Substituted pyrazolyl compounds and methods of use thereof

Abstract

Provided herein are compounds, compositions and methods useful for inhibiting lactate dehydrogenase (LDH) activity and for treating, preventing and ameliorating one or more symptoms of a disease or disorder associated with LDH activity or oxalate accumulation, including hyperoxaluria.

Description

Technical Field

[0001] Provided herein are compounds, compositions and methods useful for inhibiting lactase dehydrogenase (LDH) activity and for treating, preventing and ameliorating one or more symptoms of hyperoxaluria, including primary hyperoxaluria and stone formation in the kidney and urinary tract. Background Art

[0002] Hyperoxaluria is characterized by an increase in oxalate concentration in an individual, which is generally manifested as an increase in urine oxalate excretion. Oxalic acid is a dicarboxylic acid, which can form complexes with cations such as calcium to produce highly insoluble calcium oxalate crystals. The deposition of calcium oxalate crystals can affect renal function, resulting in the formation of stones in the entire urinary tract (urolithiasis), kidneys (kidney stones), and causing the calcium level of the kidney to gradually increase (nephrocalcinosis) (U.S. Rare Disease Organization-PH Disease Database). The overall impact is renal damage, kidney stones, urinary tract infections, chronic kidney disease, and end-stage renal disease (ESRD) in some cases. In addition, hyperoxaluria combined with reduced glomerular function can lead to systemic oxalic acidosis, whereby oxalate deposition occurs throughout the body, including bones, retina, central nervous system tissue, and vascular system inner layer (Bhasin, World J. Nephrol. 2015, 42 (2), 235-244).

[0003] Based on clinical etiology, hyperoxaluria is subdivided into primary and secondary hyperoxaluria. Primary hyperoxaluria (PH) is a metabolic genetic error caused by enzyme activity defects and is further divided into three subtypes (Harambat, Int. J. Nephrol. 2011: 864580). Type I primary hyperoxaluria (PH1) is an autosomal recessive disease caused by a lack of liver-specific peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT, gene name AGXT). This is the most serious form of PH1 and accounts for about 80% of diagnosed PH cases. PH1 usually occurs in childhood or adolescence, and the disease is characterized by recurrent kidney stones. Renal failure is observed in about 20-50% of PH1 patients. The AGT enzyme is responsible for detoxifying glyoxylate to glycine and competes with the conversion of glyoxylate to oxalate mediated by lactate dehydrogenase (LDH). Therefore, the loss of AGT function leads to increased production of oxalate. The estimated prevalence of PH1 in Europe is 1-3 cases per million people, accounting for ~1% of pediatric end-stage renal disease (ESRD) in registries in Europe, the United States, and Japan (Harambat 2011). More than 150 AGXT mutations have been identified in PH1, and this genetic diversity may explain the heterogeneous clinical presentation and disease severity of PH1 patients. Therefore, delays often occur in determining the diagnosis of PH1, and the incidence may not be fully reflected (van der Hoeven, Nephrol. Dial. Transplant 2012, 27 (10), 3855-3862). PH1 is diagnosed by confirming mutations in the AGXT gene or reduced AGT activity in liver biopsy samples (Williams, Hum. Mutat. 2009, 30, 910-917).

[0004] Type II primary hyperoxaluria (PH2) is caused by a defect in the glyoxylate reductase / hydroxypyruvate reductase (GRHPR) gene. The gene encoding this enzyme is responsible for converting glyoxylate into glycine, and mutations usually lead to loss of GRHPR function. It is generally believed that the clinical course of PH2 is lighter than PH1, and the risk of ESRD is low, although kidney stones and frequent kidney stones are common in these patients (Dhondup, Am. J. Transplant. 2018, 18, 253-257). These patients may have chronic and end-stage renal insufficiency (Kemper, Eur. J. Pediatr. 1997, 156 (7), 509-512).

[0005] Type III primary hyperoxaluria (PH3) is caused by mutations in the HOGA1 gene, which encodes the liver-specific mitochondrial enzyme 4-hydroxy-2-ketoglutarate aldolase (Belostotsky, Am. J. Hum. Genet. 2010, 87 (3), 392-399). The exact role of this enzyme in oxalate production is not fully understood, but the current hypothesis is that the substrate of HOGA1, 4-hydroxy-2-ketoglutarate (HOG), is able to inhibit GRHPR (Reidel, Biochim. Biophys. Acta. 2012, 1822 (10), 1544-1552). Although ESRD cases in PH3 patients are significantly less than those in PH1 patients, the incidence of kidney stones in this patient population is still high, and the patient and hospitalization burden is heavy. For example, approximately 50-65% of individuals with PH3 develop stones before the age of five (Monico, Clin. J. Am. Soc. Nephrol. 2011, 6, 2289-2295), and while some individuals experience fewer kidney stone events during adolescence and their adulthood, this is not the case for all individuals. It is also noted that the PH3 carrier frequency is 1:185, similar to the carrier frequency of PH1. The genetic prevalence is 1:136,000, making PH3 more common than initially thought based on clinical diagnosis (Hopp, J. Am. Soc. Nephrol. 2015, 26, 2559-2570).

[0006] Increased urinary oxalate concentrations in PH patients are associated with increased disease severity and progression to end-stage renal disease (Zhao, CJASN, 2016, 11(1), 119-126). Clinically, urinary oxalate concentrations below <0.45mmol / day are considered to be within the normal range. Patients with urinary oxalate concentrations >2.4mmol / day are at significantly higher risk of developing ESRD (hazard ratio = 3.4). Higher urinary oxalate excretion at diagnosis and follow-up is associated with poorer renal outcomes in PH patients. On average, PH1 patients have higher urinary oxalate concentrations (mean of 297 patients was 2.0mmol / day), and not surprisingly, after 30 years of follow-up, the renal survival rate was only 27%, compared to 92% and 95% for PH2 and PH3 individuals, where urinary oxalate concentrations are lower but still far above the normal range. In addition, elevated 24-hour urinary oxalate excretion is also 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 reducing urinary oxalate concentrations.

[0007] Secondary hyperoxaluria is a general term for all other hyperoxalurias not caused by genetic factors. In enterogenic hyperoxaluria, it is believed that the driving factor enhances the absorption of dietary oxalate or oxalate precursors such as glycolic acid. These patients usually suffer from chronic potential gastrointestinal disorders that cause oxalate malabsorption, such as complications of bariatric surgery, short bowel syndrome or Crohn's disease. In inflammatory bowel disease, ileal resection and modern bariatric surgery patients, the incidence of enterogenic hyperoxaluria is 5-24%, thus representing a significant unmet medical need (Esker, Am. J. Nephrol. 2016, 44, 85-91). Diabetes and obesity are independently associated with increased urinary oxalate excretion and increased risk of kidney stones, but it is unclear whether hyperoxaluria in these individuals is caused by increased dietary absorption or endogenous synthesis of oxalic acid (see Efe, Curr. Opin. Nephrol. Hypertens. 2019). All other secondary hyperoxaluria of a non-enteral nature are defined as idiopathic, meaning that the cause of the hyperoxaluria has not been determined.

[0008] There are currently no approved therapies that are universally effective for patients with hyperoxaluria. Patients are usually advised to increase their fluid intake (recommended >2 L / m) soon after clinical evidence of increased oxalate excretion. 2 / day). Dietary changes to reduce dietary sources of oxalate and increase calcium supplementation to complex free oxalate in the gastrointestinal tract and reduce oxalate absorption are also common but have limited value in patients with PH. Pyridoxine (vitamin B6) is a cofactor for AGT and has been found to be beneficial in reducing urinary oxalate by approximately 30% in patients with PH1, but is ineffective in most patients (Watts, Clin. Sci. Lond. 1985, 69, 87-90).

[0009] Double liver and kidney transplantation is the only effective means to completely reverse hyperoxaluria in PH1 patients. The timing of liver and kidney transplantation is usually determined by the stage of chronic kidney disease and the time of ESRD in patients (Cochat, Nephrol.Dial.Transplant.2012,27,1729-1736). Liver and kidney transplantation should be planned in advance before severe systemic oxalic acid hyperactivity occurs. Conventional dialysis is ineffective for removing plasma oxalate concentrations in patients with hyperoxaluria, but is commonly used in patients with CKD in stage 5 waiting for transplantation. In these patients, it is recommended to perform efficient dialysis, which can moderately slow down disease progression, but cannot prevent ESRD (Ellis, Nephrol.Dial.Transplant.2001,16,348-354).

[0010] Efforts to reduce the endogenous synthesis of oxalic acid should be effective for treating hyperoxaluria. Lactate dehydrogenase A (LDHA) catalyzes the oxidation of glyoxylic acid to oxalic acid and is the last step in oxalic acid synthesis (Lluis, Biochim et Biophys Acta. 1977, 333-342). Therefore, inhibiting LDHA will reduce the oxidative conversion of glyoxylic acid to oxalic acid and represent a promising method for treating hyperoxaluria. In fact, knockdown of LDHA expression after siRNA treatment has been shown to reduce urinary oxalate in rodent PH1 models (Lai, Mol Ther. 2018, 26 (8): 1983-1995) and early clinical studies of Nedosiran (PHYOX: A Safety and Tolerability Study of DCR-PHXC in Primary Hyperoxaluria Types 1 and 2, OHF 2019).

[0011] It is expected that liver-targeted LDH inhibition is well tolerated. It is reported that people with loss-of-function mutations in LDHA suffer from exercise-induced rhabdomyolysis (Miyajima, Muscle & Nerve. 1995, 18: 874-878), however, liver-targeted siRNA for LDHA does not cause exertional myopathy in mice (Lai, Mol Ther. 2018, 26 (8): 1983-1995), and in clinical trials, the treatment of nedoxilan is well tolerated (PHYOX: A Safety and Tolerability Study of DCR-PHXC in Primary Hyperoxaluria Types 1 and 2, OHF 2019). In addition, people with LDHB loss-of-function mutations do not have any reported phenotypes (Tanis, Am. J. Hum. Genet. 1977, 29: 419-430).

[0012] Several LDH inhibitors have been described in the literature as oncolytic agents (Granchi, J. Med. Chem. 2011, 54, 1599-1612; Ward, J. Med. Chem. 2012, 55, 3285-3306; Kohlmann, J. Med. Chem. 2013, 56, 1023-1040; Fauber, Bioorg. Med. Chem. Lett. 2013, 20, 5533–5539; Purkey, ACS Med. Chem. Lett. 2016, 7, 896-901; Rai, J. Med. Chem. 2017, 60, 9184-9204). Most of these inhibitors have modest LDH inhibition, poor cell permeability, and poor pharmacokinetic properties, making their use as therapy challenging. Furthermore, the specific requirements for an effective agent for treating hyperoxaluria differ significantly from those required for oncology. Most oncology agents have a systemic tissue distribution profile that ensures the compound inhibits cancer cells throughout the body. Additionally, for oncology indications, the compound needs to exhibit a high degree of cytotoxicity. In contrast, for hyperoxaluria, one would expect a liver-targeted tissue distribution profile with increased hepatocyte activity and little or no cytotoxicity.

[0013] There remains a need for new liver-targeted small molecule therapeutics capable of inhibiting the LDH protein for the treatment of diseases such as primary and secondary hyperoxaluria, where decreasing the amount of oxalate synthesis would be beneficial. Summary of the invention

[0014] In certain embodiments, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the compound is an inhibitor of lactate dehydrogenase (LDH) enzyme. In certain embodiments, compounds as LDH inhibitors will provide therapeutic benefits associated with reducing oxalate levels, including reducing endogenous production of oxalic acid.

[0015] In certain embodiments, provided herein are compounds having Formula (I):

[0016]

[0017] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0018] Y is O or S;

[0019] X 1 is hydrogen, fluorine or chlorine;

[0020] X 2 is hydrogen, fluorine or chlorine;

[0021] R3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0022] R 3b is hydrogen, fluorine, chlorine, cyano or C 1-3 Haloalkyl;

[0023] R 3c is hydrogen, fluorine or chlorine;

[0024] R 3d is hydrogen, fluorine or chlorine;

[0025] R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl;

[0026] The condition is (i) when R 3b is fluorine, R 3a is methoxy and R 3c and R 3d are each hydrogen, or (ii) when R 3b is hydrogen, R 3a is isopropoxy and R 3c and R 3d are each hydrogen, or (iii) when R 3a , R 3b , R 3c and R 3d When all is hydrogen, then X 1 and X 2 is fluorine or chlorine; and provided that when R 3a It is CF3, R 3b is fluorine, and R 3c and R 3d When each is hydrogen, then R 10 Not cyclopropylmethyl.

[0027] Also provided is a pharmaceutical composition formulated for administration by appropriate routes and means, containing therapeutically effective concentrations of one or more compounds provided herein or pharmaceutically acceptable salts or solvates thereof, and optionally comprising at least one pharmaceutical carrier. In certain embodiments, the pharmaceutical composition delivers an amount that effectively reduces the oxalate level of a subject in need. In certain embodiments, the pharmaceutical composition delivers an amount that effectively reduces the formation of kidney stones in a subject in need.

[0028] On the other hand, provided herein is a method for treating a disease or condition associated with elevated oxalate levels, comprising administering to a subject suffering from such disease or condition a therapeutically effective amount of one or more compounds disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein. In certain embodiments, the disease or condition is hyperoxaluria, chronic kidney disease (CKD), end-stage renal disease (ESRD) or kidney stone disease. In certain embodiments, the disease or condition is primary hyperoxaluria, idiopathic hyperoxaluria or idiopathic oxalate kidney stone disease. In certain embodiments, the disease or condition is associated with a combination of AGXT, GRHPR or HOGA1 mutations or mutations thereof.

[0029] Also provided herein are combination therapies using one or more of the compounds or compositions provided herein in combination with other agents for treating the diseases and disorders described herein.

[0030] These and other aspects of the subject matter described herein will become apparent upon reference to the following detailed description and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 Depicted are the percent reduction in urinary oxalate levels in the AGXT knockdown mouse model of primary hyperoxaluria 1 (PH1) following 5 days of PO administration of a compound of formula (I) disclosed herein at 5 mg / kg QD.

[0032] Figure 2 Depicted are the XlogP distributions of the compounds of formula (I) disclosed herein. DETAILED DESCRIPTION

[0033] A. Definition

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. Unless otherwise indicated, all patents, applications, published applications and other publications cited herein are incorporated by reference in their entirety. In the case where the terms herein have multiple definitions, unless otherwise indicated, those definitions in this section shall prevail. The term "subject" refers to an animal, including mammals, such as mice, rats, cattle, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans, including neonates, infants, teenagers, adolescents, adults or elderly patients.

[0035] As used herein and unless otherwise indicated, the term "halo," "halogen," or "halide" refers to any radical of fluorine, chlorine, bromine, or iodine.

[0036] As used herein and unless otherwise indicated, the term "alkyl" refers to a saturated hydrocarbon chain radical which may be straight or branched, which contains the specified number of carbon atoms or otherwise has 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, C 1-3 Alkyl means that the group may have 1 to 3 (including end values) carbon atoms. In some embodiments, alkyl is a C 2-alkyl group that represents a straight or branched saturated hydrocarbon group having 1 to 3 carbon atoms. 1-3 Alkyl. C 1-3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl.

[0037] As used herein and unless otherwise indicated, the term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon radical having a specified number of ring carbon atoms or having three to ten carbon atoms and being fully saturated or partially unsaturated. Polycyclic cycloalkyls can be fused, bridged or spirocyclic systems. Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, and partially unsaturated hydrocarbon rings such as cyclobutene, cyclopentene and cyclohexene. In some embodiments, cycloalkyl is a monocyclic C 3-4 Cycloalkyl. 3-4 Examples of cycloalkyl groups are cyclopropyl and cyclobutyl.

[0038] As used herein and unless otherwise indicated, the term "haloalkyl" refers to an alkyl group 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) is replaced by a halogen. In these embodiments, the hydrogen atoms can each be replaced by the same halogen (e.g., fluorine), or the hydrogen atoms can be replaced by a combination of different halogens (e.g., fluorine and chlorine). "haloalkyl" also includes an alkyl moiety (sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl, such as trifluoromethyl) in which all hydrogens are replaced by halogens.

[0039] As used herein and unless otherwise indicated, the term "alkoxy" refers to a group of formula -O-(alkyl). Alkoxy can be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy or hexoxy. The term C1-C3 alkoxy refers to a group of formula -O-(C1-C3 alkyl) and includes methoxy, ethoxy, n-propoxy and isopropoxy.

[0040] As used herein and unless otherwise indicated, the term "aryl" means any stable monocyclic or bicyclic carbocyclic group 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.

[0041] As used herein and unless otherwise indicated, the term "cycloalkylalkyl" refers to an alkyl group substituted by a cycloalkyl group, as each of the terms "alkyl" and "cycloalkyl" are defined herein. 3-4 Cycloalkyl C 1-3 Alkyl refers to C 3-4 Cycloalkyl substituted C 1-3 Alkyl groups, such as those termed "C 1-3 Alkyl" and "C 3-4 Each of "cycloalkyl" is defined herein.

[0042] As used herein and unless otherwise indicated, the term "heteroaryl" refers to a stable aromatic 5-, 6- or 7-membered monocyclic ring system or a stable 9- or 10-membered fused bicyclic ring system consisting of carbon atoms and one to four or one to three heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. In the case where the "heteroaryl" is a bicyclic group, the second ring need not contain heteroatoms and may be fused to the benzene ring. Thus, a bicyclic "heteroaryl" includes, for example, a stable 5- or 6-membered monocyclic aromatic ring consisting of carbon atoms and one to four or one to three heteroatoms as defined above fused to a benzene ring, or a second monocyclic "heteroaryl", or a "heterocyclyl", "cycloalkyl" or "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, pyrrolopyridine, imidazopyridine (such as imidazo[1,2-a]pyridine), pyrazolopyridine, pyrrolopyrimidine, and N-oxides thereof.

[0043] As used herein and unless otherwise indicated, the term "hydrate" 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.

[0044] As used herein and unless otherwise indicated, the term "in vivo" refers to a process or event that occurs in a living organism or living system.

[0045] As used herein and unless otherwise specified, the term "calcium oxalate stones" refers to crystalline material comprising calcium oxalate salts present as stones or plaques in the kidney, bladder, or urethra.

[0046] The term "hyperoxaluria" refers to a condition characterized by elevated oxalate levels in urine or plasma or the presence of kidney stones. In certain embodiments, hyperoxaluria is characterized by a urinary oxalate excretion rate greater than about 0.5 mmol / 1.73 m 2 / day, greater than about 0.7mmol / 1.73m 2 / day, greater than about 0.8mmol / 1.73m 2 , greater than about 1.0mmol / 1.73m 2 / day, greater than about 1.2mmol / 1.73m 2 / day or greater than about 2mmol / 1.73m 2 In certain embodiments, elevated oxalate levels refer to an oxalate excretion rate greater than normal urine excretion, which is less than about 0.45 mmol / 1.73 m 2 / day. In certain embodiments, the urine oxalate excretion rate is about two times higher than normal. In certain embodiments, the urine oxalate excretion rate is about four times higher than normal. In certain embodiments, hyperoxaluria is characterized by a urine oxalate / creatinine ratio greater than a reference range for age. In certain embodiments, hyperoxaluria is characterized by a glycolic acid / creatinine ratio greater than a reference range for age. Hyperoxaluria includes primary hyperoxaluria and secondary hyperoxaluria.

[0047] "Primary hyperoxaluria" refers to a condition characterized by excessive production of oxalate and / or production or functional defects of one or more enzymes that regulate oxalate levels in the body. In certain embodiments, primary hyperoxaluria is associated with a defective expression of alanine:glyoxylate aminotransferase (AGT) or a mutation in the gene AGXT encoding AGT, and can be classified as type 1 primary hyperoxaluria or PH1. In certain embodiments, primary hyperoxaluria is associated with a defective expression of glyoxylate reductase (GR) or a mutation in the gene (GRPHR) encoding GR, and it can be classified as type 2 primary hyperoxaluria or PH2. In other embodiments, primary hyperoxaluria is associated with a defective expression of 4-hydroxy-2-ketoglutarate aldolase (HOGA) or a mutation in the gene (HOGA1) encoding HOGA, and it can be classified as type 3 primary hyperoxaluria or PH3.

[0048] "Secondary hyperoxaluria" refers to a condition characterized by elevated oxalate levels in urine or plasma or the presence of kidney stones. Secondary hyperoxaluria includes enterogenic hyperoxaluria caused, for example, by increased dietary oxalate intake and intestinal absorption, excessive intake of oxalate precursors, and alterations in the intestinal microflora. Secondary hyperoxaluria also includes idiopathic hyperoxaluria of unknown etiology.

[0049] As used herein and unless otherwise indicated, the term "solvate" refers to a solvate formed by the association of one or more solvent molecules with a compound provided herein. The term "solvate" includes hydrates (eg, monohydrates, anhydrates, trihydrates, etc.).

[0050] The terms "treating", "treat" or "treatment" generally refer to the administration of one or more drug substances, particularly at least one compound of formula (I), to a patient suffering from a disease, disorder or condition, or suffering from symptoms or symptoms of a disease or disorder, or a predisposition to a disease or disorder, with the purpose of curing, healing, alleviating, altering, alleviating, improving, slowing the progression of, delaying the onset of, reducing the risk of, ameliorating or affecting the disease, disorder or condition, or one or more symptoms thereof, or susceptibility to the disease, disorder or condition, or its recurrence.

[0051] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to achieve a beneficial or desired clinical result. An effective amount can be administered in one or more administrations. An effective amount is generally sufficient to alleviate, ameliorate, stabilize, reverse, slow or delay the progression of a disease state or treat a disease, disorder or condition.

[0052] In the description herein, if there is any discrepancy between a chemical name and a chemical structure, the chemical structure shall prevail.

[0053] B. Compounds

[0054] In certain embodiments, provided herein are compounds having Formula (I):

[0055]

[0056] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0057] Y is O or S;

[0058] X 1 is hydrogen, fluorine or chlorine;

[0059] X 2 is hydrogen, fluorine or chlorine;

[0060] R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0061] R 3b is hydrogen, fluorine, chlorine, cyano or C 1-3 Haloalkyl;

[0062] R 3c is hydrogen, fluorine or chlorine;

[0063] R 3d is hydrogen, fluorine or chlorine;

[0064] R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl;

[0065] Provided that the compound is not selected from:

[0066]

[0067]

[0068] In certain embodiments, provided herein are compounds having Formula (I):

[0069]

[0070] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0071] Y is O or S;

[0072] X 1 is hydrogen, fluorine or chlorine;

[0073] X 2 is hydrogen, fluorine or chlorine;

[0074] R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0075] R 3b is hydrogen, fluorine, chlorine, cyano or C 1-3 Haloalkyl;

[0076] R 3c is hydrogen, fluorine or chlorine;

[0077] R 3d is hydrogen, fluorine or chlorine;

[0078] R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl;

[0079] The condition is (i) when R 3b is fluorine, R3a is methoxy and R 3c and R 3d are each hydrogen, or (ii) when R 3b is hydrogen, R 3a is isopropoxy and R 3c and R 3d are each hydrogen, or (iii) when R 3a , R 3b , R 3c and R 3d When all is hydrogen, then X 1 and X 2 is fluorine or chlorine; and provided that when R 3a It is CF3, R 3b is fluorine, and R 3c and R 3d When each is hydrogen, then R 10 Not cyclopropylmethyl.

[0080] In certain embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein the substituent R is selected 3a , R 3b , R 3c , R 3d , R 10 , X 1 and X 2 , so that (i) when R 3b is fluorine, R 3a is methoxy and R 3c and R 3d are each hydrogen, or (ii) when R 3b is hydrogen, R 3a is isopropoxy and R 3c and R 3d are each hydrogen, or (iii) when R 3a , R 3b , R 3c and R 3d When all is hydrogen, then X 1 and X 2 is fluorine or chlorine; and provided that when R 3a It is CF3, R 3b is fluorine, and R 3c and R 3d When each is hydrogen, then R 10 It is C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0081] In certain embodiments, provided herein are compounds of Formula (I):

[0082]

[0083] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0084] Y is O or S;

[0085] X 1 is fluorine or chlorine;

[0086] X 2 is hydrogen, fluorine or chlorine;

[0087] R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0088] R 3b is hydrogen, fluorine, chlorine, cyano or C 1-3 Haloalkyl;

[0089] R 3c is hydrogen, fluorine or chlorine;

[0090] R 3d is hydrogen, fluorine or chlorine; and

[0091] R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl.

[0092] In certain embodiments, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3b is fluorine or chlorine; R 3c is hydrogen, fluorine or chlorine; R 3d is hydrogen; and the other variables are as described elsewhere herein for Formula (I).

[0093] In certain embodiments, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3b is fluorine or chlorine; R 3c and R 3d each is hydrogen; and the other variables are as described elsewhere herein for Formula (I).

[0094] In certain embodiments, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b is fluorine or chlorine; R 3a , R 3c and R 3d each is hydrogen; and the other variables are as described elsewhere herein for Formula (I).

[0095] In certain embodiments, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a , R 3b , R 3c and R 3d is fluorine, chlorine or cyano, and R 3a , R 3b , R 3c and R 3d The remainder of is each hydrogen; and the other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a , R 3b , R 3c and R 3d is fluorine or chlorine, and R 3a , R 3b , R 3c and R 3d The remainder of is each hydrogen; and the other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a and R 3b One of them is fluorine, chlorine, cyano or C 1-3 Alkoxy; R 3a and R 3b The other of which is fluorine or hydrogen; R 3c and R 3d and other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a and R 3b One of them is fluorine, chlorine, cyano or isopropoxy; R 3a and R 3b The other of which is fluorine or hydrogen; R 3c and R 3d and other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a and R3b One of them is fluorine, chlorine or cyano; R 3a and R 3b The other of which is fluorine or hydrogen; R 3c and R 3d and other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein (i) R 3a is fluorine or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen, chlorine or C 1-3 Alkoxy; R 3b is fluorine or cyano; and R 3c and R 3d and other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein (i) R 3a is fluorine or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen, chlorine, methoxy or isopropoxy; R 3b is fluorine or cyano; and R 3c and R 3d and other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein (i) R 3a is fluorine or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen, chlorine, methoxy or isopropoxy; R 3b is fluorine or cyano; and R 3c and R 3d Each is hydrogen; X 1 is fluoro or chloro; and the other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein (i) R 3a is fluorine or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen or chlorine; R 3b is fluorine or cyano; and R 3c and R 3dand other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a and R 3b is fluorine or cyano, and R 3a and R 3b The other of which is hydrogen, methoxy or isopropoxy; R 3c and R 3d Each is hydrogen; X 1 is fluoro or chloro; and the other variables are as described elsewhere herein for Formula (I).

[0096] In certain embodiments, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a It is fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3b , R 3c and R 3d each is hydrogen; and the other variables are as described elsewhere herein for Formula (I).

[0097] In certain embodiments, provided herein are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3b is fluorine, chlorine, cyano or C 1-3 Haloalkyl; R 3a , R 3c and R 3d each is hydrogen; and the other variables are as described elsewhere herein for Formula (I).

[0098] In certain embodiments, provided herein are compounds of Formula (I) having Formula (Ia):

[0099]

[0100] or a pharmaceutically acceptable salt or solvate thereof.

[0101] In certain embodiments, provided herein are compounds of Formula (I) having Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0102] Y is O or S;

[0103] X 1 is hydrogen, fluorine or chlorine;

[0104] X 2 is hydrogen, fluorine or chlorine;

[0105] R 3aIt is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0106] R 3c is hydrogen or fluorine; and

[0107] R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; provided that when R 3a is methoxy and R 3c When it is hydrogen, then X 1 and X 2 is fluorine or chlorine; and provided that when R 3a is CF3, and R 3c When it is hydrogen, then R 10 Not cyclopropylmethyl.

[0108] In certain embodiments, provided herein are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein the substituent R is selected 3a , R 3c , R 10 , X 1 and X 2 , so that when R 3a is methoxy and R 3c When it is hydrogen, then X 1 and X 2 is fluorine or chlorine; and provided that when R 3a is CF3 and R 3c When it is hydrogen, then R 10 It is C 1-3 Alkyl or C 3-4 Cycloalkyl.

[0109] In certain embodiments, provided herein are compounds having Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluorine, chlorine, cyano or C 1-3 Alkoxy; X 1 is fluoro or chloro; and the other variables are as described elsewhere herein for Formula (I). In certain embodiments, provided herein are compounds of Formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a is hydrogen, fluorine, chlorine, cyano or isopropoxy; X 1 is fluoro or chloro; and the other variables are as described elsewhere herein for Formula (I).

[0110] In certain embodiments, provided herein are compounds of Formula (I) or (Ia) having Formula (Ib):

[0111]

[0112] or a pharmaceutically acceptable salt or solvate thereof.

[0113] In certain embodiments, provided herein are compounds of Formula (Ib), wherein R 3a is hydrogen, fluorine or chlorine; R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine or chlorine; and X 2 In certain other embodiments, provided herein is a compound of formula (Ib), wherein R 3a is hydrogen or fluorine; R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine or chlorine; and X 2 In certain other embodiments, provided herein is a compound of formula (Ib), wherein R 3a is hydrogen or fluorine; R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine; and X 2 In certain embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is hydrogen, fluorine, chlorine, cyano or difluoromethoxy, and the remaining variables are as described elsewhere herein for Formula (I) or (Ia). In certain embodiments, provided herein are compounds of Formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a is hydrogen, fluorine, chlorine, cyano or difluoromethoxy, R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine or chlorine; and X 2 In certain embodiments, provided herein is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3ais hydrogen, fluoro, chloro, cyano or isopropoxy, and the remainder of the variables are as described elsewhere herein for Formula (I) or (Ia).

[0114] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia) or (Ib), wherein R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Alkoxy or C 1-3 In certain embodiments, provided herein are compounds of Formula (I), (Ia) or (Ib), wherein R 3a is hydrogen, fluorine, chlorine, cyano or C 1-3 wherein the at least one alkyl group is a haloalkoxy group, and the other variables are as described elsewhere herein for Formula (I), (Ia) or (Ib).

[0115] In certain embodiments, provided herein are compounds of Formula (I), (Ia) or (Ib) having the formula (Ic):

[0116]

[0117] or a pharmaceutically acceptable salt or solvate thereof.

[0118] In certain embodiments, provided herein is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine or chlorine; and X 2 In certain embodiments, provided herein is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is S; R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine or chlorine; and X 2 In certain other embodiments, provided herein is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is O or S; R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine; and X 2In certain other embodiments, provided herein is a compound of formula (Ic), or a pharmaceutically acceptable salt or solvate thereof, wherein Y is S; R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 Alkyl; X 1 is fluorine; and X 2 It's hydrogen.

[0119] In certain embodiments, provided herein are compounds of formula (II):

[0120]

[0121] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0122] X 1 is hydrogen, fluorine or chlorine;

[0123] X 2 is hydrogen, fluorine or chlorine;

[0124] R 3a It is fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy;

[0125] R 3c is hydrogen, fluorine or chlorine; and

[0126] R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl.

[0127] In certain embodiments, provided herein are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluorine or chlorine and R 3c is fluorine or chlorine. In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluorine or chlorine; R 3c is fluorine or chlorine; X 1 is fluorine or chlorine; and X 2 In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a and R 3c In certain embodiments, provided herein are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R3a and R 3c All are fluorine; X 1 is fluorine or chlorine; and X 2 In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a , R 3c and X 1 is fluorine; and X 2 In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3c In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluorine, chlorine, cyano, CF3, methoxy, ethoxy or trifluoromethoxy and R 3c is hydrogen, fluorine or chlorine. In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluorine, chlorine, cyano, CF3, methoxy, ethoxy or trifluoromethoxy and R 3c is fluorine or chlorine. In certain embodiments, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 3a is fluorine, chlorine, cyano, CF3, methoxy, ethoxy or trifluoromethoxy; R 3c is fluorine or chlorine; X 1 is fluorine or chlorine; and X 2 It's hydrogen.

[0128] In certain embodiments, provided herein are compounds of formula (II) having formula (IIa)

[0129]

[0130] or a pharmaceutically acceptable salt or solvate thereof.

[0131] In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a It is fluorine, chlorine, cyano, C 1-3 Haloalkyl or C 1-3 In certain embodiments, provided herein are compounds of formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a is fluorine, chlorine, cyano, CF3 or trifluoromethoxy. In certain embodiments, provided herein are compounds of formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein R 3aIt is fluorine, chlorine, cyano, CF3, ethoxy or trifluoromethoxy.

[0132] In certain embodiments, provided herein are compounds of Formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a In certain embodiments, provided herein are compounds of formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein X 1 is fluorine or chlorine. In certain embodiments, provided herein are compounds of formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a is fluorine or chlorine and X 1 In certain embodiments, provided herein are compounds of formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein X 1 is fluorine or chlorine and X 2 In certain embodiments, provided herein are compounds of formula (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, wherein R 3a is fluorine or chlorine, X 1 is fluorine or chlorine and X 2 It's hydrogen.

[0133] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib) or (Ic), wherein Y is S, and the other variables are as described elsewhere herein for Formula (I), (Ia), (Ib) or (Ic) elsewhere herein.

[0134] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II), or (IIa), wherein R 10 It is C 3-4 Cycloalkyl C 1-3 alkyl, and the other variables are as described elsewhere herein for Formula (I), (Ia), (Ib), (Ic), (II) or (IIa).

[0135] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II), or (IIa), wherein R 10 is cyclopropylmethyl, and the other variables are as described elsewhere herein for Formula (I), (Ia), (Ib), (Ic), (II) or (IIa).

[0136] In yet certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II), or (IIa), wherein X 1is fluoro or chloro, and the other variables are as described elsewhere herein for Formula (I), (la), (lb), (Ic), (II) or (IIa).

[0137] In certain embodiments, provided herein is a compound of formula (I), wherein the compound is selected from:

[0138] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0139] 2-(3-(3-cyano-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0140] 2-(4-(3-Fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0141] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0142] 2-(5-(Cyclopropylmethyl)-3-(4-fluorophenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0143] 2-(5-(2-cyclopropylethyl)-3-(4-fluorophenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0144] 2-(5-(Cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0145] 2-(3-(3-chloro-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0146] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)oxazole-4-carboxylic acid;

[0147] 2-(4-(3-chloro-4-sulfamoylbenzyl)-5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0148] 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0149] 2-(5-(Cyclopropylmethyl)-3-(3,4-difluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0150] 2-(5-(Cyclopropylmethyl)-3-(3-(difluoromethoxy)-4-fluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0151] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0152] 2-(5-(Cyclopropylmethyl)-3-(3,5-difluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0153] 2-(3-(4-chlorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0154] 2-(3-(3-chlorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0155] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(trifluoromethyl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0156] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0157] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0158] 2-(5-(Cyclopropylmethyl)-3-(4-(difluoromethyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0159] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-(2,2,2-trifluoroethoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0160] 2-(3-(4-cyano-3-methoxyphenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0161] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0162] 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0163] 2-(5-(cyclopropylmethyl)-3-(3,5-dichlorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-

[0164] 1H-pyrazol-1-yl)thiazole-4-carboxylic acid;

[0165] 2-(5-(cyclopropylmethyl)-4-(3,5-difluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid; and

[0166] 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3,4,5-trifluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,

[0167] or a pharmaceutically acceptable salt or solvate thereof.

[0168] In certain embodiments, provided herein are isotopically enriched analogs, such as deuterated analogs, of the compounds disclosed herein to improve the pharmacokinetic (PK), pharmacodynamic (PD), and toxicity profiles of the compounds.

[0169] In certain embodiments, provided herein are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0170] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents are selected by one skilled in the art to provide stable moieties and compounds.

[0171] Compounds of the present disclosure include compounds themselves, and their salts, solvates, and solvates of salts (if applicable). Salts for the purposes of the present disclosure are preferably pharmaceutically acceptable salts of compounds of the present disclosure. Salts that are not suitable for pharmaceutical use per se but can be used, for example, to separate or purify compounds of the present disclosure are also included. For example, salts can be formed between anions and positively charged substituents (e.g., amino) on compounds described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, mesylate, trifluoroacetate, and acetate. Similarly, salts can also be formed between negatively charged substituents (e.g., carboxylates) on cations and compounds described herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium ions.

[0172] As used herein, "pharmaceutically acceptable salt" refers to acid or base addition salts, including but not limited to base addition salts formed by compounds of formula (I) having an acidic moiety and pharmaceutically acceptable cations such as sodium, potassium, magnesium, calcium, aluminum, lithium and ammonium.

[0173] Lists of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; SM Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19; and "Pharmaceutical Salts: Properties, Selection, and Use. A Handbook"; Wermuth, CG and Stahl, PH (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which is incorporated herein by reference in its entirety.

[0174] In the context of the present disclosure, solvates are designated as those forms of the compounds according to the present disclosure, which form complexes in the solid or liquid state by stoichiometric coordination with solvent molecules. Hydrates are a special form of solvates, in which coordination occurs with water. The formation of solvates is described in more 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 are incorporated herein by reference in their entirety.

[0175] In some embodiments, the compound of formula (I) exists in the form of a pharmaceutically acceptable salt. In some embodiments, the compound of formula (I) exists in the form of a free acid. In some embodiments, the compound of formula (I) exists in the form of a free acid. In some embodiments, the compound of formula (I) exists in the form of a solvate. In some embodiments, the solvate is a hydrate. In some embodiments, the compound of formula (I) exists in the form of a solvate in the form of a pharmaceutically acceptable salt.

[0176] The present disclosure also encompasses all suitable isotopic variants of the compounds according to the present disclosure, whether radioactive or not. Isotopic variants of the compounds according to the present disclosure are understood to mean compounds in which at least one atom within the compounds according to the present disclosure has been exchanged with another atom having the same atomic number but having an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into the compounds according to the present disclosure are those of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C. 14 C. 15 N. 17 O. 18 O. 18 F. 36 Cl, 82 Br, 123 I. 124 I. 125 I. 129 I and 131 I. Certain isotopic variations of the compounds according to the present disclosure, especially those into which one or more radioactive isotopes have been incorporated, can be useful, for example, in examining the mechanism of action or the distribution of the active compound in vivo. 3 H. 14 C and / or 18 F isotope-labeled compounds are suitable for this purpose. In addition, the incorporation of isotopes (e.g., deuterium) can lead to specific therapeutic benefits due to the greater metabolic stability of the compound, such as extending the half-life in vivo or reducing the required active dose. In some embodiments, the hydrogen atoms of the compounds described herein can be replaced by deuterium atoms. In certain embodiments, as applied to chemical groups and unless otherwise indicated, "deuterated" refers to a chemical group in which isotope enrichment is substantially greater than the deuterium of its natural abundance. Isotopic variants of 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 the corresponding isotope modification of a specific reagent and / or a starting compound.

[0177] In certain embodiments, the compounds provided herein have a tissue distribution feature that promotes liver targeting, and maximizes its exposure in the liver while minimizing the physicochemical properties of exposure in other tissues (e.g., plasma, muscle, spleen, testis). In certain embodiments, the compounds provided herein show tissue distribution features of liver targeting in rodents, which is demonstrated by greater drug exposure in the liver than in other tissues (e.g., plasma, muscle), such as 4h after PO administration or 24h after PO administration. In certain embodiments, the compounds provided herein have a physicochemical property of promoting the uptake of the OATP receptor subfamily expressed in the liver. OATP subfamily members OATP1B1, OATP1B3 and OATP2B1 are transporters mainly expressed on human hepatocytes, in which they mediate the uptake of substrates from the blood to the liver. Therefore, compared with systemic and peripheral tissues, OATP substrates are expected to have higher exposure in the liver. In certain embodiments, the compounds provided herein are substrates of OATP. In certain embodiments, the compound provided herein is a substrate of OATP1B1, OATP1B3, OATP2B1 or a combination thereof. In certain embodiments, the compound provided herein has a physicochemical property that minimizes the passive diffusion of the compound into off-target tissues lacking membrane transporters, thereby promoting liver selectivity. In certain embodiments, the octanol-water partition coefficient (XlogP) of the compound provided herein falls within the range of minimizing its passive diffusion potential, promoting liver targeting and reducing exposure to tissues outside the liver. In certain embodiments, the compound provided herein has a calculated octanol-water partition coefficient (XlogP) of about 4 to about 6.5. In certain embodiments, the compound provided herein has an XlogP of about 4 to about 6. In certain embodiments, the compound provided herein has an XlogP of about 4 to about 5.5. In certain embodiments, the compound provided herein has an XlogP of about 4 to about 5. In certain embodiments, the compound provided herein has an XlogP of about 4 to about 5. In certain embodiments, the compound provided herein has an XlogP of about 4 to about 5. In certain embodiments, the compound provided herein has an XlogP of about 4.5 to about 5.

[0178] C. Preparation

[0179] As used herein, the term "pharmaceutical composition" is intended to encompass products comprising active ingredients and inert ingredients constituting carriers, as well as any product obtained directly or indirectly by the combination, complexation or aggregation of any two or more ingredients, or by the dissociation of one or more ingredients, or by other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical composition of the present disclosure encompasses any composition prepared by mixing a compound of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of its salt, and a pharmaceutically acceptable carrier.

[0180] The term "pharmaceutically acceptable carrier" refers to a carrier or adjuvant that can be administered to a patient together with a compound of the present disclosure or a pharmaceutically acceptable salt, solvate, salt of a solvate, or prodrug thereof, and that does not destroy its pharmacological activity and is non-toxic when administered in a dose sufficient to deliver a therapeutic amount of the compound.

[0181] The amount administered depends on the compound formulation, route of administration, etc. and is usually determined empirically and will necessarily vary depending on the target, host, route of administration, etc. Typically, the amount of active compound in a unit dose formulation may vary or be adjusted from about 1 milligram (mg) to about 100 mg or from about 1 mg to about 1000 mg, depending on the specific application. For convenience, the total daily dose may be divided and administered in batches throughout the day.

[0182] Solid dosage forms of the pharmaceutical composition of the present invention 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 starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic, c) wetting agents such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, some silicates and sodium carbonate, e) solution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0183] 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 (milk sugar) and high molecular weight polyethylene glycols.

[0184] Solid dosage forms of the pharmaceutical compositions of the present invention in the form of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other pharmaceutical coatings. They may optionally contain opacifiers and may also be formulations that release the active ingredient only or preferably in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding pharmaceutical compositions that can be used include polymeric substances and waxes.

[0185] The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0186] Liquid dosage forms of the pharmaceutical composition of the present invention for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art (e.g., water or other solvents), solubilizers and emulsifiers (such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide), oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0187] Suspensions of the compounds of this invention, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0188] The pharmaceutical composition for injection disclosed herein comprises a pharmaceutically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion and a sterile powder for reconstructing into a sterile injectable solution or dispersion before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating material (such as lecithin), by maintaining the desired particle size in the case of a dispersion, and by using a surfactant.

[0189] In addition to inert diluents, these pharmaceutical compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, dispersants, sweeteners, flavoring agents and aromatics. Can be ensured to prevent the effect of microorganisms by adding various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugar, sodium chloride, etc. The extended absorption of injectable drug forms can be achieved by adding medicaments such as aluminum monostearate and gelatin that delay absorption. Compounds can be incorporated into sustained release or targeted delivery systems such as polymer matrix, liposomes and microspheres. Such preparations can provide more effective compound distribution.

[0190] Pharmaceutical compositions for injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0191] Dosage forms for topical administration of the compounds or pharmaceutical compositions 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 that may be required.

[0192] The compounds and compositions described herein can be administered, for example, in a range of about 0.01 milligrams per kilogram (mg / kg) to about 1000 mg / kg (e.g., about 0.01 to about 100 mg / kg, about 0.1 to about 100 mg / kg) every 4 to 120 hours or orally, parenterally (e.g., subcutaneously, intradermally, intravenously or intramuscularly), topically, rectally, nasally, sublingually or orally according to the requirements of a particular drug, dosage form and / or route of administration. Other routes of administration include enteral, intraarterial, intraperitoneal and intrathecal administration. The interrelationship of doses for animals and humans (based on milligrams per square meter of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219-244 (1966). Body surface area can be approximately determined based on the height and weight of the patient. See, for example, Scientific Tables, Geigy Pharmaceuticals, Ardsley, NY, 537 (1970). In certain embodiments, the composition is administered by oral administration or injection. The methods herein contemplate administering an effective amount of a compound or compound composition to achieve a desired or described effect. Typically, the pharmaceutical compositions of the present disclosure will be administered from about 1 to about 6 times per day, or alternatively administered as a continuous infusion. Such administration can be used as a chronic or acute treatment.

[0193] Lower or higher doses than those recited above may be required. The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition or symptom, the patient's predisposition to the disease, and the judgment of the treating physician.

[0194] The dosage form includes about 0.001 mg to about 2,000 mg (including about 0.001 mg to about 1,000 mg, about 0.001 mg to about 500 mg, about 0.01 mg to about 250 mg) of a compound of formula (I) as defined elsewhere herein, or a salt thereof (e.g., a pharmaceutically acceptable salt). The dosage form may also include a pharmaceutically acceptable carrier and / or an additional therapeutic agent.

[0195] Suitable dosage levels can be determined by any suitable method. Preferably, for topical application, the active substance is applied at a frequency of 1 to 4 times per day, or if a drug delivery system is used, the frequency is lower. However, the actual dosage level and the application time course of the active ingredient in the pharmaceutical composition of the present disclosure can vary, to obtain an amount of the active ingredient that effectively achieves the desired therapeutic response of a specific patient, composition and mode of administration without intolerable toxicity to the patient. In some cases, the dosage may deviate from the amount, particularly with the patient's age, sex, body weight, diet and general health, route of administration, individual response to the active ingredient, the nature of the preparation and the time or interval at which the application occurs. Therefore, in some cases, it is satisfactory to manage with less than the above-mentioned minimum amount, and in other cases, the upper limit may be exceeded. In the case of applying a larger amount, it may be recommended to divide these into multiple individual doses distributed within a day.

[0196] D. Evaluation of compound activity

[0197] Standard physiological, pharmacological, and biochemical procedures can be used to test compounds to identify those that possess biological activity as LDH inhibitors.

[0198] Biochemical assays include a recombinant human LDH enzyme assay, in which purified recombinant human lactate dehydrogenase A (LDHA) is incubated with a test compound, the substrate pyruvate, and the coenzyme NADH+, and its enzymatic activity is measured by the formation of NAD upon conversion of pyruvate to lactate.

[0199] LDH inhibitors can also be evaluated in an ex vivo assay consisting of primary mouse hepatocytes. After isolation, viable wild-type mouse hepatocytes are incubated with the test compound in the presence of pyruvate. The potency of the compound in modulating LDH enzyme activity is then assessed by measuring the conversion of pyruvate into lactate by the cells.

[0200] Genetically engineered mice deficient in alanine-glyoxylate aminotransferase, such as AGT knockout mice - / - It can also be used as a primary hyperoxaluria model. In addition, silencing of AGT liver expression can be achieved by sustained liver-targeted RNA interference in wild-type rats and mice. In some specific cases, the model may also require saturation of the glycolate metabolic pathway by long-term exposure to ethylene glycol or sodium glycolate. In all cases, the efficacy of the test compound is evaluated by its efficacy in reducing urinary oxalate or glycolate load [primary endpoint], which is expressed as the oxalate / creatinine ratio or as the total amount of oxalate excreted during 24 hours. Other endpoints may be considered, including histological assessment of renal structural integrity and the presence of calcium oxalate crystal deposition, as well as renal function evaluation (e.g., estimated glomerular filtration rate or eGFR).

[0201] E. How to use

[0202] LDH inhibitors can prove to be effective for diseases caused by increased oxalate or diseases in which oxalate reduction may be beneficial. An example is primary hyperoxaluria, which is caused by excessive production of oxalate, for example, due to the excessive production or accumulation of its precursor glyoxylate. Therefore, provided herein is a method for treating or preventing a disease or condition associated with elevated oxalate levels. Diseases or conditions associated with elevated oxalate levels include hyperoxaluria, chronic kidney disease (CKD), end-stage renal disease (ESRD) or kidney stone disease. In certain embodiments, hyperoxaluria is associated with various digestive or intestinal diseases, such as Crohn's disease, Hirschsprung's disease, cystic fibrosis and chronic biliary or pancreatic lesions. In certain embodiments, hyperoxaluria is associated with bariatric surgery and ileal resection. In certain embodiments, chronic kidney disease is associated with previous attacks of diabetes, hypertension, acute kidney injury, cardiovascular disease or dyslipidemia. In certain embodiments, the kidney stone disease is idiopathic kidney stone disease, or the kidney stone disease associated with hyperparathyroidism or other calcium metabolism disorders. In certain embodiments, the oxalate level of elevation is associated with diabetes, obesity or metabolic syndrome (MS). The compounds and compositions provided herein can be used to treat or prevent hyperoxaluria, including primary hyperoxaluria and subtypes PH1, PH2 and PH3, and secondary hyperoxaluria, including enterogenic hyperoxaluria and idiopathic hyperoxaluria. The compounds and compositions provided herein can be used to treat calcium oxalate stone formation, such as in the kidney, urethra or bladder, to treat calcium oxalate deposition (systemic oxalate excess) in other tissues and organs outside the kidney, or to prevent or delay the onset of renal injury or chronic kidney disease (CKD) or end-stage renal disease (ESRD).

[0203] In certain embodiments, elevated oxalate levels refer to a urinary oxalate excretion rate greater than about 0.5 mmol / 1.73 m 2 / day, greater than about 0.7mmol / 1.73m 2 / day, greater than about 0.8mmol / 1.73m 2 / day, greater than about 1.0mmol / 1.73m 2 / day, greater than about 1.2mmol / 1.73m 2 / day or greater than about 2mmol / 1.73m 2 / day. In certain embodiments, elevated oxalate levels refer to a urine oxalate excretion rate that is greater than normal urine oxalate excretion. In certain embodiments, normal urine oxalate excretion is less than about 0.45 mmol / 1.73 m 2 / day, less than about 0.46mmol / 1.73m 2 / day or less than about 0.5mmol / 1.73m 2 / day. In certain embodiments, elevated oxalate levels mean a urine oxalate excretion rate greater than about 40 mg / day. In certain embodiments, elevated oxalate levels mean a urine oxalate excretion rate greater than about 45 mg / day. In certain embodiments, the urine oxalate excretion rate is about twice as high as normal. In certain embodiments, the urine oxalate excretion rate is about four times higher than normal. In certain embodiments, elevated oxalate levels mean a normal plasma oxalate level of plasma oxalate greater than about 1 μmol / L to about 3 μmol / L. In certain embodiments, elevated oxalate levels mean a plasma oxalate level equal to or greater than about 10 μmol / L. In certain embodiments, elevated oxalate levels mean a plasma oxalate level equal to or greater than about 20 μmol / L.

[0204] The method for treating primary hyperoxaluria can include the step of selecting a patient with a potential genetic mutation of PH1, PH2 or PH3, for example, before administering any compound or composition provided herein, using a diagnostic test to detect the presence of a mutation in the AGXT, GRHPR, HOGA1 gene, or detecting the expression level or activity of the AGXT, GRHPR, HOGA1 gene. Prior to administering a compound or composition provided herein, a patient with hyperoxaluria can also be diagnosed by a kidney stone biopsy, measuring the levels of oxalate, calcium, citrate, sodium, magnesium, urate, urine pH and urine volume in urine, or any combination of such measurements.

[0205] The efficacy of a medicament can be measured in a patient by, for example, a reduction in plasma or urine oxalate over the course of days, weeks, months, or years. Plasma and urine oxalate can be measured in a patient in several ways, including the concentration or milligrams of oxalate, the moles of oxalate, or the concentration of oxalate in a biological medium (urine or plasma). In addition, oxalate can be normalized to other proteins (such as creatinine), or assessed within 24 hours, and / or normalized based on age, body weight, or body surface area.

[0206] In certain embodiments, provided herein is a method for treating a disease or condition associated with an elevated oxalate level, comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, the elevated oxalate level is an elevated urine oxalate level. In certain embodiments, the elevated oxalate level is an elevated plasma oxalate level. In certain embodiments, the disease or condition is hyperoxaluria, chronic kidney disease (CKD), end-stage renal disease (ESRD), or kidney stone disease. In certain embodiments, the disease or condition associated with an elevated oxalate level is hyperoxaluria. In certain embodiments, hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria. In certain embodiments, the disease or condition associated with an elevated oxalate level is primary hyperoxaluria, idiopathic hyperoxaluria, or idiopathic oxalate kidney stone disease. In certain further embodiments, primary hyperoxaluria is primary hyperoxaluria type 1 (PH-1), primary hyperoxaluria type 2 (PH-2), or primary hyperoxaluria type 3 (PH-3). In certain further embodiments, the disease or disorder associated with elevated oxalate levels is associated with AGXT, GRHPR, or HOGA1 mutations, or a combination of mutations thereof.

[0207] In certain embodiments, provided herein is a method for treating hyperoxaluria, comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, provided herein is a method for treating hyperoxaluria, chronic kidney disease (CKD), end-stage renal disease (ESRD), or kidney stone disease, comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0208] In certain embodiments, provided herein are methods for treating primary hyperoxaluria type 1 (PH-1), primary hyperoxaluria type 2 (PH-2), or primary hyperoxaluria type 3 (PH-3), comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods for treating a disease or condition associated with a mutation in AGXT, GRHPR or HOGA1, or a combination of mutations thereof, comprising administering to a subject suffering from such a disease or condition a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0209] In certain embodiments, provided herein are methods of reducing oxalate levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. In certain embodiments, provided herein are methods of treating kidney stone formation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0210] In certain embodiments, provided herein is a compound of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for use in treating a disease or condition associated with elevated oxalate levels.

[0211] In certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, for use in treating hyperoxaluria. In certain embodiments, provided herein are compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, for use in treating hyperoxaluria, chronic kidney disease (CKD), end-stage renal disease (ESRD), or kidney stone disease.

[0212] In certain embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, can be used in a variety of combination therapies to treat the above-mentioned conditions, diseases and disorders. Therefore, the use of compounds of Formula (I), (Ia), (Ib), (Ic), (II) or (IIa), or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, in combination with additional agents for treating the conditions, diseases and disorders described herein is also contemplated herein. Additional agents that can be used to co-administer with the compounds or compositions provided herein include, for example, additional agents that reduce glyoxylate or oxalate levels, such as RNAi therapeutics targeting GO expression (e.g., lumasiran (ALN-GO1), Alnylam's GalNAc-siRNA conjugate targeting GO), RNAi therapeutics targeting LDHA (e.g., nedocilan, Dicerna's GalNAc-siRNA conjugate targeting LDHA), other inhibitors in the oxalate synthesis pathway (e.g., stiripentol, a weak LDH inhibitor), or agents capable of reducing exogenous oxalate, such as oxalate decarboxylase (e.g., reloxaliase, formerly ALLN-177) or the oxalate-degrading bacteria, oxalobacter formigenes (e.g., The compounds or compositions provided herein can also be administered in conjunction with dietary changes such as increased water consumption or avoidance of foods rich in oxalic acid. The compounds of the compositions provided herein can also be co-administered with vitamin B6 (pyridoxine).

[0213] In certain embodiments, provided herein is a method for treating a disease or condition as described herein, which further comprises administering a therapeutically effective amount of a second therapeutic agent to a subject in need thereof. In certain embodiments, the second therapeutic agent is a glyoxylate or oxalate reduction therapeutic agent. In certain embodiments, the glyoxylate or oxalate reduction therapeutic agent is an RNAi therapeutic agent. In certain embodiments, the glyoxylate or oxalate reduction therapeutic agent is lumacillan, nedoxalan, reloxalase, stiripentol, oxalobacterium formigenes, or vitamin B6.

[0214] F. Preparation of Compounds

[0215] Starting materials 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, etc. Nuclear magnetic resonance (NMR) analysis was performed using a Bruker Acuity 300 MHz or 400 MHz spectrometer with appropriate deuterated solvents. NMR chemical shifts (δ) are expressed in parts per million (ppm). LCMS analysis was performed 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 in 3.5 minutes at a flow rate of 0.6 mL / min. Or use Shimadzu LCMS-2020, use AscentisExpress C18 2.7 μ m, 3.0 × 50 mm column, 95: 5 to 0: 100H2O: MeCN + 0.05% trifluoroacetic acid in 3.0 minutes with a flow rate of 1.5 mL / min elution. Set the MS detector to scan under positive and negative mode ions in the range of 100-1200 Daltons. The general method for preparing compounds can be modified using appropriate reagents and conditions for introducing various parts found in the structure provided herein.

[0216] Although preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Without departing from the present disclosure, those skilled in the art will now appreciate that many variations, changes, and substitutions may be made. Various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the present disclosure. The following claims are intended to define the scope of the present disclosure, and thus cover methods and structures within the scope of these claims and their equivalents.

[0217] This article uses standard abbreviations and acronyms as defined in the Journal of Organic Chemistry's Author's Guideline, available at https: / / pubs.acs.org / userimages / ContentEditor / 1218717864819 / joceah_abbreviations.pdf Other abbreviations and acronyms used in this article are as follows:

[0218] Table 1: Abbreviations

[0219]

[0220]

[0221] General synthetic scheme

[0222] In some embodiments, the compounds described herein can be prepared as outlined in the following general synthetic schemes.

[0223] Method A: S N Ar reaction

[0224]

[0225] The pyrazole intermediate A-1 is reacted with a halo or methylsulfonyl-heteroaryl carboxylate A-2 via S N Ar reaction to obtain the desired N-arylated product, followed by ester hydrolysis to obtain the corresponding formic acid target A-3.

[0226] Method B: Borylation of bromopyrazole and Suzuki coupling

[0227]

[0228] The bromopyrazole intermediate B-1 can undergo Miyaura borylation reaction in the presence of Pd catalyst and B2pin2 or HBpin as a source of pinacol boronate to give the desired borylated pyrazole product B-2. In some cases, the borylated pyrazole can be subjected to a continuous Suzuki coupling reaction with 4-bromomethyl-benzenesulfonamide B-3 in a one-pot process. Alternatively, the borylated pyrazole B-2 is isolated before the Suzuki coupling with 4-bromomethyl-benzenesulfonamide B-3. The coupling product can be hydrolyzed under ester saponification conditions to give the final formic acid product B-4.

[0229] Method C: Suzuki coupling of pyrazole triflates

[0230]

[0231] The trifluoromethanesulfonylpyrazole intermediate C-1 is reacted with various arylboronic acids or esters (C-2) via a Pd-catalyzed coupling reaction to directly obtain 2-arylpyrazoles. This step is followed by ester hydrolysis to give the corresponding formic acid target C-3.

[0232] G. Examples

[0233] Preparation of intermediates

[0234] Intermediate A: Preparation of ethyl 2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0235]

[0236] Step 1: Preparation of ethyl 2-hydrazinothiazole-4-carboxylate hydrobromide

[0237] At 23 ° C, 3-bromo-2-oxopropanoic acid ethyl ester (1.0 equivalent) was added to a stirred solution of N-(thiocarbamoylamino)acetamide (1.0 equivalent) in EtOH (0.3M). The mixture was stirred at this temperature for 30 minutes and then heated to reflux for 2h. The resulting mixture was concentrated under vacuum. The residue was purified by grinding with MeOH / EtO (1 / 6, v / v) to obtain the title product (49% yield) as a yellow solid.

[0238] Step 2: Preparation of 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-cyclopropylethan-1-one

[0239] At 23 ° C, thionyl chloride (1.0 equiv.) was added dropwise to a stirred solution of benzotriazole (4.0 equiv.) in CH2Cl2 (0.3 M). The resulting mixture was stirred at this temperature for 30 minutes. Cyclopropylacetic acid (1.0 equiv.) was added dropwise to the mixture. The mixture was stirred for another 6 h. The resulting suspension was filtered. The filtrate was washed with saturated NaHCO3 aqueous solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give the title product (63% yield, LCMS purity 72%) as a red oil, which was used directly in the next step without further purification.

[0240] Step 3: Preparation of 1-(3-bromo-4-fluorophenyl)-4-cyclopropylbutane-1,3-dione

[0241] To a stirred mixture of 1-(1,2,3-benzotriazole-1-yl)-2-cyclopropylethanone (1.0 equiv.) in CH2Cl2 (0.3 M) was added ethereal magnesium bromide (2.5 equiv.) and 1-(3-bromo-4-fluorophenyl)ethanone (1.0 equiv.) at 23 °C. The resulting mixture was stirred at this temperature for 10 minutes. N,N-diisopropylethylamine (3.0 equiv.) was added dropwise to the mixture. The resulting mixture was stirred for another 2 h. The mixture was acidified with 1M HCl aqueous solution until the pH was ~1, and the mixture was extracted with CH2Cl2 (3×3 volumes). The organic layers were combined, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography with 0% to 5% EtOAc in petroleum ether as a gradient elution to give the title product as a yellow solid (51% yield).

[0242] Step 4: Preparation of 4-(2-(3-bromo-4-fluorobenzoyl)-4-cyclopropyl-3-oxobutyl)-2-fluorobenzenesulfonamide

[0243] A mixture of 1-(3-bromo-4-fluorophenyl)-4-cyclopropylbutane-1,3-dione (1.0 equiv.), 4-(bromomethyl)-2-fluorobenzenesulfonamide (1.1 equiv.), CsCO (1.5 equiv.) and potassium iodide (1.0 equiv.) in DMSO (1.1 M) was stirred at 23 °C for 2 h and then diluted with EtOAc. The organic layer was washed with 1 M aqueous HCl, brine, dried over NaSO, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 0% to 30% EtOAc in petroleum ether to give the title product as a yellow solid (64% yield).

[0244] Step 5: Preparation of ethyl 2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0245] At 23 ° C, 4- [2- (3-bromo-4-fluorobenzoyl) -4-cyclopropyl -3-oxobutyl] -2-fluorobenzenesulfonamide (1.0 equiv) was added to a stirred solution of EtOH (0.2M) pyrrolidine (0.3 equiv) and p-toluenesulfonic acid (0.5 equiv). The resulting mixture was stirred at this temperature for 30 minutes. To the mixture was added 2-hydrazino-1,3-thiazole-4-carboxylic acid ethyl ester dihydrobromide (1.2 equiv). The reaction was stirred at 80 ° C for 2h under nitrogen. After the reaction was completed, the mixture was concentrated under vacuum. The residue was purified by C18 reverse phase column chromatography with 95: 5 to 15: 85H2O: MeCN + 0.1% formic acid as a gradient elution to give the title product as a light yellow solid (15% yield).

[0246] Intermediate B: Preparation of ethyl 2-(3-(3-bromophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0247]

[0248] Intermediate B was prepared in the same manner as Intermediate A above, starting with 3-bromoacetophenone as the starting material.

[0249] Intermediate C: Preparation of 4-(bromomethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0250]

[0251] Step 1: Preparation of 4-(bromomethyl)-2-fluorobenzenesulfonyl chloride

[0252] N-bromosuccinimide (1.1 equivalents), 2,2'-azobis(2-methylpropionitrile) (0.1 equivalents) were added to a degassed solution of 2-fluoro-4-methyl-benzenesulfonyl chloride (1.0 equivalents) in MeCN (0.4M), and the mixture was heated to 80 ° C in an oil bath for 8 hours. The mixture was concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography using 0 to 10% EtOAc in hexane as a gradient elution. The selected fractions were monitored by TLC (EtOAc: hexane 1: 9, UV). The desired fractions from the main peak eluted with 7% EtOAc in hexane as the center were combined and concentrated to give the title compound (53% yield) as a white crystalline solid.

[0253] Step 2: Preparation of 4-(bromomethyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0254] To a solution of 4-(bromomethyl-2-fluorobenzenesulfonyl chloride (1.0 eq) in CHCl (0.3 M) under nitrogen and cooled in a dry ice / acetone bath was added N-(4-methoxybenzyl)-1-(4-methoxyphenyl)methanamine (1.0 eq). Once cooled, diisopropylethylamine (1.1 eq) was added portionwise over 10 min, and the mixture was stirred in the dry ice / acetone bath for 30 min. After this time, the cooling bath was replaced with a salt / wet ice bath (-10° C.), and stirring was continued for 2 h. The mixture was quenched with ice (1 vol), water (1 vol), and then extracted with CHCl (2×1 vol). The combined organic extracts were washed with water (0.25 vol), dried over MgSO, filtered, and concentrated under vacuum to give an oil. The resulting oil was dissolved in CHCl (0.1 vol), applied to a silica gel pre-column, and purified by silica gel column chromatography using 0-20% Purification by EtOAc in CH2Cl2 as a gradient elution gave the title compound as a white solid (73% yield).

[0255] Intermediate D: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0256]

[0257] Step 1: Preparation of ethyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-4-cyclopropyl-3-oxobutanoate

[0258] To a suspension of ethyl 4-cyclopropyl-3-oxobutanoate (1.2 equiv.), 4-(bromomethyl)-2-fluoro-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide (Intermediate C, 1.0 equiv.) and lithium bromide (0.4 equiv.) in THF (0.2M) was added N,N-diisopropylethylamine (2.0 equiv.). The mixture was stirred at reflux for 6 hours. The mixture was cooled to 23 ° C and distributed between saturated NH4Cl aqueous solution (0.6 volume), water (0.6 volume) and EtOAc (2×1 volume). The combined extracts were washed with brine (0.3 volume) and then concentrated under vacuum. The oil was purified by silica gel column chromatography with 0-40% EtOAc in hexane as a gradient elution. The desired fractions were combined and concentrated under vacuum to give the title compound (77% yield) as a colorless oil.

[0259] Step 2: Preparation of 4-((5-(cyclopropylmethyl)-3-hydroxy-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0260] To a solution of ethyl 2-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-4-cyclopropyl-3-oxobutanoate (1.0 equiv) in ethanol (0.22 M) was added hydrazine hydrate (2.0 equiv). The mixture was heated to 70 °C for 2.5 hours. The solution was cooled to 23 °C to give a white solid. The solid was filtered, washed with hexanes (0.2 vol) and dried under vacuum for 18 hours to give the title compound as a white solid (86% yield).

[0261] Step 3: Preparation of 4-((1-acetyl-5-(cyclopropylmethyl)-3-hydroxy-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0262] To a solution of 4-((5-(cyclopropylmethyl)-3-hydroxy-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide (1.0 equiv) in pyridine (0.23 M) was added acetic anhydride (0.98 equiv) and the mixture was heated to 90 °C for 48 hours. The mixture was concentrated under reduced pressure. The resulting oil was partitioned between saturated aqueous NH4Cl solution (1.5 vol) and EtOAc (2 x 1.5 vol). The combined extracts were washed with brine (0.5 vol), dried over MgSO4, filtered and concentrated under vacuum to give a red oil. The oil was purified by silica gel column chromatography using a gradient of 0-30% EtOAc + 1% MeOH in CH2Cl2 followed by 100% EtOAc. Fractions from the main peak eluted with 9% EtOAc in CH2Cl2 were combined and concentrated under vacuum to give the title compound as a white solid (63% yield). Fractions from the peak eluted with 20% EtOAc in CH2Cl2 were combined to give isomeric acetates (17% yield), and fractions from the peak eluted with 100% EtOAc were combined to give the recovered starting compound (13% recovered starting material).

[0263] Step 4: Preparation of 4-((1-acetyl-5-(cyclopropylmethyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0264] A solution of 4-((1-acetyl-5-(cyclopropylmethyl)-3-hydroxy-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide (1.0 eq) in DMF (0.15 M) was cooled in an ice bath. Solid cesium carbonate (2.0 eq) was added followed by 2-(trimethylsilyl)ethoxymethyl chloride (1.5 eq). The mixture was stirred in an ice bath for 30 minutes and then at 23 °C for 1 hour. The resulting mixture was quenched with crushed ice (0.5 vol), diluted with saturated aqueous NH4Cl solution (0.5 vol) and water (0.5 vol), and extracted with diethyl ether (2 x 1.5 vol). The combined organic extracts were washed with brine and concentrated under vacuum. The resulting oil was purified by silica gel column chromatography eluting with 0-50% EtOAc in hexanes as a gradient increasing to 100% EtOAc at the end of the purification. Fractions from the main peak eluting with 40% EtOAc in hexanes were combined and concentrated in vacuo to give the title compound as a gold oil (93% yield).

[0265] Step 5: Preparation of 4-((5-(cyclopropylmethyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0266] To a solution of 4-((1-acetyl-5-(cyclopropylmethyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide (1.0 equiv) in THF / MeOH (1:1 v / v) (0.27 M) was added 1 M aqueous lithium hydroxide solution (1.25 equiv) dropwise via addition funnel. The mixture was stirred at 23 °C for 30 min. The mixture was cooled in an ice bath and 1 M aqueous HCl solution (1.1 equiv) was added dropwise via addition funnel. The mixture was further treated with saturated aqueous NH4Cl solution (1 vol) and extracted with EtOAc (2 x 2 vols). The combined extracts were washed with brine (1 vol), dried over MgSO4, filtered and concentrated. The material was dried under vacuum to give the title compound as a golden viscous oil (95% yield).

[0267] Step 6: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0268] To a solution of 4-((5-(cyclopropylmethyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)methyl)-2-fluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide (1.0 equiv) in DMF (0.18 M) under nitrogen and cooled in an ice bath was added sodium tert-amylate (1.2 equiv) in portions. The mixture was stirred at this temperature for 5 minutes. Thereafter, ethyl 2-fluorothiazole-4-carboxylate (1.1 equiv) was added. The resulting mixture was stirred in an ice bath for 15 minutes and then at 23° C. for 20 minutes. LCMS analysis indicated that starting material remained. The reaction mixture was cooled again in an ice bath. Sodium tert-amylate (0.15 equiv) was added and the mixture was stirred in an ice bath for 15 minutes and then warmed at 23° C. with stirring for 20 minutes. The mixture was distributed between ether (2 x 2 volumes) and water (1 volume) and then between saturated NH4Cl aqueous solution (1 volume). The combined organic extracts were concentrated under vacuum. The crude oil was passed through a silica gel column and purified using a 5-40% EtOAc in hexane solution as a gradient elution, which was then increased to 100% EtOAc at the end of the purification. The fractions from the early peak eluted with a 10% EtOAc in hexane solution and the large broad peak centered with a 30% EtOAc in hexane solution were combined and concentrated under vacuum to obtain the title compound (80% yield) as a sticky solid.

[0269] Step 7: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-hydroxy-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0270] To a solution of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 eq) in CHCl (0.42 M) at 23°C was added triethylsilane (5.0 eq) and trifluoroacetic acid (78 eq) and the mixture was stirred at 23°C for 5 hours. The resulting mixture was concentrated under vacuum to give a white solid. The crude solid was suspended in CHCl (3.5 vol) and stirred at 23°C for 16 hours. The mixture was filtered, washed with CHCl (2 vol) and dried under vacuum to give the title compound as a white solid (62% yield). The filtrate was concentrated under vacuum. The resulting crude filtrate was purified by column chromatography on silica gel eluting with a 0-15% MeOH in CH2Cl2 gradient to afford additional title compound as a white solid (33% yield). The combined total yield was 95%.

[0271] Step 8: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0272] To a suspension of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-hydroxy-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 eq.) in CHCl (0.1 M) was added N,N-diisopropylethylamine (1.5 eq.). The mixture was stirred at 23 °C for 15 min until all solids dissolved. The solution was cooled on a dry ice / acetone bath for 10 min, then trifluoromethanesulfonic anhydride (1.3 eq.) was added slowly over 5 min. The mixture was stirred in a dry ice / acetone bath for 15 min, then warmed in a wet ice bath and stirred at this temperature for an additional 30 min. The resulting solution was poured onto crushed ice (1 vol), diluted with saturated aqueous NHCl (4 vols.) and extracted with CHCl (2 x 2 vols.). The combined organic layers were washed with water (0.5 vol.) and concentrated under vacuum. The resulting oil was purified by silica gel column chromatography eluting with a gradient of 5-100% EtOAc + 10% MeOH in CH2Cl2. Fractions from the main peak eluting with 55% EtOAc in CH2Cl2 were combined and concentrated in vacuo to give the title compound as a white solid (74% yield).

[0273] Intermediate E: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0274]

[0275] Step 1: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0276] To a round bottom flask equipped with a magnetic stir bar and under nitrogen was added ethyl 2-(3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (Intermediate A, 1.0 eq.), 4-methoxybenzyl chloride (2.5 eq.) and DMF (0.16 M). The mixture was cooled in an ice bath and sodium hydride (60% dispersion in mineral oil, 2.5 eq.) was added portionwise to the cooled mixture. The reaction mixture was stirred cold for 10 minutes and then stirred at 23° C. for 2 hours. The mixture was partitioned between EtOAc (2×5 volumes) and water (4 volumes) and the combined organic layers were concentrated under vacuum. The crude oil was directly loaded onto a silica gel pre-column and purified by column chromatography on a silica gel column eluting with a 0-100% EtOAc in hexanes gradient. Fractions from the major peak eluting with 60% EtOAc in hexanes were concentrated in vacuo to give the title compound as an oil (76% yield).

[0277] Step 2: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0278] To a degassed mixture of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv), bis(pinacol)diboron (2.0 equiv), Pd(dppf)Cl2.CH2Cl2 (0.1 equiv) in dioxane (0.2 M) was added potassium acetate (4.0 equiv). The mixture was heated to 100°C for 4 hours. The mixture was diluted with EtOAc (4 vol), filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with a 0-50% EtOAc in hexanes gradient. Fractions from the major peak eluting with 45% EtOAc in hexanes were combined and concentrated in vacuo to give the title compound as a solid (76% yield).

[0279] Step 3: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0280] To a suspension of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv) in methanol (0.07 M) and DMF (0.07 M) was added urea-hydrogen peroxide adduct (2.0 equiv). The mixture was stirred at 23 °C for 21 hours. The mixture was concentrated under vacuum to remove MeOH. The solution was partitioned between saturated aqueous NH4Cl (2 vols), water (2 vols) and EtOAc (2 x 10 vols). The combined organic layers were concentrated under vacuum to give a crude oil. The crude product was purified by column chromatography on silica gel eluting with a gradient of 0-70% EtOAc in hexanes. Fractions from the main peak eluting with 55% EOAc in hexanes were combined and concentrated in vacuo to give the title compound as a clear viscous oil (95% yield).

[0281] Intermediate F: Preparation of 4-cyclopropyl-1-(4-fluorophenyl)butane-1,3-dione

[0282]

[0283] Step 1: Preparation of 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-cyclopropylethan-1-one

[0284] Benzotriazole (4.0 equivalents) and CH2Cl2 (0.3M) were added to a round-bottom flask equipped with a magnetic stirring bar and under N2. The resulting clear solution was cooled to 0°C in an ice bath, and thionyl chloride (1.0 equivalents) was added dropwise to the cooled solution within 10 minutes. The resulting light yellow solution was warmed and stirred at 23°C for 1h, then cooled to 0°C in an ice bath. Cyclopropylacetic acid (1.0 equivalents) was added once, and the resulting white suspension was stirred at 23°C for 16h overnight. The resulting white suspension was filtered under vacuum through Whatman#1 filter paper on a Hersch funnel and washed with CH2Cl2 (3×5 volumes). The clear filtrate was concentrated under reduced pressure, loaded onto a silica gel pre-column, and dried under vacuum. The mixture was purified by silica gel column chromatography using 95:5 to 50:50 hexane:EtOAc as a gradient elution within 25 minutes, collecting all peaks. Fractions containing the desired product were concentrated and dried under vacuum to give a clear oil which slowly crystallized upon standing (81% yield).

[0285] Step 2: Preparation of 4-cyclopropyl-1-(4-fluorophenyl)butane-1,3-dione

[0286] 1-(Benzotriazole-1-yl)-2-cyclopropyl-ethanone (1.2 eq.), 4'-fluoroacetophenone (1.0 eq.) and CH2Cl2 (0.3 M) were added to a round-bottom flask equipped with a magnetic stirring bar. The mixture was cooled to 0°C in an ice bath. Ether magnesium bromide (2.5 eq.) was added in one go with stirring. N,N-diisopropylethylamine (3.0 eq.) was added dropwise via another funnel. After addition, the reaction mixture turned yellow as the solid began to dissolve. After the addition was complete, the ice bath was removed. The reaction was warmed to room temperature and stirred for an additional 30 min. LC-MS analysis indicated that the reaction was complete. The reaction was cooled back to 0°C in an ice bath and slowly quenched to pH~2 by adding 1M HCl aqueous solution. The resulting aqueous mixture was distributed into a separatory funnel. The aqueous layer was back extracted with CH2Cl2 (3×3 volumes). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The obtained crude reaction mixture was loaded onto a silica gel pre-column and purified by column chromatography using 0:100 to 80:20 hexane:EtOAc as a gradient elution in 30 min. The desired product was eluted from 90:10 to 80:20 hexane:EtOAc. The fractions containing the desired product were concentrated and dried under vacuum to give a yellow oil (64% yield).

[0287] Intermediate G: Preparation of 4-((5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2-fluorobenzenesulfonamide

[0288]

[0289] Step 1: Preparation of 4-(4-cyclopropyl-2-(4-fluorobenzoyl)-3-oxobutyl)-2-fluorobenzenesulfonamide

[0290] 4-Cyclopropyl-1-(4-fluorophenyl)butane-1,3-dione (Intermediate F, 1.0 eq.) and DMSO (0.4 M) were added to a round-bottom flask equipped with a magnetic stirring bar. The solution was treated with cesium carbonate (1.5 eq.) and potassium iodide (1.0 eq.). The resulting suspension was stirred at 23 °C for 30 minutes. Thereafter, 4-(bromomethyl)-2-fluorobenzenesulfonamide (1.1 eq.) was added. The mixture was stirred at 23 °C for 2 h, and after the reaction was completed by LCMS, the reaction mixture was treated with EtOAc, followed by the addition of 1M HCl aqueous solution until the pH of the water layer was ~2. The mixture was stirred for 10 minutes and distributed into a separatory funnel. The organic layer was removed, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was loaded onto a silica gel pre-column and dried. Purify by silica gel column chromatography eluting with 95:5 to 10:90 hexanes:EtOAc as a gradient over 30 min, collecting all peaks. Fractions containing the desired product were concentrated and dried under vacuum to give the title product (77% yield).

[0291] Step 2: Preparation of 4-((5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2-fluorobenzenesulfonamide

[0292] 4-[4-cyclopropyl-2-(4-fluorobenzoyl)-3-oxobutyl]-2-fluorobenzenesulfonamide (1.0 equivalent) and EtOH (0.3M) are added to a round-bottom flask equipped with a magnetic stirring bar. Liquid monohydrate hydrazine (6.0 equivalent) is added to the flask, and the solution is heated to 70 ° C in an oil bath for 2h. LC-MS analysis shows the consumption of starting material and the formation of product. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The resulting yellow oil is loaded into a silica gel pre-column and dried. The mixture is purified by silica gel column chromatography in 25min with 80:20 to 0:100 hexane: EtOAc as a gradient elution. The fractions (75% to 100% EtOAc) containing the desired product are concentrated and dried under vacuum to obtain the title product (76% yield) as a white solid.

[0293] Intermediate H: Preparation of ethyl 2-(methylsulfonyl)thiazole-4-carboxylate

[0294]

[0295] Step 1: Preparation of ethyl 2-(methylsulfanyl)-1,3-thiazole-4-carboxylate

[0296] To a round-bottom flask equipped with a magnetic stirring bar, ethyl 2-chloro-1,3-thiazole-4-carboxylate (1.0 equiv.), DMF (0.9 M), K2CO3 (2 equiv.) and sodium thiomethoxide (1.2 equiv.) were added. The resulting mixture was stirred at 23 ° C for 1 h. LC-MS analysis showed the consumption of starting materials and the formation of products. The resulting mixture was poured into a separatory funnel containing water (10 volumes), and the aqueous layer was extracted with ethyl acetate (3×2 volumes). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title product (68% yield) as a dark yellow solid.

[0297] Step 2: Preparation of ethyl 2-(methylsulfonyl)thiazole-4-carboxylate

[0298] To a round-bottom flask equipped with a magnetic stirring bar was added ethyl 2-(methylsulfanyl)-1,3-thiazole-4-carboxylate (1.0 eq.) and CH2Cl2 (0.9 M). The mixture was cooled to 0 ° C in an ice-water bath. Solid m-CPBA (2.5 eq.) was slowly added over 15 minutes. The resulting solution was stirred at 23 ° C for 1 h. LC-MS analysis showed the consumption of starting material and the formation of product. The resulting mixture was diluted with CH2Cl2 (3 volumes) and washed with brine (3×1 volumes). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with petroleum ether / ethyl acetate (5: 1) to give the title product as a white solid (66% yield).

[0299] Preparation of Examples

[0300] Example 1: 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrrolidone Preparation of oxazol-1-yl)thiazole-4-carboxylic acid

[0301]

[0302] Step 1: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0303] To a round bottom flask equipped with a magnetic stir bar and under N2 was added 4-((5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2-fluorobenzenesulfonamide (Intermediate G, 1.0 eq) and DMF (0.25 M). The mixture was treated with solid sodium tert-amyl alcohol (2.0 eq) and cooled to 0 °C in an ice bath. Solid ethyl 2-fluorothiazole-4-carboxylate (1.5 eq) was added and the mixture was allowed to warm to 23 °C with stirring within 2 h. LCMS analysis thereafter showed that the product was formed as the major isomer with a regioisomer ratio of 3:7. The reaction was quenched with saturated aqueous NH4Cl (2 vols) and poured into a separatory funnel containing water and extracted with CH2Cl2 (3×4 vols). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography eluting with 95:5 to 10:90 hexanes:EtOAc as a gradient over 25 min. Fractions containing the desired product were concentrated and dried under vacuum to give the title product as a white solid (55% yield).

[0304] Step 2: Preparation of 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0305] To a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-[5-(cyclopropylmethyl)-3-(4-fluorophenyl)-4-[(3-fluoro-4-sulfamoyl-phenyl)methyl]pyrazol-1-yl]thiazole-4-carboxylate (1.0 equiv) and THF / MeOH (1:1 v / v, 0.2 M). The mixture was stirred at 23 °C until most of the solid dissolved. 1.0 M LiOH aqueous solution (2.5 equiv) was added. The reaction was stirred at 23 °C for 2 h, and the mixture was quenched by dropwise addition of concentrated formic acid. Purified by reverse phase column chromatography using a C18 column with 90:10 to 0:100 H2O:MeCN+0.1% formic acid as a gradient elution. The fractions containing the desired product were concentrated under reduced pressure to give the title compound (79% yield). 1 H NMR (400 MHz, d6-DMSO)δ H13.16(s,1H),8.28(s,1H),7.67-7.58(m,5H),7.23(dd,J=10.0,8.0Hz,2H),7.11(d,J=11.5Hz,1H),7.02(d ,J=8.0Hz,1H),4.13(s,2H),3.13(d,J=7.0Hz,2H),1.17-1.05(m,1H),0.36-0.27(m,2H),0.23-0.15(m,2H). LC-MS(ESI)m / z 531(M+H) + . MW:530.56.

[0306] Example 2: 2-(3-(3-cyano-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-aminosulfonylbenzyl)- Preparation of 1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0307]

[0308] Step 1: Preparation of ethyl 2-(3-(3-cyano-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0309] To a mixture of ethyl 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoyl-phenyl)methyl]-3-(trifluoromethylsulfonyloxy)pyrazol-1-yl]thiazole-4-carboxylate (Intermediate D, 1.0 equiv), tBuXPhos-Pd-G3 (0.1 equiv) and (3-cyano-4-fluorophenyl)boronic acid (2.0 equiv) in 1,4-dioxane (0.11 M) was added water (0.001 M) and potassium phosphate (3.0 equiv). The mixture was degassed under N2 and heated to 90 °C for 1 hour. Saturated aqueous NH4Cl solution (1 vol) and water (2.5 vol) were added to the mixture, and the mixture was extracted with EtOAc (2×5 vol). The combined organic extracts were washed with water (1.5 vol) and concentrated under vacuum. The resulting yellow oil was loaded into a silica gel pre-column and dried. The mixture was purified by silica gel column chromatography eluting with 80:20 to 0:100 hexanes:EtOAc as a gradient over 25 min. Fractions containing the desired product (75% to 100% EtOAc) were concentrated and dried under vacuum to give the title product as a white solid (75% yield).

[0310] Step 2: Preparation of 2-(3-(3-cyano-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0311] To a round-bottom flask was added ethyl 2-(3-(3-cyano-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv), THF (0.06 M), MeOH (0.06 M) and 1 M aqueous LiOH (1.0 equiv). The reaction was stirred at 23 °C for 2 hours, at which time LCMS showed complete conversion to product. Purification was performed by reverse phase column chromatography using a C18 column with a gradient elution of 90:10 to 0:100 H2O:MeCN+0.1% formic acid. The fractions containing the desired product were concentrated under reduced pressure to give the title compound (58% yield). 1 H NMR (400 MHz, d6-DMSO)δ H 8.27(s,1H),8.09(dd,J=6.0,2.5Hz,1H),7.92(ddd,J=8.0,5.0,2.5Hz,1H),7.58(m,4H),7.11(d,J=11.5Hz,1H),7 .01(d,J=8.5Hz,1H),4.18(s,2H),3.16(d,J=7.0Hz,2H),1.15-1.06(m,1H),0.35-0.29(m,2H),0.23-0.17(m,2H). LC-MS(ESI)m / z 556(M+H) + MW: 555.08

[0312] Example 3: 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl) Preparation of Thiazole-4-carboxylic Acid

[0313]

[0314] Step 1: Preparation of 4-bromo-3-(4-fluorophenyl)-5-methyl-1H-pyrazole

[0315] 3-(4-fluorophenyl)-5-methyl-1H-pyrazole (1.0 equivalent) and MeCN (0.3M) were added to a round-bottom flask. The mixture was cooled to 0 ° C in an ice bath, and N-bromosuccinimide (1.5 equivalents) was added. The reaction was stirred at 23 ° C for 18h overnight. LCMS analysis showed that all starting materials had been converted into brominated products. The reaction mixture was distributed between EtOAc (2 volumes) and saturated NaHCO3 aqueous solution (2 volumes). The organic layer was separated, and the water layer was further extracted with EtOAc (2 volumes). The organic layers were merged, dried, filtered and concentrated to obtain a yellow oily crude product, which was loaded onto a silica gel pre-column and dried. The mixture was purified by silica gel column chromatography in 17 min using 80:20 to 0:100 hexanes: EtOAc as gradient elution. The fractions containing the desired product were concentrated and dried under vacuum to obtain the title product (96% yield) as a yellow solid.

[0316] Step 2: Preparation of ethyl 2-(4-bromo-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0317] 4- bromo-3- (4- fluorophenyl) -5- methyl -1H- pyrazole (1.0 equivalent), 2- bromothiazole -4- ethyl formate (1.5 equivalent), potassium carbonate (3.0 equivalent) and DMF (0.3M) are added to a round-bottom flask. The mixture is stirred at 100 ° C for 18 h overnight. LCMS analysis shows that the reaction is complete. The mixture is filtered to remove most of the potassium carbonate solid. The filtrate is directly loaded on a silica gel pre-column and dried. The mixture is purified by silica gel column chromatography in 20 min using 80: 20 to 0: 100 hexanes: EtOAc as a gradient elution. The fraction containing the desired product is concentrated and dried under vacuum to obtain the title product (43% yield) as a yellow solid.

[0318] Step 3: Preparation of ethyl 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0319] To a reaction bottle equipped with a magnetic stir bar was added B2pin2 (1.5 eq.), ethyl 2-(4-bromo-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 eq.), Pd(PPh3)2Cl2 (0.1 eq.), potassium acetate (2.0 eq.), and 1,4-dioxane (0.3 M). The mixture was purged with nitrogen for 10 min and then heated to 100 °C for 18 hours. After borylation was completed by LCMS, the mixture was treated with Pd(dppf)Cl2·CH2Cl2 (0.1 eq.), ethyl 2-[4-bromo-3-(4-fluorophenyl)-5-methyl-pyrazol-1-yl]thiazole-4-carboxylate (1.0 eq.), and sodium carbonate (2.0 M, 2.0 eq.). The reaction was purged with nitrogen for 10 min and then stirred at 80 °C for 1 hour. LCMS analysis shows that the reaction is complete. The mixture is filtered and directly loaded on a silica gel pre-column and dried. The mixture is passed through silica gel column chromatography, and 80:20 to 0:100 hexanes: EtOAc are used as gradient elution to purify in 20min. The fraction containing the desired product is concentrated and dried under vacuum to obtain the title product (23% yield) as a yellow solid.

[0320] Step 4: Preparation of 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0321] To a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-(4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv) and THF / MeOH (1:1 v / v, 0.3 M). The mixture was stirred at 23° C. for 10 minutes until most of the solids dissolved. 1M aqueous LiOH solution (3.0 equiv) was added to give a clear solution. The reaction was stirred at 23° C. for 1 h. LC-MS analysis at this point showed complete conversion of the starting material. The reaction mixture was acidified to pH~2 with 1M aqueous HCl. Purification was performed by reverse phase preparative HPLC column (C18, 5 μm column) with 90:10 to 0:100 water:MeCN+0.1% formic acid as gradient elution over 25 minutes, collecting all peaks. Fractions containing the desired product were concentrated and lyophilized overnight to give the title product as a white powder (83% yield). LC-MS (ESI) m / z 491 (M+H) + MW:490.50

[0322] Example 4: 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrrolidone Preparation of oxazol-1-yl)thiazole-4-carboxylic acid

[0323]

[0324]

[0325] Step 1: Preparation of 1-(1H-benzo[d][1,2,3]triazol-1-yl)propan-1-one

[0326] Benzotriazole (1.0 equivalent), triethylamine (2 equivalents) and CH2Cl2 (0.54M) were added to a round-bottom flask equipped with a magnetic stirring bar. The resulting solution was cooled to 0 ° C in an ice bath. Propionyl chloride (1 equivalent) was carefully added within 30 minutes while cooling. The mixture was stirred at 0 ° C for 1 h, water (5 volumes) was added, and the organic layer was removed and concentrated under reduced pressure. The resulting yellow oil was loaded into a silica gel pre-column and dried. The mixture was purified by silica gel column chromatography using 80:20 to 0:100 hexanes: EtOAc as a gradient elution in 25 min. The fractions containing the desired product were concentrated and dried under vacuum to obtain the title product (79% yield) as a white solid.

[0327] Step 2: Preparation of 1-(3-bromo-4-fluorophenyl)pentane-1,3-dione

[0328] 1-(1H-benzo[d][1,2,3]triazol-1-yl)propan-1-one (1.5 eq.), 1-(3-bromo-4-fluorophenyl)ethan-1-one (1.0 eq.) and CH2Cl2 (0.5 M) were added to a round-bottom flask equipped with a magnetic stir bar. The mixture was cooled to 0°C in an ice bath. With stirring, ethereal magnesium bromide (2.5 eq.) was added in one portion. N,N-diisopropylethylamine (3.0 eq.) was added dropwise via an additional funnel. After addition, the reaction mixture turned yellow as the solid began to dissolve. After the addition was complete, the ice bath was removed, and the reaction was warmed to 23°C and stirred at this temperature for 30 min. LC-MS analysis indicated that the reaction was complete. The reaction was cooled to 0°C in an ice bath and slowly quenched to pH~2 by adding 1M HCl aqueous solution (5-10 volumes). The resulting aqueous mixture was distributed in a separatory funnel. The aqueous layer was stripped with CH2Cl2 (3×4 volumes). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude reaction mixture was loaded onto a silica gel pre-column and purified by column chromatography using 0:100 to 80:20 hexane:EtOAc as a gradient elution in 30 min. The desired product was eluted from 90:10 to 80:20 hexane:EtOAc. The fractions containing the desired product were concentrated and dried under vacuum to give a yellow oil (71% yield).

[0329] Step 3: Preparation of 4-(2-(3-bromo-4-fluorobenzoyl)-3-oxopentyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0330] 1-(3-bromo-4-fluorophenyl)pentane-1,3-dione (5.0 eq.) and DMSO (0.14 M) were added to a round-bottom flask equipped with a magnetic stir bar. The solution was treated with cesium carbonate (1.2 eq.) and the resulting suspension was stirred at 23 °C for 30 minutes. At this point, 4-(bromomethyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (prepared in the same manner as Intermediate C, 1.0 eq.) was added. The mixture was stirred at 23 °C for 3 h, and after the reaction was complete, the mixture was treated with EtOAc (5 vol.) followed by the addition of 1 M aqueous HCl (5 vol.), ensuring that the aqueous layer was acidic (pH ~ 2). The mixture was stirred for 10 minutes and distributed into a separatory funnel. The organic layer was removed, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was loaded onto a silica gel pre-column and dried. Purify by silica gel column chromatography eluting with 95:5 to 10:90 hexanes:EtOAc as a gradient over 30 min, collecting all peaks. Fractions containing the desired product were concentrated and dried under vacuum to give the title product (38% yield).

[0331] Step 4: Preparation of 4-((3-(3-bromo-4-fluorophenyl)-5-ethyl-1H-pyrazol-4-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0332] 4-(2-(3-bromo-4-fluorobenzoyl)-3-oxopentyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (1.0 equiv) and EtOH (0.3 M) were added to a round-bottom flask equipped with a magnetic stirring bar. Concentrated hydrazine monohydrate (6.0 equiv) was added to the flask, and the solution was heated to 70 ° C in an oil bath for 2 h. LC-MS analysis showed the consumption of starting material and the formation of product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting yellow oil was loaded into a silica gel pre-column and dried. The mixture was purified by silica gel column chromatography using 80:20 to 0:100 hexanes:EtOAc as a gradient elution in 25 min. The fractions containing the desired product eluted between 75% to 100% EtOAc in hexane were concentrated and dried under vacuum to give the title product (76% yield) as a white solid.

[0333] Step 5: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-3-(3-bromo-4-fluorophenyl)-5-ethyl-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0334] To a round bottom flask equipped with a magnetic stir bar was added 4-((3-(3-bromo-4-fluorophenyl)-5-ethyl-1H-pyrazol-4-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (1.0 eq) and DMF (0.07 M). Sodium hydride (60% dispersion in mineral oil, 1.5 eq) was added, and after stirring for 10 minutes, the reaction mixture was cooled to 0°C in an ice bath. Ethyl 2-fluorothiazole-4-carboxylate (1.2 eq) was added, and the reaction mixture was stirred at 23°C for 1 hour. The reaction mixture was diluted with water (4 vols) and extracted with EtOAc (5 vols). The organic layer was concentrated under reduced pressure, and the resulting yellow oil was loaded into a pre-column and dried. The mixture was purified by silica gel column chromatography using 80:20 to 0:100 hexanes:EtOAc as a gradient elution over 25 min. Fractions containing the desired product eluting from 75% to 100% EtOAc in hexanes were concentrated and dried under vacuum to give the title product as a white solid (62% yield).

[0335] Step 6: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-5-ethyl-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0336] To a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-3-(3-bromo-4-fluorophenyl)-5-ethyl-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv), MeOH (0.02 M) and CHCl (0.02 M). The reaction mixture was degassed and Pd / C (10 wt % loading) was added. The reaction was charged with hydrogen via a balloon and stirred at 23 °C for 6 hours. The crude mixture was purged with air, diluted with CHCl, and concentrated to a slurry. Purification was performed by reverse phase column chromatography using a C18 column with 90:10 to 0:100 H2O:MeCN+0.1% formic acid as a gradient elution. The fractions containing the desired product were concentrated under reduced pressure to give the title compound (66% yield).

[0337] Step 7: Preparation of 2-(5-ethyl-3-(4-fluorophenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0338] To a round-bottom flask was added ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl)-5-ethyl-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv) and TFA (100 equiv). The reaction was stirred at 23 °C for 1 hour and then concentrated under reduced pressure. To the resulting crude solid was added 1 M aqueous LiOH (10 equiv), MeOH (0.04 M) and THF (0.04 M). The resulting mixture was heated at 50 °C for 3 hours. Purification was performed by reverse phase column chromatography using a C18 column with a gradient elution of 90:10 to 0:100 H2O:MeCN+0.1% formic acid. Fractions containing the desired product were concentrated under reduced pressure to give the title compound (15% yield). LC-MS (ESI) m / z 487 (M+H) + MW:486.08

[0339] The following compounds were prepared in a similar manner to Example 4 by replacing propionic acid with the corresponding alkylcarboxylic acid in the first step.

[0340]

[0341]

[0342] Example 7: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-4-(3-fluoro-4-sulfamoyl)- Preparation of 1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0343]

[0344] Step 1: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0345] To a round bottom flask equipped with a magnetic stir bar was added ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-hydroxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (Intermediate E, 1.0 equiv), triphenylphosphine (2.3 equiv), isopropanol (3.0 equiv) and CHCl (0.06 M). The mixture was cooled in an ice bath and diisopropyl azodicarboxylate (2.0 equiv) was added. The reaction was stirred in an ice bath for 5 minutes and then warmed to 23 °C for 30 minutes. The mixture was directly purified by silica gel column chromatography eluting with a 0-70% EtOAc in hexanes gradient. Fractions from the main peak eluting with 25-30% EtOAc in hexanes were combined and concentrated in vacuo to give the title compound as a colorless oil (75% yield).

[0346] Step 2: Preparation of 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0347] To a solution of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv) in THF / MeOH (1:1 v / v, 0.02 M) was added 1 M aqueous LiOH (8.0 equiv) and the mixture was heated to 40 °C for 16 hours. The mixture was concentrated under vacuum to remove MeOH and THF. The residue was then acidified with formic acid (8.0 equiv). The mixture was partitioned between CH2Cl2 (2×10 vols) and water (5 vols). The combined organic layers were concentrated under vacuum to give the title compound (99% yield).

[0348] Step 3: Preparation of 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0349] To a solution of 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3-fluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluoro-3-isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid (1.0 equiv) in CHCl (0.03 M) was added triethylsilane (6.0 equiv) and trifluoroacetic acid (50 equiv). The resulting solution was stirred at 23 °C for 24 hours. The mixture was concentrated under vacuum and the resulting residue was purified by reverse phase column chromatography using a C18 column eluting with a 10-100% CHCN / water gradient containing 0.1% HCOH. Fractions from the main peak eluting at 75% CHCN were combined and lyophilized to give the title product as a white solid (67% yield). LC-MS (ESI) m / z 567.1 (M+H) + MW: 566.1

[0350] Example 8: 2-(3-(3-chloro-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)- Preparation of 1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0351]

[0352] Step 1: Preparation of ethyl 2-[3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylate

[0353] To a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-[3-(3-bromo-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylate (Intermediate A, 1.0 equiv), DMF (0.25M), FeCl3 (0.3 equiv) and CuCl (5.0 equiv). The resulting mixture was heated to 110 ° C in an oil bath for 16 h. LC-MS analysis showed consumption of starting material and formation of product. The reaction mixture was cooled to 23 ° C, and the resulting mixture was poured into a separatory funnel containing water (5 volumes), and the aqueous layer was extracted with ethyl acetate (3×5 volumes). The combined organic layers were washed with brine and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (82% yield) as a light yellow solid.

[0354] Step 2: Preparation of 2-(3-(3-chloro-4-fluorophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0355] To a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-[3-(3-chloro-4-fluorophenyl)-5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoylphenyl)methyl]pyrazol-1-yl]-1,3-thiazole-4-carboxylate (1.0 eq), MeOH (0.1 M) and H2O (0.1 M). Solid NaOH (5.0 eq) was added to the flask, and the resulting solution was stirred at 23 °C for 30 min. LC-MS analysis indicated consumption of starting material and formation of product. The resulting mixture was concentrated under reduced pressure, and the residue was acidified to pH ~5 with 3M HCl aqueous solution. The aqueous layer was extracted with ethyl acetate (3×2 volumes). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC through an XBridge PhenylOBD column eluting with 55% to 65% MeOH / water + 10 mM NH4HCO3 as a gradient. The fractions containing the product were combined, concentrated and dried under vacuum to give the title product as a white solid (58% yield). 1 H NMR (300 MHz, d6-DMSO)δ H7.91(s,1H),7.76-7.58(m,2H),7.63-7.50(m,1H),7.43-7.40(m,1H),7.34(s,1H),7.15-7.09(m ,1H),7.05-6.94(m,1H),4.17(s,2H),3.17(d,J=6.9Hz,2H),1.0-1.1(m,1H),0.38-0.15(m,4H). LC-MS(ESI)m / z 566(M+H) + MW: 565.01

[0356] Example 9: 2-(5-(Cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrrolidone Preparation of oxazol-1-yl)oxazole-4-carboxylic acid

[0357]

[0358]

[0359] Step 1: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)oxazole-4-carboxylate

[0360] To a round-bottom flask equipped with a magnetic stir bar and under N2 was added 4-((5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2-fluorobenzenesulfonamide (Intermediate G, 1.0 eq.), ethyl 2-chlorooxazole-4-carboxylate (1.5 eq.) and DMF (0.1 M). The solution was cooled to 0 °C in an ice bath and sodium tert-amyl alcohol (2.0 eq.) was added. The mixture was allowed to warm to 23 °C over 30 min and stirred at this temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution (3 vols.) and the residue was poured into a Cl phase separation column and extracted with CH2Cl2 (3 x 2 vols.). The combined organic layers were concentrated and loaded onto a C18 pre-column and dried. Purify by reverse phase column chromatography on a C18 column, eluting with 95:5 to 20:80 H2O:MeCN+0.1% HCO2H as a gradient in 25 min, collecting all peaks. Fractions containing the desired product were concentrated and dried under vacuum to give the title product (34% yield).

[0361] Step 2: Preparation of 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1-pyrazol-1-yl)oxazole-4-carboxylic acid

[0362] 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)oxazole-4-carboxylic acid ethyl ester (1.0 equiv) and THF / MeOH (1:1 v / v, 0.2M) were added to a round-bottom flask equipped with a magnetic stir bar and under N2. The solution was treated with 1.0M LiOH aqueous solution (2.5 equiv), and the mixture was stirred at 23 °C for 18h overnight. The mixture was quenched dropwise with concentrated formic acid until the pH was 4, and the mixture was concentrated under reduced pressure. The residue was loaded onto a C18 pre-column and dried. Purification was performed by C18 column reverse phase column chromatography in 25min using 90:10 to 10:90H2O:MeCN+0.1% HCO2H as gradient elution, collecting all peaks. Fractions containing the desired product were concentrated and dried under vacuum to afford the title product as a white solid (49% yield). 1 H NMR (400 MHz, d6-DMSO)δ H 8.80(s,1H),7.67–7.54(m,5H),7.22(t,J=8.5Hz,2H),7.09(d,J=11.5Hz,1H),7.01(d,J=8.5Hz, 1H), 4.14 (s, 2H), 2.96 (d, J = 7.0Hz, 2H), 1.00-0.98 (m, 1H), 0.34-0.29 (m, 2H), 0.11-0.08 (m, 2H). LC-MS(ESI)m / z 515(M+H) + MW: 514.1

[0363] Example 10: 2-(4-(3-chloro-4-sulfamoylbenzyl)-5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrrolidone Preparation of oxazol-1-yl)thiazole-4-carboxylic acid

[0364]

[0365]

[0366] Step 1: Preparation of 2-chloro-4-(4-cyclopropyl-2-(4-fluorobenzoyl)-3-oxobutyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0367] Into a round-bottom flask equipped with a magnetic stirring bar was placed 4-cyclopropyl-1-(4-fluorophenyl)butane-1,3-dione (Intermediate F, 1.0 equiv.), 4-(bromomethyl)-2-chloro-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide (prepared in the same manner as Intermediate C, 0.5 equiv.), K3PO4 (0.5 equiv.) and DMSO (0.9 M). The resulting mixture was stirred at room temperature for 12 h. When the reaction was complete, as confirmed by LCMS analysis, the reaction mixture was quenched by adding water (4 volumes), poured into a separatory funnel, and extracted with EtOAc (3×3 volumes). The organic layer was washed with brine (2 volumes), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was loaded onto a silica gel column and eluted with petroleum ether / ethyl acetate (3:2). The title compound (23% yield) was obtained as a yellow oil.

[0368] Step 2: Preparation of 2-chloro-4-[[3-(cyclopropylmethyl)-5-(4-fluorophenyl)-2H-pyrazol-4-yl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide

[0369] Into a round-bottom flask equipped with a magnetic stirring bar was placed 2-chloro-4-[4-cyclopropyl-2-(4-fluorobenzoyl)-3-oxobutyl]-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide (1.0 equivalent), hydrazine monohydrate (8.0 equivalents) and EtOH (0.11M). The resulting solution was heated to 70 ° C in an oil bath for 1 h. LC-MS analysis showed the consumption of starting material and the formation of product. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was loaded onto a silica gel column and eluted with ethyl acetate / petroleum ether (2: 3). The fractions containing the product were combined, concentrated and dried under vacuum to give the title compound as a yellow solid (50% yield).

[0370] Step 3: Preparation of ethyl 2-[4-[(4-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-3-chlorophenyl)methyl]-5-(cyclopropylmethyl)-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thiazole-4-carboxylate

[0371] To a round-bottom flask equipped with a magnetic stir bar was added 2-chloro-4-[[3-(cyclopropylmethyl)-5-(4-fluorophenyl)-2H-pyrazol-4-yl]methyl]-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide (1.0 equiv), ethyl 2-methanesulfonyl-1,3-thiazole-4-carboxylate (Intermediate H, 5.0 equiv), DMSO (0.03M) and K2CO3 (3.0 equiv). The resulting solution was heated to 120°C in an oil bath for 12 h. When the reaction was complete, as confirmed by LCMS analysis, the reaction mixture was cooled to 23°C and quenched by the addition of water (2 volumes). The resulting mixture was extracted with ethyl acetate (3×2 volumes), and the organic fractions were combined and concentrated under reduced pressure. The resulting residue was loaded onto a silica gel column and eluted with petroleum ether / ethyl acetate (1:1). The fractions containing the product were combined, concentrated and dried under vacuum to give the desired compound as a white solid (88% yield).

[0372] Step 4: Preparation of ethyl 2-(4-(3-chloro-4-sulfamoylbenzyl)-5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0373] 2-[4-[(4-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-3-chlorophenyl)methyl]-5-(cyclopropylmethyl)-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid ethyl ester (1.0 equivalent), TFA (0.12M) and triethylsilane (0.03M) were added to a round-bottom flask equipped with a magnetic stirrer. The resulting mixture was stirred at 23 ° C for 4h. The starting material consumption of the reaction was monitored, and when completed, it was concentrated under reduced pressure. The crude residue was loaded onto a silica gel column, and the column was eluted with petroleum ether / ethyl acetate (2: 1). The fractions containing the product were combined, concentrated and dried under vacuum to give the title compound as a white solid (84% yield).

[0374] Step 5: Preparation of 2-[4-[(3-chloro-4-sulfamoylphenyl)methyl]-5-(cyclopropylmethyl)-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid

[0375] To a round-bottom flask equipped with a magnetic stirrer was added ethyl 2-(4-(3-chloro-4-sulfamoylbenzyl)-5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv), MeOH (0.02 M), H2O (0.09 M) and solid NaOH (5.0 equiv). The resulting mixture was heated to 80 °C for 4 h. When the reaction was complete, as confirmed by LCMS analysis, the reaction mixture was cooled to room temperature and quenched by the addition of water (2 volumes). The mixture was extracted with ethyl acetate (3×2 volumes), and the combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative HPLC on a C18 column using 90:10 to 50:50 water:MeCN as a gradient elution over 10 min. The fractions containing the product were combined, concentrated and dried under vacuum to give the desired compound as a white solid (18% yield). 1 H NMR (300MHz, CD3OD)δ H 8.08(s,1H),7.92(d,J=8.0Hz,1H),7.58-7.53(m,2H),7.30(s,1H),7.19-7.00(m,3H),4. 13(s,2H),3.24(d,J=7.0Hz,2H),1.00-0.98(m,1H),0.37-0.35(m,2H),0.25-0.15(m,2H). LC-MS(ESI)m / z 547(M+H) + MW: 546.06

[0376] Example 11: 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H- Preparation of pyrazol-1-yl)thiazole-4-carboxylic acid

[0377]

[0378]

[0379] Step 1: Preparation of ethyl 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0380] To the reaction flask was added ethyl 2-(3-(3-bromophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (Intermediate B, 1.0 equiv), zinc cyanide (2.0 equiv), Pd(PPh3)4 (0.2 equiv) and DMF (0.2M). The mixture was heated to 100°C for 2 hours. LCMS analysis thereafter indicated that the reaction was complete. The mixture was loaded onto a silica gel pre-column and dried under vacuum. The mixture was purified by silica gel column chromatography using a gradient elution of 95:5 to 0:100 hexanes:EtOAc over 25 minutes, collecting all peaks. The fractions containing the desired product were concentrated and dried under vacuum to give a clear oil (45% yield).

[0381] Step 2: Preparation of 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0382] To a round-bottom flask equipped with a magnetic stir bar was added ethyl 2-(3-(3-cyanophenyl)-5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (1.0 equiv), THF / MeOH (1:1 v / v, 0.2 M), and 1 M aqueous LiOH (3 equiv). The mixture was stirred at 23 °C for 2 hours, after which LCMS indicated that the hydrolysis was complete. The reaction was quenched with formic acid to pH ~2. The mixture was concentrated and purified by reverse phase preparative HPLC on a C18 column using 90:10 to 0:100 water:MeCN+0.1% formic acid as a gradient elution over 25 minutes, collecting all peaks. The fractions containing the desired product were concentrated and lyophilized overnight to give the title product as a white powder (89% yield). LC-MS (ESI) m / z 538 (M+H) + MW: 537.58

[0383] Example 12: 2-(5-(cyclopropylmethyl)-3-(3,4-difluorophenyl)-4-(3-fluoro-4-sulfamoylbenzyl)- Preparation of 1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0384]

[0385] To a mixture of ethyl 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoyl-phenyl)methyl]-3-(trifluoromethylsulfonyloxy)pyrazol-1-yl]thiazole-4-carboxylate (Intermediate D) (1.0 equiv.), tBuXPhos-Pd-G3 (0.1 equiv.) and 3,4-difluorophenylboronic acid (2.0 equiv.) in 1,4-dioxane (0.05 M) was added anhydrous potassium phosphate (3.0 equiv.). The mixture was degassed with nitrogen for 10 minutes and then heated to 90 °C for 2 hours. Saturated aqueous NH4Cl solution (1 volume) and water (2.5 volumes) were added to the mixture and extracted with EtOAc (2×5 volumes). The combined extracts were washed with water (1.5 volumes) and concentrated under vacuum. The residue was dissolved in THF / MeOH (1:1 v / v) (1 volume). The 1M LiOH aqueous solution (6.0 equivalents) is added, and the mixture is stirred at 23 ℃ for 16 hours. After LCMS analysis shows that hydrolysis is completed, the mixture is acidified with formic acid (15 equivalents). The reaction mixture is directly loaded into the C18 pre-column and dried. The material is passed through reverse phase column chromatography, using the C18 post, with 10-100% CH CN / water gradient (it contains 0.1% HCO H) wash-out to purify. Will be from the pure fractions of the main peak eluted with 83% CH CN merge and freeze-drying, obtain the title product (86% yield) in the form of a white solid. 1 H NMR (400 MHz, d6-DMSO)δ H 13.16(br s,1H),8.28(s,1H),7.65-7.55(m,2H),7.58(br s,2H),7.50-7.35(m,2H),7.12(d,J=11.0Hz,1H),7.02(d,J=8.0Hz,1H),4.16(s,2 H), 3.15 (d, J = 6.5Hz, 2H), 1.15-1.07 (m, 1H), 0.36-0.28 (m, 2H), 0.23-0.17 (m, 2H). LC-MS(ESI)m / z 549(M+H) + MW: 548.1

[0386] The following examples were prepared by replacing 3,4-difluorophenylboronic acid with the necessary boronic acid or boronic acid ester as in Example 12. In addition, tBuXPhos-Pd-G3 can be replaced with other metal catalyst systems including XPhos-Pd-G3 and Pd(dppf)Cl2.CH2Cl2.

[0387]

[0388]

[0389]

[0390]

[0391] Example 27: 2-(5-(cyclopropylmethyl)-4-(3,5-difluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0392]

[0393] Step 1: Preparation of 4-(bromomethyl)-2,6-difluorobenzenesulfonyl chloride

[0394] 2,6-difluoro-4-methylbenzenesulfonyl chloride (1.0 equivalent), NBS (1.1 equivalent), AIBN (0.1 equivalent) and MeCN (0.2M) were placed in a round-bottom flask equipped with a magnetic stirring bar. The resulting suspension was stirred at -10 ° C for 4 h. LCMS analysis showed the conversion of the starting material, and the resulting mixture was concentrated under reduced pressure. The crude product was purified by C18 column preparative HPLC, eluted with 90:10 to 50:50 water: MeCN. The fractions containing the product were combined, concentrated and dried under vacuum to obtain the desired compound (55% yield) as a brown oil.

[0395] Step 2: Preparation of 4-(bromomethyl)-2,6-difluoro-N,N-bis(4-methoxybenzyl)benzenesulfonamide

[0396] Into a round-bottom flask equipped with a magnetic stirring bar was placed bis[(4-methoxyphenyl)methyl]amine (1.0 equiv.), 4-(bromomethyl)-2,6-difluorobenzenesulfonyl chloride (0.6 equiv.), Na2CO3 (3.0 equiv.) and CH2Cl2 (0.16 M). The resulting suspension was stirred at -10 °C for 4 h. The reaction was quenched with water (2 volumes), poured into a separatory funnel, and extracted with CH2Cl2 (3×2 volumes). The organic layers were combined and concentrated under reduced pressure. The residue was loaded onto a silica gel column and eluted with ethyl acetate / petroleum ether (1:1). The fractions containing the product were combined, concentrated and dried under vacuum to give the title product as a white solid (27% yield).

[0397] Step 3: Preparation of ethyl 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)-3,5-difluorobenzyl)-5-(cyclopropylmethyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0398] To a round bottom flask equipped with a magnetic stir bar, purged and maintained with an inert atmosphere of nitrogen, was added 4-(bromomethyl)-2,6-difluoro-N,N-bis[(4-methoxyphenyl)methyl]benzenesulfonamide (1.0 equiv), 2-[5-(cyclopropylmethyl)-3-(4-fluorophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-1,3-thiazole-4-carboxylic acid ethyl ester (prepared in the same manner as described in borylation step 3 for synthesis of Example 3, 1.0 equiv), Pd(dppf)Cl2 (0.1 equiv), Na2CO3 (3.0 equiv), dioxane (0.15 M) and H2O (0.03 M). The resulting mixture was heated to 40°C for 4 h. The starting material consumption of the reaction is monitored, and when completed, the reaction mixture is cooled and quenched with water (2 volumes). The resulting mixture is extracted with ethyl acetate (4×2 volumes). The organic layers are combined and concentrated under reduced pressure. The resulting residue is loaded onto a silica gel column and eluted with ethyl acetate / petroleum ether (1: 1). The fractions containing the product are combined, concentrated and dried under vacuum to obtain the title product (32% yield) as a yellow-green solid.

[0399] Step 4: Preparation of ethyl 2-(5-(cyclopropylmethyl)-4-(3,5-difluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate

[0400] Into a round-bottom flask equipped with a magnetic stir bar was placed ethyl 2-[4-[(4-[bis[(4-methoxyphenyl)methyl]sulfamoyl]-3,5-difluorophenyl)methyl]-5-(cyclopropylmethyl)-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thiazole-4-carboxylate (1.0 equiv), TFA (0.01 M) and triethylsilane (0.05 M). The resulting mixture was heated to 40 °C for 2 h. The reaction was monitored for consumption of starting material, and when complete, the cooled reaction mixture was quenched with water (2 volumes). The resulting mixture was extracted with ethyl acetate (3×2 volumes). The organic layers were combined and concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0401] Step 5: Preparation of 2-(5-(cyclopropylmethyl)-4-(3,5-difluoro-4-sulfamoylbenzyl)-3-(4-fluorophenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0402] Into a round-bottom flask equipped with a magnetic stir bar was placed ethyl 2-[5-(cyclopropylmethyl)-4-[(3,5-difluoro-4-sulfamoylphenyl)methyl]-3-(4-fluorophenyl)pyrazol-1-yl]-1,3-thiazole-4-carboxylate (1.0 equiv), solid LiOH (8.0 equiv), MeOH (0.04 M) and H2O (0.04 M). The resulting solution was stirred at room temperature for 4 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC on an XBridge C18 column using 27:82 to 57:43 MeCN:water (+10 mM NH4HCO3) as a gradient elution over 7 minutes. The fractions containing the product were combined, concentrated and dried under vacuum to give the title product as a white solid (9% yield). LC-MS (ESI) m / z 549 (M+H) + MW: 548.56

[0403] Example 28: 2-(5-(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-3-(3,4,5-trifluorophenyl)- Preparation of 1H-pyrazol-1-yl)thiazole-4-carboxylic acid

[0404]

[0405] To a mixture of ethyl 2-[5-(cyclopropylmethyl)-4-[(3-fluoro-4-sulfamoyl-phenyl)methyl]-3-(trifluoromethylsulfonyloxy)pyrazol-1-yl]thiazole-4-carboxylate (Intermediate D, 1.0 equiv), tBuXPhos-Pd-G3 (0.1 equiv) and 3,4,5-trifluorophenylboronic acid (2.0 equiv) in 1,4-dioxane (0.06 M) was added anhydrous potassium phosphate (3.0 equiv). The mixture was degassed with nitrogen for 10 minutes and then heated to 90 ° C for 2 hours. Saturated NH4Cl aqueous solution (1 volume) and water (2.5 volumes) were added to the mixture and extracted with EtOAc (2×5 volumes). The combined extracts were washed with water (1.5 volumes) and concentrated under vacuum. The residue was dissolved in THF / MeOH (1:1 v / v) (1 volume). The 1M LiOH aqueous solution (6.0 equivalents) was added, and the mixture was stirred at 23 ° C for 16 hours. When LCMS analysis showed that the hydrolysis was complete, the mixture was acidified with formic acid (15 equivalents). The reaction mixture was directly loaded into the C18 pre-column and dried. The material was passed through reverse phase column chromatography, using a C18 post, with 10-100% CH containing 0.1% HCO h 3CN / water gradient elution to purify. The pure fractions from the main peak eluted with 83% CH 3CN were merged and lyophilized to obtain the title product (55% yield) as a white solid. 1H NMR (400MHz, d6-DMSO) δH 13.22 (br s, 1H), 8.29 (s, 1H), 7.63 (d, J = 8.0Hz, 1H), 7.57 (br s,2H),7.46(dd,J=6.5,8.5Hz,2H),7.12(d,J=11.5Hz,1H),7.02(d,J=8.0Hz,1H),4.18 (s,2H),3.16(d,J=7.0Hz,2H),1.15-1.07(m,1H),0.36-0.28(m,2H),0.23-0.17(m,2H). LC-MS(ESI)m / z 567(M+H)+. MW: 566.07

[0406] Example 29: Human LDHA enzyme assay

[0407] Compounds were dissolved in DMSO and pre-incubated with human recombinant C-terminal His-tagged LDHA (0.070 μg / mL) at room temperature in a black-walled, clear-bottomed, non-binding 96-well plate in an assay buffer consisting of 50 mM Tris, pH 7.5 and 100 mM NaCl for 10 min. An equal volume of substrate solution containing 100 μM pyruvate and 100 μM NADH in assay buffer was added to each well (final concentration 0.035 μg / mL enzyme, 50 μM pyruvate, 50 μM NADH and 1% DMSO). For human serum albumin (HSA) displacement assays, compounds were pre-incubated with enzymes in an assay buffer containing 20% ​​HSA before substrate addition (final concentration 10% HSA). The reaction was monitored at 340 nm for 15 min in a kinetic mode on a microplate reader (Molecular Devices). The reaction rate was determined by plotting the absorbance versus time.

[0408] Table 2 shows the LDHA enzyme inhibition of the following compounds classified according to potency: IC 50 <1nM=+++; IC between 1 and 10nM 50 =++; IC between 10nM and 100nM 50 =+.

[0409] Table 2.

[0410] Example <![CDATA[LDHA enzyme IC 50 > <![CDATA[LDHA enzyme + HSA IC 50 > Example 1 +++ ++ Example 2 +++ ++ Example 3 +++ ++ Example 4 ++ + Example 5 +++ ++ Example 6 +++ + Example 7 +++ ++ Example 8 +++ ++ Example 9 +++ ++ Example 10 +++ + Embodiment 11 +++ ++ Example 12 +++ ++ Example 13 +++ ++ Embodiment 14 +++ ++ Embodiment 15 +++ ++ Example 16 +++ + Embodiment 17 +++ ++ Embodiment 18 +++ ++ Embodiment 19 +++ ++ Embodiment 20 +++ ++ Embodiment 21 +++ + Embodiment 22 +++ ++ Embodiment 23 +++ ++ Embodiment 24 ++ ++ Embodiment 25 +++ + Embodiment 26 +++ + Embodiment 27 +++ ++ Embodiment 28 +++ ++

[0411] Example 30: Primary mouse hepatocyte assay

[0412] Compounds were evaluated in an in vitro assay consisting of fresh primary mouse hepatocytes. Hepatocytes were isolated from wild-type mice (C57BL / 6NCrl from Charles River Labs) using a two-step collagenase perfusion technique, which involves continuous perfusion of anesthetized mice with Hanks balanced salt solution and collagenase. After separation, surviving wild-type hepatocytes (0.1M cells / well) were incubated with test compounds in the presence of pyruvic acid, and compound efficacy was evaluated by measuring the lactic acid produced by cells using liquid chromatography coupled to mass spectrometry. Chromatographic separation was achieved at a flow rate of 1 mL / min on XDB-C18 4.6 × 50 mm columns (Agilent, catalog number 927975-902). Mobile phase A was composed of an aqueous solution of 0.1% formic acid and mobile phase B was composed of acetonitrile. A gradient program was started from 5% B, held for 1 minute, and then increased from 5% B to 95% B in 1 minute. After holding for 1 minute at 95% B, the program was changed back to 5% B. The column was equilibrated with 5% B for 1.5 min before the next injection. The mass spectrometer was operated in negative mode with electrospray ionization. The following transitions and their collision energies (CE) were used: 89→43 (CE: -16 V) for lactic acid and 13 C3-lactic acid (internal standard), 92→45 (CE: -16V).

[0413] Table 3 shows the inhibition of lactate production by the following compounds in a primary mouse hepatocyte assay. 50 <100nM=+++; IC between 100 and 250nM 50 =++; IC between 250nM and 1000nM 50 =+.

[0414] Table 3.

[0415]

[0416]

[0417] *Run at a hepatocyte concentration of 0.4M cells / well

[0418] Example 31: PH1 AGXT knockdown mouse model

[0419] In order to evaluate the in vivo efficacy of LDH inhibitors, a liver knockdown mouse model of the AGXT gene was developed. The model was generated by systemic administration of 0.4 mg / kg siRNA to c57bl / 6 male mice (8-12 weeks old, Charles River Labs). AGXT siRNA was encapsulated in lipid nanoparticles (XL-10 (KL-52) LNP, as described in WO2016 / 205410), and its sequence was: 5'-AcAAcuGGAGGGAcAucGudTsdT-3' (modified sense strand sequence, N: RNA residue; dN: DNA residue; n: 2'-O-methyl residue; s: phosphorothioate residue) and 5'-ACGAUGUCCCUCcAGUUGUdTsdT-3' (modified antisense strand sequence, see above for comments on residue modification). AGXT siRNA was administered intravenously on days 0 and 7 to maintain >90% knockdown of hepatic AGXT expression throughout the experimental study. The AGXT-KD model showed a strong increase in urinary oxalate excretion to a similar extent as AGXT knockout mice within 7 days after administration (Salido, Proc Natl Acad Sci, 2006, 103(48), 18249–18254). Before starting treatment with LDH inhibitors, urinary oxalate and creatinine levels were assessed and animals were assigned to treatment groups.

[0420] Certain selected compounds disclosed herein were orally administered at 5 mg / kg QD (PO) for 5 consecutive days, starting 8 days after the initial AGXT-siRNA administration. Once oral treatment was completed, mice were placed in metabolic cages and urine was collected over 24 hours. Urine collection was completed and sacrificed, and plasma / selected organs were collected and analyzed for drug concentrations.

[0421] Urinary oxalate and creatinine were quantified using commercially available kits according to the manufacturer's protocol (Trinity Biotech USA Inc., catalog number 591; R&D Systems, Inc., catalog number KGE005). Oxalate results were normalized to creatinine to account for urine dilution. Figure 1 As shown, the tested compounds of formula (I) were found to reduce urine oxalate (normalized to creatinine) on day 5, with the reduction ranging from 17% to 55%.

[0422] Table 4.

[0423]

[0424] Example 32: Study on liver targeted tissue distribution characteristics

[0425] In rats, the plasma and liver (target organ) concentrations of the test compound were determined after a single oral (PO) administration of the test compound. Male Sprague Dawley rats (6-8 weeks old, Charles River Labs) were fasted overnight and a single dose of the test compound (10 mg / kg; as a suspension in 0.5% methylcellulose) was administered by PO gavage. The rats were then killed at 4 and 24 h after the test compound was administered, and plasma and liver tissue samples were collected. Liver tissue samples were homogenized in 5 volumes of water: acetonitrile (50 / 50; v / v) mixture using a bead mill homogenizer. Plasma and liver homogenate samples were processed by protein precipitation using acetonitrile, and the concentration of the test compound was determined by liquid chromatography-tandem mass spectrometry (SciEx triple quad 5500+ and Exion UPLC).

[0426] The liver and plasma exposure of various compounds at the 4h and 24h time points are described below in Table 5. The compound concentrations measured were as follows: ++++>10μM; 10μM≥+++>5μM; 5μM≥++>1μM; 1μM≥+>0.25μM; and

[0427] 0.25μM≥-.

[0428] Table 5.

[0429]

[0430]

[0431] *Data obtained in C57 / bl6 mice following a 20 mg / kg PO dose

[0432] The XlogP values ​​of the compounds in Table 4 were also calculated using Vortex v2018.09.76561.64-s from Dotmatics Ltd. The XlogP distribution of the compounds in Table 5 is as follows Figure 2 shown.

[0433] Example 32: Rat Tolerance Assessment

[0434] In order to assess the potential tolerance profile of the compounds provided herein, an internal 7-day dose-limiting toxicity (DLT) study was performed in rats. The main variables assessed were body weight change, CBC parameters (including red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and reticulocytes) and serum biochemistry (alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, total bilirubin and creatine kinase).

[0435] Male Sprague Dawley rats (Charles River Laboratories) aged 8 weeks were weighed daily and the test compounds were orally administered QD for 7 consecutive days. The animals were sacrificed 24 h after the 7th administration.

[0436] At the end of the study, spleen weight was recorded, and portions of liver, muscle, testes, spleen, and kidney were collected to assess drug levels in these organs. Blood was collected and divided as follows: 1) serum samples for biochemistry, 2) CBC + manual reticulocyte count (K3EDTA), 3) CBC + automated reticulocyte count (K3EDTA), and 4) plasma samples for systemic drug level assessment.

[0437] The compound of formula (I) was tested at doses of 75, 125 and 300 mg / kg PO QD and compared to the reference LDH inhibitor disclosed in WO2016 / 109559 as compound ID 408, administered at 65 and 100 mg / kg PO QD. As shown in Table 6, the measurements of body weight, spleen weight, CBC parameters and serum biochemistry after seven days were found to be within the normal range at all three doses compared to the reference LDH inhibitor, indicating that the seven-day QD dose of 300 mg / kg of the compound of formula (I) was well tolerated in rats and provided a wider therapeutic window (>40x) relative to the LDH reference inhibitor.

[0438] Table 6.

[0439]

[0440] Analysis of drug concentrations of the compound of formula (I) in liver, muscle, testis, spleen, kidney and plasma collected at the end of the study (24 h after the last PO dose) showed a higher liver to non-liver tissue ratio than that found for the reference LDH inhibitor, indicating that the compound has greatly improved liver exposure compared to the reference compound. The reference LDH inhibitor exhibited a liver to muscle ratio of about 2:1, and in certain embodiments, the compound of formula (I) exhibited a liver to muscle ratio of greater than about 20:1, greater than about 25:1, greater than about 50:1, greater than about 80:1, or greater than about 100:1. The reference LDH inhibitor exhibited a liver to testis ratio of 6:1, and in certain embodiments, the compound of formula (I) exhibited a liver to testis ratio of greater than about 20:1, greater than about 25:1, greater than about 50:1, greater than about 80:1, or greater than about 100:1.

[0441] The above embodiments are intended to be exemplary only, and those skilled in the art will recognize or will be able to ascertain numerous equivalents to the specific compounds, materials, and procedures using only routine experimentation. All such equivalents are considered to be within the scope of the claimed subject matter and are covered by the appended claims. Since modifications will be apparent to those skilled in the art, the claimed subject matter is limited only by the scope of the appended claims.

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is O or S; X 1 is hydrogen, fluorine or chlorine; X 2 is hydrogen, fluorine or chlorine; R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3b is hydrogen, fluorine, chlorine, cyano or C 1-3 Haloalkyl; R 3c is hydrogen, fluorine or chlorine; R 3d is hydrogen, fluorine or chlorine; R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl; The condition is (i) when R 3b is fluorine, R 3a is methoxy and R 3c and R 3d are each hydrogen, or (ii) when R 3b is hydrogen, R 3a is isopropoxy and R 3c and R 3d are each hydrogen, or (iii) when R 3a , R 3b , R 3c and R 3d When all is hydrogen, then X 1 and X 2 is fluorine or chlorine; and provided that when R 3a It is CF3, R 3b is fluorine, and R 3c and R 3d When each is hydrogen, then R 10 Not cyclopropylmethyl.

2. The compound of claim 1, wherein R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3b is fluorine or chlorine, R 3c is hydrogen, fluorine or chlorine and R 3d It's hydrogen.

3. The compound according to claim 1 or 2, wherein R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3b is fluorine or chlorine; R 3c and R 3d Each is hydrogen.

4. The compound according to any one of claims 1 to 3, wherein R 3b is fluorine or chlorine, and R 3a , R 3c and R 3d Each is hydrogen.

5. The compound as claimed in claim 1, wherein R 3a , R 3b , R 3c and R 3d is fluorine, chlorine or cyano, and R 3a , R 3b , R 3c and R 3d The remainder of each is hydrogen.

6. The compound of claim 1, wherein R 3a and R 3b One of them is fluorine, chlorine, cyano or C 1-3 Alkoxy; R 3a and R 3b The other of is fluorine or hydrogen; and R 3c and R 3d Each is hydrogen.

7. The compound of claim 1, wherein (i) R 3a is fluorine or cyano; and R 3b , R 3c and R 3d are each hydrogen or (ii) R 3a is hydrogen, chlorine or C 1-3 Alkoxy; R 3b is fluorine or cyano; and R 3c and R 3d Each is hydrogen.

8. The compound according to claim 1 or 2, which has formula (Ia): or a pharmaceutically acceptable salt thereof, wherein: Y is O or S; X 1 is hydrogen, fluorine or chlorine; X 2 is hydrogen, fluorine or chlorine; R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3c is hydrogen or fluorine; and R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl; The condition is that when R 3a is methoxy and R 3c When it is hydrogen, then X 1 and X 2 is fluorine or chlorine; and provided that when R 3a is CF3, and R 3c When it is hydrogen, then R 10 Not cyclopropylmethyl.

9. The compound according to any one of claims 1 to 3, which has formula (Ib): or a pharmaceutically acceptable salt thereof, Among them, Y, R 3a , R 10 , X 1 and X 2 As mentioned above.

10. The compound according to any one of claims 1 to 5, which has formula (Ic): or a pharmaceutically acceptable salt thereof, wherein Y, R 10 , X 1 and X 2 As mentioned above.

11. The compound of any one of claims 1 to 9, wherein R 3a It is hydrogen, fluorine, chlorine, cyano, C 1-3 Alkoxy or C 1-3 Halogenated alkoxy.

12. The compound of any one of claims 1 to 11, wherein Y is S.

13. A compound as claimed in any one of claims 1 to 12, wherein R 10 It is C 3-4 Cycloalkyl C 1-3 alkyl.

14. A compound as claimed in any one of claims 1 to 13, wherein R 10 It is cyclopropylmethyl.

15. The compound of any one of claims 1 to 14, wherein X 1 It is fluorine or chlorine.

16. The compound of claim 1, selected from: or a pharmaceutically acceptable salt thereof.

17. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: X 1 is hydrogen, fluorine or chlorine; X 2 is hydrogen, fluorine or chlorine; R 3a It is fluorine, chlorine, cyano, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 1-3 Haloalkoxy; R 3c is hydrogen, fluorine or chlorine; and R 10 It is C 1-3 Alkyl, C 3-4 Cycloalkyl or C 3-4 Cycloalkyl C 1-3 alkyl, Provided that the following compounds are not included:

18. The compound of claim 17, wherein R 3a is fluorine or chlorine and R 3c It is fluorine or chlorine.

19. The compound of claim 17 or 18, which has formula (IIa): or a pharmaceutically acceptable salt thereof; Where R 3a , R 10 , X 1 and X 2 As mentioned above.

20. A compound as claimed in any one of claims 17 to 19, wherein R 3a It is fluorine or chlorine.

21. A compound as claimed in any one of claims 17 to 20, wherein X 1 It is fluorine or chlorine.

22. A compound as claimed in any one of claims 17 to 21, wherein X 1 is fluorine or chlorine and X 2 It's hydrogen.

23. The compound of any one of claims 1 to 22, wherein the compound is in the form of a pharmaceutically acceptable salt.

24. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 23 and a pharmaceutically acceptable carrier.

25. Use of a compound as claimed in any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 24, in the preparation of a medicament for treating a disease or condition associated with elevated oxalate levels.

26. The use of claim 25, wherein the elevated oxalate level is elevated urinary oxalate level.

27. The use of claim 25, wherein the elevated oxalate level is elevated plasma oxalate level.

28. The use of any one of claims 25 to 27, wherein the disease or disorder is hyperoxaluria, chronic kidney disease (CKD), end-stage renal disease (ESRD), or kidney stone disease.

29. The use according to claim 28, wherein the hyperoxaluria is primary hyperoxaluria or secondary hyperoxaluria.

30. The use of claim 29, wherein the primary hyperoxaluria is primary hyperoxaluria type 1 (PH-1), primary hyperoxaluria type 2 (PH-2), or primary hyperoxaluria type 3 (PH-3).

31. The use of any one of claims 25 to 30, wherein the subject suffering from the disease or condition has an AGXT, GRHPR or HOGA1 mutation, or a combination of mutations thereof.

32. Use of a compound as claimed in any one of claims 1 to 23 or a pharmaceutical composition as claimed in claim 24 in the preparation of a medicament for reducing oxalate levels.

33. Use of a compound as claimed in any one of claims 1 to 23 or a pharmaceutical composition as claimed in claim 24 in the preparation of a medicament for the treatment of kidney stone formation.

34. Use of a compound as described in any one of claims 1 to 23 or a pharmaceutical composition as described in claim 24 in combination with a second therapeutic agent in the preparation of a medicament for treating a disease or condition associated with elevated oxalate levels, reducing oxalate levels, or treating kidney stone formation, wherein the second therapeutic agent is a therapeutic agent that lowers glyoxylate or oxalate.

35. The use of claim 34, wherein the therapeutic agent that reduces glyoxylate or oxalate is a RNAi therapeutic agent.

36. The use of claim 34, wherein the therapeutic agent that lowers glyoxylate or oxalate is lumacilline, nedocilan, reloxatase, stiripentol, Oxalobacter formigenes, or vitamin B6.

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