HETEROCYCLIC CARBOXYLATE COMPOUNDS AS GLYCOLATE OXIDASE INHIBITORS.

Abstract

This presentation refers in general to modulators of the human glycolate oxidase enzyme and to the methods of their use and preparation.

Description

HETEROCYCLIC CARBOXYLATE COMPOUNDS AS INHIBITORS OF GLYCOLATE OXIDASE CROSS REFERENCE TO RELATED REQUESTS This application claims benefit under 35 U.S.C. §119(e) of United States Provisional Application Nos. 62 / 929,476, filed November 1, 2019, and 63 / 093,094, filed October 16, 2020, each of which is incorporated herein by the reference in its entirety. FIELD The present disclosure relates to compounds, compositions and methods for the treatment of primary hyperoxaluria type 1 and recurrent kidney stone formers. The present disclosure is directed to new substituted heterocyclic carboxylate compounds and methods for their preparation and use as therapeutic or prophylactic agents. In particular, the present disclosure provides new inhibitors of the human glycolate oxidase enzyme, pharmaceutical compositions containing such compounds and methods of using these compounds to treat primary hyperoxaluria type 1 and recurrent kidney stone formers. - 2. BACKGROUND Kidney stones affect a large human population. In the United States, the prevalence of kidney stones was 8.8%, with 10.6% among men and 7.1% among women. Diseases also occur in primary hyperoxaluria type 1 (PH1), which can be caused by genetically defective enzyme activity. Due to high glycolate oxidase activity, these patients may show a significant increase in glyoxylate and oxalate production and calcium oxalate stone deposition. Medical procedures to remove kidney stones exist and are effective. However, the recurrence of kidney stones after these procedures can be high (e.g., more than 50%). Therefore, there is a need for agents that inhibit the activity of the glycolate oxidase enzyme to treat patients with PH1 and reduce the rate of kidney stone recurrence in kidney stone formers. SUMMARY The present disclosure is directed to new substituted heterocyclic carboxylate compounds, which inhibit the activity of human glycolate oxidase, including stereoisomers, their pharmaceutically acceptable salts and their prodrugs, and the use of such compounds in the treatment of primary hyperoxaluria type 1 . The compounds of the - 3 exposure can be used to treat recurrent kidney stone formers. In one aspect, a compound structure of the Formula I: Or2a « N R1'A(I) salt a tautomer mixture of stereoisomers or a pharmaceutically acceptable deuterated analogue thereof, wherein A, R: and R: are as described herein. In certain embodiments, the disclosure provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the disclosure (e.g., a compound of Formula I or additional Formulas described in each part), and at least one pharmaceutically acceptable excipient. In certain embodiments, provided herein is a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. Some embodiments provide a method of using (or administering) the compounds of Formula I, or additional Formulas described in each part, in the treatment of a disease or condition in a mammal, particularly a being. - 4 human, which is susceptible to treatment with an inhibitor of the human glycolate oxidase enzyme. Some embodiments provide a method of using (or administering) a compound as described herein in the treatment of a disease or condition in a mammal, particularly a human, that is amenable to treatment by an inhibitor of the human glycolate oxidase enzyme. . BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the plasma concentration-time profiles of Example 2 and Example 68 following an oral dose of Example 2 of 5.0 mg / kg in SD rats (mean ± SD, n=3). Figure 2 shows the plasma concentration-time profiles of Example 68 after a 30-minute intravenous infusion at 1.0 mg / kg and a PO dose of 5.0 mg / kg in SD rats (mean ± SD, n=3). Figure 3 shows the plasma concentration-time profiles of Example 168 and Example 175 in SD rats. Figure 4 shows the plasma concentration-time profiles of Example 168 and Example 175 in male Beagle dogs. - 5 DETAILED DESCRIPTION OF THE INVENTION Definitions and General Parameters The following description sets out examples of methods, parameters, and the like. It should be recognized, however, that such description is not intended to be a limitation of the scope of the present disclosure, but is provided as a description of exemplary embodiments. As used in this specification, the following words, phrases and symbols generally have the meaning set out below, except to the extent the context in which they are used indicates otherwise. A hyphen that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2 is bonded through the carbon atom. A hyphen at the beginning or end of a chemical group is a matter of convenience; Chemical groups can be represented with or without one or more hyphens without losing their ordinary meaning. A wavy line drawn through a line on a structure indicates a joining point of a group. Unless chemically or structurally required, the order in which a chemical group is written or named does not indicate or imply directionality. - 6 The prefix C..--.· indicates that the following group has u to v carbon atoms. For example, C3- alkyl indicates that the alkyl group has 1 to 6 carbon atoms. The modifier approximately used in relation to a quantity includes the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with the measurement of the particular quantity). Additionally, the singular forms un and the include plural references unless the context clearly indicates otherwise. Thus, e.g., reference to compound includes a plurality of such compounds and reference to assay includes reference to one or more assays and equivalents thereof known to those skilled in the art. Alkyl refers to a branched or unbranched saturated hydrocarbon chain. As used herein alkyl has from 1 to 20 carbon atoms (i.e., C> / q alkyl), from 1 to 8 carbon atoms (i.e., Cld alkyl, from 1 to 6 carbon atoms (i.e., C alkyl -_-d or 1 to 4 carbon atoms (i.e., Ci—í alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, nbutyl, sec-butyl, iso-butyl, tere-butyl, pentyl, 2pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by its chemical name or identified by a molecular formula, all positional isomers that have that number of carbons may be included; thus, for example, butyl includes n-butyl (i.e., - (CH2)jCH3), sec-butyl (i.e., -CH (CH ?) CH2CH3), isobutyl (i.e., -CH -CH (CH3) 2) and tere-butyl (i.e., -C (CH3) 3) ; and propyl includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH (CH3) 2) · Alkenyl refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-alkenyl). ), of 2 to 6 carbon atoms (i.e., C2--O alkenyl, or of 2 to 4 carbon atoms (i.e., C2-Y alkenyl. Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2 -butadienyl and 1,3-butadienyl). Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (1. e., C2-23 alkynyl), 2 to 8 carbon atoms (i.e., alkynyl C3-Y, from 2 to 6 carbon atoms (i.e., C2-3 alkynyl), or from 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term alkynyl also includes those groups that have a triple bond and a double bond. Alkoxy refers to the alkyl-O- group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, nhexoxy and 1,2-dimethylbutoxy. Haloalkoxy refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. Alkylthio refers to the alkyl-S- group. Acyl refers to a group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted, as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl and benzoyl. Amido refers to both a C-amido group referring to the group -C(C)NR-'R- and an N-amido group referring to the group -NR>'C (O) Rz, where R -' and R- are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which can be optionally substituted. Amino refers to the group NR-'R- wherein R-' and R- are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl or heteroaryl; each of which can be optionally substituted. Aryl refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or several rings (e.g., bicyclic or tricyclic), including systems - 9 merged. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C-:; aryl), 6 to 12 ring carbon atoms (i.e., C / -i aryl), or 6 to 10 carbon atoms in the ring (i.e., aryl Cr-r). ). Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused to a heteroaryl, the resulting ring system is heteroaryl. If one or more aryl groups are fused to a heterocyclyl, the resulting ring system is heterocyclyl. Carbamoyl refers to both an O-carbamoyl group referring to the group -O-C(O)NRyR- and an Ncarbamoyl group referring to the group -NR-C (O) OR-, where R-' and R- are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which can be optionally substituted. Carboxylic ester refers to both -OC(O)R and C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted, as defined herein. Cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including ring systems - 10 condensates, bridged and spiro. Ξ1 term cycloalkyl includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C3-25 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C-~m cycloalkyl), 3 to 10 carbon atoms in the ring (i.e., C?- cycloalkyl;:)), from 3 to 8 carbon atoms in the ring (i.e., C3s cycloalkyl), or from 3 to 6 carbon atoms in the ring (i.e. , cycloalkyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Imino refers to a group -C(NR)R, wherein each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroa1kyl or or heteroaryl; each of which may optionally be substituted, as defined herein. Halogen or halo includes fluoro, chlorine, bromine and iodine. Haloalkyl refers to a branched or unbranched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogene. For example, when a residue is substituted with more than one halogen, it can be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (di) or three (tri) halo groups, - 11 which can be, but not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF-.) and trifluoromethyl (-CF3). Heteroalkyl refers to an alkyl group wherein one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group. The term heteroalkyl includes unbranched or branched saturated chains having carbon and heteroatoms. As an example, 1, 2 or 3 carbon atoms can be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -0-, -S-, -S(O)-, -S (0) and the like, where R is H, alkyl, aryl, cycloalkyl , heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH;OCH3, -SCHj, -d-LSCH;, NRCH-, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which can be optionally replaced. As used herein, heteroalkyl includes from 1 to 10 carbon atoms, from 1 to 8 carbon atoms or from 1 to 4 carbon atoms; and from 1 to 3 heteroatoms, from 1 to 2 heteroatoms or 1 heteroatom. Heteroaryl refers to an aromatic group that has a single ring, multiple rings or multiple rings. - 12 fused, with one or more heteroatoms in the ring independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C:-2o heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon atoms in the ring (i.e., C3-- heteroaryl); and from 1 to 5 heteroatoms, from 1 to 4 heteroatoms, from 1 to 3 ring heteroatoms, from 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, ben zofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b] [1,4]dioxepinyl, 1, 4 -benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo [ 1,2a]pyridinyl, carbazolyl, cinolinyl, di benzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazclyl, imidazolyl, mdazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naftyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, - 13 1-oxidopyrazinyl 1-oxidopyridazinyl, 1-phenyl -IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinylc, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl , quinuclidinyl, isoquinolinyl , tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thiophenyl. The fused heteroaryl rings can be linked through any ring in the fused system. Any aromatic ring, having one or more fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of attachment to the rest of the molecule (i.e., through any of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. Heterocyclyl refers to a saturated or unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term heterocyclyl includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), gated heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl can be a single ring or multiple rings where the multiple rings can be fused, bridged or spiro. Any ring does not - 14 aromatic containing at least one heteroatom is considered a heterocyclyl, regardless of the linkage (i.e., it can be linked through a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of attachment to the rest of the molecule. As used herein heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-22 heterocyclyl), 2 to 12 ring carbon atoms (i.e., 02-heterocyclyl), 2 to 10 carbon atoms in the ring (i.e., Cí-d heterocyclyl, 2 to 8 carbon atoms in the ring (i.e., C2-- heterocyclyl), 3 to 12 carbon atoms in the ring (i.e., C2 heterocyclyl -22), 3 to 8 carbon atoms in the ring (i.e., heterocyclyl · 0---), or 3 to 6 ring carbon atoms (i.e., heterocyclyl C?; which has 1 to 5 heteroatoms in the ring, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen, and optionally one or more groups oxo. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. As used herein, the term bridged heterocyclyl refers to a moiety - 15 four- to ten-membered cyclic connected at two non-adjacent heterocyclyl atoms with one or more (e.g., 1 or 2) four- to ten-membered cyclic moieties having at least one heteroatom wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. As used herein, bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also used herein, the term spiro-heterocyclyl refers to a ring system wherein a three- to ten-membered heterocyclyl has one or more additional rings, wherein the one or more additional rings are three- to ten-membered cycloalkyl or three to ten membered heterocyclyl, wherein a single atom of the one or more additional rings is also an atom of the three to ten membered heterocyclyl. Examples of spiro-heterocyclyl rings include bicyclic and tricyclic ring systems, such as 2-oxa-7azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6oxa-l-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl (e.g., 2-methylisoquinolin -l(2H)-one), where the heterocyclyl can be joined through any of the rings of the fused system. Oxo refers to the group (=0) or (O). - 16 Sulfonyl refers to the group S(O);R, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl. Alkylsulfonyl refers to the group S(O)2R, where R is alkyl. Alkylsulfinyl refers to the group S(0)R, where R is alkyl. Thiol refers to the group SR, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent alkyl group, a divalent aryl group, etc., may also be called an alkylene group or alkylenyl group, arylene group or arylenyl group, respectively. Furthermore, unless explicitly stated otherwise, when combinations of groups are referred to herein as a moiety, e.g., arylalkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule. The terms optionally or optionally mean that the event or circumstance described below may or may not occur, and that the description includes cases where such event or circumstance occurs and cases where it does not occur. Furthermore, the term optionally substituted refers to one or more hydrogen atoms in the designated atom or group that may or may not be replaced by a moiety other than hydrogen. Some of the compounds exist as tautomers. The tautomers are in equilibrium with each other. For example, amide-containing compounds can exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium between the tautomers, the compounds are understood by those skilled in the art to comprise both amide and imididic acid tautomers. Therefore, amide-containing compounds are understood to include their imidic acid tautomers. Likewise, compounds containing imidic acid are understood to include their amide tautomers. Any formula or structure provided herein is also intended to represent unlabeled as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the - 18 exposure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2H (deuterium, D), 3H (tritium), 22C, -'C, -^C, —N,23F,3:P,32P,j5S,3¿C1 y:2'I. Various isotopically labeled compounds of the present disclosure, for example those where radioactive isotopes such as 3H, 23C and 2;C are incorporated. Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug testing or tissue delivery on substrates or in the radioactive treatment of patients. The disclosure also includes deuterated analogues of compounds of Formula 1 where 1 to n hydrogens attached to a carbon atom are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any compound of Formula Σ when administered to a mammal, particularly a human. See, for example, Foster, Effects of deuterium isotopes in drug metabolism studies, Trends Pharmacol.Sci. 5 (12):524-527 (1984). Said compounds are synthesized by means well known in the art, for example using - ± 9 starting materials where one or more hydrogens have been replaced by deuterium. Therapeutic exposure compounds labeled or substituted with deuterium may have improved DMPK (drug pharmacokinetics and metabolism) properties related to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, for example, a longer half-life in vivo, reduced dosage requirements and / or an improvement in therapeutic index. A compound labeled with:3F may be useful for PET or SPECT studies. The isotopically labeled compounds of this disclosure and their prodrugs can generally be prepared by carrying out the procedures described in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is considered a substituent on the compound of Formula I. The concentration of a heavier isotope, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as H or hydrogen, it is understood that the position has hydrogen- in its naturally abundant isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated deuterium (D) is intended to represent deuterium. In many cases, the compounds of this disclosure are capable of forming salts of acids and / or bases by virtue of the presence of amino and / or carboxyl groups or groups similar thereto. Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein. Pharmaceutically acceptable or physiologically acceptable refers to compounds, salts, compositions, dosage forms and other materials that are useful in the preparation of a pharmaceutical composition that is suitable for human or veterinary pharmaceutical use. The term pharmaceutically acceptable salt of a given compound refers to salts that retain the biological efficacy and properties of the given compound, and that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts or physiologically acceptable salts include, for example, salts with acids - 21 inorganic and salts with an organic acid. Furthermore, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. In contrast, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures. to prepare acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used to prepare pharmaceutically acceptable non-toxic addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, acid mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Likewise, addition salts can be prepared - 22 pharmaceutically acceptable bases from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkylamines (i.e., NH;(alkyl)), dialkylamines (i.e., HN(alkyl) 2), trialkylamines (i.e. , N(alkyl),), substituted alkylamines (i.e., NH; (substituted alkyl)), diamines(substituted alkyl) (i.e., HN(substituted alkyl);), tri-amines(substituted alkyl) (i.e., N(alkyl) substituted)); , di-amines(substituted alkenyl) (i.e., HN(substituted alkenyl);), tri-amines(substituted alkenyl) (i.e., N(substituted alkenyl)-, mono-, di- or tri-cycloalkylamines (i.e., NH; (cycloalkyl), HN(cycloalkyl);, N(cycloalkyl)3), mono-, di- or triarylamines (i.e., NH;(aryl), HN(aryl);, N(aryl);), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(npropyl)amine, ethanolamma, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the similar. - 23 The term substituted means that one or more hydrogen atoms in the designated atom or group are replaced with one or more substituents other than hydrogen, provided that the normal valency of the designated atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylic ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, here 1sulfonyl, thiocyanate, thiol, thione or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with more substituents added ad inf mitum (e.g., a substituted aryl that has a substituted alkyl that is in turn substituted with a substituted aryl group, which is also substituted by a substituted heteroalkyl, etc.) are not intended to be included herein. Unless otherwise indicated, the maximum number of substitutions in series in the compounds described herein is three. For example, series substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl - 24 substituted with 5 fluoro or heteroaryl groups having two adjacent oxygen ring atoms). Such inadmissible substitution patterns are well known to those skilled in the art. The matter. When used to modify a chemical group, the term substituted may describe other chemical groups defined herein. Unless otherwise specified, when a group is described as optionally substituted, any of the group's substituents are themselves unsubstituted. For example, in some embodiments, the term substituted alkyl refers to an alkyl group having one or more substituents including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl. In other embodiments, the one or more substituents may further be substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is substituted. In other embodiments, the substituents may further be substituted with halo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, each of which is unsubstituted. In certain embodiments, as used herein, the phrase one or more refers to one to five. In certain embodiments, as used herein, the phrase one or more refers to one to three. - 25 As used herein, pharmaceutically acceptable carrier or pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retardants and the like. The use of such means and agents for pharmaceutically active substances is well known in the art. Except to the extent that any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Complementary active ingredients may also be incorporated into the compositions. A solvate is formed by the interaction of a solvent and a compound. Also provided are solvates of salts of the compounds described herein. Hydrates of the compounds described herein are also provided. Compounds Provided herein are compounds that function as glycolate oxidase inhibitors. In certain embodiments, a compound of Formula I is provided herein: R2A b O' -c-N N R1~A Yo - 26 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein A is N or CH; R3 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R3; R2 is hydrogen, - (CH2CH2O) 2-2CH2CH2OCH2, C2-g alkyl optionally substituted with one to three R4, cycloalkyl or heteroaryl optionally substituted with one to three Recada R3 is independently cyano, halo, -L-alkyl -L-haloC alkyl ;-;, -L-O-haloalqui lo C;-.;, -NR^R3, -C(O)NR^R3, -S(O)2NR^R3, -NR~C(O)R-, -ORÓ -L-aryl, -L-heteroaryl or -Lheterocyclyl, where each is optionally substituted with one to three R'3, and each L is independently -C^C- or is absent; each R4 is independently halo, hydroxy, -0 C2-2 alkyl, -NH2, -NH-C2 alkyl-,, -N(C2- alkyl,)2, -0C (O) Ra, 0C(0)0R¿1, -0P(0) (0Rb)2, or monocyclic heterocyclyl; wherein each is optionally replaced with one to three R5s; provided that only one R4 is heterocyclyl; each R5 is independently cyano, halo, C_~i alkyl, hydroxy, -0-C2-2 alkyl, C2-2 haloalkyl or -O-C;-2 haloalkyl; each R is independently cyano, halo, -C(O)R~, C(O)OR?, -C(O)NR7R3', -S (0) 2NRR3, -NR^C(0)R3, -ORy alkyl C.-2, -O-Cg-g alkyl, C_-g haloalkyl, -O-Cg-g haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three Cg--alkyl, -C(O)OH or Cg-g haloalkyl; each of R" and R3 is independently hydrogen, Cg-g alkyl or phenyl, pyridyl, or R7 and R' together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently alkyl G7-g optionally substituted with -NHg, -NH-alkyl Cg-. , -N (C_-c alkyl)g, or OP (0) (0Rb) 2; each Rbes independently hydrogen or C:-í alkyl. In some embodiments, when A is N, at least one of the following is true: 1) R3 is a fused tricyclic ring optionally substituted with one to three R5; 2) R1 is an optionally substituted fused bicyclic ring, substituted with at least one R3 selected from cyano, -C=C-Cg-3 alkyl, -Cg-alkyl-. substituted with one to three R6, -C^c-haloalkyl Cg-g, -C^c-O haloalkyl Cg-g, -NR^R3, -C(O)NRRS, -S(O)2NRR:, -NRC( O)R-, -O-Cg-g alkyl, -0-phenyl, -L-aryl, -L-heteroaryl or -L-heterocyclyl, where each is optionally further substituted with one to three R-, and each L is independently -C=C- or absent; 3) R- is a substituted monocyclic ring, substituted with at least one R3 selected from: i) cyano, -C=C-alkyl C:-;·, -C=C-haloalkyl C2-4, -C = CO-haloalkyl C:-4, -NRTR8, -C(O)NR'R8, - S(O)2NRRC, -NR-C(O)R8, -C=C-aryl, -C^c-heteroaryl or -C^c-heterocyclyl, where each is optionally further substituted with one to three Rs ; ii) monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl, where each is further substituted with one to three cyano, -C(O)R \ -C(O)OR1, -C(O)NR~R5, -S (O) 2NR7Rs, -NR'C(O)R-, C:-4 alkyl, -Q-C^4 alkyl, C4-4 haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C4-4 alkyl, -C(O)OH or C4-4 haloalkyl; iii) optionally substituted fused aryl, optionally substituted fused heteroaryl or optionally substituted fused heterocyclyl, where each is optionally further substituted with one to three R8; or iv) a substituent of the Formula -L--L2, where L- is aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R,?; and L·2 is phenyl, heterocyclyl or heteroaryl, where each is optionally substituted with one to three C4-4 alkyl, -C(O)OH or C4-4 haloalkyl; either 4) R- is - (CH1CH2O) i-;OH;CH;OCH, C:-.;alkyl substituted with one to three R3, cycloalkyl or heteroaryl optionally substituted with one to three R"; and In some embodiments, when A is CH, R-::o is 10-membered heteroaryl substituted with methoxy and methyl; c R-;io is C aryl? optionally substituted with 1-3 substituents independently selected from cyano, halo, Cm-i alkyl, ~OR~, C> haloalkyl.; and NR'R', where R~ and R are each independently hydrogen or alkyl-C_~y or R:-o is unsubstituted Cu aryl; or R3;,o is unsubstituted heterocyl. In one aspect, there is provided a compound having the structure of Formula I: Or2J !d O V'N L,n R1 AI or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein A is N or CH; R- is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R3; - 30 R2 is hydrogen, - (CH~.CH.-O) ;.-íCH.;.CH..OCH3, C:-alkyl optionally substituted with one to three R4, or heteroaryl optionally substituted with one to three Rr ; each R3 is independently cyano, halo, -L-C2-2 alkyl, -L-C2-4 haloalkyl, -L-O-Cia haloalkyl, -MR'R', -C(O)NR~R, -S (0) 2NR”RS, -NR7C(0)R% -OR, -L-aryl, -L-heteroaryl or -Lheterocyclyl, where each is optionally substituted with one to three R':, and each L is independently a bond or -C=C-; each R4 is independently halo, hydroxy, -0-Cl-3 alkyl, -NH2, -NH-C2-alkyl, -N (C2-g alkyl)2 or monocyclic heterocyclyl; wherein each is optionally replaced with one to three R5s; provided that only one R4 is heterocyclyl; each R3 is independently cyano, halo, C.-λ alkyl, hydroxy, -O-C;-4 alkyl, C2- haloalkyl: or -O-C;-4 haloalkyl; each R- is independently cyano, halo, -C(O)R~, C(O)ORg -C(0)NRR', -S(O);NR'R-, -NRC(O)R3, -OR ', C~-4 alkyl, -O-C;-4 alkyl, C>4 haloalkyl, -O-C;-4 haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three O-j alkyl, -C(O)OH or C2-4 haloalkyl; R and R are each independently hydrogen, C2-4 alkyl, or phenyl, pyridyl, or R and R“ together with the nitrogen atom to which they are attached form a heterocyclyl. In certain embodiments, when R3 is phenyl, then R3 is aryl or heteroaryl, each of which is optionally substituted with one to three RE. In certain embodiments, when R3 is heteroaryl, then R2 is not C^--: unsubstituted alkyl. In certain modalities, A is N or CH; R3 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R3; R2 is hydrogen, - (CH2CH2O) i-vCHiCHiOCHj, 0-6 alkyl optionally substituted with one to three R4, or heteroaryl optionally substituted with one to three R3; each R3is independently halo, -L-alkyl C-?, C(O)NR'R3, -S(O)2NR2Ra, -ΝΗΟ(0)Η®, -0R, -L-heteroari lo of 5-6 members or -L- 5-6 membered heterocyclyl, wherein each is optionally substituted with one to three R', and each L is independently a bond or -C=C-; each R4 is independently halo, hydroxy, -0-C1-6 alkyl, -NH2, -NH-C>é alkyl, -N(C2-2 alkyl)2 or monocyclic heterocyclyl; wherein each is optionally replaced with one to three R3; provided that only one R4 is heterocyclyl; each R5 is independently cyano, halo, C.-q alkyl, hydroxy, -0-C2-2 alkyl, Cl- haloalkyl; or -O-C2-i haloalkyl; - 32 each R6is independently cyano, halo, C..-.alkyl;, hydroxy, -0-Ci-.alkyl;, Cl-3o haloalkyl -Q-C.-.haloalkyl;; and R~ and R8 are each independently hydrogen or alkyl Cl-.·,, or R7 and R8 together with the nitrogen atom to which they are attached form a - (CU) ?-0-(CH:). Also provided is a compound of the Formula lia: EITHER R?1 H Ό ! N lia or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein R: is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R:; R2 is hydrogen, - (CHíCHiO) _-,?CH-CH;.OCH, d-alkyl optionally substituted with one to three R8, or heteroaryl optionally substituted with one to three R-; each R8is independently cyano, halo, C_-· alkyl, 0-4 haloalkyl, -O-C;-^ haloalkyl, -NR~R:, -C(O)NR'R‘, S(O):NRR8, -NR~C(O)R;, -OR\ aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R', and each L is independently an o-bond C=C-; - 33 each Rá is independently halo, hydroxy, -0-Cl-í alkyl, -NHz, -NH-alkyl -N(C alkyl;--) or monocyclic heterocyclyl; wherein each is optionally replaced with one to three R5s; provided that only one R4 is heterocyclyl; each R5 is independently cyano, halo, C;-^¡ alkyl, hydroxy, -0-Ca-a alkyl, Cl- haloalkyl: or -O-Ca-a haloalkyl; each R is independently cyano, halo, -C(O)R~, C(O)OR7, -C(0)NR7Rs, -SfORNRR-, -NRC(0)R;, -OR\ alkyl C;-^ , -0-alkyl Ca-a, haloalkyl C;-j, -O-haloalkyl C.-q, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three Cl-z alkyl, -C(O)OH or O-j haloalkyl; R and R5 are each independently hydrogen, Ci-^ alkyl or phenyl, pyridyl, or Ri and R- together with the nitrogen atom to which they are attached form a heterocyclyl. In certain embodiments, a compound of Formula Ha is provided: O R21 H O X--N I N Ha or a pharmaceutically acceptable deuterated salt, tautomer, stereoisomer, mixture of stereoisomers or analogue thereof, wherein - 34 R- is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R2; R2 is hydrogen, - (CH2CH2O) 1-5CH2CH2OCH·, alkyl optionally substituted with one to three R4, cycloalkyl or heteroaryl optionally substituted with one to three R2; each R3 is independently cyano, halo, -L-C alkyl;-2, -L-C1-4 haloalkyl, -L-O-C:-haloalkyl;, -NR^R3, -C(O)NRR’, -S(O);NRRs, -NR7C(O)R-, -OR\ -L-aryl, -L-heteroar i lo or -Lheterocyclyl, where each is optionally substituted with one to three R, and each L is independently -C = C- or absent; each R4 is independently halo, hydroxy, -O alkyl -NH2, -NH-alkyl C;-¿, -N (Ci-Js alkyl, -0C (O) R\ OC(O)ORa, -OP(O) (OR2)-, or monocyclic heterocyclyl; where each one is optionally replaced with one to three R2, provided that only one R4 is heterocyclyl; each R2 is independently cyano, halo, C:-j alkyl, hydroxy, -0-C2-^ alkyl, G>-¿ haloalkyl or -O-C;-2 haloalkyl; each R6is independently cyano, halo, -C(O)R\ C(O)OR, -C(O)NR?RS, -S(0).MR·, -NR“C(O)R-, ~OR ~, C.-alkyl,, -0-C2-4alkyl, C:-^ haloalkyl, -C-haloC_-^, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C2-_ alkyl:, -C(O)OH or Ci-j haloalkyl; - each of and R® is independently hydrogen, C.-3 alkyl or phenyl, pyridyl, or R' and R- together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently C:-alkyl, optionally substituted with -NH2, -NH-C;-alkyl, -N (C:-, alkyl)2, or OR (O) (ORb) 2; each Rbes independently hydrogen or C:-3 alkyl. In some embodiments, for compounds of Formula 1, at least one of the following is true: 1) R: is a fused tricyclic ring optionally substituted with one to three R'; 2) R1 is an optionally substituted fused bicyclic ring, substituted with at least one. R' selected from cyano, -C=C-C1-2-alkyl, -C.-alkyl substituted with one to three R6, -C^c-C2v-haloalkyl, -C^c-O-C:-.-haloalkyl;, -NRR?, -C(O)NR7RS, -S(O)2NR^R;, -NR-C(O)R-, -O-alkyl C:-;, -O-phenyl, -L-aryl, -L-heteroaryl or -L-heterocyclyl, where each is optionally further substituted with one to three R?, and each L is independently -C^c- or is absent; 3) R- is a substituted monocyclic ring, substituted with at least one R3 selected from: i) cyano, -C=C- alkyl C;-., -C^c-haloalkyl C^i, -C=CO-haloalkyl C:-a, -NR“R5, -C(0)NR“R3, -S(O)2NRRs, -NRO(O)R3, -C=C-aryl, -C = C-heteroaryl or -C = C-heterocyclyl, where each is optionally further substituted with one to three ii) monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl, where each is further substituted with one to three cyano, -C(O)R, -C(O)OR~, -CtOjNR'R'u -S (O) 2NR ~Rs, -NRC(O)R-, C;-; alkyl, -0-Cl-alkyl;, C;-; haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C;-; alkyl, -C(O)OH or C_-l haloalkyl; iii) optionally substituted fused aryl, optionally substituted fused heteroaryl or optionally substituted fused heterocyclyl, where each is optionally further substituted with one to three Rs; or iv) a substituent of the Formula -L--L2, where L· is aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R'; and L- is phenyl, heterocyclyl or heteroaryl, where each is optionally substituted with one to three C;-; alkyl, -C(O)OH or C;-; haloalkyl; either 4) R‘ is - (CH2CH2O) _-2CH._CH.OCH ·, C;-· alkyl: substituted with one to three R3, cycloalkyl or heteroaryl optionally substituted with one to three R-'. Also provided is a compound of Formula Ilb: - 38 each R- is independently cyano, halo, -C(O)k , C(O)ORd -C(O)NRR3, -S(O)2NR7R3, -NR'C(O)RA -OR, alkyl C .-u, -O-Ci-q alkyl, Cim haloalkyl, -O-Ch-q haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C;-q alkyl, -C(O)OH or C2-q haloalkyl; each of R~ and R- is independently hydrogen, C_-q alkyl or phenyl, pyridyl, or R and R- together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently C^-.· alkyl optionally substituted with -NH2, -NH-C;-.· alkyl, -N(C:-á: alkyl, or OP(0) (0Rfc) 2; each Rbes independently hydrogen or C;-j alkyl. In some embodiments, for compounds of Formula Ilb, R3No is 10-membered heteroaryl substituted with methoxy and methyl; or R3No is Cu aryl optionally substituted with 1-3 substituents independently selected from cyano, halo, C2-q alkyl, -OR, C:- haloalkyl; and NRR3, where R and R3 are each independently hydrogen or C2-q alkyl; o R-Not unsubstituted Cío aryl; or R-':o is unsubstituted heterocylyl. In certain embodiments, A is N. In certain embodiments, A is CH. In certain embodiments, R: is aryl optionally substituted with one to three R-. - 39 In certain embodiments, R- is heteroaryl optionally substituted with one to three F In certain embodiments, R1 is heterocyclyl optionally substituted with one to three R'. In certain embodiments, R1 is cycloalkyl optionally substituted with one to three R-'. In certain embodiments, R- is each n is independently one, two, or three, and, Y is CR-R-, C(O), O, or NR::; each of R¿and R;' is independently hydrogen, halo or C-.-4 alkyl; and R~;is hydrogen or Cl-¿ alkyl. In certain embodiments, L is a link (i.e., it is absent). In certain modalities, L is -C=C-. In certain embodiments, each of R“ and R·' are halo. In certain embodiments, each of R9 and Ryson fluoro. - 40 In certain embodiments, each of R8 and R-' is hydrogen. In certain embodiments, R- is hydrogen. In certain embodiments, R3 is halo, 0;-- alkyl, Ci-j haloalkyl or -OR-. In certain embodiments, at least one R' is halo, C:-· alkyl or -OR-. In certain embodiments, R' is halo, 0:-· alkyl or -OR-. In certain embodiments, at least one R' is fluoro, chloro, bromo, methyl, tert-butyl, netoxy or phenoxy. In certain embodiments, R' is fluoro, chloro, bromo, methyl, tert-butyl, methoxy or phenoxy. In certain embodiments, R3 is aryl optionally substituted with one to three R'. In certain embodiments, R- is In certain embodiments, R~ is aryl substituted with phenyl, heterocyclyl or heteroaryl. - 42 In certain embodiments, R' is substituted with heteroaryl whose heteroaryl is substituted with Ci-j alkyl, -C(O)OH or haloalkyl C;-j. In certain modalities, R- is aryl substituted with heteroaryl, whose heteroaryl is substituted with Cim alkyl, -C(C)OH or C>4 haloalkyl. In certain embodiments at least one heterocyclyl Rjes optionally substituted with one to three R3. In certain embodiments, R3 is heterocyclyl optionally substituted with one to three R5. - 44 In certain modalities, at least one Rjes In certain embodiments, at least one R-' is heteroaryl optionally substituted with one to three R'. In certain replaced with modalities, R-- is optionally heteroaryl In certain modalities In certain embodiments, R- is hydrogen, Ci-alkyl, optionally substituted with one to three R4o cycloalkyl; each R4is independently -OC(O)R:;, -OC(O)OR'·, -0P(0) (OR:;); or monocyclic heterocyclyl; provided that only one R4 is heterocyclyl; each R2is independently alkyl C;-.; optionally substituted with -NH; or -0P(O) (OR·7);; and R;:is hydrogen. In certain embodiments, a compound of Formula III is provided herein: R~ 0 O 14---'N'-----4N R4-¾. -—· III or a salt, a tautomer, a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable deuterated analogue thereof, wherein: R2 is hydrogen, - (CH;CH;O) i-.;CH..CH.;OCHj, alkyl optionally substituted with one to three R4, cycloalkyl or heteroaryl optionally substituted with one to three Recada R2 is independently aryl, heteroaryl or heterocyclyl, wherein each is optionally substituted with one to three R4; each R4 is independently halo, hydroxy, -0 C alkyl;-;, —NH;, -NH-C alkyl;-¿, -N(alkyl -OC(O)R7;, OC(O)ORa, -OP (O) (0Rb);, or monocyclic heterocyclyl; where -46each is optionally replaced with one to three R-; provided that only one R3 is heterocyclyl; each R5 is independently cyano, halo, C.-alkyl, hydroxy, -O-C2-4alkyl, Ci-i haloalkyl or -O-C?-haloalkyl,; each R3is independently cyano, halo, -C(O)R\ C(O)OR-, -C(O)NR~RS, -S(O)?NRR:, -NR%(O)R?, -OR ~, Ci-alkyl, -O-Ci-4-alkyl, C--4-haloalkyl, -O-Cl-j-haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C?-? alkyl, -C(O)OH or Ci-4 haloalkyl; each of R~ and Rsis independently hydrogen, C;-4 alkyl, phenyl or pyridyl, or R and R3 together with the nitrogen atom to which they are attached form a heterocyclyl; each R1is independently alkyl C?-? optionally substituted with -NH?, -NH-alkyl C;-?, -N(alkyl C.-,)2, or OP(O)(ORb)?; and each Rbes independently hydrogen or C?-4 alkyl. In certain embodiments, a compound of Formula IV is provided herein: R O You .... V\. .... AND I DON'T H\ J—Á Á__ / ? \N V_____ N - 47 or a salt, a tautomer, a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable deuterated analogue thereof, wherein: R2 is hydrogen, - (CH2CH2O) i-2CH2CH2OCH;, C2-?alkyl optionally substituted with one to three R2, cycloalkyl or heteroaryl optionally substituted with one to three R2; each R2is independently halo, hydroxy, -0 C:-2 alkyl, -NH2, -NH-Q·^ alkyl, -Nfalkyl C2-,)2, -OC(O)Ra, OC(O)ORa, -0P( 0) (0Rb)2, or monocyclic heterocyclyl; wherein each is optionally replaced with one to three R1'; provided that only one R2 is heterocyclyl; each R5 is independently cyano, halo, C;~: alkyl, hydroxy, -0-Cí-g alkyl, C2-2o haloalkyl -O-C_-haloalkyl:; each Ra is independently Ci-e alkyl optionally substituted with -NH2, -NH C:-¿ alkyl, -N (C2- alkyl. )2, or OP(O)(ORb)2; and each Rbes independently hydrogen or CÍ-j alkyl. In certain embodiments, R2 is hydrogen, C^-c alkyl optionally substituted with one to three R2o cycloalkyl. In certain embodiments, R2 is hydrogen or Ci-2 alkyl optionally substituted with one to three R2. In certain embodiments, R2 is hydrogen or Cl-alkyl, optionally substituted with an R2. In certain embodiments, R2 is hydrogen. In certain embodiments, R2 is C;-alkyl, optionally substituted with one to three R2. In certain embodiments, R2 is Ci-g alkyl. In certain embodiments, R2 is C>4 alkyl. In certain embodiments, R2 is hydrogen, C.-¿ alkyl optionally substituted with one to three R2o cycloalkyl; each R2 is independently -O-Ct-í alkyl, -OC(O)R:, OC(O)ORa, -OP(O) (0Rb)¿, or monocyclic heterocyclyl; each Raes independently alkyl Ci-; optionally substituted with -NH? or -OP (0) (OR2)?; and Rbes hydrogen. In certain embodiments, each R2 is independently 0-C;-c alkyl, -0C(0)R2, -OC(O)OR-, -OP(0) (0Rc).:, or monocyclic heterocyclyl; wherein each Ra is independently C:-alkyl optionally substituted with NH.: or -0P(0) (0Rb)?, and Rbes hydrogen. In certain embodiments, each R2 is independently OC(O)Ra, -OC(O)ORa, -0P(0) (0Rb). , or monocyclic heterocyclyl; wherein each Ra is independently Cl-g alkyl optionally substituted with -NH- or -OP (0) (0Rb)._, and Rbes hydrogen. In certain embodiments, a compound selected from Table 1 is provided with a salt, a tautomer, a stereoisomer, a mixture of stereoisomers or a pharmaceutically acceptable deuterated analog thereof. In certain embodiments, the compound is selected from a compound in Table 1: -49TABLE 1 - ου No. Structure 35 ΗΟ-^° \^Vnh 36 ΗΟ-γ° / Γ3χ / / nh (> / n^ —N 37 ΗΟ-^° / T~\\ / y θ= / ΛτΝ N^7 38 0 ΗΟ -Ύ A~NH ddy ' ó £ í J N 39 ZO N HO^ ci^ / / nh \= / V 40 ΞΕ Z Z oy2> o ¡ I rj 2 41 0 Γ l| Az X I ° 2\ t^Ad z z T 42 d~\ zO Z7 % HO-^ / T~7\ / / NH L / wV No. Structure 43 n y I T ° ^x^ / Ad zz 44 HO-U0 / ~Ά / ~~A #NH N= / \= / N'N 45 zo / =\ ΗΟ-γ V / A / 1Ah \= / A= / \rN 46 ZO / =\ HO— / 2 NH 47 ,0 / =\ ΗΟ-Ϋ N\\ A=\ / T~\ Anh t / wV 48 HO^° / T~\ # NH N \ / \ / 7 'N I 7=7 7=7 N'N ^N 49 ZO HO^2 / ΓΆ / / NH c|H. y-y yx ¿ yy ^=7 n'n 50 Cl H°~+° / ~Λ / NH V / WVn 51 ΗΟ^>0 Br-PW-W'y - 54 10 -5610 - 5 9- In certain embodiments, a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In certain embodiments, the compound is selected from: - 62 In certain embodiments, a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In certain embodiments, the compound is selected from: where R2 is as defined herein. In certain embodiments, R2 is C:-,- alkyl optionally substituted with one to three R2. In certain embodiments, R2 is Ci-« alkyl. In certain embodiments, R- is ethyl. In certain embodiments, the compound is selected from: Cl Cl and Cl In general, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, it is understood that other names may be used to identify compounds of the same structure. In particular, compounds may also be named using other nomenclature systems and symbols that are commonly recognized in the art of chemistry, including, for example, the Chemical Abstracted Service (CAS) and the International Union of Puree and Applied Chemistry (IUPAC). . Other compounds or radicals may be named by common names, or by systematic or non-systematic names. - 64 In certain embodiments, optical isomers, racemates or other mixtures thereof of the compounds described herein or a pharmaceutically acceptable salt or mixture thereof are provided. In those situations, the single enantiomer or diastereoisomer, i.e., the optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high pressure liquid chromatography (HPLC) column. Compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, isomers or mixtures thereof may include racemic mixtures or mixtures containing an enantiomeric excess of an individual enantiomer or diastereomers or mixtures of diastereomers. All isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed. In certain embodiments, chelates, non-covalent complexes and mixtures thereof, of the compounds described herein or a salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or - 65 pharmaceutically acceptable deuterated analogue thereof. A chelate is formed by the coordination of a compound with a metal ion at two (or more) points. A non-covalent complex is formed by the interaction of a compound and another molecule where a covalent bond is not formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonds, and electrostatic interactions (also called ionic bonds). In certain embodiments, prodrugs of the compounds described herein are provided. Prodrug refers to any compound that, when administered to a biological system, generates the drug substance, or active ingredient, as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis and / or metabolic chemical reactions. Therefore, a prodrug is a covalently modified analogue or latent form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, glycol moieties and the like. In certain embodiments, a compound of Formula I or lia is provided, wherein R1 is - 6 6- R—OR12OR12 O / R—OR120OR12 O / R—OR12 OR12 EITHER P—OR12 OR12 eleven R—OR12 OR12 ^OR12 EITHER P-R'2 OR12 Ρς—N(R12)2 N(R12)2 O1119 p—N(R12)2 N(R12)2o N(R12)2 II Ρς—N(R12)2 N(R12)2 P^—N(R12)2 n(R12)2 P-N(R12)2 HOR12 o^ / Bread<r OR12 either II Pc-N(R12)2 OR12o Ρς—R12 N(R12)2 R / R12 N(R12)2 \ 19 N(R12)2 X19 N(R12)2where each R:: is independently hydrogen, 0-2 alkyl, C;-r alkenyl, O-n alkynyl, cycloalkyl aryl, heteroaryl or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z-'r groups; and each Z-bes independently oxo, thioxo, hydroxy, halo, -NO;, -Na, cyano, C>··alkyl, alkenyl alkynyl C;-;, cycloalkyl C;-;s, haloalkyl CN-a, aryl, heteroaryl, heterocyclyl, O (C;-; alkyl), O (C;-J alkenyl, 0 (C;-; alkynyl), O (C3-;; cycloalkyl), O (C;-; haloalkyl), -O (aryl), O (heteroaryl), -O (heterocyclyl), NH;, NH (C.-alkyl;·), NH (C;-; alkenyl), NH (C2-H alkynyl, -NH (CN-cycloalkyl) o ), -NH (C haloalkyl;--;), -NH(aryl), -NH (heteroaryl), NH (heterocyclyl), N(C;-? alkyl);, N (C;~u cycloalkyl); , N (C;-; alkenyl);, -N (C;-e alkynyl);, -N (C<-; cycloalkyl; = ) ;, N (C;-; haloalkyl);, -N(aryl); , -N (heteroaryl) :, N(heterocyclyl);, -N(C;-; alkyl) (C;-;^ cycloalkyl), N (C;-; alkyl) (C;~.? alkenyl), N (C;-;. alkyl) (C:- alkynyl), N (C1-9 alkyl) (C;-;; cycloalkyl), N (C;-? alkyl) (C;-2 haloalkyl), N(C;-alkyl) C;-;) (aryl), -N(C;--· alkyl) (heteroaryl), N(C;-? alkyl) (heterocyclyl), C (O) (C:-d alkyl, C (O) (C;-a alkenyl), -C (O) (C;- / alkynyl), C (O) (C;-;; cycloalkyl), C(O) (C;--haloalkyl), -C (O ) (aryl), C (O) (heteroaryl), -C (O) (heterocyclyl), -C (O) O (C;-· alkyl), C (O) O (C;-c alkenyl), C (O) O (C;-¿ alkynyl), C (O) O (C--_; cycloalkyl), -C (O) O (C_~ haloalkyl;), C(O)O(aryl), -C (O)O(heteroaryl), -C(O)O(heterocyclyl), C(O)NH;, -C (O) NH (C alkyl;-;·), C (O) NH (C alkenyl;- .), C (O) NH (C;-< alkynyl), C (O) NH (C -x cycloalkyl), C (O) NH (C;-; haloalkyl), -C (O) NH (aryl) , - 68 C(O)NH(heteroaryl), -C(O)NH(heterocyclyl), C(O)N(Czr alkyl)2, C(O)N (C;-dz cycloalkyl, C(O)N ( alkenyl C.dz, C (O) N (alkynyl Cz-d m C (O)N (cycloalkyl C--aAa, C (O) N (C2-2 haloalkyl)z, -C (O) N (aryl) 2, ~C (O)N(heteroaryl)2, -C (O)N(heterocyclyl)z, NHC (O ) (Ctb alkyl, NHC (O) (Cz-d alkenyl, NHC (O) (Cz-d alkynyl, NHC (O) (C2-zd cycloalkyl, NHC (O) (C2-d haloalkyl, NHC(O)( aryl), -NHC(O)(heteroaryl), -NHC(O) (heterocyclyl), -NHC (O) 0 (Ca-a alkyl), -NHC (O) O (C_-d alkenyl, NHC (O)O(Cz-d alkynyl, NHC (O)O(C-n cycloalkyl), NHC (O) O (C;-d haloalkyl, -NHC (O) O (aryl), NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH (Cz-d alkyl, NHC(O)NH (Cz-d alkenyl, NHC (O) NH (Cz alkynyl) -d, -NHC (O)NH (C:-_a cycloalkyl), NHC (O) NH (C2-3 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), NHC (O) NH (heterocyclyl), -SH, -S (Ca-a alkyl), S (Czd alkenyl, S (Cz-d alkynyl, -S (C cycloalkyl;<d, -S (C:-d haloalkyl) , -S(aryl), -S(heteroaryl), -S(heterocyclyl), -S(O)(C2-d alkyl), -N(Ca-a alkyl), S(O)(C2-d alkyl, S( O) N (Ci-z alkyl)2, -S (O) (Ca-a alkyl), -S (O) (NH) (Cz alkyl), S (O) (Cz-d alkenyl, S (O ) (alkynyl Cz-d, S (O) (Cj-;d cycloalkyl, -S (O) (Ca-A haloalkyl, S(O) (aryl), -S(O) (heteroaryl), -S(O)(heterocyclyl), S (O) 2 (Ca-a alkyl), -S (O) z (C2-d alkenyl, S (O) 2 (a Iqu mi lo C2d, S (O) 2 (Cz-.d cycloalkyl, -S (O)z(C2-d haloalkyl, S (O)2(aryl), -S (0)2(heteroaryl), -S (0)2(heterocyclyl), S (0)2NH (C1-2 alkyl), or S (0)2N (C alkyl ;-?)2; wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four halo, O-alkyl;.·, C:-o haloalkyl, -OH, NH.-, NH(C1-9 alkyl), NH (C;-o cycloalkyl), -NH (C;-; haloalkyl), -NH (aryl), -NH (heteroaryl), NH(heterocyclyl), N (C:~ 2)2 alkyl, N (C cycloalkyl --::):, NHC(O) (C--a cycloalkyl), NHC (0) (C:-- haloalkyl), -NHC (0) (aryl), NHC(0) (heteroaryl), -NHC (0) (heterocyclyl), -NHC(0) 0(C2-9 alkyl), NHC (0) 0 (C.-·Η alkynyl), NHC (0) 0 (C3-15 cycloalkyl), NHC (0) 0 (Ci-g haloalkyl), -NHC (0) O (aryl) , NHC(0)0 (heteroaryl) , -NHC(0)0(heterocyclyl) , NHC (0) NH (C-·alkyl), -S (0) (NH) (O-alkyl), S (O) 2 (Cy-- alkyl) z S (O) 2 (C-a cycloalkyl) , -S (0) 2 (C:-- haloalkyl), S (0) 2 (aryl), -S (0)2 (heteroaryl), -S (0)2 (heterocyclyl) , S (0) 2NH ( C1-9 alkyl), S (0) 2N (Ci- / alkyl)2, 0 (C25 cycloalkyl), 0 (C_- haloalkyl), -0 (aryl), -0 (he Leroaryl), ( heterocyclyl) u 0(C;-? alkyl). In certain embodiments, a compound of Formula I or any of the sub-formulas provided herein is provided, wherein R: is EITHER P.OR12 OR12 O .I¡v / R—OR120OR12 EITHER R—OR12 OR12 0 - 1i, Ρ—N(R12)2 N(R12)2 11V p—N(R12)2 N(R12)2 o ¡I 19 p—N(R12)2 OR12 Ρς—N(R12)2 N(R12)2 either Λ 1, / ^ / R^N(R12)2 N(R12)2o 1119 R—N(R12)2 OR12 O \-RN(R,2)2 or ^p—R12° N(R12)2 O11 R—N(R12)2 OR12o Pq—R12 N(R12)2 either II 19 p—R12 N(R12)2 O / \.o^p-R12¥ N(R12)2o Such substituents also include all individual stereoisomers and mixtures thereof, including, but not limited to, chirality on the phosphorus atom, such as in the example moieties shown above. Also provided herein are the in vivo metabolic products of the compounds described herein. Such products may result, for example, from oxidation, reduction, hydrolysis, nesting, esterification and the like of the administered compound, mainly due to enzymatic processes. Therapeutic Uses of Compounds Treatment or treating is a procedure to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical outcomes may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition and / or decreasing the degree of the disease or condition); b) slow or stop the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilize the disease or condition, prevent or delay the worsening or progression of the disease or condition and / or prevent or delay the spread ( e.g., metastasis) of the disease or condition); and / or c) alleviate the disease, that is, cause the regression of clinical symptoms (e.g., improve the state of the disease, provide a partial or total remission of the disease or condition, enhance the effect of another medication, delay the progression of the disease, increase quality of life and / or prolong survival. Prevention or prevent refers to any treatment of a disease or condition that causes the - 72 clinical symptoms of the disease or condition do not develop. The compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition. Primary hyperoxaluria type 1 may result in the need for a kidney transplant. After transplant, remission is very likely. In certain embodiments, the compounds described herein are administered to a patient after transplantation in order to prevent remission. Subject means an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human being. The term therapeutically effective amount or effective amount of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as improving symptoms or slowing disease progression. For example, a quantity - 73 therapeutically effective may be an amount sufficient to reduce a symptom of a disease or condition that responds to the inhibition of glycolate oxidase activity. The therapeutically effective amount may vary depending on the subject, the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, which can be readily determined by one skilled in the art. . The term inhibition indicates a decrease in the initial activity of a biological activity or process. Inhibition of glycolate oxidase activity or variants thereof refers to a decrease in the activity of the glycolate oxidase enzyme as a direct or indirect response to the presence of a compound of the present application in relation to the activity of glycolate oxidase. in the absence of the compound of the present application. Glycolate oxidase inhibition refers to a decrease in the activity of the glycolate oxidase enzyme as a direct or indirect response to the presence of a compound described herein in relation to the activity of glycolate oxidase in the absence of the compound described herein. . In some embodiments, inhibition of glycolate oxidase enzymatic activity can be compared in the same subject before treatment, or in other subjects not receiving treatment. - 74 The methods described herein can be applied to cell populations in vivo or ex vivo. In vivo means within a living individual, such as within an animal or human. In this context, the methods described in 4.a herein can be used therapeutically in an individual. Ex vivo means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Said samples can be obtained by methods well known in the art. Examples of biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Examples of tissue samples include tumors and biopsies thereof. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal schedule and / or dosage of administration of a glycolate oxidase inhibitor for a given indication, cell type, individual, and other parameters. The information obtained from such use can be used for experimental purposes or in the clinic to establish protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suitable are - 75 described below or will be apparent to those skilled in the art. Selected compounds can be further characterized to examine dosage safety or tolerance in human or non-human subjects. Such properties can be examined using methods commonly known to those skilled in the art. The compounds described herein are useful for the treatment, prevention, diagnosis or monitoring of diseases or conditions mediated by glycolate oxidase. Non-limiting examples of glycolate oxidase-mediated diseases or conditions include, without limitation, nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, hyperoxaluria type 1, Bird's disease, glycolic aciduria, end-stage renal disease (ESRD). , kidney failure, kidney transplant failure and type II diabetes. In certain embodiments, the compounds described herein are useful for the treatment, prevention, diagnosis or monitoring of diseases or conditions mediated by oxalate, calcium oxalate or glycolate oxidase. In some embodiments, the disease or condition is nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, hyperoxaluria type 1, Bird's disease, glycolic aciduria, end-stage renal disease. - 76 (ESRD), kidney failure, kidney transplant failure and type II diabetes. In additional embodiments, the methods are provided for alleviating a symptom of a disease or disorder mediated by glycolate oxidase. In some embodiments, the methods include, identifying a mammal that has a symptom of a glycolate oxidase-mediated disease or disorder and providing the mammal with an amount of a compound as described herein effective to improve (i.e., decrease the severity). of the symptom. In additional embodiments, methods are provided for alleviating a symptom of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase. In some embodiments, the methods include identifying a mammal that has a symptom of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase, and providing the mammal with an amount of a compound as described herein effective to improve (i.e. , decrease the severity) of the symptom. In some embodiments, the glycolate oxidase-mediated disease or condition is kidney stone formation. In some embodiments, the oxalate- or calcium oxalate- or glycolate oxidase-mediated disease or condition is kidney stone formation. In particular embodiments, kidney stone formation is recurrent. In - 77 particular modalities, kidney stone formation is associated with primary hyperoxaluria type 1. In some embodiments, the glycolate oxidase-mediated disease or condition is renal failure, including failure of a single kidney and both kidneys. In some embodiments, the oxalate or calcium oxalate or glycolate oxidase mediated disease or condition is renal failure. In some embodiments, renal failure is failure of a single kidney or both kidneys. In some embodiments, the disease or condition that is prevented is kidney transplant failure. In some embodiments, the glycolate oxidase-mediated disease or condition is diabetes, including type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting blood glucose, and impaired glucose tolerance. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is diabetes. In some embodiments, diabetes is type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting blood glucose, or impaired glucose tolerance. Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM). Type 2 is also known as non-insulin dependent diabetes mellitus (NIDDM). - 78 In some embodiments, the glycolate oxidase-mediated disease or condition is bladder stone formation. In some embodiments, the oxalate- or calcium oxalate- or glycolate oxidase-mediated disease or condition is bladder stone formation. Useful criteria for the evaluation of disease activity in subjects with primary hyperoxaluria type 1 can be found in Brooks et al. (2016) Am. J. Nephrol. 43, 4:293-303. The amount of oxylate and calcium in the urine can be monitored. The treatment methods described herein can also be applied at any point in the course of the disease. In certain embodiments, the methods are applied to a subject having primary hyperoxaluria type 1 during a period of time of remission (i.e., inactive disease, after kidney transplant). In such embodiments, the present methods provide benefits by extending the time period of remission (e.g., extending the period of inactive disease) or by preventing, reducing or delaying the onset of active disease. An example would be the increase in time between incidents of kidney stones. In other embodiments, the methods may be applied to a subject having primary hyperoxaluria type 1 during a period of active disease. Such methods provide benefits by reducing the duration of the period of active disease, reducing - 79 or improve one or more symptoms of primary hyperoxaluria type 1 or treat primary hyperoxaluria type 1. Such improvement may be a reduction in the size, number or frequency of kidney stones. Measures to determine the effectiveness of treatment of primary hyperoxaluria type 1 in clinical practice have been described and include, for example, the following: symptom control; calcium oxalate concentration in body fluids; kidney function tests; and improvement in quality of life. In certain embodiments, provided herein is a method for the treatment of primary hyperoxaluria type 1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutical composition such as described herein, or a compound of Formula I: OR · Á S N or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein A is N or CH; - 80 R: is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R2; R2is hydrogen, - (CH;CH;O) ;-;CH;.CH;OCH3, alkyl C;-.; optionally substituted with one to three R4, cycloalkyl or heteroaryl optionally substituted with one to three R2; each R2is independently cyano, halo, -L-alkyl Ci-?, -L-haloalkyl Ci-i, -L-O-haloalkyl C;-;, -NR”R?, -C(O)KR'R·, - S(O)2NR7RS, - NR7C(O)R2, -OR, -L-aryl, -L-heteroaryl or -Lheterocyclyl, where each is optionally substituted with one to three R2, and each L is independently -C ^c- or is absent; each R4 is independently halo, hydroxy, -0 Cl--alkyl, -NH;, -NH-C;-c alkyl, -N (Cl--alkyl)l, -OC(O)R2, OC (O) OR2, -OP(O)(OR2);, or monocyclic heterocyclyl; wherein each is optionally replaced with one to three R=; provided that only one R4 is heterocyclyl; each R4 is independently cyano, halo, C.-alkyl, hydroxy, -0-C;-alkyl, C.-haloalkyl; or -O-haloalkyl Cl-·:; each R2is independently cyano, halo, -C(O)R, C(O)OR7, -C(O)NR7RS, -S (O) ¿NRR;, -NR“C(O)R2, -OR, C alkyl >;, -0-alkyl Cl-a, haloalkyl Cl-l, -O-haloalkyl Cl-l, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C;-; alkyl, -C(O)OH or Cl-l haloalkyl; - 81 each of R~ and R is independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R' and R8 together with the nitrogen atom to which they are attached form a heterocyclyl; each Raes independently alkyl optionally substituted with -NH2, -NH-alkyl -N(alkyl or OP (O) (ORb) 2; and each Rbes independently hydrogen or C:-4 alkyl. In certain embodiments, when R- is phenyl, then R-' is aryl or heteroaryl, each of which is optionally substituted with one to three R'; and when R- is heteroaryl, then R:no is Ci-3no substituted alkyl. In certain embodiments, a method for treating recurrent kidney stone formers is provided herein, comprising administering to a patient in need thereof, a therapeutically effective amount of a compound described herein, a pharmaceutical composition as described herein. herein, or a compound of Formula I: EITHER R2Á U O' V-N: N r'ate a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein A is N or CH; - 82 R2 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R'; R2 is hydrogen, - (CH2CH2O) K-CfkCHiOCH·, C2-5 alkyl optionally substituted with one to three R';, cycloalkyl or heteroaryl optionally substituted with one to three Recada R3 is independently cyano, halo, -L-C alkyl; -?, -L-C1-4haloalkyl, -L-O-C1-.1haloalkyl, -NR^R3, -C(0)NR-R, -S(O)2NR7R8, - NR2C(O)R3, - 0R\ -L-aryl, -L-heteroaryl or -Lheterocyclyl, where each is optionally substituted with one to three Rc, and each L is independently -C^C- or absent; each R2 is independently halo, hydroxy, -0 Ci-í alkyl, -NH2, -NH-Q_-alkyl,, -N(C>A alkyl, -OC(O)Ra, 0C(0)0R5, -OP (O ) (OR2)?, or monocyclic heterocyclyl; where each is optionally substituted with one to three RI;; provided that only one R2 is heterocyclyl; each R5 is independently cyano, halo, C:-2 alkyl, hydroxy, -0-C2-4 alkyl, haloalkyl or -0-halo C_-alkyl.and each R6 is independently cyano, halo, -C(O)R~, C( O)ORJ -C(O)NR2R3, -S(O)2NRR, -NR2C(O)R', -ORj alkyl -0-C2-4 alkyl, C1-4 haloalkyl, -O-C2-4 haloalkyl, phenyl , heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C1-4alkyl, -0(0)OH or C1-4haloalkyl; - 83 each of R~ and R;is independently hydrogen, C.-g alkyl or phenyl, pyridyl, or PC and R3 together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently Cg-g alkyl optionally substituted with -NH?, -NH-C3-^ alkyl, -N (Cg-alkyl. )„, or OP(O)(ORb)2; and each Rbes independently hydrogen or C;-, alkyl. In certain embodiments, when R1 is phenyl, then Res is aryl or heteroaryl, each of which is optionally substituted with one to three R3; and when R3 is heteroaryl, then R- is not unsubstituted Cg-alkyl. In certain embodiments, a method of inhibiting glyoxylate and / or oxalate production and / or inhibiting glycolate oxidase (GO) is provided herein, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as set forth herein. Described herein, the pharmaceutical composition as described herein, or a compound of Formula I: Or r2a id O YN ,N R1 A, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein A is N or CH; - 84 R: is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R3; R2 is hydrogen, - (CH2CH2O) 0;-ξalkyl optionally substituted with one to three Re, cycloalkyl or heteroaryl optionally substituted with one to three R7; each R?is independently cyano, halo, -L-alkyl C_-Ír -L-haloalkyl Cl-á, -L-O-haloalkyl C;~;, -NR Rc, -C(O)NR R3, -S(O) 2NR7R3, - NR7C(O)R3, -OR~, -L-aryl, -L-heteroaryl or -Lheterocyclyl, where each is optionally substituted with one to three R;;, and each L is independently -C = C- or is absent; each R4 is independently halo, hydroxy, -0 C.-alkyl,, -NH;., -NH-C;-,, -N (C;-,)alkyl, -0C(0)Rp OC(O) ORa, -OP(O) (OR2);, or monocyclic heterocyclyl; wherein each is optionally replaced with one to three R=; provided that only one R4 is heterocyclyl; each R' is independently cyano, halo, C;-; alkyl, hydroxy, -0-C;-; haloalkyl; or -O-haloalkyl C:-;; each R3is independently cyano, halo, -C(O)R-, C(O)OR7, -C(O)NR7R5, -S(O);NR7R\ -NR%(O)R', -OR”, alkyl C;-;, -0-alkyl C;-;, haloalkyl C;-;, -O-haloalkyl C;~;, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C;-; alkyl, -C(O)OH c 0:-; haloalkyl; - 85 each of R and R- is independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R~ and R3 together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently C;-s alkyl optionally substituted with -NH?, -NH-alkyl -N(Ci-alkyl)2, or OP(O)(ORb)2; and each Rb is independently hydrogen or Cl-2 alkyl. In some embodiments, when R- is phenyl, then R3 is aryl or heteroaryl, each of which is optionally substituted with one to three R'; and when R- is heteroaryl, then R- is not unsubstituted alkyl. In certain embodiments, the use of a compound as described herein or a pharmaceutical composition as described herein is to control or inhibit the production of recurrent kidney stone formers, in a patient in need thereof. In certain embodiments, the use of a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, is to control or inhibit the production of recurrent kidney stone formers, in a patient who needs the same, wherein a compound of Formula I: - 86 O A is N or CH; R3 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, where each is optionally substituted with one to three R3; R2 is hydrogen, - (CH2CH2O) 1-2CH2CH2OCH;, C2-¿ alkyl optionally substituted with one to three R4, cycloalkyl or heteroaryl optionally substituted with one to three R'; each R3 is independently cyano, halo, -L-alkyl -L-haloC2-2alkyl, -L-O-haloC2-2alkyl, -NR^R3, -C(O)NR''RS, -S(O)2NR7R3, - NRO(O)Rq -ORg -L-aryl, -L-heteroaryl or -Lheterocyclyl, where each is optionally substituted with one to three R6, and each L is independently -C = C- or is absent; each R4 is independently halo, hydroxy, -O C.-5 alkyl, -NH2, -NH-C2 alkyl-,, -N(C2Y alkyl.¿, -OC(O)R', OC(O)OR¿!, -OP(O) (ORb)2, or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R:; provided that only one R7 is heterocyclyl; each R3 is independently cyano, halo, Σ-α alkyl, hydroxy, -O-C2-2 alkyl, C2-2 haloalkyl or -O-C;-2 haloalkyl; each Rrjes independently cyano, halo, -C(O)R~, C(O)OR7, -C(O)NR~R3, -S (O) 2NRR3, -NR^C (O) Ry -OR\ alkyl C .-2, -O-C1-4alkyl, C:-4haloalkyl, -O-C:nhaloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C;-.alkyl:, -C(O)OH or C1-4 haloalkyl; each of R~ and R3 is independently hydrogen, C:-4 alkyl or phenyl, pyridyl, or R~ and R3 together with the nitrogen atom to which they are attached form a heterocyclyl; each R is independently C1-.5 alkyl optionally substituted with -NH2, -NH-Ch-¿ alkyl, -N(O-,alkyl)2, or OP(O)(ORb)2; and each Rbes independently hydrogen or alkyl C;-;; provided that when R3 is phenyl, then R3 is aryl or heteroaryl, each of which is optionally substituted with one to three R'> and when R- is heteroaryl, then R3no is unsubstituted C1-4 alkyl. Combination Therapies In one embodiment, the compounds described herein may be used in combination with one or more additional therapeutic agents or interventions that are being used and / or developed to treat primary hyperoxalurla type 1. Examples of such therapeutic agents are crystallization inhibitors of calcium oxalate, oxalate-degrading enzyme inhibitors, SiRNA, oxazime and lumasiran. Examples of such - 88 therapeutic interventions are high fluid intake, dialysis and kidney transplant. In some embodiments, the compounds described herein may be used in combination with an SGLT2 inhibitor. Non-limiting examples of an SGL2 inhibitor include dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, ipragliflozin, empagliflozin and potassium citrate. In some embodiments, the methods described herein further comprise the administration of an additional therapeutic agent. In some embodiments, uses as described herein in combination with an additional therapeutic agent are provided. In some embodiments, the additional therapeutic agent is an inhibitor of calcium oxalate crystallization, an inhibitor of the oxalate-degrading enzyme, SiRNA, oxazime, lumasiran, nedosiran, oxabate or reloxaliase. In some embodiments, the additional therapeutic agent is an SGLT2 inhibitor. In some embodiments, the SGL2 inhibitor is dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, ipragliflozin, empagliflozin or potassium citrate. Equipment Also provided herein are kits that include a compound of Formula I (or any other - 89 Formula described herein), or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof, and a suitable container. In one embodiment, a kit also includes instructions for use. In one aspect, a kit includes a compound of Formula I (or any other Formula described herein), or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof, and a label and / or instructions for the use of the compounds in the treatment of the indications, including the diseases or conditions, described herein. Also provided herein are articles of manufacture that include a compound described herein or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof, in a suitable container. The container may be a vial, bottle, ampoule, prefilled syringe, and intravenous bag. Pharmaceutical Compositions and Modes of Administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Therefore, also provided herein are pharmaceutical compositions containing one or more of the compounds described herein or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof and one or more pharmaceutical carriers. - 90 acceptable selected carriers, adjuvants and excipients. Suitable pharmaceutically acceptable carriers may include, for example, diluents and fillers, inert solids, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekk.er, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.). The pharmaceutical compositions may be administered in single or multiple doses. The pharmaceutical composition can be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical injection, or as an inhalant. One mode of administration is parenteral, for example, by injection. The ways in. where the pharmaceutical compositions described herein for administration by injection may be incorporated include, for example, aqueous or oily suspensions or emulsions, with sesame oil, corn oil, cottonseed oil or oil. - 91 peanut, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles. Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, enteric-coated capsules or tablets. In preparing pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog, the active ingredient is generally diluted with an excipient and / or or is enclosed within such carrier which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be presented in the form of tablets, pills, powders, lozenges, sachets, stamps, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or in liquid medium), ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, - 92 acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulations may further include lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservative agents such as methyl and propyl hydroxybenzoates; sweetening agents; and flavoring agents. Compositions that include at least one compound described herein or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof may be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the subject by employing of known procedures. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods described herein employs transdermal delivery devices (patches). These transdermal patches can be used - 93 to provide a continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for the administration of pharmaceutical agents are well known in the art. Such patches can be constructed for continuous, pulsatile or on-demand delivery of pharmaceutical agents. To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug. , or pharmaceutically acceptable deuterated analogue thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient can be dispersed uniformly throughout the composition so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. Tablets or pills of the compounds described herein may be coated or otherwise combined to provide a dosage form that provides the advantage of prolonged action, or to protect from acidic conditions of the stomach. For example, the pill or - 94 pill may include an internal dispenser and an external dosing component, the latter being in the form of a casing over the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allow the internal component to pass intact into the duodenum or its release to be delayed. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate. Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered via the oral or nasal respiratory route for a local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents can be nebulized through the use of inert gases. Nebulized solutions can be inhaled directly from the nebulizer device or the nebulizer device can be attached to a face mask tent or intermittent positive pressure breathing machine. The - 95 compositions in solution, suspension or powder can be administered, preferably orally or nasally, from devices that deliver the formulation appropriately. Dosage The specific dosage level of a compound of the present application for any particular subject will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dose may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg / kg). Doses between approximately 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalization according to the subject's body weight is particularly useful when adjusting doses between subjects of very different size, such as when using the drug in both children and adult humans or when converting a - 96 effective dose in a non-human subject such as a dog at a dose appropriate for a human subject. The daily dosage may also be described as a total amount of a compound described herein, administered per dose or per day. The daily dosage of a compound of Formula I may be between about 1 mg and 4000 mg, between about 2000 and 4000 mg / day, between about 1 and 2000 mg / day, between about 1 and 1000 mg / day, between about 10 and 500 mg / day, between about 20 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 15 and 150 mg / day. When administered orally, the total daily dose for a human subject may be between 1 mg and 1000 mg, between about 1000 and 2000 mg / day, between about 10 and 500 mg / day, between about 50 and 300 mg / day , between approximately 75 and 200 mg / day, or between approximately 100 and 150 mg / day. The compounds of the present application or compositions thereof may be administered one, two, three or four times a day, using any suitable manner described above. Furthermore, administration or treatment with the compounds can be continued for several days; For example, commonly treatment would continue for at least 7 days, 14 days or 28 days, for a treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. Treatment cycles, in other modalities, can also be continuous. In a particular embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose in increments until clinical efficacy is achieved. Increments of approximately 5, 10, 25, 50, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, or once a week. Synthesis of Compounds of Formula I The compounds can be prepared using the methods described herein and routine modifications thereof, which will be evident given the description herein and the methods well known in the art. Conventional and well-known synthesis methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein can be carried out as described in the following examples. If available, reagents can be purchased commercially, - 98 for example, from Sigma Aldrich or other chemical suppliers. General Summary Typical embodiments of the compounds described herein can be synthesized using the general reaction schemes described below. It will be apparent, given the description herein, that the general schemes can be altered by replacing the starting materials with other materials having similar structures to result in products that are correspondingly different. The syntheses are described below to provide numerous examples of how starting materials can be varied to provide the corresponding products. Given a desired product for which substituent groups are defined, the necessary starting materials can usually be determined by inspection. Inncic materials are typically obtained from commercial sources or synthesized using published methods. To synthesize compounds that are embodiments described herein, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally make the identity of the necessary starting materials evident through a simple inspection process, given - 99 examples herein. In general, the compounds described herein are generally stable and isolable at ambient temperature and pressure. Synthetic Reaction Parameters The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions are given (i.e., reaction temperatures, times, molar ratios of reactants, solvents, pressures, etc.), other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the particular reagents or solvent used, but such conditions can be determined by one skilled in the art through routine optimization procedures. Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups, as well as conditions suitable for protecting and deprotecting particular functional groups, are well known in the art. For example, numerous protecting groups are described in T. - 100 W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein. The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). . Others can be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001) , and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). The term solvent generally refers to a solvent inert under the conditions of the reaction described together with it (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THE), - 101 dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol and the like). Unless otherwise specified, the solvents are inert organic solvents and the reactions may be carried out under an inert gas, preferably argon or nitrogen. The term q.s. means adding a quantity sufficient to achieve an established function, e.g., to bring a solution to the desired volume (i.e., 1001). In Scheme 1, A, R2, R2, R2, and Rfc are as defined herein, each , 4,4,5,5-tetramethyl1,3,2-dioxaborolane), and PG is a protecting group attached to a heteroatom. Scheme 10(-ro? h oRO^'·- - V Y . J K l· ÓN k-Yk-j· J Γ'ΥwUnprotect ° Y'Y Λ-γ. · " ·*· Yo .. ' . N y'r'~ 200 R1”’”*> 100' 300 i Ff X 500 O R~ íR-GígH R, xr’ \<N..pG100' 600 *r;;::γ Y B400 R22 - 102 In Scheme 1, the compounds of Formula I are prepared by coupling the suitably protected compound 100' with the corresponding boronic acid or ester 200 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.), followed by vulnerability. Compound 300 for use in the repair of compounds of Formula I as shown in Scheme 1 is also prepared by coupling the suitably protected compound 400 with the corresponding halo substituted compound 500 in the presence of a catalyst (e.g., palladium, nickel , copper, etc.). Compound 400 is prepared by coupling the properly protected compound 100' with the corresponding boronic acid or ester 600 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.). Various compounds of Formula 100', 200, 500 and 600 for use in the methods provided herein can be purchased from commercial sources or synthesized by known methods. In some embodiments, compound 300, where R-- is hydrogen, can be esterified to form a compound 300, where R2 is as defined herein (e.g., (CHgCHgO)jCFbCHgOCHj, alkyl Cf-.:optionally substituted with de one to three R4, cycloalkyl, or heteroaryl optionally substituted with one to three R2) through standard coupling conoitions. - 103 EXAMPLES The following examples are included to demonstrate specific modalities of exposure. Those skilled in the art should appreciate that the techniques described in the following examples represent techniques to work well in exposure practice and therefore may be considered to constitute specific modes for its practice. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made to the specific modalities set forth and still obtain the same or similar result without N·, 0 Stage 1 A OEt Stage 2 ....................................... ......·- NC' '|í ..................................... .....· Ó etfl 2- etfl 2-cyano-cyanoacetate 2-diazoacetate 2 deviate from the spirit and scope of the exhibition. Synthesis of intermediates 3, 4 and 6 (and their methyl esters 3', 4' and 6') (MeO) q f ​​10--^ KNHEstage 3 Br —·<' । etfl 4-bromo-lff-L2,3triazol- 5-carboxflate (for Me 3' ester) (McO) or I tOΛ (MeO)Q EtO-q etfl 5-(4,4,5,5-tetrametfl-L3,2dioxoborolan-2-fl)fenfl)-2 - ((2(trimetflsfl)ethoxy )m etfl ]-2H1;23-triazole-4-carboxflate (for esther Me, 6') 'SEM Stage 4 L4-bis(4,4:5ó-tetrarnetfl-l,3,2dioxaborolan-2-fljbenc eno etfl 5-bromo-2-((2(trimetflsflfl) ethoxy) metfl)-2 / f-L23triazol-4-carboxflato ( for ester Me, 4') - 104 Stage 1 To a mixture of sodium azide (150.0 g, 2.25 mol) and tetrabutylammonium bisulfate (41.9 g, 123 mmol) in water (2.3 1) a solution of triflicc anhydride (375 ml, 2.25 mol) was added slowly at 0°C. in hexane (900 mi). The resulting mixture was then stirred at 0°C for 1 h, the soluble organic material was extracted with hexane (1.81), dried over sodium hydroxide granules and decanted. Ά Ethyl 2-cyanoacetate, 1 (150.0 g, 0.8 mol) in acetonitrile (1.1 1) and pyridine (300 ml, 4.0 mol) were added to the solution. The resulting mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (1:6) to give impure ethyl 2-cyano2-diazoacetate, 2 (111 g, 99%). Stage 2 Hydrogen bromide gas was bubbled into a solution of ethyl 2-cyano-2-diazoacetate, 2 (111 g, 795 mmol) in dioxane (7 1) at 0°C for 3 h. The reaction mixture was concentrated under reduced pressure to give crude ethyl 4-bromo-1H-1,2,3triazole-5-carboxylate, 3 (125 g), which was used directly for the next step without further purification. - 105 Stage 3 To a solution of crude ethyl 4-bromo-lH-l,2,3-triazole-5-carboxylate, 3 (50 g, 227 mmol) in DMF (500 ml) was added sodium hydride (60=-, 10.1 g, 275 mmol) at 0°C and stirred for 30 min in N2 before adding 2(trimethylsilyl)ethoxymethyl chloride (40.5 g, 238 mmol) at C°C. After stirring for 1 h at 0°C, the reaction mixture was quenched with 5% aqueous lithium chloride and the product was extracted with ethyl acetate. The organic fraction was dried (MgSOz), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexane (2:5) to provide an isomeric mixture of 5-bromo-2-((2(trimethiIsilyl)ethoxy)methyl)-2H Ethyl -1,2,3-triazole-4-carboxylate (4, 30 g, 381) as colorless oil: ES / MS m / z: calculated for CcH;-BrN-NaOgSi (M+Na*) : 372.04, found: 372.15. An isomeric mixture of methyl 5-bromo-2((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4carboxylate (4') was also prepared as an oil similarly to the above procedure. from commercially available methyl 4-bromo-1H-1,2,3triazole-5-carboxylate (3') : ES / MS m / z: calculated for Ci)H:<.BrN3NaO-Si (M+Na) : 337.27, found: 336.53. - 106 Stage 4 Ά a solution of the isomeric mixture ethyl 5-bromo-2-((2(tramethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4.45 g, 129 mmol) and 1,4 -bis(4,4,5,5-tetramethyl-1,3,2dioxaborlan-2-yl)benzene (5, 85.0 g, 257 mmol) in 1,4-dioxane (800 ml) aqueous sodium carbonate 2.0 was added M (193 mi, 386 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(11) (9.45 g, 12.9 mmol). The reaction mixture was stirred under N2a atmosphere at 70°C for 4 h. After the reaction mixture was cooled to room temperature and diluted with water, the product was extracted with ethyl acetate (3 x 1 1). The organic fractions were washed with brine, dried (Na2SO...;) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (1:30) to provide an isomeric mixture of 5-(4-(4,4,5,5-tetramethyl-l, 3,2) ethyl dioxaborolan-2-yl)phenyl)-2-((2-(trimethi 1s i 1 i 1)ethoxy)methyl)2H-1,2,3-triazole-4-carboxylate (6, 25.5 g, 43í) as an oil: ES / MS m / z: calculated for C23H:.:BN;NaO = Si (M+Na) : 496.44, found: 496.45. - 107 Synthesis of Intermediary 8 Stage 1 4A-bis(4A5ó-tetramethyl-l A2dioxabor oyán-2 -fl)-1;1 '-biphenium ethi 5 - (4b(4 A 5 Atenmmethyl-1A 2 dioxaborolan-2-yl)-[l, 1 '-biphenyl-4-ñ) 2-((2-íAmetfls®etoM)methyl 1-2271A3-triazol-4 -carboxylate S Stage 1 To the isomeric mixture of ethyl 5-bromo-2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4.25 g, 71.3 mmol) and 4,4 '-bis(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1,1'-biphenyl (7.45 g, 110.8 mmol) in 1,4-dioxane (500 mi) 2.0 M aqueous Na...CCL (106 mi, 215.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (11) (5.2 g, 7.1 mmol) were added. The reaction mixture was stirred under N2a atmosphere at 70°C overnight. After the reaction mixture was cooled to room temperature and diluted with water, the product was extracted with ethyl acetate (3 x 500 ml). The organic fractions were washed with brine, dried (Na2SO2) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (1:30) to provide an isomeric mixture of 5-(4'-(4,4,5,5-tetramethyl-1 ,3,2dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl) - ethyl 108 ethoxy)methyl)-2Η-1,2,3-triazole-4-carboxylate (8, 11.5 g, 29%) as an oil: ES / MS m / z: calculated for CcoHj ;BN.<O = Yes (M+H): 550.29, found: 550.45. Synthesis of Intermediary 10 C.. .Of t Stage 1 / / AND / / \ .................................................. .......................► Br—(zÓ—(zy—<\ i o / \ / ι,,Ν r— 'NSEM pr__ / / __pr \— / ethyl 5-(4'-bromo-[l:l'-bifettil]-4-yl}-2 1,4-dibromobenzene ((2-(trimetflSffil)e^ g l:23-tnazol-4-carboxylate Stage 1 To the isomeric mixture of 5-(4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)2H-1 Ethyl 2,3-triazole-4-carboxylate (6,358 mg, 0.76 mmol) and 1,4-dibromobenzene (9,178 mg, 0.76 mmol) in 1,4dioxane (3 ml) added tetrakis(triphenylphosphine) palladium (0) (87 mg, 0.076 mmol) and Na2CO; aqueous 2.0 M (1.13 mi) . After purging the mixture with argon gas for 10 min, the reaction mixture was stirred at 110°C for 40 min. After the reaction mixture was cooled to room temperature and diluted with saturated NaHCOj, the product was extracted with ethyl acetate, washed, dried (MgSO.;) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 1-100¾ ethyl acetate in hexane to provide an isomeric mixture of 5-(4'-bromo-[1,1'-biphenyl]-4-yl) Ethyl -2-((2- 10 9 (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (10, 380 mg, 83%) as an oil. Synthesis of Intermediaries 11 and 12 O EtO-y Stage 1 Br—q. i m NNPMB ethyl 5-bromo-2-(4methoxybencfl)227-1.2.3-triazole-4carboxyate 11 Stage 1 The isomeric mixture of 1,2,3-triazole-4-carboxylate prepared as a process oil for the mixture ethyl 2-(4-methoxybenzyB-5-(4(4A5p-tetramethyl-l;3:2dioxaborolan-2-yl)phenyl} -227- L2 dtriazole-4-carboxylate 12 5-bromo-2-(4-methoxybenzyl)-2Hetyl (11.27 g, 49a) is similar to that of the isomeric 5-bromo-2-((2(trimethylsilyl)ethoxy)methyl)-2H-l, Ethyl 2,3-triazol-4-carboxylate (3) using para-methoxybenzyl chloride instead of 2-(trimethylsilyl)ethoxymethyl chloride, except that the reaction was carried out at room temperature for 8 h: ES / MS m / z: calculated for CmH;jBrN2NaO - (M+H) : 362.01, found: 362.05. Stage 2 An isomeric mixture of 2-(4-methoxybenzyl)-5-(4(4,4,5,5-tetramethyl-l,3,2-dioxaborlan-2-yl)phenyl)-2H-1,2,3triazole- Ethyl 4-carboxylate (12) was prepared as an oil in a similar manner to the procedure for the mixture - 110 isomeric of 5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)phenyl)-2 - ((2-(trimethylsilyl)ethoxy)methyl)-2H-1 ethyl ,2,3-triazol4-carboxylate (6). Synthesis of Intermediary 13 or. OEt _ 'T —b-rí 1z%— / 'm-N / U ' ' --- '' PMB ethyl 2-(4-methoxybenzi)-5-(4'(4A5;5-tetramethyl-l:3:2dioxabor olan-2 -Π)- [ 1.1 ' -biphenyl] -4ü)-2 / f-1.2:3-triazole-4-carboxyate 13 Stage 1 An isomeric mixture of 2-(4-methoxybenzyl)-5-(4'(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]4 -yl)-2H-1,2,3-triazole-4-carboxylate ethyl (13, 10.5 g, 26cs) was prepared as an oil in a manner similar to that of the procedure for the isomeric mixture of 5-(4'-(4,4,5,5tetramethi 1-1,3,2-dioxaborolan-2-yl)-[1 Ethyl ,1'-biphenyl]-4-yl)-2((2-(trimethi1silyl)ethoxy)methi 1)-2H-1,2,3-triazole-4carboxylate (8) : ES / MS m / z: calculated for CEH-BíHl (M+H): 540.27, found: 540.55. - 111 Synthesis of Intermediaries 15 and 16 MeOx^O Stage 1Br-X''xNH methyl 4-bromol / / -pyrazole-5car sweet potato MeO...<:O | Stage Br EE*,'' ................i, Emethyl 4-bromo-1-((2(trimethylsiEl)ethoxy)methyl)- l / f-pyrazole-5carboxylate methyl 4-(4:4;5,5-tetramethyl1 X2-dioxaborolan-2-yl)phenyl}-1 ((2-(trimethylsilyl)ethoxy.)methyl)h¥-pyrazole-5-carboxylate Stage 1 Methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methi 1)-1Hpyrazole-5-carboxylate (15, 5.1 g, 591) was prepared as an oil from 4-bromo-lrr-pyrazole - Methyl 5-carboxylate (14, 5.0 g, 24.5 mmol) similarly to the procedure for the preparation of intermediate 4::H NMR (400 MHz, Chloroform-α') δ 7.56 (s, 1H), 5.81 ( s, 2H), 3.96 (s, 3H), 3.54 (t, J = 8.0 Hz, 2H), 0.88 (t, J = 8.0 Hz, 2H), 0.04 (s, 9H). ES / MS m / z: calculated for CXzBrNiO-Si (M+H): 335.04, no molecular mass detected. Stage 2 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-5carboxylate was prepared of methyl (16, 5.83 g, 381) as an oil in a manner similar to that of the procedure for the preparation of 6 using potassium carbonate instead of sodium carbonate, except that the reaction was carried out at 110°C overnight: :H NMR (400 MHz, Chlorof ormo-d) δ 7.82 (d, J = 8.4 Hz, 112 2Η), 7.60 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 5.85 (s, 2H), 3.77 (s, 3H), 3.60 (t, J = 7.2 Hz, 2H), 1.32 ( s, 12H), 0.89 (t, J = 7.2 Hz, 2H), 0.04 (s, 9H). ES / MS m / z: calculated for C?íHmBN / OgSi (M+H): 459.25, no molecular mass detected. Synthesis of Intermediate 18 í ti)ethyl 3-bromo-127pyr azole-4- c arboxylate 17 ethyl 3 -bromo-1-((2 (trimethylsilyl)ethoxy,)methyl) -lrf-poirazol-4-carbo?tylate Ethyl 3-bromo-lH-pyrazole-4-carboxylate (18,511 mg, 96%) was prepared as an oil from ethyl 3-bromo-lHpyrazole-4-carboxylate (17,335 mg, 1.53 mmol) in a manner similar to that of the procedure for the preparation of intermediate 15 as a mixture of two regioisomers: ES / MS m / z: calculated for Cm-HsiBrNíO-Si (M+H): 349.06, found: 348.46. Intermediary Synthesis 20 SE M methyl 4-bromo-\Himidazol- 5 - c arboxylate 19 methyl 4-bromo-1-((2(trimethylsilyl)ethoxy)methyl) - 12f-imidazole-5-carboxylate - 113 Methyl 4-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)lH-imidazole-5-carboxylate (20,690 mg, 77%) was prepared as an oil from 4-bromo-lH -imidazole-methyl 5-carboxylate (19, 335 mg, 1.53 mmol) similarly to the procedure for the preparation of intermediate 15 as a mixture of two-region isomers: ES / MS m / z: calculated for CisHsüBrNjOu. Yes (M+H) : 335.04, found: 334.86. Representative Procedure of the Suzuki Reaction .0 MeO γζnΛν □ Γ —YX In'Nsem Suzuki reaction 4:4:5,5 - tetr amethyl- 2 - (or toEl)-13,2 -dioxaborolane ίmetí 5-bromo-2-((2(trimethylsilyl)ethoxy) methyl)-2 / / -l:23ο MeO γ / Y “\ NSEMmethyl 5-(o-tolyl')-2-((2(trimethylsffl)eto3)metY 2H-1,2,3-triazol-4-c arboxylate triazole-4-c arboxylate 1S In a 5 ml microwave vial, the isomeric mixture of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2B1,2,3-triazole~4-carboxylate (4', 46 mg, 0.14 mmol), 4, 4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxaborolane (17, 20 mg, 0.15 mmol), tetrak.is (triphenylphosphine) palladium (0) (16 mg, 0.014 mmol), 2 N potassium carbonate (0.14 mi) and dioxane (2 mi). After purging with argon gas for 5 minutes, the resulting mixture was stirred at 110°C for 1 hour. After cooling, the reaction mixture is diluted with saturated NaHCO3 before extracting the product with ethyl acetate, dried - 114 (MgSOJ, was concentrated and purified by column chromatography on silica gel eluting with ethyl acetate in hexane to obtain 5-(o-tolyl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H- 1, Methyl 2,3-triazole-4-carboxylate (18) : ES / MS m / z: calculated for C:-H..,N;O;:Si (M+H) : 348.17, found: 347.58. Representative SEM deprotection procedure by HC1 SEM Deprotection (HCI) M methyl 5-(o-toll)-2-((2(trimethylsilyl)ethoxy'taiethyl) 1H-1,23-triazol-4-crboxylate O MeO NH methyl 4-(o-tolyl)- 1H-1,23triazol- 5 - c arboxylate 1S To a solution of methyl 5-(o-tolyl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (18.49 mg, 0.14 mmol) in tetrahydrofuran (1 ml) and methanol (1 ml) 3 N HCl (0.21 ml) was added and the resulting mixture was stirred at 80°C for 2 h and then at 50°C overnight. The resulting reaction mixture was concentrated to obtain crude methyl 4-(o-tolyl)-1H-1,2,3-triazole-5carboxylate (19): ES / MS m / z: calculated for ΑΜΑ (M-H): 216.08, found: 216.15 - 115 Representative SEM deprotection procedure by TBAF SEM deprotection by TBAF ethyl 4-(4'-(morphbnüosuttbml)-[l:1'-biphenyl] —lil)-1 -((2-tametüsiin)etoM)methyl)-1 / / -1 _.2:3 triazole-5-c arboxylate ethyl 4-(4'-motfolinosulfonyl)[ 1:Γ-biphenyl]-4-yl)-1 Η-1,2;3 triazole- 5-c arb oxylate 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4yl)-l-((2-(trimethiIsilyl)ethoxy)methyl)-1H-1,2,3-triazole-5carboxylate was dissolved of ethyl (20) in TBAF IN (5 eq.) and the solution was heated to 60°C for 3 hours. After cooling, the reaction mixture was diluted with saturated NaHCCh before extracting the product with ethyl acetate, dried (MgSO.i), concentrated and purified by column chromatography on silica gel eluting with ethyl acetate in hexane to obtain ethyl 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3 triazole-5-carboxylate (21): ES / MS m / z: calculated for C21H23N4O5 (M+H): 443.49, found: 443.16. Representative procedure for deprotection of PMB by TFA Deprotection ___PMB TFA ethyl l-(4-methoxybenzyl)-4-(4,-(5-methyl13,4-thiadiazol-2-yl)-[l;1'-biphenyl]-4 -yl)1:2,3-triazole -5-carboxylate ethyl 4-(4'-(5-methyl-l:3:4thiadiazol-2-yl)-[ld'biphenyl]-4-yl)-1 / 7-1:2;3triazol-5 - c arboxylate - 116 1-(4-Methoxybenzyl)-4-(4'-(5-methyl-1, 3, 4thiadiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H- was dissolved ethyl 1,2,3-triazole-5carboxylate (22) in 1 ml of TEA and the mixture was heated at 40°C for 80 minutes. After cooling, the reaction mixture was concentrated and diluted with saturated NaHCOg before the product was extracted with ethyl acetate, dried (MgSCs), concentrated and purified by column chromatography on silica gel eluting with ethyl acetate. in hexane and 10% methanol in ethyl acetate to obtain 4-(4'-(5-methyl-1,3,4-thiadiazol-2-yl) [1, 1'-biphenyl]-4-yl)- 1 ethyl Η-1,2,3-1riazole-5-carboxylate (23) : ES / MS m / z : calculated for C; ;H; 3N2O2S (M+H) : 392.45, found: 392.16. Representative Ester Hydrolysis ProcedureΜθ°γΡΗθγ° NH Hydrolysis „ y--y XNHcx...... \ \ methyl 4-(o-toH)- 1H-1,2,3- 4-(o-tolyI)- 1H-1,2,3triazole-5-carboxylate triazole-5-carboxylic acid 24 To crude methyl 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylate (21) in tetrahydrof urane (1 ml) and methanol (1 ml) 2 N NaOH (1 ml) was added. and the resulting mixture was stirred at 80°C for 2h. After the reaction mixture was cooled and neutralized with HC1 IN, the solids were filtered and the solids were purified by HPLC and freeze-dried to - 117 get acid 4-(o-tolyl)-1H-1, 2,3-triazole-5-carboxylic (24): ES / MS m / z: ES / MS m / z: calculated for CrENO: (M-H): 202.08, found : 201.97. Representative SEM Protection Procedure of N-H Heterocyclic Wa · semn-n 4-bromo-l / / - 4-bromo-2-((2l:23-triazole (trimetüsilñ)ethoxy) * methyl)- 1H-1,2,3-triazole A solution of 5-bromo-lH-l,2,3-triazole (25,996.3 mg, 6,733 mmol) in DMF (20 ml) was stirred in an ice bath such as 60% sodium hydride in mineral oil ( 410 mg, 10.25 mmol) added in portions. After 30 min, (2(chloromethoxy)ethyl)trimethylsilane (1.25 ml, 7.063 mmol) was added to the reaction mixture and the resulting mixture was stirred in an ice bath for 1 h followed by room temperature overnight. After 19 h, the reaction mixture was diluted with saturated aqueous NHrCl solution (-100 ml) and ethyl acetate (-100 ml) and the two layers were separated. After extracting the aqueous fraction with ethyl acetate (x 1), the organic fractions were washed with water (-150 ml x 1), combined, dried (MgSOz), and concentrated. The residual oil was purified by column chromatography on silica gel eluting with 0-30% ethyl acetate in hexane to obtain 726.0 mg (39%) of 4-bromo-2-( (2 118 (trimethylsilyl)ethoxy)methi 1)-2Η-1, 2, 3-triazole (26): -H NMR (400 MHz, Chlorophorin-d) δ 7.63 (s, 1H), 5.63 (s, 2H), 3.72 3.60 (m, 2H), 0.99 - 0.86 (m, 2H), -0.02 (s, 9H). ES / MS m / z: calculated for CirHrjBrNrOiSi (M=H): 335.04, no molecular mass detected. Representative Procedure for the Preparation of Boronate Ester from Aryl Bromide 444'4'5:5:5',5'-octamet32:2‘-bi(L3:2-dioxaborolane) Pd(dppf)CI2KOAc 4-bromo-2-((2dioxane (trimethyls33)ethoxy) metü)-2íf-1;2;3-triazole 26 4-(4:4=5..5-tetramethyl-1=352 dioxaborolan -2-3)-2- ((2 (trimet3s33)ethoxy)methyl) -2H- 1,2,3-triazole A mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (26, 359 mg, 1.29 mmol), bis(pinacolato)diboron (27, 362 mg, 1.43 mmol), dichloro 1,1'bis (diphenylphosphino) ferroce.no palladium (II) dichloromethane (116 mg, 0.14 mmol) and potassium acetate (384 mg, 3.92 mmol) in 1,4-dioxane (6 mi) in a 20 ml pW vial was purged with Ar gas for 15 min before heating the mixture to 110°C for 1 h. The reaction mixture was diluted with ethyl acetate (-60 ml), treated with Na2SCL and filtered. The filtrate was concentrated and the residue was purified by column chromatography in - 119 silica gel eluting with 0-401 ethyl acetate in hexane to obtain 282 mg (671) of 4 -(4,4,5,5-tetramethi 11,3,2-dioxaborolan-2-yl)-2 -((2-(trimethylsilyl)ethoxy)methyl)2H-1,2,3-triazole (28)::H NMR (400 MHz, Chloroform-d) δ 7.99 (s, 1H), 5.74 (s, 2H) , 3.70 - 3.56 (m, 2H) , 1.37 (s, 12H) , 0.96 - 0.85 (m, 2H) , -0.04 (s, 9H) . The following compounds were prepared similarly to the representative procedures of the Suzuki reaction, SEM or PMB deprotections described above, and ester hydrolysis using the aforementioned bromide intermediates, 4 (or 4'), 10 or 15 with commercially available boronates, or using the aforementioned bchronate intermediates, 6 (or 6'), 8, 12, 13 and 16 with commercially available bromides: Example 1: Ethyl 4-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole5-carboxylate -H NMR (400 MHz, Chloroform-d) δ / .9o (dd, J = 8.0, o . / Hz, 2H), 7.65 (dd, J = 8.2, 5.5 7.43 (dd, J = 8.5, 1 . 9 Hz, 2H) , 7.2, 4.8 Hz, 2H), 1.41 (t, J calculated for CmH^ClN-CL (M-H) : Hz, 2H), 7.60 - 7.49 (m, 2H), 5.90 (s, 1H), 4.45 (qd, J = = 7.1 Hz, 3H). ES / MS m / z: 326.08, found: 326.31. - 120 Example 2: ethyl 4-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylate,O EtO... % / ΠNH H?N -=y / N'N -H NMR (400 MHz, Methanol-at) δ 7.99 - 7.91 (m, 2H), 7.8S (d, J = 8.1 Hz, 2H), 7.72 (dd, J = 8.4, 1.8 Hz, 4H), 4.38 ( q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). ES / MS m / z: calculated for CisHi-tRO- (M+H): 337.13, found: 337.03. Example 3: 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylic acid :H NMR (400 MHz, Methanol-at) δ 7.42 - 7.31 (m, 2H), 7.31 7.21 (m, 2H), 2.17 (s, 3H). ES / MS m / z: calculated for CioHioNjOz (M+H) : 204.08, found: 347.58. Example 4: 4-(m-tolyl)-1H-1,2,3-triazole-5-carboxylic acid O HO—\___ NH — N'NLH NMR (400 MHz, Methanol-d) δ 7.65 - 7.55 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 2.40 (s, 3H). ES / MS m / z: calculated for CcE-NA (M+H): 204.20, found: 203.92. - 121 Example 5: 4-(p-tolyl)-1H-1,2,3-triazole-5-carboxylic acid __ + NH \=- ^N^:H NMR (400 MHz, Methanol-α';) δ 7.81 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 2.36 (s, 3H). ES / MS m / z: calculated for C2H:oN302 (M+H): 204.20, found: 203.92. Example 6: 4-(3-ethylphenyl)-1H-1,2,3-triazole-5carboxylic acid EITHER HO— N.H. N'N - H NMR (400 MHz, Methanol-dJ δ 7.68 - 7.56 (m, 2H), 7.42 - 7.28 (m, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). ES / MS m / z: calculated for C-HmlMO. (M+H): 218.09, found: 217.97 Example 7: 4-(2-fluorophenyl)-1H-1,2,3-triazole-5carboxylic acid F - H NMR (400 MHz, Methanol-dd: δ 7.61 - 7.45 (m, 2H), 7.32 - 7.17 (m, 2H) . ES / MS m / z: calculated for C5H-FNO2 (M+H) : 208.04, found: 207.94. - 122 Example 8: 4-(3-fluorophenyl)-1H-1,2,3-triazole-5carboxylic acid EITHER - H NMR (400 MHz, Methanol-d,) δ 7.74 - 7.66 (m, 2H), 7.46 (td, J = 8.1, 5.9 Hz, 1H), 7.16 (td, J = 8.6, 2.5 Hz, 1H). ES / MS m / z: calculated for CRH-FlROa (M+H) : 208.04, found: 207.91. Example 9: 4-(4-chlorophenyl)-1H-1,2,3-triazole-5carboxylic acid - H NMR (400 MHz, Methanol-d;) : δ 7.89 - 7.81 (m, 2H), 7.51 - 7.42 (m, 2H) . ES / MS m / z: calculated for C / H-ClNsO.: (M+H) : 224.01, found: 223.94. Example 10: 4-(3-methoxyphenyl)-1H-1,2,3-triazole-5carboxylic acid EITHER -wh ho^- LH NMR (400 MHz, Methanol-dJ δ 7.45 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 7.1 Hz, 2H), 7.06 - 6.98 (m, 1H), 3.84 (s, 3H). - 123 ZS / MS m / z: calculated (M-H): 218.20, 217.98. Example 11: acid 4-(4-methoxyphenyl)-1H-1,2,3-triazole-5carboxylic NH n'n -H NMR (400 MHz, Methanol-d·;) δ 7.78 (d, J = 8.4 Hz, 2H), 7.06 - 6.98 (m, 2H), 3.85 (s, 3H). ES / MS m / z: calculated for GHcHicNO· (M+H): 220.06, found: 219.93. Example 12: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid N.H. N:H NMR (4 00 MHz, Methanol-d;) δ 8.34 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.78 (dt, J = 7.8, 1.4 Hz, 1H), 7.64 ( t, J = 7.9 Hz, 1H). ES / MS m / z: calculated for CrH-MO; (M+H): 215.05, found: 214.96. Example 13: 4-(3-(trifluoromethyl)phenyl)-1H-1,2,3triazole-5-carboxylic acid - 124 - -H NMR (400 MHz, Methanol-d,·) δ 8.24 (t, J = 1.7 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H). ES / MS m / z: calculated for Czmi; (M+H) : 258.07, found: 257.97 Example 14: 4-(3-(tert-butyl)phenyl)-1H-1,2,3-triazole-5carboxylic acid :H NMR (400 MHz, Methanol-d;) δ 7.90 (t, J = 1.9 Hz, 1H), 7.59 (dt, J = 7.6, 1.4 Hz, 1H), 7.51 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 1.36 (s, 9H). ES / MS m / z: calculated for C; ;H;lN;O; (M+H) : 246.12, found: 246.04. Example 15: 4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazole-5carboxylic acid EITHER HO-—, \ l~c / NH:H NMR (400 MHz, Methanol-d;): δ 7.78 - 7.70 (m, 2H), 7.55 7.47 (m, 2H), 1.36 (s, 9H). ES / MS m / z: calculated for C;;H>;N3O;_ (M+H) : 246.12, found: 246.01. Example 16: 4-(3-(trifluoromethoxy)phenyl)-1H-1,2,3triazole-5-carboxylic acid - 125 O f3coho' \___ NH V_ ' N:H NMR (400 MHz, Methanol-d-;) δ 7.89 (d, J = 7.8 Hz, 2H), 7.55 (td, J = 7.9, 7.4, 1.0 Hz, 1H), 7.39 - 7.31 (m , 1 HOUR). ES / MS m / z: calculated for C_;H--FN3O3(M+H) : 274.04, found: 273.95. Example 17: 5-(3-chloro-4-fluorophenyl)-1-methyl-lH-l,2,3triazole-4-carboxylic acid EITHER ClHO\P__% = y*:H NMR (400 MHz, Chloroform-d) δ 8.00 (dd, J = 7.1, 2.2 Hz, 1H), 7.83 (ddd, J = 8.7, 4.6, 2.2 Hz, 1H) , 7.21 (t, J = 8.7 Hz, 1H), 4.32 (s, 3H). ES / MS m / z: calculated for C::H:.C1FN3O2 (M-H) : 254.63, found: 254.04. Example 18: 4-(3-chloro-4-fluorophenyl)-lH-pyrazole-3carboxylic acid EITHER ClΗΟγ / 7-¾ N F —< \i1\_ / a-NH -H NMR (400 MHz, Methanol-d-) δ 7.80 (s, 1H), 7.71 (dd, J = 7.2, 2.2 Hz, 1H), 7.50 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.22 (dd, J = 9.2, 8.6 Hz, 1H) . ES / MS m / z: calculated for C:;H-C1FN2O2 (M+H) : 241.01, found: 240.88. - 126 Example 19: 4-(3,4-dichlorophenyl)-1H-1,2,3-triazole-5carboxylic acid -H NMR (400 MHz, Methanol-d,·) δ 8.13 (d, J = 2.1 Hz, 1H) , 7.85 (dd, J = 8.4, 2.1 Hz, 1H) , 7.61 (d, J = 8.5 Hz, 1H) ). ES / MS m / z: calculated for CyHzClzNjOz (M+H) : 257.98, found: 257.95. Example 20: 4-(3,5-dichlorophenyl)-1H-1,2,3-triazole-5carboxylic acid O Cl HO W nN Cl':H NMR (400 MHz, Methanol-dz) δ 7.95 (s, 2H), 7.52 (s, 1H). ES / MS m / z: calculated for CyH.ClzNzOz (M+H) : 257.98, found: 257.92. Example 21: 4-(3,5-dichlorophenyl)-lH-pyrazole-3carboxylic acid / CL -H NMR (400 MHz, DMSO-dd: δ 8.00 (s, 1H), 7.68 (s, 2H), 7.58 - 7.44 (m, 1H) . ES / MS m / z: calculated for ΟζζΗζΕΙζΝζΟζ (Μ- Η) : 254.98, found: 255.02. - 127 Example 22: 4-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole5-carboxylic acid EITHER ΗΟ-γ \ Cl F -H NMR (400 MHz, Methanol-d-;) δ 7.59 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H), 7.50 (ddd, J = 7.9, 6.3, 1.7 Hz, 1H), 7.27 (td, J = 7.9, 1.2 Hz, 1H). ES / MS m / z: calculated for C;H / C1 FN;O2 (M+H): 242.01, found: 241.94. Example 23: 5-(4-bromo-3-chlorophenyl)-1H-1,2,3-triazole4-carboxylic acid CL Br -H NMR (400 MHz, Methanol-d.;): δ 8.04 (s, 1H), 1.70 - 7.65 (m, 2H). ES / MS m / z: calculated for CnH^BrClNOi (M-H) : 299.93, found: 300.02. Example 24: 4-(3,5-dichloro-4-fluorophenyl)-1H-1,2,3triazole-5-carboxylic acid EITHER Cl HO-d \____ \ f- / a_^ W n^nciz - H NMR (400 MHz, Methanol-d-;) δ 8.09 (d, J = 6.4 Hz, 2H). ES / MS m / z: calculated for C9H.1CI2FN-O¿ (M+H) : 275.97, found: 275.96. - 128 Example 25: 4-(3-phenoxyphenyl)-1H-1,2,3-triazole-5carboxylic acid :H NMR (408 MHz, Methanol-cd) δ 7.57 (ddd, J = 7.7, 1.6, 1.0 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.40 - 7.31 (m, 2H), 7.18 7.08 (m , 1H) , 7.08 - 6.99 (m, 3H) . ES / MS m / z: calculated for CiíHu-NsCu (M+H) : 282.08, found: 282.01. Example 26: 4-(4-phenoxyphenyl)-1H-1,2,3-triazole-5carboxylic acid - H NMR (400 MHz, Methanol-ad) δ 7.83 (d, J = 8.4 Hz, 2H), 7.44 - 7.34 (m, 2H), 7.21 - 7.12 (m, 1H), 7.10 - 7.01 (m, 4H) . ES / MS m / z: calculated for CIgH—NbOj (M+H) : 282.08, found: 281.98. Example 27: 4-([1,1'-biphenyl]-3-yl)-1H-1,2,3-triazole-5carboxylic acid - 12 9 - - H NMR (400 MHz, Methanol-d;) δ 8.03 (t, J = 1.8 Hz, 1H), 7.71 (dt, J = 7.7, 1.4 Hz, 1H), 7.67 - 7.54 (m, 3H), 7.46 ( t, J = 7.8 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.31 - 7.22 (m, 1H). ES / MS m / z: calculated for CcHcNA (M+H): 266.09, found: 266.01. Example 28: 4-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5carboxylic acid :H NMR (400 MHz, Methanol-d-) δ 7.92 (d, J = 8.0 Hz, 2H), 7.77 - 7.64 (m, 4H), 7.51 - 7.41 (m, 2H), 7.41 - +.32 (m , 1 HOUR) . ES / MS m / z: calculated for CvHmN+O: (M+H) : 266.09, found: 265.96. Example 29: 4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)1H-1,2,3-triazole-5-carboxylic acid - H NMR (400 MHz, Methanol-d,·) δ 7.79 (dd, J = 1.7, 0.5 Hz, 1H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.29 (d, J = 8.4 Hz , 1 HOUR) . ES / MS m / z: calculated for Cl ¿HgCF-N >0.: (M+H) : 270.02, found: 269.97. Example 30: 4-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3 triazole-5-carboxylic acid - 130 - 2H NMR (400 MHz, Methanol-d;) δ 7.35 (d, J = 1.7 Hz, 2H), 6.95 - 6.86 (m, 1H), 6.02 (s, 2H). ES / MS m / z: calculated for CiqH.NO; (M-H): 232.04, found: 232.00. Example 31: 4-(4-(2,2-difluorobenzo[d][1,3]dioxol-5yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid - H NMR (400 MHz, Methanol-d;) δ 7.46 - 7.3b (m, 3H), / .32 (dt, J = 8.4, 1.6 Hz, 1H), 7.19 (dd, J = 8.4, 1.3 Hz, 1H), 6.89 - 6.81 (m, 2H). ES / MS m / z: Calculated for C —H-Ed / tO! (Μ- Η) = 344.06; found 344.04. Example 32: 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H1,2,3-triazole-5-carboxylic acid :H NMR (400 MHz, Methanol-d,) δ 7.39 (s, 1H), 7.31 (d, J = 7.1 Hz, 1H), 6.90 (d, J - 8.5 Hz, 1H), 4.32 - 4.24 (s, 4H). ES / MS m / z: calculated for CcHuNG? (M+H) : 248.06, found: 248.00. - 131 Example 33: 4-(naphthalen-2-yl)-1H-1,2,3-triazole-5carboxylic acid - H NMR (400 MHz, Methanol-d-;): δ 8.39 (s, 1H), 7.98 - 7.86 (m, 4H), 7.59 - 7.49 (m, 2H). ES / MS m / z: calculated for C-HICIFNjO; (M+H): 242.01, found: 239.97. Example 34: 4-(pyridin-3-yl)-1H-1,2,3-triazole-5carboxylic acid HO-^° \ p 'NH N“ NN:H NMR (400 MHz, Methanol-da) δ 9.61 - 9.53 (m, 1H), 9.24 (dt, J = 8.2, 1.7 Hz, 1H) , 8.89 (dt, J = 5.7, 1.2 Hz, 1H ), 8.18 (ddd, J = 8.2, 5.8, 0.8 Hz, 1H). ES / MS m / z: calculated for CsH-NgO; (M+H): 191.05, found: 191.01. Example 35: 4-(pyridin-3-yl)-lH-pyrazole-3-carboxylic acid Or HO-. . + -N ·-------------' I -H NMR (400 MHz, Methanol-d-·) δ 9.40 (d, J = 1.9 Hz, 1H), 9.00 (ddd, J = 8.2, 2.0, 1.5 Hz, 1H), 8.79 (ddd, J = 5.6, 1.4, 0.7 Hz, 1H), 8.35 (s, 1H), 8.03 (ddd, J = 8.2, 5.7, 0.8 Hz, 1H). ES / MS m / z: calculated for C-HcN / Cp (M-H): 190.05, found: 190.02. Example 36: 4-(quinolin-7-yl)-1H-1,2,3-triazole-5carboxylic acid :H NMR (400 MHz, DMSO-d¿) δ 9.05 - 8.98 (m, 1H), 8.62 8.52 (m, 1H), 8.11 (d, J = 11.3 Hz, 1H), 7.69 - 7.48 (m, 4H) . ES / MS m / z: calculated for C2-H-.NcC+ (M+H) : 241.06, found: 241.07. Example 37: 4-(isoquinolin-7-yl)-1H-1,2,3-triazole-5carboxylic acid HO^ :H NMR (400 MHz, Methanol-d,) δ 9.80 (s, 1H), 9.11 (s, 1H), 8.74 (d, J = 9.3 Hz, 1H), 8.60 (d, J = 6.6 Hz, 1H), 8.47 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H) . ES / MS m / z: calculated for C:cH¿N3O2 (M+H): 241.06, found: 241.05. Example 38: 4-(6-phenylnaphthalen-2-yl)-1H-1,2,3-triazole acid 5-carboxylic - 133 - :H NMR (400 MHz, Methanol-d;) δ 8.43 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 7.89 - 7.81 ( m, 1H) , 7.81 - 7.74 (m, 2H) , 7.49 (t, J = 7.7 Hz, 2H) , 7.43 7.34 (m, 1H) . ES / MS m / z: calculated for Cr;.H — NsO¿ (M+H) : 316.10, found: 316.00. Example 39: 4-(3-chloroisoquinolin-7-yl)-1H-1,2,3triazole-5-carboxylic acid O NH0Y NH -H NMR (400 MHz, Methanol-dz) δ 9.17 (s, 1H), 8.70 (s, 1H), 8.29 (dd, J = 8.6, 1.7 Hz, 1H), 8.12 - 7.86 (m, 2H). ES / MS m / z: Calculated for CvH-ClN.;Cr (M+H) = 275.03; Found 275.05. Example 40: 4-(3-methoxyisoquinolin-7-yl)-1H-1,2,3triazole-5-carboxylic acid EITHER N ΙΟγ / F nh \= / Vn - 134 -2H NMR (400 MHz, Methanol-αΐ) δ 9.06 (d, J = 0.9 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.12 (dd, J = 8.7, 1.9 Hz, 1H), 7.94 id, J = 8.8 Hz, 1H), 7.19 (s, 1H), 4.04 (s, 3H). Example 41: 4-(3-phenylisoquinolin-7-yl)-1H-1,2,3triazole-5-carboxylic acid O—NHOA At t ' 1 NH2H NMR (400 MHz, Methanol-d;) δ 9.55 (s, 1H), 8.86 (s, 1H), 8.45 (d, J = 15.6 Hz, 2H), 8.20 (d, J = 8.5 Hz , 1H), 8.07 (d, J = 7.7 Hz, 2H), 7.64 - 7.51 (m, 3H). ES / MS m / z: Calculated for C23H1A4O2 (M+H) = 317.10; Found 317.09. Example 42: 4-(4-(naphthalen-l-yl)phenyl)-1H-1,2,3triazole-5-carboxylic acid x O 2H NMR (400 MHz, Methanol-αΐ) δ 8.02 - 7.85 (m, 5H), 7.61 - 7.40 (m, 6H) . ES / MS m / z: Calculated for C_ ?ΗΑΑ (M+H) 316.11; Found 316.03. Example 43: 4-(4-(pyridin-2-yl)phenyl)-1H-1,2,3-triazole5-carboxylic acid O HO^1 / d NH NNN - 135:H NMR (400 MHz, DMSO-dr) δ 8.69 (dt, J = 4.7, 1.5 Hz, 1H), 8.19 (d, J = 12.8 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H ), 7.90 (td, J = 7.7, 1.9 Hz, 3H), 7.38 (dd, J = 7.6, 4.9 Hz, 1H). ES / MS m / z: calculated for Ci4HmN.;0z (M+H) : 267.08, found: 267.10. Example 44: 4-(4-(pyridin-3-yl)phenyl)-lH-l,2,3-triazole5-carboxylic acid Or HO—, t. NH N 'NN7H NMR (400 MHz, Methanol-d;) δ 9.17 (d, J = 2.1 Hz, 1H), 8.88 - 8.76 (m, 2H), 8.11 (d, J = 8.4 Hz, 2H), 8.06 ( dd, J = 8.2, 5.6 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H). ES / MS m / z: calculated for CiíHmN^Or (M+H): 267.09, found: 267.04. Example 45: 4-(4-(naphthalen-2-yl)phenyl)-1H-1,2,3triazole-5-carboxylic acid -H NMR (400 MHz, DMSO-dd δ 8.31 (s, 1H), 8.09 - 7.99 (m, 2H), 7.93 (tt, J = 8.6, 4.4 Hz, 6H), 7.54 (tt, J - 6.9, 5.4 Hz, 2H).ES / MS m / z: calculated for Cl-HvNO: (M-H): 314.10, found: 314.14. Example 46: 4-(4-(6-chloronaphthalen-2-yl)phenyl)-1H-1,2,3triazole-5-carboxylic acid 136 - -H NMR (400 MHz, DMSO-cú) δ 8.31 (s, 1H), 8.07 - 7.91 (m, 6H), 7.89 (s, 2H), 7.51 (dd, J = 8.7, 2.2 Hz, 1H). ES / MS m / z: calculated for CvHljCINjCu (M-H): 350.06, found: 350.00. Example 47: 4-(4-(isoquinolin-6-yl)phenyl)-1H-1,2,3triazole-5-carboxylic acid -H NMR (400 MHz, Methanol-d,·) δ 9.51 (s, 1H), 8.59 (o, 6.0 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 4H). ES / MS m / z: calculated for C14H1-.N4O2 (M+H) : 267.09, found: 267.04. Example 48: 4-(4-(1-methyl-lH-benzo[d]imidazol-5yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid :H NMR (400 MHz, DMSO-di) δ 8.36 (s, 1H), 8.00 (s, 1H), 7.85 (t, J = 15.5 Hz, 4H), 7.70 (s, 2H), 3.88 (s, 3H). ES / MS m / z: calculated for CmHnjNsCt (M+H): 320.11, found: 320.14. - 137 Example 49: 4-(4'-chloro-[l,l'-biphenyl]-4-yl)-lH-l,2,3triazole-5-carboxylic acid - H NMR (400 MHz, Methanol-d,·) δ 7.94 (d, J = 8.0 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.71 - 7.65 (m, 2H), 7.65 - 7.55 (m, 1H), 7.61-7.58(m, 1H), 7.55 - 7.42 (m, 2H). ES / MS m / z: calculated for CilHuCIN.^O; (M+H) : 300.05, found: 299.97. Example 50: 4-(3'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid CL HO-, ° N.H. - H NMR (400 MHz, Methanol-d,·) δ 8.02 - 7.90 (m, 2H), 7.76 - 7.66 (m, 3H), 7.65 - 7.59 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.38 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H). ES / MS m / z: calculated for Ci-HuClN-O, (M+H): 300.05, found: 299.98. Example 51: 4-(4'-bromo-[l,l'-biphenyl]-4-yl)-lH-l,2,3-triazole-5-carboxylic acid - 138 - - H NMR (400 MHz, DMSO-dd δ 7.88 (s, 2H), 7.77 (d, J = 7.9 Hz, 2H), 7.72 7.60 (m, 4H). ES / MS m / z: calculated for C —HziBrNzO / (M+H): 344.00, found: 344.06. Example 52: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid EITHER Br.HO-f v NH - H NMR (400 MHz, DMSO-dd δ 7.92 (t, J = 1.9 Hz, 2H), 7.84 - 7.69 (m, 3H), 7.58 (dt, J = 7.9, 1.4 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H).ES / MS m / z: calculated for Ci<;BrN-O: (M+H) : 344.00, found: 343.95. Example 53: 4-(4'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid HO- ° / -% A .^NH - H NMR (400 MHz, Methanol-d,) δ 7.90 (d, J = 8.0 Hz, 2H), 7.71 (d, u = 8.1 Hz, 2H), 7.61 - 7.53 (m, 2H), 7.31 - 7.24 ( m, 2H) , 2.38 (s, 3H) .ES / MS m / z: calculated for GN.HizNzO: (M+H): 280.10, found: 279.96. Example 54: 4-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid - 139 -2H NMR (400 MHz, Methanol-o4) δ 7.90 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.66 - 7.58 (m, 2H), 7.55 - 7.46 (m, 2H) , 1.36 (s, 9H) . ES / MS m / z: calculated for C^H-NO? (M+H): 322.15, found: 322.06. Example 55: 4-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid F3CO:H NMR (400 MHz, Methanol-dd δ 7.95 (d, J - 8.1 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.41 7.34 (m, 2H).ES / MS m / z: calculated for CcjHcFjN.Oj (M+H) : 350.08, found: 350.00. Example 56: 4-(4'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid NH2H NMR (400 MHz, Methanol-al) δ 7.89 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.02 (d , J = 8.8 Hz, 2H) , 3.84 (s, 3H) . ES / MS m / z: calculated for C—H24NjOj (M+H) : 296.10, found: 296.03. Example 57: 4-(4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3 triazole-5-carboxylic acid - 140 -:H NMR (400 MHz, Methanol-cR) δ 7.57 - 7.48 (m, 2H), 7.43 - 7.36 (m, 2H), 7.14 - 7.05 (m, 2H), 6.87 - 6.80 (m, 2H) . ES / MS m / z: Calculated for CmH-FNO.: (M+H) = 284.08; Found 284.31. Example 58: 4-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid O Cl HO .. 1-=. / N''N - H NMR (400 MHz, Methanol-d,·) δ 7.96 (d, J = 7.9 Hz, 2H), 7.87 (d, u = 1.7 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.68 7.58 (m, 2H) . ES / MS m / z: calculated for CiWoClcNaO;’ (M+H) : 334.02, found: 334.08. Example 59: 4-(4'-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid O HO-= • 1 + NH NC '----; ----\ — V- n-N - H NMR (400 MHz, Methanol-d;) δ 8.00 (d, J = 7.9 Hz, 2H), 7.93 - 7.77 (m, 6H). ES / MS m / z: calculated for Ci^H-NcOj- (M-H) = 289.07; Found: 289.01. Example 60: 4-(4'-Chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole-5-carboxylic acid F HO·^ ° 141 - H NMR (400 MHz, Methanol-αΐ) δ 7.96 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.69 - 7.48 (m, 5H). ES / MS m / z: calculated for CigHsClFNr.Cc (M-H): 316.04, found: 316.09. Example 61: 4-(3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)- acid - H NMR (400 MHz, Methanol-d;) δ 7.95 (d, J = 8.3 Hz, 2H), 7.81 (dd, J = 7.0, 2.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H) , 7.65 (ddd, J = 8.6, 4.5, 2.3 Hz, 1H) , 7.34 (t, J = 8.9 Hz, 1H) . ES / MS m / z: calculated for C-H-ClFNiCc (M+H): 318.04, found: 317.97. Example 62: 4-(3'-phenoxy-[l,l'-biphenyl]-4-yl)-lH-l,2,3triazole-5-carboxylic acid - H NMR (400 MHz, Methanol-d;) δ 7.91 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.49 - 7.42 (m, 2H), 7.41 - 7.31 ( m, 2H), 7.29 (dt, J = 2.4, 1.0 Hz, 1H), 7.17 - 7.08 (m, 1H), 7.06 - 7.00 (m, 2H), 7.00 - 6.95 (m, 1H). ES / MS m / z: calculated for C2iH>;N?O.: (M+H): 358.11, found: 358.01. Example 63: 4-(4'-phenoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid - 142 - - H NMR (4 00 MHz, Methanol-d.;) δ 7.91 (d, J = 8.0 Hz, 2H), 7.78 - 7.63 (m, 4H), 7.37 (dd, J = 8.5, 7.3 Hz, 2H), 7.12 (d, J = 7.4 Hz, 1H), 7.09 - 6.97 (η, 4H). ES / MS m / z: calculated for CsiHLgNjOj (M+H): 358.11, found: 357.98. Example 64: 4-(4'-(pyridin-2-yloxy)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid HO^. EITHER :H NMR (400 MHz, Methanol-d.;) δ 8.16 (ddd, J = 5.0, 2.0, 0.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.84 (ddd, J = 8.3, 7.2, 2.0 Hz, 1H), 7.77 - 7.68 (m, 4H), 7.27 - 7.19 (m, 2H), 7.14 (ddd, J = 7.2, 5.0, 1.0 Hz, 1H), 6.99 (dt, J = 8.3, 0.9Hz, 1H). ES / MS m / z: calculated for CrsHigNuO· (M+H) : 359.11, found: 359.14. Example 65: 4-(4'-acetyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid - 143 -2H NMR (400 ΜΗζ, Methanol-al) δ 8.14 - 8.07 (m, 2Η), 7.98 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 11.8, 8.3 Hz, 4H), 2.65 (s, 3H) . ES / MS m / z : Calculated for C2-H24N;-O; (M-H) = 308.10; Found 308.00. Example 66: 4-(3'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid HO^° / ¥nh h2n—zo2H NMR (400 MHz, Methanol-d·;) δ 8.21 (t, J = 1.9 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.89 (dd, J = 7.8, 1.9 Hz, 2H), 7.83 7.74 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H). ES / MS m / z: calculated for CirH2jN4O; (M+H) : 309.09, found: 309.09. Example 67: 4-(3'-(methylcarbamoyl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid HO-^ ° \ NH r - : ' --------------- i W \= / vn N.H. - H NMR (400 MHz, Methanol-d;) δ 8.14 (t, J = 1.8 Hz, 1H), 8.01 - 7.91 (m, 2H), 7.91 - 7.74 (m, 4H), 7.56 (t, J = 7.8 Hz, 1H), 2.95 (s, 3H). ES / MS m / z: calculated for CcH;;N-Oi (M+H): 323.11, found: 323.12. - 145 3Η). ES / MS m / z: calculated for CmH—NgC; (M+H): 337.35, found: 338.06. Example 71: 4-(4'-Carbamoyl-3'-chloro-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid HO-,° .O— 'NHH2N j—'X--zNNCl - H NMR (400 MHz, Methanol-α';) δ 7.97 (d, J = 8.0 Hz, 2H), 7.86 - 7.74 (m, 3H), 7.70 (dd, J = 8.1, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H) . ES / MS m / z: calculated for CigHi.-ClNgO; (M+H) : 343.05, found: 343.13. Example 72: 4-(3'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid HO-^ ° , / -¾_,>NH h2n- yes, 0° - H NMR (400 MHz, Methanol-at) δ 8.22 (t, J = 1.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.91 (dtt, J = 8.5, 3.6, 1.8 Hz, 2H), 7.84 - 7.73 (m, 2H), 7.65 (t, J = 7.9 Hz, 1H). ES / MS m / z: calculated for CigHuNgOúS (M-H): 345.06, found: 345.03. Example 73: 4-(3'-(N,N-dimethylsulfamoyl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid - 146 ΗΟ N.H. N-S. Ο^°:Η NMR (40C MHz, Methanol -α+) : δ 8.06 - 7.97 (m, 4H), 7.85 7.69 (m, 4H), 2.74 (s, 6H) . ES / MS m / z: calculated for CO-H.-AC+S (M+H): 373.09, found: 373.11. Example 74: 4-(3'-(piperidin-1-ylsulfonyl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid 2H NMR (400 MHz, DMSO-cA) δ 8.09 (d, J = 6.6 Hz, 1H), 7.96 (s, 2H), 7.93 - 7.79 (m, 3H), 7.77 (d, J = 6.6 Hz, 2H) , 2.95 (t, J = 5.5 Hz, 4H), 1.56 (dt, J = 10.7, 5.9 Hz, 4H), 1.42 - 1.30 (m, 2H). ES / MS m / z: calculated for C2uH2:N.:O2S (M+H): 413.13, found: 413.17. Example 75: 4-(3'-(morpholirxosulfonyl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid - 147 - -H NMR (400 MHz, Methanol-d,·): δ 8.08 - 7.96 (m, 4H), 7.86 - 7.65 (m, 4H), 3.78 - 3.65 (m, 4H), 3.07 - 2.95 (m, 4H) . ES / MS m / z: calculated for C; -H;;N;O S (M+H) : 415.10, found: 415.11. Example 76: 4-(4'-Chloro-3'-sulfamoyl-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid LH NMR (400 MHz, Methanol-d;) δ 8.35 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.90 - 7.83 (m, 1H), 7.82 - 7.72 (m , 2H), 7.71 - 7.62 (m, 1E) . ES / MS m / z: calculated for C; '-HmCIN.iOgS (M+H): 379.02, found: 379.07. Example 77: 4-(4'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid O HO —γ o^h ya AA_A nh H2N NN -H NMR (400 MHz, Methanol-d;) δ 7.99 (d, J = 8.2 Hz, 4H), 7.86 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H). ES / MS m / z: calculated for CcH;<AS (M-H) : 343.06, found: 342.31 . Example 78: 4-(4'-(N,N-dimethylsulfamoyl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid 148:H NMR (400 MHz, Methanol-d;) δ 8.01 (d, J = 8.2 Hz, zH), 7.96 - 7.93 (m, 2H), 7.91 - 7.86 (m, 211), 7.83 (dd, J = 7.6, 5.6 Hz, 2H), 2.73 (s, 6H). ES / MS m / z: calculated for C^HmNjQ.iS (M+H): 373.09, found: 373.06. Example 79: 4-(4'-(piperidin-1-ylsulfonyl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid / HO, ° or Y -H NMR (400 MHz, DMSO-dz) δ 8.01 (d, J = 8.2 Hz, 2H), 7.97 - 7.85 (m, 4H), 7.82 (d, J = 8.3 Hz, 2H), 2.94 (t, J = 5.5 Hz, 4H), 1.56 (p, J = 6.2, 5.4 Hz, 4H), 1.45 - 1.32 (m, 2H). ES / MS m / z: calculated for CvH-lHCHS (M+H): 413.13, found: 413.10. Example 80: 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid :H NMR (400 MHz, Methanol-d;) δ 8.05 - 7.93 (m, 4H), 7.93 - 7.76 (m, 4H), 3.78 - 3.65 (m, 4H), 3.07 - 2.96 (m, 4H). ES / MS m / z: calculated for C-#<03 (M+H): 415.11, found: 415.07. - 149 Example 81: 4-(3'-acetamido-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid '=0 or HNHO- ^X \\ Á- NHLH NMR (400 MHz, Methanol-d-;): δ 8.06 - 7.85 (m, 3H), 7.77 - 7.68 (m, 2H), 7.60 - 7.51 (m, 1H), 7.47 - 7.32 (m, 2H), 2.15 (s, 3H). ES / MS m / z: calculated for CltHlsN^Oí (M+H) : 323.11, found: 323.13. Example 82: 4-(4'-acetamido-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid O or HO-. :H NMR (400 MHz, DMSO-dd δ 10.03 (s, 1H), 7.85 (s, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.68 (s, 4H), 2.05 (s, 3H). ES / MS m / z: calculated for CcH;;N;O; (M+H): 323.11, found: 323.12. Example 83: 4-(4'-(2-oxopyrrolidin-l-yl)-[1,1'20biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid -H NMR (400 MHz, DMSO-d¿.) δ 7.76 (m, 8H), 3.87 (t, J = 7.0 Hz, 2H), 2.52 (d, J = 8.0 Hz, 2H), 2.07 (p, J = 7.6 Hz, - 150 2Η). ES / MS m / z: calculated for CoHuNX (M+H) : 349.12, found: 349.13. Example 84: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid NMR (400 MHz, Methanol-ct) δ 7.88 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.93 - 3.81 (m, 4H), 3.23 - 3.16 (m, 4H). ES / MS m / z: calculated for C:?HmN.:02 (M+H) : 351.14, found: 350.01 . Example 85: 4-(4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole-5-carboxylic acid (400 MHz, Methanol-ct) δ 7.94 - 7.87 (m, 2H), 7.44 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.29 - 7.18 (m, -H NMR - 7.37 (m, 2H), 2.27 (s, 3H). ES / MS m / z: Calculated for CXuClN-íl (M+H) = 314.07; Found 314.01. Example 86: 4-(9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid - 151 - - H NMR (400 MHz, Methanol-d.) δ 8.02 (s, 1H), 7.94 - 7.80 (m, 3H), 7.58 (dt, J = 7.3, 1.0 Hz, 1H), 7.43 - 7.29 (m, 2H ), 3.97 (s, 2H). ES / MS m / z: calculated for CxH-NC; (M+H) : 278.09, found: 278.02. Example 87: 4-(dibenzo[b,d]furan-3-yl)-1H-1,2,3triazole-5-carboxylic acid - H NMR (400 MHz, Methanol-dJ δ 8.16 (dd, J = 1.3, 0.6 Hz, 1H), 8.14 - 8.04 (m, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 (dt, ES / MS m / z: calculated for CvH-NgOa (M+H): 280.06, found: 280.00. Example 88: 4-(9H-carbazole-2-yl)-1H-1,2,3-triazole-5carboxylic acid N OH0V ‘ / . / ^nh - H NMR (400 MHz, Acetonitrile-cd) δ 6.77 (dd, J = 18.7, 8.0 Hz, 2H), 6.64 (s, 1H), 6.23 (s, 1H), 6.12 (d, J = 8.1 Hz, 1H ), 6.05 (t, J = 7.6 Hz, 1H), 5.83 (t, J = 7.4 Hz, 1H). - 152 ES / MS m / z: Calculated for CmE.iNxOi (M+H) = 279.09; Found, 279.01. Example 89: 4-(9-oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole5-carboxylic acid:H NMR (400 MHz, Methanol-d,9 δ 8.11 (d, J = ES / MS m / z: calculated for Οι-ΈοΑ-Οχ (M+H): 292.06, found: 292.08. Example 90: 4-(9,9-dimethyl-9H-fluoren-2-yl)-1H-1,2,3triazole-5-carboxylic acid -H NMR (400 MHz, Methanol-dx) δ 7.96 (d, J = 1.5 Hz, 1H), 7.88 - 7.76 (m, 3H), 7.50 (dd, J = 5.8, 2.9 Hz, 1H), 7.39 7.29 ( η, 2H), 1.51 (s, 6H). ES / MS m / z: Calculated for C28H15N3O2 (M+H) = 306.12; Found 306.06. Example 91: 4-(4'-chloro-3'-methyl-[1,1'-biphenyl]-4-yl) acid 1H-1,2,3-triazole-5-carboxylic acid 153 - H NMR (400 MHz, DMSO-de) δ 7.12 (d, J = 7.9 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 2.3 Hz, 1H), 6.72 - 6.52 (m, 3H), 1.64 (s, 3H). ES / MS m / z: calculated for CvHvCINíOz (M-H) : 312.06, found: 312.08. Example 92: 4-(4'-carbamoyl-3'-methyl-[1,1'-biphenyl]-4- acid :H NMR (400 MHz, Methanol-d·?) δ 7.95 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.62 - 7.45 (m, 3H), 2.53 (s , 3H). ES / MS m / z: calculated for CvHvN^Co (M+H): 323.11, found: 323.10 . Example 93: 4-(4-(1-oxo-l,2,3,4-tetrahydroisoquinolin6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid - H NMR (400 MHz, Methanol-d·;) δ 8.01 (t, J = 7.3 Hz, 2H), 7.79 (d, J = 8.0 Hz, 3H), 7.74 - 7.63 (m, 2H), 3.55 (t , J = 6.7 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H). ES / MS m / z: calculated for (M+H): 335.11, found: 335.16. Example 94: 4-(4-(1-oxo-l,2,3,4-tetrahydroisoquinolin6-yl)phenyl)-lH-pyrazole-5-carboxylic acid - 154 - - H NMR (400 MHz, DMSO-d?) δ 7.89 (d, J = 8.1 Hz, 2H), 7.77 - 7.56 (m, 5H), 3.40 (dt, J = 7.2, 3.6 Hz, 2H), 2.97 ( t, J = 6.6 Hz, 2H). ES / MS m / z: calculated for C^H^NO. (M+H) : 334.11, found: 334.13. Example 95: 4-(4-(3-methyl-l-oxo-l,2,3,4tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5carboxylic acid - H NMR (400 MHz, Methanol-d,·) δ 8.01 (d, J = 8.1 Hz, 1H), 7.99 - 7.93 (m, 2H), 7.82 - 7.75 (m, 2H), 7.69 (dd, J = 8.1, 1.8 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 3.84 (dqd, J = 12.9, 6.5, 4.6 Hz, 1H), 3.11 (dd, J = 15.8, 4.5 Hz, 1H), 2.84 (dd, J = 15.7, 10.1 Hz, 1H), 1.33 (d, J = 6.5 Hz, 3H). ES / MS m / z: calculated for CiaHiaNaCm (M+H): 349.13, found: 349.10. Example 96: 4-(4-(2-methyl-l-oxo-l,2,3,4tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5carboxylic acid - 155 -H NMR (400 MHz, DMSO-cO) δ 13.14 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.85 (m, 4H), 7.72 (dd, J = 8.2, 1.8 Hz , 1H) , 7.69 (s, 2H) , 3.59 (t, J = 6.6 Hz, 2H) , 3.07 (t, J = 6.6 Hz, 2H) , 3.05 (s, 3H) . ES / MS m / z: calculated for CsH-NA (M+H) : 349.13, found: 349.09. Example 97: 4-(4-(l-oxoisoindolin-5-yl)phenyl)-1H1,214,3-triazole-5-carboxylic acid,0 HO—2+ ηνΎ_ ,_ YΖΥΥ ti,__ / / ti. Ynh or Wnnh:H NMR (400 MHz, Methanol-at): δ 8.00 (m, 3H), 7.94 - 7.77 (m, 4H), 4.55 (s, 2H). ES / MS m / z: calculated for Ci-Ht-N^Oa (M+H): 321.09, found: 321.07. Example 98: 4-(4-(3,3-dimethyl-l-oxoisoindolin-5yl)phenyl)-1H-1,214,3-triazole-5-carboxylic acid \ ,O >HO·^ HN \__\ Y.-.<O^y^h O \^ / NNH - H NMR (400 MHz, Methanol-ct) δ 7.98 (d, J = 8.0 Hz, 2H), 7.90 - 7.76 (m, 5H), 1.60 (s, 6H). ES / MS m / z: Calculated for C^HisNgO· (M+H) - 349.13; Found 349.13 Example 99: 4-([1,1':3',l-terphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid - 156 - - H NMR (400 MHz, DMSO-ds) δ 8.06 - 7.83 (m, 5H), 7.81 7.76 (m, 2H), 7.73 - 7.62 (m, 2H), 7.57 (t, J = 7.7 Hz, 1H), 7.48 (dd, J = 8.4, 6.9 Hz, 2H), 7.43 - 7.30 (m, 1H). ES / MS m / z: calculated for CtiHiíNjCl (M+H) : 342.12, found: 342.01. Example 100: 4-([1,1':4',1''-terphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid - H NMR (400 MHz, DMSO-dd δ 7.97 - 7.63 (m, 10H), 7.48 (t, J = 7.6 Hz, 2H), 7.46 - 7.25 (m, 2H). ES / MS m / z: calculated for CziHxNqOq (M-H): 340.12, found: 339.95. Example 101: 4-(4'-(pyridin-2-yl)-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole-5-carboxylic acid :H NMR (400 MHz, Methanol-d,) δ 8.83 (d, J = 5.3 Hz, 1H), 8.62 (s, 2H), 8.41 (d, J = 9.3 Hz, 1H), 8.17 - 7.93 (m, 6H), - 157 7.87 (d, J = 9.7 Hz, 2H) . ES / MS m / z: calculated for CgjH^AO: (M+H): 343.11, found: 343.15. Example 102: 4-(4'-(pyridin-3-yl)-[1,1'-biphenyl]-4-yl) 1H-1,2,3-triazole-5-carboxylic acid EITHER - H NMR (400 MHz, Methanol-d,·) δ 9.04 (s, 1H), 8.67 (d, J = 5.0 Hz, 1H), 8.56 - 8.50 (m, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.94 - 7.86 (m, 4H), 7.83 (d, J = 8.1 Hz, 3H). ES / MS m / z: calculated for C22H25N.;O2(M+H): 343.12, found: 343.13. Example 103: 4-(4'-(pyridin-4-yl)-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole-5-carboxylic acid HO-TN= =n-N - H NMR (400 MHz, Methanol-d.;) δ 8.79 (d, J = 6.1 Hz, 2H), 8.30 - 8.23 ​​(m, 2H), 8.07 (d, J = 8.2 Hz, 2H), 8.02 (d , J = 8.0 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H). ES / MS m / z: calculated for C2;H:=N2O2(M+H): 343.12, found: 343.13. Example 104: 4-(4'-(pyrimidin-2-yl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid - 158 -2H NMR (400 MHz, Methanol-cü) δ 8.87 (d, J = 4.8 Hz, 2H), 8.52 (d, J = 8.5 Hz, 2H), 7.98 (s, 2H), 7.85 (dd, J = 8.2, 6.4 Hz, 4H), 7.37 (t, J = 4.9 Hz, 1H). ES / MS m / z: Calculated for C—H—N5O2 (M+H) = 344.11; Found 344.03 Example 105: 4-(4'-(1-methyl-lH-l,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3 acid -triazole-5-carboxylic Oxn-γ γγ _ / iNHn<n<-= / n'N - H NMR (400 MHz, Methanol-d) δ 8.33 (s, 1H), 7.95 (dd, J = 14.0, 8.3 Hz, 4H), 7.79 (d, J = 8.2 Hz, 4H), 4.18 (s, 3H) ). ES / MS m / z: Calculated for C:sH25N¿02 (M+H) = 341.13; Found 347.14. Example 106: 4-(4'-(l-methyl-lH-l,2,4-triazol-3-yl)-[l,l'biphenyl]-4-yl)-1H-1,2,3 - triazole-5-carboxylic acid - H NMR (400 MHz, DMSO-cR) δ 8.53 (s, 1H), 8.14 - 8.04 (m, 2H), 7.84 (d, J = 8.7 Hz, 6H), 3.93 (s, 3H). ES / MS m / z: calculated for CisHidNO? (M+H): 347.12, found: 347.10. Example 107: 4-(4'-(l-methyl-lH-pyrazol-3-yl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid 159 CR OH Ύ N 'N+ λ N-LH NMR (400 MHz, DMSO-dp δ 7.96 - 7.87 (m, 4H) , 7.83 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H) , 7.76 (d, J = 2.2 Hz, 1H) , 6.76 (d, J = 2.3 Hz, 1H) , 3.91 (s, 3H) ES / MS m / z: calculated for Cu.HvNjOt (M+H): 346.13, found: 346.15 Example 108: 4-(4'-(thiazol-2-yl)-[1,1'-biphenyl]-4-yl)- acid 1H-1,2,3-triazole-5-carboxylic O HO-,S..........+ Mh - H NMR (400 MHz, Methanol-d-;) δ 8.07 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 3.3 Hz, 1H), 7.83 (t, J = 8.7 Hz, 4H), 7.63 (d, J = 3.3 Hz, 1H). ES / MS m / z: calculated for Cib-HvNuO'S (M+H): 349.07, found: 349.03. Example 109: 4-(4'-(5-methylthiazol-2-yl)-[1,1'-biphenyl]4-yl)-1H-1,2,3-triazole-5-carboxylic acid - H NMR (400 MHz, OMSO-dz): δ 8.03 - 7.74 (m, 8H), 7.62 (s, 1H), 2.50 (s, 3H). ES / MS m / z: calculated for CmHuNnOX (M+H): 362.08, found: 362.11. - 160 Example 110: 4-(4(5-(trifluoromethyl)thiazol-2-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid - H NMR (400 MHz, DMSO-ds) δ 8.58 (s, 1H), 8.15 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.94 - 7.85 (m, 4H) ). ES / MS m / z: calculated for CmH:2F2N.4O2S (M+H): 417.06, found: 417.00. Example 111: 4-(4'-(5-methyl-l,3,4-thiadiazol-2-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole acid -5-carboxylic HO-^ ° NN.=1 . i 'NH - H NMR (400 MHz, DMSO-di) δ 8.03 (d, J = 6.5 Hz, 1H), 8.00 (d, J = 16.3 Hz, 2H), 7.96 - 7.89 (m, 3H), 7.85 (d, J = 8.3 Hz, 2H), 2.78 (s, 3H). ES / MS m / z: calculated for C1SH12N5O2S (M-H): 362.07, found: 362.03. Example 112: 4-(4'-(oxazol-2-yl)-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole-5-carboxylic acid - 161:H NMR (400 MHz, Methanol-d;) δ 8.13 (s, 1H), δ 8.09-7.91 (m, 4H), δ 7.91-7.77 (m, 3H), δ 7.39-7.28 (s, 2H ). ES / MS m / z: Calculated for CuHnMO;, (M+H) = 333.10; found 333.00. Example 113: 4-(4'-(isoxazol-3-yl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid :H NMR (400 MHz, DMSO-dd δ 9.02 (d, J = 1.7 Hz, 1H), 8.07 - 7.97 (m, 3H), 7.93 - 7.86 (m, 5H), 7.24 - 7.19 (m, 1H). ES / MS m / z: Calculated for CnHnN;O; (M+H) = 333.10; found 333.05. Example 114: 4-(4'-(4-methylthiazol-2-yl)-[1,1'-biphenyl]4-yl)-1H-1,2,3-triazole-5-carboxylic acid O.^, OH <s__é f f \N H / n V= / ' \=- N'N:H NMR (400 MHz, DMSO-de) δ 8.03 (d, J = 8.4 Hz, 2H) , 7.95 (d, J = 8.0 Hz, 2H), 7.87 (t, J = 7.9 Hz, 4H), 7.36 (d, J = 1.2 Hz, 1H), 3.33 (s, 3H). ES / MS m / z: calculated for CzaHmNaOzS (M+H): 363.09, found: 363.08. Example 115: 4-(4'-(2-methyl-2H-l,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3 acid -triazole-5-carboxylic acid - 162 - - H NMR (400 MHz, DMSO-da) δ 8.30 (s, 1H), 7.95 (t, J = 7.0 Hz, 4H), 7.90 - 7.80 (m, 4H), 4.22 (s, 3H). ES / MS m / z: calculated for CmHmNíO? (M+H): 347.13, found: 347.02. Example 116: 4-(4'-(thiazol-5-yl)-[1,1'-biphenyl]-4-yl)- acid 1H-1,2,3-triazole-5-carboxylic acid <5\ / Λ / ^nh - H NMR (400 MHz, DMSO-d?) δ 9.10 (s, 1H), 8.39 (s, 1H), 7.81 (q, J = 8.4 Hz, 8H). ES / MS m / z: calculated for CvHmNjCRS (M+H): 349.07, found: 348.96. Example 117: 4-(4'-(1,5-dimethyl-lH-pyrazol-3-yl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5 acid -carboxylic - H NMR (400 MHz, DMSO-d?) δ 7.92 (d, J = 8.1 Hz, 2H), 7.88 - 7.79 (m, 4H), 7.76 (d, J = 8.2 Hz, 2H), 6.54 (s, 1H), 3.78 (s, 3H), 2.30 (s, 3H). ES / MS m / z: calculated for CcoHiaN^O; (M+H): 360.15, found: 360.16. Example 118: 4-(4'-(1,5-dimethyl-lH-l,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl)-1H-1,2 acid ,3-triazole-5-carboxylic N'\ ..+ t / y__ NH . N w j\|' N\ - 163 - - H NMR (400 MHz, DMSO-cN) δ 13.13 (s, 1H), 7.95 - 7.90 (m, 1H), 7.89 - 7.75 (m, 8H), 4.00 (s, 3H), 2.51 (s, 3H) . ES / MS m / z: calculated for Co;.H;-N.O: (M+H) : 361.14, found: 361.13. Example 119: 4-(4'-(lH-pyrazol-l-yl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid - H NMR (400 MHz, Methanol-cd) δ 8.28 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.91 - 7.62 (m, 6H), 6.56 (d, J = 2.4 Hz, 2H). ES / MS m / z: Calculated for CmH^NjO; (M+H) = 332.11; found 332.14. Example 120: 4-(4'-(1H-1,2,3-triazol-l-yl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazol-5 acid -carboxylic H NMR (400 MHz, Methanol-d,) δ 8.59 (s, 1H), 8.07 (s, 2H), 8.01 - 7.85 (m, 5H), 7.79 (d, J = 8.2 Hz, 2H). ES / MS m / z: Calculated for Ci-Hi;N¿O_- (M+H) = 333.11; found 333.11. Example 121: 4-(4'-(5-methyl-lH-l,2,3-triazol-l-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3 acid -triazole-5-carboxylic - 164 - -H NMR (400 MHz, Methanol-co) δ 8.01 (d, J = 8.0 Hz, 2H), 7.97 - 7.90 (m, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.70 - 7.61 (m, 3H), 2.42 (d, J = 0.9 Hz, 3H). ES / MS m / z: calculated for CisHvNrO: (M+H): 347.13, found: 347.09. Example 122: 4-(4'-(benzo[d]thiazol-2-yl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid Ο ΌΗ -H NMR (400 MHz, DMSO-ds) δ 8.20 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.96 ( d, 15 J = 8.2 Hz, 5H), 7.88 (d, J = 8.3 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H). ES / MS m / z: calculated for CzzHvNjOíS (M+H): 399.09, found: 399.08. Example 123: 4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H1,2,3-triazole-5-carboxylic acid) nA / hn7 HO° Acid 4,4' O^OH Π'Ο / 'νη -([1,1'-biphenyl]-4,4'-diyl)bis(1H-) was prepared 1, 2,3-triazole-5-carboxylic) from ethyl 5-bromo-2-(4-methoxybenzyl)-2Η-1,2,3-triazole-4-carboxylate (11) and 2- ( 4-methoxybenzyl)-5-(4'-(4,4,5,5-tetramet i 1-1,3,2dioxaborlan-2-yl)-[1,1'-biphenyl]-4-yl)-2H Ethyl -1,2,3-triazole-4carboxylate (13) similar to general Suzuki reaction procedures, followed by PMB deprotection and ester::H hydrolysis NMR (400 MHz, DMSO-d6) δ 7 .95 (s, 4H) , 7.86 (d, J = 8.1 Hz, 4H) . ES / MS m / z: calculated for CioHijNíOj (M+H) : 377.10, found: 377.03. Example 181: 4-(4'-(5,6-dihydro-4H-cyclopenta[d]thiazol2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3- acid triazole-5-carboxylic acid -H NMR (400 MHz, DMSO-dz) δ 7.99 (d, J = 8.1 Hz, 2H), 7.86 (m, 6H), 3.17 (s, 2H), 2.96 (s, 2H), 2.89 - 2.78 (m , 2H). ES / MS m / z: calculated for C-lH:'-N.;O¿S (M+H) : 389.11, found: 389.11. The following compounds were prepared similarly to the representative procedures of the Suzuki reaction and SEM or PMB deprotections described above, followed by ester hydrolysis using the aforementioned boronate intermediates 6 or 8, with commercially available heterocycle-containing bromides after of SEM protection of N-H heterocyclic: - 16 6 Example 124: 4-(4'-(lH-pyrazol-4-yl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid 2H NMR (400 MHz, DMSO-d¿) δ 8.11 (s, 2H), 7.79 (d, J = 14.4 Hz, 4H), 7.72 (s, 4H) . ES / MS m / z: calculated for C2= H2.-,N5O2 (M+H) : 332.11, found: 332.07. Example 125: 4-(4'-(lH-pyrazol-5-yl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid 2H NMR (400 MHz, DMSO-cu) δ 7.99 - 7.86 (m, 4H), 7.88 7.74 (m, 4H), 7.72 (d, J = 2.2 Hz, 1H), 6.76 (t, J = 2.3 Hz, 1H ). ES / MS m / z: calculated for 073Η;4Ν5θ2 (M+H): 332.11, found: 332.11. Example 126: 4-(4-(iH-benzo[d]imidazol-5-yl)phenyl)-1H1,2,3-triazole-5-carboxylic acid -H NMR (400 MHz, Methanol-cd) δ 9.31 (s, 1H), 8.09 (dd, J = 1.6, 0.8 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 8.02 - 7.89 (m , - 167 3Η), 7.88 - 7.79 (m, 2H). ES / MS m / z: calculated for Cg.H; _Ν-Ο^ (M+H): 306.09, found: 306.14. Example 127: 4-(4'-(1H-1,2,3-triazol-5-yl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazol-5 acid -carboxylic HO^ ° H __ __ n'nx t Va Y \= / nn:H NMR (4 00 MHz, Methanol-d;) δ 7.96 (d, J = 7.6 Hz, 4H), 7.80 (d, J = 7.9 Hz, 5H). ES / MS m / z: calculated for Cg-H^M-O; (M+H): 333.10, found: 333.07. Example 128: 4-(4'-(lH-imidazol-2-yl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid :H NMR (400 MHz, Methanol-d-·) δ 7.29 - 7.05 (m, 4H), 6.95 - 6.62 (m, 6H) . ES / MS m / z: Calculated for CcHjNd; (M+H) 332.11; found 332.12. Example 129: 4-(4'-(lH-imidazol-4-yl)-[1,1'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid HO-d° •N__. +,__.:\__ Υη HN Ύ / nN:H NMR (400 MHz, Methanol-d;): δ 9.02 (d, J = 1.4Hz, 1H), 8.10-7.95 (m, 3H), 7.85 (dt , J = 24.3, 8.3 Hz, 6H). ES / MS - 168 m / z: Calculated for C=H:>0- (M+H) = 332.11; found 332.12 Example 130: 4-(4'-(4-methyl-lH-pyrazol-3-yl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid HOr+A__ü__ / y > NH -NNw2H NMR (400 MHz, DMSO-A) δ 12.98 (s, 2H), 7.82 (d, J = 8.1 Hz, 4H), 7.75 (d, J = 8.1 Hz, 2H), 7.51 (s, 1H), 2.23 (d, J = 0.7 Hz, 3H) . ES / MS m / z: Calculated for CAAA (M+H) = 346.13; found 346.18. The following compounds were prepared similarly to the representative procedures of the Suzuki reaction and SEM deprotection by HCl, followed by ester hydrolysis using the aforementioned bromide intermediates, 4 or 10, with commercially available bromides after conversion to pinacol boronates: Example 131: 4-(4'-(5-methyl-lH-l,2,3-triazol-4-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3 acid -triazole-5-carboxylic acid HO_ O N'\__;% or +_ NH HN. W NN2H NMR (400 MHz, D2O + NaHCO2) δ 7.5 - 8.0 (m, 8H), 2.48 (s, 3H). ES / MS m / z: calculated for CAisNA (M+H) : 347.13, found: 347.12. - 169 Example 132: 4-(6-chloronaphthalene-2-yl)-1H-1,2,3triazole-5-carboxylic acid :H NMR (400 MHz, Methanol-d,·) δ 8.45 (m, 1H) 7.92 (dd, J = 13.0, 8.2 Hz, 4H), 7.50 (d, J = 8.7 Hz, 1H). ES / MS m / z: calculated for CigHiClNjOg (M+H) : 274.04, found: 273.96. Example 133: 4-(phenanthren-2-yl)-1H-1,2,3-triazole-5carboxylic acid -H NMR (400 MHz, DMSO-dz) δ 8.88 (s, 2H), 8.43 (s, 1H), 8.22 - 7.82 (m, 4H), 7.80 - 7.59 (m, 3H). ES / MS m / z: Calculated for CvHvNgCu (M+H) = 290.09; found, 290.03. Example 134: 4-(7-amino-9H-fluoren-2-yl)-1H-1,2,3triazole-5-carboxylic acid -H NMR (400 MHz, Methanol-d,·) δ 8.07 (s, 1H), 7.97 (dd, J = 14.0, 8.1 Hz, 2H), 7.88 (d, J = 7.9 Hz, 1H), 7.55 (s , 1H), 7.36 (d, J = 8.3 Hz, 1H), 4.05 (s, 2H). ES / MS m / z: calculated for CvHijN^O? (M+H): 293.10, found: 293.05. - 170 Example 135: 5-(3-chloro-4-fluorophenyl)-1H-1,2,3triazole-4-carboxylic acid Stage 1 MeO V .SEM „ / 'Ν' Br—1' । Stage 1 To a solution of methyl 4-bromo-3-methyl-lH-pyrazole-5carboxylate (275 mg, 1.255 mmol) in DMF was added sodium hydride (601 suspension, 1.38 mmol) at 0°C, followed by SEM- C1 (0.233 ml, 1.31 mmol). After 10 min, the reaction mixture was diluted with saturated NaHCCt before the product was extracted with ethyl acetate, dried (MgSO), concentrated and purified by column chromatography on silica gel eluting with ethyl acetate. in hexane to obtain an isomeric mixture of methyl 4-bromo-3-methyl-l-((2(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-5-carboxylate: ES / MS m / z: calculated for ΟνΗ, ηΒΓί / ΕΟ^ί (M+H) : 349.05, found: 348.93. Stage 2, Stage 3 and Stage 4 4-(3-Chloro-4-fluorophenyl)-3-methyl-1Hpyrazole-5-carboxylic acid was prepared similarly to the general procedures of the Suzuki reaction using (3-chloro4-fluorophenyl)boronic acid, followed by deprotection SEM by HC1 and hydrolysis of ester::H NMR (400 MHz, Methanol-cu) δ 7.43 (ddd, J = 7.2, 1.9, 0.5 Hz, 1H), 7.31 - 7.19 (m, 2H), 2.22 171 (s, 3H) . ES / MS m / z: calculated for CEjClE^ (M+H): 255.03, found: 254.94. Example 136: 4-(3-chloro-4-fluorophenyl.)-3-methyl-1Hpyrazole-5-carboxylic acid ........ Μβθγ° k. SIM Stage Stage 3 * Stage F-< N.H. N Stage 1 A solution of 1-(3-chloro-4fluorophenyl)ethan-l-one (301, 5.00 g, 29.0 mmol) in dimethyl carbonate (4.9 ml, 58 mmol) was added dropwise to a stirred solution of potassium tert-butoxide. (6.50 g, 57.9 mmol) in THE (30 mL) under N¿ and cooled in a water bath. After 90 min, the reaction mixture was cooled in an ice bath and then quenched with 2 M HC1. The mixture was then extracted with ethyl acetate and the organic extract was dried (MgSOJ) and concentrated in vacuo. The resulting crude residue was purified by column chromatography on silica gel eluting with 0-40 ethyl acetate in hexanes to obtain methyl 3-(3chloro-4-fluorophenyl)-3-oxopropanoate (2.97 g, 441). LC / MS m / z: calculated for CvHjClFO; (M+H): 231.02, found: 231.0. - 172 Stage 2 A mixture of methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropanoate (537 mg, 2.33 mmol), p-methoxybenzyl azide (400 mg, 2.45 mmol) and potassium carbonate (1.36 g, 9.80 mmol ) in dimethyl sulfoxide (5 ml) was stirred vigorously at 80°C overnight. After the reaction mixture was cooled and diluted with water, the resulting solids were isolated by filtration and then further purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in hexanes to obtain 5- Methyl (3-chloro-4-fluorophenyl)-1(4-methoxybenzyl)-1H-1,2,3-triazole-4-carbcxylate (400 mg, 43%) as a white solid: ES / MS m / z : calculated for CmHmClFNjCL (M+H): 376.09, found 376.1. Stage 3 and Stage 4 To a solution of methyl 5-(3-chloro-4-fluorophenyl)-l-(4methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (75 mg, 0.20 mmol) in 1:1 THF / methanol (2 ml) 1 M LiOH (1.0 ml, 1.0 mmol) was added at room temperature. After stirring for 1 h, the reaction mixture was acidified with 2N HC1 and the product was extracted with ethyl acetate (x3). The combined organic extracts were dried (MgSOb) and concentrated in vacuo. The resulting residue was then dissolved in TFA and stirred at 65°C for 2 h. After concentrating the reaction mixture in vacuo, the residue was purified by HPLC. reverse phase preparation for - 173 produce 5-(3-chloro-4-fluorophenyl)-1H-1,2, 3-triazole-4carboxylic acid::H NMR (400 MHz, DMSO-d-) δ 13.33 (br s, 1H), 8.07 (br s, 1H) , 7.84 (br s, 1H) , 7.54 (br t, J = 8.0 Hz, 1H) . ES / MS m / z: calculated for CgHsClFNgO; (M+H) : 242.01, found 242.0. Example 137: 4-phenyl-lH-l,2,3-triazole-5-carboxylic acid O^. .OH ΥΆ Xnh 4-Phenyl-lH-1,2,3-triazole-5-carboxylic acid was prepared similarly to the procedure in Example 136 from acetophenone::H NMR (400 MHz, DMSO-cb) δ 13.14 ( br s, 1H), 7.79 (br s, 2H), 7.51 - 7.42 (m, 3H). ES / MS m / z: calculated for CyHsNyO; (m+H): 190.06, found 190.0. Example 138: 4-(3-chlorophenyl)-1H-1,2,3-triazole-5carboxylic acid Os ΌΗ Cl. Ύ / / “+ - NH 4-(3-Chlorophenyl)-1H-1,2,3-triazole-5carboxylic acid was prepared similarly to the procedure of Example 136 from 3-chloroacetofenone::H NMR (400 MHz, DMSO-de ) δ 7.92 (s, 1H), 7.80 (br s, 1H), 7.54 - 7.48 (m, 2H). ES / MS m / z: calculated for CNH-ClNyO; (M+H) : 224.02, found 224.0. - 174 Example 139: 4-(pyridin-2-yl)-1H-1,2,3-triazole-5carboxylic acid 0o + 7 r—,P., M (f '·)------<·. I ------------------* / 7 / / +=N \_n' 'j^N Stage 1 In a 5 ml microwave vial, the isomeric mixture of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H1,2,3-triazole-4-carboxylate (192 mg, 0.55 mmol), 2(tributylstanni1)pyridine (222 mg, 0.193 ml, 0.60 mmol), tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.055 mmol) and toluene (2 ml). After purging with argon gas for 5 minutes, the resulting mixture was stirred at 110°C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCOj before extracting the product with ethyl acetate, dried (MgSCu), concentrated and purified by column chromatography on silica gel eluting with ethyl acetate in hexane to obtain ethyl 5-(pyridin-2-ί1)2- ( (2 - (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4carboxylate: ES / MS m / z: calculated for fhO-Si (M+H): 349.16, found: 349.05. Stage 2 and Stage 3 4-(Pyridin-2-i1)-1H-1,2,3-1riazole-5carboxylic acid was prepared similarly to the general procedures - 175 SEN deprotection by HC1 followed by ester hydrolysis: -H NMR (400 MHz, DMSO-cM δ 8.78 (d, J - 5.2 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.25 ( t, J = 8.0 Hz, 1H), 7.69 (dd, J = 7.4, 5.4 Hz, 1H). ES / MS m / z: calculated for CsH-NjO¿ (M+H): 191.05, found: 190.99. Example 140: 4-(pyridin-2-yl)-lH-pyrazole-5-carboxylic acid 4-(Pyridin-2-ii)-lH-pyrazole-5carboxylic acid was prepared similarly to the procedure of Example 141 from 4-(tributylstannyl)pyridine: -H NMR (400 MHz, Methanol-dJ δ 8.85 - 8.78 (m, 1H), 8.70 (s, 1H), 8.54 (td, J = 8.0, 1.6 Hz, 1H), 8.43 (dt, J = 8.4, 1.0 Hz, 1H), 7.89 (ddd, J = 7.3 , 5.9, 1.2 Hz, 1H).ES / MS m / z: calculated for Cc,HsNjO2(M+H): 190.05, found: 190.00. Example 141: 4-(thiazol-4-yl)-1H-1,2,3-triazole-5carboxylic acid HO, °S. 'N.H. W VN 4-(thiazol-4-yl)-1H-1,2,3-triazole-5carboxylic acid was prepared similarly to the procedure of Example 141 from 4-(tributylstannyl)thiazole::H NMR - 176 (400 MHz, DMSO-di) : δ 9.32 (s, 1H), 8.65 (s, 1H), 3.15 (s, 1H). ES / MS m / z: calculated for C2H,N2O2S (M-H): 191.05, found: 194.95. Examples 142 and 143: 4-(3'-(dimethylcarbamoyl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid and 4-(3'carboxylic acid -[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid O.^ ^OEt Stage 1 An isomeric mixture of 5-(3'-(dimethylcarbamoyl)-[1,1'biphenyl]-4-yl)-2 - ((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3triazol-4 -Ethyl carboxylate was prepared in a manner similar to that of the general Suzuki reaction procedure from 3-bromo-N,N-dimethylbenzamide: Stage 2 and Stage 3 4-(3'-(dimethylcarbamoyl)-[l,l·,biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid and 4—(3'—carboxy-carboxylic acid) were prepared. [1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid in a manner similar to the general SEM deprotection procedure by HC1 followed by ester hydrolysis. The two compounds were separated by precipitation followed by preparative HPLC purifications: Example 142: 4-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-45yl)-1H-1,2,3-triazole-5-carboxylic acid O-H2H NMR (400 MHz, Methanol-d·;) δ 8.33 (t, J = 1.7 Hz, 1H), 8.10 - 7.87 (m, 3H), 7.87 - 7.71 (m, 2H), 7.59 (t, J = 7.9 Hz, 2H). ES / MS m / z: calculated for CidcltO.: (M+H) : 310.07, found: 310.05. Example 143: 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H15 1,2,3-triazole-5-carboxylic acid h -H NMR (400 MHz, Metahol-d,·) δ 7.96 (d, J = 8.4 Hz, 2H), 20 7.86 - 7.72 (m, 4H), 7.57 (td, J = 7.7, 0.6 Hz, 1H), 7.44 (dt, J = 7.6, 1.3 Hz, 1H), 3.14 (s, 3H), 3.06 (s, 3H). ES / MS m / z: calculated for C:=H2-NjO;(M+H): 337.12, found: 337.17. Example 144: 4-(4-(lH-indazol-5-yl)phenyl)-1H-1,2,325 triazole-5-carboxylic acid - 178 - Stage 1 To a solution of 5-bromo-lH-indazole (100 mg, 0.49 mmol) in dichloromethane (2.0 mL) was added p-toluenesulfonic acid (9.0 mg, 0.049 mmol) and 3,4-dihydropyran (0.089 mL, 0.97 mmol) . After heating the mixture to 35°C overnight, the reaction mixture was diluted with saturated aqueous NaHCCu before extracting the product with ethyl acetate (x 2). The combined organic layers were washed with water (x1), dried (NauSO-j), and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexane to provide 5-brcmo-l(tetrahydro-2H-pyran-2-yl)-IH-indazole::H NMR (400 MHz, Acetonitrile -cA) δ 8.03 - 7.93 (m, 2H), 7.62 (dt, J = S.9, 0.8 Hz, 1H), 7.52 (dd, J = 8.9, 1.9 Hz, 1H), 5.77 (dd, J = 9.8 , 2.6 Hz, 1H), 4.89 (t, J = 3.8 Hz, OH), 4.01 - 3.91 (m, 1H), 3.86 - 3.72 (m, 1H), 3.48 (dd, J = 11.0, 6.0 Hz, OH) , 2.47 (dddd, J= 13.7, 12.2, 9.7, 4.0 Hz, 1H), 2.17 - 1.97 (m, 2H), 1.87 - 1.60 (m, 3H), 1.64 - 1.48 (m, 1H). ES / MS m / z : Calculated for CüH^BrNiO (M+H) = 281.03; Found 280.75. - 179 Stage 2, 3 and 4 4-(4-(1H-Indazol-5-i1)phene1)-1Η-1,2,3-1riazole5-carboxylic acid was prepared similarly to the general procedures of the Suzuki reaction with intermediate 6 and 5 -bromo-1-(tetrahydro-2H-pyran-2-i 1)-1Hindazol and deprotection of PMB and THP by TEA, followed by hydrolysis of the ester::H NMR (400 MHz, Methanol-dd δ 8.10 8.05 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.50 - 7.35 (m, 6H). ES / MS m / z: calculated for CmHmClNaOi (M+H): 300.05, found: 300.00. Example 145: 4-(4-(lH-indazol-6-yl)phenyl)-1H-1,2,3triazole-5-carboxylic acid 4-(4-(IH-indazol-6-yl)phenyl)-1H-1,2,3triazole-5-carboxylic acid was prepared from 6-bromo-IH-indazole similarly to the procedures of Example 146 :2H NMR (400 MHz, Methanol-d,') δ 8.10 - 7.92 (m, 3H), 7.81 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.2 Hz , 2H), 7.46 (d, J = 8.7 Hz, 2H). ES / MS m / z: Calculated for Cl^H—NsOz (M+H) = 306.10; Found 306.15 Example 146: 4-(4'-chloro-3'-(morpholinosulfonyl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid - 180 - ii.-O / 1 ii,. EITHER Cl-S / O N-S; \\ Stage 1 ’ ' 3 a Cl—(' Br --------► Cl—[y- Br Stage! Stage! Stage 7 — ► ► Stage 1 Ά a solution of chlorobenzenesulfonyl (366 mg, added morpholine (220 mg, 3 minutes, the reaction mixture 5-bromo-210 mmol chloride) in THF (3 ml) se nol) at 0°C. After 10 minutes it was diluted with ethyl acetate, washed with HC1 IN (x 2), water (x 1) and NaHCO; saturated (x 1) . The resulting organic fraction was dried (MgSO.;) and concentrated. The residue was purified by column chromatography on silica gel eluting with 0100¾ ethyl acetate in hexane to obtain 4-((5-bromo-2chlorophenyl)sulfonyl)morpholine: -H NMR (400 MHz, chloroformod): δ 7.60 ( s, 1H), 7.60 (d, 1H), 7.29 (d, 1H), 3.70 (m, 4H), 3.28 (m, 4H). Stage 2, 3 and 4 4-(4'-Chloro-3'-(morpholinosulfonyl)[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxyric acid was prepared in a manner similar to those general Suzuki reaction procedures with intermediate 6 and 4-((5-bromo-2chlorophenyl)sulfonyl)morpholine, and deprotection of PMB, - 181 followed by hydrolysis of the ester:3H NMR (400 MHz, Methanol-d.;) δ 8.30 (d, J = 2.3 Hz, 1H), 8.07 - 7.91 (m, 3H), 7.76 (dd, J = 16.0, 8.2 Hz, 3H), 3.75 - 3.65 (m, 4H), 3.29 (m, 4H) : ES / MS m / z: calculated for Cx.HisCIN.jC+S (M+H) : 449.06, found: 449.16. Example 147: 4-(3-bromophenyl)-1H-1,2,3-triazole-5carboxylic acid Stage 1 The isomeric mixture of methyl 5-(3-aminophenyl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared similarly to the general procedures of the Suzuki reaction using the 4' intermediate and (3-aminophenyl)boronic acid: ES / MS m / z: calculated for C;rH2;N;O;Si (M+H) : 347.17, found: 348.96. Stage 2 To a solution of methyl 4-(3-aminofer.yl)-1-((2(trimethylsilyl)ethoxy)methy 1)-1H-1,2,3-triazole-5-carboxylate (102 mg, 0.29 mmol) in 3 ml of acetonitrile - 182 added tert-butyl nitrite (0.042 ml, 0.35 mmol) and copper (II) bromide (78 mg, 0.35 mmol) at 0°C. After 30 minutes, the reaction mixture was diluted with saturated NaHCO- before extracting the product with ethyl acetate, dried (MgSOa), concentrated and purified by column chromatography on silica gel eluting with ethyl acetate in hexane to obtain the isomeric mixture methyl 5-(3-bromophenyl)-2( (2-(trimethiIsili1)ethoxy)methyl)-2H-1,2,3-triazole-4carboxylate:LH NMR (400 MHz, Chloroform-d ) : δ 8.12-7.30 (m, 4H), 6.18-5.76 (m, 2H), 3.98 (d, 3H), 3,783,684 (m, 2H), 0.95 (m, 2H), 0.00 (d, 9H) . Stage 3 and Stage 4 5-(4-Bromofeni1)-1H-1,2,3-triazole-4carboxylic acid was prepared similarly to the general SEM deprotection procedures by HC1, followed by hydrolysis of the ester::H NMR (400 MHz, Methanol- d,·) δ 8.07 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H). ES / MS m / z: calculated for C?H~BrN.O2(M + H) : 267.96, found: 267.90. Example 148: 4-(2-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3triazole-5-carboxylic acid - 183 Cl. Cl x- x M C¡^.L· Stage 1 Stage? X •Μ-X MB. Γ Br—4 / }—<\ ' v_y i_y m-n. υ\NStM or ahoM Stage 3 Stage-l Stage i q Mi, z^NH ” * ’ Stage 1 and 2 The isomeric mixture of methyl 5-(4-bromo-3-chloropheni1)-2-((Οί t r imeth i Is i 1yl)ethoxy)methyl)-2H-1, 2, 3-triazole-4-carboxylate was prepared similarly to the procedures of Example 149, Step 1 and 2 using 2-chloro-4-(4,4,5,5tetramethyl-1,3,2-dioxaborlan-2-i1)aniline: ES / MS m / z : calculated for CicHzzBrClN-0-Si (M-H): 446.03, found: 445.69. Stage 3, Stage 4 and Stage 5 4-(2-Chloro-[l,l'-biphenyl]-4-yl)-lH1,2,3-triazole-5-carboxylic acid was prepared similarly to the general Suzuki reaction procedures using phenylboronic acid. , SEM deprotection by HC1 and hydrolysis of ester::H NMR (400 MHz, Methanol-d-;) δ 8.10 - 8.05 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.50 - 7.35 (m , 6H). ES / MS m / z: calculated for CisHlíCINíO; (M+H): 300.05, found: 300.00. Example 149: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H1,2,3-triazole-5-carboxylic acid - 184 - 4-(2,4'-Dichloro-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole~5-carboxylic acid was prepared similarly to the general procedure of the Suzuki reaction from the isomeric mixture of methyl 5-(4-bromo-3-chlorophenyl)-2-((2 (trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate and acid 4 -chlorophemelboronic, followed by general SEM deprotection procedures by HC1 and hydrolysis of ester::H NMR (400 MHz, Methanol-cA) δ 8.00 (d, J = 1.7 Hz, 1H), 7.81 (dd, J = 8.0, 1.8 Hz, 1H), 7.37 (m, 5H). ES / MS m / z: calculated for CmHmCliNaO; (M+H) : 334.01, found: 333.97. Example 150: 4-(3-chloro-4-fluorophenyl)-1-methyl-lH- acid 1,2,3-triazole-5-carboxylic 0 0 Cl χ Step 1 Cl \ / ΥΛ Y'NH '........... ......Υλ FY Ó +' ! F—+ ; 1 1 \_Z To a solution of acid 5-(3-chloro-4-fluoropheni1)-1H- 1,2,3-Triazol-4-carboxylic acid (10 mg, 0.038 mmol) in 0.5 ml of DMF was added NaH (60% oil suspension, 6 mg) at 0°C. After 10 min at 0°C, iodomethane (7 μΐ, 0.11 mmol) was added and the resulting mixture was stirred at 0°C for 10 min. After inactivating the reaction by adding 185 of methanol, the product was purified by purification of HPLC to give 5-(3-chloro-4-fluorophenyl)-l-methyl-lH1,2,3-triazole-4-carboxylic acid: -H NMR (400 MHz, Chloroform-d) δ 7.99 (dd, J = 7.1, 2.2 Hz, 1H), 7.82 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.7 Hz, 1H), 4.31 (s, 3H). ES / MS m / z: calculated for CicHíCIFNzO.- (M-H): 254.01, found: 253.96. Example 151: 4-(4'-(1-methyl-lH-l,2,3-triazol-5-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3 acid Η N / \___ Stage 1 .................................................. .* Stage 2 Stage 3 Stage _ *· Stage 1 To a solution of 4-(4-bromofeni1)-1H-1,2, 3-1riazole (242 mg, 1.05 mmol) in 2 ml of DMF, 60s2 NaH in oily suspension (48 mg, 1.2 mmol) was added at 0° c. After 10 min at 0°C, iodomethane (71 μΐ, 1.1 mmol) was added and the resulting mixture was stirred at 0°C for 10 min. The reaction mixture was extracted using ethyl acetate with brine, the organic layer was concentrated and purified by column chromatography on silica gel eluting with ethyl acetate and hexane to give 5-(4-bromophenyl)-1-methyl1H- 1,2,3 -triazole: ES / MS m / z: calculated for CjH^BrN? (M+H) : 237.99, found: 238.09. - 186 Stage 2, Stage 3 and Stage 4 4-(4'-(l-methyl-lH-l,2,3-triazol-5-yl)[1,1'-biphenyl]-4-yl)-1H-1,2,3- acid was prepared triazole-5-carboxylic acid similar to the general procedures of the Suzuki reaction with compound 28, followed by SEM deprotection by HC1 and hydrolysis of the ester: -H NMR (400 MHz, DMSO-cü) δ 8.27 (s, 1H ), 8.09 (s, 2H), 7.97 - 7.88 (m, 2H), 7.81 (dt, J = 13.6, 5.3 Hz, 4H), 4.20 (s, 3H). ES / MS m / z: calculated for / ΙίΗνΝςΟ: (M+H): 347.12, found: 347.04. Example 152: 4-(4-(2,3,3-trimethyl-l-oxoisoindolin-5yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid Stage 1 Stage 2 Stage! Stage 1 Stage 1 To a solution of 5-bromo-3,3-dimethylisoindolin-l-one (205 mg, 0.85 mmol) in N,N-dimethi 1 formamide (2 ml) was added 60% sodium hydride in mineral oil (43 mg, 1.08 mmol) at 0°C. After 15 min, iodomethane (0.1 ml, 1.61 mmol) was added to the reaction mixture. The resulting solution was stirred at 0°C for 1 hour. The reaction mixture was diluted - 187 with ethyl acetate (—25 ml) before washing it with a saturated ~50 i NH^Cl solution. After extracting the aqueous fraction with ethyl acetate (25 ral x 1), the organic fractions were combined, dried (MgSOg) and concentrated. The residue was purified by column chromatography on silica gel eluting with 0-100% EA in hexane to obtain 5-bromo-2,3,3-trimethylisoindolin-l-one: ES / MS m / z: calculated for C-H ^BrNO (M+H): 254.02, found: 254.12 Stage 2, Stage 3 and Stage 4 4-(4-(2,3,3-trimethyl-l-oxoisoindolin-5i1)pheni1)-1H-1,2,3-triazole-5-carboxylic acid was prepared similarly to the procedure for the general procedures of the Suzuki reaction with intermediate 6 and 5-bromo-2,3,3trimethylisoindolin-l-one, and deprotection of PMB, followed by hydrolysis of ester::H NMR (400 MHz, DMSO-d?) δ 8.10 (d, J = 1.5 Hz, 1H), 8.00 (s, 2H), 7.89 (dd, J = 7.7, 5.6 Hz, 2H), 7.83 (dd, J = 7.9, 1.6 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 2.95 (s, 3H), 1.50 (s, 6H). ES / MS m / z: calculated for C2oH>jN40j (M+H): 363.15, found: 363.12. Example 153: 4-(4-(3,3-dimethyl-l-oxo-2-(2,2,2trifluoroethyl)isoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid - 188 - Stage 1 Stage 2 Stage S Stage 4 4-(4-(3,3-dimethyl-l-oxo-2-(2,2,2 trifluoroethyl)isoindolin-5-yl)phenyl)-1H-1,2,3-trrazole-5-carboxylic acid was prepared from 5-bromc-3,3-dinetilisoindolin-l-one similarly to the procedures of Example 154 using 2,2,2-1rifluoroethyl trifluoromethanesulfonate: -H NMR (400 MHz, DMSO-dd δ 8.11 (d ES / MS m / z: calculated for CmHgoFgNgOg (M+H): 431.13, found: 431.15. Example 154: 4-(9-methyl-9H-carbazole-2-yl)-1H-1,2,3triazole-5-carboxylic acid - 189 Stage 1 Ethyl 5-(9H-carbazole-2-yl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate was prepared similarly to the procedure for the procedures generalities of the Suzuki reaction with intermediate 4 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-9H-carbazole. Stage 2 To a solution of ethyl 5-(9H-carbazole-2-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-4-carboxylate (0.060 g; 0.068 mmol ) in dimethylformamide (1 ml) 60% sodium hydride in mineral oil (0.008 g; 0.21 mmol) was added and stirred for 30 min before the addition of Mel (0.009 ml; 0.13 mmol). The solution was left stirring at room temperature overnight. Once complete, the mixture was diluted with ethyl acetate (10 mL) and washed with saturated NHuCl (1 mL). The aqueous fraction was then extracted with ethyl acetate (2 x 10 ml), the organic fractions were combined and washed with 5% LiCl (3 x 5 ml). Finally, the organic fraction was washed with water (5 ml), dried (Na^SO;) and concentrated to dryness before purification by column chromatography on silica gel eluting with ethyl acetate in hexanes to produce 5- Ethyl (9-methyl-9Hcarbazol-2-yl)-2-((2-(trimethylsi1i1)ethoxy)methyl)-2H-1, 2,3- 190 triazole-4-carboxylate: ES / MS m / z Calculated for C24H31N4O3YES (M+H) = 451.22, Found 450.90. Stage 3 4-(9-methyl-9H-carbazole-2-yl)-1H-1,2,3triazole-5-carboxylic acid was prepared similarly to the procedure for general SEM deprotection procedures by TBAF, followed by ester hydrolysis : -H NMR (400 MHz, Methanol-d;) δ 8.21 - 8.09 (m, 2H), 8.06 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.23 (ddd, 0 = 7.9, 6.6, 1.6 Hz, 1H), 3.92 (s, 3H). ES / MS m / z: Calculated for CyH-CEOj (M-H) = 291.09; Found 291.11. Example 155: 4-(4-(6-(1H-1,2,3-triazol-4-yl)pyridazin3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid O^OEt β Stage 1 N-N -—?, L.w?\ — / \ — / Κι N. -- -- NSEM HO. „0 T Stage2 Stage! Stage4 7 / / \\ 'NH H 0=7^7 Stage 1 An isomeric mixture of ethyl 5-(4-(6-bromopyridazin-3yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole4-carboxylate was prepared from of intermediate 6 and 3,6-dibromopyridazira similarly to the procedure for the preparation of intermediate 10: ES / MS - 191 m / z: calculated for CyiHi-BrNsOjSi (M+H) : 504.11, found: 504.14 and 504.18 . Stage 2, Stage 3 and Stage 4 4-(4-(6-(lH-l,2,3-triazol-4i1)pyridazin-3-i1)pheni1)-1H-l,2,3-triazole-5-carboxylic acid was prepared in a similar manner to the general procedures of the Suzuki reaction with compound 28, followed by SEM deprotection by HC1 and hydrolysis of the ester::H NMR (400 MHz, Methanol-d,·) δ 8.53 (s, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.24 - 8.15 (m, 2H), 8.12 - 8.03 (m, 2H). ES / MS m / z: calculated for C-^-.ΝαΟ,· (M+H): 335.10, found: 335.11. Example 156: 4-(4-(5-(1H-1,2,3-triazol-4-yl)pyrazin-2yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid 0.,....051 ,—I c . / / u „ Stage 1 yj—N3,.R,Mv < Of '**““'4,’ F ~ \\ \\ ,·sv N—Z N-- N 'SEM H.O. ..0 r Stage 2 StageS Stage 4 N<Z / / Y or \\ y / NH ....................28..............* .............. ..................* ............................... ............* 4-(4-(5-(1H-1,2,3-triazol-4-yl)pyrazin2-i1)pheny1)-1H-1,2,3-1ryazol-5-carboxy1ic acid was prepared from 2,5dibromopyrazine similarly to the procedures of Example 157: -H NMR (400 MHz, Methanol-d;) δ 9.30 (s, 1H), 9.22 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 8.2 Hz, 2H), 8.06 (d, J = - 192 - 7.7Hz, 3H). ES / MS m / z: calculated for CmHmN30? (M+H) : 335.10, found: 335.10. Example 157: 4-(3'-methyl-4'-(1H-1,2,3-triazol-5-yl)[1,1'-biphenyl]-4-yl)-1H-1,2 acid, 3-triazole-5-carboxylic acid Stage 1 An isomeric mixture of ethyl 5-(4-(6-bromopyridazin-3yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole4-carboxylate was prepared from of intermediate 6 and l-bromo-4-iodo-2-methylbenzene similarly to the procedure for the preparation of intermediate 10: ES / MS m / z: calculated for CjuHmBrNOjSi (M+H): 516.11, found: 516.02. Stage 2, Stage 3 and Stage 4 4-(3'-methyl-4'-(lH-l,2,3-triazol-4-yl)[ 1,1'-bipheni1]-4-yl)-1H-1,2,3 acid was prepared -5-carboxylic triazole similar to the general procedures of the Suzuki reaction with compound 28, followed by SEM deprotection by HCl and hydrolysis of the ester::H NMR (400 MHz, Methanol-d;) δ 7.97 (d , J = 8.0 Hz, 3H), 7.77 (d, J = 8.3 Hz, 2H), 7.73 7.53 (m, 3H), 2.54 (s, 3H). ES / MS m / z: calculated for C:3H:5N5O2S (M+H): 347.12, found: 347.15. - 193 Example 158: 4-(4'-chloro-2-cyano-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole-5-carboxylic acid Stage 1 Combined were (5-bromo-2-iodobenzonitrile (1000 mg; 3.25 mmol), (4-chlorophenyl)boronic acid (559 mg; 3.57 mmol), triphenylphosphine (26 mg; 0.097 mmol), palladium acetate (36 mg; 0.162 mmol), potassium phosphate (1347 mg; 9.74 mmol), toluene (4 ml) and water (2 ml) in a flask and purged with Ar for 5 minutes. The reaction was then heated to 60°C for 70 minutes. The reaction mixture was then diluted with water and extracted with ethyl acetate before filtering through diatomaceous earth / celite before concentrating to dryness under reduced pressure. The crude reaction mixture was purified by flash chromatography (0 to 100% of ethyl acetate / hexanes) to give 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carbonitrile: 1H NMR (400 MHz, chloroform -d) δ 7.89 (d , J = 2.1 Hz, 1H), - 194 - 7.77 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (s, 4H), 7.36 (d, J = 8.4 Hz, 1H). Stage 2 4'-Chloro-4-(4,4,5,5-tetramethyl-l, 3,25 dioxaborolan-2-yl)-[1,1'-biphenyl]-2-carbonitrile was prepared from 4-bromo -4'-chloro-[1,1'-biphenyl]-2-carbonitrile in a similar manner to the representative procedure for the preparation of the boronate ester. Stages 3, 4 and 5 4-(4'-Chloro-2-cyano-[l,l'-biphenyl]-4yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared similarly to the general reaction procedures. of Suzuki with the compound 4 and 4'-chloro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-[1,1'-biphenyl]-2-carbonitrile, followed SEM deprotection by TBAF and ester hydrolysis: -H NMR (400 MHz, Methanol-d,·) δ 8.46 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.72 - 7.59 (m, 3H) ), 7.58 - 7.50 (m, 2H). ES / MS m / z: Calculated for CoíH;:C1N.:O.; (M+H) = 325.05; Found 325.03. Example 159: 4-(4'-(lH-imidazol-l-yl)-[1,1'-biphenyl]-420yl)-1H-1,2,3-triazole-5-carboxylic acid Stage 2 - 195 Stage 1 Tris(benzylideneacetone)dipalladium (20 mg; 0.0039 mmol), 2-di-tert-butyphosphino-3,4,5,6-tetramethyl2',4',6'-triisopropyl-1,1'-biphenyl (8) were loaded mg; 0.016 mmol) and tribasic potassium phosphate (83 mg, 0.39 mmol) into the reaction vessel and the headspace was purged with nitrogen gas for 10 minutes. Separately, imidazole (16 mg; 0.23 mmol) and ethyl 5-(4'-bromo-[1,1'biphenyl]-4-yl)-2-((2-(tramethiIsilyl)ethoxy)methyl)- were dissolved 2H-1,2,3triazole-4-carboxylate (98 mg; 0.2 mmol) in toluene-dioxane 5:1 (v / v) (3.0 ml) and purged with nitrogen gas for 10 minutes. The imidazole solution was added to the reaction vessel and the reaction was heated to 110 °C until the reaction was complete. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH.;C1 (3x5 mL). The aqueous layer was extracted with ethyl acetate (2x5 ml) and the combined organic fractions were washed with water (2x5 ml). Finally, the organic fraction was dried (Na2SO4) and concentrated to dryness before purification by column chromatography on silica gel eluting with ethyl acetate in hexanes to obtain 5-(4'-(IH-imidazol1-yl)- [1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: Calculated for C26H32N5O3YES (M+H) = 490.23; Found 490.39. - 19 6 Stages 2 and 3 4-(4'-(IH-imidazole-l-yl)-[1, 1' biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxy1ic acid was prepared similarly to general SEM deprotection procedures by TBAF followed by ester hydrolysis: -H NMR (400 MHz, Methanol-dd δ 9.48 (s, 3H) , 8.145(t, 1H) 8.00 (dd, J = 12.2, 8.5 Hz, 3H ), 7.83 (dd, J = 8.4, 6.2 Hz, 4H). ES / MS m / z: Calculated for C2gH24N2O2(M+H) = 332.11; Found 332.14. Example 160: 4-((4-chlorophenyl)ethynyl acid )-1H-1,2,3-triazole5-carboxylic acid Stage 1 A mixture of elyl 5-bromo-2-((2(trimethiIsili1)ethoxy)methi 1)-2H-1,2,3-triazole-4-carboxylate (114 mg, 0.033 mmol), copper(I) iodide ( 19 mg, 0.0098 mmol), l-chloro-4-ethynylbenzene (55 mg, 0.40 mmol), triethylamine (0.363 ml, 3 mmol), and dichlorobis(triphenylphosphine)palladium(II) (41 mg; 0.0065 mmol) in acetonitrile ( 3 ml) was purged with N2 for 10 min and heated to 60°C overnight. More copper(I) iodide and - 197 dichlorobis(triphenyl-phosphine)palladium(II) as necessary to improve conversion to the desired product. Once deemed sufficiently complete by LC / MS, the reaction was diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was washed sat. NH..;C1 (2x9 mi) and NaHCO3(aq). The aqueous layers were extracted with ethyl acetate (1 x 10 ml). The combined organic extracts were washed with water (1 x 10 ml), dried (NazSO.¡) and concentrated before purification by column chromatography on silica gel eluting with 0-100% ethyl acetate in hexanes to provide 5 -( (4-chlorophenyl)ethynyl)2- ((2-(trimethiIsili1)ethoxy)methyl)-2H-1,2,3-triazole-4carboxylate ethyl: -H NMR (400 MHz, Acetonitrile-d;) δ 7.64 - 7.56 (m, 1H), 7.52 - 7.45 (m, 1H), 5.98 (d, J = 9.7 Hz, 1H), 5.72 (s, OH), 4.51 - 4.37 (m, 1H), 3.75 - 3.58 ( m, 1H), 2.14 (s, 2H), 2.11 (d, J = 1.2 Hz, OH), 1.45 - 1.34 (m, 2H), 1.29 (s, OH), 0.97 - 0.83 (m, 1H). ES / MS m / z Calculated for CisHgíClNgOíSi (M+H) = 406.14 ; Found 406.86. Stages 2 and 3 4-((4-Chlorophenyl)ethynyl)-1H-1,2,3-triazole-5carboxylic acid was prepared using general procedures for SEM deprotection by TBAF followed by hydrolysis of the ester:3H NMR (400 MHz, Methanol- d,·) δ 7.57 (d, J = 8.4 Hz, 2H) , 7.43 (d, J = 8.4 Hz, 2H) , . ES / MS m / z: calculated for CmH^ClNjOx (M+H) = 248.02; Found: 247.96. 198 Example 161: 4-(1-(oxetan-3-yl)piperidin-4-yl)-1H1,2,3-triazole-5-carboxylic acid Stage 1 Stage 2 bA Boc-N N. 'SEM Stage 3,\AnH Stage 5 HO- A '-NH A Stage 1 In a microwave reaction vial, the isomeric mixture of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4, 285mg, 0.814 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)3,6-dihydropyridin-1(2H)-carboxylate (277 mg, 0.89 mmol), tetrakis(triphenylphosphine)palladium (0) (94 mg, 0.081 mmol), potassium carbonate 2N (1022 mi, 2 mmol) and 1,4dioxane (4 mi). After purging with argon gas for 5 minutes, the resulting mixture was stirred at 110°C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCO:· before extracting the product with ethyl acetate, dried (MgSO4), concentrated and purified by column chromatography on silica gel eluting with ethyl acetate in hexane to obtain tert-butyl 4— (5 — (ethoxycarbonyl)-2-((2-(trimethiIsyl 1)ethoxy)methyl)-2H-1,2,325 triazole-4-rl)-3,6-dihydropyridine-1( 2H)-carboxylate: ES / MS - 199 m / z: calculated for C;;H.;,N;O = Si (M+H) : 453.25, found: 452.68. Stage 2 A solution of tert-butyl carboxylate 4-(5(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)motyl)-2H-1,2,3triazol-4-yl)-3,6-dihydropyridine- l(2H) (120 mg, 0.27 mmol) in 4N HC1 in 1,4-dioxane (2 ml) was stirred at room temperature overnight. After concentrating the reaction mixture, the residue was purified using column chromatography on silica gel eluting with methanol in ie ethyl acetate to obtain 4-(1,2,3,6-tetrahydropyridin-4-yl)-1H1,2 Impure ethyl ,3-triazole-5-carboxylate.: ES / MS m / z: calculated for Cl-Hx-IDO, (M+H): 223.11, found: 223.01. Stage 3 A mixture of ethyl 4-(l,2,3,6-tetrahydropyridin-4-yl)-lH1,2,3-triazole-5-carboxylate (22 mg, 0.01 mmol) and 10% palladium on carbon (20 mg) in ethanol (1 ml) was stirred under a hydrogen atmosphere for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to obtain ethyl 4-(piperidin4-i 1)-1H-1,2,3-1riazole-5-carboxylate: ES / MS m / z: calculated for C10H1-N4O2 (M+H ): 225.13, found: 225.17. Stage 4 To a suspension of ethyl 4-(piperidin-4-11)-1H-1,2,3-1rrazole5-carboxylate (22 mg, 0.01 mmol) and 3-oxetanone (35 - 200 mg, 0.05 mmol) in TEF (1 ml) sodium triacetoxyborohydride (104 mg, 0.05 mmol) was added followed by a drop of acetic acid. The reaction mixture was stirred at room temperature overnight. After concentrating the reaction mixture, the residue was purified by preparative HPLC to obtain ethyl 4-(1-(oxetan-3-i1)piperidin-4-yl)-1H-1,2,3triazole-5-carboxylate: ES / MS m / z: calculated for CmHíiN-Cp (M+H) : 281.15, found: 281.18. Stage 5: 4-(l-(oxetan-3-yl)piperidin-4-yl)-lH1,2,3-triazole-5-carboxylic acid was prepared from 4-(1-(oxetan-3yl)piperidine -4- ethyl)-1H-1,2,3-triazole-5-carboxylate similarly to general ester hydrolysis procedures: -H NMR (400 MHz, Methanol-cL): δ 4.89 (m, 4H), 4.17 - 4.01 (m, 1H), 3.80 (m, 1H), 3.72 - 3.42 (m, 3H), 3.26 - 3.05 (m, 1H), 2.37 - 2.02 (m, 4H). ES / MS m / z: calculated for C — Hi-NjOj (M+H) : 253.12, found: 253.13. Example 162: 4-(4-(1-acetyl-l,2,3,6-tetrahydropyridin4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid □ EEO-m Stage 3 PMB - 201 Stage 1 The isomeric mixture of tert-butyl carboxylate 4-(4-(5(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4yl)phenyl)-3,6-dihydropyridine-l (2H)- Prepared from intermediate 11 and 4-(4-(4,4,5,5-tetramethi11,3,2-dioxaborolan-2-yl)phenyl)-3,6-tert-butyl carboxylate dihydropyridin1 (2H)- similarly to the general Suzuki reaction procedures: ES / MS m / z: calculated for CcH;<;0; (M+H) : 519.26, found: 518.98 and 518.96. Stage 2 To a flask containing the isomeric mixture of tert-butyl carboxylate 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)phenyl)- 3,6-dihydropyridin -1(2H)- (128 mg, 0.25 mmol) 4N HC1 in 1,4-dioxane (3 ml) was added and the resulting mixture was stirred at room temperature for 15 min. After completely concentrating the solution, acetic anhydride (0.05 ml, 0.53 mmol) was added to the residue and pyridine (0.05 ml, 0.62 mmol) in dichloromethane (3 ml) at 0°C. After 30 min at 0°C and 30 min at room temperature, the reaction mixture was diluted with ethyl acetate (—25 ml) and washed with saturated aqueous ammonium chloride (x 1), saturated aqueous sodium bicarbonate (x 1) and brine (xl) . After extracting the aqueous fractions with ethyl acetate (~20 ml x 1), the organic fractions were combined, dried (MgSOg), and concentrated. The residue - 202 was purified by column chromatography on silica gel eluting with 50-100% ethyl acetate in hexane followed by 0-20% methanol in ethyl acetate to obtain the isomeric mixture of 5-(4- (1- ethyl acetyl-1,2,3,6-tetrahydropyridin -4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4carboxylate: ES / MS m / z: calculated for C2._H22N40q (M+H): 461.22, found: 460.94 and 461.17. Stage 3 and Stage 4 4-(4-(1-acetyl-1,2,3,6tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedures of deprotection of PMB followed by hydrolysis of the ester::H NMR (400 MHz, Methanol-d-;) δ 7.82 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 6.24 (s , 1H), 4.23 (dq, J = 5.8, 2.6 Hz, 2H), 3.81 (t, J = 5.8 Hz, 0.83H), 3.76 (t, J = 5.7 Hz, 1.17H), 2.66 (d, J = 6.6 Hz, 1.17H), 2.59 (s, 0.83H), 2.18 (s, 1.755H), 2.15 (s, 1.245H). ES / MS m / z: calculated for C;¿H; N+Cn (M+H): 313.13, found: 313.10. Example 163: 4-(4-(l-acetylpiperidin-4-yl)phenyl)-1H1,2,3-triazole-5-carboxylic acid oHO. ° í to.Λ Stage 1 O / —sr—<. k.,., Stage? Stage 3 O, / \ y y / -NH25--- W W w* -----* W / \ / \.._ / m-N / V—yx= / N'n To a flask containing the isomeric mixture of 4-(4-(1acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-(4 - ethyl 203 methoxybenzyl)-1Η-1,2,3-triazole-5-carboxylate. (The product of Example 164 step 2, 55 mg, 0.12 mmol) 20% palladium hydroxide on carbon (6.6 mg) and ethanol (4 ml) were added, and the resulting mixture was stirred under H2 atmosphere. For 3.5 hours at room temperature. The reaction mixture was diluted with methanol and dichloromethane before filtering through a pad of celite. After washing the celite layer with ethanol, the filtrate was completely concentrated, co-evaporated with toluene (x 1), to obtain a crude isomeric mixture of 5-(4-(1-acetylpiperidin-4yl)phenyl)- Ethyl 2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: calculated for C2-H3iN4O-¡ (M+H) : 463.23, found: 463.04 and 463.06. Stage 2 and Stage 3 4-(4-(l-acetylpiperidin-4-yl)phenyl)-lH1,2,3-triazole-5-carboxylic acid was prepared similarly to the general PMB deprotection procedures followed by ester hydrolysis:2H NMR (400 MHz, Methanol-ch) δ 7.80 7.70 (m, 2H), 7.41 - 7.30 (m, 2H), 4.68 (ddt, J = 13.2, 4.4, 2.2 Hz, 1H), 4.15 - 3.95 (m, 1H) , 3.25 (dt, J = 13.0, 2.9 Hz, 1H), 2.89 (tt, J = 12.1, 3.6 Hz, 1H), 2.+3 (td, J = 13.0, 2.7 Hz, 1H), 2.14 (s, 3H), 1.92 (dot, J = 17.2, 14.8, 2.9 Hz, 2H), 1.73 and 1.62 (two qd, J = 12.5, 4.1 Hz, 2H). ES / MS m / z: calculated for C.cH-gNgOs (M + H) : 315.15, found: 315.14. - 204 Example 164: 4-(4'-(pyrazin-2-yl)-[1,1'-biphenyl]-4-yl)1H-1,2,3-triazole-5-carboxylic acid l! Hü ¿r—N C+B~ / z K)—Br __—.....» (j V-Br HC)X-=' N=-Z'ώ / O HOStage 1 Stage 4 Stage 5 \· Z^NH Stage 1 A mixture of pyrazine (200 mg; 2 mmol), 4-bromophenylboronic acid (552 mg; 3 mmol), trifluoroacetic acid (0.191 ml; 2 mmol), tetrabutylammonium bromide (40 mg; 0.125 mmol), potassium persulfate (2.0 g; 7 mmol) and iron (iii) acetylacetonate (440 mg, 1 mmol) in CH2Cl2 (10 ml) and water (10 ml) were stirred at room temperature overnight. The reaction mixture was diluted with ch2cl2 (10 ml) and water (10 ml) and solid potassium carbonate was added until pH>8. After separating two layers, the aqueous fraction was extracted with dichloromethane (2 x 10 ml) and the combined organic fractions were dried (NazSCt), concentrated and purified by column chromatography on silica gel eluting with 0-ethyl acetate. 100 í in hexanes) to produce 2(4-bromophenyl)pyrazine: -H NMR (400 MHz, chloroform-d) δ 9.01 (d, J = 1.5 Hz, 1H), 8.63 (dd, J = 2.5, 1.5 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.69 - 7.61 (m, 2H). - 205 ES / MS m / z calculated for C;YBrN2 (n+H) = 234.99; found, 235.05. Stages 2, 3 and 4 4-(4'-(pyrazin-2-yl)-[l,l'-biphenyl]4-i1)-1H-1,2,3-triazole-5-carboxylic acid was synthesized from 2-(4Bromophenyl )pyrazine using representative procedures for the Suzuki reaction with intermediate 6, SEM deprotection with HC1 and ester hydrolysis.:H NMR (400 MHz, DMSO-dr) δ 13.21 (s, 1H), 9.32 (d, J = 1.6 Hz, 1H), 8.73 (dd, J = 2.5, 1.5 Hz, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.30 - 8.23 ​​(m, 2H), 7.96 - 7.86 (m, 6H). ES / MS m / z: Calculated for CljHlíNsO; (M+H) = 344.11; Found 344.04. Example 165: 4-(4'-(1H-1,2,4-triazol-5-yl)-[1,1'biphenyl]-4-yl)-1H-1,2,3-triazol-5 acid -carboxylic Stage 2 - 206 Stage 1 An isomeric mixture of 5-(4'-carbamoi1-[1,1'-bifeni1] 4-yl)-2 - ((2-(trimethiIsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4carboxylate Ethyl was prepared similarly to the general Suzuki reaction procedure from 4-bromobenzamide and intermediate 6: ES / MS m / z: calculated for C24H30N4O4YES (M+H) = 467.2; Found 467.16. Stage 2 To a solution of 5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)2-((2-(trimethiIsili1)ethoxy)methyl)-2H-1,2,3-triazole-4carboxylate of ethyl (117 mg; 0.25 mmol) in THF (1 ml), t-butoxybis(dimethylamino)methane (Bredereck's reagent; 62 pl; 0.30 mmol) was added. The mixture was then heated to 60°C until the starting material was consumed and (E)-5-(4'-(((dimethylamino)methylen)carbamoyl)-[1, 1' biphenyl]-4 appeared. -yl)-2-( (2-(trimethiIsilyl)ethoxy)methyl)-2H-1,2,3triazole-4-carboxylate ethyl. The material from this reaction was used directly in step 3: ES / MS m / z: calculated for CvHa^N-CnSi (M+H) = 522.25; Found 522.11. Stage 3 Hydrazine (39 μΐ; 1 mmol) and acetic acid (109 μΐ; 2.0 mmol) were added to the reaction mixture from step 2 and heated to 60°C. Once completed by LC / MS, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NaHCOj (2x5 mL). After extracting the fraction - 207 aqueous with ethyl acetate (2 x 10 ml), the organic fractions were combined, washed with 1N HCl (5 ml) and water (5 ml), dried (Na^SO^) and concentrated to dryness. The crude product, 5-(4'-(1Η-1,2,4-1riazol-5-yl)-[1, 1'-bifeni1 ] 4-yl)-2-((2-(trimethylsilyl)ethoxy) ethyl methi1)-2H-1,2,3-triazole-4carboxylate, was used directly in step 4 without additional purification::H NMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.18 (d , J = 8.0 Hz, 1H), 7.94 (dd, J = 26.9, 8.1 Hz, 1H), 7.70 (ddd, J = 21.3, 12.8, 7.8 Hz, 3H), 7.58 (t, J= 7.2 Hz, OH) , 7.53 - 7.45 (m, OH), 6.05 (s, OH), 5.77 (s, 1H) , 4.50 - 4.36 (m, 1H) , 4.12 (q, J = 7.1 Hz, 2H) , 3.81 3.72 (m, 1H), 3.70 - 3.61 (m, OH), 2.11 (s, 1H), 2.04 (s, 3H), 1.45 - 1.31 (m, 2H), 1.25 (t, J = 7.1 Hz, 4H), 0.95 (dt , J = 15.9, 8.3 Hz, 1H). ES / MS m / z: calculated for C25H30N.O3YES (M-H) = 491.21; Found 491.25. Stages 4 and 5 4-(4'-(lH-l,2,4-triazol-5-yl)-[l,l'biphenyl]-4-yl)-1H-1,2,3-triazol-5- acid was prepared carboxylic acid similarly to general SEM deprotection procedures by HCl, followed by hydrolysis of the ester::H NMR (400 MHz, DMSO-di) δ 8.49 (s, 1H), 8.15 - 8.08 (m, 2H), 7.96 - 7.81 (m, 6H) . ES / MS m / z calculated for C:-HmN.;O:. (m+H) 333.10; found 333.11. Example 166: 4-(7-bromo-9H-fluoren-2-yl)-1H-1,2,3triazole-5-carboxylic acid - 208 Stage 1 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-9H-fluoren-2-amine was prepared similarly to the representative procedure for the synthesis of boronate from aromatic bromide using bis (pinacolato)diboron (27): Stage 2 The isomeric mixture of ethyl 5-(7-amino-9H-fluoren2-yl)-2 - ((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4carboxylate of intermediate 4 was prepared and 7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-amine similarly to the general Suzuki reaction procedures: ES / MS m / z: calculated for Cg^HjiN^OjSi (M+H) : 451.22, found: 451.33. Stage 3 To a solution of 5-(7-amino-9H-fluoren-2-yl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate - 209 ethyl (1.00 g, 2.22 mmol) in acetonitrile (12 ml) t-butyl nitrite (0.32 ml, 2.69 mmol) and cupric bromide (595 mg, 2.66 mmol) were added at 0°C. After 45 min, the reaction mixture was quenched with Na-SiO solution; 1M and the product was extracted with ethyl acetate. The extract was dried (MgSCh), concentrated and purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in hexane to obtain a mixture of 5-(7-bromo-9H-fluoren-2 Desired ethyl -yl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate with deaminated by-product. The mixture was used for the next reaction without further purification. Stages 4 and 5 4-(7-Bromo-9H-fluoren-2-yl)-1H-1,2,3triazole-5-carboxylic acid was prepared similarly to the general SEM deprotection procedures by HC1 and ester hydrolysis: -H NMR (400 MHz, Methanol-d,) δ 8.03 (s, 1H), 7.94 - 7.82 (m, 2H), 7.81 - 7.71 (m, 2H), 7.54 (dd, J = 8.1, 1.8 Hz, 1H), 3.98 (s, 2H) . ES / MS m / z: calculated for CmHmBrClNO; (M+H): 355.92, found: 356.00. Example 167: 4-(7-chloro-9H-fluoren-2-yl)-1H-1,2,3triazole-5-carboxylic acid - 210 - 4-(7-Chloro-9H-fluoren-2-yl)-1H-1,2,3triazole-5-carboxylic acid (56) was prepared similarly to the procedure of Example 168 Step 3 using copper(II) chloride. instead of copper(II) bromide, followed by the general SEN deprotection procedures by HC1 and ester hydrolysis: NMR (400 MHz, Methanol-ch) δ 8.03 (s, 1H), 7.94 - 7.81 (m, 3H), 7.60 (s, 1H), 7.39 (dd, J = 8.1, 1.9 Hz, 1H), 3.99 (s , 2H). ES / MS m / z: calculated for CigHcClNgOg (M+H) : 312.05, found: 311.93. Example 168: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2yl)-1H-1,2,3-triazole-5-carboxylic acid Stage 1 5-(7-(4,4,5,5-tetramethi1-1,3,2-dioxaborolan2-rl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl was prepared ethyl )-2H1,2,3-triazole-4-carboxylate similarly to - 211 representative procedure for the synthesis of boronate from aromatic bromide using bis(pinacolato)diboron (27). Stages 2, 3 and 4 4-(7-(1H-1,2,3-triazol-4-i1)-9Hfluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared similarly to the procedures generalities of the Suzuki reaction from 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-9H-fluoren-2-yl)-2-((2- ethyl (trimethi 1silyl)ethoxy)methi 1)-2H1,2,3-triazole-4-carboxylate and the boronate 28, followed by SEM deprotection by HC1 and hydrolysis of the ester: -H NMR (400 MHz, Methanol-dj) δ 7.80 - 7.70 (m, 2H), 7.41 7.30 (m, 2H), 4.68 (ddt, J = 13.2, 4.4, 2.2 Hz, 1H), 4.15 3.95 (m, 1H), 3.25 (dt, J = 13.0, 2.9 Hz, 1H), 2.89 (tt, J = 12.1, 3.6 Hz, 1H), 2.73 (td, J = 13.0, 2.7 Hz, 1H), 2.14 (s, 3H), 1.92 (ddt, J = 17.2, 14.8 , 2.9 Hz, 2H), 1.73 and 1.62 (two qd, J = 12.5, 4.1 Hz, 2H) . ES / MS m / z: calculated for CigHiaNgCh (M+H) : 345.10, found: 345.11. Example 169: 4-(9,9-difluoro-7-(1H-1,2,3-triazol-4-yl)9H-fluoren-2-yl)-1H-1,2,3-triazol-5 acid -carboxylic - 212 - Stage 1 4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole was prepared in a similar manner to the general procedures of the Suzuki reaction from 2-bromo-9,9-difluoro-7-iodo-9Hfluorene and boronate 28: ES / MS m / z: calculated for C-zHzyBrFzNzOSi (M+H): 478.08, found: 477.76. Step 2, 4-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-( (2(trimethylsi1i1)ethoxy)methyl)-2H-1,2, 3-1riazole from 4(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-((2(trimethylsilyl )ethoxy)methyl)-2H-1,2,3-triazole similarly to the representative procedure for the synthesis of boronate from aromatic bromide using - 213 bis(pinacolato)diboron (27): ES / MS m / z: calculated for C2 / H^BF. / NjCpSi (M+H) : 526.25, found: 525.96. Step 5, Step 6 and Step 7 prepared 4-(9,9-difluoro-7-(lH-l,2,3-triazol-4yl)-9H-fluoren-2-i1)-1H-1,2 acid ,3-triazole-5-carboxylic acid in a manner similar to the general procedures of the Suzuki reaction using the intermediate 4 and 4-(9,9-difluoro-7(4,4,5,5-tetramethi1-1,3, 2-dioxaborolan-2-yl)-9H-fluoren-2yl)-2 - ((2-(trimethylsilyl)ethoxy)methyl)-2H-1, 2, 3-triazole, followed by SEM deprotection by HC1 and ester hydrolysis : -H NMR (400 MHz, Methanol-d,) δ 8.45 - 8.01 (m, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 8.13 - 8.01 (m, 2H), 7.85 (t, J = 7.0 Hz, 2H). ES / MS m / z: calculated for C;-E; LF2N.O2 (M+H) : 381.09, found: 381.06. Example 170: 4-(9,9-difluoro-7-(lH-l,2,3-triazol-4-yl)9H-fluoren-2-yl)-lH-pyrazole-5-carboxylic acid EITHER F F HO Y HN __ Y ' NH 4-(9,9-difluoro-7-(lH-l,2,3-triazol-4yl)-9H-fluoren-2-yl)-lH-pyrazole-5-carboxylic acid was prepared similarly to the procedures generalities of the Suzuki reaction of intermediate 15 and acid 4-(9,9-difluoro-7-(1H1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2 ,3-triazole-5carboxylic acid, followed by SEM deprotection by HC1 and - 214 ester hydrolysis: -H NMR (400 MHz, Methanol-d,) δ 8.2 / (s, 1H), 8.11 (d, J = 1.7 Hz, 1H), 8.03 (dd, J = 7.9, 1.5 Hz, 1H), 7.89 (s, 1H), 7.88 - 7.84 (m, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.77 - 7.70 (m, 2H). ES / MS m / z: calculated for C19H12F2N5O2 (M+H): 380.10, found: 380.11. Example 171: 4-(7-(1,5-dimethyl-lH-l,2,3-triazol-4-yl)9,9-difluoro-9H-fluoren-2-yl)-1H-1,2 acid 3-triazole-5-carboxylic acid Stage 1 A mixture of 2,7-dibrcmo-9,9-difluoro-9H-fluorene (2000 mg, 5.56 mmol), bis(pinacolato)diboron (5646 mg, 22.2 mmol), dichloro 1,1'-bis(diphenylphosphino)ferrocene Palladium(II) dichloromethane (679 mg, 0.83 mmol) and potassium acetate (2903 mg, 29.6 mmol) in 1,4-dioxane (50 mL) were purged with argon gas for 15 min and then stirred at 80°C. for 16 hours. The reaction mixture was completely concentrated and the residue was dissolved in ethyl acetate (-300 ml) and washed with water (-250 ml x 2). The aqueous fractions were then extracted with ethyl acetate (-100 ml x 1), the organic fractions were combined, dried (Na2SO.j) and concentrated. He - 215 residue was purified by column chromatography on silica gel eluting with 0-20% ethyl acetate in hexanes to obtain 2,2'-(9,9-difluoro-9H-fluorene-2,7diyl)bis(4 ,4,5,5-tetramethyl-l,3,2-dioxaborolane)::H NMR (400 MHz, Chloroform-d) δ 8.08 (dt, J = 2.0, 0.9 Hz, 2H), 7.95 7.89 (m, 2H ), 7.60 (dd, J = 7.5, 0.9 Hz, 2H), 1.36 (s, 24H). without mass. Stage 2 An isomeric mixture of 5-(9,9-difluoro-7-(4,4,5,5tetramethyl1-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-(( Ethyl 2(t ri metí 1 si 1 i 1)ethoxy)metí 1)-2H-1,2,3-triazo]-4-carboxylate was prepared similarly to the general procedures of the Suzuki reaction from the intermediate 4 and 2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(4,4,5,5tetramethyl-1,3,2-dioxaborolane) : ES / MS m / z : calculated for CmHjiBFzNaCtSi (M+H) : 598.27, found: 597.81 and 597.67. Stage 3, Stage 4 and Stage 5 4-(7-(1,5-dimethi 1-1H-1,2,3-1riazol-4yl)-9,9-difluoro-9H-fluoren-2-yl)-lH-l,2 acid was prepared ,3-triazole-5carboxylic acid similarly to the general Suzuki reaction procedures using 4-bromo-l,5-dimethyl-lH1,2,3-triazole and the isomeric mixture of 5-(9,9-difluoro- 7(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-9H-fluoren-2í1)-2- ((2-(trimethylsilyl)ethoxy)methyl)-2H-1, Ethyl 2,3-triazole-4carboxylate, followed by SEM deprotection by HC1 e - 216 hydrolysis of ester::H NMR (400 MHz, Methanol-ah) δ 8.20 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 4.06 (s, 3H), 2.54 (s, 3H). ES / MS m / z: calculated for C2:HvF2N¿02 (M+H) : 409.12, found: 409.14. Example 172: 4-(9,9-difluoro-7-(2-methyl-2H-l,2,3triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3 acid triazole-5carboxylic p R. F HO-7 n-n X Xnh ‘ \\ 77-+. / 7 ' 4-(9,9-difluoro-7-(2-methyl-2H-l,2,3triazol-4-yl)-9H-fluoren-2-yl)-lH-l,2,3-triazole acid was prepared -5-carboxylic acid similarly to the general procedures of the Suzuki reaction using 4-bromo-2-methi1-2H-1,2,3triazole and the isomeric mixture of 5-(9,9-difluoro- 7-(4 ,4,5,5tetramethi 1-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2 - ((2(trimethiIsili1)ethoxy)methi 1)-2H-1,2, Ethyl 3-triazol-4-carboxylate, followed by SEM deprotection by HC1 and hydrolysis of the ester::H NMR (400 MHz, Methanol-d,;) δ 8.19 (s, 1H), 8.11 (s, 3H), 8.03 (d, J = 7.9 Ez, 1H), 7.83 (d, J = 8.0 Hz, 2H), 4.24 (s, 3H) . ES / MS m / z: calculated for C7,H_-F2N,O; (M+H) : 395.11, found: 395.03. Example 173: 4-(6-chloro-9H-fluoren-2-yl)-lH-l,2,3triazole-5-carboxylic acid - 217 - Stage 1 A mixture of l-bromo-4-iodobenzene (1.00 g, 3.5 mmol), 4-chlorobenzonitrile (973 mg, 7.1 mmol), bis(acetonitrile)palladium(II) chloride (92 mg, 0.35 mmol), and silver oxide (I) (901 mg, 3.9 mmol) in trifluoroacetic acid (35 ml) and dimethylacetamide (1.75 ml) was purged with argon gas. After 15 min, water (64 μΐ) was slowly added dropwise to the mixture while purged with argon. After 1 min, the flask was kept airtight and heated at 140 °C for 90 h. After cooling, the reaction mixture was diluted with dichloromethane, filtered through a pad of celite, and the resulting filtrate was concentrated. After dissolving the residue in dichloromethane and aqueous HC1, the insoluble material was filtered again through a layer of celite and the two layers of filtrate were separated. The fraction -218 organic was dried (MgSCq), concentrated and purified by column chromatography on silica gel eluting with 0-100% ethyl acetate in hexane to obtain 2-bromo-6chloro-9H-fluoren-9-one. Stage 2 To a solution of 2-bromo-6-chloro-9H-fluoren-9-one (33 mg, 0.11 mmol) in tetrahydrof urane (1 ml) was added 1M lithium triethylborohydride (0.34 ml) at -78°C. After 25 min, the reaction mixture was quenched with aqueous NHqCl. After extracting the product with ethyl acetate (x 4), the organic extracts were combined, washed with brine (x 1), dried (MgSOJ, and concentrated to obtain 2-bromo-6-chlorc-9H-fluoren- crude 9-ol, which was used for the next step. Stage 3 To the crude 2-bromo-6-chloro-9H-fluoren-9-ol, triethylsiline (0.3 ml) and trifluoroacetic acid (0.3 ml) were added, and the resulting mixture was stirred at room temperature for 1.7 h. After concentration, the residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexane to obtain 2-bromo-6chloro-9H-fluorene. Stage 4 A mixture of 2-bromo-6-chloro-9H-fluorene (27 mg, 0.095 mmol), bis(pinacolato)diboron (29 mg, 0.11 mmol), [1,1' - 219 bis(diphenylphosphino)ferrocene]dichloropalladium(11) (7.8 mg, 9.5 pmol) and potassium acetate (28 mg, 0.29 mmol) in dioxane (1.5 ml) was placed in a microwave reaction vial and purged with gas argon. After the resulting mixture was stirred at 95°C for 2.25 h and cooled, the mixture was diluted with water and the product was extracted with ethyl acetate (x 4). The combined organic extracts were dried (MgSO4), concentrated and purified by column chromatography on silica gel eluting with 0-100 i ethyl acetate in hexane to obtain 2-(6-chloro-9ff-f luoren-2-yl )-4, 4, 5, 5tetramethi1-1,3,2-dioxaborolane. Stage 5, Stage 6 and Stage 7 4-(6-Chloro-9-oxo-9n-fluoren-2-yl)-lH1,2,3-triazole-5-carboxylic acid was prepared similarly to the general Suzuki reaction procedures using intermediate 4 and 2-(6-chloro-9H-fluoren-2-yl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane, followed by SEN deprotection by HC1 and ester hydrolysis: -H NMR (400 MHz , Methanol-cL) δ 8.05 (s, 1H) , 7.94 (d, J = 8.0 Hz, 1H) , 7.92 - 7.84 (m, 2H) , 7.57 (d, J = 8.0 Hz, 1H) , 7.33 (dd, J = 8.0, 2.0 Hz, 1H), 3.98 (s, 2H). ES / MS m / z: calculated for C_.;H;;C1N;CL (M+H) : 312.05, found: 311.96. Example 174: 4-(2-(piperidin-4-yl)-4'-(lH-l,2,3triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H acid 1,2,3-triazole-5 carboxylic acid - 220 - Stage 1 A mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (28, 403 mg, 1.45 mmol), l,4-bis(4, 4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-i1)benzene (5, 1.93 q, 5.84 mmol) and palladium tetrakis(triphenylphosphine) (0) (168 mg, 0.15 mmol) in 2 M potassium carbonate (2.9 ml) and 1,4dioxane (15 ml) in a 20 ml microwave reaction vial was purged with Ar for 10 minutes and then stirred in a bath at 110°C for 1.25 hours. The reaction mixture is -221 dissolved in ethyl acetate (-100 ml) and washed with ~50s of saturated NaHCO.. (x 1) and water (x 1). The aqueous fractions were then extracted with ethyl acetate (-50 ml x 1), the organic fractions were combined, dried (MgSO;) and concentrated. The residue was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in hexane. The partially purified product was further purified by column chromatography on silica gel eluting with 0-20% ethyl acetate in hexane to obtain 4-(4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-211)phenyl)-2 - ( (2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole: ES / MS m / z: calculated for C: lHvBNlCDYes (M+H) : 402.24, found: 401.96. Stage 2 A mixture of 5-bromo-2-iodobenzaldehyde (3.11 g, 10.00 mmol), diethyl malonate (6.45 g, 40.27 mmol), and potassium carbonate (5.57 g, 40.30 mmol) in DMF (20 mL) was stirred at 85°. C in a bath for 18 h. After cooling and diluting the reaction mixture with water (100 ml), the product was extracted with ethyl acetate (100 ml x 4). After washing the extracts with water (100 ml x 1), the combined extracts were dried (NazSO;) and concentrated. After treating the residue with concentrated HC1 (25 ml), the mixture was heated at reflux for 36 h. After the resulting mixture cooled in the refrigerator, the - 222 insoluble material was filtered and washed with water. The solids were dissolved in ethyl acetate (~100 ml), dried (MgSOJ and concentrated to obtain crude 3-(5-bromo-2iodophenyl)pentanedioic acid: ES / MS m / z: calculated for CmH — BrlCg (M +H) : 412.89, found: 412.58. Stage 3 A mixture of the above crude 3-(5-bromo-2-iodophenyl) pentanedioic acid in acetic anhydride (∼10 mL) was heated to reflux in a 155°C bath for 3 h. After concentrating the resulting solution, the remaining syrup was coevaporated with toluene (x 2) and dried under vacuum. The residue was dissolved in THE (50 ml) and stirred at room temperature as a 28° aqueous solution. NH solution was added; (0.65 mi each) three times with an interval of approximately 15 min. The resulting mixture was stirred at room temperature for 7 h. The resulting suspension was completely concentrated, co-evaporated with toluene (x 2) and dried. The residue was refluxed with acetic anhydride (15 ml) in a bath at 155°C for 4 h and cooled. The solution was concentrated and the residue was purified by silica gel column chromatography eluting with 060i ethyl acetate in hexanes to obtain 4-(5-bromo-2iodofeni1)piperidine-2,6-dione::H NMR (400 MHz, DMSO-d) δ 10.98 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.55 (d, J - 2.4 Hz, 1H), 7.25 (dd, J = 8.4, 2.4 Hz, 1H ), 3.52 (tt, J = 12.0, 4.1 - 223 Hz, 1H), 2.90 - 2.78 (m, 2H), 2.63 (dd, J = 16.7, 4.1 Hz, 2H). Stage 4 4-(5-Bromo-2-iodophenyl)piperidine-2,6-dione (1.60 g, 4.06 mmol) in THE (5 mL) was stirred at 0°C as a solution of 1.0 M borane tetrahydrofuran complex in THF (10.2 e) added drop by drop. After refluxing the resulting mixture for 20 h, concentrated HC1 (16 ml) was added to the mixture and the resulting solution was heated to reflux in a bath at 105°C for 4.5 h. The solution was stirred in an ice bath while NaOH (solid) was added to neutralize the mixture. The resulting basic solution was diluted with some NaHCOg solution and the product was extracted with ethyl acetate (—60 ml x 2). The extracts were washed with brine (x1), combined, dried (Na2SCg), and concentrated to obtain 4-(5-bromo-2-iodophenyl)piperidine as an oil. A solution of crude 4-(5-bromo-2-iodophenyl)piperidine in methanol (—25 ml) was stirred at 0°C while Boc2O (1078 mg, 4939 mmol) and triethylamine (0.8 ml, 5740 mmol) were added. After 2 h at C°C and at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate before washing with water (x2). The resulting organic fraction was dried (MgSO;), concentrated and purified by column chromatography on silica gel eluting with 0-10% EA in hexa.no to obtain ter - 224 butyl-4-(5-bromo-2-iodophenyl)piperidine-l-carboxylate: -H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.4 Hz, 1H), 4.27 (s, 2H), 2.94 - 2.85 (tt, J = 3.4, 12.9 Hz, 1H), 2.82 (s, 2H), 1.84 (d, J - 12.9 Hz, 2H) , 1.51 (dd, J =3.8, 12.9 Hz, 2H) , 1.48 (s, 9H) . Stage 5 A mixture of tert-butyl 4-(5-bromo-2iodophenyl)piperidine-l-carboxylate (250 mg, 0.63 mmol), 4-(4(4,4,5,5-tetramethyl-l,3,2-dioxaborolan -2-yl)phenyl)-2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (273 mg, 0.68 mmol), tetrakis (triphenylphosphine)palladium (0) (75 mg, 0.06 mmol) and 2 N potassium carbonate (0.6 ml) in dioxane (6 ml) was purged with Ar gas for 10 min and stirred in a 110°C bath for 1.5 h. After cooling, the mixture was diluted with ethyl acetate, dried (MgSO.;), concentrated and purified by column chromatography on silica gel eluting with 0-50% ethyl acetate in hexane to obtain ter- Butyl 4 - (4-bromo-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2 -yl)piperidine-1carboxylate: ES / MS m / z: calculated for C=H,iBrN,NaO-Si (M+Na) : 635.20, found: 635.14. Stage 6 A mixture of tert-butyl 4-(4-bromo-4'-(2-((2(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1, 1' - 225 biphenyl]-2-i1)piperidine-l-carboxylate (201 mg, 0.33 mmol), bis(pinacolato)diboron (27, 27 mg, 0.66 mmol), dichloro 1,1'bis(diphenylphosphino)ferrocene palladium (II) ) dichloromethane (116 mg, 0.03 mmol) and potassium acetate (102 mg, 1.04 mmol) in 1,4-dioxane (3 mL) in a microwave reaction vial was purged with Ar gas for 15 min before heating the mixture at 120°C for 1.5 h. After cooling, the reaction mixture was diluted with ethyl acetate, dried (MgSOJ) and concentrated. The residue was purified by column chromatography on silica gel eluting with 035% ethyl acetate in hexane to provide tert-butyl 4-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2 , 3-triazol-4-yl)-[1, 1'-biphenyl]-2yl)piperidine-l-carboxylate: ES / MS m / z: calculated for CvHmBNgNaCnSi (M+Na): 683.38, found: 683.35. Stage 7, Stage 8 and Stage 9 Acid 4-(2-(piperidin-4-i1)-4 '-(1H-1,2,3triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1Η -1 was prepared ,2,3-triazole-5carboxylic acid similarly to the general Suzuki reaction procedures using intermediate 4 and tert-butyl 4-(4-(4,4,5,5-tetramethi 1-1,3,2-dioxaborolan -2-i1) -4'(2-( (2-(trimethylsili1)ethoxy)methyl)-2 H-l,2,3-triazol-4-yl)[1,1'-biphenyl]-2-yl)piperidine -1-carboxylate, followed by SEM deprotection by HC1 and hydrolysis of the ester: -H NMR (400 MHz, Methanol-d,·) δ 8.23 ​​(s, 1H), 7.99 (d, J = 1.8 Hz, 1H), - 22 6 7.98 - 7.91 (m, 2H) , 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.49 7.41 (m, 2H) , 7.36 (d, J = 7.9 Hz, 1H) , 3.41 (dd, J = 12.8, 3.2 Hz, 2H), 3.21 - 3.03 (m, 1H), 2.93 (ddd, J = 16.6, 8.6, 5.2 Hz, 2H), 2.03 (tt, J = 8.6, 3.4 Hz, 4H). ES / MS m / z: calculated for C22H22N-O2 (M+H): 416.18, found: 416.14. Example 175: Ethyl 4-(7-(lH-l,2,3-triazol-4-yl)-9H-fluoren-2-yl)~ 1H-1,2,3-triazole-5-carboxylate PMB, N-N “γ-Ο 9 Ν ·1·.γ Br— ϊ 3 Yv--Br Stage 1 --9 8---. \\ / ·>—B. A~ Stage! +. / ............................ . ύ ϊ ; -----eleven; ϊ v » / PMB Eto-w Stage! Ν -N >N Ñ ​​.-.'--A 3, 9 '+-R .. Ñ '+-— 7 2 ^.-2 m PMB N y >· + O ' '11+ A 7 +' . / N PMB TheU^< Stage! AnH * HMA~N '2. 3 +-λ·Α Stage 1, Stage 2, Stage 3 and Stage 4 Ethyl 4-(7-(l+f-l,2,3-triazol-4-yl)-9H-fluoren-2yl)-1H-1,2,3-triazole-5-carboxylate was prepared similarly to those procedures described herein using intermediate 11 and 2,7-dibromo-9H-fluorene, followed in a similar manner to the general PMB::H deprotection procedures NMR (400 MHz, DMSO-di) δ 8.39 (s, 1H), 8.14 (s, 1H), 8.07 - 8.02 (m, 3H), 7.95 (d, J = 8.0 Hz, 1H), 7.82 (m, 1H), 4.32 (q, J = 7.0 Hz, 2H), 4.08 (s, 2H), - 227 1.28 (t, J = 7.0 Hz, 3H). ES / MS m / z: calculated for C22HVN.O2 (M+H): 373.14, found: 373.30. Example 176: 2-morpholinoethyl 4-(7-(lH-l,2,3-triazol-4-yl)-9H-fluoren-2-yl)1H-1,2,3-triazole-5-carboxylate Stage 1 To a stirred solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-i1)-9H-fluoren-2-yl)- 2H1,2,3-triazole-4-carboxylate (18 g, 29.4 mmol) in MeOH (36 ml), THF (108 ml) and water (36 ml) at room temperature under argon lithium hydroxide monohydrate (3.7 ml) was added g, 88.18 mmol). The reaction mixture was heated to 60°C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was diluted with water and acidified with HC1 IN solution and stirred for 10 min. The precipitated solid was filtered and washed with water and dried under vacuum to obtain 2-(4methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4yl) acid. -9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic: ES / MS - 228 m / z: calculated for (M+H): 585.23, found: 585.41. Stage 2 To a stirred solution of acid 2-(4-methoxybenzyl)-5-(7(2 -(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl) 2H-1,2,3-triazole-4-carboxylic acid (3.0 g, 5.14 mmol) in DMF (30 ml) at room temperature under argon, potassium carbonate (1.41 g, 10.3 mmol) was added, followed by 4-( 2chloroethyl)morpholine (1.53 g, 10.3 mmol). The mixture was heated to 50°C and stirred for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (NauSOj) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 80-100% ethyl acetate in petroleum ether to obtain 2-morpholinoethyl-2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)- 2E-l,2,3-triazol-4yl)-9H-fluoren-2-yl)-2H-l,2,3-triazol-4-carboxylate: ES / MS m / z: calculated for CcHxN-Cf (M +H) : 683.31, found: 698.52. Stage 3 A mixture of 2-morpholinoeti 1-2-(4-methoxybenzyl)-5-(7 (2 -(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2- il)2H-1,2,3-triazole-4-carboxylate (3.0 g, 4.3 mmol) in TFA (30 ml) was heated at 8°C for 16 h. Then, the reaction mixture was concentrated under reduced pressure and the residue - 229 crude oil was neutralized with a saturated NaHCO· solution; The product was extracted with ethyl acetate. The organic layer was dried (NasSO.;) and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC (Neutral method), and the pure fraction was lyophilized to obtain 2-morpholinoethyl 4-(7-(lH-l,2,3-triazol-4-yl)-9H-fluoren- 2-yl)-lH-l,2,3triazol-5-carboxylate: -H NMR (400 MHz, DMSO-d;) δ 8.41 (s, 1H), 8.14 (s, 1H), 8.05 (t, J = 8.4 Hz, 2H), 8.00 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 5.6 Hz, 2H), 4.08 (s, 2H), 3.49 (t, J = 4.6 Hz, 4H), 2.61 (t, J = 5.6 Hz, 2H), 2.49-2.33 (m, 4H). ES / MS m / z: calculated for C2-4H24N;O3 (M+H): 458.19, found: 458.32. Example 177: 3-morpholinopropyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)1H-1,2,3-triazole-5-carboxylate PMB n-n N EITHER Γ 1 N' O N-and y!'—I I PMB 'ri n-nM Stage 1 ’ Ny V· / / N,r„,„ - n—2 / N PMB StageY IÍN, .J--;'··' 7, 3 ' r-~ N \ '— / N Stage 1 and Stage 2 3-morpholinopropyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1Η-1,2,3-triazole-5-carboxylate was prepared. - 230 a manner similar to the procedures of Example 175, step 2 and step 3, using 4-(3-chloropropyl)morpholine and 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl) acid) -2H-1,2,3triazol-4-yl)-9H-fluoren-2-yl)-2H-l,2,3-triazol-4 carboxylic, followed in a manner similar to the general PMB deprotection procedures: :H NMR (400 MHz, DMSO-dd δ 15.18 (s, 1H) , 8.42 (s, 1H) , 8.14 (s,1H) , 8.04 (m, 2H), 7.98 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 4.27 (t, J = 6.2 Hz, 2H), 4.08 (s,2H) , 3.42 (t, J = 4.4 Hz, 4H), 2.22 - 2.18 (m, 6H), 1.77 (qn, J = 6.7Hz, 2H). ES / MS m / z: calculated for C?5H.= N-O? (M+H) : 472.21, found: 472.50. Example 178: 2-((L-valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazol-4yl)-9H-fluoren-2-yl)-1H-1,2,3- triazole-5-carboxylate 231 BodIN Stage 1 Stage 2 Ϊ ° ' O ·· '· N BocHN γ O yN_PMB \ EITHER Ν' ,___ Ñ ​​OH Br 178 a 178b Stage 1 Stage 1 Stage 3 178-3^ Ηζ.ΗΝ To a stirred solution of 5-bromo-2-(4-methoxybenzyl)-2H Ethyl 1,2,3-triazole-4-carboxylate (11.5.0 g, 14.74 mmol) in MeOH (10 ml), THF (30 ml) and water (10 ml) at room temperature under argon lithium hydroxide monohydrate (1.85 g, 44.24 mmol) was added. After stirring the reaction mixture at room temperature for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and acidified with 1N HC1 solution before stirring for 10 min. The precipitated solid - 232 filtered, washed with water and dried under vacuum to obtain 5-bromo-2-(4-methoxybenzyl)-2H-Í, 2, 3-triazole-4carboxylic acid (178-a): ES / MS m / z: calculated for CMH;'BrN-NaO;:(M+H): 333.98, found: 334.10. Stage 2 To a stirred solution of Boc-L-valine (3.0 g, 13.82 mmol), ethane-1,2-diol (1.11 g, 17.96 mmol) in dichloromethane (45 ml) at 0°C under argon was added 4-dimethylaminopyridine ( 0.33 g, 2.76 mmol) followed by a solution of dicyclohexylcarbodiimide (3.69 g, 17.96 mmol) in dichloromethane (15 ml). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting crude residue was purified by column chromatography on silica gel eluting with 0-30 / ethyl acetate in petroleum ether to obtain 2-hydroxyethyl (tert-butoxycarbonyl)-Lvalinate. (178-b)::H NMR (400 MHz, DMSO-ds) δ 7.11 (d, 2ZH), 4.77 (t, J = 5.4 Hz, 1H), 4.06 (m, 2H), 3.87 (dd, J = 7.8 and 6.0 Hz, 1H), 3.56 (appt q, J = 5.2 Hz, 2H), 2.50 (m, 1H), 2.01 (m, 1H), 1.39 (s, 9H), 0.87 (d, J = 6.6 Hz , 6H). Stage 3 To a stirred solution of 5-bromo-2-(4methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid (178-a, 2.55 g, 8.17 mmol), 2-hydroxyethyl (tert-butoxycarbonyl)- L-valinate (178-b, 2.77 g, 10.62 mmol) in dichloromethane (37.5 ml) at 0°C - 233 in an argon atmosphere, 4-dimethylaminopyridine (0.2 g, 1.63 mmol) was added followed by a solution of dicyclohexylcarbodiimide (2.18 g, 10.62 mmol) in dichloromethane (12.5 ml). The mixture was stirred at room temperature for 16 h. After concentrating the reaction mixture under reduced pressure, the residue was purified by column chromatography on silica gel eluting with 0-60% ethyl acetate in petroleum ether to obtain 2(((tert-butoxycarbonyl)-L- valyl)oxy)ethyl-5-bromo-2-(4methoxybenzyl)-2H-1,2,3-trrazole-4-carboxylate: ES / MS m / z: calculated for CjjHssBrNqO-· (M+H) : 555.15, found: 555.34. Stage 4 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl 2(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole) was prepared. 4yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate in a manner similar to the general procedures of the Suzuki reaction using 2-(4-methoxybenzyl)-4-( 7-(4,4,5,5tetramethi1-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2H1,2,3-triazole and 2-(((tert-butoxycarbonyl) -L-valyl)oxy)ethyl 5bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: calculated for ( / / :.N-NaO· ,- (M+Na) : 850.35, found: 850.86. Stage 5 A mixture of 2-(((tert-butoxycarboni1)-L-vali1)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3- triazol- 234 4-i1)-9Η-fluoren-2-i 1)-2Η-1,2,3-triazole-4-carboxylate (4.5 g, 5.44 mmol) in trifluoroacetic acid (45 ml) was stirred at 70° C for 48 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by Prep-HPLC S and the combined pure fractions were lyophilized to obtain 2-((L-valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9Hfluoren-2-yl)-1H -1,2,3-triazole-5-carboxylate::H NMR (400 MHz, DMSO-dd δ 8.42 (s, 1H), 8.28 (s, 3H), 8.14 (s, 1H), 8.07 - 8.03 (m, 3H), 7.96 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 6.0 Hz, 1H), 4.56 (m, 1H), 4.55 (m, 2H), 4.43 (m, 1H), 4.0 8 (s, 2H), 3.92 (m, 1H), 2.05 (h, J = 6.8 Hz , 1H), 0.86 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). ES / MS m / z: calculated for C25H2ÍN-O4 (M+H): 488.20, found: 488.39. Example 179: 2-(phosphonooxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)15 9H-fluoren-2-yl)-1H-1,2,3-triazol-5 -carboxylate EITHER BnO-^-OH OBn HCR. Stage 1 OTBS EITHER BnO P 0 OBn Stage 2 or ΒπΟ P OEtaP3 OBn' or ()H ΒπΟ -Ρ-Ό0OBn'’—and O BnO-íj’-O Stage 4 N-N o~N Stage 5 OBn \ «λ x . 7· .7 , c u üMsN1_ ··.—··· _ / N f Vh HO-^-O OH '—P ó-d - 235 Stage 1 To a stirred solution of dibenzyl hydrogen phosphate (117.20 g, 71.94 mmol), 2-((tert-butyldimethylsilyl)oxy)ethanl-ol (15.22 g, 86.33 mmol) in THF (200 ml) at 0°C under Argon triphenylphosphine (28.27 g, 107.91 mmol) was added, followed by diethyl azadicarboxylate (18.83 g, 107.91 mmol). The resulting mixture was stirred at room temperature for 5h. After the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to obtain dibenzyl phosphate (2-((ter -butyldimethylsi_yl)oxy)ethyl: ES / MS m / z: calculated for C22H34O3PSÍ (M+H): 437.19, found: 437.34. Stage 2 To a stirred solution of dibenzyl(2-((tert-butyldimethylsilyl)oxy)ethyl) phosphate (23 g, 52.75 mmol) in MeOH (230 ml) at room temperature under argon was added Dowex-50W. The mixture was stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by column chromatography on silica gel eluting with 0-2% MeOH in dichloromethane to obtain dibenzyl (2-hydroxyethyl) phosphate: ES / MS m / z: calculated for C:?H2;O? P (M+H): 323.10, found: 323.24. - 236 Stage 3 To a stirred solution of dibenzyl(2hydroxyethyl) phosphate (5 g, 15.52 mmol) in dichloromethane (50 ml) at 0°C under argon, NEt was added; (3.23 ml, 23.28 mmol), followed by MsCl (2.13 g, 18.63 mmol). After stirring the mixture at room temperature for 5 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (NazSCg) and concentrated under reduced pressure to obtain crude 210(bis(benzyloxy)phosphoryl)oxy)ethyl methanesulfonate, which was used directly in the next step without further purification: ES / MS m / z: calculated for CL-HmO-PS (M+H) : 401.08, found: 401.27. Stage 4 To a stirred acid mixture of 2-(4-methoxybenzyl)-5(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2yl)- 2H-1,2,3-triazol-4-carboxy1 ico (4 g, 6.84 mmol) and potassium carbonate (1.41 g, 10.26 mmol) in DMF (40 ml) at 0°C under argon, 220 methanesulfonate was added ( (bis(benzyloxy)phosphoryl)oxy)ethyl (3.28 g 8.21 mmol). After stirring the mixture for 14 hours at 50 °C, the reaction mixture was diluted with ice water and the product was extracted with ethyl acetate. The organic extract was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by gel column chromatography. - 237 silica eluting with 0-60 / ethyl acetate in petroleum ether to obtain 2-((bis(benzyloxy)phosphoryl)oxy)ethyl 2(4-methoxybenzyl)-5-(7-(2-(4- methoxybenzyl)-2H-1,2,3-triazol-4yl)-9H-fluoren-2-yl)-2H-1,2,3-triazol-4-carboxylate: ES / MS m / z: calculated for C2- H;.;N.:O-P (M+H) : 889.31, found: 889.77. Stage 5 A mixture of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl 2-(4methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4i1)-9H -fluoren-2-yl)-2H-1,2,3-triazcl-4-carboxylate (11.5 g, 12.94 mmol) in trifluoroacetic acid (45 ml) was stirred at 70°C for 20 h. After the reaction mixture was concentrated under reduced pressure, the crude residue was purified by Prep-HPLC to obtain 2-(phosphonooxy)ethyl 4-(7(lH-l,2,3-triazol-4-yl)- 9H-fluoren-2-yl)-lH-l,2,3-triazole-5carboxylate: -H NMR (400 MHz, DMSO-d,) δ 8.39 (s, 1H), 8.19 (s, 1H), 8.11 ( s, 1H), 8.01 - 7.97 (m, 3H), 7.92 (d, J = 7.3 Hz, 1H), 4.36 (m, 2H), 4.06 (s, 2H), 4.03 (m, 2H). ES / MS m / z: calculated for C2cH2=N.OíP (M+H): 469.10, found: 469.16. Example 180: ( ( (2-(phosphonooxy)ethoxy)carbonyl)oxy)methyl 4-(7(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1 ,2,3-triazole-5carboxylate - 238 9 Gl +> C „ ü l+U P < Stage 1λ+pp OBn '—\ ” 6nc+'FlÜ oh cbn EITHER BnO-P-O ¿Bn '—\ O Or me I.B. N N _ , - , _ N N y, / \\ ¡l ' V~ . N, . .. ... \ --Q i N PMh Stage 2 Stage 1 To a stirred solution of dibenzyl (2hydroxyethyl) phosphate (5 g, 15.52 mmol) and pyridine (2.5 ml, 31.04 mmol) in dichloromethane (100 ml) at 0°C under an argon atmosphere, chloromethyl carbon hydrochloride (2.97 g, 23.29 mmol). After stirring the mixture at room temperature for 6 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (NazSCg) and concentrated under reduced pressure to obtain crude 2-((bis(benzyloxy)phosphori1)oxy)ethyl (chloromethi 1) carbonate, which was used directly in the next step without further purification: ES / MS m / z: calculated for CmEL-ClO-P (M+H): 415.07, found: 415.31. Stage 2 To a stirred solution of acid 2-(4-methoxybenzyl)-5-(7(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl) - 239 2Η-1,2,3-triazole-4-carboxylic acid (5.0 g, 8.56 mmol) and potassium carbonate (1.77 g, 12.84 mmol) in DMF (50 ml) at 0°C under argon 2-carbonate was added ((bis(benzyloxy)phosphoryl)oxy)ethyl(chloromethyl) (.25 g, 10.27 mmol). The mixture was stirred at 50 °C for 18 h. After diluting the reaction mixture with ice water, the product was extracted with ethyl acetate. The organic extract was dried (Na2SO¿) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0-11 MeOH in dichloromethane to obtain (((2((bis(benzyloxy)phosphoryl)oxy)ethoxy)carbonyl)oxy)methyl-2-(4-methoxybenzyl )-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4yl)-9H-fluoren-2-yl)-2H-l,2,3-triazol-4- carboxylate: ES / MS m / z: calculated for GAFANíOilP (M+H) : 963.31, found: 963.39. Stage 3 A mixture of (((2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)carbonyl)oxy)methyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1, 2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H1,2,3-triazol-4-carboxylate (5.5 g, 5.71 mmol) in trifluoroacetic acid (55 ml) was stirred at 70° C for 20 h. After the reaction mixture was concentrated under reduced pressure, the crude residue was purified by Prep-HPLC to obtain (((2-(phosphonooxy)ethoxy)carboni1)oxy)methi 1 4-(7(1H-1,2 ,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5 - 240 carboxylate:2H NMR (400 MHz, Methanol-aL) δ 8.42 (s, 1H), 8.15 (s, 1H), 8.06 (t, J = 8.0 Hz, 2H), 8.00 (s, 1H), 7.95 ( d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H), 4.32 (m, 2H), 4.08 (s, 2H), 4.01 (m, 2H). ES / MS m / z: calculated for C22H20N6O9P (M+H): 543.10, found: 543.40. The following compounds were prepared similarly to representative procedures of the Suzuki reaction, SEM or PMB deprotections described above, and ester hydrolysis using the aforementioned bromide intermediates, 18 or 20 with commercially available boronates: Example 182: 3-(3-chloro-4-fluorophenyl)-lH-pyrazole-4carboxylic acid :H NMR (400 MHz, Methanol-cL) δ 8.17 (s, 1H), 7.90 (dd, J = 7.2, 2.2 Hz, 1H), 7.71 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.29 (t, J = 8.9 Hz, 1H). ES / MS m / z: calculated for C20H-CIFN2O2 (M+H): 241.02, found: 241.02. Example 183: 3-(3,5-dichlorophenyl)-lH-pyrazole-4carboxylic acid O Cl HO-v CL - 241 - - H NMR (400 MHz, Methanol-dJ δ 8.21 (s, 1H), 7.77 (d, J = 2.0 Hz, 2H), 7.47 (t, J - 2.0 Hz, 1H). ES / MS m / z: calculated for C22H-CI2N2O2 (M+H): 256.99, found: 257.03. Example 184: 4-(3-chloro-4-fluorophenyl)-lH-imidazole-5carboxylic acid HO \iΛ 7 / T-NH N Cl' - H NMR (400 MHz, Methanol-do) 8.12 (dd, J = 7.4, 2.2 Hz, 1H), 7.90 (ddd, J = 8.6, 4.7, 2.2 Hz, 1H), 7.68 (s, 1H), 7.20 ( dd, J = 9.2, 8.7 Hz, 1H). ES / MS m / z: calculated for C2CH-C1FN2O2 (M+H): 241.02, found: 240.94. Example 185: 4-(3,5-dichlorophenyl)-lH-imidazole-5carboxylic acid EITHER C| HO-, S.....\H Cl' - H NMR (400 MHz, Methanol-d-;) δ 8.03 (s, 2H), 7.67 (s, 1H), 7.31 (s, 1H). ES / MS m / z: calculated for C2:-H-C12N2C>2 (M+H): 256.99, found: 257.03. Biological assays Biological assay 1: Biochemical Cellular Assays Materials - 242 Glycolate oxidase (GO) was generated at Gilead using the HAO1 sequence by Jones et al., 2000 (J. Biol. Chem. 275: 12590-12597). The Amplex© Red hydrogen peroxide / peroxidase assay kit (catalog #A22188) was purchased from Thermo Fisher (Waltham, MA). Glycolic acid (catalog no. 124737) and 1M Tris, pH 7.8 (catalog no. T2569-1L) were from Sigma (St. Louis, MO), ±10% ween-20 (catalog no. catalog 51-12-02) was from SeraCare (Milford, MA.), 2% BSA (catalog no. BSA-1000) was from Rockland Immunochemicals (Pottstown, PA), and the black low binding plate from 384 wells (catalog #3860) were from Corning (Sunnyvale, CA). Methods 1. GO biochemical assay The GO biochemical enzymatic reaction was performed on a 384-well black low binding plate in a total volume of 25 μΐ. The reaction mixture contained 5 nM GO, 100 μΜ glycolate, 0.1 U / ml HRP, 50 μΜ Amplex Red, and test compounds serially diluted 1:3 in a buffer containing 50 mM Tris, pH 7.8, 0.0025¾ Tween-20. and BSA at 0.02¾. Twenty-five nanoliters of 1000X test compounds were pre-plated into a 384-well low binding plate using Echo 555 Liquid Handler (Labcyte Inc., San Jose, CA) with a final starting concentration of 10 μΜ, followed by the addition of 5 μΐ / well of 25 nM GO (5X of 5 nM of - 243 final concentration) and incubated for 15 min. Ten microliters of 2.5X 0.1 U / ml final concentration of HRP were added to each well, followed by the addition of 10 μΐ of 2.5X 100 μΜ final concentration of glycolate substrate and 2.5X 50 μΜ final concentration of Amplex Red. The reaction was mixed and incubated at room temperature for 20 min followed by reading the plates using an EnVision plate reader (Perkin Elmer, San Jose, CA) with excitation at 570 nm and emission at 585 nm. The wells with DMSO were used as negative controls (as 0i inhibition) while the wells without GO enzymes were used as positive controls (as 1001 inhibition). The % inhibition calculated as 100%x (Well-Negative) / (PositiveNegative). 2. HRP Contrast Screening Assay The HRP contrast screening assay was performed in parallel with the GO biochemical assay to exclude compounds that could inhibit HRP directly but had no effect on GO inhibition. Twenty-five nanoliters of the same set of 100CX test compounds were pre-plated on a 384-well low binding plate as described above in the GO biochemical assay, followed by the addition of 10 μΐ final concentration of 2.5X 0.1 U / ml in a buffer containing 50 mM Tris, pH 7.8, 0.0025% Tween, 0.02% BSA, - 244 and incubated for 15 min. Then 15 μΐ of a final concentration of 1.67 X 50 μΜ of Amplex Red and a final concentration of 1.67 X 10 μΜ of H-02 were added to each well. The reaction was mixed and incubated at room temperature for 20 min. At the end of incubation, plates were read by Envision with excitation at 570 nm and emission at 585 nm. wells with DMSO were used as negative controls (as 0% inhibition) while wells without HR enzymes were used as positive controls (as 100% inhibition). % inhibition was calculated as described above. GO cell-based assays 1. GO Transient Transfection Cell-Based Assay Materials HAO1 plasmid DNA was generated by PCR cloning of HAO1 cDNA (Jones et al., 2000) into the pcDNA3.1(+)-neomycin vector from LakePharma (Belmont, CA). FuGENE 6 transfection reagents (catalog no. E2692) were purchased from Promega (Madison, WI). The CHO-K1 cell line (ATCC catalog no. CCL-61) and F-12K medium (catalog no. 30-2004) were obtained from ATCC (Manassas, VA). OptiMEM I reduced serum medium (catalog #31985-070) was from Gibco / Life Technologies (Grand Island, NY). Fetal bovine serum (FBS) (catalog #SH30071.03) was from HyClone (Logan, Utah), and 100X Penicillin / Streptomycin / L-Glutamine (catalog #30-009-C1) was from Corning (Fremont, CA) . Black 384-well tissue culture plates (catalog #781086) were purchased from Greiner Bio-One (Monroe, NC). Methods Transient transfection was performed by mixing 3 parts FuGENE 6 reagent in μΐ with one part HAO1 plasmid DNA or vector control DNA in pg in OptiMEM I reduced serum medium and incubated at room temperature for 15 min. The mixture was mixed with CHO-K1 cells and dispensed at a rate of 45 µl / well containing 0.025 pg of HAO1 plasmid DNA, 0.075 µl of FuGENE 6 and 4000 cells in F-12K medium plus 10% FBS. Cells were incubated for 48 h in a 37°C incubator for GO to be expressed. The cell culture media was then removed and replaced with 25 μl of test compounds serially diluted 1:3 with an initial concentration of 1 pM, and incubated for 1 hour at room temperature. Next, 25 μl of reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) containing HRP (final concentration of 0.1 U / ml), 300 pM glycolate, and 50 μM of glycolate were added to each well. pM of Amplex Red. The reaction was mixed and incubated at room temperature for 20 min followed by reading the plates with the plate reader. - 246 EnVision as described above. Wells with DMSO were used as negative control (0% inhibition) while wells with vector control DNA transfection were used as positive controls (as 100% inhibition). % inhibition was calculated as described above. 2. Cell-based assay of stable GO clones Materials Reagents and tissue culture media for transient transfection were described in the transient transfection assay section. Rabbit anti-HAOl antibody (catalog no. ab93137) was purchased from Abcam (Cambridge, MA) and anti-rabbit IgG (H + L), F(ab')2 fragment, Alexa Fluor© 555 conjugate. (Catalog #4413)) was obtained from Cell Signaling Technology (Danvers, MA). Methods 1) Generation of stable CHO-K1-HAO1 clones Stable GO clones were generated in-house by performing massive transient transfection of GO plasmid DNA into CHO-K1 cells and incubated for 48 hours as described above. The cells were then treated with trypsin and 2000 cells / 200 μl were added to the Al well followed by 1:2 serial dilutions to A2 and so on up to A12 for 10 96-well tissue culture plates. Cells in A1-A12 were serially diluted - 247 1:2 further up to H1-H12 and incubated for two weeks in F-12K medium with 10% FBS supplemented with G418 at 500 pg / ml. Each plate was monitored for colony formations under the microscope. Twenty-eight individual colonies were selected and expanded to test GO expression. Immunocytochemistry for intracellular GO staining Intracellular GO staining was performed by first fixing cells with 50 μΐ / well 4% formaldehydeC' in PBS in a 384-well plate for 30 min at room temperature, followed by washing 3 times with 80 μΐ / well buffer. wash (PBS with 0.05% Tween-20). Cells were then permeabilized with 50 μΐ / well 0.1% Triton in PBS for 30 min, washed 3 times, and blocked for 1 hour with 50 μΐ / well 3% BSA in PBS with Tween-20. 0.05%. Cells were washed again 3 times and 50 μΐ of rabbit anti-human GO at 1:100 dilutions in PBS with 1% BSA and 0.05% Tween-20 were added to each well and incubated overnight at 4°. c. Cells were washed 4 times with 15 min of incubation between each wash, followed by the addition of 40 μΐ of Alexa Fluor 555-conjugated anti-rabbit IgG F(ab')2 fragments (H + L) at a dilution of 1 :250 and Hoechst at a Dilution of 1:500 in BSA all % and Tween-20 at 0.05% in each well. The plates were incubated for 160 - 248 min at room temperature and washed four times at the end of incubation. Sixty microliters of PBS was added to each well, and cell images were examined with the Arrayscan XTI HCS reader from Thermo Fisher Scientific (Waltham, MA). 2) Cell-based assay of 2D2 GO stable clone enzymatic activity 384-well tissue culture plates were prestained with 25 μΐ of test compound per well, followed by dispensing 5000 cells / well / 25 μΐ of clone 2D2 in reaction buffer (50 mM Tris, pH 7.8, Tween at 0.0025a and 0.02% BSA) to all wells except column 22, where 5000 cells / well / 25 μΐ of clone 1A1 vector control were added. Test compounds were incubated with the cells for 1 hour at room temperature, followed by the addition of 25 μΐ of reaction buffer (50 mM Tris, pH 7.8, 0.0025% Tween, and 0.02% BSA) containing HRP (concentration final 0.1 U / ml), glycolate 160 μΜ and Amplex Red 50 μΜ. The reaction was mixed and incubated for 20 min at room temperature and the fluorescence of the resorufin product described above was measured. The wells with 2D2 and DMSO were used as a negative control (0% inhibition) while the wells with the 1A1 vector control clone were used as - 249 positive controls (as 1001 inhibition). Percent inhibition was calculated as described above (Table 2). - 250 TABLE 2. Ex- ICso GO AR-384 EC50 GO CHO K1 AR ECso GO CHO K1 STABLE Ex. ICso GO AR-384 ECso GO CHO K1 AR EC50 GO CHO K1 STABLE 5 1 1000 1000 1000 19 196.34 2 1000 1000 1000 20 293.95 3 10000 21 173.23 4 616.16 22 158.54 10 5 10000 23 298.91 6 666.77 24 239.81 7 3772.2 25 730.69 8 1311.7 26 250.73 9 348.49 27 362.7 15 10 677.77 28 101.96 11 4725.8 29 329.78 12 130.04 30 845.14 13 210.52 31 1000 10000 20 14 1196.6 32 1254.9 15 1603.9 33 338.57 16 452.59 34 7499.4 17 10000 35 10000 25 18 250.27 36 345.81 852.16 Ex. ICso GO AR-384 ECso GO CHO K1 AR ECso GO CHO K1 STABLE 37 91.823 38 230.25 1003.9 39 30.686 106.34 40 1000 10000 1000 41 71.628 306.82 42 96.619 840 .3 240.81 43 268.41 44 510.18 1000 1000 45 316.55 1024.4 46 437.21 2210.4 47 46.556 262.95 96.174 48 159.94 950.06 508.67 49 24,817 109.17 47,096 50 123.55 250 51 35,923 100.27 49,044 52 174.38 485.77 53 3 77.06 54 4298.1 Ex. ICso GO AR-384 ECso GO CHO K1 AR ECso GO CHO K1 STABLE 55 562.63 1000 942.08 56 178.64 869.54 312.6 57 731.16 5013 58 192.17 703.93 59 26.737 60 29. 699 170.35 61 97.918 575.96 62 392.22 1000 572.94 63 34.621 115.78 77.353 64 29.115 162.16 83.25 65 23.651 214.06 60.122 66 125.9 505.14 67 164.4 569.68 68 7.656 23.288 25.251 69 21.44 117.07 70 109.51 448.23 71 47,717 264.27 174.01 72 342.59 1161.7 857.3 - 252 - Ex. IC50 GO AR-384 ECso GO CHO K1 AR ECso GO CHO K1 STABLE 73 357.95 1000 599.85 74 31.797 157.85 57.913 75 18.638 137.34 60.402 76 399.49 978.17 77 94 .591 531.48 267.24 78 228.07 851.35 434.21 79 243.65 877.5 420.34 80 174.11 847.9 419.5 81 187.24 428.73 82 113.91 305.12 83 135.5 738.62 297.65 84 1000 1000 85 47.901 209.46 119.22 86 29.151 79.666 87 23.836 83.049 50. 715 88 77,555 127.24 89 13,554 37,294 90 32,184 153.65 Ex- ICso GO AR-384 ECso GO CHO K1 AR ECso GO CHO K1 STABLE 91 64.456 632.02 141.26 92 57.012 412.33 208.79 93 8.411 68.469 27.488 94 57.171 307.15 142.7 9 95 12,091 23,553 96 33,951 199.44 44,832 97 13,504 41,277 28,132 98 18,959 66,126 46,147 99 408.36 1331.3 100 195.53 1109.3 101 11.122 89.987 27.577 102 223.5 1000 443.36 103 93.231 283.25 130.53 104 125.41 651.91 232.61 105 37,445 252.33 84.69 106 9,662 78,035 49,673 107 10,322 32,526 27,695 108 7,911 44,339 22,084 - 253 - Ex. ICso GO AR-384 EC50 GO CHO K1 AR ECso GO CHO K1 STABLE 109 22.687 124.41 40.268 110 49.903 245.53 86.854 111 11.204 121.88 32.356 112 37.547 303.85 112.63 113 20,247 91,754 38,705 114 15,491 105.88 24,459 115 16.2 79,849 34,063 116 58,559 374.15 136.34 117 19.73 97.778 27.55 118 18,502 65,156 23,054 119 21,725 ​​88,296 33.84 120 11,282 80,822 26,481 121 38,174 176.11 73,873 122 10,657 25,201 12,205 123 40,929 209.73 78,786 124 16,093 82,772 106.78 125 5.24 45,738 16,697 126 13,069 51,529 47.04 Ex. ICso GO AR-384 ECso ECso GO GO CHO CHO Kl K1 AR STABLE 127 4.143 14.021 7.801 128 123.15 649.59 405.2 129 23.984 105.64 112.57 130 4.136 20.032 7.14 3 131 4.672 14.962 5.128 132 133.41 133 19.227 113.09 48.603 134 127.99 196.86 135 1543.8 136 211.25 1302.7 407.28 137 4079.5 138 269.64 139 10000 140 10000 141 10000 142 322.5 1000 143 1000 1000 144 124.67 469.06 435.83 - 254 - Ex. IC50 GO AR-384 ECso GO CHO K1 AR EC50 GO CHO K1 STABLE 145 552.54 1000 1000 146 33.572 267.94 98.667 147 114.13 148 267.19 149 43.534 150 10000 15 1 220.03 948.57 392.55 152 45.76 132.18 61.594 153 119 214.58 124.14 154 50.564 132.36 155 96.924 622.18 260.87 156 114.56 145.39 157 13,661 71,458 34,998 158 31,739 162.98 159 176.59 898.94 486.71 160 225.95 1135.7 161 10000 10000 162 88.223 160.04 Ex. lC?o GO AR-384 EC50 GO CHO K1 AR EC50 GO CHO K1 STABLE 163 1000 1000 164 27.63 245.17 73.178 165 7.348 47.415 19.059 166 24.063 55.932 33.095 16 7 21,715 52,202 30,777 168 7,132 13,808 10,154 169 6,681 13,318 170 16,504 31,092 173 7,338 26,523 13,329 182 >10,000 183 >10,000 184 >10,000 185 >10,000 - 255 Biological Test 2: Oral Bioavailability and PK Studies An oral dose of Example 2 was formulated in a sterile solution of 50% water, 37.51 PEG 300 and 12.5¾ DMSO at 1.0 mg / ml. The dosing group consisted of three fasted male Sprague Dawley rats. At the time of dosing, the animals weighed between 0.26 and 0.27 kg. For the oral dosing group, the formulated dose was administered by oral gavage at 5.0 ml / kg for a dose of 5.0 mg / kg. A non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. TABLE 3 Animal Animal Weight (kg) Target Conc (mg / ml) Measurement Conc (mg / ml) Dose Vol (mi) Dose (mg / kg) Dose (nmol / kg) 1 0.26 1.00 1.00 1.30 5.04 16344 2 0.26 1.00 1.00 1.30 4.96 16094 3 0.27 1.00 1.00 1.40 5.20 16881 Table 3 shows the mean plasma pharmacokinetic parameters of Example 2 following an Example 2 PO dose of 5 mg / kg in SD rats (mean ± SD, n=3). Table 4 shows the mean plasma pharmacokinetic parameters of Example 68 following an Example 2 PO dose of 5 mg / kg in SD rats (mean ± SD, n=3). As shown in Tables 4 and 5, the AUC^i of Example 2 was 1600 ± 280 nM«h and - 2 5 6 the C~ax was 2390 ± 246 nM. The AUCL— of Example 68 was 3250 ± 242 nM'h and the C-ax was 2270 + 171 NM. The bioavailability of Example 68 was estimated to be 19.0.1 or 1.4 1. TABLE 4 PO Rat 001 002 003 Mean SD AUCo-24h (nM»h) 1270 1550 1850 1560 288 AUCini(nM*h) 1340 1570 1900 1600 280 Cmax (nM) 2540 2530 2110 2390 246 Tmax (hr) 0.25 0.25 0.50 0.33 0.14 F (%) NC NC NC NC NC TABLE 5 PO Rat 001 002 003 Mean SD AUCo-24h (nM'h) 3150 3360 2930 3140 216 AUCmf(nM'h) 3320 3450 2980 3250 242 Cmax (nM) 2120 2220 2450 2270 171 Tmax (hr) ) 0.50 0.25 0.50 0.42 0.14 * F (%) 19.4 20.2 17.4 19.0 1.4 *Based on IV exposure (AUCin? = 3420 nM-hr) of Example 68 at 1.0 mg / kg from Table 7, below. Apparent systemic clearance for Example 68 (CL = 0.95 ± 0.09 1 / h / kg) was low relative to hepatic blood flow in rats (CL = 4.0 1 / h / kg). The volume of distribution (Vss = 0.44 ± 0.06 1 / kg) was less than the volume of total body water (0.7 1 / kg). The terminal you - 257 of Example 68 was 1.C2 ± 0.06 hr and the mean residence time (MRT) was 0.47 + 0.02 hr. Oral bioavailability (aG) was estimated at 2.37 ± 0.3a. See Table 7, Table 8 and Figure 2. TABLE 7. Mean plasma pharmacokinetic parameters of Example 68 after a 30-minute IV infusion at 1 mg / kg in SD rats (mean ± SD, n=3). IV Rat A B C Mean SD Parameter AUCiast (nM-hr) 3680 3090 3450 3400 296 AUCinf(nM'hr) 3690 3110 3460 3420 295 Cmax (nM) 4940 5100 5350 5130 208 MRT (hr) 0.47 0. 49 0.44 0.47 0.02 ti 2 (hr ) 1.01 1.08 0.96 1.02 0.06 Vss (1 / kg) 0.41 0.51 0.41 0.44 0.06 CL (1 / hr / kg) 0.87 1.04 0.93 0.95 0.09 TABLE 8. Mean plasma pharmacokinetic parameters of Example 68 after a 5 mg / kg PO dose in SD rats (mean ± SD, n=3). - 258 - Rat D E F Mean SD Parameter AUCiast (nM'hr) 429 334 396 386 48 AUCinf (nM'hr) 485 383 479 449 57 Cmax (nM) 90.4 65.0 182 113 61.7 Tmax (hr) 0.25 2.00 0.25 0.83 1.01 F (%) 2.5 1.9 2.3 2.3 0.3 Example 168 or Example 175 was formulated in a sterile solution of 15% N-methyl-2-pyrrolidone, 55% PEG and 30% water for oral administration or intravenous administration. The dosing group consisted of three fasted male SD rats or three fasted male beagle dogs. At the time of dosing, rats weighed between 0.2 and 0.3 kg and dogs weighed between 10.72 and 10.82 kg. For the oral dosing group, the formulated dose was administered by oral gavage at 5.0 ml / kg for a dose of 5.0 mg / kg or 5.4 mg / kg. For the intravenous dosing group, the formulated dose was 1.00 mg / kg. A non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. Data from these studies are shown in Figure 3 and Figure 4.

Claims

1. A compound of Formula I: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein A is N or CH; R2 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each is optionally substituted with one to three R2 ; R2 is hydrogen, - (CH2CH2O) 1-3CH2CH2OCH;., optionally substituted Ci-g alkyl with one to three R·, cycloalkyl or heteroaryl optionally substituted with one to three R·. Each RJ is independently cyano, halo, -L-alkyl C:-2, -L-haloalkyl C2-4, -LO-haloalkyl C2-J, -NR'R2, -C(O)NR~R3, -S (O) 2NRRs, - NRC(O)R;, -0R\ -L-aryl, -L-heteroaryl or -Lheterocyclyl, wherein each is optionally substituted with one to three R2, and each L is independently -C=C- or absent; each R4 is independently halo, hydroxy, -O C1-6 alkyl, -NH2, -NH-C:-2 alkyl, -N (C>O2 alkyl, -OC(O)R··, OC(O)ORa, -OP(O) (ORb)2, or monocyclic heterocyclyl; wherein - 260 each is optionally substituted with one to three R= and provided that only one R2 is heterocyclyl; each Rc' is independently cyano, halo, C alkyl.-4, hydroxy, -O-C:-4 alkyl, C>-4 haloalkyl or -O-haloalkyl each R6 is independently cyano, halo, -C(O)R , O(O) 0R\ -C(O)NR R3, -S(O)2NR7R% -NR~C(O)R-, -OR\ C;-4 alkyl, -O-C;-4 alkyl, C;-4 haloalkyl, -O-C;-4 haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C;-, -C(O)OH or C;-4 haloalkyl; each of R^ and R8 is independently hydrogen, C;-4 alkyl or phenyl, pyridyl, or R~ and R8 together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently GR- alkyl.; optionally substituted with -NH;, -NH-alkyl O:-?, -N (alkyl O;-;);, or OR (O) (ORb) 2; each Rb is independently hydrogen or C:-4 alkyl; provided that when A is N, at least one of the following is true: 1) R2 is a fused tricyclic ring optionally substituted with one to three R';. 2) R2 is an optionally substituted fused bicyclic ring, substituted with at least one R8 selected from cyano, -C^c C--alkyl, -C:-alkyl;· substituted with one to three R'2, -C=C-C2-haloalkyl, -C=CO-C;-4 haloalkyl, -NR~R-, - 2 61 -C(O)NRR3, -S(O)2NR^R;, -NR'C(O)R3, -O-Cl-2 alkyl, -O-phenyl, -L-aryl, -L-heteroaryl or -L-heterocyclyl, wherein each is optionally further substituted with one to three R'-, and each L is independently -C=C- or absent; 3) R- is a substituted monocyclic ring, substituted with at least one R3 selected from: i) cyano, -C=C-alkyl Ci-, -C≡C-haloalkyl Ci-, -C=C-haloalkyl -NR'R3, -C(O)NRRS, -S(O)2NR~R3, -NRC(O)R3, -C≡C-aryl, -C≡C-heteroaryl or -C=C-heterocyclyl, wherein each is optionally further substituted with one to three R6; (ii) monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclyl, wherein each is further substituted with one to three cyano, -C(O)R, -C(O)OR, -C(O)NRR3, -S(O)2NR2Rs, -NR2C(O)R3, C1-alkyl, -C1-alkyl, C1-4 haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C2-4 alkyl, -C(O)OH or C1-4 haloalkyl; (iii) optionally substituted fused aryl, optionally substituted fused heteroaryl or optionally substituted fused heterocyclyl, wherein each is optionally further substituted with one to three R3;or iv) a substituent of Formula -L3-L2, wherein L: is aryl, heteroaryl or heterocyclyl, wherein each one is optionally substituted with one to three R-; and L· is phenyl, heterocyclyl or heteroaryl, wherein each one is optionally substituted with one to three C2-alkyl, C2-OH or C2-haloalkyl; or; 4) R2 is -(CH2CH2O)>.-CH.;CH2OCH3, C>c alkyl substituted with one to three R2 groups, cycloalkyl, or heteroaryl optionally substituted with one to three R= groups; and provided that when A is CH, R: is not a 10-membered heteroaryl substituted with methoxy and methyl; or R: is not a Cf aryl optionally substituted with 1-3 substituents independently selected from cyano, halo, C2-2 alkyl, -OR7, Cu haloalkyl, and NR'R3, wherein R; and R- are each independently hydrogen or alkyl, or R: is not an unsubstituted C22 aryl; or R2 is not an unsubstituted heterocyl.

2. The compound of claim 1, wherein: A is N or CH; R: is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each is optionally substituted with one to three R3; R2 is hydrogen, - (CH2CH2O) 2-2CH2CH2OCH2, alkyl C: optionally substituted with one to three R2, or heteroaryl optionally substituted with one to three R'; each R3 is independently halo, -L-alkyl C.-·, C(O)NR7R9, -S(O)2NR~R3, -NR“C(O)R3, -OR7, 5-6-membered -L-heteroaryl or 5-6-membered -L-heterocyclyl, wherein each - 263 one is optionally substituted with one to three R', and each L is independently a bond or -C^c-; each Re is independently halo, hydroxy, -O-C:-6 alkyl, -NH2, -NH-C:e alkyl, -N(C:-g alkyl)2 or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R5; provided that only one R is heterocyclyl; each R5 is independently cyano, halo, C1-1 alkyl, hydroxy, -O-C:m alkyl, C1-1 haloalkyl; or -O-C1-m haloalkyl; each R£ is independently cyano, halo, Cf-j alkyl, hydroxy, -O-C1-2 alkyl, C1-1 haloalkyl or -O-Cr-haloalkyl; and R~ and Rs are each independently hydrogen c C1-4 alkyl, or R and R- together with the nitrogen atom to which they are attached form a - (CH2) 2-O- (CH2) 2-. 3.A compound of Formula I1: O R2 JH o' rN f ,N R1 N lia or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R2 and R2 are as defined in claim 1.

4. A compound of Formula I1b: ti 1 N I1b - 264 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein R3 and R3 are as defined in claim 1.

5. The compound of any preceding claim, wherein R3 is an aryl group optionally substituted with one to three R3 groups.

6. The compound of any of claims 1-4, wherein R3 is a heteroaryl group optionally substituted with one to three R3 groups.

7. The compound of any of claims 1-4, wherein R3 is a heterocyclyl optionally substituted with one to three R-. 8.The compound of any of claims 1-4, wherein R3 is cycloalkyl optionally substituted with one to three R3 groups.

9. The compound of any of claims 1-4, wherein R: is independently one, two, or three, each and R: is independently hydrogen, halo, or C2-alkyl; and R: is hydrogen or C2-alkyl.

10. The compound of any preceding claim, wherein at least one R: is halo, C2-alkyl, or -OR-.

11. The compound of any of claims 1-9, wherein at least one R: is fluoro, chloro, bromo, methyl, tert-butyl, methoxy, or phenoxy.

12. The compound of any of claims 1-9, wherein at least one R- is an aryl group substituted with phenyl, heterocyclyl, or heteroaryl.

13. The compound of any of claims 1-9, wherein at least one R- is: - 266 - 14.The compound of any of claims 1-9, wherein at least one R' is an aryl group substituted with a heteroaryl group, the heteroaryl group being substituted with a C₁₂, C₂O₆OH alkyl or a C₁₂ haloalkyl group. The compound of any of claims 1-9, wherein at least one R2 is - 267 - 16. The compound of any of claims 1-9, wherein at least one R' is a heterocyclyl group optionally substituted with one to three R' groups.

17. The compound of any of claims 1-9, wherein at least one R3 is 18. The compound of any of claims 1-9, wherein at least one R3 is a heteroaryl group optionally substituted with one to three R' groups.

19. The compound of any of claims 20.The compound of any of claims 1-19, wherein: R2 is hydrogen, C3 alkyl optionally substituted with one to three R3s or cycloalkyl; each Fu is independently -OC(O)R© -OC(O)ORa, OP(O)(ORb)~ or monocyclic heterocyclyl; provided that only one R4 is heterocyclyl; each Ra is independently alkyl optionally substituted with -NH2 or -OP(O)(ORb)2; and Rb is hydrogen. 21.A compound of Formula III: R2 or III or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein: R2 is hydrogen, -(CH2CH2O)2-2CH2CH2OCH2, C>g alkyl optionally substituted with one to three R4, cycloalkyl or heteroaryl optionally substituted with one to three RU; each R2 is independently aryl, heteroaryl or heterocyclyl, wherein each is optionally substituted with one to three R5; each R4 is independently halo, hydroxy, -O-Cg alkyl, -NH2, -NH-Cg alkyl, -N-Cg alkyl, -OC(O)Ra, OC(O)ORa, -OP(O)(ORb)2, or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R5; provided that only one R4 be heterocyclyl; - 269 each R5 is independently cyano, halo, Cl-4 alkyl, hydroxy, -0-C2-4 alkyl, C haloalkyl.-2 or -O-C2-2 haloalkyl; each R6 is independently cyano, halo, -C(O)R, C(O)ORq -C(O)NR7RS, -S(O)2NRR2, -NRC(O)R3, -OR, C2-4 alkyl, -O-C2-4 alkyl, C2-haloalkyl, -O-C2-4 haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C2-2 alkyl, -C(O)OH or C2-4 haloalkyl; each of R7 and R3 is independently hydrogen, C2-4 alkyl, phenyl or pyridyl, or R7 and R5 together with the nitrogen atom to which they are attached form a heterocyclyl; Each RJ is independently C2-alkyl optionally substituted with -NH2, -NH-C2-alkyl, -N(C2-b alkyl)2, or -OP(O) (ORfc)2; and each Rb is independently hydrogen or C2-alkyl.

22. A compound of Formula IV: \ -N _ . x *.....-NH -- N -¾ IV or a salt, tautomer, stereoisomer, mixture of stereoisomers or pharmaceutically acceptable deuterated analogue thereof, wherein: R2 is hydrogen, - (CH2CH2O) ; <VH2CH2OCH2, alquilo C2-e opcionalmente sustituido con de uno a tres R!, cicloalquilo o heteroarilo opcionalmente sustituido con de uno a tres R2; - 270 cada R4 es independientemente halo, hidroxi, -0 alquilo C:-?, -NH?, -NH-alquilo C:-?, -N(alquilo 0:-·;);, -0C(0)Ra, OC(O)ORi:, -OP(O) (OR-):, o heterociclilo monocíclico; en donde cada uno se sustituye opcionalmente con de uno a tres R-; siempre que solo un R4 sea heterociclilo; cada R5 es independientemente ciano, halo, alquilo 0;-;, hidroxi, -O-alquilo 0:-;, haloalquilo O;-; o -O-haloalquilo 0.-?; cada Ra es independientemente alquilo C?-¿ opcionalmente sustituido con -NH:, -NH-alquilo C> .;, -N (alkyl C:-?)?, or OP(O)(ORb)?; and each Rb is independently hydrogen or alkyl C:-z. 23.The compound of claim 22, wherein: R2 is hydrogen, C-alkyl, optionally substituted with one to three R4 or cycloalkyl; each R4 is independently -O-C-alkyl, -OC(O)Ra, OC(O)ORa, -OP(O)(ORb) or monocyclic heterocyclyl; each Ra is independently O-alkyl optionally substituted with -NH₂ or -OP(O)(ORb); and R' is hydrogen.

24. A compound selected from: - 271 - 25. A compound selected from Table 1.

26. A compound selected from: Cl - 272 - wherein R2 is as defined in claim 1.

27. The compound of claim 26 wherein the compound is selected from: Cl Cl and Cl - 273 - 28. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, of any of claims 127. 29.A method for the treatment of primary hyperoxaluria type 1, comprising administering to a patient in need a therapeutically effective amount of a compound of any of claims 1-27, or the pharmaceutical composition of claim 28, or a compound of Formula I: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is N or CH; R2 is alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, wherein each is optionally substituted with one to three R3s; R2 is hydrogen, -(CH2CH2O) > .CHiCHiOCHq, alkyl Cl-i optionally substituted with one to three R3s, cycloalkyl, or heteroaryl optionally substituted with one to three R2s; - 274 each R3 is independently cyano, halo, -L-alkyl C:-,·, -L-haloalkyl -LO-haloalkyl Ci-.j, -NRR-, -C(O)NRR-, -S (O) 2NR”R=, -NR7C(O)R;, -OR, -L-aryl, -L-heteroaryl or -Lheterocyclyl, wherein each is optionally substituted with one to three Rc, and each L is independently -C = C- or absent; each R4 is independently halo, hydroxy, -O-alkyl Ci-6, -NH2, -NH-alkyl Ci~í, -N(alkyl C:-c)2, -OC (O) Ra, OC(O)ORa, -OP(O) (OR~)2, or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R3; provided that only one R4 is heterocyclyl; each R5 is independently cyano, halo, hydroxyalkyl, -O-alkyl C_~2, haloalkyl C;-; or -O-haloalkyl C_-y each Rb is independently cyano, halo, -C(O)R, 0 (0) 0R\ -C(O)NRR3, -S(O)2NRR3, -NR~C(O)R3, -OR / alkyl C;u, -O-alkyl C1-4, haloalkyl C2-2, -O-haloalkyl O;-.;, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three alkyl O;-;, -O(O) OH or C2-2 haloalkyl; each of R' and R8 is independently hydrogen, C:vo alkyl phenyl, pyridyl, or R^ and R3 together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently C^^_ alkyl. optionally substituted with -NH2, -NH-C -N (C2-¿)2 alkyl, or 0P (O) (ORfc) 2; - 276 each RJ is independently cyano, halo, -L-C alkyl.-,, -L-haloalkyl C;-g, -LO-haloalkyl C_-u, -NR;R8, -C(O)NRR5, -S(O)2NR7Rs, - NR^C(O)R~, -ORj -L-aryl, -L-heteroaryl or -Lheterocyclyl, wherein each is optionally substituted with one to three R';, and each L is independently -C = C- or absent; each R4 is independently halo, hydroxy, -o alkyl C;-i, -NH2, -NH-alkyl C;-¿, -N (alkyl C;-¿)2, -OC(O)R\ OC(O)ORa, -OP (O) (ORb)2, or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R3; provided that only one R4 is heterocyclyl; each R5 is independently cyano, halo, C1-alkyl, hydroxy, -O-C1-alkyl, C1-haloalkyl or -O-C1-haloalkyl; each R6 is independently cyano, halo, -C(O)R, -C(O)OR, -C(O)NR7R3, -S(O)NR~R3, -NRTC(O)R3, -ORJ, C1-alkyl, -O-C1-alkyl, C1-haloalkyl, -O-C1-haloalkyl.phenyl, heterocyclyl, or heteroaryl; wherein each is optionally substituted with one to three C1-alkyl, -C(O)OH, or C1-4 haloalkyl groups; each of R and R- is independently hydrogen, C1-3 alkyl, or phenyl, pyridyl, or R and R together with the nitrogen atom to which they are attached form a heterocyclyl group; each Ra is independently C1-2 alkyl optionally substituted with -NH2, -NH-C1-2 alkyl, -N(C1-2 alkyl), or OP(O)(ORb)2; and each Rb is independently hydrogen or C1-2 alkyl; provided that when R1 is phenyl, then RJ is aryl or heteroaryl, each of which is optionally substituted with one to three Rc; and when R1 is heteroaryl, then R- is not an unsubstituted C1-2 alkyl group. 31.A method for inhibiting the production of glyoxylate and / or oxalate, and / or inhibiting glycolate oxidase (GO), comprising administering to a patient in need, a therapeutically effective amount of a compound of any of claims 1-27, the pharmaceutical composition of claim 28, or a compound of Formula I: O R2 Λ d N or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein Ά is N or CH; R2 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each is optionally substituted with one to three R2 groups; R2 is hydrogen, - (CHzCH.O) 2-zCH2CH2OCH2, C:- alkyl.< optionally substituted with one to three Rp cycloalkyl or heteroaryl optionally substituted with one to three R2; - 27 8 each R3 is independently cyano, halo, -L-alkyl Cm,, -L-haloalkyl C2-2, -LO-haloalkyl C2-2, -NRR3, -C(O)NRR-, -S(O)2NR3R3, - NR“C(O)R;, -OR, -L-aryl, -L-heteroaryl or -Lheterocyclyl, wherein each is optionally substituted with one to three R, and each L is independently -C=C- or absent; each R4 is independently halo, hydroxy, -O alkyl C.-í, -NH2, -NH-alkyl C.-¿, -N(alkyl Ornó, -OC(O)R-·, OC(O)ORa, -OP(O) (ORc).or monocyclic heterocyclyl; wherein each is optionally substituted with one to three R3; provided that only one R4 is heterocyclyl; each R5 is independently cyano, halo, C2-2 alkyl, hydroxy, -O-C2-2 alkyl, C2-2 haloalkyl or -O-haloalkyl; each R1 is independently cyano, halo, -C(O)R, C(O)ORO, -C(O)NR7R5, -S(O)NRRJ, -NRC(O)R3, -OR, C2-2 alkyl, -O-C1-4 alkyl, C2-2 haloalkyl, -O-C2-2 haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three C2-α alkyl, -O(O)OH, or C2-2 haloalkyl; each of R and R3 is independently hydrogen, C2-2 alkyl or phenyl, pyridyl, or R and R3 together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently C2-alkyl optionally substituted with -NH₂, -NH-C2-2 alkyl, -N(C2-alkyl)₂, or OP(0)(0Rb)₂; and - 279 each Rb is independently hydrogen or C2-2 alkyl.:; provided that when R- is phenyl, then R- is aryl or heteroaryl, each of which is optionally substituted with one to three R3 groups; and when R3 is heteroaryl, then R2 is not an unsubstituted alkyl group.

32. The use of a compound of any one of claims 1-27, or the pharmaceutical composition of claim 28, for controlling or inhibiting the production of recurrent kidney stone formers in a patient in need.

33. The use of a compound of Formula I, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, for controlling or inhibiting the production of recurrent kidney stone formers in a patient in need, wherein in a compound of Formula I: O R2 JH ohn rAa Ά is N or CH; R- is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein each is optionally substituted with one to three R3; R2 is hydrogen, - (CH2CH2O) - -.CH2CH2OCH2, optionally substituted alkyl C1-1 with one to three R4, cycloalkyl or -280 heteroaryl optionally substituted with one to three R3; each R' is independently cyano, halo, -L-alkyl C1-1, -L-haloalkyl C2-4, -LO-haloalkyl C1-NRR3, -C(O)NRR3, -S(O)2NR-R3, -NR-C(O)R3, -OR-, -L-aryl, -L-heteroaryl or -Lheterocyclyl, wherein each is optionally substituted with one to three R-, and each L is independently -C=C- or absent; each R4 is independently halo, hydroxy, -O C2-I alkyl, -NH2, -NH-alkyl, -N(alkyl 1 h , -OC(O)RJ, OC(O)ORa, -OP(O) (ORfc)2, or monocyclic heterocyclyl; wherein each is optionally substituted with one to three Pí; provided that only one R4 is heterocyclyl; each R5 is independently cyano, halo, C2-4 alkyl, hydroxy, -O-C alkyl.-4, O-3 haloalkyl or -O-C2-halokyl; each R6 is independently cyano, halo, -C(O)R-, C(O)OR\ -C(O)NRR=, -S(O)2NR7R3, -NR-C(O)R3, -OR-, C:-4 alkyl, -O-C2-4 alkyl, C2-4 haloalkyl, -O-C.-a haloalkyl, phenyl, heterocyclyl or heteroaryl; wherein each is optionally substituted with one to three O-alkyl, -C(O)OH or C2-4 haloalkyl; each of R- and R3 is independently hydrogen, C.-4 alkyl or phenyl, pyridyl, or R- and R3 together with the nitrogen atom to which they are attached form a heterocyclyl; each Ra is independently C2-alkyl. optionally substituted with -NH2, -NH-C2-c alkyl, -N (C2-J alkyl 2 - 281 OP (O) (ORb) 2; and each Rb is independently hydrogen or Cf-g alkyl; provided that when R- is phenyl, then R' is aryl or heteroaryl, each of which is optionally substituted with one to three R'; and when R- is heteroaryl, then R- is not Ci-, unsubstituted alkyl. 34.The method of any one of claim 29-31, further comprising administering an additional therapeutic agent.

35. The use of any one of claims 32-33, in combination with an additional therapeutic agent.

36. The method of claim 34, or the use of claim 35, wherein the additional therapeutic agent is a calcium oxalate crystallization inhibitor, an oxalate-degrading enzyme inhibitor, RNAi, oxazime, lumasiran, nedosiran, oxabate, or reloxaliase.

37. The method of claim 34, or the use of claim 35, wherein the additional therapeutic agent is an SGLT2 inhibitor.

38. The method or use of claim 37, wherein the SGL2 inhibitor is dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, empagliflozin, or potassium citrate.