Compounds and methods for treating oxalate-related disorders

Abstract

Disclosed herein are compounds and compositions that modulate glycolate oxidase, which are useful in the treatment of oxalate-related disorders, such as hyperoxaluria, and modulation of glycolate oxidase is expected to have therapeutic benefit in patients in need thereof. Methods for modulating glycolate oxidase activity in a human or animal subject are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 890,378, filed August 22, 2019, the entire disclosure of which is incorporated by reference for all purposes.

[0002] The present disclosure relates to novel compounds and compositions for treating diseases and their application as pharmaceuticals. Methods for treating oxalate-related diseases, including hyperoxaluria and related conditions, in human or animal subjects are also provided. [Background technology]

[0003] Oxalate-related diseases are characterized by the accumulation of oxalate or defective glyoxylate metabolism in a subject. Hyperoxaluria is an oxalate-related disease characterized by high urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical manifestations of hyperoxaluria. Primary hyperoxaluria is an inborn error of metabolism caused by mutations in at least one of several different hepatic enzymes involved in glyoxylate and hydroxyproline (HYP) metabolism. Oxalate is endogenously produced in humans through a pathway in which glycolate oxidase (GO or hGOX) oxidizes glycolate to glyoxylate. Glyoxylate is then subsequently converted to oxalate by lactate dehydrogenase (LDH). Mutations in hepatic enzymes involved in these related metabolic pathways result in the formation of excess oxalate, which is excreted through the kidneys.

[0004] In contrast, secondary hyperoxaluria is caused by increased dietary intake and absorption of oxalate and oxalate precursors or alterations in the intestinal microflora. Dietary oxalate comes from spinach, bran, rhubarb, sugar beets, potatoes, nuts, nut butter, and other foods. As urinary oxalate levels increase in hyperoxaluria, insoluble calcium oxalate crystals begin to form in the urinary tract and deposit in the renal tubules, resulting in impaired renal function. The spectrum of hyperoxaluria ranges from recurrent kidney stones (nephrolithiasis), nephrocalcinosis, and urinary tract infections to chronic kidney disease and ultimately end-stage renal disease. If the calcium oxalate load exceeds renal excretion capacity, calcium oxalate is also deposited in various organ systems via systemic oxalosis.

[0005] Increased urinary oxalate levels can help establish an early diagnosis of hyperoxaluria, while high plasma oxalate levels may be more indicative of when a patient has developed chronic kidney disease. The definitive diagnosis of primary hyperoxaluria is best achieved by genetic analysis, and if genetic studies prove indeterminate, a liver biopsy is attempted to confirm the diagnosis. Diagnostic clues pointing to secondary hyperoxaluria are a supplemental dietary history and tests to detect increased intestinal absorption of oxalate.

[0006] Conservative treatment for both types of hyperoxaluria involves active hydration and administration of crystallization inhibitors to reduce calcium oxalate precipitation. Pyridoxine has also been found to help approximately 30% of patients with primary hyperoxaluria type 1. Onset of the disease can occur anywhere from infancy to adulthood, is early onset in the absence of an organ transplant, and is usually fatal. Liver-kidney and isolated kidney transplants are treatment options for primary hyperoxaluria types 1 and 2, respectively. Data are scarce regarding the role of transplantation in primary hyperoxaluria type 3.

[0007] Currently, there are no widely effective treatment options for primary hyperoxaluria. More and better options are needed, such as compounds that inhibit glycolate oxidase, thereby reducing the concentration of glyoxylate available for conversion to oxalate. Early treatment to inhibit GO (often referred to as "substrate depletion therapy") reduces urinary oxalate concentrations before organ function is impaired. Summary of the Invention [Means for solving the problem]

[0008] Thus, novel compositions and methods are disclosed herein for targeting glycolate oxidase inhibition and treating hyperoxaluria. [Brief explanation of the drawings]

[0009] [Figure 1] Figure 1 shows urinary oxalate as a percentage of the vehicle-treated control group over time in days for Compound 1 administered at 10 and 30 mg / kg in the alanine-glyoxylate aminotransferase knockout (Agxt- / -) mouse model of primary hyperoxaluria 1 (PH-1). [Figure 2] Figure 1 shows urinary glycolic acid (μg / mL) over time in days for Compound 1 administered twice daily at 10 and 30 mg / kg to Agxt- / - mice. [Figure 3] 1 shows the mean plasma 24-hour AUC(fold) for compounds 1, 302, 343, and 356 in CD-1 mice at a dose of 10 mg / kg. [Figure 4] Plasma glycolic acid concentrations (μg / mL) are shown for vehicle and Compound 302 on Study Days 1, 2, and 4. Compound 302 was administered orally to male C57B1 / 6 mice at 30 mg / kg twice daily on days 1-4. [Figure 5]Figure 1 shows urinary oxalate (μM) over time in days for compound 302 administered orally twice daily at 3, 10, and 30 mg / kg to Agxt- / - mice on study days 0-4. [Figure 6] Figure 1 shows urinary glycolic acid (μg / mL) over time in days for compound 302 administered orally twice daily at 3, 10, and 30 mg / kg to Agxt- / - mice on study days 0-4. [Figure 7] Figure 1 shows urinary oxalate concentrations expressed as mg / g creatinine over a 24-hour period. These concentrations are plotted against time (days) for Compound 343 administered orally twice daily at 10 mg / kg to Agxt- / - mice compared to vehicle in Agxt- / - and wild-type C57B1 / 6 mice. [Figure 8] Figure 1 shows urinary glycolic acid concentrations expressed as mg / g creatinine over a 24-hour period. These concentrations are plotted against time (days) for Compound 343 administered orally twice daily at 10 mg / kg to Agxt- / - mice compared to vehicle in Agxt- / - and wild-type C57B1 / 6 mice. [Figure 9] 1 shows the plasma concentrations (ng / mL) of Compound 343 measured 6 hours after the first dose (day 1) and the last dose (day 7) in a 7-day dosing study in Agxt − / − mice. [Figure 10] Urinary oxalate concentrations expressed as mg / g creatinine over a 24-hour period are shown. These concentrations were plotted versus time (days) relative to vehicle. Agxt− / − mice were orally dosed once daily with compounds 343 and 356, respectively, on days 0-6 of the study. [Figure 11] Urinary glycolic acid concentrations (μg / mL) plotted against time (days) are shown for vehicle and compounds 343 and 356, each administered orally at 10 mg / kg once daily to Agxt− / − mice on study days 0–6. DETAILED DESCRIPTION OF THE INVENTION

[0010] Novel compounds and pharmaceutical compositions have been discovered, some of which have been found to treat oxalate-related disorders, including all types of hyperoxaluria, along with methods of synthesizing and using the compounds, including methods of treating hyperoxaluria in patients by administering the compounds.

[0011] Certain compounds disclosed herein have useful glycolate oxidase inhibitory activity and can be used to treat or prevent oxalate-related diseases. Accordingly, in a broad aspect, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods for preparing and using the compounds and compositions. Certain embodiments provide methods for modulating glycolate oxidase. Other embodiments provide methods for treating oxalate-related diseases in patients in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition disclosed herein. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for treating diseases or conditions ameliorated by modulation of glycolate oxidase.

[0012] The following specific embodiments are provided herein:

[0013] Embodiment 1: A compound of structural formula I [ka] wherein W is selected from N, NH, S, O, and CCH; X is selected from NH, S, O, and CH; Y is N or NH; R 1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 cycloalkyl; L is O, S, CH2, NH, NR 4 , S(O), SO2, and CR 4 =CR 5Selected from; A is selected from monocyclic or bicyclic aryl, and monocyclic or bicyclic heteroaryl; R 2 are independent, C6~C 10 selected from aryl, 5-10 membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, cyano, and halogen; n is 0, 1, or 2; R 3 is a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, a C6-C 10 Aryl, C1-C6 alkyl, C1-C6 sulfonyl, C3-C6 cycloalkyl, 3-10 membered heterocycloalkylalkyl, 5-10 membered heteroarylalkyl, C6-C 10 arylalkyl, and C3-C6 cycloalkylalkyl; R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl, or together with the atom to which they are attached, R 4 and R 5 forms a cycloalkenyl; and R 6 are each independently selected from 4- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, carboxyl, cyano, halogen, hydroxyl, methyl-4- to 6-membered heterocycloalkyl, and phenyl; and m is 0, 1, 2, or 3. or a salt, polymorph, or tautomer thereof.

[0014] Embodiment 2: wherein W is N, X is N, and Y is NH; W is CCH3, X is NH, and Y is N; W is CCH3, X is O, and Y is N; W is N, X is O, and Y is N; or The compound of embodiment 1, wherein W is N, X is CH, and Y is NH.

[0015] Embodiment 3: The compound of embodiment 2, wherein W is N, X is N, and Y is NH.

[0016] Embodiment 4: wherein R 2 are each independently a 5- to 10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C 10 The compound of any one of embodiments 1-3, wherein the aryl is selected from aryl, cyano, and halogen.

[0017] Embodiment 5: wherein R 3 is 3 to 10-membered heterocycloalkyl, 5 to 10-membered heteroaryl, C1 to C6 alkyl, C1 to C6 sulfonyl, C3 to C6 cycloalkyl, C3 to C6 cycloalkylalkyl, C6 to C 10 Aryl and C6-C 10 The compound of any one of embodiments 1-4, wherein the compound is selected from arylalkyl.

[0018] Embodiment 6: Structural Formula II [ka] (In the formula, R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is O, S, CH2, NH, NR 4 , S(O), SO2, and CR 4 =CR 5 Selected from; A is selected from monocyclic or bicyclic aryl, and monocyclic or bicyclic heteroaryl; R2 are each independently a 5- to 10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C 10 selected from aryl, cyano, and halogen; n is 0, 1, or 2; R 3 is a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, a C1-C6 alkyl, a C1-C6 sulfonyl, a C3-C6 cycloalkyl, a C3-C6 cycloalkylalkyl, a C6-C 10 Aryl and C6-C 10 arylalkyl; R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl, or together with the atom to which they are attached, R 4 and R 5 forms a cycloalkenyl; and R 6 are each independently selected from 4- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, carboxyl, cyano, halogen, hydroxyl, methyl-4- to 6-membered heterocycloalkyl, and phenyl; and m is 0, 1, 2, or 3. or a salt, polymorph, or tautomer thereof.

[0019] Embodiment 7: The compound of any one of embodiments 1-6, wherein A is selected from indazolyl, indolyl, naphthalenyl, oxazolyl, oxodihydropyridinyl, phenyl, pyridazinyl, pyridinyl, and thiazolyl.

[0020] Embodiment 8: The compound of any one of embodiments 1-6, wherein A is monocyclic aryl.

[0021] Embodiment 9: The compound of embodiment 8, wherein A is phenyl.

[0022] Embodiment 10: Structural Formula III [ka] (In the formula, R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is O, S, CH2, NH, NR 4 , S(O), SO2, and CR 4 =CR 5 Selected from; R 2 are each independently a 5- to 10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C 10 selected from aryl, cyano, and halogen; n is 0, 1, or 2; R 3 is a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, a C1-C6 alkyl, a C1-C6 sulfonyl, a C3-C6 cycloalkyl, a C3-C6 cycloalkylalkyl, a C6-C 10 Aryl and C6-C 10 arylalkyl; R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl, or together with the atom to which they are attached, R 4 and R 5 forms a cycloalkenyl; and R 6are each independently selected from 4- to 6-membered heterocycloalkyl, 5- to 10-membered heteroaryl, amino, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, carboxyl, cyano, halogen, hydroxyl, methyl-4- to 6-membered heterocycloalkyl, and phenyl; and m is 0, 1, 2, or 3. or a salt, polymorph, or tautomer thereof.

[0023] Embodiment 11: wherein R 3 is selected from methyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, cyclohexyl, tetrahydropyranyl, piperidinyl, dihydropyranyl, indazolyl, benzodioxolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, benzoxazolyl, oxodihydropyridinyl, thiazolyl, tetrazolyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, dioxaspirodecanyl, oxocyclohexyl, and bicyclo[1.1.1]pentyl, any of which may be selected from one, two, or three R 6 The compound of any one of embodiments 1 to 10, optionally substituted with a group.

[0024] Embodiment 12: wherein R 3 is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkylalkyl, any of which is selected from 1, 2, or 3 R 6 The compound of any one of embodiments 1 to 10, optionally substituted with a group.

[0025] Embodiment 13: wherein R 3 The compound of any one of embodiments 1-10, wherein is selected from propyl and cyclopropylmethyl.

[0026] Embodiment 14: wherein R 6 is selected from methyl, hydroxyl, amino, dimethylamino, propyl, cyclopropylmethyl, indazolyl, benzodioxolyl, cyclopropyl, tetrahydrofuranyl, cyclohexyl, tetrahydropyranyl, piperidinyl, methylpiperidinyl, phenyl, fluoro, chloro, methylsulfonyl, cyano, trifluoromethyl, methoxy, carboxyl, and fluoromethyl.

[0027] Embodiment 15: wherein R 6 is selected from chloro, methyl, cyano, fluoro, methylsulfonyl, methoxy, carboxyl, trifluoromethyl.

[0028] Embodiment 16: The compound of any one of embodiments 1 to 15, wherein m is 0.

[0029] Embodiment 17: Structural Formula IV [ka] (In the formula, R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is O, S, CH2, NH, NR 4 , S(O), SO2, and CR 4 =CR 5 Selected from; A is selected from monocyclic or bicyclic aryl, and monocyclic or bicyclic heteroaryl; R 2 are each independently a 5- to 10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C 10 selected from aryl, cyano, and halogen; n is 0, 1, or 2; R 3is selected from C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkylalkyl; and R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl, or together with the atom to which they are attached, R 4 and R 5 forms a cycloalkenyl) or a salt, polymorph, or tautomer thereof.

[0030] Embodiment 18: The compound of any one of embodiments 1 to 17, wherein L is selected from O, S, CH2, and NH.

[0031] Embodiment 19: The compound of embodiment 18, wherein L is O or S.

[0032] Embodiment 20: A compound of any one of embodiments 15-19, wherein A is selected from indazolyl, indolyl, naphthalenyl, oxazolyl, oxodihydropyridinyl, phenyl, pyridazinyl, pyridinyl, and thiazolyl.

[0033] Embodiment 21: The compound of embodiment 20, wherein A is monocyclic aryl.

[0034] Embodiment 22: The compound of embodiment 21, wherein A is phenyl.

[0035] Embodiment 23: wherein R 2 are each independently selected from fluoro, chloro, methyl, methoxy, trifluoromethyl, methylthio, methylsulfonyl, trifluoromethoxy, trifluoroethoxy, phenyl, and pyrazolyl.

[0036] Embodiment 24:R 2are each independently selected from fluoro, chloro, methyl, trifluoromethyl, methylsulfonyl, and methoxy.

[0037] Embodiment 25: The compound of any one of embodiments 1 to 24, wherein n is 0.

[0038] Embodiment 26:R 3 The compound of any one of embodiments 17-25, wherein is selected from isobutyl and cyclopropylmethyl.

[0039] Embodiment 27: Structural Formula V [ka] (In the formula, R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is selected from O and S; R 2 are each independently a 5- to 10-membered heteroaryl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 alkylsulfonyl, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkyl, C6-C 10 selected from aryl, cyano, and halogen; n is 0, 1, or 2; R 3 is selected from C2-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkylalkyl; and R 6 are respectively C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, cyano, halogen, and hydroxyl; and m is 0, 1, 2, or 3 11. The compound of embodiment 10, having:

[0040] Embodiment 28:R 1 28. The compound of embodiment 27, wherein is hydrogen.

[0041] Embodiment 29: The compound of embodiment 27 or 28, wherein n is 0.

[0042] Embodiment 30: n is 0 or 1, and, if present, R 6 30. The compound of any one of embodiments 27-29, wherein is halogen.

[0043] Embodiment 31:R 3 The compound of any one of embodiments 27-30, wherein is selected from C2-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkylmethyl.

[0044] Embodiment 32:R 3 is selected from ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and bicyclo[1.1.1]pentylmethyl.

[0045] Embodiment 33:R 3 is selected from ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0046] Embodiment 34:R 3 The compound of any one of embodiments 26-33, wherein is selected from isobutyl and cyclopropylmethyl.

[0047] Embodiment 35: Structural Formula VI, [ka] (In the formula, R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is selected from O, S, CH, and NH; and R 3 is selected from C2-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkylalkyl or a salt, polymorph or tautomer thereof.

[0048] Embodiment 36:R 1 The compound of any one of embodiments 1-35, wherein is selected from methyl, ethyl, isopropyl, t-butyl, and hydrogen.

[0049] Embodiment 37:R 1 The compound of embodiment 36, wherein is hydrogen.

[0050] Embodiment 38: The compound of embodiment 35, wherein L is O or S.

[0051] Embodiment 39:R 3 is selected from isobutyl and cyclopropylmethyl.

[0052] Embodiment 40: A compound selected from Examples 3 to 414, or a salt, polymorph, or tautomer thereof.

[0053] Embodiment 41: [ka] [ka] [ka] [ka] [ka] or a salt, polymorph or tautomer thereof.

[0054] Embodiment 42: A compound according to any one of embodiments 1 to 41, or a salt, polymorph, or tautomer thereof, for use as a medicament.

[0055] Embodiment 43: A compound according to any one of embodiments 1 to 41, or a salt, polymorph, or tautomer thereof, for use in the manufacture of a medicament for the prevention or treatment of an oxalate-related disease.

[0056] Embodiment 44: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 41, or a salt, polymorph, or tautomer thereof, together with a pharmaceutically acceptable carrier.

[0057] Embodiment 45: A pharmaceutical composition according to any one of embodiments 1 to 41, formulated for oral administration.

[0058] Embodiment 46: The pharmaceutical composition of any one of embodiments 1 to 41, further comprising another therapeutic agent.

[0059] Embodiment 47: A method for inhibiting glycolate oxidase (GOX) activity in a biological sample, comprising contacting the biological sample with a pharmaceutical composition according to any one of embodiments 44 to 46, or a compound according to any one of embodiments 1 to 41, or a salt, polymorph, or tautomer thereof.

[0060] Embodiment 48: A method of treating an oxalate-related disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition according to any one of embodiments 44-46, or a compound according to any one of embodiments 1-41, or a salt, polymorph, or tautomer thereof.

[0061] Embodiment 49: The method of embodiment 48, wherein the subject is a human.

[0062] Embodiment 50: The method of embodiment 49, wherein the oxalate-related disorder is hyperoxaluria.

[0063] Embodiment 51: The method of embodiment 50, wherein the oxalate-related disease is primary oxaluria.

[0064] Embodiment 52: The method of embodiment 50, wherein the oxalate-related disease is enteric hyperoxaluria.

[0065] Embodiment 53: The method of embodiment 48, wherein the oxalate-related disease is calcium oxalate kidney stones.

[0066] Embodiment 54: The method of embodiment 48, wherein the oxalate-related disease is idiopathic calcium oxalate stone disease (ICSF).

[0067] Embodiment 55: The method of embodiment 48, wherein the oxalate-related disease is calcium oxalate kidney stones after bariatric surgery.

[0068] Embodiment 56: The method of embodiment 48, wherein the oxalate-related disease is urolithiasis or nephrolithiasis for gastrointestinal diseases such as Crohn's disease and ulcerative colitis.

[0069] Embodiment 57: A method of treating an oxalate-related disorder in a subject in need thereof, comprising sequentially or simultaneously administering a pharmaceutical composition according to any one of embodiments 44-46, or a compound according to any one of embodiments 1-41, and a second therapeutic agent.

[0070] Embodiment 58: A pharmaceutical composition according to any one of embodiments 44 to 46, or a compound according to any one of embodiments 1 to 41, or a salt, polymorph or tautomer thereof, for use in human therapy.

[0071] Embodiment 59: A pharmaceutical composition according to any one of embodiments 44 to 46, or a compound according to any one of embodiments 1 to 41, or a salt, polymorph, or tautomer thereof, for use in treating an oxalate-related disorder.

[0072] Embodiment 60: Use of a compound according to any one of embodiments 1 to 41, or a salt, polymorph, or tautomer thereof, for the manufacture of a medicament for treating an oxalate-related disorder.

[0073] Formula Ia: [ka] Provided herein is a compound of the formula: wherein W is selected from N, NH, S, and CCH3; X is selected from N, NH, S, and O; When W is NH, S, or CH3, then Y is N; when W is N, then Y is NH; R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is CH2, NH, NR 4 , O, S, S(O), SO2, and CR 4 =CR 5 Selected from; A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, biaryl, and biheteroaryl; R 2are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; n is 0, 1, 2, or 3; R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 and any of the aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C3-C6 cycloalkyl C1-C6 alkylsulfonyl, C3-C6 heterocycloalkyl C1-C6 alkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl, including cyclic groups, is selected from 1, 2, or 3 R 6 optionally substituted with a group; R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl; and R 6are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl.

[0074] In certain embodiments, [ka] teeth, [ka] is selected from.

[0075] In certain embodiments, X is N.

[0076] Structural formula IIa [ka] Also provided is a compound of the formula: wherein W is selected from N, NH, S, and CCH3; When W is NH, S, or CH3, then Y is N; when W is N, then Y is NH; R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is CH2, NH, NR 4 , O, S, S(O), SO2, and CR 4 =CR 5Selected from; A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, biaryl, and biheteroaryl; R 2 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; n is 0, 1, 2, or 3; R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 and any of the aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C3-C6 cycloalkyl C1-C6 alkylsulfonyl, C3-C6 heterocycloalkyl C1-C6 alkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl, including cyclic groups, is selected from 1, 2, or 3 R 6 optionally substituted with a group; R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl; and R6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 6-membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl.

[0077] In certain embodiments, W is N or NH.

[0078] In certain embodiments, W is NH and Y is N.

[0079] In certain embodiments, [ka] teeth, [ka] is selected from.

[0080] In certain embodiments, [ka] teeth, [ka] is selected from.

[0081] In certain embodiments, L is O.

[0082] In certain embodiments, R 1 is hydrogen.

[0083] In certain embodiments, A is selected from phenyl and C6 monocyclic heteroaryl.

[0084] In certain embodiments, A is chosen from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyridinonyl.

[0085] In certain embodiments, A is one or more R 2 In certain embodiments, A is a monocyclic aryl optionally substituted with one or more R 2 In certain embodiments, A is biaryl optionally substituted with one or more R 2 In certain embodiments, A is a bicyclic aryl optionally substituted with one or more R 2 In certain embodiments, A is a monocyclic heteroaryl optionally substituted with one or more R 2 is a bicyclic heteroaryl optionally substituted with a group.

[0086] In certain embodiments, A is selected from phenyl, biphenyl, naphthyl, pyridinylphenyl, phenylpyridinyl, and bipyridinyl, any of which is selected from one or more R 2 The group is optionally substituted.

[0087] In certain embodiments, A is one or more R 2 In certain embodiments, A is phenyl optionally substituted with one or more R 2 In certain embodiments, A is biphenyl optionally substituted with one or more R 2 In certain embodiments, A is naphthyl optionally substituted with one or more R 2 In certain embodiments, A is a pyridinylphenyl optionally substituted with one or more R 2In certain embodiments, A is phenylpyridinyl optionally substituted with one or more R 2 Bipyridinyl optionally substituted with a group.

[0088] In certain embodiments, n is selected from 0, 1, or 2.

[0089] In certain embodiments, R 3 is selected from phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and 3-10 membered heterocycloalkyl.

[0090] In certain embodiments, R 3 is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridinonyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, pyranyl, and piperidinyl.

[0091] Structural formula IIIa [ka] Also provided is a compound of the formula: wherein W is selected from N, NH, S, and CCH3; When W is NH, S, or CH3, then Y is N; when W is N, then Y is NH; R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is CH2, NH, NR 4 , O, S, S(O), SO2, and CR 4 =CR 5 Selected from; A is one or more R 2 aryl, monocyclic or bicyclic heteroaryl, biaryl, and biheteroaryl, optionally substituted with a substituted or unsubstituted aryl group; B is C3-C6 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; R 2 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; n is 0, 1, 2, or 3; R 4 and R 5 are each independently selected from hydrogen or C1-C6 alkyl; R 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; and m is 0, 1, 2, or 3.

[0092] In certain embodiments, W is N or NH; when W is NH, Y is N; and when W is N, Y is NH.

[0093] In certain embodiments, W is N or NH.

[0094] In certain embodiments, W is NH and Y is N.

[0095] In certain embodiments, [ka] teeth [ka] is selected from.

[0096] In certain embodiments, [ka] teeth [ka] is selected from.

[0097] In certain embodiments, L is O.

[0098] In certain embodiments, R 1 is hydrogen.

[0099] In certain embodiments, A is selected from phenyl and C6 monocyclic heteroaryl.

[0100] In certain embodiments, A is chosen from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyridinonyl.

[0101] In certain embodiments, A is one or more R 2 In certain embodiments, A is a monocyclic aryl optionally substituted with one or more R2 In certain embodiments, A is biaryl optionally substituted with one or more R 2 In certain embodiments, A is a bicyclic aryl optionally substituted with one or more R 2 In certain embodiments, A is a monocyclic heteroaryl optionally substituted with one or more R 2 is a bicyclic heteroaryl optionally substituted with a group.

[0102] In certain embodiments, A is selected from phenyl, biphenyl, naphthyl, pyridinylphenyl, phenylpyridinyl, and bipyridinyl, any of which is selected from one or more R 2 The group is optionally substituted.

[0103] In certain embodiments, A is one or more R 2 In certain embodiments, A is phenyl optionally substituted with one or more R 2 In certain embodiments, A is biphenyl optionally substituted with one or more R 2 In certain embodiments, A is naphthyl optionally substituted with one or more R 2 In certain embodiments, A is a pyridinylphenyl optionally substituted with one or more R 2 In certain embodiments, A is phenylpyridinyl optionally substituted with one or more R 2 Bipyridinyl optionally substituted with a group.

[0104] In certain embodiments, n is selected from 0, 1, or 2.

[0105] In certain embodiments, B is selected from phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and 3-10 membered heterocycloalkyl.

[0106] In certain embodiments, B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridinonyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, pyranyl, and piperidinyl.

[0107] Also provided is a compound selected from Examples 3-231, or a salt or prodrug thereof.

[0108] In certain embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and / or salts or esters thereof.

[0109] In certain embodiments, compounds disclosed herein are provided in which one or more carbon-bonded hydrogen atoms can be replaced with deuterium. Such compounds are particularly useful for assays, monitoring metabolic studies, and internal standards.

[0110] Also provided herein are compounds disclosed herein, or salts or prodrugs thereof, for use as medicaments.

[0111] Also provided herein is a compound disclosed herein, or a salt or prodrug thereof, for use in the manufacture of a medicament for the prevention or treatment of an oxalate-related disease.

[0112] Also provided herein are pharmaceutical compositions comprising a compound disclosed herein, or a salt or prodrug thereof, in association with a pharmaceutically acceptable carrier.

[0113] In certain embodiments, the pharmaceutical composition is formulated for oral administration.

[0114] In certain embodiments, the pharmaceutical composition further comprises another therapeutic agent.

[0115] Also provided herein are methods for inhibiting glycolate oxidase (GOX) activity in a biological sample, the methods comprising contacting the biological sample with a pharmaceutical composition disclosed herein, a compound disclosed herein, or a salt or prodrug thereof.

[0116] Also provided herein are methods of treating an oxalate-related disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein, a compound disclosed herein, or a salt or prodrug thereof.

[0117] In certain embodiments, the subject is a human.

[0118] In certain embodiments, the oxalate-related disorder is hyperoxaluria.

[0119] In certain embodiments, the oxalate-related disease is primary hyperoxaluria.

[0120] In certain embodiments, the oxalate-related disease is primary hyperoxaluria type 1 (PH1).

[0121] In certain embodiments, the oxalate-related disease is enteric / secondary hyperoxaluria.

[0122] In certain embodiments, the oxalate-related disease is systemic oxalosis.

[0123] In certain embodiments, the oxalate-related disease is nephrolithiasis.

[0124] In certain embodiments, the oxalate-related disease is ureteral stones.

[0125] In certain embodiments, the oxalate-related disease is calcium oxalate kidney stones.

[0126] Also provided herein are methods of treating an oxalate-related disorder in a subject in need thereof, comprising the sequential or simultaneous administration of a pharmaceutical composition disclosed herein, or a compound disclosed herein, and a second therapeutic agent.

[0127] Also provided herein are pharmaceutical compositions disclosed herein, or compounds disclosed herein, or salts or prodrugs thereof, for use in human therapy.

[0128] Also provided herein are pharmaceutical compositions disclosed herein, or compounds disclosed herein, or salts or prodrugs thereof, for use in treating oxalate-related disorders.

[0129] Also provided herein is the use of a compound disclosed herein, or a salt or prodrug thereof, for the manufacture of a medicament for treating an oxalate-related disorder.

[0130] The following exemplary embodiments are also provided herein:

[0131] Embodiment P1: Formula I: [ka] wherein W is selected from N, NH, S, and CCH; X is selected from N, NH, S, and O; When W is NH, S, or CH3, then Y is N; when W is N, then Y is NH; R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is CH2, NH, NR 4 , O, S, S(O), SO2, and CR 4 =CR 5 Selected from; A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, biaryl, and biheteroaryl; R 2 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; n is 0, 1, 2, or 3; R 3is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 and any of the aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C3-C6 cycloalkyl C1-C6 alkylsulfonyl, C3-C6 heterocycloalkyl C1-C6 alkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl, including cyclic groups, is selected from 1, 2, or 3 R 6 optionally substituted with a group; R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl; and R 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6-membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl). or a salt or prodrug thereof.

[0132] Embodiment P2: [ka] but [ka] The compound according to embodiment P1, selected from:

[0133] Embodiment P3: A compound according to embodiment P1 wherein X is N.

[0134] Embodiment P4: Structural Formula II [ka] wherein W is selected from N, NH, S, and CCH; When W is NH, S, or CH3, then Y is N; when W is N, then Y is NH; R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is CH2, NH, NR 4 , O, S, S(O), SO2, and CR 4 =CR 5 Selected from; A is selected from monocyclic or bicyclic aryl, monocyclic or bicyclic heteroaryl, biaryl, and biheteroaryl; R 2 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; n is 0, 1, 2, or 3; R 3 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C 10 and any of the aryl, 5-10 membered heteroaryl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C3-C6 cycloalkyl C1-C6 alkylsulfonyl, C3-C6 heterocycloalkyl C1-C6 alkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl, including cyclic groups, is selected from 1, 2, or 3 R 6 optionally substituted with a group; R 4 and R 5 are each independently selected from hydrogen and C1-C6 alkyl; and R 6 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6-membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl). The compound of any one of embodiments P1 to P3, or a salt or prodrug thereof, having

[0135] Embodiment P5: The compound of any one of embodiments P1 to P4, wherein W is N or NH.

[0136] Embodiment P6: The compound of any one of embodiments P1 to P5, wherein W is NH and Y is N.

[0137] Embodiment P7: [ka] but [ka] The compound according to any one of embodiments P1 to P5, selected from:

[0138] Embodiment P8: [ka] but [ka] The compound according to embodiment P7, selected from:

[0139] Embodiment P9: The compound of any one of embodiments P1 to P8, wherein L is O.

[0140] Embodiment P10:R 1 The compound of any one of embodiments P1 to P9, wherein is hydrogen.

[0141] Embodiment P11: A compound according to any one of embodiments P1 to P10 wherein A is selected from phenyl and C6 monocyclic heteroaryl.

[0142] Embodiment P12: A compound according to embodiment P11 wherein A is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyridinonyl.

[0143] Embodiment P13: A is one or more R 2 The compound according to any one of embodiments P1 to P10, wherein the compound is monocyclic aryl optionally substituted with a group.

[0144] Embodiment P14: A is selected from one or more R 2 The compound according to any one of embodiments P1 to P10, which is biaryl optionally substituted with a group.

[0145] Embodiment P15: A is one or more R 2 The compound according to any one of embodiments P1 to P10, wherein the compound is a bicyclic aryl optionally substituted with a group.

[0146] Embodiment P16: A is selected from one or more R 2 The compound according to any one of embodiments P1 to P10, which is monocyclic heteroaryl optionally substituted with a group.

[0147] Embodiment P17: A is one or more R 2 The compound according to any one of embodiments P1 to P10, wherein the compound is a bicyclic heteroaryl optionally substituted with a group.

[0148] Embodiment P18: A is selected from phenyl, biphenyl, naphthyl, pyridinylphenyl, phenylpyridinyl, and bipyridinyl, any of which is selected from one or more R 2 The compound according to any one of embodiments P1 to P10, optionally substituted with a group.

[0149] Embodiment P19: A is one or more R 2 The compound according to any one of embodiments P1 to P10, wherein R is phenyl optionally substituted with a group.

[0150] Embodiment P20: A is one or more R 2 The compound according to any one of embodiments P1 to P10, which is biphenyl optionally substituted with a group.

[0151] Embodiment P21: A is selected from one or more R 2 The compound according to any one of embodiments P1 to P10, wherein the N-substituted naphthyl is optionally substituted with a group.

[0152] Embodiment P22: A is selected from one or more R 2 The compound according to any one of embodiments P1 to P10, which is pyridinylphenyl optionally substituted with a group.

[0153] Embodiment P23: A is selected from one or more R 2 The compound according to any one of embodiments P1 to P10, which is phenylpyridinyl optionally substituted with a group.

[0154] Embodiment P24: A is selected from one or more R 2 The compound according to any one of embodiments P1 to P10, which is bipyridinyl optionally substituted with a group.

[0155] Embodiment P25: A compound according to any one of embodiments P1 to P24, wherein n is selected from 0, 1, or 2.

[0156] Embodiment P26:R 3 The compound according to any one of embodiments P1 to P25, wherein is selected from phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and 3-10 membered heterocycloalkyl.

[0157] Embodiment P27:R 3 Compounds according to embodiment P26, wherein is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridinonyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, pyranyl, and piperidinyl.

[0158] Embodiment P28: Structural formula III [ka] wherein W is selected from N, NH, S, and CCH; When W is NH, S, or CH3, then Y is N; when W is N, then Y is NH; R 1 is selected from hydrogen, C1-C6 alkyl, and C1-C6 cycloalkyl; L is CH2, NH, NR 4 , O, S, S(O), SO2, and CR 4 =CR 5 Selected from; A is one or more R 2 aryl, monocyclic or bicyclic heteroaryl, biaryl, and biheteroaryl, optionally substituted with a substituted or unsubstituted aryl group; B is C3-C6 cycloalkyl, 3- to 12-membered heterocycloalkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl; R 2 are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; n is 0, 1, 2, or 3; R 4 and R 5 are each independently selected from hydrogen or C1-C6 alkyl; R 6are each independently selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-6 membered heterocycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylthio, C1-C6 haloalkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, pentafluorosulfanyl, sulfamoyl, C1-C6 alkylsulfamoyl, C1-C6 dialkylsulfamoyl, cyano, amino, N-acetylamino, C1-C6 alkylamino, C1-C6 dialkylamino, hydroxy, and C1-C6 hydroxyalkyl; and m is 0, 1, 2, or 3. or a salt or prodrug thereof.

[0159] Embodiment P29: A compound according to embodiment P28, wherein W is N or NH; when W is NH, Y is N; and when W is N, Y is NH.

[0160] Embodiment P30: A compound according to any one of embodiments P28-P29, wherein W is N or NH.

[0161] Embodiment P31: A compound according to embodiment P30 wherein W is NH and Y is N.

[0162] Embodiment P32: [ka] but, [ka] The compound according to any one of embodiments P28 to P31, selected from:

[0163] Embodiment P33: [ka] but, [ka] The compound according to embodiment P32, selected from:

[0164] Embodiment P34: A compound according to any one of embodiments P28 to P33, wherein L is O.

[0165] Embodiment P35:R 1 The compound according to any one of embodiments P28 to P34, wherein is hydrogen.

[0166] Embodiment P36: A compound according to any one of embodiments P28 to P35 wherein A is selected from phenyl and C6 monocyclic heteroaryl.

[0167] Embodiment P37: A compound according to embodiment P36 wherein A is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyridinonyl.

[0168] Embodiment P38: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, wherein the compound is monocyclic aryl optionally substituted with a group.

[0169] Embodiment P39: A is one or more R 2 The compound according to any one of embodiments P28 to P35, which is biaryl optionally substituted with a group.

[0170] Embodiment P40: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, wherein the compound is a bicyclic aryl optionally substituted with a group.

[0171] Embodiment P41: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, which is monocyclic heteroaryl optionally substituted with a group.

[0172] Embodiment P42: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, which is a bicyclic heteroaryl optionally substituted with a group.

[0173] Embodiment P43: A is phenyl, biphenyl, naphthyl, pyridinylphenyl, phenylpyridinyl, and bipyridinyl, any of which may be one or more R 2 The compound according to embodiment P42, optionally substituted with a group.

[0174] Embodiment P44: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, wherein the R is phenyl optionally substituted with a group.

[0175] Embodiment P45: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, which is biphenyl optionally substituted with a group.

[0176] Embodiment P46: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, wherein the compound is naphthyl optionally substituted with a group.

[0177] Embodiment P47: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, which is pyridinylphenyl optionally substituted with a group.

[0178] Embodiment P48: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, which is phenylpyridinyl optionally substituted with a group.

[0179] Embodiment P49: A is selected from one or more R 2 The compound according to any one of embodiments P28 to P35, which is bipyridinyl optionally substituted with a group.

[0180] Embodiment P50: A compound according to any one of embodiments P28 to P49, wherein n is selected from 0, 1, or 2.

[0181] Embodiment P51: A compound according to any one of embodiments P28 to P50 wherein B is selected from phenyl, 5-10 membered heteroaryl, C3-C6 cycloalkyl, and 3-10 membered heterocycloalkyl.

[0182] Embodiment P52: A compound according to embodiment P51 wherein B is selected from phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridinonyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furanyl, pyranyl, and piperidinyl.

[0183] Embodiment P53: A compound selected from Examples 3 to 231, or a salt or prodrug thereof.

[0184] Embodiment P54: A compound according to any one of Examples P1 to P53, or a salt or prodrug thereof, for use as a medicament.

[0185] Embodiment P55: A compound according to any one of embodiments P1 to P53, or a salt or prodrug thereof, for use in the manufacture of a medicament for the prevention or treatment of an oxalate-related disorder.

[0186] Embodiment P56: A pharmaceutical composition comprising a compound, a salt or a prodrug thereof according to any one of Examples P1 to P53, together with a pharmaceutically acceptable carrier.

[0187] Embodiment P57: A pharmaceutical composition according to embodiment P56 formulated for oral administration.

[0188] Embodiment P58: A pharmaceutical composition according to any one of embodiments P56-P57, further comprising another therapeutic agent.

[0189] Embodiment P59: A method for inhibiting glycolate oxidase (GOX) activity in a biological sample, comprising contacting the biological sample with a pharmaceutical composition described in any one of embodiments P56 and P58, or a compound described in any one of embodiments P1 to P53, or a salt or prodrug thereof.

[0190] Embodiment P60: A method of treating an oxalate-related disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition described in any one of embodiments 56 to 58, or a compound described in any one of embodiments P1 to P53, or a salt or prodrug thereof.

[0191] Embodiment P61: The method of embodiment P60, wherein the subject is a human.

[0192] Embodiment P62: The method of any one of embodiments P59P60, wherein the oxalate-related disorder is hyperoxaluria.

[0193] Embodiment P63: The method of any one of embodiments P59P60, wherein the oxalate-related disease is primary hyperoxaluria.

[0194] Embodiment P64: The method of any one of embodiments P63, wherein the oxalate-related disease is primary hyperoxaluria type 1 (PH1).

[0195] Embodiment P65: The method of any one of embodiments P59P60, wherein the oxalate-related disorder is enteric / secondary hyperoxaluria.

[0196] Embodiment P66: The method of any one of embodiments P59P60, wherein the oxalate-related disease is systemic oxalosis.

[0197] Embodiment P67: The method of any one of embodiments P59P60, wherein the oxalate-related disease is nephrolithiasis.

[0198] Embodiment P68: The method of any one of embodiments P59P60, wherein the oxalate-related disease is ureteral lithiasis.

[0199] Embodiment P69: The method of any one of embodiments P59P60, wherein the oxalate-related disease is calcium oxalate kidney stones.

[0200] Embodiment P70: A method of treating an oxalate-related disorder in a subject in need thereof, comprising the sequential or simultaneous administration of a pharmaceutical composition according to any one of embodiments P56 and P58, or a compound according to any one of embodiments P1 to P53, or a salt or prodrug thereof, and a second therapeutic agent.

[0201] Embodiment P71: A pharmaceutical composition according to any one of embodiments P56P58 or a compound according to any one of embodiments P1 to P53, or a salt or prodrug thereof, for use in human therapy.

[0202] Embodiment P72: A pharmaceutical composition according to any one of embodiments P56 to P58, or a compound according to any one of embodiments P1 to P53, or a salt or prodrug thereof, for use in the treatment of an oxalate-related disorder.

[0203] Embodiment P73: Use of a compound according to any one of embodiments P1 to P53, or a salt or prodrug thereof, for the manufacture of a medicament for treating an oxalate-related disorder.

[0204] In certain embodiments, compounds disclosed herein are provided in which one or more carbon-bonded hydrogen atoms can be replaced with deuterium. Such compounds are particularly useful for assays, monitoring metabolic studies, and internal standards.

[0205] definition As used herein, the following terms have the meanings indicated.

[0206] When introducing elements of the disclosure or embodiments thereof, the articles "a," "an," "one," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprise," "include," and "have" are inclusive and mean that there may be additional elements other than the listed elements.

[0207] When referring to a list of two or more items, the term "and / or" means that any of the listed items can be used alone or in combination with one or more other listed items. For example, the phrase "A and / or B" means either or both of A and B, i.e., A alone, B alone, or a combination of A and B. The phrase "A, B, and / or C" is intended to mean A alone, B alone, C alone, A and B in combination, A and C in combination, B and C in combination, or A, B, and C in combination.

[0208] When a range of values ​​is disclosed and the expression "n1... to n2" or "between n1 and n2" is used, if n1 and n2 are numbers, this expression is intended to include the number itself and the range between those numbers unless otherwise specified. The range may be an integer or continuous range, including values ​​between and including the end values. As an example, since carbon is an integer unit, a range of "2 to 6 carbons" is intended to include 2, 3, 4, 5, and 6 carbons. By way of comparison, a range of "1 to 3 μM (micromolar)" is intended to include 1 μM, 3 μM, and all significant digits therebetween (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0209] The term "about" qualifies the numerical value it modifies and indicates a variable value within a margin of error. When no margin of error is present, such as a standard deviation for the mean value shown in a chart or table of data, the term "about" refers to a range that encompasses the recited value and that can be rounded to the nearest significant figure.

[0210] As used herein, the term "acyl," alone or in combination, refers to a carbonyl linked to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom linked to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group linked to the parent molecule via a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl, and aroyl.

[0211] The term "alkenyl," as used herein alone or in combination, refers to a straight- or branched-chain hydrocarbon radical having one or more double bonds and containing 2 to 20 carbon atoms. In certain embodiments, an alkenyl contains 2 to 6 carbon atoms. The term "alkenylene" refers to a carbon-carbon double bond system connected at two or more positions, such as ethenylene (-CH=CH-, -C::C-). Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl, and the like. Unless otherwise specified, the term "alkenyl" can encompass an "alkenylene" group.

[0212] The term "alkoxy," as used herein alone or in combination, refers to an alkyl ether radical, where the term alkyl is defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0213] The term "alkyl," as used herein alone or in combination, refers to a straight- or branched-chain alkyl radical containing 1 to 20 carbon atoms. In certain embodiments, alkyl has 1 to 10 carbon atoms. In further embodiments, alkyl contains 1 and 8 carbon atoms. Alkyl groups are optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl, and the like. The term "alkylene," as used herein alone or in combination, refers to a saturated aliphatic group derived from a straight- or branched-chain saturated hydrocarbon linked at two or more positions, such as methylene (-CH-). Unless otherwise specified, the term "alkyl" can encompass an "alkylene" group.

[0214] The term "straight chain alkyl" means an alkyl radical containing 1 to 20 carbon atoms in an unbranched, linear arrangement. Examples of straight chain alkyl radicals include n-octyl (-CH2CH2CH2CH2CH2CH2CH2CH2-), n-butyl (-CH2CH2CH2CH2-), and ethyl (-CH2CH2-).

[0215] The term "alkylamino," as used herein alone or in combination, refers to an alkyl group linked to a parent molecule via an amino group. Suitable alkylamino groups can be mono- or di-alkylated to form, for example, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-ethylmethylamino, etc. Additionally, the alkyl groups of a dialkylamino can be joined to form heterocycloalkyls, either of which is optionally substituted.

[0216] The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0217] The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (RS-) radical, where the term alkyl is defined above and the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0218] The term "alkynyl," as used herein alone or in combination, refers to a straight- or branched-chain hydrocarbon radical having one or more triple bonds and containing 2 to 20 carbon atoms. In certain embodiments, the alkynyl contains 2 to 6 carbon atoms. In further embodiments, the alkynyl contains 2 to 4 carbon atoms. The term "alkynylene" refers to a carbon-carbon triple bond connected at two positions, such as ethynylene (-C:::C-, C≡C). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butynyl, butyn-2-yl, pentynyl, 3-methylbutynyl, hexyn-2-yl, and the like. Unless otherwise specified, the term "alkynyl" can encompass an "alkynylene" group.

[0219] The terms "amido" and "carbamoyl" refer to an amino group, as defined below, linked to the parent molecular moiety through a carbonyl group, or vice versa. As used herein, the term "C-amido" refers to a -C(O)N(RR') group with R and R' as defined herein or by the designated "R" groups specifically enumerated. As used herein, the term "N-amido" refers to a -RC(O)N(R')- group with R and R' as defined herein or by the designated "R" groups specifically enumerated. As used herein, the term "acylamino" refers to an acyl group linked to the parent molecule through an amino group. An example of an "acylamino" group is acetylamino-(CHC(O)NH-).

[0220] As used herein, the term "amino," alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R' may join to form a heterocycloalkyl, any of which may be optionally substituted.

[0221] The term "aryl," as used herein alone or in combination, refers to a carbocyclic aromatic system containing one, two, or three rings to which such polycyclic ring structures are fused. The term "aryl" encompasses aromatic groups such as phenyl, naphthyl, anthracenyl, and phenanthryl.

[0222] As used herein, the term "arylene" refers to phenylene ( [ka] and the corresponding meta and para isomers. Unless otherwise specified, the term "aryl" can include "arylene" groups.

[0223] The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group linked to the parent molecule through an alkenyl group.

[0224] The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group linked to the parent molecule through an alkoxy group.

[0225] The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group linked to the parent molecule through an alkyl group.

[0226] The term "arylalkynyl" or "aralkynyl" as used herein, alone or in combination, refers to an aryl group linked to the parent molecule through an alkynyl group.

[0227] The terms "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein alone or in combination, refer to acyl radicals derived from aryl-substituted alkanecarboxylic acids, such as benzoyl, naphthoyl, phenylacetyl, 3-phenylpropionyl(hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0228] The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy.

[0229] The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent radical CH= derived from benzene. Examples include benzothiophene and benzimidazole.

[0230] As used herein, the term "biaryl" refers to a first aryl group linked to a parent molecular moiety, where the first aryl group is substituted with a second aryl group. Examples of biaryl groups include biphenyl, 2-(2-pyridyl)phenyl, and 5-(2-naphthyl)-thien-1-yl.

[0231] As used herein, the term "biheteroaryl" refers to a first heteroaryl group linked to a parent molecular moiety, where the first heteroaryl group is substituted with a second heteroaryl group. An example of a biaryl group is 3,3'-bipyridinyl.

[0232] The term "carbamate," as used herein, alone or in combination, means an ester of carbamic acid (-NHCOO-), which may be attached to the parent molecular moiety from either the nitrogen or the acid terminus, and is optionally substituted as defined herein.

[0233] The term "O-carbamyl" as used herein, alone or in combination, refers to an -OC(O)NRR'- group, with R and R' as defined herein.

[0234] The term "N-carbamyl" as used herein, alone or in combination, refers to an ROC(O)NR'- group, with R and R' as defined herein.

[0235] As used herein, the term "carbonyl" when alone includes formyl (-C(O)H) and in combination is a -C(O)- group.

[0236] As used herein, the terms "carboxyl" or "carboxy" refer to -C(O)OH or the corresponding "carboxylate" anion, e.g., in the form of a carboxylic acid salt. An "O-carboxy" group refers to an RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR- group, where R is as defined herein.

[0237] The term "cyano," as used herein, alone or in combination, refers to --CN.

[0238] The term "cycloalkyl" or "carbocycle," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, where each cyclic radical moiety contains 3 to 12 carbon atom ring members, and may optionally be a benzo-fused ring structure, optionally substituted as defined herein. In certain embodiments, a cycloalkyl contains 5 to 7 carbon atoms. When a cycloalkyl is partially saturated, it can be referred to as a "cycloalkenyl," which is partially unsaturated and contains at least one C=C. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl, and the like.

[0239] As used herein, "bicyclic" and "tricyclic" are intended to encompass both fused ring structures, such as decahydronaphthalene, octahydronaphthalene, and polycyclic (multi-center) saturated or partially unsaturated types. Isomers of the latter type are generally exemplified by bicyclo[1.1.1]pentane, camphor, adamantane, and bicyclo[3,2,1]octane.

[0240] The term "cycloalkylene" refers to cyclohexylene ( [ka] and the corresponding 1,2- and 1,4-isomers, -CH 10 "cycloalkyl" refers to a cycloalkyl group that is linked at two or more positions, such as -. Unless otherwise specified, the term "cycloalkyl" can include "cycloalkylene" groups.

[0241] The term "diazanaphthalene," as used herein alone or in combination, refers to an analog of naphthalene having the formula CHN in which more than two CH groups are replaced with more than two N groups. Examples of diazanaphthalenes include cinnoline, phthalazine, and 1,8-diazanaphthalene.

[0242] As used herein, the term "bicyclic ring structure" refers to a group containing two different rings of atoms. In certain embodiments, the bicyclic ring structure contains a single atom common to both ring structures. In certain embodiments, the bicyclic ring structure contains two or more atoms common to both ring structures. Examples of compounds having bicyclic ring structures include decalin, norbornane, and pinene. Further examples of compounds having bicyclic ring structures include bicyclo[1.1.1]pentane, bicyclo[3.1.0.]hexane, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene, and 7-oxabicyclo[2.2.1]heptadiene. In certain embodiments, the bicyclic ring structure is [ka] is.

[0243] As used herein, the term "tricyclic ring structure" refers to a group containing three different rings of atoms. In certain embodiments, a bicyclic ring structure contains a single atom common to the two rings. In certain embodiments, a bicyclic ring structure contains two or more atoms common to the two rings. Examples of compounds having tricyclic ring structures include perhydroanthracene, cedrene, and taxadiene. Further examples of compounds having tricyclic ring structures are tricyclo[3.1.0.02,4]hexane, tricyclo[3.3.1.13,7]decane, and cyclopentadiene diepoxide.

[0244] The term "deuterium enrichment" refers to the percentage of deuterium incorporated at a given position in a molecule in place of hydrogen. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the natural distribution of deuterium is approximately 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is approximately 0.0156%. Deuterium enrichment can be determined using conventional analytical methods such as mass spectrometry and nuclear magnetic resonance spectroscopy.

[0245] The term "deuterium" when used to represent a given position in a molecular structure diagram is R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 , and R 11 or the symbol "D", when used to describe a given position in a molecule, means that the specified position is enriched with deuterium above the natural distribution of deuterium. In one embodiment, deuterium enrichment is about 1% or more, in another embodiment about 5% or more, in another embodiment about 10% or more, in another embodiment about 20% or more, in another embodiment about 50% or more, in another embodiment about 70% or more, in another embodiment about 80% or more, in another embodiment about 90% or more, or in another embodiment about 98% or more deuterium at the specified position.

[0246] The term "ester" as used herein, alone or in combination, refers to a carboxy group bridging two moieties joined by a carbon atom.

[0247] The term "ether" as used herein, alone or in combination, refers to an oxy group bridging two moieties joined by a carbon atom.

[0248] The terms "halo" or "halogen," as used herein, alone or in combination, mean fluorine, chlorine, bromine, or iodine.

[0249] The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0250] The term "haloalkyl," as used herein alone or in combination, refers to an alkyl radical having the meaning defined above in which one or more hydrogen atoms have been replaced with halogen. Specifically, monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals are included. For example, a monohaloalkyl radical may have an iodo, bromo, chloro, or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. "Haloalkylene" refers to a haloalkyl group connected at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCl-), and the like.

[0251] The term "halocycloalkyl," as used herein alone or in combination, refers to a cycloalkyl radical, as defined above, in which one or more hydrogen atoms have been replaced with halogen. The halocycloalkyl may be a saturated or partially saturated monocyclic, bicyclic, or tricyclic alkyl group, where each cyclic radical contains 3 to 12 carbon atom ring members and may optionally be a benzo-fused ring structure, optionally substituted as defined herein. Specific examples include monohalocycloalkyl, dihalocycloalkyl, and polyhalocycloalkyl radicals. For example, a cyclohaloalkyl radical may have iodo, bromo, chloro, or fluoro atoms within the radical. Dihalo and polyhalocycloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of halocycloalkyl include fluorocyclopropyl, fluorocyclobutyl, difluorocyclobutyl, fluorocyclohexyl, and difluorocyclohexyl.

[0252] The term "heteroalkyl," as used herein, alone or in combination, means a stable straight or branched chain, or cyclic, hydrogen radical, or combination thereof, fully saturated or containing one to three degrees of unsaturation, and consisting of the specified number of carbon atoms and one to three heteroatoms selected from O, N, and S, wherein the N and S atoms can be optionally oxidized. The N heteroatom can be optionally quaternized. The heteroatom can be replaced at any interior position of the heteroalkyl group. Up to two heteroatoms can be consecutive, for example, -CH-NH-OCH.

[0253] The term "heteroaryl," as used herein alone or in combination, refers to a 3- to 15-membered unsaturated heteromonocyclic ring or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one fused ring is aromatic and contains at least one atom selected from O, S, and N. In certain embodiments, a heteroaryl contains 1 to 4 heteroatoms as ring members. In further embodiments, a heteroaryl contains 1 to 2 heteroatoms as ring members. In certain embodiments, a heteroaryl contains 5 to 7 atoms. The term also encompasses fused polycyclic groups in which a heterocyclic ring is fused to an aryl ring, a heteroaryl ring is fused to another heteroaryl ring, a heteroaryl ring is fused to a heterocycloalkyl ring, or a heteroaryl ring is fused to a cycloalkyl ring. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, benzothiazolyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, and the like. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0254] As used herein, the term "heteroarylene," alone or in combination, refers to pyrimidinylene (2,3 isomers: [ka] "Heteroaryl" refers to heteroaryl groups linked at two or more positions, such as -CHN- (and including 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-isomers). Unless otherwise specified, the term "heteroaryl" can include "heteroarylene" groups.

[0255] As used herein, the terms "heterocycloalkyl" and, interchangeably, "heterocycle," used alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated (but non-aromatic) monocyclic, bicyclic, or tricyclic heterocyclic group containing at least one heteroatom as a ring member, where each heteroatom may be independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, a heterocycloalkyl comprises a spirocyclic ring system. In certain embodiments, a heterocycloalkyl comprises 1 to 4 heteroatoms as ring members. In further embodiments, a heterocycloalkyl comprises 1 to 2 heteroatoms as ring members. In certain embodiments, a heterocycloalkyl comprises 3 to 8 ring members in each ring. In further embodiments, a heterocycloalkyl comprises 3 to 7 ring members in each ring. In yet further embodiments, a heterocycloalkyl comprises 5 to 6 ring members in each ring. In further embodiments, a heterocycle comprises a bicyclic ring system. In further embodiments, a heterocycle comprises a tricyclic ring system. In further embodiments, heterocycles include bicyclic ring systems, bicyclic ring systems containing a three-atom ring. In further embodiments, heterocycles include bicyclic ring systems, bicyclic ring systems containing a four-atom ring. In further embodiments, heterocycles include bicyclic ring systems, bicyclic ring systems containing a five-atom ring. In further embodiments, heterocycles include bicyclic ring systems, bicyclic ring systems containing a pyrrolidine ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfone, sulfoxide, N-oxide of tertiary nitrogen ring members and carbocyclic fused and benzofused ring systems; further, both terms encompass systems in which a heterocycle is fused to an aryl group, as defined herein, or to an additional heterocyclic group.Examples of heterocyclic groups include 3-azabicyclo[3.1.0]hexan-6-yl, aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihydropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, etc. Heterocyclic groups are optionally substituted unless specifically prohibited.

[0256] The term "heterocycloalkylene" means a heterocycloalkyl group connected at two or more positions, such as piperazinylene (-C4H8N2-). Unless otherwise specified, the term "heterocycloalkyl" can include "heterocycloalkylene" groups.

[0257] The term "hydrazinyl," as used herein, alone or in combination, refers to two amino groups linked by a single bond, i.e., --NN--.

[0258] The term "hydroxy," as used herein, alone or in combination, refers to --OH.

[0259] The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

[0260] The term "imino," as used herein, alone or in combination, refers to =N-.

[0261] The term "iminohydroxy," as used herein, alone or in combination, refers to ═N(OH) and ═NO—.

[0262] The phrase "in the backbone" means the longest contiguous or contiguous chain of carbon atoms beginning at the point of attachment of a group to a compound of any one of the formulas disclosed herein.

[0263] The term "isocyanato" refers to an --NCO group.

[0264] The term "isothiocyanato" refers to the group -NCS.

[0265] The phrase "linear chain of atoms" means the longest linear chain of atoms independently selected from carbon, nitrogen, oxygen, and sulfur.

[0266] The term "lower," as used herein, alone or in combination, unless otherwise defined, means containing 1 to 6 carbon atoms (ie, C1-C8 alkyl).

[0267] As used herein, the term "lower aryl," alone or in combination, means phenyl or naphthyl, either of which is optionally substituted as provided.

[0268] As used herein, the term "lower heteroaryl," as used alone or in combination, means either 1) a monocyclic heteroaryl containing 5 or 6 ring members, 1 to 4 of which can be heteroatoms selected from O, S, and N, or 2) a bicyclic heteroaryl containing 5 or 6 ring members, each of the fused rings containing 1 to 4 heteroatoms selected from O, S, and N therebetween.

[0269] As used herein, the term "lower cycloalkyl," alone or in combination, refers to a monocyclic cycloalkyl having 3 to 6 ring members (i.e., C3-C6 cycloalkyl). A lower cycloalkyl can be an unsaturated alkyl. Examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0270] As used herein, the term "lower heterocycloalkyl," alone or in combination, refers to a monocyclic heterocycloalkyl having 3 to 6 ring members (i.e., C3-C6 heterocycloalkyl), 1 to 4 of which may be heteroatoms selected from O, S, and N. Examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyls may be unsaturated.

[0271] As used herein, the term "lower amino," as used alone or in combination, refers to -NRR', where R and R' are independently selected from hydrogen, alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, R and R' of a lower amino group may combine to form a 5- or 6-membered heterocycloalkyl, any of which may be optionally substituted.

[0272] The term "mercapto," as used herein, alone or in combination, refers to an RS-group, where R is defined herein.

[0273] The term "nitro," as used herein, alone or in combination, refers to --NO.sub.2.

[0274] The terms "oxy" or "oxa," as used herein, alone or in combination, refer to --O--.

[0275] The term "oxo", as used herein, alone or in combination, means =O.

[0276] The term "perhaloalkoxy" means an alkoxy group in which halogen atoms replace all hydrogen atoms.

[0277] The term "perhaloalkyl," as used herein, alone or in combination, refers to an alkyl group in which halogen atoms replace all of the hydrogen atoms.

[0278] The term "spirocyclic ring system" means a polycyclic ring system comprising two rings such that one atom is common to both rings.

[0279] As used herein, the terms "sulfonate," "sulfonic acid," and "sulfonic" used alone or in combination refer to the -SO3H group and its anion when sulfonic acid is used to form a salt.

[0280] The term "sulfanyl," as used herein, alone or in combination, refers to --S--.

[0281] The term "sulfinyl," as used herein, alone or in combination, refers to --S(O)--.

[0282] The term "sulfonyl," as used herein, alone or in combination, refers to -S(O)2-.

[0283] The term "N-sulfonamido" or "sulfamoyl" means an RS(=O)2NR' group, with R and R' as defined herein.

[0284] The term "S-sulfonamido" means an S(=O)2NRR' group, with R and R' as defined herein.

[0285] As used herein, the terms "thia" and "thio," alone or in combination, refer to an -S- group or ether where the oxygen is replaced by a sulfur. The oxidized derivatives of the thio group, namely, sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0286] The term "thiol", as used herein, alone or in combination, refers to a -SH group.

[0287] As used herein, the term "thiocarbonyl," alone and in combination, includes thioformyl-C(S)H, a -C(S)- group.

[0288] The term "N-thiocarbamyl" means an ROC(S)NR' group, with R and R' as defined herein.

[0289] The term "O-thiocarbamyl" means an --OC(S)NRR' group, with R and R' as defined herein.

[0290] The term "thiocyanato" refers to a -CNS group.

[0291] The term "trihalomethanesulfonamide" refers to a X3CS(O)2NR- group, where X is a halogen and R is as defined herein.

[0292] The term "trihalomethanesulfonyl" refers to a X3CS(O)2- group where X is a halogen.

[0293] The term "trihalomethoxy" refers to a X3CO- group where X is a halogen.

[0294] As used herein, the term "trisubstituted silyl," alone or in combination, refers to a silicone group substituted at its three free valences with a group described herein under the definition of substituted amino. Examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, etc.

[0295] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the appendant of any such definition is the link to the parent moiety. For example, the composite group alkylamido represents an alkyl group linked to the parent molecule via an amide group, and the term alkoxyalkyl represents an alkoxy group linked to the parent molecule via an alkyl group.

[0296] When a group is defined to be "zero", what is meant is that the group is absent.

[0297] The term "optionally substituted" means that the preceding group can be substituted or unsubstituted. When substituted, the substituents on the "optionally substituted" group include, but are not limited to, the following groups: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, and lower carboxy ester. The alkyl group may contain one or more substituents independently selected from the set of groups listed above, alone or in combination: lower carboxyamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N, SH, SCH, C(O)CH, COCH, COH, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea, or a specifically specified group. When two are structurally feasible, two substituents may be joined together to form a 5-, 6-, or 7-membered fused carbocyclic or heterocyclic ring consisting of 0 to 3 heteroatoms, for example, to form methylenedioxy or ethylenedioxy. Optionally substituted groups can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CF3). When a substituent is recited without any qualification as to substitution, both substituted and unsubstituted forms are encompassed. When a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents for a site can be defined as desired; in these cases, the defined optional substitution IS often immediately follows the phrase "optionally substituted with."

[0298] Unless otherwise defined, the terms R or R', appearing by themselves and without a number designation, refer to a moiety selected from hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, and heterocycloalkyl, any of which are optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether or not the R group is designated by a number, R, R', and R n All R groups, all substituents, and all terms, such as (n = (1, 2, 3, ... n)), should be understood to be independent of all others with respect to selection from a group. Any variable substituent or term (e.g., aryl, heterocycle, R, etc.) may occur more than once in a formula or generic structure; its definition at each occurrence is independent of its definition at every other occurrence. It will be further recognized by those skilled in the art that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as described. For example, an unsymmetrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.

[0299] Asymmetric centers exist in the compounds disclosed herein. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. The present disclosure encompasses all isomeric stereochemical forms, including diastereoisomeric, enantiomeric, and epimeric forms, as well as d- and 1-isomers, and mixtures thereof. Individual stereoisomers of the compounds can be synthetically prepared from commercially available starting materials containing chiral centers, or by preparation of a mixture of enantiomeric products, followed by separation, such as conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or other suitable methods known in the art. Starting compounds of particular stereochemistry are commercially available compounds or can be prepared and separated by techniques known in the art. Additionally, the compounds disclosed herein can exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, opposite (E), and same-side (Z) isomers as well as the appropriate mixtures thereof.

[0300] Compounds can exist as tautomers. The present disclosure provides all tautomeric isomers. For example, many embodiments contain a carboxylate group and a triazole ring substituted at the second position. In one tautomer, hydrogen is substituted at the position of Formula IIc: [ka] on the nitrogen adjacent to the carboxylate group, as shown in

[0301] In other tautomers, the hydrogen is represented by formula IIb: [ka] As shown in Figure 1, the hydroxyl group is on the nitrogen adjacent to the second site.

[0302] Crystallographic studies have yielded the tautomer of Formula IIb, which has a hydrogen atom on the nitrogen adjacent to the second position. Thus, the drawings and diagrams in this disclosure are shown for this tautomer as the primary tautomer. However, those skilled in the art will recognize that both tautomers are equivalent, and each compound, drawing, and diagram can be drawn for either isomer shown.

[0303] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In general, the solvated forms are considered equivalent to the unsolvated forms.

[0304] The term "bond" means a covalent bond between two atoms or two moieties, when the atoms connected by the bond are part of a larger substructure. Unless otherwise specified, the bond may be a single, double, or triple bond. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may or may not be present at that position.

[0305] The term "disease" as used herein is generally synonymous with, and used interchangeably with, the terms "disorder," "syndrome," and "pathology" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or parts thereof that impairs normal function, is usually manifested by distinct signs and symptoms, and reduces the lifespan or quality of life of a human or animal.

[0306] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disease described in this disclosure. Such administration includes co-administration of these agents substantially simultaneously, for example, in a single capsule having a fixed ratio of active ingredients, or in separate multiple capsules for each active ingredient. Such administration also includes the use of each type of therapeutic agent sequentially. In either case, the therapeutic regimen provides a beneficial effect of the drug combination in treating the condition or disease described herein.

[0307] The phrase "therapeutically effective" is intended to quantify the amount of active ingredient used in the treatment of a disease or disorder or for the effect of a clinical endpoint.

[0308] The term "therapeutically acceptable" means a compound (or salt, prodrug, tautomer, zwitterionic form, etc.) that is suitable for use in contact with the tissues of a patient without undue toxicity, irritation, or allergic response, and that is effective for its intended use, commensurate with a reasonable benefit / risk ratio.

[0309] As used herein, "treatment" of a patient is intended to include prevention. Treatment may be prophylactic, i.e., include prevention of disease. Prevention of disease may include complete prevention of disease, such as in the case of prevention of infection with a pathogen, or may include prevention of exacerbation. For example, prevention of disease may not mean complete loss of disease-related effects at any level. Instead, it may mean preventing disease symptoms to a clinically significant or detectable level. Prevention of disease may also mean preventing the progression of disease until a late stage of disease.

[0310] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0311] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds disclosed herein may also exist as prodrugs. A prodrug of a compound described herein is a structurally modified form of the compound that readily undergoes chemical changes under physiological conditions to provide the compound. Furthermore, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions relative to the parent drug. A wide variety of prodrug derivatives are known in the art, including derivatives that rely on hydrolysis or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound (the "prodrug") that is administered as an ester but is then metabolically hydrolyzed to the carboxylic acid, the active entity. A further example includes peptidyl derivatives of a compound.

[0312] Salts and Polymorphs The compounds disclosed herein can exist as therapeutically acceptable salts. The present disclosure encompasses the compounds shown above in the form of salts, such as acid addition salts. Suitable salts include salts formed with both organic and inorganic acids. Such acid addition salts are generally pharmaceutically acceptable. However, pharmaceutically unacceptable salts can be used in the preparation and purification of the compounds. Basic addition salts can also be formed and are pharmaceutically acceptable.

[0313] As used herein, the term "therapeutically acceptable salt" refers to a water- or oil-soluble or dispersible salt or zwitterionic form of a compound disclosed herein that is therapeutically acceptable as defined herein. The salt can be prepared during the final isolation and purification of the compound or separately by reacting the free base of the compound with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, cinnamate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethioate), lactate, maleate, and malonate. Salts include, for example, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Additionally, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfate; decyl chlorides, bromides, and iodides; lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Salts can also be formed by coordinating the compound with an alkali metal or alkaline earth ion. Thus, the present disclosure contemplates sodium, potassium, magnesium, calcium, and other salts of the compounds disclosed herein.

[0314] Basic addition salts are prepared during the final isolation and purification of compounds by reacting the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation, or with ammonia or an organic primary, secondary, or tertiary amine. Therapeutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0315] Salts of compounds can be prepared by reacting the appropriate acid with the free base form of the appropriate compound.

[0316] Formulation While the disclosed compounds can be administered as raw chemicals, they can also be presented as pharmaceutical formulations. Accordingly, provided herein are pharmaceutical formulations comprising one or more specific compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers / excipients thereof, and, optionally, one or more other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Appropriate dosage forms depend on the route of administration chosen. Any of the known techniques, carriers, and excipients may be used, as appropriate, and as understood in the art. The pharmaceutical compositions disclosed herein may be manufactured by any method known in the art, for example, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0317] Dosage forms include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal, and topical (including transdermal, buccal, sublingual, and ocular) administration. However, the most suitable route may vary, for example, depending on the condition and disease of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. In general, these methods include the step of bringing into association a compound disclosed herein or a pharmaceutically acceptable salt, ester, amide, prodrug, or solvate thereof (the "active ingredient") with the carrier, which constitutes one or more accessory ingredients. Generally, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired dosage form.

[0318] Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary, or paste.

[0319] Pharmaceutical preparations that can be used orally include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are made by compressing a free-flowing form such as a powder or granules in a suitable machine, optionally mixed with a binder, inert diluent, or lubricant, surface active agent, or dispersing agent. Molded tablets can be made by molding a mixture of an inert liquid diluent and a powdered compound in a suitable machine. Tablets can optionally be coated or scored and formulated to provide slow or controlled release of the active ingredient therein. All preparations for oral administration should be in dosages suitable for such administration. Push-fit capsules can contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. Stabilizers may also be added. The dragee core may be provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to tablets or dragee coatings to identify or characterize various combinations of active compound doses.

[0320] The compound can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers with added preservatives. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The formulations can be provided in single-dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a powdered or lyophilized condition, requiring only the addition of a sterile liquid carrier, for example, physiological saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the type described above.

[0321] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or excipients include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0322] In addition to the above-mentioned formulations, the compound can also be formulated as a depot preparation. Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or intramuscular injection. Thus, for example, the compound can be formulated with suitable polymers or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0323] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or conventionally formulated gels. Such compositions may comprise the active ingredient in a flavored base such as sucrose and acacia or tragacanth gum.

[0324] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0325] Certain compounds disclosed herein can be administered by non-systemic administration, including topical, i.e., external application of the compounds disclosed herein to the epidermis or oral cavity, and instillation of such compounds into the ear, eye, and nose so that the compounds do not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0326] Dosage forms suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, as well as drops suitable for otic, ocular, or nasal administration. For topical administration, the active ingredient may comprise, for example, 1 to 10% (w / w) (by weight) of the formulation. In certain embodiments, the active ingredient may comprise as much as 10% (w / w). In other embodiments, it may comprise 5% (w / w). In certain embodiments, the active ingredient may comprise 2 to 5% (w / w). In other embodiments, it may comprise 0.1 to 1% (w / w) of the formulation.

[0327] For administration by inhalation, the compound can be conveniently delivered from an insufflator, a nebulizer pressurized pack, or other convenient means for delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound can be a dry powder composition, for example, a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be provided in unit dosage form, for example, in capsules, cartridges, gelatin, or blister packs, from which the powder can be administered using an inhaler or insufflator.

[0328] Dosage unit formulations are those containing an effective amount, as hereinafter recited, or an appropriate fraction thereof, of the active ingredient.

[0329] In addition to the ingredients particularly mentioned above, the above-described formulations may contain other agents conventionally used in the art for the type of formulation in question, for example, flavoring agents suitable for oral administration.

[0330] The compounds may be administered orally or by injection at a dose of 0.1 to 500 mg / kg / day. The dose range for adults is generally 5 mg to 2 g / day. Tablets or other dosage forms of the formulation provided in discrete units conveniently contain one or more compounds in an amount that is effective in such a dosage amount, or as a multiple thereof, with each unit containing, for example, 5 to 500 mg, usually about 10 to 200 mg.

[0331] The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0332] The compound can be administered in various ways, for example, orally, topically, or by injection. The exact amount of compound administered to a patient is the responsibility of the attending physician. The specific dose level for a particular patient will vary depending on various factors, such as the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, excretion rate, drug combinations, the exact disease being treated, and the severity of the indication or condition being treated. The route of administration may also vary depending on the condition and its severity.

[0333] Combination therapy In certain cases, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in conjunction with other therapeutic agents. For example, it may be appropriate to administer an antihypertensive agent in conjunction with the primary therapeutic agent only if hypertension is one side effect experienced by the patient when administering one of the compounds described herein. Or, for example, the therapeutic effectiveness of one of the compounds described herein may be improved by administering an adjunct agent (i.e., the adjunct agent by itself may have only minimal therapeutic benefit, but when combined with other therapeutic agents, the overall therapeutic benefit to the patient is improved). Or, for example, the benefit received by the patient may be enhanced by administering one of the compounds described herein in conjunction with other therapeutic agents (including therapies) that also have therapeutic benefits. For example, in a treatment for primary hyperoxaluria that includes administering one of the compounds described herein, the therapeutic benefit may be enhanced by also providing the patient with other therapeutic agents for primary hyperoxaluria. In either case, regardless of the disease, disorder, or condition being treated, the overall benefit experienced by the patient may simply be the additive effect of the two therapeutic agents, or the patient may experience a synergistic benefit.

[0334] Therapies for treating glycolate oxidase-mediated disorders may be combined with the compounds described herein, including vitamin B-6, bacterial or recombinant enzyme degraders of dietary oxalate, and calcium phosphate and citrate, potassium phosphate and citrate supplements. Other therapies that may benefit from combination with the compounds described herein include those focused on oligonucleotide-mediated knockout of glycolate oxidase (e.g., Alnylam, Dicerna), lactate dehydrogenase A (LDHA) enzyme knockout (e.g., Dicerna), or CRISPR-Cas9-mediated disruption of glycolate oxidase (e.g., Intellia, Precision Biosciences), as well as treatments that require time to be effective, such as treatment with oxalate-metabolizing bacteria, such as Oxalobacter formigenesis (e.g., OxThera), which break down oxalate in the gastrointestinal tract.

[0335] In either case, the multiple therapeutic agents (at least one of which is a compound disclosed herein) can be administered in any order, or even simultaneously. If simultaneously, the multiple therapeutic agents can be provided in a single dosage form, a combined dosage form, or multiple dosage forms (by way of example only, as a single pill or as two separate pills). One of the therapeutic agents can be administered in multiple doses, or both can be administered in multiple doses. If not simultaneously, the timing between the multiple doses can be anywhere from a few minutes to four weeks.

[0336] Indications Accordingly, in another aspect, certain embodiments provide a method of treating a glycolate oxidase-mediated disease in a human or animal subject in need of such treatment, comprising administering to the subject a compound disclosed herein in combination with at least one additional agent known in the art for treating the disease in an amount effective to reduce or prevent the disease in the subject. In a related aspect, certain embodiments provide a therapeutic composition comprising at least one compound disclosed herein in combination with one or more additional agents for treating a glycolate oxidase-mediated disease.

[0337] Specific diseases treated by the compounds, compositions, and methods disclosed herein include oxalate-related diseases, e.g., hyperoxaluria, e.g., primary hyperoxaluria, enteric hyperoxaluria, idiopathic hyperoxaluria, oxalate toxicity, and kidney stones. The disease can be primary hyperoxaluria. The primary hyperoxaluria can be type 1 (PH-1). The primary hyperoxaluria can be type 2 (PH2). The primary hyperoxaluria can be type 3 (PH3). The disease can be enteric hyperoxaluria. The disease can be idiopathic hyperoxaluria. The disease can be oxalate toxicity. The symptom can be kidney stones.

[0338] Hyperoxaluria involves excessive urinary excretion of oxalate. Individuals with hyperoxaluria often have calcium oxalate kidney stones. It is sometimes called Bird's disease, named after Golding Bird, who first described the condition.

[0339] There are three known types of primary hyperoxaluria. Without being bound by theory, type 1 primary hyperoxaluria (PH-1) is caused by alanine-glyoxylate aminotransferase (AGXT), a key enzyme involved in the breakdown of oxalate. AGXT is expressed exclusively in the liver, and the encoded protein is largely localized to peroxisomes, where it is involved in glyoxylate detoxification. Mutations in this gene, some of which alter its intracellular targeting, cause type 1 primary hyperoxaluria. PH-1 is an example of a protein mistargeting disorder, in which AGXT exhibits a trafficking defect. Instead of being transported to peroxisomes, it is targeted to mitochondria, where it is catalytically active yet metabolically defective.

[0340] Without being bound by theory, primary hyperoxaluria type II (PH2) is associated with glyoxylate reductase / hydroxypyruvate reductase (GRHPR). Mutations in the GRHPR gene cause type II hyperoxaluria. PH2 is a complication of jejunoileal bypass or in patients who have lost much of their ileum but have an intact colon, causing excessive absorption of oxalate from the colon.

[0341] Without being bound by theory, type III primary hyperoxaluria (PH3) is associated with mutations in the mitochondrial dihydrodipicolinate synthase-like (DHDPSL) gene on chromosome 10, which encodes 4-hydroxy-2-oxoglutarate aldolase (HOGA1). This enzyme catalyzes the final step in the metabolic pathway of hydroxyproline. Using heterozygosity mapping, which searches for long heterozygosity patterns unique to all patients in each family and overlaps between families, and reconstructs haplotypes, we determined the allelic fragment shared by all patients of Ashkenazi Jewish descent who carry a three-base-pair deletion in DHDPSL. Overall, six mutations were detected: four missense mutations, one in-frame deletion, and one splice-site mutation.

[0342] The term "systemic oxalosis" refers to an excessively high level of oxalate in a subject's systemic circulation. Systemic oxalosis occurs when the kidneys stop excreting calcium oxalate crystals from the body through the urine, such as in subjects with primary and intestinal causes of hyperoxaluria. Because the kidneys have stopped functioning, oxalate crystals are deposited elsewhere in the body, such as in blood vessels, bones and organs, liver, kidneys, skin, nails, teeth, eyes, etc.

[0343] Prior to this disclosure, the primary therapeutic approach to primary hyperoxaluria was limited to symptomatic treatment, i.e., liver-kidney transplantation once the disease had already reached mature or end-stage stages. Genomics and proteomics approaches have been reported to elucidate some of the kinetics of AGXT folding that are directly related to its targeting to the appropriate subcellular location. Secondary hyperoxaluria is significantly more common than primary hyperoxaluria and is treated by dietary oxalate restriction and calcium supplementation. Children with primary hyperoxaluria must be treated with liver and kidney transplantation. When kidney transplantation is supplemented with liver transplantation, there is a tendency for a favorable outcome, assuming the disease originates from the liver.

[0344] Thus, the present disclosure fulfills a long felt and unmet need to treat hyperoxaluria, including types I, II, and III primary hyperoxaluria and secondary hyperoxaluria, particularly in children. The disclosed compounds and compositions can treat hyperoxaluria before the disease destroys the kidneys and liver and transplants are required.

[0345] In addition to being useful for human treatment, certain compounds and formulations disclosed herein may also be useful for veterinary treatment of mammals, companion animals such as rodents, exotic animals, and farm animals. Further examples of suitable animals include horses, dogs, and cats.

[0346] List of abbreviations Ac2O = acetic anhydride; AcCl = acetyl chloride; AcOH = acetic acid; AIBN = azobisisobutyronitrile; aq. = aqueous; BAST = bis(2-methoxyethyl)aminosulfur trifluoride; Bu = butyl; Bu3SnH = tributyltin hydroxide; CD3OD = deuterated methanol; CDCl3 = deuterated chloroform; CDI = 1,1'-carbonyldiimidazole; DAST = (diethylamino)sulfur trifluoride; dba = dibenzylideneacetone; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM = dichloromethane; DEAD = Diethyl azodicarboxylate; DIBAL-H = Diisobutylaluminum hydride; DIEA = DIPEA = N,N-diisopropylethylamine; DMAP = 4-dimethylaminopyridine; DMF = N,N-dimethylformamide; DMSO-d6 = Deuterated dimethyl sulfoxide; DMSO = Dimethyl sulfoxide; DPPA = Diphenylphosphoryl azide; dppf = 1,1'-bis(diphenylphosphino)ferrocene; EDC·HCl = EDCI·HCl = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride Salt; Et = ethyl; Et2O = diethyl ether; EtOAc = ethyl acetate; EtOH = ethanol; h = hour; HATU = 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium methanaminium hexafluorophosphate; HMDS = hexamethyldisilazane; HOBT = 1-hydroxybenzotriazole; iPr = i-Pr = isopropyl; iPrOH = i-PrOH = isopropanol; LAH = lithium aluminum hydride; LDA = lithium diisopropylamide; LiHMDS = Lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = methyl iodide; MeOH = methanol; MP-carbonate resin = macroporous triethylammonium methyl polystyrene carbonate resin; MsCl = mesyl chloride; MTBE = methyl tert-butyl ether; n-BuLi = n-butyllithium; NaHMDS = sodium bis(trimethylsilyl)amide; NaOEt = sodium ethoxide; NaOMe = sodium methoxide; NaOtBu = sodium t-butoxide; NBS = N-bromosuccinimide;NCS = N-chlorosuccinimide; NIS = N-iodosuccinimide; NMP = N-methyl-2-pyrrolidone; Pd(Ph3)4 = tetrakis-(triphenylphosphine)palladium(0); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); PdCl2(PPh3)2 = bis(triphenylphosphine)palladium(II) dichloride; PG = protecting group; Ph = phenyl; prep-HPLC = preparative high-performance liquid chromatography; PMBCl = para-methoxybenzyl; PMBCl = para-methoxybenzyl chloride; PMBOH = para-methoxybenzyl alcohol; PyBop = (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate; Pyr = pyridine; RT = room temperature; RuPhos = 2-dicyclohexylphos Phino-2',6'-diisopropoxybiphenyl; sat. = saturated; ss = saturated solution; tBu = t-Bu = tert-butyl 1,1-dimethylethyl; TBAF = tetrabutylammonium fluoride; TBDPS = t-butyldiphenylsilyl; t-BuOH = tert-butanol; T3P = propylphosphonic anhydride; TEA = Et3N = triethylamine; TFA = trifluoroacetic acid; TFAA = trifluoroacetic anhydride; THF = tetrahydrofuran; TIPS = triisopropylsilyl; Tol = toluene; TsCl = tosyl chloride; Trt = trityl (triphenyl)methyl; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. [Example]

[0347] General synthetic methods for preparing compounds Unless otherwise specified, all experiments were performed under an atmosphere of dry argon in oven-dried glassware using standard Schlenk techniques. Experiments performed in an oil bath were performed using Fisher Scientific silicone oil in Pyrex crystallization dishes on an IKARCT Basic Model electromagnetic hotplate stirrer equipped with an ETS-D5 electronic contact thermometer. Glovebox operations were performed in an MBraun Unilab glovebox under an atmosphere of dry argon. All reagents were purchased from Sigma-Aldrich or Alfa Aesar and used without further purification unless otherwise specified. Precatalyst was purchased from Total Synthesis Ltd. (Toronto, Canada). All reaction vials (15 x 45 mm with screw-top lids and caps) were purchased from Fisher Scientific. Analytical thin-layer chromatography (TLC) was performed on EMD60F254 precoated glass plates, and spots were visualized under UV light (254 nm). Column chromatographic purification was carried out using flash techniques on ZEOprep 60 silica gel (40-63 μm).

[0348] In general, the following scheme can be used to practice the present disclosure. [ka]

[0349] Scheme I shows the formation of a chlorotriazole formed from the reaction of ethyl diazoacetate with carbonimidic dichloride. The chlorotriazole is then reacted with a halogen-substituted aryl group (L is oxygen, nitrogen, or sulfur) under basic conditions to give a bromophenyl-linked triazole. Bromine is then reacted in a Sonogashira cross-coupling reaction in the presence of a palladium and copper catalyst and an alkynyl reagent. [ka]

[0350] Scheme II shows an alternative route for triazole formation. Thus, benzyl chloride is converted to an azide by nucleophilic substitution. Cycloaddition of the azide with diethyl malonate gives a hydroxytriazole, which is converted to a chlorotriazole. The chlorotriazole is further reacted with a halogen-substituted aryl group (L is oxygen, nitrogen, or sulfur) to produce a bromophenoxytriazole. Similar to Scheme I, bromine is then reacted in a Sonogashira cross-coupling reaction in the presence of a palladium and copper catalyst and an alkynyl reagent. [ka]

[0351] Scheme III shows the reaction of an acetylene-substituted phenol with chlorotriazole under basic conditions to give an alkynylphenoxytriazole. The above method can be modified to accommodate alternative reagents in the first step, such as substituted or unsubstituted monocyclic or bicyclic aryls, monocyclic or bicyclic heteroaryls, biaryls, and biheteroaryls, such as biphenyl, naphthyl, pyridinylphenyl, phenylpyridinyl, or bipyridinyl. [ka]

[0352] Scheme IV shows a synthetic method for preparing O-linked 1H-1,2,3-triazole-4-carboxylic acids via a Sonogashira cross-coupling. The bromine is replaced with a protected ethynyl group, which is then deprotected to give a terminal alkyne. This terminal alkyne is coupled to a bromo or iodoaryl group in a second Sonogashira cross-coupling. [ka]

[0353] Scheme V shows an alternative Sonogashira cross-coupling in which the alkynyl reagent already contains a phenyl group. [ka]

[0354] Scheme VI shows the chlorination of the aminopyrazole followed by protection. The chloropyrazole is then displaced under basic conditions with a halogenated aryl group (L is oxygen, nitrogen, or sulfur) to give a halogenated phenyl-linked pyrazole, which is converted to the final compound as described in Scheme II. [ka]

[0355] Scheme VII shows the conversion of phenylacetic acid to ethyl 3-oxo-4-phenyl butanoate, which is cyclized in the presence of an azide to form a triazole. The triazole is first deprotected. After hydrolysis, similar to Scheme II, the aryl halide is then coupled with a substituted trimethylsilylacetylene under Sonogashira coupling conditions to give the desired compound. [ka]

[0356] Scheme VIII shows the alkylation of 3-bromopyridin-2(1H)-one with iodomethane under basic conditions. 3-Bromo-1-methylpyridin-2(1H)-one is then converted to a boronic ester in the presence of an iridium catalyst. The boronic ester is then oxidized to 3-bromo-5-hydroxy-1-methylpyridin-2(1H)-one, which is used to displace chlorotriazole to give a substituted triazole. This triazole is then converted to the final compound using the method described in Scheme II. [ka]

[0357] Scheme IX shows the conversion of an aminooxadiazole to a nitrooxadiazole. The nitrodiazole was replaced with an acetylene-substituted phenol to give the final compound.

[0358] S N General sulfination procedure with Ar An oven-dried, argon-filled vial (A) (8 mL) containing a magnetic stir bar was charged with 36 mg (0.75 mmol, 1.1 equiv.) of sodium hydride and thiophenol (0.780 mmol, 1.15 equiv.). The vial was sealed with a screw cap and refilled with argon three times. N,N-dimethylformamide (3 mL) was then added via syringe, and the solution was stirred for 10 minutes. A second oven-dried, argon-filled vial (B) (8 mL) containing a magnetic stir bar was then charged with an aryl halide (0.68 mmol, 1.0 equiv.), sealed with a screw cap, and refilled with argon three times. The contents of vial A were then transferred to vial B via syringe. Vial B was then placed in a preheated oil bath at 70 °C and stirred for 24 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (5×20 mL), brine (20 mL), and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel to give the desired product.

[0359] General sulfination procedure via cross-coupling An oven-dried, argon-filled vial (A) (8 mL) containing a magnetic stir bar was charged with 52.7 mg (0.470 mmol, 1.10 equiv.) of potassium tert-butoxide and thiophenol (0.490 mmol, 1.15 equiv.). The vial was sealed with a screw cap and refilled with argon three times. Toluene (1 mL) was then added via syringe, and the solution was stirred for 10 minutes. A second oven-dried, argon-filled vial (B) (8 mL) containing a magnetic stir bar was then charged with the aryl halide (0.43 mmol, 1.0 equiv.), 2.8 mg (0.043 mmol, 0.1 equiv.) of lithium isopropoxide, and Pd-PEPPSI™-IPent. Cl Vial B was then sealed with a screw cap, backfilled with argon three times, and toluene (3 mL) was added via syringe. The contents of vial B were then transferred via syringe to vial A and stirred for 24 hours. The reaction mixture was then cooled to room temperature and passed through a plug of silica with ethyl acetate. The filtrate was concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel to give the desired product.

[0360] Common S in phenoxide N Ar procedure An oven-dried, argon-filled vial (A) (8 mL) containing a magnetic stir bar was charged with 36 mg (0.75 mmol, 1.1 equiv.) of sodium hydride and phenol (0.780 mmol, 1.15 equiv.). The vial was sealed with a screw cap and backfilled with argon three times. N,N-Dimethylformamide (3 mL) was then added via syringe, and the solution was stirred for 30 minutes. A second oven-dried, argon-filled vial (B) (8 mL) containing a magnetic stir bar was then charged with an aryl halide (0.68 mmol, 1.0 equiv.), sealed with a screw cap, and backfilled with argon three times. The contents of vial A were then transferred to vial B via syringe. Vial B was then placed in a preheated oil bath at 80 °C and stirred for 24 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (150 mL), washed with water (5×20 mL), brine (20 mL), and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel to give the desired product.

[0361] General PMB group removal procedure A vial (8 mL) containing a magnetic stir bar was charged with a molecule containing a PMB group (50–200 mg) and 3 mL of trifluoroacetic acid. The vial was sealed with a screw cap, placed in a preheated oil bath at 70 °C, and stirred for 24 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate (150 mL), washed with 5% sodium bicarbonate (2 × 50 mL), brine (20 mL), and the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel to give the desired product.

[0362] General ethyl ester hydrolysis procedure A charged vial (8 mL) containing a magnetic stir bar was charged with the ethyl ester (20 mg-150 mg) and 5 mL of 1N KOH. The vial was sealed with a screw cap and stirred at room temperature for 6 hours. The pH was adjusted to 2-3 using 0.1N HCl, and the contents of the vial were extracted with ethyl acetate (3 x 50 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by trituration in diethyl ether to give the desired product.

[0363] The following compounds are prepared by the method of Scheme IV: Intermediate 1: Synthesis of ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate Step 1-Ethyl 5-chloro-1,2,3-triazole-4-carboxylate: [ka] A 100 mL round-bottom flask containing a stir bar was charged with 6.2 mL (58 mmol, 2.0 equiv.) of ethyl diazoacetate, sealed with a rubber septum, and backfilled with argon three times. Acetonitrile (35 mL) was transferred to the flask via syringe, and the flask was then cooled to 0 °C. Next, 2.2 mL (29 mmol, 1.0 equiv.) of phosgene was added dropwise, and the reaction mixture was stirred at room temperature for 20 h. The solvent was removed in vacuo, and the crude product was purified by silica gel column chromatography (4% ethyl acetate / hexanes) to afford the title compound (1.6 g, 26%) as a colorless oil.

[0364] Step 2-4-Methoxybenzyl chloride [ka] A 250 mL round-bottom flask containing a stir bar was charged with 4-methoxybenzyl alcohol (8.34 g, 6.00 mmol, 1.00 equiv.), sealed with a rubber septum, and refilled with argon three times. The alcohol was then dissolved in 100 mL of diethyl ether transferred via syringe, followed by the dropwise addition of 8.9 mL (12 mmol, 2.0 equiv.) of thionyl chloride via syringe. The reaction mixture was stirred at room temperature for 5 h. Water (50 mL) was then slowly added to quench the reaction mixture (Caution: HCl gas was evolved). The aqueous and organic phases were separated, and the aqueous layer was extracted with dichloromethane (2 × 50 mL). The organic layers were combined, washed with saturated sodium bicarbonate (2 × 50 mL), water (2 × 50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed in vacuo to give 4-methoxybenzyl chloride (8.9 g, 94%) as a colorless oil. 1 H-NMR(300MHz, CDCl3)δ:7.32(d,2H),6.89(d,2H),4.57(s,2H),3.81(s,3H).

[0365] Step 3-4-Methoxybenzyl azide [ka] A 50 mL round-bottom flask A containing a stir bar was charged with 2.10 g (31.8 mmol, 1.00 equiv.) of sodium azide, sealed with a rubber septum, and refilled with argon three times. A 50 mL round-bottom flask B was charged with 5.00 g (31.8 mmol, 1.00 equiv.) of 4-methoxybenzyl chloride, sealed with a rubber septum, and refilled with argon three times. N,N-Dimethylformamide (20 mL) was added to flask B to dissolve the 4-methoxybenzyl chloride, which was then transferred to flask A and stirred at room temperature for 24 h. The mixture was then diluted with water (200 mL) and extracted with diethyl ether (3 × 50 mL). The combined extracts were washed with water (5 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to give the title compound (4.94 g, 95%) as a colorless oil. 1H-NMR(400MHz, CDCl3)δ:7.25(d,2H),6.91(d,2H),4.26(s,2H),3.81(s,3H).

[0366] Step 4-Ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate [ka] A 100 mL round-bottom flask containing a stir bar was charged with 4.19 g (26.0 mmol, 1.00 equiv.) of diethyl malonate, 10.0 mL of 30% sodium ethoxide in ethanol (26.0 mmol, 1.00 equiv.), and ethanol (30 mL). The flask was sealed with a rubber septum and refilled with argon three times. After stirring for 30 minutes, a solution of 4.25 g (26.0 mmol, 1.00 equiv.) of 4-methoxybenzyl azide in ethanol (10 mL) was added dropwise with stirring. The mixture was then refluxed for 18 hours. After cooling, the ethanol was removed in vacuo, and water was added. The pH was adjusted to 2 with hydrochloric acid to give a crystalline precipitate, which was filtered, washed with water, and purified with PO. 10 It was dried in vacuo over a desiccant and recrystallized from chloroform-pentane to give the title compound (4.6 g, 67%) as an off-white solid. 1 H-NMR(400MHz,DMSO-d6)δ:7.20(d,2H),6.90(d,2H),5.25(s,2H),4.23(q,2H),3.72(s,3H),1.26(t,3H).

[0367] Step 5: Synthesis of ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate [ka] A 100 mL round-bottom flask containing a stir bar was charged with 3.70 g (13.3 mmol, 1.00 equiv.) of ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and 40 mL of toluene. While stirring, 3.0 g (14 mmol, 1.1 equiv.) of phosphorus pentachloride was slowly added to the round-bottom flask. The mixture was stirred at 40° C. under argon for 90 minutes. The solvent was removed in vacuo, and the residue was dissolved in diethyl ether, washed with saturated sodium bicarbonate (3×50 mL), water (2×50 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed in vacuo. Recrystallization from diethyl ether-pentane afforded the title compound (2.53 g, 65%) as an off-white solid. 1 HNMR(300MHz,CDCl3)δ:7.26(d,2H),6.87(d,2H),5.50(s,2H),4.42(q,2H),3.79(s,3H),1.40(t,3H).

[0368] Example 1: 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid Step 1: Ethyl 5-(3-((triisopropylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate [ka] A 10 mL round-bottom flask containing a stir bar was charged with ethyl 5-(3-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate (265 mg, 0.85 mmol, 1.00 equiv.), ethynyltriisopropylsilane (0.25 mL, 2.55 mmol, 3.00 equiv.), (PhP)PdCl (120 mg, 0.17 mmol, 0.20 equiv.), and CuI (34.0 mg, 0.17 mmol, 0.20 equiv.), sealed with a rubber septum, and refilled with argon three times. Diisopropylamine (4 mL) was added at room temperature, and the flask was heated to 80 °C for 48 h. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and filtered through a pad of Celite. The filtrate was washed with water (3 × 25 mL), brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography with 5% diethyl ether / dichloromethane to give ethyl 5-(3-((triisopropylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate as a yellow oil (105 mg, 30%). 1 H-NMR (400MHz, CDCl3)δ:7.33(m,3H),7.09(s,1H),4.38(q,2H),1.27(m,6H),1.10(s,18H).

[0369] Step 2: Ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate [ka] A 10 mL round-bottom flask containing a stir bar was charged with ethyl 5-(3-((triisopropylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (98.0 mg, 0.24 mmol, 1.00 equiv.) as a yellow oil, sealed with a rubber septum, and refilled with argon three times. THF (1 mL) was added, followed by TBAF (0.48 mL, 0.48 mmol, 2.00 equiv.) in THF. Stirred at room temperature for 2 h. Diluted with ethyl acetate (50 mL), washed with water (3 × 25 mL), brine (25 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography with 5% diethyl ether / dichloromethane to give ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate as a yellow oil (44.0 mg, 71%), which was used crude in the next step without purification.

[0370] Step 3: 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] A vial (8 mL) containing a magnetic stir bar was charged with ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate (40 mg, 0.16 mmol) as a yellow oil and 3 mL of 1N KOH. The vial was then sealed with a screw cap and stirred at room temperature for 18 h. The pH was adjusted to 2-3 using 1N HCl, and the contents of the vial were extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by trituration in a dichloromethane / pentane mixture to give 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid as a pale yellow solid (19.2 mg, 55%). 1 H-NMR (400 MHz, acetone-d6) δ: 7.42 (d, 1H), 7.30-7.21 (m, 3H), 3.72 (s, 1H).

[0371] Example 2: 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared by the method described in Example I using ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate (265 mg, 0.85 mmol, 1.00 equiv.) and ethynyltriisopropylsilane (0.25 mL, 2.55 mmol, 3.00 equiv.) as reagents in step 1 to afford 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid as a pale yellow solid (19.9 mg, 12%). 1 H-NMR(400MHz,DMSO-d6)δ:7.61(d,2H),7.11(d,2H).3.33(s,1H).

[0372] Example 5: 5-(4-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: 4-Methoxybenzyl azide To a mixture of sodium azide (31.1 g, 479 mmol, 1.0 equiv.) in DMF (300 mL) was added PMBCl (75.0 g, 479 mmol, 1.0 equiv.) dropwise at room temperature under N. The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (1 L) and extracted with EtO (3 × 500 mL). The combined organic layers were washed with brine (3 × 1 L), dried over anhydrous NaSO, and concentrated to give the title compound (100 g, crude) as a colorless oil. 1 H-NMR(400MHz, CDCl3)δ:7.25(d,2H),6.91(d,2H),4.26(s,2H),3.81(s,3H).

[0373] Step 2: Ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a solution of sodium ethoxide (32.6 g, 479 mmol, 1.0 equiv.) in anhydrous EtOH (780 mL) was added diethyl malonate (76.6 g, 479 mmol, 1.0 equiv.) at room temperature under N2. The resulting mixture was stirred at room temperature for 0.5 h. A solution of 1-(azidomethyl)-4-methoxybenzene (crude 100 g, 479 mmol, 1.0 equiv.) was added slowly. The reaction mixture was refluxed overnight. After removing most of the solvent, the residue was diluted with water (500 mL) and adjusted to pH 2 with 4 N HCl. The resulting precipitate was collected and recrystallized from Et2O to give the title compound (60.0 g, yield: 45%) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:7.20(d,2H),6.90(d,2H),5.25(s,2H),4.23(q,2H),3.72(s,3H),1.26(t,3H).

[0374] Step 3: Ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (26.0 g, 93.5 mmol, 1.0 equiv.) in toluene (580 mL) was added PCl5 (49.0 g, 234 mmol, 2.5 equiv.) in portions. The reaction mixture was stirred at 40 °C under N2 for 3 h. The solvent was removed in vacuo, and the residue was dissolved in diethyl ether (500 mL), washed with saturated sodium bicarbonate (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 15:1) to give the title compound (24.0 g, yield: 63%) as a pale yellow solid. 1 H-NMR(400MHz, CDCl3)δ:7.26(d,2H),6.87(d,2H),5.50(s,2H),4.42(q,2H),3.79(s,3H),1.40(t,3H).

[0375] Step 4: 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of NaH (60% in mineral oil, 1.62 g, 40.6 mmol, 1.5 equiv.) in DMF (240 mL) was added 4-bromophenol (7.03 g, 40.6 mmol, 1.5 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (8 g, 27.1 mmol, 1.0 equiv.) was added to the mixture and stirred at 80 °C for 4 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (100 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from (PE:EtOAc = 10:1) to give the title compound (8.70 g, yield: 74%) as a white solid. MS(ESI) m / z 432.1[M+H]+.

[0376] Step 5: Ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (8.70 g, 20.1 mmol) in TFA (110 mL) was heated at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was washed with (PE: EtOAc = 3:1, 150 mL) to give the title compound (5.00 g, yield: 80%) as a white solid. MS (ESI) m / z 312.0 [M+H] + .

[0377] Step 6: Ethyl 5-(4-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate (260 mg, 0.83 mmol, 1.0 equiv.), prop-1-yne (1 M in THF, 14.2 mL, 14.2 mmol, 17 equiv.), Pd(PPh3)2Cl2 (167 mg, 0.24 mmol, 0.29 equiv.), and CuI (67 mg, 0.36 mmol, 0.43 equiv.) in diisopropylamine (4 mL) in a sealed tube was heated at 80 °C under N2 for 6 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (5–95% CH3CN in water) to give the title compound (80 mg, 36% yield) as a yellow oil. MS(ESI)m / z 272.2[M+H] + .

[0378] Step 7: 4-(4-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid A mixture of ethyl 5-(4-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (80.0 mg, 0.294 mmol, 1.0 equiv.) in 1N KOH (4 mL, 4 mmol, 13.6 equiv.) was stirred at room temperature for 3 h. The reaction was adjusted to pH ∼3 and extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–95% CH3CN in water) to afford the title compound (29.1 mg, 40% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:13.34(brs,1H),7.37(d,J=8.8Hz,2H),7.02(d,J=8.4Hz,2H),2.02(s,3H).MS(ESI)m / z 244.1[M+H] + .

[0379] Example 6: 5-(3-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: 5-(3-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of NaH (60% in mineral oil, 1.62 g, 40.6 mmol, 1.5 equiv.) in DMF (240 mL) was added 3-bromophenol (7.03 g, 40.6 mmol, 1.5 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (8 g, 27.1 mmol, 1.0 equiv., Example 1, Step 3) was added to the mixture and stirred at 80 °C for 4 h. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (100 mL). The separated organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from (PE: EtOAc = 20:1) to give the title compound (8.50 g, yield: 73%) as a white solid. MS(ESI)m / z 432.1[M+H] + .

[0380] Step 2: Ethyl 1-(4-methoxybenzyl)-5-(3-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(3-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (750 mg, 1.74 mmol, 1.0 equiv.), prop-1-yne (1 M in THF, 5.22 mL, 5.22 mmol, 3.0 equiv.), Pd(PPh3)2Cl2 (244 mg, 0.35 mmol, 0.2 equiv.), and CuI (99 mg, 0.52 mmol, 0.3 equiv.) in diisopropylamine (8 mL) in a sealed tube was heated at 80 °C for 4 h under N2. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (10–95% CH3CN in water) to give the title compound (600 mg, 88% yield) as a yellow oil. MS(ESI)m / z 392.2[M+H] + .

[0381] Step 3: Ethyl 5-(3-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 1-(4-methoxybenzyl)-5-(3-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (600 mg, 1.53 mmol) in TFA (6 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was treated with saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by prep-HPLC (5-65% CH3CN in water) to give the title compound (180 mg, yield: 43%) as a white solid. MS (ESI) m / z 272.1 [M+H] + .

[0382] Step 4: 4-(3-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid A mixture of ethyl 5-(3-(prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (180 mg, 0.664 mmol, 1.0 equiv.) in 1N KOH (10 mL, 10 mmol, 15.0 equiv.) was stirred at room temperature for 3 h. The reaction was adjusted to pH ∼3 and extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–65% CH3CN in water) to afford the title compound (108 mg, yield: 67%) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:13.28(brs,1H),7.34(t,J=8.0Hz,1H),7.15(d,J=7.6Hz,1H),7.06-7.03(m,2H),2.03(s,3H).MS(ESI)m / z 244.1[M+H] + .

[0383] Example 9: 5-(4-(3-methylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate and 3-methylbut-1-yne to give 5-(4-(3-methylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.23(brs,1H),7.35(d,J=8.8Hz,2H),7.01(d,J=8.8Hz,2H),2.82-2.75(m,1H),1.20(d,J=6.8Hz,6H).MS(ESI)m / z 272.1[M+H] + .

[0384] Example 10: 5-(3-(3-methylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-(3-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and 3-methylbut-1-yne to give 5-(3-(3-methylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.30(brs,1H),7.34(t,J=8.0Hz,1H),7.14(d,J=7.6 Hz,1H),7.06-7.00(m,2H),2.81-2.77(m,1H),1.20(d,J=6.8Hz,6H).MS(ESI)m / z 272.1[M+H] + .

[0385] Example 13: 5-(4-(3-hydroxy-3-methylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-methylbut-3-yn-2-ol to give 5-(4-(2-cyclopropylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.29(d,J=8.8Hz,2H),6.86(d,J=8.8Hz,2H),1.44-1.50(s,6H).MS(ESI)m / z 286.0[MH] - .

[0386] Example 16: 5-(4-(3,3-dimethylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 3,3-dimethylbut-1-yne to give 5-(4-(3,3-dimethylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.36-7.32(m,2H),7.03-6.99(m,2H),1.28(s,9H).MS(ESI)m / z 286.1[M+H] + .

[0387] Example 17: 5-(3-(3,3-dimethylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 3,3-dimethylbut-1-yne to give 5-(3-(3,3-dimethylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.26(brs,1H),13.20(brs,1H),7.33(t,J=8.0Hz,1H ),7.13(d,J=7.6Hz,1H),7.06-7.03(m,4H),6.98(s,1H),1.27(s,9H).MS(ESI)m / z 286.1[M+H] + .

[0388] Example 20: 5-(4-(2-cyclopropylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate and ethynylcyclopropane to give 5-(4-(2-cyclopropylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.49(brs,1H),7.35(d,J=8.8Hz,2H),7.01(d,J=8 .8Hz,2H),1.54-1.50(m,1H),0.89-0.84(m,2H),0.73-0.69(m,2H).MS(ESI)m / z 270.1[M+H] + .

[0389] Example 21: 5-(3-(2-cyclopropylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-(3-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate and ethynylcyclopropane to give 5-(3-(2-cyclopropylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.49(brs,1H),7.35(d,J=8.8Hz,2H),7.01(d,J=8 .8Hz,2H),1.54-1.50(m,1H),0.89-0.84(m,2H),0.73-0.69(m,2H).MS(ESI)m / z 270.1[M+H] + .

[0390] Example 24: 5-(4-(2-cyclobutylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and ethynylcyclobutane to give 5-(4-(2-cyclobutylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.29(d,J=8.8Hz,2H),6.83(d,J=8.4Hz,2H),3.29-3 .16(m,1H),2.32-2.24(m,2H),2.13-2.08(m,2H),1.96-1.82(m,2H).MS(ESI)m / z 284.1[M+H] + .

[0391] Example 25: 5-(3-(2-cyclobutylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and ethynylcyclobutane to give 5-(3-(2-cyclobutylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.28(brs,1H),13.26(brs,1H),7.34(t,J=8.0Hz,1H),7.15(d,J=7.6Hz,1H), 7.06-7.02(m,2H),3.34-3.24(m,1H),2.32-2.24(m,2H),2.14-2.07(m,2H),1.96-1.83(m,2H).MS(ESI)m / z 284.1[M+H] +

[0392] Example 28: 5-(4-(2-cyclopentylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and ethynylcyclopentane to give 5-(4-(2-cyclopentylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.36-7.34(m,2H),7.02-7.00(m,2H),2.86-2.82(m,1H),1.97-1.94(m,2H),1.71-1.54(m,6H).MS(ESI)m / z 296.0[MH] - .

[0393] Example 29: 5-(3-(2-cyclopentylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and ethynylcyclopentane to give 5-(3-(2-cyclopentylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.24(brs,1H),13.26(brs,1H),7.33(t,J=8.0Hz,1H),7.14(dd,J=7.6Hz ,0.8Hz,1H),7.06-7.00(m,2H),2.86-2.80(m,1H),1.99-1.92(m,2H),1.71-1.54(m,6H).MS(ESI)m / z 298.1[M+H] +

[0394] Example 36: 5-(4-(2-cyclohexylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and ethynylcyclohexane to give 5-(4-(2-cyclohexylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.22(brs,1H),7.36(d,J=8.4Hz,2H),7.01(d,J=8.8Hz,2H),2.64-2. 58(m,1H),1.83-1.79(m,2H),1.68-1.67(m,2H),1.50-1.45(m,2H),1.35-1.31(m,2H).MS(ESI)m / z 312.1[M+H] + .

[0395] Example 37: 5-(3-(2-cyclohexylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and ethynylcyclohexane to give 5-(3-(2-cyclohexylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.25(brs,1H),13.27(brs,1H),7.33(t,J=8.0Hz,1H),7.14(dd,J=7.6Hz,0.8Hz,1H),7.06- 7.01(m,2H),2.64-2.60(m,1H),1.82-1.79(m,2H),1.69-1.65(m,2H),1.50-1.44(m,2H),1.35-1.30(m,2H).MS(ESI)m / z 312.2[M+H] + .

[0396] Example 40: 5-(4-(2-(tetrahydro-2H-pyran-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromophenol, and ethynyl-tetrahydro-2H-pyran to give 5-(4-(2-(tetrahydro-2H-pyran-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. MS (ESI) m / z 314.2 [M+H] +

[0397] Example 41: 5-(3-(2-(tetrahydro-2H-pyran-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, and ethynyl-tetrahydro-2H-pyran to give 5-(3-(2-(tetrahydro-2H-pyran-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. MS (ESI) m / z 314.2 [M+H] +

[0398] Example 108: 5-(4-(2-(1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 5-bromo-1H-indazole to give 5-(4-(2-(1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.32(brs,1H),13.26(brs,1H),8.12(s,1H),8.01(s,1H),7.59-7.46(m,4H),7.11(d,J=8.8Hz,2H).MS(ESI)m / z 346.1[M+H] +

[0399] Example 138: 5-(4-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 5-(4-((trimethylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate (2.0 g, 6.40 mmol, 1.0 equiv.), ethynyltrimethylsilane (6.60 g, 67.3 mmol, 10.5 equiv.), Pd(PPh3)2Cl2 (950 mg, 1.35 mmol, 0.21 equiv.), and CuI (384 mg, 2.02 mmol, 0.32 equiv.) in diisopropylamine (30 mL) in a sealed tube was heated at 80 °C under N2 for 4 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (10–95% CH3CN in water) to give the title compound (1.99 g, 94% yield) as a brown solid. MS (ESI) m / z 330.1 [M+H] + .

[0400] Step 2: 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid A mixture of ethyl 5-(4-((trimethylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (600 mg, 1.82 mmol, 1.0 equiv.) in 1N KOH (20 mL, 20 mmol, 11 equiv.) was stirred at room temperature for 3 h. The reaction was adjusted to pH ∼3 with 1N HCl and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by prep-HPLC (5-95% CH3CN in water) to give the desired product (220 mg, yield: 53%) as a white solid. MS (ESI) m / z 230.1 [M+H] + .

[0401] Step 3: 4-(4-(phenylethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid A mixture of ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate (150 mg, 0.65 mmol, 1.0 equiv.), iodobenzene (265 mg, 1.30 mmol, 2.0 equiv.), Pd(PPh3)2Cl2 (91 mg, 0.13 mmol, 0.2 equiv.), and CuI (25 mg, 0.13 mmol, 0.2 equiv.) in diisopropylamine (6 mL) in a sealed tube was heated at 50 °C under N2 for 6 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (5–95% CH3CN in water) to give the desired product (30.1 mg, 15% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ:13.41(brs,1H),7.57-7.53(m,4H),7.44-7.41(m,3H),7.10(dd,J=6.8,2.0Hz,2H).MS(ESI)m / z 304.1[MH] - .

[0402] Example 139: 5-(3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-(3-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and ethynylbenzene to give 5-(3-(3-methylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.40(brs,1H),7.58-7.55(m,2H),7.45-7.41(m,4 H),7.34(d,J=7.6Hz,1H),7.22(d,J=2.0Hz,1H),7.16-7.13(m,1H).MS(ESI)m / z 306.1[M+H] + .

[0403] Example 146: 5-(3-fluoro-4-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromo-3-fluorophenol, and ethynylbenzene to give 5-(3-fluoro-4-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.57-7.42(m,5H),6.90(dd,J=11.2,2.0Hz,1H),6.78(dd,J=8.4,2.0Hz,1H),.MS(ESI)m / z 324.1[M+H] + .

[0404] Example 147: 5-(4-chloro-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-chlorophenol, and ethynylbenzene to give 5-(4-chloro-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.60-7.57(m,3H),7.47-7.44(m,3H),7.39(d,J=3.2Hz,1H),7.18(dd,J=8.8,3.2Hz,1H).MS(ESI)m / z 337.9[MH] - .

[0405] Example 149: 5-(4-(methylsulfonyl)-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-(methylsulfonyl)phenol and ethynylbenzene to give 5-(4-(methylsulfonyl)-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.95(d,J=8.8Hz,1H),7.62-7.61(m,2H),7.51-7.42 (m,3H),7.24-7.20(m,1H),7.14(dd,J=8.8,2.4Hz,1H),3.36(s,3H).MS(ESI)m / z 384.1[M+H] + .

[0406] Example 165: 5-(3-(2-(pyrimidin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromopyrimidine to give 5-(3-(2-(pyrimidin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.30(brs,1H),8.85(d,J=4.8Hz,2H),7.55-7.44(m,3H),7.34(d,J=2.4Hz,1H),7.26-7.23(m,1H).MS(ESI)m / z 308.1[M+H] + .

[0407] Example 178: 5-(4-(2-(1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-iodo-1H-pyrazole to give 5-(4-(2-(1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.28(brs,1H),7.93(s,2H),7.47(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,2H).MS(ESI)m / z 296.1[M+H] + .

[0408] Example 187: 5-(3-(2-(3-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 1-chloro-3-ethynylbenzene to give 5-(3-(2-(3-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.30(brs,1H),13.27(brs,1H),7.66(t,J=1.2Hz,1H),7.5 5-7.43(m,4H),7.37-7.35(m,1H),7.25(t,J=1.2Hz,1H),7.19-7.16(m,1H).MS(ESI)m / z 339.8[M+H]+ .

[0409] Example 190: 5-(4-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid and 1-bromo-4-(methylsulfonyl)benzene to give 5-(4-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.33(brs,1H),13.28(brs,1H),7.96(d,J=8.4Hz,2H),7.80 (d,J=8.4Hz,2H),7.61(d,J=8.8Hz,2H),7.14(d,J=8.8Hz,2H),3.26(s,3H).MS(ESI)m / z 382.0[MH] - .

[0410] Example 191: 5-(3-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 1-bromo-3-(methylsulfonyl)benzene to give 5-(3-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:15.30(brs,1H),13.23(brs,1H),8.10(t,J=1.2Hz,1H),7.97-7.90(m,2H),7.72(t,J=8.0 Hz,1H),7.46(t,J=8.0Hz,1H),7.41-7.39(m,1H),7.29(t,J=1.6Hz,1H),7.21-7.18(m,1H),3.28(s,3H).MS(ESI)m / z 382.0[MH] - .

[0411] Example 208: 4-(4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 5-bromo-1-methylpyridin-2(1H)-one to give 4-(4-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.36(brs,1H),8.14(d,J=2.0Hz,1H),7.53-7.47 (m,3H),7.09(d,J=8.8Hz,2H),6.41(d,J=9.6Hz,1H),3.45(s,3H).MS(ESI)m / z 337.1[M+H] + .

[0412] Example 209: 4-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 5-bromo-1-methylpyridin-2(1H)-one to give 4-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.17(d,J=2.4Hz,1H),7.52(dd,J=2.4,9.2Hz,1H),7.33(t,J=8.0Hz,1H),7.13 (d,J=7.6Hz,1H),6.99(dd,J=2.0,8.4Hz,1H),6.86(s,1H),6.38(d,J=9.2Hz,1H),3.43(s,3H).MS(ESI)m / z 337.1[M+H] + .

[0413] Example 215: 5-(3-(3-hydroxy-3-methylbut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-(3-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-methylbut-3-yn-2-ol to give 5-(4-(2-cyclopropylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.30(brs,1H),7.37(t,J=8.0Hz,1H),7.17(d,J=7.6Hz,1H),7.09(d,J=8.0Hz,1H),7.01(s,1H),1.45(s,6H).MS(ESI)m / z 286.1[MH] - .

[0414] Example 220: 5-(4-(2-(1-methyl-1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-iodo-1-methyl-1H-pyrazole to give 5-(4-(2-(1-methyl-1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,CD3OD)δ:13.32(brs,1H),8.05(s,1H),7.67(s,1H),7.49-7.45(m,2H),7.09-7.05(m,2H),3.85(s,3H).MS(ESI)m / z 310.1[M+H] + .

[0415] Example 221: 5-(3-(2-(1-methyl-1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 4-iodo-1-methyl-1H-pyrazole to give 5-(3-(2-(1-methyl-1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:8.08(s,1H),7.69(s,1H),7.39(t,J=8.0Hz,1H),7.25(d,J=7.6Hz,1H),7.12-7.09(m,2H),3.85(s,3H).MS(ESI)m / z 310.1[M+H] +

[0416] Example 254: 5-(4-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 1-bromo-3-(methylsulfonyl)benzene to give 5-(4-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.33(brs,1H),13.28(brs,1H),8.07(t,J=1.6Hz,1H),7.95-7.88(m, 2H),7.71(t,J=8.0Hz,1H),7.61(d,J=9.2Hz,2H),7.13(d,J=8.8Hz,2H),3.28(s,3H).MS(ESI)m / z 382.0[MH] - .

[0417] Example 255: 5-(3-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 1-bromo-4-(methylsulfonyl)benzene to give 5-(3-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.96(d,J=8.4Hz,2H),7.83(d,J=8.4Hz,2H),7.45(t,J=7.6Hz ,1H),7.39(d,J=7.6Hz,1H),7.26(s,1H),7.18(d,J=8.0Hz,1H),3.26(s,3H).MS(ESI)m / z 382.0[MH] - .

[0418] Example 256: 4-(4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-bromo-1-methylpyridin-2(1H)-one to give 4-(4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.73(d,J=6.8Hz,1H),7.58(dd,J=2.4,6.8Hz,2H),7.11(dd,J=2 .0,6.8Hz,2H),6.53(d,J=2.0Hz,1H),6.29(dd,J=1.6,6.8Hz,1H),3.42(s,3H).MS(ESI)m / z 337.1[M+H] + .

[0419] Example 257: 4-(3-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 138 using 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-bromo-1-methylpyridin-2(1H)-one to give 4-(3-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-5-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.71(d,J=7.2Hz,1H),7.38(t,J=8.0Hz,1H),7.24(d,J=7.6Hz,1H), 7.06-7.00(m,2H),6.55(d,J=2.0Hz,1H),6.31(dd,J=2.0,7.2Hz,1H),3.42(s,3H).MS(ESI)m / z 337.1[M+H] + .

[0420] Example 258: 5-(3-fluoro-5-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-5-fluorophenol, and ethynylbenzene to give 5-(3-fluoro-5-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:15.35(brs,1H),13.28(brs,1H),7.59-7.56(m,2H),7 .46-7.42(m,3H),7.29-7.23(m,1H),7.15-7.11(m,1H),7.08(s,1H).MS(ESI)m / z 321.9[MH] - .

[0421] Example 259: 5-(4-fluoro-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-fluorophenol, and ethynylbenzene to give 5-(4-fluoro-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.35(brs,1H),7.59-7.56(m,2H),7.46-7.42(m,3H),7.38-7.34(m,2H),7.25-7.21(m,1H).MS(ESI)m / z 324.1[M+H] + .

[0422] Example 260: 5-(2-fluoro-4-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 2-fluoro-4-iodophenol, and ethynylbenzene to give 5-(2-fluoro-4-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.44(brs,1H),7.64(dd,J=11.2,2.0Hz,1H),7.58-7. 55(m,2H),7.45-7.43(m,3H),7.40-7.37(m,1H),7.26(t,J=8.4Hz,1H).MS(ESI)m / z 321.9[MH] - .

[0423] Example 261: 5-(2-fluoro-5-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 5-bromo-2-fluorophenol, and ethynylbenzene to give 5-(2-fluoro-5-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.56-7.54(m,2H),7.47-7.42(m,6H).MS(ESI)m / z 321.9[MH] - .

[0424] Example 262: 5-(4-methyl-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-methylphenol, and ethynylbenzene to give 5-(4-methyl-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.27(brs,1H),13.27(brs,1H),7.58-7.56(m,2H),7.44-7.42(m,3H), 7.32(d,J=8.4Hz,1H),7.18(d,J=2.8Hz,1H),7.05(dd,J=8.4,2.8Hz,1H),2.44(s,3H).MS(ESI)m / z 318.0[MH] - .

[0425] Example 263: 5-(4-(trifluoromethyl)-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-(trifluoromethyl)phenol and ethynylbenzene to give 5-(4-(trifluoromethyl)-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.46(brs,1H),13.36(brs,1H),7.82(d,J=8.8Hz,1H ),7.57-7.54(m,2H),7.49-7.45(m,4H),7.26(dd,J=8.4,2.0Hz,1H).MS(ESI)m / z 374.1[M+H] + .

[0426] Example 264: 5-(4-methoxy-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-methoxyphenol, and ethynylbenzene to give 5-(4-methoxy-3-(2-phenylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.13(brs,1H),13.19(brs,1H),7.53-7.51(m,2H),7.43-7.41(m,3H), 7.24(d,J=2.8Hz,1H),7.17(dd,J=8.8,2.8Hz,1H),7.08(d,J=9.2Hz,1H),3.86(s,3H).MS(ESI)m / z 333.9[MH] - .

[0427] Example 265: 5-(3-fluoro-5-(2-(4-carboxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-5-fluorophenol, and ethyl 4-ethynylbenzoate to give 5-(3-fluoro-5-(2-(4-carboxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. MS (ESI) m / z 366.6 [M−H] - .

[0428] Example 266: 5-(4-fluoro-3-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-fluorophenol, and 1-ethynyl-4-(methylsulfonyl)benzene to give 5-(4-fluoro-3-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.98(d,J=8.8Hz,2H),7.84(d,J=8.8Hz,2H),7.44-7.37(m,2H),7.30-7.26(m,1H),3.27(s,3H),.MS(ESI)m / z 402.1[M+H] + .

[0429] Example 267: 5-(4-fluoro-3-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-fluorophenol, and 1-ethynyl-3-(methylsulfonyl)benzene to give 5-(4-fluoro-3-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:8.11(t,J=1.6Hz,1H),8.00-7.91(m,2H),7.73(t, J=8.0Hz,1H),7.45-7.37(m,2H),7.30-7.26(m,1H),3.29(s,3H).MS(ESI)m / z 399.9[MH] - .

[0430] Example 268: 4-(3-((4-cyanophenyl)ethynyl)-4-fluorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-fluorophenol, and 4-ethynylbenzonitrile to give 4-(3-((4-cyanophenyl)ethynyl)-4-fluorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.91(d,J=8.0Hz,2H),7.77(d,J=8.4Hz,2H),7.36(t,J=9.2Hz,1H),7.32-7.20(m,2H).MS(ESI)m / z 349.1[M+H] + .

[0431] Example 269: 5-(4-((4-cyanophenyl)ethynyl)-3-fluorophenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromo-3-fluorophenol, and 3-ethynylbenzonitrile to give 5-(4-((4-cyanophenyl)ethynyl)-3-fluorophenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.91(d,J=8.8Hz,2H),7.74(d,J=8.4Hz,2H),7.70(t,J =8.4Hz,1H),7.20(dd,J=10.8,2.4Hz,1H),6.97(dd,J=8.8,2.4Hz,1H).MS(ESI)m / z 349.1[M+H] + .

[0432] Example 270: 5-(4-((3-cyanophenyl)ethynyl)-3-fluorophenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromo-3-fluorophenol, and 3-ethynylbenzonitrile to give 5-(4-((3-cyanophenyl)ethynyl)-3-fluorophenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.07(t,J=1.6Hz,1H),7.92-7.88(m,2H),7.65(t,J=8.0Hz,2H),7.74(d,J=8 .4Hz,2H),7.70(t,J=8.4Hz,1H),7.20(dd,J=10.8,2.4Hz,1H),6.97(dd,J=8.4,2.4Hz,1H).MS(ESI)m / z 349.1[M+H] + .

[0433] Example 271: 5-(4-((3-cyanophenyl)ethynyl)-3-fluorophenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-4-fluorophenol, and 3-ethynylbenzonitrile to give 5-(4-((3-cyanophenyl)ethynyl)-3-fluorophenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.09(s,1H),7.93-7.90(m,1H),7.65(t,J=8.0Hz,1H),7.40-7.36(m,2H),7.29-7.25(m,1H).MS(ESI)m / z 349.1[M+H] + .

[0434] Example 272: 5-(3-fluoro-4-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromo-3-fluorophenol, and 1-ethynyl-4-(methylsulfonyl)benzene to give 5-(3-fluoro-4-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:7.97(d,J=8.4Hz,2H),7.82(d,J=8.8Hz,2H),7.68(t,J= 8.4Hz,1H),7.21(dd,J=10.8,2.4Hz,1H),6.98(dd,J=8.4,2.4Hz,1H),.MS(ESI)m / z 402.1[M+H] + .

[0435] Example 273: 5-(3-fluoro-4-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromo-3-fluorophenol, and 1-ethynyl-3-(methylsulfonyl)benzene to give 5-(3-fluoro-4-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.08(s,1H),7.97(d,J=7.6Hz,1H),7.91(d,J=8.0Hz,1H),7. 75-7.66(m,2H),7.21(dd,J=10.8,2.4Hz,1H),6.98(dd,J=8.8,2.4Hz,1H),.MS(ESI)m / z 402.1[M+H] + .

[0436] Example 274: 5-(3-fluoro-5-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-5-fluorophenol, and 1-ethynyl-4-(methylsulfonyl)benzene to give 5-(3-fluoro-5-(2-(4-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.98(d,J=8.8Hz,2H),7.83(d,J=8.8Hz,2H),7.31(d,J=8.0Hz,1H),7.22-7.18(m,1H),7.15(s,1H),3.27(s,3H).MS(ESI)m / z 399.9[MH] - .

[0437] Example 275: 5-(3-fluoro-5-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-5-fluorophenol, and 1-ethynyl-3-(methylsulfonyl)benzene to give 5-(3-fluoro-5-(2-(3-(methylsulfonyl)phenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.37(brs,1H),13.27(brs,1H),8.12(s,1H),8.11-7.90(m,2H) ,7.72(t,J=8.0Hz,1H),7.30(d,J=8.8Hz,1H),7.19-7.15(m,2H),3.28(s,3H),.MS(ESI)m / z 399.9[MH] - .

[0438] Example 276: 4-(3-((4-cyanophenyl)ethynyl)-5-fluorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-5-fluorophenol, and 4-ethynylbenzonitrile to give 4-(3-((4-cyanophenyl)ethynyl)-5-fluorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.91(d,J=8.4Hz,2H),7.76(d,J=8.4Hz,2H),7.29(d, J=8.0Hz,1H),7.72(t,J=8.0Hz,1H),7.21-7.17(m,1H),7.14(s,1H).MS(ESI)m / z 346.9[MH] - .

[0439] Example 277: 4-(3-((3-cyanophenyl)ethynyl)-5-fluorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromo-5-fluorophenol, and 3-ethynylbenzonitrile to give 4-(3-((3-cyanophenyl)ethynyl)-5-fluorophenoxy)-1H-1,2,3-triazole-5-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:8.09(t,J=1.2Hz,1H),7.93-7.89(m,2H),7.65(t, J=8.0Hz,1H),7.29-7.26(m,1H),7.21-7.17(m,1H),7.11(s,1H).MS(ESI)m / z 346.9[MH] - .

[0440] Example 278: 5-(4-(2-(3-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 1-ethynyl-3-fluorobenzene to give 5-(4-(2-(3-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.59-7.56(m,2H),7.50-7.39(m,3H),7.30-7.25(m,1H),7.14-7.10(m,2H).MS(ESI)m / z 322.0[MH] - .

[0441] Example 279: 5-(3-(2-(3-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 1-ethynyl-3-fluorobenzene to give 5-(3-(2-(3-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid.1 H-NMR(400MHz,DMSO-d6)δ:15.31(brs,1H),13.30(brs,1H),7.49-7.16(m,8H).MS(ESI)m / z 322.0[MH] - .

[0442] Example 280: 5-(4-(2-(4-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 1-ethynyl-4-methoxybenzene to give 5-(4-(2-(4-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.52-7.47(m,4H),7.10-7.08(m,2H),6.99-6.97(m,2H),3.79(s,3H).MS(ESI)m / z 334.0[MH] - .

[0443] Example 281: 5-(4-(2-(3-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 1-ethynyl-3-methoxybenzene to give 5-(4-(2-(3-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:15.28(brs,1H),13.20(brs,1H),7.51-7.49(m,2H),7.41(t,J=8.0 Hz,1H),7.30(d,J=7.6Hz,1H),7.18(s,1H),7.13-7.10(m,1H),6.99-6.97(m,2H).MS(ESI)m / z 334.0[MH] -

[0444] Example 282: 5-(4-(2-(6-methoxypyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 5-(4-((trimethylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(4-bromophenoxy)-1H-1,2,3-triazole-4-carboxylate (2.0 g, 6.40 mmol, 1.0 equiv.), ethynyltrimethylsilane (6.60 g, 67.3 mmol, 10.5 equiv.), Pd(PPh3)2Cl2 (950 mg, 1.35 mmol, 0.21 equiv.), and CuI (384 mg, 2.02 mmol, 0.32 equiv.) in diisopropylamine (30 mL) in a sealed tube was heated at 80 °C under N2 for 4 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (10–95% CH3CN in water) to give the desired compound (1.99 g, crude) as a brown solid. MS (ESI) m / z 330.1 [M+H] +

[0445] Step 2: Ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 5-(4-((trimethylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (1.99 g, crude, 6.40 mmol, 1.0 equiv.) in THF (20 mL) was added to TBAF (1 M in THF, 12 mL, 12 mmol, 1.9 equiv.) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated, and the residue was adjusted to pH 2 with 1 N HCl. The aqueous layer was extracted with EtOAc (3 × 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC (5–95% CH3CN in water) to give the desired compound (600 mg, yield: 37% over two steps) as a yellow solid. MS (ESI) m / z 258.2 [M+H] +

[0446] Step 3: Ethyl 5-(4-((6-methoxypyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate (310 mg, 1.20 mmol, 1.0 equiv.), 5-iodo-2-methoxypyridine (564 mg, 2.40 mmol, 2.0 equiv.), Pd(PPh3)2Cl2 (84 mg, 0.12 mmol, 0.1 equiv.), and CuI (23 mg, 0.12 mmol, 0.1 equiv.) in DMF / DIEA (3 mL / 1.5 mL) in a sealed tube was heated at 50 °C under N2 for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:methanol = 50:1) to give the desired compound (360 mg, 82% yield) as a brown gel. MS (ESI) m / z 365.1 [M+H] +

[0447] Step 4: 5-(4-((6-methoxypyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid A mixture of ethyl 5-(4-((6-methoxypyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (360 mg, 1.0 mmol, 1.0 equiv) in 1N KOH (4 mL, 4 mmol, 4.0 equiv) and THF / methanol (4 mL / 4 mL) was stirred at room temperature overnight. The reaction was adjusted to pH ∼3 and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (5–95% CH3CN in water) to give the desired compound (105 mg, 31% yield) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ:8.39(d,J=2.0Hz,1H),7.86(dd,J=8.4Hz,2.0Hz,1H),7. 56-7.53(m,2H),7.10-7.08(m,2H),6.88(d,J=8.8Hz,1H),3.89(s,3H).MS(ESI)m / z 336.8[M+H] +

[0448] Example 283: 5-(4-(2-(2-methoxypyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-((trimethylsilyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate, 5-iodo-2-methoxypyridine to give 5-(4-(2-(2-methoxypyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.19(d,J=5.2Hz,1H),7.56-7.54(m,2H),7.08(dd, J=5.2Hz,1.2Hz,1H),6.99-6.97(m,2H),6.94(s,1H),3.86(s,3H).MS(ESI)m / z 336.8[M+H] +

[0449] Example 284: 5-(3-(2-(6-methoxypyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 5-iodo-2-methoxypyridine to give 5-(3-(2-(6-methoxypyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.28(brs,1H),13.25(brs,1H),8.40(d,J=1.6Hz,1H),7.88(dd,J=8.4Hz,2.4Hz,1H),7.43(t,J= 8.0Hz,'1H),7.30(d,J=7.6Hz,1H),7.21(t,J=2.4Hz,1H),7.16-7.13(m,1H),6.88(d,J=8.8Hz,1H),3.89(s,3H).MS(ESI)m / z 336.9[M+H] +

[0450] Example 285: 5-(3-(2-(2-methoxypyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 4-iodo-2-methoxypyridine to give 5-(3-(2-(2-methoxypyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid.1 H-NMR(400MHz,DMSO-d6)δ:15.29(brs,1H),13.23(brs,1H),8.21(d,J=5.2Hz,1H),7.46(t,J=8.4Hz,1H),7.39(d, J=7.6Hz,1H),7.28(s,1H),7.22-7.19(m,1H),7.11(dd,J=5.2Hz,1.2Hz,1H),6.98(s,1H),3.87(s,3H).MS(ESI)m / z 336.9[M+H] + .

[0451] Example 286: 5-(4-(2-(3-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 1-ethynyl-3-methoxybenzene to give 5-(4-(2-(3-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.58-7.54(m,2H),7.33(t,J=8.0Hz,1H),7.13-7.09(m,4H),7.00-6.97(m,1H),3.79(s,3H).MS(ESI)m / z 335.8[M+H] +

[0452] Example 287: 5-(3-(2-(3-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 1-ethynyl-3-methoxybenzene to give 5-(3-(2-(3-methoxyphenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.29(brs,1H),13.23(brs,1H),7.43(t,J=8.0Hz,1H),7.33( t,J=8.0Hz,2H),7.22(t,J=2.0Hz,1H),7.17-7.12(m,3H),7.02-6.99(m,1H).MS(ESI)m / z 335.9[M+H] + .

[0453] Example 288: 5-(4-(2-(4-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 1-ethynyl-4-fluorobenzene to give 5-(4-(2-(4-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.63-7.54(m,4H),7.30-7.25(m,2H),7.11(dd,J=6.8,2.0Hz,2H).MS(ESI)m / z 321.9[MH] -

[0454] Example 289: 5-(3-(2-(4-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 1-ethynyl-4-fluorobenzene to give 5-(3-(2-(4-fluorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.85-7.61(m,2H),7.43(t,J=8.0Hz,1H),7.35-7.21(m,4H),7.16-7.13(m,1H).MS(ESI)m / z 321.9[MH] - .

[0455] Example 290: 5-(4-(2-(4-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 1-chloro-4-ethynylbenzene to give 5-(4-(2-(4-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.58-7.55(m,4H),7.50-7.48(m,2H),7.12-7.10(m,2H).MS(ESI)m / z 337.9[MH] -

[0456] Example 291: 5-(4-(2-(3-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 1-chloro-3-ethynylbenzene to give 5-(4-(2-(3-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.63-7.47(m,6H),7.13-7.11(m,2H).MS(ESI)m / z 337.8[MH] - .

[0457] Example 292: 5-(3-(2-(4-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 1-chloro-4-ethynylbenzene to give 5-(3-(2-(4-chlorophenyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.85-7.61(m,2H),7.43(t,J=8.0Hz,1H),7.35-7.21(m,4H),7.16-7.13(m,1H).MS(ESI)m / z 339.8[M+H] +

[0458] Example 293: 5-(4-(2-(6-methylpyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate, 2-bromo-6-methylpyridine to give 5-(4-(2-(6-methylpyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,CD3OD)δ:8.05(t,J=8.0Hz,1H),7.70-7.69(m,3H),7.53(d,J=8.0Hz,1H),7.22-7.19(m,2H),2.66(s,3H).MS(ESI)m / z 320.9[M+H] +

[0459] Example 294: 5-(3-(2-(6-methylpyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 4-bromo-2-methylpyridine to give 5-(3-(2-(6-methylpyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.80-7.78(m,1H),7.53-7.34(m,4H),7.28(s,1H),7.20(dd,J=8.4Hz,2.0Hz,1H),2.50(s,3H).MS(ESI)m / z 320.9[M+H] + .

[0460] Example 295: 5-(3-(2-(6-methylpyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 5-bromo-2-methylpyridine to give 5-(3-(2-(6-methylpyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.31(brs,1H),13.30(brs,1H),8.64(d,J=2.0Hz,1H),7.80(dd,J=8.0Hz,2.4Hz,1 H),7.45(t,J=8.0Hz,1H),7.37-7.33(m,2H),7.24(t,J=2.0Hz,1H),7.18-7.15(m,1H),2.50(s,3H).MS(ESI)m / z 320.9[M+H] +

[0461] Example 296: 5-(3-(2-(2-methylpyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 4-bromo-2-methylpyridine to give 5-(3-(2-(2-methylpyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,CD3OD)δ:8.63(d,J=6.0Hz,1H),7.92(s,1H),7.82(dd,J=6.0H z,1.2Hz,1H),7.52-7.41(m,3H),7.32-7.29(m,1H),2.74(s,3H).MS(ESI)m / z 320.9[M+H] +

[0462] Example 297: 5-(4-(2-(6-methylpyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromophenol, ethynyltrimethylsilane, and 5-bromo-2-methylpyridine to give 5-(4-(2-(6-methylpyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.32(brs,1H),13.33(brs,1H),8.65(s,1H),7.88(dd,J=8.0,2.0Hz, 1H),7.58(d,J=8.8Hz,2H),7.35(d,J=8.4Hz,1H),7.12(d,J=8.8Hz,2H),2.51(s,3H).MS(ESI)m / z 321.1[M+H] +

[0463] Example 298: 5-(4-(2-(2-methylpyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromophenol, ethynyltrimethylsilane, and 4-bromo-2-methylpyridine to give 5-(4-(2-(2-methylpyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:13.36(brs,1H),7.57(d,J=5.6Hz,1H),7.64-7.62(m,2 H),7.59(s,1H),7.48(d,J=5.2Hz,1H),7.17-7.14(m,2H),2.54(s,3H).MS(ESI)m / z 321.1[M+H] +

[0464] Example 299: 5-(4-(pent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and pent-1-yne to give 5-(4-(pent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.32(brs,1H),7.39-7.36(m,2H),7.04-7.00(m,2 H),2.38(t,J=6.8Hz,2H),1.60-1.51(m,2H),0.99(t,J=7.2Hz,3H).MS(ESI)m / z 272.1[M+H] +

[0465] Example 300: 5-(3-(pent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and pent-1-yne to give 5-(3-(pent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:7.25(t,J=8.0Hz,1H),7.02(d,J=7.6Hz,1H),6.92-6.89(m,1H),6.8 0(t,J=2.0Hz,1H),2.38(t,J=6.8Hz,2H),1.60-1.51(m,2H),0.99(t,J=7.2Hz,3H).MS(ESI)m / z 272.1[M+H] +

[0466] Example 301: 5-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 3 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and (3-cyclopropylprop-1-ynyl)trimethylsilane to give 5-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.29(d,J=8.8Hz,2H),6.83(d,J=8.4Hz,2H),2.44(d,J =6.0Hz,2H),1.01-0.95(m,1H),0.49-0.44(m,2H),0.26-0.22(m,2H).MS(ESI)m / z 284.1[M+H] +

[0467] Example 302: 5-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 5-(3-iodophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of NaH (60% in mineral oil, 1.85 g, 46.2 mmol, 1.5 equiv.) in DMF (375 mL) was added 3-iodophenol (12.0 g, 54.5 mmol, 1.5 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (12.4 g, 42.0 mmol, 1.0 equiv.) was added to the mixture and stirred at 85 °C overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 4:1) to give the desired compound (18.0 g, yield: 89%) as a yellow oil. MS(ESI)m / z 480.0[M+H] + .

[0468] Step 2: Ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 5-(3-iodophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (18.0 g, 37.5 mmol) in TFA (200 mL) was heated at 65 °C for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EtOAc = 3:1) to give the desired compound (12.3 g, yield: 91%) as a brown solid. MS (ESI) m / z 360.0 [M+H] + .

[0469] Step 4: (3-Cyclopropylprop-1-ynyl)trimethylsilane To a solution of ethynyltrimethylsilane (5 g, 51.0 mmol) in anhydrous THF (25 mL) was added n-BuLi (2.5 M in hexanes, 25 mL, 62.5 mmol, 1.2 equiv.) dropwise at −78° C. under N. After stirring the resulting mixture at 0° C. for 10 min, HMPA (13.9 g, 77.5 mmol, 1.5 equiv.) was added slowly at −78° C. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with EtO (80 mL) and washed with brine. The separated organic layer was dried over anhydrous sodium sulfate and concentrated to give the desired crude product (8 g) as a pale yellow liquid, which was used directly in the next step without further purification.

[0470] Step 5: Ethyl 5-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate (324 mg, 0.9 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (1.8 g, crude), Pd(PPh)Cl (63.2 mg, 0.09 mmol, 0.1 equiv.), CuI (17.1 mg, 0.09 mmol, 0.1 equiv.), and TBAF (1 M in THF, 16.2 mL, 16.2 mmol, 18.0 equiv.) in DIEA (12 mL) in a sealed tube was heated at 70 °C under N for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE: EtOAc = 5:1) to give the desired compound (167 mg, yield: 59%) as a brown solid. MS(ESI)m / z 312.1[M+H] + .

[0471] Step 6: 5-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid A mixture of ethyl 5-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (167 mg, 0.53 mmol) and 3N KOH (2 mL, 4 mmol, 7.5 equiv.) in methanol / THF (2 mL / 2 mL) was stirred at room temperature overnight. The reaction was adjusted to pH ∼3 with 1N HCl and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (5-95% CH3CN in water) to give (50 mg, yield: 33%) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:13.2(br,1H),7.34(t,J=7.6Hz,1H),7.16(d,J=8.0,1H),7.06-7.03(m ,2H),2.45(d,J=6.0Hz,2H),1.01-0.94(m,1H),0.49-0.44(m,2H),0.24-0.20(m,2H).MS(ESI)m / z 284.1[M+H] +

[0472] Example 303: 5-(4-(but-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and but-1-ynyltrimethylsilane to give 5-(4-(but-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.29(d,J=8.8Hz,2H),6.83(d,J=8.4Hz,2H),2.39(q,J=7.6Hz,2H),1.15(t,J=7.6Hz,3H).MS(ESI)m / z 258.1[M+H] +

[0473] Example 304: 5-(3-(but-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and but-1-ynyltrimethylsilane to give 5-(3-(but-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.34(t,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H),7.06-7.02(m,2H),2.40(q,J=7.6Hz,2H),1.15(t,J=7.6Hz,3H).MS(ESI)m / z 258.1[M+H] +

[0474] Example 305: 5-(4-(4,4,4-trifluorobut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] A mixture of ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate (320 mg, 1.40 mmol, 1.0 equiv.), 1,1,1-trifluoro-2-iodoethane (1.47 g, 7.00 mmol, 5.0 equiv.), DABCO (940 mg, 8.40 mmol, 6.0 equiv.), Pd(dba) (128 mg, 0.14 mmol, 0.1 equiv.), and DPE-Phos (151 mg, 0.28 mmol, 0.2 equiv.) in toluene (6 mL) was heated at 80 °C under N for 2.5 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (10–95% CHCN in water) to give the desired compound (10.2 mg, yield: 2%) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ:7.45(d,J=8.8Hz,2H),7.05(d,J=8.8Hz,2H),3.76(q,J=10.4Hz,2H).MS(ESI)m / z 310.0[MH] -

[0475] Example 306: 5-(3-(4,4,4-trifluorobut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 305 using 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylic acid and 1,1,1-trifluoro-2-iodoethane to give 5-(3-(4,4,4-trifluorobut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.40(t,J=8.0Hz,1H),7.24(d,J=7.6Hz,1H),7.14-7.12(m,2H),3.79(q,J=10.4Hz,2H).MS(ESI)m / z 312.0[M+H] +

[0476] Example 307: 5-(3-(2-(1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 5-bromo-1H-indazole to give 5-(3-(2-(1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:8.10(s,1H),8.03(s,1H),7.56(d,J=8.4Hz,1H),7.48(dd,J=8.4 Hz,0.8Hz,1H),7.35(t,J=8.4Hz,1H),7.21(d,J=7.6Hz,1H),6.99-6.97(m,2H).MS(ESI)m / z 346.1[M+H] +

[0477] Example 308: 5-(4-(2-(pyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 2-ethynylpyridine to give 5-(4-(2-(pyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.34(brs,1H),13.33(brs,1H),8.61(d,J=4.0Hz,1H),7.8 8-7.84(m,1H),7.65-7.61(m,3H),7.43-7.40(m,1H),7.13(d,J=8.8Hz,2H).MS(ESI)m / z 307.1[M+H] +

[0478] Example 309: 5-(4-(2-(pyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 3-ethynylpyridine to give 5-(4-(2-(pyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.77(t,J=0.8Hz,1H),8.60(dd,J=4.4Hz,1.6Hz,1H),8.0 2-7.99(m,1H),7.61-7.59(m,2H),7.50-7.47(m,1H),7.15-7.12(m,2H).MS(ESI)m / z 307.1[M+H] +

[0479] Example 310: 5-(4-(2-(pyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-iodophenol, and 4-ethynylpyridine hydrochloride to give 5-(4-(2-(pyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.41(brs,1H),13.27(brs,1H),8.63(d,J=5.2Hz,2H ),7.62(d,J=8.8Hz,2H),7.54(d,J=5.6Hz,2H),7.14(d,J=8.8Hz,2H).MS(ESI)m / z 307.1[M+H] + .

[0480] Example 311: 5-(3-(2-(pyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 2-ethynylpyridine to give 5-(3-(2-(pyridin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.30(brs,1H),13.26(brs,1H),8.61(d,J=4.4Hz,1H),7.88-7.84(m,1 H),7.66(d,J=8.0Hz,1H),7.49-7.29(m,3H),7.20(d,J=2.0Hz,1H),7.19-7.18(m,1H).MS(ESI)m / z 307.1[M+H] +

[0481] Example 312: 5-(3-(2-(pyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 3-ethynylpyridine to give 5-(3-(2-(pyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.80(s,1H),8.63-8.61(m,1H),8.05-8.02(m,1H),7.52-7.38( m,3H),7.27(d,J=2.0Hz,1H),7.19(dd,J=8.0Hz,2.0Hz,1H),7.19-7.18(m,1H).MS(ESI)m / z 307.1[M+H] +

[0482] Example 313: 5-(3-(2-(pyridin-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 6 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 4-ethynylpyridine hydrochloride to give 5-(3-(2-(pyridin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.38(brs,1H),8.69(d,J=6.0Hz,2H),7.65(d,J=6.0H z,2H),7.50-7.41(m,2H),7.32(s,1H),7.22(dd,J=8.0Hz,1.6Hz,1H).MS(ESI)m / z 307.1[M+H] +

[0483] Example 314: 5-(4-(2-(1-methyl-1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-bromo-1-methyl-1H-indazole to give 5-(4-(2-(1-methyl-1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO- d6)δ:13.27(brs,1H),8.23(d,J=1.2Hz,1H),7.73-7.67(m,3H),7.45-7.34(m,2H),7.16-7.13(m,2H),4.09(s,3H).MS(ESI)m / z 360.1[M+H]+

[0484] Example 315: 5-(3-(2-(1-methyl-1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-bromo-1-methyl-1H-indazole to give 5-(3-(2-(1-methyl-1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.36(brs,1H),8.26(s,1H),7.73(t,J=8.4Hz,1H),7.47-7.37(m,5H),7.19-7.16(m,1H),4.07(s,3H).MS(ESI)m / z 360.1[M+H] +

[0485] Example 316: 5-(4-(2-(1-methyl-1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 5-bromo-1-methyl-1H-indazole to give 5-(4-(2-(1-methyl-1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:15.32(brs,1H),13.23(brs,1H),8.09(s,1H),8.00(s,1H),7 .70(d,J=8.8Hz,1H),7.58-7.52(m,3H),7.11(d,J=8.8Hz,1H),4.07(s,3H).MS(ESI)m / z 360.1[M+H] +

[0486] Example 317: 5-(3-(2-(1-methyl-1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 5-bromo-1-methyl-1H-indazole to give 5-(3-(2-(1-methyl-1H-indazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.29(brs,1H),13.25(brs,1H),8.09(s,1H),8.02(s,1H),7.70(d,J=8.8Hz,1H),7.54(d,J=8.8 ,1.2Hz,1H),7.43(t,J=8.0Hz,1H),7.34(d,J=7.6Hz,1H),7.22(d,J=2.0Hz,1H),7.15-7.12(m,1H),4.07(s,3H).MS(ESI)m / z 360.1[M+H] +

[0487] Example 318: 5-(4-(2-(1-methyl-1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 6-bromo-1-methyl-1H-indazole to give 5-(4-(2-(1-methyl-1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.32(brs,1H),8.09(d,J=1.2Hz,1H),7.93(d,J=0.8Hz,1H),7.79(d,J=8 .4Hz,1H),7.61-7.57(m,2H),7.26(dd,J=8.0,1.2Hz,1H),7.15-7.12(m,2H),4.07(s,3H).MS(ESI)m / z 360.1[M+H] +

[0488] Example 319: 5-(3-(2-(1-methyl-1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 6-bromo-1-methyl-1H-indazole to give 5-(3-(2-(1-methyl-1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.35(brs,1H),8.09(s,1H),7.95(s,1H),7.79(d,J=8.0Hz,1H ),7.45(t,J=8.0Hz,1H),7.37(d,J=7.6Hz,1H),7.29-7.15(m,3H),4.07(s,3H).MS(ESI)m / z 360.1[M+H] +

[0489] Example 320: 5-(3-(2-(1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 4-iodo-1H-pyrazole to give 5-(3-(2-(1H-pyrazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.28(brs,2H),7.94(brs,2H),7.41-7.37(m,1H),7.25(d,J=7.6Hz,1H),7.10-7.08(m,2H).MS(ESI)m / z 296.1[M+H] +

[0490] Example 321: 5-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 5-bromo-1-methyl-1H-pyrazole to give 5-(4-(2-(1-methyl-1H-pyrazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.61(d,J=9.2Hz,2H),7.51(d,J=2.0Hz,1H),7.13(d,J=8.8Hz,2H),6.61(d,J=2.0Hz,1H),3.93(s,3H).MS(ESI)m / z 310.1[M+H] +

[0491] Example 322: 5-(3-(2-(1-methyl-1H-pyrazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-bromophenol, ethynyltrimethylsilane, and 5-bromo-1-methyl-1H-pyrazole to give 5-(3-(2-(1-methyl-1H-pyrazol-5-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.52-7.39(m,3H),7.32(s,1H),7.18(d,J=7.6Hz,1H),6.63(d,J=1.2Hz,1H),3.94(s,3H).MS(ESI)m / z 310.1[M+H] + .

[0492] Example 323: 5-(4-(2-(1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 7-bromo-1H-indazole to give 5-(4-(2-(1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:13.58(brs,1H),8.19(s,1H),7.83(dd,J=8.0,0.4Hz,1H),7.74(d,J=8.8H z,1H),7.54(dd,J=7.2,0.8Hz,1H),7.18-7.15(m,3H),6.61(d,J=2.0Hz,1H),3.93(s,3H).MS(ESI)m / z 346.1[M+H] +

[0493] Example 324: 5-(3-(2-(1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 7-bromo-1H-indazole to give 5-(3-(2-(1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:15.30(brs,1H),13.58(brs,1H),8.20(s,1H),7.85(d,J=7.6Hz,1H),7.57-7.45(m,4H),7.18-7.15(m,2H).MS(ESI)m / z 346.1[M+H] +

[0494] Example 325: 5-(4-(2-(1-methyl-1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 7-bromo-1-methyl-1H-pyrazole to give 5-(4-(2-(1-methyl-1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.27(brs,1H),8.15(s,1H),7.83(dd,J=8.0,0.8Hz,1H),7.67-7.59(m,3H),7.19-7.15(m,3H),4.42(s,3H).MS(ESI)m / z 360.1[M+H] +

[0495] Example 326: 5-(3-(2-(1-methyl-1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 326 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 7-bromo-1-methyl-1H-indazole to give 5-(3-(2-(1-methyl-1H-indazol-7-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.15(s,1H),7.85(dd,J=8.0Hz,0.8Hz,1H),7.62(dd,J =7.2Hz,0.8Hz,1H),7.47-7.35(m,3H),7.19-7.15(m,2H),4.40(s,3H).MS(ESI)m / z 360.1[M+H] +

[0496] Example 327: 5-(4-(2-(1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-bromo-1H-indazole to give 5-(4-(2-(1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.33(brs,1H),8.25(d,J=0.8Hz,1H),7.70-7.60(m,3H),7.41-7.32(m,2H),7.16-7.14(m,2H).MS(ESI)m / z 346.1[M+H] +

[0497] Example 328: 5-(3-(2-(1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-bromo-1H-indazole to give 5-(3-(2-(1H-indazol-4-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:8.26(s,1H),7.62(d,J=7.6Hz,1H),7.44-7.34(m,4H),7.26(s,1H),7.10-7.07(m,1H).MS(ESI)m / z 346.1[M+H] +

[0498] Example 329: 5-(4-(2-(1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 6-bromo-1H-indazole to give 5-(4-(2-(1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.25(brs,1H),8.12(s,1H),7.80(d,J=8.4Hz,1H),7.73( s,1H),7.59(d,J=8.8Hz,2H),7.24(d,J=8.4Hz,1H),7.12(d,J=9.2Hz,2H).MS(ESI)m / z 346.1[M+H] +

[0499] Example 330: 5-(3-(2-(1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 6-bromo-1H-indazole to give 5-(3-(2-(1H-indazol-6-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.25(brs,2H),8.12(s,1H),7.82-7.76(m,2H),7.46-7.37(m,2H),7.27-7.24(m,2H),7.16-7.14(m,1H).MS(ESI)m / z 346.1[M+H] +

[0500] Example 331: 5-(4-(2-(1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromo-1H-imidazole to give 5-(4-(2-(1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.15(brs,2H),7.57(d,J=8.8Hz,2H),7.14-7.15(m,3H).MS(ESI)m / z 296.1[M+H] +

[0501] Example 332: 5-(3-(2-(1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromo-1H-imidazole to give 5-(3-(2-(1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.45(brs,1H),7.52-7.40(m,4H),7.27-7.25(m,2H).MS(ESI)m / z 296.1[M+H] +

[0502] Example 333: 5-(4-(2-(1-methyl-1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromo-1-methyl-1H-imidazole to give 5-(4-(2-(1-methyl-1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.71-7.69(m,2H),7.62(s,1H),7.44(s,1H),7.20-7.18(m,2H),3.86(s,3H).MS(ESI)m / z 310.1[M+H] + .

[0503] Example 334: 5-(3-(2-(1-methyl-1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromo-1-methyl-1H-imidazole to give 5-(3-(2-(1-methyl-1H-imidazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.59(s,1H),7.58-7.38(m,4H),7.27-7.25(m,1H),3.84(s,3H).MS(ESI)m / z 310.1[M+H] + .

[0504] Example 335: 5-(4-(3,3,3-trifluoroprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 5-(4-(3,3,3-trifluoroprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate To a mixture of ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate (645 mg, 2.5 mmol, 1.0 equiv.), 1,10-phenanthroline (180 mg, 1.0 mmol, 0.4 equiv.), CuI (95 mg, 0.5 mmol, 0.2 equiv.), and KCO (690 mg, 5.0 mmol, 2.0 equiv.) in DCM (40 mL) was slowly added 1,3-dihydro-3,3-dimethyl-1-(trifluoromethyl)-1,2-benziodoxole (1.24 g, 3.75 mmol, 1.5 equiv.) in DCM (20 mL). The resulting mixture was stirred at 25 °C for 4 days. The reaction mixture was concentrated to give the crude product, which was purified by prep-HPLC (20-95% CH3CN in water) to give the desired compound (35 mg, yield: 4%) as a white solid. MS (ESI) m / z 326.1 [M+H] + .

[0505] Step 2: 5-(4-(3,3,3-trifluoroprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. A mixture of ethyl 5-(4-(3,3,3-trifluoroprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (35 mg, 0.13 mmol, 1.0 equiv) in 3N KOH (1 mL, 1 mmol, 7.7 equiv) and methanol (3 mL) was stirred at 35 °C for 16 h. The reaction was adjusted to pH ∼3 and extracted with EtOAc (3 × 20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–95% CHCN in water) to give the desired compound (3.3 mg, 10% yield) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ:7.66(d,J=8.8Hz,2H),6.98(d,J=8.8Hz,2H).MS(ESI)m / z 298.1[M+H] +

[0506] Example 336: 5-(4-(2-(pyrimidin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromopyrimidine to give 5-(4-(2-(pyrimidin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.25(brs,1H),8.84(d,J=4.8Hz,2H),7.67(d,J=8.8Hz,2H),7.51(t,J=4.8Hz,1H),7.15(d,J=8.8Hz,2H).MS(ESI)m / z 308.1[M+H] +

[0507] Example 337: 5-(4-(2-(pyrazin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-iodopyrazine to give 5-(4-(2-(pyrazin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:13.32(brs,1H),8.88(d,J=1.2Hz,1H),8.70-8.63(m,2H),7.67(d,J=8.8Hz,2H),7.16(d,J=8.4Hz,2H).MS(ESI)m / z 308.1[M+H] +

[0508] Example 338: 5-(3-(2-(pyrazin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-iodopyrazine to give 5-(3-(2-(pyrazin-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.25(brs,1H),8.90(d,J=0.8Hz,1H),8.71-8.65( m,2H),7.49-7.44(m,2H),7.34(d,J=2.0Hz,1H),7.26-7.23(m,1H).MS(ESI)m / z 308.1[M+H] +

[0509] Example 339: 5-(4-(2-(pyridazin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 3-bromopyridazine to give 5-(4-(2-(pyridazin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:13.42(brs,1H),9.22(dd,J=4.8Hz,1.6Hz,1H),9.22(dd,J=4.8Hz,1.6Hz,1 H),7.93(dd,J=4.8Hz,1.6Hz,1H),7.78-7.68(m,2H),7.70-7.68(m,2H),7.18-7.16(m,2H).MS(ESI)m / z 308.1[M+H] +

[0510] Example 340: 5-(3-(2-(pyridazin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 3-bromopyridazine to give 5-(3-(2-(pyridazin-3-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:12.75(brs,1H),9.24(dd,J=4.8Hz,1.6Hz,1H),7.96(dd,J=8.4Hz,1.6Hz ,1H),7.77(dd,J=8.4Hz,5.2Hz,1H),7.50-7.46(m,2H),7.36(s,1H),7.26-7.23(m,1H).MS(ESI)m / z 308.1[M+H] +

[0511] Example 341: 5-(4-(2-(thiazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(4-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromothiazole to give 5-(4-(2-(thiazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.96-7.92(m,2H),7.67-7.65(m,2H),7.15-7.12(m,2H).MS(ESI)m / z 313.0[M+H] +

[0512] Example 342: 5-(3-(2-(thiazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 282 using ethyl 5-(3-ethynylphenoxy)-1H-1,2,3-triazole-4-carboxylate and 2-bromothiazole to give 5-(3-(2-(thiazol-2-yl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.35(brs,1H),7.99-7.95(m,2H),7.50-7.44(m,2H),7.36(s,1H),7.25-7.22(m,1H).MS(ESI)m / z 313.0[M+H] +

[0513] Example 343: 5-(3-(4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 5-(3-(4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate (270 mg, 0.75 mmol, 1.0 equiv.), 4-methylpent-1-yne (315 mg, 3.75 mmol, 5.0 equiv.), Pd(PPh3)2Cl2 (52.7 mg, 0.075 mmol, 0.1 equiv.), and CuI (14.3 mg, 0.075 mmol, 0.1 equiv.) in DMF / DIEA (1.5 mL / 1.5 mL) in a sealed tube was heated at 50 °C under N2 for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE: EtOAc = 3:1) to give the crude desired product (80 mg, 33% yield) as a colorless oil. MS (ESI) m / z 314.1 [M+H] + .

[0514] Step 2: 5-(3-(4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid A mixture of ethyl 5-(3-(4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (80 mg, 0.25 mmol) and 3N KOH (2 mL, 6 mmol, 24 equiv.) in methanol / THF (2 mL / 2 mL) was stirred at room temperature overnight. The reaction was adjusted to pH ∼3 with 1N HCl and extracted with EtOAc (3 × 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–95% CH3CN in water) to give 5-(3-(4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid (50 mg, 69% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:13.35(brs,1H),7.36-7.32(m,1H),7.16(d,J=7.6Hz,1H),7.06 -7.04(m,2H),2.31(d,J=6.8Hz,2H),1.86-1.82(m,1H),0.98(d,J=6.8Hz,6H).MS(ESI)m / z 286.1[M+H] +

[0515] Example 344: 5-(3-(3-cyclopentylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate and prop-2-ynylcyclopentane to give 5-(3-(3-cyclopentylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.35(brs,1H),7.34(t,J=8.0Hz,1H),7.16(d,J=7.6Hz,1H),7.06-7.03(m,2H),2 .41(d,J=6.4Hz,2H),2.11-2.04(m,1H),1.81-1.73(m,2H),1.63-1.49(m,4H),1.33-1.23(m,2H).MS(ESI)m / z 312.2[M+H] + .

[0516] Example 345: 5-(3-(3-cyclobutylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Prop-2-ynylcyclobutane To a solution of lithium acetylide ethylenediamine complex (2.12 g, 23 mmol, 2.3 equiv.) in DMSO (20 mL) / THF (10 mL) was added (bromomethyl)cyclobutane (1.49 g, 10 mmol, 1.0 equiv.) slowly at 0 °C. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with EtO (80 mL) and washed with brine. The separated organic layer was dried over anhydrous sodium sulfate and concentrated to give the desired crude product (2 g) as a pale yellow liquid, which was used directly in the next step without further purification.

[0517] Step 2: 5-(3-(3-cyclobutylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and prop-2-ynylcyclobutane to give 5-(3-(3-cyclobutylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,CD3OD)δ:7.28(t,J=8.0Hz,1H),7.14(d,J=7.6Hz,1H),7.08-7.02(m,2H),2 .59-2.47(m,1H),2.46(d,J=6.8Hz,2H),2.15-2.09(m,2H),1.94-1.81(m,4H).MS(ESI)m / z 298.1[M+H] +

[0518] Example 346: 5-(3-(3-cyclohexylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and prop-2-ynylcyclopentane to give 5-(3-(3-cyclohexylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.25(brs,1H),7.36-7.31(m,1H),7.16(d,J=7.6Hz,1H),7.06-7.03(m, 2H),2.31(d,J=6.4Hz,2H),1.78(d,J=13.2Hz,2H),1.71-1.49(m,5H),1.26-1.01(m,5H).MS(ESI)m / z 326.2[M+H] +

[0519] Example 347: 5-(3-(2-(4,4-difluorocyclohexyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: 4,4-Difluorocyclohexanecarbaldehyde To a solution of ethyl 4,4-difluorocyclohexanecarboxylate (5.0 g, 26.0 mmol) in toluene (25 mL) was added DIBAL-H (31.2 mL, 1 M in toluene, 31.2 mmol, 1.2 equiv.) at -70 °C under N2. The reaction mixture was stirred at -70 °C for 30 min. It was quenched with methanol and washed with brine. The mixture was extracted with EtOAc (2 × 300 mL), dried over anhydrous Na2SO4, and concentrated to give the desired compound (5 g, crude) as a yellow oil. MS (ESI) m / z 149.1 [M+H] + .

[0520] Step 2: 4-ethynyl-1,1-difluorocyclohexane To a solution of 4,4-difluorocyclohexanecarbaldehyde (2 g, crude, 10.4 mmol) and K2CO3 (5.74 g, 41.6 mmol, 4.0 equiv.) in methanol (25 mL) was added dimethyl 1-diazoacetonylphosphonate (2.60 g, 13.5 mmol, 1.3 equiv.) slowly at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was treated with brine and extracted with Et2O (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the desired compound (1.94 g, crude) as a yellow oil. MS (ESI) m / z 145.1 [M+H] + .

[0521] Step 3: 5-(3-(2-(4,4-difluorocyclohexyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-ethynyl-1,1-difluorocyclohexane to give 5-(3-(2-(4,4-difluorocyclohexyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.20(brs,1H),7.37-7.33(m,1H),7.18(d,J=8.0Hz,1H),7 .08-7.05(m,2H),2.90-2.80(m,1H),2.08-1.84(m,6H),1.73-1.65(m,2H).MS(ESI)m / z 348.1[M+H] +

[0522] Example 348: 5-(4-(3-phenylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(4-iodophenoxy)-1H-1,2,3-triazole-4-carboxylic acid and prop-2-ynylbenzene to give 5-(4-(3-phenylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.38(brs,1H),7.45-7.24(m,7H),7.04(d,J=8.8Hz,2H),3.88(s,2H).MS(ESI)m / z 320.1[M+H] +

[0523] Example 349: 5-(3-(3-phenylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylic acid and prop-2-ynylbenzene to give 5-(3-(3-phenylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.35(brs,1H),7.41-7.33(m,5H),7.27-7.22(m,2H),7.12-7.06(m,2H),3.89(s,2H).MS(ESI)m / z 320.1[M+H] +

[0524] Example 350: 5-(3-(4-cyanobut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and pent-4-ynenitrile to give 5-(3-(4-cyanobut-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.29(t,J=8.0Hz,1H),7.14(d,J=7.6Hz,1H),7.10-7.05(m,2H),2.80-2.73(m,4H).MS(ESI)m / z 283.0[M+H] +

[0525] Example 351: 5-(3-(1,4-dioxaspiro[4.5]decan-8-ylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 8-ethynyl-1,4-dioxaspiro[4.5]decane to give 5-(3-(1,4-dioxaspiro[4.5]decan-8-ylethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.33(t,J=8.0Hz,1H),7.15(d,J=7.6Hz,1H),7.05-7.02(m,2H),3.86 (s,4H),2.73-2.70(m,1H),1.88-1.82(m,2H),1.74-1.61(m,4H),1.56-1.51(m,2H).MS(ESI)m / z 370.1[M+H] +

[0526] Example 352: 5-(3-((4-oxocyclohexyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 3-iodophenol, and 4-ethynylcyclohexanone to give 5-(3-((4-oxocyclohexyl)ethynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.28(brs,1H),7.35(t,J=8.0Hz,1H),7.20(t,J=7.6Hz,1H),7.10-7. 06(m,2H),3.12-3.08(m,1H),2.50-2.31(m,4H),2.14-1.92(m,2H),1.90-1.87(m,2H).MS(ESI)m / z 326.1[M+H] + .

[0527] Example 353: 5-(4-(3-(4-fluorophenyl)prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(4-iodophenoxy)-1H-1,2,3-triazole-4-carboxylic acid and 1-fluoro-4-(prop-2-ynyl)benzene to give 5-(4-(3-(4-fluorophenyl)prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.25(brs,1H),7.45-7.42(m,4H),7.18(t,J=8.8Hz,2H),7.04(d,J=9.2Hz,2H),3.88(s,2H).MS(ESI)m / z 338.1[M+H] +

[0528] Example 354: 5-(3-(3-(4-fluorophenyl)prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and 1-fluoro-4-(prop-2-ynyl)benzene to give 5-(3-(3-(4-fluorophenyl)prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.43-7.40(m,2H),7.27(t,J=8.0Hz,1H),7.17(t,J=8.8Hz,2H), 7.08(d,J=8.0Hz,1H),6.91(dd,J=8.0Hz,2.4Hz,1H),6.86(m,1H),3.86(s,2H).MS(ESI)m / z 338.1[M+H]+ .

[0529] Example 355: 5-(4-(3-cyclopropylprop-1-ynyl)phenylthio)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 5 using ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate, 4-bromobenzenethiol, and (3-cyclopropylprop-1-ynyl)trimethylsilane to give 5-(4-(3-cyclopropylprop-1-ynyl)phenylthio)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.25(d,J=8.4Hz,2H),7.14(d,J=8.4Hz,2H),2.45(d,J =6.0Hz,2H),1.01-0.97(m,1H),0.49-0.44(m,2H),0.25-0.22(m,2H).MS(ESI)m / z 300.1[M+H] +

[0530] Example 356: 5-(3-(3-cyclopropylprop-1-ynyl)phenylthio)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of ethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (26.0 g, 93.5 mmol, 1.0 equiv.) in toluene (580 mL) was added PCl5 (49.0 g, 234 mmol, 2.5 equiv.) in small portions. The reaction mixture was stirred at 40 °C under N2 for 3 h. The solvent was removed in vacuo, and the residue was dissolved in diethyl ether (500 mL), washed with saturated sodium bicarbonate (3 × 100 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 15:1) to give the title compound (24.0 g, yield: 63%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ:7.26(d,2H),6.87(d,2H),5.50(s,2H),4.42(q,2H),3.79(s,3H),1.40(t,3H)

[0531] Step 2: Ethyl 5-((3-bromophenyl)thio)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of NaH (60% in mineral oil, 158 mg, 3.96 mmol, 1.2 equiv.) in DMF (10 mL) was added 4-bromobenzenethiol (811 mg, 4.29 mmol, 1.3 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (974 mg, 3.30 mmol, 1.0 equiv.) was added to the mixture and stirred at 80 °C for 3 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1) to give the title compound (1.10 g, yield: 74%) as a yellow oil. MS(ESI)m / z 448.0[M+H] + .

[0532] Step 3: Ethyl 5-((3-bromophenyl)thio)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 5-((3-bromophenyl)thio)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (1.1 g, 2.45 mmol) in TFA (10 mL) was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=200:1) to give the desired compound (780 mg, yield: 97%) as a yellow solid. MS (ESI) m / z 328.0 [M+H] + .

[0533] Step 4: Ethyl 5-((3-(3-cyclopropylprop-1-ynyl)phenyl)thio)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-((3-bromophenyl)thio)-1H-1,2,3-triazole-4-carboxylate (600 mg, 1.67 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (2.05 g, 12.5 mmol, 7.5 equiv.), Pd(PPh)Cl (252 mg, 0.36 mmol, 0.2 equiv.), CuI (68.4 mg, 0.36 mmol, 0.2 equiv.), and TBAF (1 M in THF, 15 mL, 15 mmol, 9.0 equiv.) in DIEA / DMF (6 mL / 6 mL) in a sealed tube was heated at 70 °C overnight under N. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the title compound (90 mg, 15% yield) as a yellow solid. MS(ESI)m / z 328.1[M+H] + .

[0534] Step 5: 5-((4-(3-cyclopropylprop-1-ynyl)phenyl)thio)-1H-1,2,3-triazole-4-carboxylic acid A mixture of 5-((3-(3-cyclopropylprop-1-ynyl)phenyl)thio)-1H-1,2,3-triazole-4-carboxylic acid (90 mg, 0.27 mmol) and 3N KOH (1 mL, 3 mmol, 11 equiv.) in MeOH / THF (1 mL / 1 mL) was stirred at room temperature overnight. The reaction was adjusted to pH ∼3 with HCl and extracted with EtOAc (3 × 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (15–95% CH3CN in water) to give the desired compound (50 mg, yield: 61%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ: 7.30-7.22 (m, 4H), 2.45 (d, J = 5.6 Hz, 2H), 1.00-0.96 (m, 1H), 0.48-0.44 (m, 2H), 0.25-0.21 (m, 2H), -NH and COH protons not observed. MS (ESI) m / z 300.0 [M+H] +

[0535] Example 357: Ethyl 5-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate [ka] A mixture of ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate (4.5 g, 12.5 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (8 g, crude), Pd(PPh)Cl (878 mg, 1.25 mmol, 0.1 equiv.), CuI (228 mg, 1.25 mmol, 0.1 equiv.), and TBAF (1 M in THF, 150 mL, 150 mmol, 12.0 equiv.) in DIEA (75 mL) was heated at 70 °C under N for 2 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE: EtOAc = 5:1) to give the desired compound (1.4 g, yield: 36%) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ:7.31(t,J=8.0Hz,1H),7.11(d,J=7.6Hz,1H),7.03-6.97(m,2H),4.15(q,J=7.2Hz,2H), 2.44(d,J=5.6Hz,2H),1.13(t,J=7.2Hz,3H),1.00-0.97(m,1H),0.49-0.44(m,2H),0.25-0.20(m,2H).MS(ESI)m / z 312.1[M+H] +

[0536] Example 358: Ethyl 3-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylate [ka] Step 1: Ethyl 3-chloro-5-methyl-1H-pyrazole-4-carboxylate To a mixture of ethyl 3-amino-5-methyl-1H-pyrazole-4-carboxylate (10 g, 59 mmol, 1.0 equiv.) and CuCl (11.7 g, 118 mmol, 2.0 equiv.), t-BuNO (7.3 g, 71 mmol, 1.2 equiv.) was slowly added at 0 °C. The resulting mixture was refluxed for 2 h. It was quenched with 4 N HCl and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous NaSO and concentrated to give the crude product, which was purified by silica gel column chromatography (PE:EA = 3:1) to give the desired compound (4.7 g, yield: 42%) as a white solid. MS (ESI) m / z 189.0 [M+H] + .

[0537] Step 2: Ethyl 3-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate To a solution of ethyl 3-chloro-5-methyl-1H-pyrazole-4-carboxylate (4.7 g, 24.9 mmol, 1.0 equiv.) in DMF (30 mL) was added NaH (60% in mineral oil, 1.2 g, 29.8 mmol, 1.2 equiv.) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h, and then SEMCl (4.5 g, 27.4 mmol, 1.1 equiv.) was added slowly at 0 °C. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was poured into ice water and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1) to give the desired compound (6.5 g, yield: 82%) as a colorless oil. MS (ESI) m / z 319.1 [M+H] + .

[0538] Step 3: Ethyl 3-(3-iodophenoxy)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate To a solution of 3-iodophenol (2.64 g, 12.0 mmol, 1.2 equiv) in DMF (26 mL) was added NaH (60% in mineral oil, 480 mg, 12.0 mmol, 1.2 equiv) in portions at 0 °C. The resulting mixture was stirred at room temperature for 1 h, and then ethyl 3-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (3.19 g, 10 mmol, 1.0 equiv) was added to SEMCl (4.5 g, 27.4 mmol, 1.1 equiv) at 0 °C. The resulting mixture was stirred at 110 °C for 3 days. The reaction mixture was quenched with ice water (100 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 5:1) to give the desired compound (1.1 g, yield: 22%) as a white solid. MS (ESI) m / z 503.1 [M+H] + .

[0539] Step 4: Ethyl 3-(3-iodophenoxy)-5-methyl-1H-pyrazole-4-carboxylate A solution of ethyl 3-(3-iodophenoxy)-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate (1.1 g, 2.19 mmol) in TFA / DCM (3 mL / 3 mL) was stirred at room temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the residue was treated with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to give the desired compound (820 mg, yield: 100%) as a yellow gel. MS (ESI) m / z 373.0 [M+H] + .

[0540] Step 5: Ethyl 3-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylate A mixture of ethyl 3-(3-iodophenoxy)-5-methyl-1H-pyrazole-4-carboxylate (410 mg, 1.10 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (835 mg, 5.5 mmol, 5.0 equiv.), Pd(PPh)Cl (77 mg, 0.11 mmol, 0.1 equiv.), CuI (21 mg, 0.11 mmol, 0.1 equiv.), and TBAF (1 M in THF, 5.5 mL, 5.50 mmol, 5.0 equiv.) in DIEA / DMF (1.5 mL / 3 mL) in a sealed tube was heated at 50 °C under N for 3 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the desired compound (110 mg, 31% yield) as a colorless gel. 1H-NMR(400MHz,CDCl3)δ:7.22(t,J=8.0Hz,1H),7.13-7.08(m,2H),7.00(dd,J=8.0Hz,2.0Hz,1H),4.17(q,J=7.2Hz,2H),2.5 0(s,3H),2.44(d,J=5.6Hz,2H),1.16(t,J=7.2Hz,3H),1.01-0.97(m,1H),0.52-0.48(m,2H),0.30-0.26(m,2H).MS(ESI)m / z 325.2[M+H] +

[0541] Example 359: 3-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylic acid [ka] A mixture of ethyl 3-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylate (95 mg, 0.29 mmol, 1.0 equiv.) in 3N KOH (2 mL, 6 mmol, 20.7 equiv.) and methanol (3 mL) was stirred at reflux for 30 h. The reaction was adjusted to pH ∼3 with HCl and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–95% CH3CN in water) to give the desired compound (43 mg, 50% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:12.75(brs,1H),12.10(brs,1H),7.28(t,J=8.0Hz,1H),7.07(d,J=7.6Hz,1H),6.95(dd,J=8.4Hz,2.0Hz,1H ),6.88(t,J=2.0Hz,1H),2.50-2.42(m,5H),1.16(t,J=7.2Hz,3H),1.01-0.97(m,1H),0.49-0.44(m,2H),0.25-0.20(m,2H).MS(ESI)m / z 297.1[M+H] +

[0542] Example 360: Ethyl 3-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylate [ka] The title compound was prepared according to the procedure described for Example 358 using ethyl 3-chloro-5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carboxylate, 4-iodophenol, and (3-cyclopropylprop-1-ynyl)trimethylsilane to give ethyl 3-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylate. 1 H-NMR(400MHz,CDCl3)δ:7.34(d,J=8.8Hz,2H),6.96(d,J=8.8Hz,2H),4.16(q,J=7.2Hz,2H),2.49(s,3H),2.4 4(d,J=6.0Hz,2H),1.14(t,J=7.2Hz,3H),1.02-0.97(m,1H),0.52-0.48(m,2H),0.31-0.26(m,2H).MS(ESI)m / z 325.2[M+H] + .

[0543] Example 361: 3-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 358 using ethyl 3-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylate to give 3-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-5-methyl-1H-pyrazole-4-carboxylic acid. 1H-NMR(400MHz,CD3OD)δ:7.20(d,J=8.8Hz,2H),6.84(d,J=8.8Hz,2H),2.40(s,3H),2.3 4(d,J=6.0Hz,2H),0.92-0.88(m,1H),0.42-0.37(m,2H),0.20-0.16(m,2H).MS(ESI)m / z 297.1[M+H] + .

[0544] Example 362: 5-(4-(3-cyclopropylprop-1-ynyl)phenylamino)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 5-amino-1-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of 4-bromoaniline (2 g, 59 mmol, 1.0 equiv.) in TFA (10 mL) was added NaNO (4.9 g, 71 mmol, 1.2 equiv.) dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. Sodium azide (4.6 g, 71 mmol, 1.2 equiv.) in water (5 mL) was added. The mixture was stirred in an ice bath for 1 h and concentrated in vacuo to remove TFA. The residue was diluted with DCM (100 mL), dried over NaSO, and concentrated to give 1-azido-4-bromobenzene (2.2 g, crude), which was dissolved in EtOH (30 mL). Sodium ethoxide (4.8 g, 71 mmol, 1.2 equiv.) and ethyl 2-cyanoacetate (10 g, 88.5 mmol, 1.5 equiv.) were then added. The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was washed with (PE: EtOAc = 10:1, 50 mL) to give the desired product (3.3 g, yield: 91%) as a yellow solid. MS (ESI) m / z 311.0 [M+H] + .

[0545] Step 2: Ethyl 5-((4-bromophenyl)amino)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 5-amino-1-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxylate (1 g, 3.22 mmol, 1.0 equiv.) in pyridine (10 mL) was refluxed overnight. After removing most of the pyridine, the residue was washed with (PE: EtOAc = 10:1, 20 mL) to give the desired product (600 mg, 60% yield) as a yellow solid. MS (ESI) m / z 311.0 [M+H] + .

[0546] Step 3: Ethyl 5-((4-(3-cyclopropylprop-1-ynyl)phenyl)amino)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-((4-bromophenyl)amino)-1H-1,2,3-triazole-4-carboxylate (400 mg, 1.29 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (588 mg, 3.87 mmol, 3.0 equiv.), Pd(PPh)Cl (181 mg, 0.26 mmol, 0.2 equiv.), CuI (51 mg, 0.26 mmol, 0.2 equiv.), and TBAF (1 M in THF, 3.87 mL, 3.87 mmol, 3.0 equiv.) in DIEA / DMF (2 mL / 2 mL) in a sealed tube was heated at 90 °C under N for 5 h. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE:EtOAc = 10:1) to give the desired product (400 mg, crude) as a white solid. MS(ESI)m / z 311.1[M+H] + .

[0547] Step 4: 5-((4-(3-cyclopropylprop-1-ynyl)phenyl)amino)-1H-1,2,3-triazole-4-carboxylic acid A mixture of 5-((4-(3-cyclopropylprop-1-ynyl)phenyl)amino)-1H-1,2,3-triazole-4-carboxylate (200 mg, 0.64 mmol) in 3N KOH (2 mL, 6 mmol, 9.4 equiv.) and methanol / THF (2 mL / 2 mL) was stirred at room temperature overnight. The reaction was adjusted to pH ∼3 and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–95% CH3CN in water) to give the desired product (13.5 mg, 7% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:15.00(brs,1H),13.45(brs,1H),8.31(brs,1H),7.54(d,J=8.0Hz,2H),7.29(d ,J=8.0Hz,2H),2.45(d,J=5.6Hz,2H),1.02-0.98(m,1H),0.51-0.44(m,2H),0.26-0.20(m,2H).MS(ESI)m / z 283.1[M+H] + .

[0548] Example 363: 5-(3-(3-cyclopropylprop-1-ynyl)phenylamino)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 362 using ethyl 5-((3-bromophenyl)amino)-1H-1,2,3-triazole-4-carboxylate and (3-cyclopropylprop-1-ynyl)trimethylsilane to give 5-(3-(3-cyclopropylprop-1-ynyl)phenylamino)-1H-1,2,3-triazole-4-carboxylic acid. 1H-NMR(400MHz,DMSO-d6)δ:8.91(brs,1H),7.72(s,1H),7.33(dd,J=8.0Hz,2.0Hz,1H),7.20(t,J=8.0Hz,1H),6. 83(d,J=7.6Hz,1H),2.47(d,J=5.6Hz,2H),1.05-0.98(m,1H),0.51-0.46(m,2H),0.28-0.20(m,2H).MS(ESI)m / z 283.1[M+H] +

[0549] Example 364: 5-(4-(3-cyclopropylprop-1-ynyl)benzyl)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: Ethyl 4-(4-iodophenyl)-3-oxobutanoate To a solution of 2-(4-iodophenyl)acetic acid (2.62 g, 10 mmol, 1.0 equiv.) in EtOAc (30 mL), CDI (2.92 g, 18 mmol, 1.8 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature overnight. Then, potassium 3-ethoxy-3-oxopropanoate (1.87 g, 11 mmol, 1.1 equiv.), MgCl (1.05 g, 11 mmol, 1.1 equiv.), and TEA (1.34 g, 13.2 mmol, 1.3 equiv.) were added. The resulting mixture was stirred at 45 °C overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with 1N HCl, dried over NaSO, and concentrated to give the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 5:1) to give the target product (1.35 g, yield: 41%) as a colorless oil. MS(ESI)m / z 333.0[M+H] + .

[0550] Step 2: Ethyl 5-(4-iodobenzyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 4-(4-iodophenyl)-3-oxobutanoate (333 mg, 1 mmol, 1.0 equiv.), PMBN (196 mg, 1.2 mmol, 1.2 equiv.), and KCO (414 mg, 3 mmol, 3.0 equiv.) was heated at 80 °C overnight under N. The reaction was treated with brine (100 mL) and extracted with EtO (100 mL). The separated organic layer was dried over NaSO and concentrated to give the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 5:1) to give the desired product (300 mg, yield: 63%) as a yellow oil. MS (ESI) m / z 478.1 [M+H] + .

[0551] Step 3: Ethyl 5-(4-iodobenzyl)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 5-(4-iodobenzyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (300 mg, 0.63 mmol, 1.0 equiv.) in TFA (6 mL) was heated at 60° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (15-95% CH CN in water, 0.1% TFA) to give the desired product (130 mg, 58% yield) as a yellow solid. MS (ESI) m / z 358.0 [M+H] + .

[0552] Step 4: Ethyl 5-(4-(3-cyclopropylprop-1-ynyl)benzyl)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(4-iodobenzyl)-1H-1,2,3-triazole-4-carboxylate (130 mg, 0.36 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (219 mg, 1.44 mmol, 4.0 equiv.), Pd(PPh)Cl (26 mg, 0.036 mmol, 0.1 equiv.), CuI (6.8 mg, 0.036 mmol, 0.1 equiv.), and TBAF (1 M in THF, 1.44 mL, 1.44 mmol, 4.0 equiv.) in DIEA / DMF (0.5 mL / 0.5 mL) in a sealed tube was heated at 50 °C overnight under N. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE:EtOAc = 5:1) to give the desired product (70 mg, yield: 64%) as a yellow solid. MS(ESI)m / z 310.2[M+H] + .

[0553] Step 5: 5-(4-(3-cyclopropylprop-1-ynyl)benzyl)-1H-1,2,3-triazole-4-carboxylic acid A mixture of 3-NKOH (1 mL, 3 mmol, 13.6 equiv.) and ethyl 5-(4-(3-cyclopropylprop-1-ynyl)benzyl)-1H-1,2,3-triazole-4-carboxylate (70 mg, 0.22 mmol) in methanol / THF (1 mL / 1 mL) was stirred at room temperature overnight. The reaction was adjusted to pH ∼3 and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–95% CH3CN in water) to give the desired product (39 mg, 63% yield) as a white solid. 1 H-NMR(400MHz,DMSO-d6)δ:7.24(s,4H),4.22(s,2H),2.43(d,J=6.0Hz,2H),1.00-0.96(m,1H),0.48-0.44(m,2H),0.26-0.21(m,2H).MS(ESI)m / z 282.1[M+H] + .

[0554] Example 365: 5-(3-(3-cyclopropylprop-1-ynyl)benzyl)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 364 using 2-(3-iodophenyl)acetic acid, potassium 3-ethoxy-3-oxopropanoate, PMBN3, and (3-cyclopropylprop-1-ynyl)trimethylsilane to give 5-(3-(3-cyclopropylprop-1-ynyl)benzyl)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:7.25-7.17(m,4H),4.24(s,2H),2.43(d,J=6.0H z,2H),1.02-0.95(m,1H),0.48-0.44(m,2H),0.25-0.21(m,2H).MS(ESI)m / z 282.1[M+H] + .

[0555] Example 366: Ethyl 5-(3-(4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and 4-methylpent-1-yne to give ethyl 5-(3-(4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate. 1 H-NMR(400MHz,CDCl3)δ:7.29-7.18(m,3H),7.09-7.07(m,1H),4.38(q,J=7.2Hz,2H),2.28( d,J=6.4Hz,2H),1.93-1.85(m,1H),1.32(t,J=7.2Hz,2H),1.02(d,J=6.8Hz,6H).MS(ESI)m / z 314.1[M+H]+ .

[0556] Example 367: 5-(3-(3-(3,3-difluorocyclobutyl)prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and (3-(3,3-difluorocyclobutyl)prop-1-ynyl)trimethylsilane to give 5-(3-(3-(3,3-difluorocyclobutyl)prop-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:13.20(brs,1H),7.35(t,J=8.0Hz,1H),7.18(d,J=7 .6Hz,1H),7.08-7.06(m,2H),2.71-2.64(m,4H),2.45-2.38(m,3H).MS(ESI)m / z 334.1[M+H] +

[0557] Example 368: 5-(5-(3-cyclopropylprop-1-ynyl)-1,6-dihydro-1-methyl-6-oxopyridin-3-yloxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] Step 1: 3-Bromo-1-methylpyridin-2(1H)-one A mixture of 3-bromopyridin-2(1H)-one (10 g, 57.5 mmol, 1.0 equiv.), KCO (15.9 g, 115 mmol, 2.0 equiv.), and MeI (12.2 g, 86.3 mmol) in DMF (50 mL) was stirred at room temperature overnight. The reaction was treated with water (150 mL) and extracted with EtOAc (4 × 150 mL). The combined organic layers were dried over anhydrous NaSO and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:1) to give the desired product (8.3 g, yield: 77%) as a yellow oil. MS (ESI) m / z 188.0 [M+H] + .

[0558] Step 2: 3-Bromo-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one A mixture of 3-bromo-1-methylpyridin-2(1H)-one (2.26 g, 12.0 mmol, 1.0 equiv.), BPD (4.6 g, 18.0 mmol, 1.5 equiv.), [Ir(OMe)(cod)] (150 mg, 0.24 mmol, 0.02 equiv.), and dtbpy (136 mg, 0.48 mmol, 0.04 equiv.) in THF (70 mL) was stirred overnight at 45 °C under N. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 2:1) to give the desired product (2.06 g, yield: 41%) as a white solid. MS (ESI) m / z 314.1 [M+H] + .

[0559] Step 3: 3-Bromo-5-hydroxy-1-methylpyridin-2(1H)-one To a mixture of 3-bromo-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (1.46 g, 4.65 mmol, 1.0 equiv.) and NaOH (2.0 M, 10 mL, 20 mmol, 4.3 equiv.) in THF (20 mL), hydrogen peroxide (30 wt %, 2 mL, 22 mmol, 4.7 equiv.) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. After removing the solvent in vacuo, the residue was diluted with water and extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by prep-HPLC (10–95% CH3CN in water) to give the desired product (900 mg, yield: 95%) as a white solid. MS(ESI)m / z 204.0[M+H] + .

[0560] Step 4: Ethyl 5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate To a mixture of NaH (60% in mineral oil, 212 mg, 5.29 mmol, 1.2 equiv.) in DMF (25 mL) was added 3-bromo-5-hydroxy-1-methylpyridin-2(1H)-one (900 mg, 4.41 mmol, 1.0 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. Ethyl 5-chloro-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (1.3 g, 4.41 mmol, 1.0 equiv.) was added to the mixture and stirred at 95 °C for 5 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (PE: EtOAc = 3:1) to give the desired product (800 mg, yield: 39%) as a gray solid. MS(ESI)m / z 463.1[M+H] + .

[0561] Step 5-Ethyl 5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-1H-1,2,3-triazole-4-carboxylate A solution of ethyl 5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (710 mg, 1.53 mmol) in TFA (17 mL) was heated at 55° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE: EtOAc = 3:2) to give the desired product (540 mg, yield: 91%) as a gray solid. MS (ESI) m / z 343.0 [M+H] + .

[0562] Step 6: Ethyl 5-((5-(3-cyclopropylprop-1-ynyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-((5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-1H-1,2,3-triazole-4-carboxylate (470 mg, 1.37 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (1.04 g, 6.85 mmol, 5.0 equiv.), Pd(PPh)Cl (98 mg, 0.14 mmol, 0.1 equiv.), CuI (27 mg, 0.14 mmol, 0.1 equiv.), and TBAF (1 M in THF, 7 mL, 7 mmol, 5.0 equiv.) in DIEA / DMF (2.5 mL / 5 mL) in a sealed tube was heated at 50 °C under N overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:methanol=50:1) to give the target product (170 mg, yield: 35%) as a yellow solid. MS (ESI) m / z 343.1 [M+H] + .

[0563] Step 7: 5-((5-(3-cyclopropylprop-1-ynyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-1H-1,2,3-triazole-4-carboxylic acid A mixture of ethyl 5-((5-(3-cyclopropylprop-1-ynyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-1H-1,2,3-triazole-4-carboxylate (166 mg, 0.48 mmol) and 3N KOH (2 mL, 6 mmol, 12.5 equiv.) in methanol / THF (2 mL / 2 mL) was stirred at 35°C for 3 h. The reaction was adjusted to pH 3 with 1N HCl and extracted with EtOAc (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10-95% CH3CN in water) to give the desired product (100 mg, yield: 65%) as a yellow solid. 1 H-NMR(400MHz,DMSO-d6)δ:15.20(brs,1H),13.20(brs,1H),7.90(d,J=3.2Hz,1H),7.64(d,J=2.8Hz,1H) ,3.42(s,3H),2.49(d,J=6.0Hz,2H),0.98-0.94(m,1H),0.46-0.44(m,2H),0.28-0.21(m,2H).MS(ESI)m / z 315.1[M+H] + .

[0564] Example 369: 4-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-1,2,5-oxadiazole-3-carboxylic acid [ka] Step 1: Ethyl 4-nitro-1,2,5-oxadiazole-3-carboxylate At 0°C, sulfuric acid (21 mL) was slowly added to hydrogen peroxide (21 mL, 30 wt%), followed by sodium tungstate (2.06 g, 7 mmol, 1.0 equiv.), to which ethyl 4-amino-1,2,5-oxadiazole-3-carboxylate (1.10 g, 17 mmol, 1.00 equiv.) was added. The resulting mixture was heated to 15°C and reacted for 3 hours. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over aqueous NaSO and concentrated under reduced pressure to give the desired product (1.3 g, 100% yield) as a colorless oil. MS (ESI) m / z 188.0 [M+H] + .

[0565] Step 2: 4-(3-cyclopropylprop-1-ynyl)phenol A mixture of 4-iodophenol (660 mg, 3 mmol, 1.0 equiv.), (3-cyclopropylprop-1-ynyl)trimethylsilane (1.82 g, 12 mmol, 4.0 equiv.), Pd(PPh3)2Cl2 (210 mg, 0.3 mmol, 0.1 equiv.), CuI (57 mg, 0.3 mmol, 0.1 equiv.), and TBAF (1 M in THF, 12 mL, 12 mmol, 4.0 equiv.) in DIEA / DMF (4 mL / 4 mL) in a sealed tube was heated at 50 °C for 5 h under N2. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE: EtOAc = 15:1) to give the desired product (550 mg, 71% yield) as a brown oil. MS (ESI) m / z 173.1 [M+H] + .

[0566] Step 3: Ethyl 4-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-1,2,5-oxadiazole-3-carboxylate A mixture of ethyl 4-nitro-1,2,5-oxadiazole-3-carboxylate (280 mg, 1.5 mmol, 1.0 equiv.), 4-(3-cyclopropylprop-1-ynyl)phenol (310 mg, 1.8 mmol, 1.2 equiv.), and K2CO3 (620 mg, 4.5 mmol, 3.0 equiv.) in DMSO (6 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over aqueous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (PE: EtOAc = 50:1) to give the desired product (180 mg, yield: 38%) as a yellow oil. 1 H-NMR(400MHz,CDCl3)δ:7.50(d,J=8.8Hz,2H),7.25(d,J=8.8Hz,2H),4.51(q,J=6.8Hz,2H),2.4 6(d,J=6.0Hz,2H),1.43(t,J=6.8Hz,3H),1.03-0.96(m,1H),0.52-0.44(m,2H),0.26-0.21(m,2H)

[0567] Step 4: 4-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-1,2,5-oxadiazole-3-carboxylic acid A mixture of ethyl 4-(4-(3-cyclopropylprop-1-ynyl)phenoxy)-1,2,5-oxadiazole-3-carboxylate (110 mg, 0.35 mmol, 1.0 equiv.) and LiOH.HO (44 mg, 1.05 mmol, 3.0 equiv.) in THF / methanol / HO (5 mL / 5 mL / 5 mL) was stirred at room temperature for 3 h. The reaction was adjusted to pH ∼3 and extracted with EtOAc (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC (10–95% CHCN in water) to give the desired product (11.7 mg, 12% yield) as a white solid. 1H-NMR(400MHz,DMSO-d6)δ:12.54(brs,1H),7.48-7.44(m,2H),7.27-7.23(m,2H),2.47 (d,J=6.0Hz,2H),1.02-0.96(m,1H),0.50-0.45(m,2H),0.26-0.20(m,2H).MS(ESI)m / z 285.1[M+H] +

[0568] Example 370: 4-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-1,2,5-oxadiazole-3-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 369 using ethyl 4-nitro-1,2,5-oxadiazole-3-carboxylate and 3-(3-cyclopropylprop-1-ynyl)phenol to give 4-(3-(3-cyclopropylprop-1-ynyl)phenoxy)-1,2,5-oxadiazole-3-carboxylic acid. 1 H-NMR(400MHz,DMSO-d6)δ:12.50(brs,1H),7.45-7.25(m,4H),2.48(d,J=6.0 Hz,2H),1.02-0.99(m,1H),0.50-0.46(m,2H),0.26-0.20(m,2H).MS(ESI)m / z 285.4[M+H] +

[0569] Example 371: Ethyl 5-(3-(4,4-dimethylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and 4,4-dimethylpent-1-yne to give ethyl 5-(3-(4,4-dimethylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate. 1 H NMR(400MHz,CDCl3)δ:7.29-7.19(m,3H),7.08(dd,J=8.0Hz and 1.2Hz,1H),4.38(q,J=7.2Hz,2H),2.26(s,2H),1.32(t,J=7.2Hz,3H),1.04(s,9H).MS(ESI)m / z 328.1[M+H] +

[0570] Example 372: 5-(3-(4,4-dimethylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate and 4,4-dimethylpent-1-yne to give 5-(3-(4,4-dimethylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H NMR(400MHz,DMSO-d6)δ:13.20(brs,1H),7.36-7.32(m,1H),7.17(d,J=7.6Hz,1H),7.06-7.04(m,2H),2.30(s,2H),1.01(s,9H).MS(ESI)m / z 300.1[M+H] +

[0571] Example 373: Ethyl 5-(3-(4-methylpent-1-ynyl)phenylsulfinyl)-1H-1,2,3-triazole-4-carboxylate [ka] Step 1: Ethyl 5-((3-bromophenyl)sulfinyl)-1H-1,2,3-triazole-4-carboxylate To a solution of ethyl 5-((3-bromophenyl)thio)-1H-1,2,3-triazole-4-carboxylate (1.16 g, 3.54 mmol, 1.0 equiv.) in DCM (50 mL) was added m-CPBA (85%, 611 mg, 3.54 mmol, 1.0 equiv.) at 0° C. The reaction mixture was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH=60:1) to afford the title compound (750 mg, 61%) as a colorless gel. MS (ESI) m / z 344.0 [M+H] + .

[0572] Step 2: Ethyl 5-((3-(4-methylpent-1-ynyl)phenyl)sulfinyl)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-((3-bromophenyl)sulfinyl)-1H-1,2,3-triazole-4-carboxylate (320 mg, 0.93 mmol, 1.0 equiv.), 4-methylpent-1-yne (380 mg, 4.63 mmol, 5.0 equiv.), Pd(PPh)Cl (63 mg, 0.09 mmol, 0.1 equiv.), and CuI (18 mg, 0.09 mmol, 0.1 equiv.) in DIEA / DMF (3 mL / 1.5 mL) in a sealed tube was heated at 50 °C overnight under N. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH=40:1) to give the title compound (220 mg, 72%) as a colorless gel. 1 H NMR(400MHz,CDCl3)δ:7.84(s,1H),7.74(d,J=8.0Hz,1H),7.50(d,J=8.0Hz,1H),7.41(t,J=8.0Hz,1H),4.47-4 .41(m,1H),2.28(d,J=6.4Hz,2H),1.93-1.87(m,1H),1.40(t,J=7.2Hz,3H),1.02(d,J=6.8Hz,6H).MS(ESI)m / z 346.1[M+H] +

[0573] Example 374: 5-(3-(4-methylpent-1-ynyl)phenylsulfinyl)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 343 using ethyl 5-((3-bromophenyl)sulfinyl)-1H-1,2,3-triazole-4-carboxylate and 4-methylpent-1-yne, followed by hydrolysis to give 5-(3-(4-methylpent-1-ynyl)phenylsulfinyl)-1H-1,2,3-triazole-4-carboxylic acid. 1 H NMR(400MHz,DMSO-d6)δ 7.72(s,1H),7.68-7.65(m,1H),7.57-7.52(m,2H),2.34(d,J=6.0Hz,2H),1.89-1.82(m,1H),1.00(d,J=6.4Hz,6H).MS(ESI)m / z 318.1[M+H] +

[0574] Example 375: Ethyl 5-(3-(4-methylpent-1-ynyl)phenylsulfonyl)-1H-1,2,3-triazole-4-carboxylate [ka] The title compound was prepared according to the procedure described for Example 373 using 5-((3-bromophenyl)thio)-1H-1,2,3-triazole-4-carboxylate, m-CPBA, and 4-methylpent-1-yne to give ethyl 5-(3-(4-methylpent-1-ynyl)phenylsulfonyl)-1H-1,2,3-triazole-4-carboxylate. 1H NMR(400MHz,DMSO-d6)δ:7.94-7.93(m,2H),7.76(d,J=7.6Hz,1H),7.65(t,J=8.0Hz,1H),4.34(q,J=7.2H) MS(ESI)m / z 362.1[M+H] +

[0575] Example 376: 5-(3-(4-methylpent-1-ynyl)phenylsulfonyl)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 373 using 5-((3-bromophenyl)thio)-1H-1,2,3-triazole-4-carboxylate, m-CPBA, and 4-methylpent-1-yne, followed by hydrolysis to give 5-(3-(4-methylpent-1-ynyl)phenylsulfonyl)-1H-1,2,3-triazole-4-carboxylic acid. 1 H NMR(400MHz,DMSO-d6)δ:7.72(s,1H),7.68-7.65(m,1H),7.57-7.52(m,2H), 2.34(d,J=6.0Hz,2H),1.89-1.82(m,1H),1.00(d,J=6.4Hz,6H).MS(ESI)m / z 334.8[M+H] +

[0576] Example 377: Ethyl 5-(3-(4-fluoro-4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate [ka] Step 1: Ethyl 5-(3-(4-hydroxy-4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate A mixture of ethyl 5-(3-iodophenoxy)-1H-1,2,3-triazole-4-carboxylate (900 mg, 2.5 mmol, 1.0 equiv.), 2-methyl-5-(triisopropylsilyl)pent-4-yn-2-ol (3.0 g, 11.8 mmol, 4.7 equiv.), Pd(PPh3)2Cl2 (176 mg, 0.25 mmol, 0.1 equiv.), CuI (48 mg, 0.25 mmol, 0.1 equiv.), and TBAF (1 M in THF, 12 mL, 12 mmol, 4.8 equiv.) in DMF / DIEA (8 mL / 4 mL) in a sealed tube was heated at 50 °C under N2 for 6 h. The reaction mixture was concentrated, and the residue was purified by prep-HPLC (15-95% CH3CN in water) to give the desired product (340 mg, yield: 41%) as a colorless gel. MS (ESI) m / z 330.1 [M+H] + .

[0577] Step 2: Ethyl 5-(3-(4-fluoro-4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate To a mixture of ethyl 5-(3-(4-hydroxy-4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate (183 mg, 0.55 mmol, 1.0 equiv.) in DCM (15 mL) was added DAST (530 mg, 3.30 mmol, 6.0 equiv.) at 0 °C. The resulting mixture was stirred at 0 °C for 15 min. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 × 150 mL). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure to give the crude product, which was purified by prep-HPLC (5–95% CHCN in water) to give the desired product (100 mg, yield: 54%) as a pale yellow solid. 1 H NMR(400MHz,CDCl3)δ:7.30-7.19(m,3H),7.11(dd,J=8.0Hz and 1.2Hz,1H),4.38(q,J=7.2Hz,2H),2.73(d,J=15.2Hz,2H),1.50(d,J=21.6Hz,6H),2.26(s,2H),1.32(t,J=7.2Hz,3H).MS(ESI)m / z 330.0[MH] -

[0578] Example 378: 5-(3-(4-fluoro-4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid [ka] The title compound was prepared according to the procedure described for Example 377 using 5-(3-(4-fluoro-4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylate and 3N KOH to give 5-(3-(4-fluoro-4-methylpent-1-ynyl)phenoxy)-1H-1,2,3-triazole-4-carboxylic acid. 1 H NMR(400MHz,CD3OD)δ:7.21(t,J=8.0Hz,1H),7.08(d,J=8.0Hz,1H),7.02(s,1H),6.9 6(dd,J=8.0,1.6Hz,1H),2.64(d,J=16.0Hz,2H),1.38(d,J=20.8Hz,6H),.MS(ESI)m / z 304.1[M+H] +

[0579] Compounds 1, 2, 5, 6, 9, 10, 13, 16, 17, 20, 21, 24, 25, 28, 29, 36, 37, 40, 41, 108, 138, 139, 146, 147, 149, 165, 178, 187, 190, 191, 208, 209, 215, 220, 221, and 254-378 in Table 1 were produced or prepared using the methods described above. Other compounds in Table 1 can be prepared by the methods described above.

[0580] [Table 1]

[0581] [Table 2]

[0582] [Table 3]

[0583] Table 4

[0584] Table 5

[0585] Table 6

[0586] Table 7

[0587] Table 8

[0588] Table 9

[0589] Table 10

[0590] Table 11

[0591] Table 12

[0592] Table 13

[0593] Table 14

[0594] Table 15

[0595] Table 16

[0596] Table 17

[0597] Table 18

[0598] Table 19

[0599] Table 20

[0600] Table 21

[0601] Table 22

[0602] Table 23

[0603] Table 24

[0604] Table 25

[0605] Table 26

[0606] Table 27

[0607] Table 28

[0608] Table 29

[0609] Table 30

[0610] Table 31

[0611] Table 32

[0612] Table 33

[0613] Table 34

[0614] Table 35

[0615] Table 36

[0616] Table 37

[0617] Table 38

[0618] Table 39

[0619] Table 40

[0620] Table 41

[0621] Table 42

[0622] Table 43

[0623] Table 44

[0624] Table 45

[0625] Table 46

[0626] Table 47

[0627] Table 48

[0628] Table 49

[0629] Table 50

[0630] Table 51

[0631] Table 52

[0632] Table 53

[0633] Table 54

[0634] Table 55

[0635] Table 56

[0636] Table 57

[0637] Table 58

[0638] Table 59

[0639] Table 60

[0640] Table 61

[0641] Table 62

[0642] Table 63

[0643] Table 64

[0644] Table 65

[0645] Also provided are alkyl esters of the compounds disclosed above, which may be produced by the above methods and are particularly useful as prodrugs. Ethyl esters are shown, and other esters, such as methyl, n-propyl, isopropyl, etc., are also provided herein. Such alkyl esters can be used as prodrugs of the compounds disclosed herein and are often prepared by the route to the carboxylic acid compounds disclosed herein, as disclosed above. Similarly, deesterification can be used to generate carboxylic acid analogs of the esters disclosed herein.

[0646] Bioactivity assays In-Vitro Human Glycolate Oxidase (hGOX) Assay In vitro glycolate oxidase assays were performed using recombinant full-length human hydroxyacid oxidase 1 (HAO1), the equivalent of hGOX. The enzyme was obtained from AbCam (catalog number ab113144) and purified to >95% purity using conventional chromatography. Purified HAO1 was dissolved in assay buffer consisting of 10 mM NaCl, 110 mM KCl, 2 mM MgCl, 50 mM HEPES (pH 7.4), and 0.01% Triton™ X-100. Corning 3575 384-well flat-bottom, low-flange, non-binding surface, black polystyrene plates were used for this assay.

[0647] Test compounds in DMSO were preincubated with purified recombinant human GO (6 nM) at different concentrations for 10 min, followed by the addition of glycolate substrate (85 μM) to initiate the reaction. The plate was incubated at room temperature for 10 min, at which point Amplex Red reagent (50 μM) was added.

[0648] Fluorescence intensity signals were measured on a VariosKanLUX instrument using excitation at 560 nm and emission at 590 nm. 50Values ​​were calculated using Graphpad Prism. The fluorescence signal of wells containing only DMSO was defined as 100% GO activity, while the fluorescence signal without glycolic acid substrate was defined as 0% GO activity. Table 2 shows the IC values ​​of the compounds tested in this in vitro assay. 50 Indicates the value.

[0649] [Table 66]

[0650] [Table 67]

[0651] These compounds and those disclosed herein are useful in inhibiting human glycolate oxidase, which is encoded by the human hydroxyacid oxidase 1 gene (HAO1), and are therefore expected to be useful in diseases associated with oxalate accumulation, such as hyperoxaluria.

[0652] HepaRG-CAR cell-based assay for quantification of glycolate oxidase inhibition The HepaRG human hepatocyte cell line was transfected for stable overexpression of the constitutive androstane receptor (i.e., HepaRG-CAR cells) as reported by van der Mark et al. Drug Metab. Dispos., 2017, 45:56-67, and overexpression of CAR in these cells resulted in higher levels of glycolate oxidase (GOX) expression compared to parental HepaRG cells. HepaRG-CAR cells were plated in 12-well plates and incubated for 4 weeks until fully differentiated.

[0653] To measure cellular glycolate flux, HepaRG-CAR cells were incubated in Williams medium supplemented with 10% fetal bovine serum (FBS), 5 μg / mL insulin, 50 μM hydrocortisone hemisuccinate, 2 mM glutamine, 5000 U / mL penicillin, and 5 mg / mL streptomycin. Test compounds were added to the medium at 0, 0.3, 1, 3, or 10 μM and incubated for 30 minutes. 500 μM glycolate was then added. After 48 hours of incubation, 400 μL of medium was removed from the culture plate and added to 60 μL of 37% HCl.

[0654] Internal standard (2,2-d2 glycolic acid, 1,2- 13 C2 oxalic acid, and 13 C2-glyoxylic acid) and hydroxylamine were added, followed by an additional 30-minute incubation at 80°C. Ethyl acetate with NaCl was used to extract the acids. The organic phase was dried under nitrogen and derivatized with N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide (MTBSTFA) at 80°C for 30 minutes. The amounts of glycolic, glyoxylic, and oxalic acids were determined by gas chromatography-mass spectrometry (GC-MS) using a 25-meter CP-Sil 5CB low-bleed column. Standard curves were used to calculate the concentrations of each acid in the medium.

[0655] [Table 68]

[0656] Solubility, metabolic stability, and protein binding assays Both the solubility of a compound in relevant physiological pathologies and the metabolic stability of a compound are properties that can be important to its suitability for use as a pharmaceutical composition and drug product without resorting to complex formulations. Accordingly, representative compounds disclosed herein were tested for aqueous and saline solubility, for metabolic stability in liver microsomes and human plasma, as disclosed below.

[0657] Solubility. To test the solubility of compounds in phosphate-buffered saline (PBS), compound stock solutions were prepared in 100% DMSO. For testing in aqueous solutions, deionized or distilled water was used instead of phosphate buffer. 11 g of NaHPO (FW: 141.96 g / mol) and 3.5 g of NaHPO·2H O (FW: 156.03 g / mol) were added to 1 L of Milli-Q water, and the pH was adjusted to 7.4 with phosphoric acid or sodium hydroxide. For incubation, the medium was preheated to 37°C. 8 μL aliquots of the reference and test compounds and stock solutions (10 mM) were added to 792 μL of 100 mM phosphate buffer (pH 7.4). The final DMSO concentration was 1%. The sample tubes were shaken at 1000 rpm for 1 h at room temperature.

[0658] Calibration curves were generated with spike solutions (SS) in MeOH:acetonitrile (4:1). 6 μL of 10 mM compound was added to 194 μL of MeOH / acetonitrile (4:1). Samples were centrifuged at 12,000 rpm for 10 minutes to precipitate undissolved particles. The supernatant was transferred to a new tube or plate and diluted 10- and 100-fold with 100 mM buffer. Samples were prepared for LC-MS / MS analysis by adding 5 μL of each sample (undiluted, 10-fold diluted, and 100-fold diluted) and 5 μL of the standard curve sample to 95 μL of acetonitrile (containing the internal standard).

[0659] Metabolic Stability. To evaluate metabolic stability in human liver microsome preparations, three buffers were prepared. Buffer A contained 1.0 L of 0.1 M potassium dihydrogen phosphate buffer containing 1.0 mM EDTA. Buffer B contained 1.0 L of 0.1 M dipotassium phosphate buffer containing 1.0 mM EDTA. Buffer C contained 0.1 M potassium phosphate buffer, 1.0 mM EDTA, adjusted to pH 7.4 by titrating 700 mL of buffer B with buffer A. Reference compound (ketanserin) and test compound spike solutions (500 μM) were prepared by adding 10 μL of 10 mM DMSO stock compound solution to 190 μL of acetonitrile. 1.5 μL of the 500 μM spike solution and 18.75 μL of 20 mg / mL human liver microsomes were added to 479.75 μL of buffer C on ice. NADPH was dissolved in buffer C to prepare a 6 mM NADPH stock solution.

[0660] The wells of the assay plate were chilled on ice and filled with 30 μL of a 1.5 μM spike solution containing 0.75 mg / mL microsome solution at various designated time points (0, 5, 15, 30, and 45 min). For the 0 min time point, 135 μL of acetonitrile containing the internal standard was added, followed by 15 μL of 6 mM NADPH stock solution. All other plates were preincubated at 37°C for 5 min, and 15 μL of 6 mM NADPH stock solution was added to the plate to initiate the reaction. At 5, 15, 30, and 45 min, 135 μL of acetonitrile containing the internal standard was added to the corresponding wells to terminate the reaction. After quenching, the plate was shaken at 600 rpm on a shaker (IKA, MTS2 / 4) for 10 min and then centrifuged at 5594 × g for 15 min (Thermo Multifuge ×3R). For LC / MS analysis, 50 μL of supernatant from each well was transferred to a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01).

[0661] Table 4 shows the aqueous solubility (μM) of the compounds in PBS and water (μM), human liver microsome metabolic stability half-life (t 1 / 2(min)), metabolic stability Cl int In vitro drug metabolism-pharmacokinetic (DMPK) results are shown, including (mL / min / kg).

[0662] [Table 69]

[0663] Solubility in Human Plasma. To test solubility in human plasma, stock compounds were prepared. First, 0.05 M sodium phosphate and 0.07 M NaCl buffer, pH 7.4, was preheated. 14.505 g / L NaHPO₄·12H₂O, 1.483 g / L NaH₂PO₄·2H₂O, and 4.095 g / L NaCl were dissolved in deionized water. The basic solution was titrated to pH 7.40 with phosphoric acid. Frozen plasma was quickly thawed at 37°C. The plasma was centrifuged at 3,000 rpm for 8 minutes to remove clots, then pipetted and pooled as plasma stock for experiments. Only plasma within the pH range of 7.4 to 8 was used. Plasma higher than 8 was discarded. The initial pH of the plasma was not adjusted to pH 7.4 with acid or by aeration with carbon dioxide. By using a 5% carbon dioxide incubator and PBS buffer, a pH of 7.4 was achieved after 4 hours of equilibrium dialysis. The plasma was kept on ice until use.

[0664] Spiking solution A containing 0.5 mM test compound was prepared by adding 10 μL of a 10 mM stock solution of the test compound to 190 μL of DMSO. Spiking solution B containing 0.02 mM test compound was prepared by adding 40 μL of spiking solution A to 960 μL of 0.05 mM sodium phosphate buffer containing 0.5% BSA. Plasma and spiking solution B were preheated at 37°C for 5 minutes. 10 μL of preheated spiking solution B was added to designated wells for all time points (5, 15, 30, 45, and 60 minutes). For the 0-minute time point, 400 μL of acetonitrile containing the internal standard was added to the wells of the 0-minute plate, followed by the addition of 90 μL of plasma. For the other time points, 90 μL of preheated plasma was added to the wells (5, 15, 30, 45, and 60 minutes) and timing was initiated. At 5, 15, 30, 45, and 60 minutes, 400 μL of acetonitrile containing the internal standard was added to the corresponding wells of the plate to stop the reaction. After quenching, the plate was shaken at 600 rpm on a shaker (IKA, MTS2 / 4) for 10 minutes and then centrifuged at 5594 × g for 15 minutes (Thermo Multifuge ×3R). For LC / MS analysis, 50 μL of supernatant from each well was transferred to a 96-well sample plate containing 50 μL of ultrapure water (Millipore, ZMQS50F01).

[0665] The methods disclosed above yielded the data disclosed below in Table 6 for Example 1. Other compounds disclosed herein have been and can be tested using the following alternative protocol.

[0666] Metabolic Stability. To assess metabolic stability in liver microsome preparations, two buffers were prepared. Buffer A consisted of 10 mM NADPH and 0.5 mg / mL microsomes in 100 mM phosphate buffer. The reference compound (verapamil) and test compounds were prepared as 100 μM DMSO stocks. The sources of liver microsomes were as follows: human (BD Gentest, #452117), monkey (RILD, #LM-SXH-02M), dog (BD, #452601), rat (BioIVT, #M00001), and mouse (BioIVT, #M00501).

[0667] The reaction was initiated by adding 2.5 μL of 100 μM control compound or test compound solution to 216.25 μL of preheated (37°C) assay buffer. The final concentrations of control and test compounds were 1 μM. 30 μL aliquots were removed from the reaction solution at 0.5 and 60 minutes. The reaction was stopped by adding 5 volumes of cold acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). The samples were centrifuged at 3,220 g for 30 minutes. A 100 μL aliquot of the supernatant was mixed with 100 μL of ultrapure water and then used for LC-MS / MS analysis.

[0668] Plasma Stability. Stock compounds were prepared to test stability in human (BioIVT, #BRH1589665), dog (BioIVT, #BGL102122), and mouse (BioIVT, #MSE37887) plasma. A 1 mM test compound standard solution in DMSO was prepared. A 1 mM propantheline standard solution in acetonitrile was prepared. Propantheline was used as a positive control for human, dog, and mouse plasma in this assay.

[0669] Plasma (398 μL) for each compound was added to an incubation plate, which was preheated to 37°C for 15 minutes. 2 μL of a 1 mM standard solution (test compound or control compound) was added to the plasma to initiate the reaction, achieving a final concentration of 5 μM. The reaction was incubated at 37°C. 50 μL aliquots were removed from the reaction sample at 0 and 60 minutes. The reaction was stopped by adding 450 μL of cold acetonitrile containing the internal standard. Once the reaction was stopped, the sample was vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes to precipitate the protein. The supernatant (100 μL) was transferred to a new plate and diluted with ultrapure water according to the LC-MS signal response and peak shape. The sample was analyzed by LC-MS / MS.

[0670] Other compounds disclosed herein (e.g., Examples 255, 302, and 343) were tested in the alternative liver microsomal metabolic stability assay described above and were found to exhibit robust stability profiles, with 100% and 45-97% of the compound remaining intact at 30 and 60 minutes, respectively, in all species tested.

[0671] Caco-2 permeability. Luciferase yellow (LY) dye was used to test stock compounds solubilized in dimethyl sulfoxide (DMSO). For donor solutions in the apical to basolateral (A to B) direction, Hank's balanced salt solution (HBSS) buffer containing 0.3% DMSO and 5 μM LY was prepared by adding 150 μL of DMSO and 50 μL of LY (5 mM) to 50 mL of HBSS buffer (pH 7.4). For donor solutions in the apical to basolateral (B to A) direction, HBSS buffer containing 0.1% DMSO and 5 μM LY was prepared by adding 50 μL of DMSO and 50 μL of LY (5 mM) to 50 mL of HBSS buffer (pH 7.4). For donor solutions in the apical to basolateral (B to A) direction, HBSS buffer containing 0.3% DMSO was prepared by adding 150 μL of DMSO to 50 mL of HBSS buffer (pH 7.4). HBSS buffer containing 0.1% DMSO was prepared by adding 50 μL of DMSO to 50 mL of HBSS buffer (pH 7.4).

[0672] The receiver solution buffer from A to B was HBSS buffer containing 0.4% DMSO, prepared by adding 200 μL of DMSO to 50 mL of HBSS buffer (pH 7.4). From B to A, HBSS buffer containing 0.4% DMSO and 5 μM LY was prepared by adding 200 μL of DMSO and 50 μL of LY (5 mM) to 50 mL of HBSS buffer (pH 7.4).

[0673] The cell culture plate was removed from the incubator, and the cell monolayer was washed with HBSS buffer, after which the transepithelial electrical resistance (TEER) was measured at room temperature. Before loading the sample into the donor chamber, the compound solution was centrifuged at 4000 rpm for 5 minutes. The solutions were added as shown in Table 5.

[0674] [Table 70]

[0675] To determine the LY concentration in the apical chamber, 100 μL of sample was transferred from the apical chamber to the opaque plate containing LYTO. The apical and basolateral plates were warmed at 37°C for approximately 5 minutes, and the apical plate was placed on the basolateral plate. The combined plates were incubated at 37°C for 90 minutes.

[0676] For standard curves, 20x solutions of compounds were prepared. For 300 μM compound solutions, 6 μL of compound stock solution was added to 192 μL of MeOH / HO (1:1). After 90 min of incubation, the luminal plate was separated from the basolateral plate. 100 μL of sample was transferred from the basolateral plate to the opaque plate as LYT90. LY concentrations were measured for LYT0 and LYT90 using a fluorometer at excitation 485 nm and emission 535 nm. Samples for LC-MS / MS analysis were prepared from the donor and receiver chambers by dilution with 0.4% DMSO HBSS and then mixing with acetonitrile containing either osalmid or imipramine internal standards.

[0677] The methods disclosed above yielded the data disclosed below in Table 6 for Example 1. Example 1 and other compounds disclosed herein have been and can be tested using the following alternative protocols. The data for Example 1 was consistent between protocols.

[0678] Standard solutions for the Caco-2 permeability assay were prepared by diluting test compound stock solutions (2 mM in DMSO) with HBSS (10 mM, pH 7.4) to 10 μM standard solutions. Metoprolol, erythromycin, and cimetidine were used as control compounds.

[0679] To determine the rate of drug transport from the apical to the basolateral (AB) direction, 125 μL of standard solution was added to the Transwell insert (apical compartment). 50 μL of each sample was immediately transferred from the apical compartment to 200 μL of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (AB). The samples were vortexed at 1000 rpm for 10 minutes, and then the wells in the receiver plate (basolateral compartment) were filled with 235 μL of transport buffer. The plate was incubated at 37°C for 2 hours.

[0680] To determine the rate of drug transport from the basolateral to the apical (BA) direction, 285 μL of standard solution was added to the receiver plate wells (basolateral compartment). 50 μL of each sample was immediately transferred from the basolateral compartment to 200 μL of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) in a new 96-well plate as the initial donor sample (BA). The samples were vortexed at 1000 rpm for 10 minutes, and 75 μL of transport buffer was added to the Transwell insert (apical compartment). The plate was incubated at 37°C for 2 hours.

[0681] At the end of the 2-hour incubation, 50 μL from the donor side (the apical compartment for AB flux and the basolateral side for BA flux) was transferred to a well of a new 96-well plate, followed by the addition of four volumes of acetonitrile containing internal standards (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide). The sample was vortexed for 10 minutes, and 50 μL of the sample was transferred to a well of a new 96-well plate, followed by the addition of 50 μL of Hepes and 200 μL of the internal standards. All samples were vortexed for 10 minutes and then centrifuged at 3,220 g for 40 minutes. A 150 μL aliquot of the supernatant was mixed with an appropriate volume of ultrapure water before LC-MS / MS analysis.

[0682] To determine Lucifer Yellow leakage after a 2-hour transport period, a Lucifer Yellow stock solution was prepared in DMSO and diluted with HBSS (10 mM HEPES, pH 7.4) to reach a final concentration of 100 μM. 100 μL of Lucifer Yellow solution was added to each Transwell insert (apical compartment), and then the wells of the receiver plate (basolateral compartment) were filled with 300 μL of HBSS (10 mM HEPES, pH 7.4). The plate was incubated at 37°C for 30 minutes. 80 μL of sample was removed directly from the apical and basolateral wells (using the basolateral access hole) and transferred to wells of a new 96-well plate. Lucifer Yellow fluorescence (to monitor monolayer integrity) signal was measured in a fluorescence plate reader at 480 nM excitation and 530 nM emission.

[0683] Protein Binding. To test the protein binding of stock compounds solubilized in DMSO, spike solutions of test and reference compounds were prepared. Solution A (0.5 mM) was prepared by adding 10 μL of the 10 mM stock solution to 190 μL of DMSO. Solution B (0.02 mM) was prepared by adding 8 μL of Solution A to 192 μL of 0.05 M sodium phosphate buffer. The final DMSO concentration in Solution B was 4%.

[0684] To prepare test and reference compounds in plasma, a 96-well plate containing 380 μL aliquots of plasma was designated for plasma and buffer, respectively. 20 μL of Solution B (0.02 mM test and reference compounds) was spiked into the pre-loaded plasma in the 96-well plate. The final test concentration was 1 μM containing 0.2% DMSO.

[0685] For the plasma loading dialysis samples, a buffer system was prepared by applying a 100 μL aliquot of fresh dialysis buffer to the receiver side of the dialysis chamber, followed by a 100 μL aliquot of plasma spiked with the test and reference compounds to the donor side of the dialysis chamber. A 25 μL aliquot of plasma spiked with the test and reference compounds was added to a 96-well specimen plate as the TO plasma sample. The aliquot was mixed with an equal volume of fresh buffer (50:50, vol:vol). The sample was quenched with 200 μL of acetonitrile containing the internal standard. The dialysis block was covered and shaken at 60 rpm at 37°C for 5 hours.

[0686] After 5 hours of incubation, dialyzed samples were prepared from 25 μL aliquots from both the donor and receiver sides of the dialysis machine into a specimen plate. The aliquots were mixed with the same volume of different matrices. The samples were quenched with 200 μL of acetonitrile containing an internal standard. All 0-hour and 5-hour samples were vortexed at 600 rpm for 10 minutes, followed by centrifugation at 5594 × g for 15 minutes (Thermo Multifuge ×3R). 50 μL of the supernatant was transferred to a new 96-well plate and mixed with 50 μL of Milli-Q water. The sample plate was covered and frozen at -20°C until LC / MS / MS analysis.

[0687] The methods disclosed above yielded the data disclosed below in Table 6 for Example 1. Other compounds disclosed herein have been and can be tested using the following alternative protocols:

[0688] To test the protein binding of stock compounds solubilized in DMSO, spike solutions of test and reference compounds were prepared. A basic solution was prepared by dissolving 14.2 g / L NaHPO and 8.77 g / L NaCl in deionized water. An acidic solution was prepared by dissolving 12.0 g / L NaHPO and 8.77 g / L NaCl in deionized water. The basic solution was titrated to pH 7.4 with the acidic solution. Frozen plasma was quickly thawed at 37°C. Dialysis membranes were prepared by soaking them in ultrapure water for 60 minutes, followed by 20% ethanol (20 minutes), and finally dialysis buffer for 20 minutes. The membranes were loaded onto a dialysis device and preheated to 37°C.

[0689] Control samples at time 0 were prepared by adding 597 μL of blank plasma solution to each vial in a new plastic plate, followed by 3 μL of a standard solution of the test compound. The solutions were quickly vortexed at 1000 rpm for 2 minutes. The final concentration of the test compound was 5 μM. 50 μL of the spiked plasma solution was immediately transferred to a 96-well plate to serve as the T=0 control sample. All remaining spiked plasma solutions were kept at 37°C for the remainder of the experiment. The remaining spiked plasma solutions in the plastic plate were incubated at 37°C with 5% CO2 in a CO2 incubator for 6 hours. At T=6 hours, 50 μL of the original spiked plasma solution was transferred to a 96-well plate for analysis.

[0690] Compound stability in plasma samples was determined by equilibrium dialysis. Cells were loaded with 120 μL of each plasma sample and dialyzed against an equal volume of dialysis buffer (PBS). Stability reactions were incubated at 37°C for 6 hours on an orbital shaker in a CO2 incubator with 5% CO2 at 100 rpm. At the end of the incubation, 50 μL of the dialyzed samples from both the buffer and plasma solution chambers were transferred to separate 96-well plates for analysis.

[0691] Stability was analyzed by adding 50 μL of plasma solution to the buffer sample and adding an equal volume of PBS to the collected plasma solution sample. The resulting mixture was shaken at 1000 rpm for 2 minutes to precipitate proteins and release compounds before adding 400 μL of acetonitrile containing the appropriate internal standard (IS). The sample was vortexed at 1000 rpm for 10 minutes and then centrifuged at 3,220 g for 30 minutes. 250 μL of the supernatant was transferred to a new 96-well plate and centrifuged again (3,220 g, 30 minutes). 100 μL of the supernatant was transferred to a new 96-well plate, mixed with 100 μL of distilled water, and analyzed by LC-MS / MS.

[0692] Table 6 shows the plasma stability half-life (T 1 / 2 (min)), Caco-2 permeability (P app , BA / AB), and further DMPK results of bound protein bound fraction (%), and protein bound recovery (%) are shown.

[0693] [Table 71]

[0694] Other compounds disclosed herein (e.g., Examples 190, 255, 302, and 343) were tested in the alternative plasma stability assay described above and found to have similarly long or even longer half-lives. Other compounds disclosed herein were tested in the alternative Caco-2 permeability assay and general trends were noted. 3 The compounds substituted with aryl groups have high P app Although Examples 302, 343, and 356 all had single-digit P app Other compounds disclosed herein were tested in alternative protein binding assays and found to have fractions bound of 95% to greater than 99%, and percent recoveries of 97% to 113%.

[0695] In vivo pharmacokinetic evaluation In vivo exposure of test compounds was determined in 5-6 week-old male CD-1 mice. Mice (n = 2 / compound) were administered 10 mg / kg of each compound formulated in 20% (2-hydroxypropyl)-β-cyclodextrin (10 μL / g) by oral gavage. Blood samples were collected from the submandibular vein at 0.5, 2, and 6 h post-dose using EDTA as an anticoagulant and stored on ice. Plasma samples were obtained by centrifugation at 4 °C and analyzed immediately or stored at -20 °C until analysis. Compounds were extracted from mouse plasma with acetonitrile and quantified by LC-MS-MS in negative ion mode using a standard curve.

[0696] Table 7 shows the results of the aforementioned study, represented as fold-over Example 1 in AUC.

[0697] [Table 72]

[0698] As shown in the table, the trend toward increased AUC is seen with alkyl (especially C2-C6 alkyl), cycloalkyl, and cycloalkylalkyl as R 3 was identified among meta-substituted compounds.

[0699] In Vivo Efficacy of hGOX Inhibitors The in vivo activity of test compounds was evaluated using alanine-glyoxylate aminotransferase (AGXT) knockout mice obtained from the Jackson Laboratory (Bar Harbor, ME) as reported by Martin-Higuerrell et al., Molecular Therapy, vol. 24, no. 4, 719-725, 2016. Male AGXT knockout mice (Agxt- / -) aged 10-15 weeks were used to evaluate the in vitro activity of test compounds against urinary oxalate and glycolate.

[0700] Male Agxt mice were housed under standard conditions (5 animals / cage) with free access to food and water. At the beginning of the study, animals were treated with test compounds by oral gavage formulated in 20% (2-hydroxypropyl)-β-cyclodextrin (10 μL / g). Prior to compound administration and multiple times throughout the study, mice were individually housed overnight in metabolic cages to collect urine samples. Collection chambers were cooled to 4-7°C to minimize evaporation. Age-matched wild-type male C57Bl / 6 mice served as controls.

[0701] Urine samples were collected and handled as described by Liebow et al., An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria. J Am Soc Nephrol, 28:494-503 (2017). For determination of oxalate levels, a portion of the collected urine was charcoal-treated and acidified to pH 1 with 6N hydrochloric acid (5% v / v) before storage at -20°C to prevent potential oxalate crystallization and oxalate production. 6N sodium hydroxide (5% v / v) was added immediately before measuring oxalate concentrations to neutralize the acidified urine. The remaining non-acidified urine was frozen at -20°C for measurement of other urine parameters. Blood samples were collected from the submandibular vein using EDTA as an anticoagulant and stored on ice. Plasma samples were obtained by centrifugation at 10,000 rpm for 5 minutes at 4°C and stored at -20°C until analysis.

[0702] To determine the effect of test compounds on plasma glycolic acid, 5-6 week-old male C57Bl / 6 mice were treated by oral gavage with the compound formulated in 20% (2-hydroxypropyl)-β-cyclodextrin (10 μL / g). At different time points, blood samples were collected from the submandibular vein using EDTA as an anticoagulant and stored on ice. Plasma samples were obtained by centrifugation at 10,000 rpm for 5 minutes at 4°C and either analyzed immediately or stored at -20°C until analysis.

[0703] Urinary oxalate was measured using a commercially available clinical oxalate oxidase assay (Trinity Biotech, Wicklow, Ireland) according to the manufacturer's instructions.

[0704] Plasma and urinary glycolic acid were determined using liquid chromatography coupled with electrospray ionization and mass spectrometry detection (LC / MS) on a triple quadrupole instrument with multiple reaction monitoring, according to the method described in Dutta et al., Inhibition of Glycolate Oxidase with Dicer-Substrate siRNA Reduces Calcium Oxalate Deposition in a Mouse Model of Primary Hyperoxaluria Type 1. Mol Ther., 24(4)770-778 (2016). After sample dilution, urine samples were analyzed by hydrophilic interaction liquid chromatography (HILIC) with MS detection in negative electrospray ionization mode. Plasma glycolic acid was determined by two-step protein precipitation. The analysis was performed by HILIC LC / MS / MS detection in negative electrospray ionization mode with multiple reaction monitoring. Stable-labeled internal standards in appropriate surrogate matrices were used. 、13 A calibration curve of C2-glycolic acid was used for quantification.

[0705] Urinary creatinine was measured using a commercially available creatinine detection kit (Enzo Life Sciences AG, Lausen, Switzerland) according to the manufacturer's recommendations.

[0706] In vivo pharmacokinetics / exposure of test compounds were determined in 5-6 week-old male CD-1 mice. Mice were divided into groups of 3 and administered a single dose of 10 mg / kg of each compound formulated in 20% (2-hydroxypropyl)-β-cyclodextrin (10 μL / g) by oral gavage.

[0707] Blood samples were collected from the submandibular vein at multiple time points within the first 24 hours using EDTA as an anticoagulant and stored on ice. Plasma samples were obtained by centrifugation at 4°C and either analyzed immediately or stored at -20°C until analysis. Compounds were extracted from mouse plasma with acetonitrile and quantified by LC-MS-MS in negative ion mode using a standard curve.

[0708] Unsubstituted alkynes showed minimal activity in the primary hyperoxaluria 1 (PH-1) alanine-glyoxylate aminotransferase Agxt- / - mouse model. Figure 1 shows urinary oxalate (days) over time for Compound 1 administered at 10 and 30 mg / kg to Agxt- / - mice, expressed as a percentage of vehicle-treated control values. Figure 2 shows glycolate (μg / mL) over time for these same mice. Unsubstituted alkyne Compound 1 inhibited urinary oxalate by approximately 30%, which was accompanied by an increase in urinary glycolate. This activity was reversed when the compound was washed out.

[0709] The substituted alkynes had excellent mouse pharmacokinetic profiles. Figure 3 shows the mean plasma AUC over the first 24 hours after administration (fold) for compounds 1, 302, 343, and 356 in CD-1 mice dosed at 10 mg / kg. Substituted alkyne compounds 302, 343, and 356 exhibited mean plasma AUCs 6-7 times higher than unsubstituted alkyne compound 1.

[0710] Substituted alkynes also increa...

Claims

1. Structural formula III: 【Chemistry 1】 (In the formula, R １ But hydrogen, C １ ~C ６ Alkyl, and C １ ~C ６ cycloalkyl; L is O, S, CH ２ , N.H., N.R. ４ , S(O), SO ２ , and C.R. ４ =CR ５ Selected from: R ２ are each independently a 5- to 10-membered heteroaryl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkoxy, C １ ~C ６ Haloalkyl, C ６ ~C １０ selected from aryl, cyano, and halogen; n is 0, 1, or 2; R ３ is 3 to 10-membered heterocycloalkyl, 5 to 10-membered heteroaryl, C １ ~C ６ Alkyl, C １ ~C ６ Sulfonyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkylalkyl, C ６ ~C １０ Aryl, and C ６ ~C １０ arylalkyl; R ４ and R ５ are each independently hydrogen and C １ ~C ６ alkyl, or together with the atom to which they are attached, R ４ and R ５ forms a cycloalkenyl; and R ６ each independently represents a 4- to 6-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, amino, dimethylamino, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ selected from cycloalkylalkyl, carboxyl, cyano, halogen, hydroxyl, methyl 4-6 membered heterocycloalkyl, and phenyl; and m is 0, 1, 2, or 3. or a salt or tautomer thereof.

2. R ３ is selected from methyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, tetrahydrofuranyl, cyclohexyl, tetrahydropyranyl, piperidinyl, dihydropyranyl, indazolyl, benzodioxolyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, benzoxazolyl, oxodihydropyridinyl, thiazolyl, tetrazolyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, dioxaspirodecanyl, oxocyclohexyl, and bicyclo[1.1.1]pentyl, any of which may be selected from one, two, or three R ６ The compound of claim 1 , optionally substituted with a group.

3. R ３ But C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C ３ ~C ６ cycloalkylalkyl, any of which is selected from 1, 2 or 3 R ６ The compound of claim 1 , optionally substituted with a group.

4. R ３ The compound according to any one of claims 1 to 3, wherein is selected from propyl and cyclopropylmethyl.

5. R ６ is selected from methyl, hydroxyl, amino, dimethylamino, propyl, cyclopropylmethyl, indazolyl, benzodioxolyl, cyclopropyl, tetrahydrofuranyl, cyclohexyl, tetrahydropyranyl, piperidinyl, methylpiperidinyl, phenyl, fluoro, chloro, methylsulfonyl, cyano, trifluoromethyl, methoxy, carboxyl, and fluoromethyl.

6. R ６ The compound of claim 5, wherein is selected from chloro, methyl, cyano, fluoro, methylsulfonyl, methoxy, carboxyl, trifluoromethyl.

7. The compound according to any one of claims 1 to 6, wherein m is 0.

8. Structural formula V 【Chemistry 2】 (In the formula, R １ is hydrogen, C １ ~C ６ Alkyl, and C １ ~C ６ cycloalkyl; L is selected from O and S; R ２ are each independently a 5- to 10-membered heteroaryl, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Alkylsulfonyl, C １ ~C ６ Alkylthio, C １ ~C ６ Haloalkoxy, C １ ~C ６ Haloalkyl, C ６ ~C １０ selected from aryl, cyano, and halogen; n is 0, 1, or 2; R ３ is C ２ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C ３ ~C ６ cycloalkylalkyl; and R ６ are respectively, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ cycloalkyl, cyano, halogen, and hydroxyl; and m is 0, 1, 2, or 3 2. The compound of claim 1 having the formula:

9. R １ The compound of claim 8 , wherein is hydrogen.

10. 10. The compound of claim 8 or 9, wherein n is 0.

11. n is 0 or 1; and R ６ A compound according to any one of claims 8 to 10, wherein, when present, is halogen.

12. R ３ But C ２ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C ３ ~C ６ 12. The compound according to any one of claims 8 to 11, selected from cycloalkylmethyl.

13. R ３ is selected from ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and bicyclo[1.1.1]pentylmethyl.

14. R ３ is selected from ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

15. R ３ A compound according to any one of claims 8 to 14, wherein is selected from isobutyl and cyclopropylmethyl.

16. Structural formula VI 【Transformation 3】 (In the formula, R １ is hydrogen, C １ ~C ６ Alkyl, and C １ ~C ６ cycloalkyl; L is O, S, CH ２ and NH; and R ３ is C ２ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, and C ３ ~C ６ cycloalkylalkyl) 2. The compound of claim 1 having the formula:

17. R １ The compound of any one of claims 1 to 16, wherein is selected from methyl, ethyl, isopropyl, t-butyl, and hydrogen.

18. R １ 18. The compound of claim 17, wherein is hydrogen.

19. 17. The compound of claim 16, wherein L is O or S.

20. R ３ 17. The compound of claim 16, wherein is selected from isobutyl and cyclopropylmethyl. 【Request Item 21】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 or a salt or tautomer thereof.

22. A drug comprising the compound according to any one of claims 1 to 21, or a salt or tautomer thereof.

23. 22. Use of a compound according to any one of claims 1 to 21, or a salt or tautomer thereof, in the manufacture of a medicament for preventing or treating an oxalate-related disease.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

25. 25. The pharmaceutical composition of claim 24 formulated for oral administration.

26. 26. The pharmaceutical composition of claim 24 or 25, further comprising another therapeutic agent.

27. 27. A method for inhibiting glycolate oxidase (GOX) activity in a biological sample, comprising contacting the biological sample with a pharmaceutical composition according to any one of claims 24 to 26, or a compound according to any one of claims 1 to 21, or a salt or tautomer thereof.

28. A pharmaceutical composition according to any one of claims 24 to 26, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a salt or tautomer thereof, for use in human therapy.

29. A pharmaceutical composition according to any one of claims 24 to 26, or a pharmaceutical composition comprising a compound according to any one of claims 1 to 21, or a salt or tautomer thereof, for use in treating an oxalate-related disease.

30. 30. The pharmaceutical composition of claim 29, for administration to a human subject.

31. 31. The pharmaceutical composition of claim 30, wherein the oxalate-related disease is hyperoxaluria.

32. 32. The pharmaceutical composition of claim 31, wherein the oxalate-related disease is primary hyperoxaluria.

33. 32. The pharmaceutical composition of claim 31, wherein the oxalate-related disease is enteric hyperoxaluria.

34. 30. The pharmaceutical composition of claim 29, wherein the oxalate-related disease is calcium oxalate kidney stones.

35. 30. The pharmaceutical composition of claim 29, wherein the oxalate-related disease is idiopathic calcium oxalate stone disease (ICSF).

36. 30. The pharmaceutical composition of claim 29, wherein the oxalate-related disease is calcium oxalate kidney stones after bariatric surgery.

37. 30. The pharmaceutical composition of claim 29, wherein the oxalate-related disease is urolithiasis or nephrolithiasis for gastrointestinal disease.

38. 30. The pharmaceutical composition of claim 29, for administration sequentially or simultaneously with a second therapeutic agent.

39. 22. Use of a compound according to any one of claims 1 to 21, or a salt or tautomer thereof, for the manufacture of a medicament for treating an oxalate-related disease.

40. Structural formula: 【Transformation 8】 or a salt or tautomer thereof.

41. Structural formula: 【Chemistry 9】 or a salt or tautomer thereof.

42. Structural formula: 【Chemistry 10】 or a salt or tautomer thereof.

43. 41. A pharmaceutical composition comprising a compound of claim 40, or a salt or tautomer thereof, in association with a pharmaceutically acceptable carrier.

44. 42. A pharmaceutical composition comprising a compound of claim 41, or a salt or tautomer thereof, in association with a pharmaceutically acceptable carrier.

45. 43. A pharmaceutical composition comprising a compound of claim 42, or a salt or tautomer thereof, in association with a pharmaceutically acceptable carrier.

46. 41. A medicament comprising a compound of claim 40, or a salt or tautomer thereof, for use in treating an oxalate-related disease selected from hyperoxaluria, primary hyperoxaluria, enteric hyperoxaluria, calcium oxalate kidney stones, idiopathic calcium oxalate nephrolithiasis (ICSF), calcium oxalate kidney stones after bariatric surgery, urolithiasis, and nephrolithiasis for a gastrointestinal disease selected from Crohn's disease and ulcerative colitis.

47. 42. A medicament comprising a compound of claim 41, or a salt or tautomer thereof, for use in the treatment of an oxalate-related disorder selected from hyperoxaluria, primary hyperoxaluria, enteric hyperoxaluria, calcium oxalate kidney stones, idiopathic calcium oxalate nephrolithiasis (ICSF), calcium oxalate kidney stones after bariatric surgery, urolithiasis, and nephrolithiasis for a gastrointestinal disorder selected from Crohn's disease and ulcerative colitis.

48. 43. A medicament comprising a compound of claim 42, or a salt or tautomer thereof, for use in the treatment of an oxalate-related disease selected from hyperoxaluria, primary hyperoxaluria, enteric hyperoxaluria, calcium oxalate kidney stones, idiopathic calcium oxalate nephrolithiasis (ICSF), calcium oxalate kidney stones after bariatric surgery, urolithiasis, and nephrolithiasis for a gastrointestinal disease selected from Crohn's disease and ulcerative colitis.

49. The pharmaceutical composition of any one of claims 46 to 48, wherein the hyperoxaluria is selected from recurrent kidney stones and chronic kidney disease.

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