of the disclosure. When compounds contain stereochemistry, the compounds are designated as ‘(racemic)’ or “rac” if the stereoisomers have not been separated and ‘(R) or (S)’ if the stereoisomers have been resolved. In certain embodiments, the compounds disclosed herein contain axial chirality, particularly in the case of the spirocyclic[3.3]heptane containing compounds. These have also been designed as either ‘(R_a) or (S_a)’ when there is a single stereoisomer, where the ‘a’ denotes axial chirality. [00057] All isomers, whether separated, pure, partially pure, or in racemic mixture, of the compounds of this disclosure are encompassed within the scope of this disclosure. The purification of said isomers and the separation of said isomeric mixtures may be accomplished by various methods. For example, diastereomeric mixtures can be separated into the individual isomers by chromatographic processes or crystallization, and racemates can be separated into the respective enantiomers either by chromatographic processes on chiral phases or by resolution. The compounds of the present disclosure include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as mixtures thereof. The compounds of the present disclosure may also be represented in multiple tautomeric forms, in such instances, the present disclosure expressly includes all tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented. In addition, where a term used in the present disclosure encompasses a group that may tautomerize, all tautomeric forms are expressly included thereunder. For example, hydroxy substituted heteroaryl includes 2- hydroxypyridine as well as 2-pyridone, 1-hydroxyisoquinoline as well as 1-oxo-1,2- dihydroisoquinoline, and the like. All such isomeric forms of such compounds are expressly included in the present disclosure. The compounds of the present disclosure include the compounds themselves, as well as their salts, solvate, solvate of the salt and their prodrugs, if applicable. Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of the compounds according to the present disclosure. Salts which are not themselves suitable for pharmaceutical uses but can be used, for example, for isolation or purification of the compounds according to the disclosure are also included. A salt, for example, can be formed between an anion and a positively charged substituent (e.g., amino) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion. [00058] As used herein, “pharmaceutically acceptable salts” refer to acid or base addition salts, including but not limited to, base addition salts formed by the compound of Formula (I) having an acidic moiety with pharmaceutically acceptable cations, for example, sodium, potassium, magnesium, calcium, aluminum, lithium, and ammonium. Acid addition salts include salts formed by the compound of Formula (I) having a basic moiety with an inorganic acid, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate and the like; as well as with an organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and the like. Also, if a compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an acid addition salt, particularly a pharmaceutically acceptable acid addition salt, may be produced by dissolving the free base in a suitable solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. [00059] Lists of suitable salts may be found in Remington’s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418; S. M. Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci.1977, 66, 1-19; and “Pharmaceutical Salts: Properties, Selection, and Use. A Handbook”; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety. [00060] Solvates in the context of the present disclosure are designated as those forms of the compounds according to the present disclosure which form a complex in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a specific form of solvates, in which the coordination takes place with water. The formation of solvates is described in greater detail in “Solvents and Solvent Effects in Organic Chemistry”; Reichardt, C. and Welton T.; John Wiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which is incorporated herein by reference in its entirety. [00061] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. An isotopic variant of a compound according to the present disclosure is understood to mean a compound in which at least one atom within the compound according to the present disclosure has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I. Particular isotopic variants of a compound according to the present disclosure, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active compound distribution in the body. Compounds labelled with ³H, ¹⁴C and/or ¹⁸F isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, can lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required. In some embodiments, hydrogen atoms of the compounds described herein may be replaced with deuterium atoms. In certain embodiments, “deuterated” as applied to a chemical group and unless otherwise indicated, refers to a chemical group that is isotopically enriched with deuterium in an amount substantially greater than its natural abundance. Isotopic variants of the compounds according to the present disclosure can be prepared by various, including, for example, the methods described below and in the working examples, by using corresponding isotopic modifications of the particular reagents and/or starting compounds therein. [00062] The present disclosure includes within its scope prodrugs of the compounds of Formula (I). Prodrugs are generally drug precursors that, following administration to a subject are converted to an active, or a more active species via some process, such as conversion by chemical hydrolysis or a metabolic pathway. Thus, in the methods of treatment of the present disclosure, the terms “administration of” or “administering a” compound shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985 (Amsterdam, NL). Examples of prodrugs include C₁-C₆ alkyl esters of carboxylic acid group, which, upon administration to a subject, are capable of providing active compounds. C. FORMULATION [00063] The term “pharmaceutical composition” as used herein is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure encompass any composition made by admixing a compound of the present disclosure, or a pharmaceutically acceptable salt, or solvate or solvate of the salt thereof, and a pharmaceutically acceptable carrier. [00064] The term “pharmaceutically acceptable carrier” refers to a carrier or an adjuvant that may be administered to a patient, together with a compound of the present disclosure, or a pharmaceutically acceptable salt, solvate, salt of the solvate or prodrug thereof, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound. [00065] The amount administered depends on the compound formulation, route of administration, etc. and is generally empirically determined, and variations will necessarily occur depending on the target, the host, and the route of administration, etc. Generally, the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 milligram (mg) to about 100 mg or from about 1 mg to about 1000 mg, according to the particular application. For convenience, the total daily dosage may be divided and administered in portions during the day. [00066] Pharmaceutical compositions of the present disclosure for injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [00067] These pharmaceutical compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of micro-organisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. The compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres. Such formulations may provide more effective distribution of the compounds. [00068] The pharmaceutical compositions that are injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [00069] Solid dosage forms of the instant pharmaceutical compositions for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. [00070] Solid pharmaceutical compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. [00071] The solid dosage forms of the instant pharmaceutical compositions of tablets, dragées, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other pharmaceutical coatings. They may optionally contain opacifying agents and can also be of a formulation that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding pharmaceutical compositions which can be used include polymeric substances and waxes. [00072] The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients. [00073] Liquid dosage forms of the instant pharmaceutical compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, diethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. [00074] Besides inert diluents, the oral pharmaceutical compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. [00075] Suspensions of the instant compounds, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. [00076] Dosage forms for topical administration of a compound or pharmaceutical composition of the present disclosure include powders, patches, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants which may be required. [00077] The compounds and compositions described herein can, for example, be administered orally, parenterally (e.g., subcutaneously, intracutaneously, intravenously, intramuscularly, intraarticularly, intraarterially, intrasynovially, intrasternally, intrathecally, intralesionally, and by intracranial injection or infusion techniques), by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, by injection, subdermally, intratumorally, intraperitoneally, transmucosally, or in an ophthalmic preparation, with a dosage ranging from about 0.01 milligrams per kilogram (mg/kg) to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 to about 100 mg/kg) every 4 to 120 hours, or according to the requirements of the particular drug, dosage form, and/or route of administration. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep.50, 219-244 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions are administered by oral administration or by injection. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve a desired or stated effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. [00078] Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, and the judgment of the treating physician. [00079] Dosage forms include from about 0.001 mg to about 2,000 mg (including, from about 0.001 mg to about 1,000 mg, from about 0.001 mg to about 500 mg, from about 0.01 mg to about 250 mg) of a compound of Formula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereof as defined anywhere herein. The dosage forms can further include a pharmaceutically acceptable carrier and/or an additional therapeutic agent. [00080] Appropriate dosage levels may be determined by any suitable method. Preferably, the active substance is administered at a frequency of 1 to 4 times per day for topical administration, or less often if a drug delivery system is used. Nevertheless, actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve a desired therapeutic response for a particular patient, composition and mode of administration, without being intolerably toxic to the patient. In certain cases, dosages may deviate from the stated amounts, in particular as a function of age, gender, body weight, diet and general health status of the patient, route of administration, individual response to the active ingredient, nature of the preparation, and time or interval over which administration takes place. Thus, it may be satisfactory in some cases to manage with less than the aforementioned minimum amount, whereas in other cases the stated upper limit may be exceeded. It may in the event of administration of larger amounts be advisable to divide these into multiple individual doses spread over the day. D. EVALUATION OF THE ACTIVITY OF THE COMPOUNDS [00081] Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess biological activity as GO inhibitors. [00082] Biochemical assays include recombinant human GO enzymatic assays in which purified recombinant human glycolate oxidase (GO or HAO1) is incubated with test compound, and its enzymatic activity measured upon addition of the substrate glycolate, using horseradish peroxidase as a label enzyme to detect hydrogen peroxide by-product. [00083] GO inhibitors can also be evaluated in an assay consisting of primary mouse hepatocytes. Following isolation, viable AGXT-silenced murine hepatocytes are incubated with test compound in presence of glycolate. Compound potency to modulate glycolate conversion is then evaluated by measuring the oxalate produced by the cells. GO inhibitors provided herein may also be evaluated in a glycolate PD analysis. Briefly, Sprague Dawley rats may be administered a GO inhibitor, for example, a compound of Formula (I), and blood samples collected at different time points, for example, from pre-dose to 24 h post-dose. Glycolate levels at the different time points may be assessed by ultra-high performance liquid chromatography (UHPLC). [00084] In vivo hyperoxaluria model may be generated in both rats and mice through oral gavage of sodium glycolate. In such model, test compounds are administered prior or concurrently to the glycolate challenge, and GO inhibition is assessed by levels of oxalate measured in urine and plasma at timepoints up to 24 hours. [00085] Genetically engineered alanine-glyoxylate aminotransferase-deficient mice such as double-knockout AGXT^-/- may also serve as a primary hyperoxaluria model. In addition, silencing of AGXT hepatic expression can be rendered via sustained liver-targeted RNA interference in both wild-type rats and mice. In some specific cases, model may also require saturation of the glycolate metabolic pathway through chronic exposure to ethylene glycol or sodium glycolate. In all instance, the efficacy of test compounds is assessed by their potency to reduce the urinary oxalate or glycolate burden [primary endpoint], which is expressed either as oxalate (or glycolate)/creatinine ratio, or as the total amount of oxalate (or glycolate) excreted over a 24-hour period. Additional endpoints can be considered, including histological evaluation of structural integrity of kidneys and presence of calcium oxalate crystal deposition, as well as renal function assessment (eg. eGFR). E. METHODS OF USE [00086] GO inhibitors may prove to be effective for diseases resulting from an increase in glyoxylate or where glyoxylate reduction may be beneficial. An example is primary hyperoxaluria, which is a disease resulting from an overproduction of oxalate. As glyoxylate is converted to oxalate in vivo, an agent which can reduce glyoxylate levels may be beneficial in this disease. Provided herein therefore are methods of treating or preventing diseases mediated by GO activity or HAO1 gene expression. For example, the compound or composition provided herein may be used to treat or prevent hyperoxaluria, including primary hyperoxaluria and the subtypes PH1, PH2 and PH3. The compound or composition provided herein may be used to treat calcium oxalate stone formation, for example, in the kidney, urinary tract or bladder, or prevent or delay kidney damage or the onset of chronic kidney disease or end stage renal disease. In certain embodiments, provided herein are methods of treating or preventing diseases associated with elevated oxalate levels comprising administering to a subject having such disease or disorder, a therapeutically effective amount of one or more compounds disclosed herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical compositions disclosed herein. In certain embodiments, the disease or disorder associated with elevated levels of oxalate is hyperoxaluria, chronic kidney disease (CKD), end stage renal disease (ESRD) or kidney stone disease. In yet certain embodiments, the disease or disorder is associated with the AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof. In certain embodiments, elevated oxalate levels means having a urinary oxalate excretion rate of greater than about 0.5 mmol/1.73 m² per day, greater than about 0.7 mmol/1.73 m² per day, greater than about 0.8 mmol/1.73 m² per day, greater than about 1.0 mmol/1.73 m² per day, greater than about 1.2 mmol/1.73 m² per day or greater than about 2 mmol/1.73 m² per day. In certain embodiments, elevated oxalate level means having a urinary oxalate excretion rate that is greater than normal urinary oxalate excretion. In certain embodiments, normal oxalate urinary excretion is less than about 0.45 mmol/1.73 m² per day, less than about 0.46 mmol/1.73 m² per day or less than about 0.5 mmol/1.73 m² per day. In certain embodiments, elevated oxalate level means having a urinary oxalate excretion rate that is greater than about 40 mg/day. In certain embodiments, elevated oxalate level means having a urinary oxalate excretion rate that is greater than about 45 mg/day. In certain embodiments, the urinary oxalate excretion rate is about two-fold higher than normal. In certain embodiments, the urinary oxalate excretion rate is about four-fold higher than normal. In certain embodiments, elevated oxalate level means having a plasma oxalate levels greater than normal plasma oxalate levels of about 1 µmol/L to about 3 µmol/L. In certain embodiments, elevated oxalate levels means having a plasma oxalate level equal to or greater than about 10 µmol/L. In certain embodiments, elevated oxalate level means having a plasma oxalate level equal to or greater than about 20 µmol/L. [00087] Method of treating primary hyperoxaluria may include the step of selecting patients with the genetic mutation underlying PH1, PH2 or PH3, for example, using a diagnostic test to detect the presence of mutation in the AGXT, GRHPR, HOGA1 genes, or to detect the level of expression of the AGXT, GRHPR, HOGA1 genes, before administering any of the compound or composition provided herein. Hyperoxaluria patients may also be diagnosed by kidney stone biopsy, measurement of urinary levels of oxalate, calcium, citrate, sodium, magnesium, urate, urinary pH and volume, or a combination of any such measurements, prior to administering a compound or composition provided herein. [00088] Efficacy of the agent can be measured in a patient by reduction in the urinary oxalate. Urinary oxalate can be measured in patients in several ways, including mg of oxalate, moles of oxalate or concentration of oxalate in the biological media (urine or plasma). In addition, oxalate can be normalized to other proteins, such as creatinine, or evaluated over a 24 h period and/or normalized based on age, body mass or body surface area. [00089] In addition, plasma glycolate or urinary glycolate increases may be used to monitor and assess the impact of the GO-inhibitor in a patient, as well as decreases in GO product glyoxylate. [00090] Additional agents which may be utilized for co-administration with the compound or composition provided herein, such as co-administration with Vitamin B6 (Pyridoxine), a GO-siRNA agent (e.g. lumasiran [ALN-GO1], Alnylam’s GalNAc-siRNA conjugate targeting GO) or a LDHA-siRNA agent (e.g. nedosiran, Dicerna’s GalNAc-siRNA conjugate targeting LDHA), other inhibitors in the oxalate synthesis pathways (e.g. stiripentol an LDH-inhibitor), agents capable of reducing exogenous oxalate, such as oxalate decarboxylase (e.g. reloxaliase, formerly ALLN-177) or oxalobacter formigenes (e.g. Oxabact^®). The compound or composition provided herein may also be administered in conjunction with dietary modifications such as increased water consumption or avoidance of oxalate-rich food. F. PREPARATION OF THE COMPOUNDS [00091] The starting materials used for the synthesis were synthesized according to known literature procedures or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Bruker Acuity 300 MHz spectrometer with an appropriate deuterated solvent. NMR chemical shift (δ) is expressed in units of parts per million (ppm). LCMS analysis was conducted using a Waters Acquity UPLC with a QDA MS detector using a Waters C18 BEH 1.7 µM, 2.1 × 50 mm column, eluting with 95:5 to 0:100 H₂O:MeCN + 0.1% formic acid at a flow rate of 0.6 mL/min over 3.5 minutes. The QDA MS detector was set up to scan under both positive and negative mode ions ranging from 100-1200 Daltons. General methods for the preparation of compounds can be modified using appropriate reagents and conditions for the introduction of the various moieties found in the structures as provided herein. [00092] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. [00093] Standard abbreviations and acronyms as defined in Journal of Organic Chemistry’s Author’s Guideline at https://pubs.acs.org/userimages/ContentEditor/1218717864819/joceah_abbreviations.pdf are used herein. Other abbreviations and acronyms used herein are as follows: Table 2: Abbreviations Bn benzyl

g grams

μL microliter

GENERAL SYNTHETIC SCHEME [00094] In some embodiments, compounds described herein can be prepared as outlined in the following general synthetic schemes. [00095] General Structure: Part 1: Preparation of cyclic alcohol [00096]

SF5 subst tuted p eny brom de can undergo a t um- a ogen exchange when treated with n-butyllithium, which reacts with a series of protected hydroxyl cyclic ketones via a nucleophilic addition. The resulting tertiary alcohol can be treated with TFA/TES followed by palladium-catalyzed hydrogenation conditions, resulting in desired cyclic alcohol. Part 2: Triazole ether formation [000

e cyc c a co o ca u e go a su o u eac o 3, w h hydroxyl triazole, which can be synthesized according to a literature procedure (Buckle, D. R., Rockell, C. J. M. J. Chem. Soc., Perkin Trans.1, 1982, 0, 627−630). When R is a tert- butyl group, both the tert-butyl group and PMB protecting group can be removed by treatment of TFA, resulting in the target acid directly. Alternatively, when R is an ethyl group, an additional saponification step (LiOH, THF/MeOH/water) is needed to yield the target compound. G. EXAMPLES PREPARATION OF INTERMEDIATES Intermediate A: Ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate

[00098] Step 1: Preparation of 1-(azidomethyl)-4-methoxybenzene [00099] Into a 1 L round-bottom flask was placed 4-methoxybenzyl chloride (35.0 g, 224 mmol, 1.0 equiv), DMF (500 mL) and NaN₃ (14.5 g, 224 mmol, 1.0 equiv). The resulting solution was stirred for 12 h at room temperature, after which the reaction mixture was quenched with water (500 mL) at 25 °C. The resulting mixture was poured into a separatory funnel and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1-(azidomethyl)-4-methoxybenzene as a brown yellow solid (32 g, 88% yield). [000100] Step 2: Preparation of ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3- triazole-4-carboxylate [000101] Into a 500 mL round-bottom flask was placed diethyl malonate (31.4 g, 196 mmol, 1.0 equiv), EtOH (200 mL) and EtONa (32.0 g, 471 mmol, 2.4 equiv). The resulting solution was stirred for 1 h at 25 °C. To the above mixture was added 1-(azidomethyl)-4- methoxybenzene (32.0 g, 196 mmol, 1.0 equiv). The resulting solution was stirred while being heated to 85 °C in an oil bath for 18 h overnight. The reaction was cooled to room temperature and quenched with water (500 mL). The resulting mixture was poured into a separatory funnel and the aqueous layer was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (3 × 500 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The reaction mixture was treated with petroleum ether (100 mL) and the precipitated solids were collected by filtration and washed with petroleum ether (2 × 10 mL). The desired compound, ethyl 5- hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, was obtained as a yellow solid (20 g, 37% yield).

PREPARATION OF EXAMPLES Example 1: Preparation of 5-(((trans)-4-(4-(Pentafluoro-λ⁶- sulfanyl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-4-carboxylic acid

[000102] Step 1: Preparation of 4-(benzyloxy)-1-[4-(pentafluoro-λ⁶- sulfanyl)phenyl]cyclohexan-1-ol: [000103] Into a 250 mL 3-necked round-bottom flask, equipped with a magnetic stir bar and under nitrogen was added 1-bromo-4-(pentafluoro-λ⁶-sulfanyl)benzene (9.0 g, 31.8 mmol, 1.0 equiv) and THF (30 mL). The mixture was cooled to -78 °C in a dry ice/acetone bath and treated with drop-wise addition of n-BuLi (19 mL, 47.7 mmol, 1.5 equiv) over 15 minutes. After stirring at -78 °C for another 30 minutes, 4-(benzyloxy)cyclohexan-1-one (7.1 g, 35.0 mmol, 1.1 equiv) in THF (10 mL) was added drop-wise. The resulting mixture was maintained at -78 °C for 10 minutes before being warmed to room temperature and stirred at 25 °C for 16 h. The reaction was then quenched with saturated aqueous NH4Cl (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative-HPLC under the following conditions: Column, C18 silica gel; Mobile phase, water:MeCN (90:10), increasing to water:MeCN (40:60) within 20 min; Detector, UV 220 nm. The product containing fractions were combined, concentrated and dried under vacuum to afford the title product as a light yellow solid (1.5 g, 34% yield). [000104] Step 2: Preparation of 1-[4-(benzyloxy)cyclohex-1-en-1-yl]-4-(pentafluoro- λ⁶-sulfanyl)benzene: [000105] Into a 250 mL round-bottom flask equipped with a magnetic stir bar was placed 4-(benzyloxy)-1-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohexan-1-ol (1.5 g, 3.7 mmol, 1.0 equiv), TFA (15 mL) and Et3SiH (0.6 mL, 3.7 mmol, 1.0 equiv). The resulting mixture was heated to 60 °C for 3 h. The reaction mixture was cooled to room temperature. The product-containing fractions were concentrated and dried under vacuum to afford the crude product as a yellow oil (1.8 g, crude). LCMS indicated dehydroxylation product (4-(4- (benzyloxy)cyclohexyl)phenyl)pentafluoro-l6-sulfane as the minor impurity. The mixture was used in the next step without further purification. [000106] Step 3: Preparation of cis-4-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohexan- 1-ol: [000107] Into a 100 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was added 1-[4-(benzyloxy)cyclohex-1-en-1-yl]-4-(pentafluoro-λ⁶-sulfanyl)benzene (1.5 g, 3.8 mmol, 1.0 equiv), MeOH (20 mL), TFA (2.0 mL) and Pd/C (10% weight/weight, 430 mg). The resulting suspension was heated to 60 °C for 16 h in an oil bath under hydrogen (1 atm). The reaction mixture was cooled to room temperature and filtered through a Celite pad and concentrated under reduced pressure. The crude product was purified by preparative- HPLC under the following conditions: Column, C18 silica gel; Mobile phase, water:MeCN (60:40), increasing to water:MeCN (40:60) within 40 min; Detector, UV 220 nm. The product containing fractions were combined, concentrated and dried under vacuum to afford the title product as a colorless oil (400 mg, 34% yield). [000108] Step 4: Preparation of ethyl 1-[(4-methoxyphenyl)methyl]-5-[[(trans)-4-[4- (pentafluoro-λ⁶-sulfanyl)phenyl]cyclohexyl]oxy]-1,2,3-triazole-4-carboxylate: [000109] Into a 50 mL round-bottom flask equipped with a magnetic stir bar and under nitrogen was placed cis-4-[4-(pentafluoro- λ⁶-sulfanyl)phenyl]cyclohexan-1-ol (400 mg, 1.3 mmol, 1.0 equiv), THF (8.0 mL), ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4- carboxylate (Intermediate A, 370 mg, 1.3 mmol, 1.0 equiv), Ph₃P (520 mg, 2.0 mmol, 1.5 equiv) and diisopropyl azodicarboxylate (0.39 mL, 2.0 mmol, 1.5 equiv). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluting with petroleum ether:EtOAc (2:1) to afford title product as a white solid (880 mg, crude). [000110] Step 5: Preparation of ethyl 5-[[(trans)-4-[4-(pentafluoro- λ⁶- sulfanyl)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4-carboxylate: [000111] Into a 50 mL round-bottom flask, equipped with a magnetic stir bar was placed ethyl 1-[(4-methoxyphenyl)methyl]-5-[[(trans)-4-[4-(pentafluoro-λ⁶- sulfanyl)phenyl]cyclohexyl]oxy]-1,2,3-triazole-4-carboxylate (860 mg, 1.5 mmol, 1.0 equiv) and TFA (10 mL). The resulting mixture was heated to 60 °C for 5 h. The reaction mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure. The crude product was purified by preparative-HPLC under the following conditions: Column, C18 silica gel; Mobile phase, water:MeCN (80:20), increasing to water:MeCN (30:70) within 10 min; Detector, UV 254 nm. The product containing fractions were combined, concentrated and dried under vacuum to afford the title product as a white solid (230 mg, 34% yield). [000112] Step 6: Preparation of 5-(((trans)-4-(4-(pentafluoro-λ⁶- sulfanyl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-4-carboxylic acid: [000113] Into a 50 mL round-bottom flask, equipped with a magnetic stir bar was added ethyl 5-[[(trans)-4-[4-(pentafluoro- λ⁶-sulfanyl)phenyl]cyclohexyl]oxy]-1H-1,2,3-triazole-4- carboxylate (230 mg, 0.52 mmol, 1.0 equiv), EtOH (4 mL), NaOH (104 mg, 2.6 mmol, 5.0 equiv) and H₂O (1 mL). The resulting mixture was heated to 60 °C for 3 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was acidified to pH=2 with 1 M aqueous HCl solution. The precipitated solids were collected by filtration and washed with water (2 × 20 mL). Upon further drying under vacuum, the title compound was obtained as a white solid (204 mg, 94% yield).¹H-NMR (300 MHz, CD₃OD) δ 7.74-7.55 (m, 2H), 7.46-7.29 (m, 2H), 4.82-4.74 (m, 1H), 2.80-2.73 (m, 1H), 2.38-2.31 (m, 2H), 2.01-1.91 (m, 2H), 1.77-1.65 (m, 4H). Example Structure MW MS (ESI+)

Example 2: Human HAO-1 Enzymatic Assay [000114] Test compound was serially diluted in DMSO then 1 µL of compound was added to 50 µL of 0.24 µg/mL human HAO1 (Creative Biomart) in buffer containing 25 mM HEPES, pH 8.0 in a black-bottom, non-binding 96-well plate (Greiner 655900). The mixture was agitated by shaking briefly on a platform shaker and then incubated at room temperature for 10 minutes. Equal amount of substrate solution containing 120 µM glycolic acid (Sigma G8284), 100 µM Amplex Red (Invitrogen A12222) and 0.02 U/mL horseradish peroxidase (Sigma P8375) in buffer was added to the sample. The reaction was mixed by shaking briefly on a platform shaker before measuring the enzyme activity with fluorescence at Ex544/Em590 on a plate reader (Molecular Devices) in kinetic mode for 10 min at room temperature. Enzyme Activity Table: E _l ^{Human HAO-1 Enzyme}

Example 3: Formulation, PK and PD analysis [000115] Compounds were formulated in 0.5% methocel + 1.0 equiv NaOH at 20 mg/kg and a dose volume of 5 mL/kg and dosed orally to 3 to 8-weeks-old male fasted Sprague Dawley rats (Envigo). The rat whole blood samples were collected using a syringe and collected serially from a jugular catheter at different timepoints, including predose, 15 min, 30 min, 1 h, 2 h, 6 h and 24 h post-dose. Blood samples then spun at 1500 rcf for 15 min at 4 °C to afford rat plasma samples, which were stored at -80 °C before used for PK and PD analysis. [000116] To quantify Example 1 in rat plasma by LC-MS/MS, plasma samples (25 µL) were subjected to protein precipitation with 150 µL of acetonitrile containing 0.2 µM of the internal standard (IS). For time course studies in rats orally administered 20 mg/kg of Example 1, plasma samples collected from 15 min to 4 h time points and from 6 h to 24 h time points were diluted 10× and 5×, respectively, with naïve rat plasma, before the addition of acetonitrile-containing IS. The samples were then centrifuged at 4,300 g for 20 min at 4 °C, and 80 µL of the supernatants were transferred to a deep well 96 well plate containing equal volume of LC-MS grade H2O. The plate was mixed for 5 min at room temperature, and 5 µL of the sample was injected into UHPLC. Chromatographic separation was achieved using Agilent Zorbax SB-C8 RRHD 2.1 × 50 mm column, with 0.1% acetic acid in water (mobile phase A) and 0.1% acetic acid in acetonitrile (mobile phase B) run at 0.4 mL/min as per the following gradient: 5% B for 0.5 min, 5-90% B over 0.5 min, 95% B for 1 min, 95- 5% B over 0.1 min, and 5% B for 1.4 min. Total run time was 3.5 min. The samples were analyzed using Sciex QTRAP 5500 linear ion trap mass spectrometer operated in multiple reaction monitoring (MRM) mode under negative ionization. The MRM transitions were m/z 411.92 to m/z 84.0 for Example 1 and m/z 287.88 to m/z 215.9 for the IS. Pharmacokinetic data were analyzed by noncompartmental analysis using Phoenix WinNonlin version 8.1. [000117] To quantify glycolate levels in rat plasma by LC-MS/MS, plasma samples (25 µL) were subjected to protein precipitation with 150 µL of acetonitrile containing 100 µM of ¹³C2-glycolate as the internal standard (IS), followed by centrifugation at 4,300 g for 20 min at 4 °C. Supernatants (120 µL) were transferred to a deep well 96 well plate containing 50 µL of LC-MS grade H2O. The plate was mixed for 5 min at room temperature, and 5 µL of the sample was injected into UHPLC. Chromatographic separation was achieved using Atlantis HILIC Silica 3 µm 2.1 × 50mm column, with mobile phase A (10 mM ammonium acetate in water) and mobile phase B (10 mM ammonium acetate in 90% acetonitrile and 10% water), run at 0.75 mL/min as per the following gradient 100% B for 0.5 min, 100-30% B over 1 min, 30% B for 0.5 min, 30-100% B over 0.1 min, and then 100% B for 3.4 min. Total run time was 5.5 min. The samples were analyzed using Sciex QTRAP 5500 linear ion trap mass spectrometer operated in multiple reaction monitoring (MRM) mode under negative ionization. The MRM transitions were m/z 74.877 to m/z 47.1 for glycolate and m/z 76.863 to m/z 48.1 for ¹³C2-glycolate (IS). [000118] As shown in FIG.1, Example 1 exhibited good plasma exposure in rats, with a Cmax of 4 hours. Example 1 also achieved a durable PD affect, as shown by the significant increase (5-8 ×) in glycolate levels at the 4- and 6-hour timepoints. Example 4: PH1 AGXT Knockdown or Knockout Mouse Model [000119] A mouse model with hepatic knockdown/knockout of the AGXT gene may be used to assess the in vivo efficacy of GO inhibitors in reducing the rate of conversion of glycolate to glyoxylate, and effectively in reducing LDH substrate levels and the conversion by LDH of glyoxylate to oxalate. AGXT knockout mice have been previously described in the literature (Salido, Proc Natl Acad Sci, 2006, 103(48), 18249–18254) and can be derived using similar technologies or modern gene-editing methods such as CRISPR-Cas9. The AGXT knockdown model is generated through systemic administration of 0.4 mg/kg siRNA to c57bl/6 male mice (8 – 12 weeks of age, Charles River Labs). The AGXT siRNA is encapsulated in a lipid nanoparticle (XL-10 (KL-52) LNP as described in WO2016/205410) and its sequence is: 5'-AcAAcuGGAGGGAcAucGudTsdT-3' (modified sense strand sequence, N: RNA residues; dN: DNA residues; n: 2'-O-methyl residues; s: phosphorothioate residues) and 5'-ACGAUGUCCCUCcAGUUGUdTsdT-3' (modified antisense strand sequence, see annotation above for residue modifications). Administration of the AGXT siRNA is done intravenously on day 0 and day 7 to maintain >90% knockdown of hepatic AGXT expression throughout the experimental study. The AGXT-KD model presents robust elevation of the urinary oxalate excretion within 7 days post-administration to a similar extent as AGXT-null mice (Salido, Proc Natl Acad Sci, 2006). Prior to initiation of treatment with the GO inhibitors, oxalate and creatinine levels in urine are assessed and animals are assigned to treatment groups. [000120] Compounds of Formula (I) disclosed herein may be administered at 1-50 mg/kg QD or BID (PO) per os over 5 consecutive days. If a knockdown model is used, treatment should start 8 days after initial AGXT-siRNA administration. Once oral treatment is completed, mice are placed in metabolic cages and urine is collected over 24 hours. Sacrifice is performed after completion of the urine collection, and plasma / selected organs are collected and analyzed for drug concentrations. [000121] Urinary oxalate and creatinine are quantified using commercially available kits according to manufacturer’s protocol (Trinity Biotech USA Inc, catalog #591; R&D Systems, Inc., catalog #KGE005). Oxalate results are normalized to creatinine to account for urine diluteness to determine whether the compounds of Formula (I) disclosed herein reduce urinary oxalate levels. [000122] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials and procedures. All such equivalents are considered to be within the scope of the claimed subject matter and are encompassed by the appended claims. Since modifications will be apparent to those of skill in the art, it is intended that the claimed subject matter be limited only by the scope of the appended claims.

Claims

CLAIM OR CLAIMS 1. The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, a single stereoisomer or a mixture of stereoisomers, a racemic mixture of stereoisomers or an isotopic variant thereof: I)

wherein: R¹ is hydrogen or a group converted to hydrogen in vivo, which is selected from alkyl, aryl, aralkyl ; L¹ is -O-;

Ring A is monocyclic cycloalkyl; Ring B is aryl or heteroaryl; each R⁶ is independently halo, oxo, haloalkyl; or two R⁶ groups, together with the same carbon atom to which they are attached, form cycloalkyl or heterocyclyl, or two R⁶ groups, each on separate carbon atoms form alkylene; each R⁸ is independently halo, haloalkyl, cycloalkyl; R^x and R^y are each independently alkyl, haloalkyl, cyanoalkyl or cycloalkyl; each R^u is independently a direct bond or -alkylene-O-; j is 0, 1, 2, 3 or 4; and k is 0, 1, 2, 3 or 4.

2. The compound of claim 1 wherein j is 0, 1 or 2 and k is 0, 1 or 2.

3. The compound of claim 1 or 2 wherein j is 0 and k is 0.

4. The compound of any one of claims 1-3 having the Formula (II): I) wherein m is 1, 2 or 3 and n is

5. The compound of any one of claims 1-4 having the Formula (III): I).

6. The compound of claim 5 w

ans-substitutions.

7. The compound of claim 5 wherein L¹ and Ring B are cis-substitutions.

8. The compound of any one of claims 1-5 having the Formula (IIIa-1) or (IIIa-2):

O H 1 N RO N L¹ N R⁶ j B -1) or FS R⁸ (IIIa _{5 k} (IIIa-2).

9. The compound of any one of claims 1-5 having the Formula (IIIb-1) or (IIIb-2): O H 1 N RO N L¹ N R⁶ j B R⁸ (IIIb-1) orF₅S _k (IIIb-2)^.

10. The compound of any one of claims 1 to 4 having the Formula (IV): (IV) wherein each Y is C or N provided no more than two Ys are N; m is 1,2 or 3 and n is 1 or 2.

11. The compound of claim 10 having the Formula (V): ).

r N provided no more than two Ys are N; m is 1,2 or 3 and n is 1 or 2.

12. The compound of claim 10 or 11 wherein Y is C.

13. The compound of claim 10 or 11 wherein one Y is N or two Ys are N and the remainder of Ys are C.

14. The compound of claim 1 wherein the compound is 5-((4-(4-(pentafluoro-λ⁶- sulfanyl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-4-carboxylic acid or 5-(((trans)-4-(4-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclohexyl)oxy)-1H-1,2,3-triazole-4- carboxylic acid.

15. A pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, solvate of the salt, hydrate, a single stereoisomer, a mixture of stereoisomers, a racemic mixture of stereoisomers, or isotopic variant thereof, and a pharmaceutically acceptable carrier.

16. A method of treating lithiasis or calcium oxalate stone formation in a patient comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

17. A method of treating hyperoxaluria in a patient comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-14 or the pharmaceutical composition of claim 15.

18. The method of claim 17 wherein the hyperoxaluria is primary hyperoxaluria.

19. The method of claims 16 or 17 wherein the primary hyperoxaluria is primary hyperoxaluria type 1 (PH-1), primary hyperoxaluria type 2 (PH-2) or primary hyperoxaluria type 3 (PH-3).

20. The method of any one or claims 17 to 19 wherein the subject with hyperoxaluria has an AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof.