Heterocyclic carboxylate compounds as glycolate oxidase inhibitors

Abstract

The present disclosure generally relates to a regulator of human glycolate oxidase and the use and preparation of the same. (I)

Description

Technology Field

[0001] This application claims priority under 35 USC § 119(e) to U.S. Provisional Application No. 62 / 929,476 filed November 1, 2019 and U.S. Provisional Application No. 63 / 093,094 filed October 16, 2020, each of which is incorporated herein by reference in its entirety.

[0002] 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 relates to novel substituted heterocyclic carboxylate compounds and methods for preparing and using them as therapeutic or prophylactic agents. In particular, the present disclosure provides novel inhibitors of human glycolate oxidase, pharmaceutical compositions containing such compounds, and methods for using these compounds to treat primary hyperoxaluria type 1 and recurrent kidney stone formers. Background Technology

[0003] Kidney stones affect a large population. In the United States, the prevalence of kidney stones is 8.8%, with 10.6% among men and 7.1% among women. This condition also occurs as primary hyperoxaluria type 1 (PH1), which can be caused by genetically defective enzyme activity. Due to high glycolate oxidase activity, these patients may exhibit a significant increase in the production of glyoxylates and oxalates, as well as the deposition of calcium oxalate stones. Medical methods to remove kidney stones exist and are effective. However, the recurrence rate of kidney stones after these methods is high (e.g., exceeding 50%). Therefore, there is a need for agents that inhibit glycolate oxidase activity to treat PH1 patients and reduce the recurrence rate of kidney stones in stone-forming patients.

[0004] The present disclosure relates to novel substituted heterocyclic carboxylate compounds that inhibit human glycolate oxidase activity and stereoisomers thereof, pharmaceutically acceptable salts and prodrugs, and the use of such compounds in the treatment of primary hyperoxaluria type 1. The compounds of this disclosure may be used to treat patients with recurrent kidney stone formation.

[0005] In one embodiment, a compound having the structure of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog thereof is provided:

[0006]

[0007] In the above equation, A, R 1 and R 2 is as defined herein.

[0008] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula (I) or any additional formula described throughout) and at least one pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog thereof.

[0009] Some embodiments provide a method of using (or administering) a compound of formula (I) or formula(s) described throughout in the treatment of a disease or pathological condition in mammals, particularly humans, that are compliant with treatment by an inhibitor of human glycolate oxidase.

[0010] Some embodiments provide a method of using (or administering) a compound as described herein in the treatment of a disease or pathological condition in mammals, particularly humans, that are compliant with treatment by an inhibitor of human glycolate oxidase. Brief explanation of the drawing

[0011] Figure 1 shows the plasma concentration-time profiles of Example 2 and Example 68 after oral administration of 5.0 mg / kg of Example 2 in SD rats (mean ± SD, n=3). Figure 2 shows the plasma concentration-time profile of Example 68 after a 30-minute intravenous infusion of 1.0 mg / kg and administration of 5.0 mg / kg PO in SD rats (mean ± SD, n=3). Figure 3 shows the plasma concentration-time profiles of Examples 168 and 175 in SD rats. Figure 4 shows the plasma concentration-time profiles of Examples 168 and 175 in male Beagle dogs. Specific details for implementing the invention

[0012] Definitions and General Parameters

[0013] The following description describes exemplary methods and parameters, etc. However, it should be understood that such description is not intended to limit the scope of the present disclosure, but rather is provided as an explanation of exemplary embodiments.

[0014] The following words, phrases, and symbols used in this specification are generally intended to have the meanings described below, except to the extent that the context in which they are used otherwise indicates.

[0015] A dash ("-") not between two letters or symbols is used to indicate a bonding point for a substituent. For example, -C(O)NH2 is bonded through a carbon atom. The dash at the beginning or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. Wavy lines drawn through lines in the structure indicate bonding points of the groups. Unless chemically or structurally required, directionality is not indicated or implied by the order in which chemical groups are written or named.

[0016] Prefix "C u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0017] The modifier "about" used in relation to quantity encompasses the mentioned value and has the meaning indicated by the context (e.g., including the degree of error associated with a measurement of a specific quantity). Additionally, the singular form includes plural references unless the context explicitly indicates otherwise. Thus, for example, a reference to "compound" includes plural such compounds, and a reference to "analysis" includes one or more analyses and their equivalents known to a person skilled in the art.

[0018] "Alkyl" indicates an unbranched or branched saturated hydrocarbon chain. As used herein, alkyls have 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4It has an alkyl group. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, secondary-butyl, iso-butyl, tertiary-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. Where an alkyl residue having a specific number of carbons is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbons are included; accordingly, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), secondary-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tertiary-butyl (i.e., -C(CH3)3); "Prop" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] "Alkenyl" contains at least one carbon-carbon double bond and 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 It represents an alkyl group having an alkenyl. Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (1,2-butadienyl and 1,3-butadienyl).

[0020] "Alkynyl" contains at least one carbon-carbon triple bond and 2 to 20 carbon atoms (i.e., C 2-20 alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 It represents an alkyl group having an alkynyl. The term "alkynyl" also includes groups having one triple bond and one double bond.

[0021] "Alkoxy" represents an "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tertiary-butoxy, secondary-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Halloalkoxy" represents the alkoxy group defined above, in which one or more hydrogen atoms are substituted by a halogen.

[0023] "Alkylthio" represents an "alkyl-S-" group.

[0024] "Acyl" represents a -C(O)R group, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0025] "Amido" is -C(O)NR y R z "C-amido" group and -NR representing the group y C(O)R z Representing both "N-amido" groups, where R y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of these may be optionally substituted.

[0026] "Amino" is -NR y R z Representing Qi, and here, R y and R z is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl; each of these may be optionally substituted.

[0027] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including fused systems (e.g., bicyclic or tricyclic). As used herein, aryls have 6 to 20 cyclic carbon atoms (i.e., C 6-20 aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 It has an aryl group. Examples of aryls include phenyl, naphthyl, fluorenyl, and anthryl. However, aryls do not in any way encompass or overlap with the heteroaryls defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclil, the resulting ring system is a heterocyclil.

[0028] "Carbamoil" is -OC(O)NR y R z "O-carbamoyl" group and -NR representing the group y C(O)OR z Represents both "N-carbamoyl" groups, where R y and R z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl; each of these may be optionally substituted.

[0029] "Carboxyl" represents both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be optionally substituted as defined above.

[0030] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused, bridging, and spiro-ring systems. The term "cycloalkyl" comprises a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyls have 3 to 20 cyclic carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] “Imino” represents a -C(NR)R group, wherein each R is an alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of these may be optionally substituted as defined herein.

[0032] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodo. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are substituted by a halogen. For example, where a residue is substituted by one or more halogens, it may be indicated using a prefix corresponding to the number of attached halogen moiety. Dihaloalkyl and trihaloalkyl refer to alkyls substituted with two ("di") or three ("tri") halos, which may, but are not necessarily, the same halogen; examples of haloalkyls include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0033] "Heteroalkyl" refers to an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" comprises an unbranched or branched saturated chain having carbons and heteroatoms. For example, one, two, or three carbon atoms may be independently replaced by the same or different heteroatom groups. However, the heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, and -S(O)2-, etc., wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclil, each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. The heteroalkyl used herein comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0034] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings with one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryls have 1 to 20 cyclic carbon atoms (i.e., C 1-20 Heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 Heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); and independently selected from nitrogen, oxygen, and sulfur It includes 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom. Non-limiting examples of heteroaryl groups are, but are not limited to, azefinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxephinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxadoliryl, benzodioxolyl, benzodioxynyl, benzopyranil, benzopyranonil, benzofuranyl, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazoo[l,2-a]pyridinyl, carbazolyl, cinolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, Imidazolyl, Indazolyl, Indolyl, Indazolyl, Isoindolyl, Indolinyl, Isoindolinyl, Isoquinolyl, Indoliginil, Isoxazolyl, Nathiridinyl, Oxadiazolyl, 2-Oxozepinil, Oxazolyl, Oxiranil, 1-Oxidopyridinyl, 1-Oxidopyrimidinyl, 1-Oxidopyrazinyl, 1-Oxidopyridazinyl, 1-Phenyl-IH-Pyrrolyl, Fenazinyl, Fenothiazinyl, Fenooxazinyl, Phthalaginyl, Pteridinyl, Furanyl (purinyl), Pyrrolyl, Pyrazolyl, Pyridinyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Quinazolinyl, Quinoxalinyl, Quinolinyl, Quinuclidinyl, Isoquinolinyl, Includes tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. The fused heteroaryl ring may be bonded through the ring of the fused system. Any aromatic ring having a single or multiple fused rings containing at least one heteroatom is considered a heteroaryl regardless of its bonding to the rest of the molecule (i.e., through any one of the fused rings). The heteroaryl does not include or overlap with the aryl as defined above.

[0035] "Heterocyclile" refers to a saturated or unsaturated cyclic alkyl group having one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclile" includes a heterocycloalkenyl group (i.e., a heterocyclile group having at least one double bond), a bridged heterocyclile group, a fused heterocyclile group, and a spiro-heterocyclile group. A heterocyclile may be a single ring or multiple rings, wherein the multiple rings may be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclile regardless of bonding (i.e., bonded through a carbon atom or a heteroatom). Additionally, the term heterocyclile is intended to include any non-aromatic ring containing at least one heteroatom, such ring may be fused to an aryl or heteroaryl ring regardless of bonding to the rest of the molecule. The heterocyclils used herein have 2 to 20 cyclic carbon atoms (i.e., C 2-20 Heterocyclile), 2 to 12 ring carbon atoms (i.e., C 2-12 Heterocyclile), 2 to 10 ring carbon atoms (i.e., C 2-10 Heterocyclile), 2 to 8 ring carbon atoms (i.e., C 2-8 Heterocyclile), 3 to 12 ring carbon atoms (i.e., C 3-12 Heterocyclile), 3 to 8 ring carbon atoms (i.e., C 3-8 Heterocyclile), or 3 to 6 ring carbon atoms (i.e., C 3-6It has a heterocyclile; and has 1 to 5 cyclic heteroatoms, 1 to 4 cyclic heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom and optionally one or more oxo groups independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclile groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanil, dioxolaninyl, azetidinyl, and morpholinyl. As used herein, the term “bridging-heterocyclile” refers to a 4- to 10-membered cyclic moiety connected at two non-adjacent atoms of a heterocyclile having at least one heteroatom and one or more (e.g., 1 or 2) 4- to 10-membered cyclic moiety, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The bridging-heterocycliles used herein include bicyclic and tricyclic systems. Additionally, the term "spiro-heterocyclile" as used herein refers to a ring system in which a 3- to 10-membered heterocyclile has one or more additional rings, wherein one or more additional rings are 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclile, and a single atom of one or more additional rings is also an atom of a 3- to 10-membered heterocyclile. Examples of spiro-heterocyclile rings include bicyclic and tricyclic ring systems, e.g., 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclil rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl (e.g., 2-methylisoquinoline-1(2H)-one), wherein the heterocyclil may be joined through any ring of the fused system.

[0036] "Oxo" represents (=O) or (O) energy.

[0037] "Sulfonyl" represents an S(O)2R group, where R is an alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyls are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0038] "Alkylsulfonyl" represents an S(O)2R group, where R is alkyl.

[0039] "Alkylsulfinyl" represents an S(O)R group, where R is alkyl.

[0040] "Thiol" represents an SR group, where R is an alkyl, haloalkyl, heterocyclil, cycloalkyl, heteroaryl, or aryl.

[0041] Certain commonly used alternative chemical names may be used. For example, divalent groups, such as divalent "alkyl" groups, divalent "aryl" groups, etc., may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups or "arylenyl" groups, respectively. Additionally, unless otherwise explicitly indicated, a combination of groups contains atoms in which the last mentioned group is bonded to the rest of the molecule, for example, in the case where one moiety is referred to herein as an arylalkyl group.

[0042] The terms "arbitrary" or "arbitrarily" mean that the subsequently described event or environment may or may not occur, and that the description includes cases where said event or environment occurs and cases where it does not. Additionally, the term "arbitrarily substituted" indicates that any one or more hydrogen atoms on a specified atom or apparatus may or may not be replaced by a non-hydrogen moiety.

[0043] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, an amide-containing compound may be in equilibrium with an imidic acid tautomer. Regardless of which tautomer is illustrated and regardless of the nature of the equilibrium between the tautomers, a compound is understood by a person skilled in the art to contain both an amide and an imidic acid tautomer. Thus, an amide-containing compound is understood to contain its imidic acid tautomer. Similarly, an imidic acid-containing compound is understood to contain its amide tautomer.

[0044] Any chemical formula or structure given herein is also intended to represent the isotope-labeled form of a compound as well as the unlabeled form. The isotope-labeled compound has the structure illustrated by the chemical formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be included in the compounds of the present disclosure are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, e.g., but not limited thereto 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 Includes I. Various isotope-labeled compounds of the present disclosure, for example, 3 H, 13 C and 14This includes those containing radioactive isotopes such as C. Such isotope-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 the analysis of drug or substrate tissue distribution, or in the radiotherapy of patients.

[0045] The present disclosure also comprises “deuterium isotope analogs” of a compound of formula (I) in which 1 to n hydrogens bonded to a carbon atom are replaced by deuterium, wherein n is the number of hydrogens in the molecule. Such compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound of formula (I) when administered to mammals, particularly humans. Reference Example [Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527(1984)]. Such compounds are synthesized by means known in the art, for example, by using a starting material in which one or more hydrogens are replaced by deuterium.

[0046] The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved drug metabolism and pharmacokinetics (DMPK) properties regarding distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope, e.g., deuterium, may provide specific therapeutic benefits resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced dosing requirements, and / or improvements in therapeutic indices. 18F-labeled compounds may be useful for PET or SPECT studies. The isotope-labeled compounds and their prodrugs of the present disclosure can generally be implemented by replacing a non-isotope-labeled reagent with an readily available isotope-labeled reagent, or by carrying out the procedures disclosed in the schematic or in the examples and methods described below. It will be understood that in this context, deuterium is considered as a substituent in the compound of formula (I).

[0047] The concentration of such heavier isotopes, in particular deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope means that it represents any stable isotope of that atom. Unless otherwise noted, where a position is specifically designated as “H” or “hydrogen,” the position is understood to have hydrogen in its isotopic composition of natural abundance. Accordingly, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means that it represents deuterium.

[0048] In many cases, the compounds of the present disclosure can form acid and / or base salts by the presence of amino and / or carboxyl groups or similar groups.

[0049] Additionally, pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein are provided. “Pharmaceutically acceptable” or “physiologically acceptable” refers to compounds, salts, compositions, dosage forms, and other substances useful for preparing pharmaceutical compositions suitable for veterinary or human therapeutic use.

[0050] The term “pharmaceutically acceptable salt” for a given compound refers to a salt that retains the biological efficacy and properties of the given compound and is biologically or otherwise undesirable. “Pharmaceutically acceptable salt” or “physiologically acceptable salt” includes, for example, salts with inorganic acids and salts with organic acids. Furthermore, if a compound described herein is obtained as an acid addition salt, a free base may be obtained by basicizing a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with the usual procedure for preparing an acid addition salt from a base compound. A person skilled in the art will be aware of various synthesis methods that can be used to produce non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromide, sulfuric acid, nitric acid, and phosphoric acid, etc. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvate, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid, etc. Similarly, pharmaceutically acceptable base addition salts may be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.Salts derived from organic bases are, but are not limited to, primary, secondary, and tertiary amines, e.g., alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), and tri(substituted alkenyl) amines (i.e., It includes salts of N(substituted alkenyl)3, mono-, di-, or tri-cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines. Specific examples of suitable amines include, only as examples, isopropylamine, trimethylamine, diethylamine, tri(iso-propyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0051] The term “substituted” means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more non-hydrogen substituents, provided that the normal valence of the specified atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amino, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar infinite structures achieved by defining a substituent as an infinitely additional additional substituent (e.g., a substituted aryl having a substituted alkyl that is itself substituted by a substituted aryl group further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise specified, the maximum number of series of substitutions in the compounds described herein is three. For example, a series of substitutions of a substituted aryl group by two different substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition is not intended to include unacceptable substitution patterns (e.g., a methyl group substituted with five fluorine atoms or a heteroaryl group having two adjacent oxygen ring atoms). Such unacceptable substitution patterns are well known to those skilled in the art. When used to change a chemical group, the term “substituted” may describe other chemical groups defined herein. Unless otherwise specified, where a group is described as optionally substituted, any substituent of the group is itself 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, heterocyclil, aryl, and heteroaryl.In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclil, aryl, or heteroaryl, each of which is substituted. In other embodiments, substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclil, aryl, or heteroaryl, each of which is unsubstituted.

[0052] In certain embodiments, the phrase “one or more” as used herein represents 1 to 5. In certain embodiments, the phrase “one or more” as used herein represents 1 to 3.

[0053] The terms "pharmaceuticalally acceptable carriers" or "pharmaceutically acceptable excipients" as used herein include any and all solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic agents, absorption retardants, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is considered except where any conventional media or agent is not compatible with the active ingredient. An auxiliary active ingredient may also be included in the composition.

[0054] "Solvents" are formed by the interaction between a solvent and a compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0055] compound

[0056] In the present invention, a compound acting as an inhibitor of glycolate oxidase is provided. In certain embodiments, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog thereof:

[0057]

[0058] In the above formula,

[0059] A is N or CH;

[0060] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0061] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0062] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently -C≡C- or absent;

[0063] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0064] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0065] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0066] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0067] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0068] Each R b is independently hydrogen or C1-4 It is an alkyl.

[0069] In some embodiments, where A is N, at least one of the following definitions is:

[0070] 1) R 1 1 to 3 R 3 It is a fused tricyclic ring arbitrarily substituted with;

[0071] 2) R 1 cyano, -C≡CC 1-9 Alkyl, 1 to 3 R 6 -C replaced with 1-9 Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OC 1-4 At least one R selected from alkyl, -O-phenyl, -L-aryl, -L-heteroaryl, or -L-heterocyclil 3 It is an arbitrarily substituted fused bicyclic ring substituted with, where each additionally has 1 to 3 R 6 It is arbitrarily substituted by, and each L is independently -C≡C- or absent;

[0072] 3) R 1 is at least one R 3 It is a monocyclic ring substituted with, and at least one R 3 silver,

[0073] i) Cyano, -C≡CC 1-9 Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R8 , -NR 7 C(O)R 8 , -C≡C-aryl, -C≡C-heteroaryl, or -C≡C-heterocyclil (wherein each additionally 1 to 3 R 6 Arbitrarily substituted by);

[0074] ii) monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclil (wherein, each having 1 to 3 cyano, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Further substituted with a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with haloalkyl;

[0075] iii) an optionally substituted and fused aryl, an optionally substituted and fused heteroaryl, or an optionally substituted and fused heterocyclil (wherein each additionally has 1 to 3 R 6 Arbitrarily replaced with); or

[0076] iv) Chemical formula -L 1 -L 2 substituent of (here, L 1 is an aryl, heteroaryl, or heterocyclil, where each is 1 to 3 R 6 Arbitrarily substituted with; L 2 is a phenyl, heterocyclyl, or heteroaryl, wherein each is 1 to 3 C1-4 alkyl, -C(O)OH, or C 1-4 Selected from (optionally substituted with haloalkyl);

[0077] 4) R 2 -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C substituted with 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with .

[0078] In some embodiments, when A is CH, R 1 is not a 10-membered heteroaryl substituted with methoxy and methyl; R 1 C cyano, halo, C 1-4 Alkyl, -OR 7 , C 1-4 Haloalkyl, and NR 7 R 8 It is not a C6 aryl arbitrarily substituted with 1 to 3 substituents independently selected from, where R 7 and R 8 Each independently consists of hydrogen or C 1-4 Alkyl or; R 1 Unsubstituted C 10 Not Aril or; R 1 It is not an unsubstituted heterocyclile.

[0079] In one embodiment, a compound having the structure of formula (I), a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, or a deuterium analog is provided:

[0080]

[0081] In the above formula,

[0082] A is N or CH;

[0083] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0084] R 2 is hydrogen, -(CH2CH2O) 1-9CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 alkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0085] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently combined or -C≡C- and;

[0086] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, or monocyclic heterocyclile; wherein each is optionally substituted with 1 to 3 R5s; provided that only one R4 is heterocyclile;

[0087] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0088] Each R 6 is independently cyano, halo, C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8, -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0089] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded.

[0090] In a specific embodiment, R 1 If it is phenyl, R 3 It is an aryl or heteroaryl, and each of these has 1 to 3 R 6 It is arbitrarily substituted by.

[0091] In a specific embodiment, R 1 If this is heteroaryl, R 2 is unsubstituted C 1-6 It is not an alkyl.

[0092] In a specific embodiment,

[0093] A is N or CH and;

[0094] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0095] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as1-6 alkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0096] Each R 3 is independently halo, -LC 1-9 Alkyl, -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-5-6-membered heteroaryl or -L-5-6-membered heterocyclil, wherein each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently combined or -C≡C- and;

[0097] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, or monocyclic heterocyclile; wherein each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0098] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0099] Each R 6 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0100] R 7 and R 8 Each independently consists of hydrogen or C 1-4alkyl or R 7 and R 8 They form -(CH2)2-O-(CH2)2- together with the nitrogen atoms to which they are bonded.

[0101] Additionally, a compound of formula (IIa), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog is provided:

[0102]

[0103] In the above formula,

[0104] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0105] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 alkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0106] Each R 3 is independently cyano, halo, C 1-9 Alkyl, C 1-4 Haloalkyl, -OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , aryl, heteroaryl, or heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently combined or -C≡C- and;

[0107] Each R 4is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, or monocyclic heterocyclile; wherein each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0108] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0109] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0110] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded.

[0111] In certain embodiments, a compound of formula (IIa), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog is provided:

[0112]

[0113] In the above formula,

[0114] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0115] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0116] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently -C≡C- or absent;

[0117] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0118] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0119] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0120] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0121] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0122] Each R b is independently hydrogen or C 1-4 It is an alkyl.

[0123] In some embodiments, for a compound of formula (IIa), at least one of the following definitions is:

[0124] 1) R 1 1 to 3 R 3 It is a fused tricyclic ring arbitrarily substituted with;

[0125] 2) R 1 cyano, -C≡CC 1-9 Alkyl, 1 to 3 R 6 -C replaced with 1-9 Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OC 1-4 At least one R selected from alkyl, -O-phenyl, -L-aryl, -L-heteroaryl, or -L-heterocyclil 3 It is an arbitrarily substituted fused bicyclic ring substituted with, where each additionally has 1 to 3 R 6 It is arbitrarily substituted by, and each L is independently -C≡C- or absent;

[0126] 3) R 1 is at least one R 3 It is a monocyclic ring substituted with, and at least one R 3 silver,

[0127] i) Cyano, -C≡CC 1-9Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -C≡C-aryl, -C≡C-heteroaryl, or -C≡C-heterocyclil (wherein each additionally 1 to 3 R 6 Arbitrarily substituted by);

[0128] ii) monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclil (wherein, each having 1 to 3 cyano, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Further substituted with a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with haloalkyl;

[0129] iii) an optionally substituted and fused aryl, an optionally substituted and fused heteroaryl, or an optionally substituted and fused heterocyclil (wherein each additionally has 1 to 3 R 6 Arbitrarily replaced with); or

[0130] iv) Chemical formula -L 1 -L 2 substituent of (here, L 1 is an aryl, heteroaryl, or heterocyclil, where each is 1 to 3 R 6Arbitrarily substituted with; L 2 is a phenyl, heterocyclyl, or heteroaryl, wherein each is 1 to 3 C1-4 alkyl, -C(O)OH, or C 1-4 Selected from (optionally substituted with haloalkyl);

[0131] 4) R 2 -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C substituted with 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with .

[0132] Additionally, a compound of formula (IIb), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog is provided:

[0133]

[0134] In the above formula,

[0135] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0136] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0137] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8, -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently -C≡C- or absent;

[0138] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0139] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0140] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0141] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0142] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0143] Each R b is independently hydrogen or C 1-4 It is an alkyl.

[0144] In some embodiments, in the case of a compound of formula (IIb), R 1 is not a 10-membered heteroaryl substituted with methoxy and methyl; R 1 C cyano, halo, C 1-4 Alkyl, -OR 7 , C 1-4 Haloalkyl, and NR 7 R 8 It is not a C6 aryl arbitrarily substituted with 1 to 3 substituents independently selected from, where R 7 and R 8 Each independently consists of hydrogen or C 1-4 Alkyl or; R 1 Unsubstituted C 10 Not Aril or; R 1 It is not an unsubstituted heterocyclile.

[0145] In a specific embodiment, A is N. In a specific embodiment, A is CH.

[0146] In a specific embodiment, R 1 1 to 3 R 3 It is an aryl arbitrarily substituted with

[0147] In a specific embodiment, R 1 1 to 3 R 3 It is a heteroaryl arbitrarily substituted with

[0148] In a specific embodiment, R 1 1 to 3 R 3 It is a heterocyclile arbitrarily substituted with

[0149] In a specific embodiment, R 1 1 to 3 R 3 It is a cycloalkyl arbitrarily substituted with

[0150] In a specific embodiment, R 1 silver

[0151] and; each n is independently 1, 2, or 3, and Y is CR 8 R 9 , C(O), O, or NR 10 and; R 8 and R 9 Each of these is independently hydrogen, halo, or C 1-4 It is alkyl; R 10 Silver is hydrogen or C 1-4 It is an alkyl.

[0152] In a specific embodiment, L is a combination (i.e., a member). In a specific embodiment, L is -C≡C-.

[0153] In a specific embodiment, R 8 and R 9 Each of is a halo. In a specific embodiment, R 8 and R 9 Each of them is a fluoro.

[0154] In a specific embodiment, R 8 and R 9 Each of them is hydrogen.

[0155] In a specific embodiment, R 2 is hydrogen.

[0156] In a specific embodiment, R 3 Eun Halo, C 1-9 Alkyl, C 1-4 Haloalkyl or -OR 7 am.

[0157] In a specific embodiment, at least one R 3 Eun Halo, C 1-9 alkyl or -OR 7 is. In a specific embodiment, R 3 Eun Halo, C 1-9 alkyl or -OR 7 am.

[0158] In a specific embodiment, at least one R 3 is fluoro, chloro, bromo, methyl, tert-butyl, methoxy, or phenoxy. In certain embodiments, R 3 It is fluoro, chloro, bromo, methyl, tert-butyl, methoxy, or phenoxy.

[0159] In a specific embodiment, R 3 is an aryl optionally substituted with 1 to 3 R6s.

[0160] In a specific embodiment, R 3 silver

[0161]

[0162] am.

[0163] In a specific embodiment, at least one R 3 is an aryl substituted by a phenyl, heterocyclile, or heteroaryl. In certain embodiments, R 3 is an aryl substituted by a phenyl, heterocyclil, or heteroaryl group.

[0164] In a specific embodiment, at least one R 3 silver

[0165]

[0166]

[0167] am.

[0168] In a specific embodiment, R 3 silver

[0169]

[0170]

[0171] am.

[0172] In a specific embodiment, at least one R 3 is an aryl substituted with a heteroaryl, and such a heteroaryl is C 1-4 Alkyl, -C(O)OH or C 1-4 It is substituted with a haloalkyl group. In a specific embodiment, R 3 is an aryl substituted with a heteroaryl, and such a heteroaryl is C 1-4 Alkyl, -C(O)OH or C 1-4 It is substituted with a haloalkyl group.

[0173] In a specific embodiment, at least one R 3 silver

[0174]

[0175] am.

[0176] In a specific embodiment, R 3 silver

[0177] am.

[0178] In a specific embodiment, at least one R 3 1 to 3 R 6 It is a heterocyclile arbitrarily substituted with . In a specific embodiment, R 3 1 to 3 R 6 It is a heterocyclile arbitrarily substituted with

[0179] In a specific embodiment, at least one R 3 silver

[0180] is. In a specific embodiment, R 3 silver

[0181] am.

[0182] In a specific embodiment, at least one R 3 1 to 3 R 6 It is a heteroaryl arbitrarily substituted with . In a specific embodiment, R 3 1 to 3 R 6 It is a heteroaryl arbitrarily substituted with

[0183] In a specific embodiment, at least one R 3 silver is. In a specific embodiment, R 3 silver am.

[0184] In a specific embodiment, R 2 is hydrogen, 1 to 3 R 4 C arbitrarily substituted as 1-6 alkyl, or cycloalkyl; and each R 4 -OC(O)R independently a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; provided, only one R 4 is a heterocyclile; and each R a is independently -NH2 or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl; R b is hydrogen.

[0185] In certain embodiments, a compound of formula (III), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog is provided:

[0186]

[0187] In the above formula,

[0188] R 2is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0189] Each R 3 is independently an aryl, heteroaryl, or heterocyclil, where each is 1 to 3 R 6 Arbitrarily replaced with;

[0190] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0191] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0192] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C1-4 Haloalkyl, -OC 1-4 It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0193] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl, phenyl, or pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0194] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0195] Each R b is independently hydrogen or C 1-4 It is an alkyl.

[0196] In certain embodiments, a compound of formula (IV), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog is provided:

[0197]

[0198] In the above formula,

[0199] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0200] Each R 4 is independently halo, hydroxy, -OC 1-6Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0201] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0202] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0203] Each R b is independently hydrogen or C 1-4 It is an alkyl.

[0204] In a specific embodiment, R 2 is hydrogen, 1 to 3 R 4 C arbitrarily substituted as 1-6 It is an alkyl, or cycloalkyl. In certain embodiments, R 2 is hydrogen or 1 to 3 R 4 C arbitrarily substituted as 1-6 It is an alkyl. In a specific embodiment, R 2 is hydrogen or 1 R 4 C arbitrarily substituted as 1-6 It is an alkyl. In a specific embodiment, R 2 is hydrogen. In a specific embodiment, R 2 is 1 to 3 R 4 C arbitrarily substituted as1-6 It is an alkyl. In a specific embodiment, R 2 is C 1-6 It is an alkyl. In a specific embodiment, R 2 is C 1-4 It is an alkyl.

[0205] In a specific embodiment, R 2 is hydrogen, C optionally substituted with 1 to 3 R4s. 1-6 alkyl, or cycloalkyl; and each R 4 -OC independently 1-6 Alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; and each R a is independently -NH2 or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl; R b is hydrogen.

[0206] In a specific embodiment, each R 4 -OC independently 1-6 Alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where, each R a is independently -NH2 or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl, and R b is hydrogen.

[0207] In a specific embodiment, each R 4 -OC(O)R independently a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where, each R a is independently -NH2 or -OP(O)(OR b C arbitrarily substituted with )2 1-6It is alkyl, and R b is hydrogen.

[0208] In certain embodiments, a compound selected from Table 1 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog is provided. In certain embodiments, the compound is selected from the compounds of Table 1:

[0209] Table 1

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221] In certain embodiments, the compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analogue thereof is provided. In certain embodiments, the compound is selected from the following compounds:

[0222]

[0223] In certain embodiments, the compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analogue thereof is provided. In certain embodiments, the compound is selected from the following compounds:

[0224]

[0225] In the above formula,

[0226] R 2 is as defined herein.

[0227] In a specific embodiment, R 2 is 1 to 3 R 4 C arbitrarily substituted as 1-6 It is an alkyl. In a specific embodiment, R 2 is C 1-6 It is an alkyl. In a specific embodiment, R 2 is ethyl.

[0228] In a specific embodiment, the compound is selected from the following compounds:

[0229]

[0230] Generally, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, other names may be used to identify compounds of the same structure. In particular, compounds may also be named using other naming systems and symbols generally recognized in the field of chemistry, including, for example, the Chemical Abstract Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). Other compounds or radicals may be named by their generic names, or by their taxonomic or non-taxonomic names.

[0231] In certain embodiments, optical isomers, racemic mixtures, or other mixtures thereof of the compound described herein or a pharmaceutically acceptable salt or mixture thereof are provided. In such cases, a single enantiomer or diastereomer, i.e., an optically active form, may be obtained by asymmetric synthesis or by separation. Separation may be achieved by conventional methods, such as, for example, crystallization in the presence of a separating agent, or, for example, chromatography using a chiral high-pressure liquid chromatography (HPLC) column.

[0232] The compositions described herein comprising the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof may comprise racemic mixtures, or mixtures containing an excess of one enantiomer, or a single diastereomer or a mixture of diastereomers. All such isomers of these compounds are clearly included in the present invention, just as each and all isomer forms are specifically and individually listed.

[0233] In certain embodiments, chelate compounds, non-covalent complexes, and mixtures thereof of the compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterium analogs thereof are also provided. “Chelate compounds” are formed by the coordination of the compound to metal ions at two (or more) sites. “Non-covalent complexes” are formed by the interaction of the compound with another molecule, wherein no covalent bond is formed between such compound and the molecule. For example, complexation may occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonding).

[0234] In certain embodiments, a prodrug of the compound described herein is provided. "A prodrug represents any compound that, when administered into a biological system, produces a drug substance or active ingredient as a result of spontaneous chemical reaction(s), enzyme-catalyzed chemical reaction(s), photodegradation, and / or metabolic chemical reaction(s). Thus, a prodrug is a covalently modified analog or potential form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moiety, quaternary ammonium moiety, and glycol moiety, etc.

[0235] In certain embodiments, as a compound of formula (I) or (IIa),

[0236] R 1 silver

[0237]

[0238] And;

[0239] Here, each R 12 is independently hydrogen, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-15 It is cycloalkyl, aryl, heteroaryl, or heterocyclil; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil is 1 to 4 Z 1b Arbitrarily substituted with gi;

[0240] Each Z 1b is independently ioxo, thioxo, hydroxy, halo, -NO2, -N3, cyano, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 3-15 Cycloalkyl, C 1-8 Haloalkyl, aryl, heteroaryl, heterocyclil, -O(C 1-9 alkyl), -O(C 2-6 alkenyl), -O(C 2-6 alkynyl), -O(C 3-15cycloalkyl), -O(C 1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclil), -NH2, -NH(C 1-9 alkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15 cycloalkyl), -NH(C 1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclil), -N(C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2, -N(C 2-6 Alkenyl)2, -N(C 2-6 alkynyl)2, -N(C 3-15 cycloalkyl)2, -N(C 1-8 haloalkyl)2, -N(aryl)2, -N(heteroaryl)2, -N(heterocyclyl)2, -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 alkynyl), -N(C 1-9 Alkyl)(C 3-15 cycloalkyl), -N(C 1-9 Alkyl)(C 1-8 haloalkyl), -N(C 1-9 Alkyl)(aryl), -N(C 1-9 Alkyl)(heteroaryl), -N(C 1-9 Alkyl)(heterocyclile), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 alkynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(C 1-8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclil), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 alkinyl), --C(O)O(C 3-15cycloalkyl), -C(O)O(C 1-8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclil), -C(O)NH2, -C(O)NH(C 1-9 alkyl), -C(O)NH(C 2-6 alkenyl), -C(O)NH(C 2-6 alkynyl), -C(O)NH(C 3-15 cycloalkyl), -C(O)NH(C 1-8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclil), -C(O)N(C 1-9 Alkyl)2, -C(O)N(C 3-15 cycloalkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 alkynyl)2, -C(O)N(C 3-15 cycloalkyl)2, -C(O)N(C 1-8 haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclyl)2, -NHC(O)(C 1-9 alkyl), -NHC(O)(C 2-6 alkenyl), -NHC(O)(C 2-6 alkinyl), -NHC(O)(C 3-15 cycloalkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclil), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 alkinyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclil), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 alkinyl), -NHC(O)NH(C 3-15cycloalkyl), -NHC(O)NH(C 1-8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclil), -SH, -S(C 1-9 alkyl), -S(C 2-6 alkenyl), -S(C 2-6 alkinyl), -S(C 3-15 cycloalkyl), -S(C 1-8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclil), -NHS(O)(C 1-9 alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 alkyl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(NH)(C 1-9 alkyl), -S(O)(C 2-6 alkenyl), -S(O)(C 2-6 alkynyl), -S(O)(C 3-15 cycloalkyl), -S(O)(C 1-8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclil), -S(O)2(C 1-9 alkyl), -S(O)2(C 2-6 alkenyl), -S(O)2(C 2-6 alkynyl), -S(O)2(C 3-15 cycloalkyl), -S(O)2(C 1-8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclil), -S(O)2NH(C 1-9 alkyl), or -S(O)2N(C 1-9 Alkyl)2 and;

[0241] Here, any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclile has 1 to 4 halos, halo, C 1-9 Alkyl, C 1-8 haloalkyl, -OH, -NH2, -NH(C 1-9 alkyl), -NH(C 3-15 cycloalkyl), -NH(C 1-8haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclil), -N(C 1-9 Alkyl)2, -N(C 3-15 cycloalkyl)2, -NHC(O)(C 3-15 cycloalkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclil), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 2-6 alkinyl), -NHC(O)O(C 3-15 cycloalkyl), -NHC(O)O(C 1-8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclil), -NHC(O)NH(C 1-9 alkyl), -S(O)(NH)(C 1-9 alkyl), S(O)2(C 1-9 alkyl), -S(O)2(C 3-15 cycloalkyl), -S(O)2(C 1-8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclil), -S(O)2NH(C 1-9 alkyl), -S(O)2N(C 1-9 alkyl) 2, -O(C 3-15 cycloalkyl), -O(C 1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclil), or -O(C 1-9 A compound of formula (I) or (IIa) is provided, optionally substituted with an alkyl group.

[0242] In certain embodiments, as a compound of formula (I) provided herein or a compound of any sub-formula, R 2 go

[0243]

[0244] A compound of chemical formula (I) or a compound of any sub-chemical formula is provided.

[0245] Such substituents also include all individual stereoisomers, and mixtures thereof, which include, but are not limited to, chirality at the phosphorus atom, for example, in the exemplary moiety shown above.

[0246] In addition, the present invention provides in vivo metabolic products of the compounds described herein. Such products may be produced from the oxidation, reduction, hydrolysis, amidation, and esterification of the administered compounds, primarily through enzymatic processes.

[0247] Therapeutic use of compounds

[0248] "Therapeutics" or "treating" is an approach to obtain beneficial or desired outcomes, including clinical outcomes. Beneficial or desired clinical outcomes may include one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms arising from the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or stopping the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the exacerbation or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis); and / or c) alleviating the disease, i.e., causing a regression of clinical symptoms (e.g., improving the disease state, providing partial or total remission of the disease or condition, enhancing the effect of another drug treatment, delaying disease progression, improving quality of life, and / or prolonging survival).

[0249] “Prevention” or “preventing” means any treatment of a disease or condition that prevents the occurrence of clinical symptoms of the disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of the disease or condition or have a family history of such disease or condition. Primary hyperoxaluria type 1 may result in the need for a kidney transplant. After transplantation, the likelihood of remission is very high. In certain embodiments, the compound disclosed herein is administered to post-transplant patients for the purpose of preventing remission.

[0250] "Subject" refers to an animal that is or may be the subject of treatment, observation, or experiment, e.g., a mammal (including humans). The methods described herein may be useful in human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0251] The “therapeutic effective dose” or “effective amount” of the compounds described herein or their pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterium analogs means an amount sufficient to perform treatment to provide therapeutic benefits, such as relief of symptoms or slowing of disease progression, when administered to a subject. For example, the therapeutic effective dose may be an amount sufficient to reduce the symptoms of the disease or condition in response to the inhibition of glycolate oxidase activity. The therapeutic effective dose may vary depending on the subject, the disease or condition being treated, the subject’s body weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by a person skilled in the art.

[0252] The term “inhibition” indicates a reduction in the baseline activity of biological activity or process. “Inhibition of glycolate oxidase activity” or a variant thereof indicates a reduction in glycolate oxidase activity as a direct or indirect response to the presence of the compound of the present application compared to the glycolate oxidase activity in the absence of the compound of the present application. “Inhibition of glycolate oxidase” indicates a reduction in glycolate oxidase activity as a direct or indirect response to the presence of the compound described herein compared to the glycolate oxidase activity in the absence of the compound described herein. In some embodiments, inhibition of the enzymatic activity of glycolate oxidase may be compared in the same subject prior to treatment or in another subject not treated.

[0253] The methods described herein may be applied to cell populations in vivo or in vitro. “In vivo” means within a living organism, such as within an animal or human. In the context of this document, the methods described herein may be used therapeutically within an organism. “In vitro” means outside of a living organism. Examples of in vitro cell populations include in vitro cell cultures and biological samples, including body fluid or tissue samples obtained from an organism. Such samples may be obtained by methods well known in the art. Exemplary biological body fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In the context of this document, the compounds and compositions described herein may be used for various purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used to determine the optimal schedule and / or dosage of glycolate oxidase inhibitors for a given symptom, cell type, organism, and other parameters in vitro. Information obtained from such use may be used clinically for experimental purposes or to establish a draft for in vivo treatment. Other in vivo uses to which the compounds and compositions described herein are adapted will be described below or will be obvious to those skilled in the art. Selected compounds may be further characterized to test safety or acceptable dosages in human or non-human subjects. Such characteristics may be tested using methods generally known to those skilled in the art.

[0254] The compounds disclosed herein are useful for the treatment, prevention, diagnosis, or monitoring of diseases or conditions mediated by glycolate oxidase. Non-limiting examples of diseases or conditions mediated by glycolate oxidase include, without limitation, nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, hyperoxaluria type 1, bird's disease, glycolic aciduria, end-stage renal disease (ESRD), renal failure, kidney transplant failure, and type II diabetes.

[0255] In certain embodiments, the compounds disclosed herein are useful for the treatment, prevention, diagnosis, or monitoring of diseases or conditions mediated by oxalate or calcium oxalate or glycolate oxidase. In some embodiments, the diseases or conditions are renal calcification (kidney stones), renal calcification, bladder stones, hyperoxaluria type 1, avian disease, glycolic aciduria, end-stage renal disease (ESRD), renal failure, transplant renal failure, and type II diabetes mellitus.

[0256] In further embodiments, a method is provided to alleviate symptoms of a disease or disorder mediated by glycolate oxidase. In some embodiments, such a method comprises identifying a mammal having symptoms of a disease or disorder mediated by glycolate oxidase and providing a certain amount of the compound described herein that is effective in alleviating the symptoms (i.e., reducing the severity) in such mammal.

[0257] In further embodiments, the method is provided to alleviate symptoms of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase. In some embodiments, the method comprises identifying a mammal having symptoms of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase and providing a certain amount of the compound described herein that is effective in alleviating symptoms (i.e., reducing the severity) in such mammal.

[0258] In some embodiments, the disease or condition mediated by glycolate oxidase is renal stone formation. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is renal stone formation. In certain embodiments, renal stone formation is recurrent. In certain embodiments, renal stone formation is associated with primary hyperoxaluria type 1.

[0259] In some embodiments, the disease or condition mediated by glycolate oxidase is renal failure, including failure of one kidney and both kidneys. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is renal failure. In some embodiments, the renal failure is failure of one kidney and both kidneys.

[0260] In some specific examples, the disease or condition prevented is transplant renal failure.

[0261] In some embodiments, the disease or condition mediated by glycolate oxidase is diabetes mellitus, including type 1 and type 2 diabetes mellitus, gestational diabetes mellitus, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glycaemia, and impaired glucose tolerance. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is diabetes mellitus. In some embodiments, diabetes mellitus is type 1 and type 2 diabetes mellitus, gestational diabetes mellitus, prediabetes mellitus, insulin resistance, metabolic syndrome, impaired fasting glycaemia, or impaired glucose tolerance. Type 1 diabetes mellitus is also known as insulin-dependent diabetes mellitus (IDDM). Type 2 diabetes is also known as non-insulin-dependent diabetes mellitus (NIDDM).

[0262] In some embodiments, the disease or condition mediated by glycolate oxidase is bladder stone formation. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is bladder stone formation.

[0263] Criteria useful for the analysis of disease activity in subjects with primary hyperoxaluria type 1 can be found in the literature [Brooks et al. (2016) Am. J. Nephrol. 43, 4:293-303]. The amounts of oxalate and calcium in the urine can be monitored.

[0264] The treatment method disclosed herein may also be applied at any point in the course of the disease. In certain embodiments, the method is applied to a subject with primary hyperoxaluria type 1 during the period of regression (i.e., inactive disease after kidney transplantation). In such embodiments, the method of the present invention provides benefit by extending the period of regression (e.g., by extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. Such an example may be an increase in the time between occurrences of kidney stones. In other embodiments, the method may be applied to a subject with primary hyperoxaluria type 1 during the period of active disease. Such a method provides benefit by reducing the period of active disease, reducing or alleviating one or more symptoms of primary hyperoxaluria type 1, or treating primary hyperoxaluria type 1. Such alleviation may be a reduction in the size, number, or frequency of kidney stones.

[0265] Measures for measuring the efficacy of treatment for primary hyperoxaluria type 1 in clinical practice are described and include the following: symptom control; calcium oxalate concentration in body fluids; renal function analysis; and improvement in quality of life.

[0266] In a specific embodiment, the present invention provides a method for treating primary hyperoxaluria type 1, comprising administering a therapeutically effective amount of the compound described herein, the pharmaceutical composition described herein, or the compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog thereof to a patient requiring treatment for primary hyperoxaluria type 1:

[0267]

[0268] In the above formula,

[0269] A is N or CH;

[0270] R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0271] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0272] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently -C≡C- or absent;

[0273] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0274] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0275] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0276] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0277] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0278] Each R b is independently hydrogen or C 1-4 It is an alkyl.

[0279] In a specific embodiment, R 1In the case of this phenyl, R 3 It is an aryl or heteroaryl, and each of these has 1 to 3 R 6 Arbitrarily substituted by; R 1 In the case of this heteroaryl, R 2 is unsubstituted C 1-6 It is not an alkyl.

[0280] In a specific embodiment, the present invention provides a method for treating a recurrent kidney stone-forming patient by administering a therapeutically effective amount of the compound described herein, the pharmaceutical composition described herein, or the compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog thereof to a patient requiring treatment for a recurrent kidney stone-forming patient:

[0281]

[0282] In the above formula,

[0283] A is N or CH;

[0284] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0285] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0286] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently -C≡C- or absent;

[0287] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0288] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0289] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0290] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0291] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0292] Each R b is independently hydrogen or C 1-4 It is an alkyl.

[0293] In a specific embodiment, R 1 In the case of this phenyl, R 3 It is an aryl or heteroaryl, and each of these has 1 to 3 R 6 Arbitrarily substituted by; R 1 In the case of this heteroaryl, R 2 is unsubstituted C 1-6 It is not an alkyl.

[0294] In certain embodiments, the present invention provides a method for inhibiting the formation of glyoxylates and / or oxalates or inhibiting glycolate oxidase (GO), comprising administering a therapeutically effective amount of the compound described herein, the pharmaceutical composition described herein, or the compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analog thereof to a patient in need thereof:

[0295]

[0296] In the above formula,

[0297] A is N or CH;

[0298] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0299] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0300] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently -C≡C- or absent;

[0301] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0302] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0303] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0304] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0305] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0306] Each R b is independently hydrogen or C 1-4 It is an alkyl.

[0307] In some specific examples, R 1 In the case of this phenyl, R 3 It is an aryl or heteroaryl, and each of these has 1 to 3 R 6 Arbitrarily substituted by; R 1 In the case of this heteroaryl, R 2 is unsubstituted C 1-6 It is not an alkyl.

[0308] In certain embodiments, the use of the compound or pharmaceutical composition described herein is intended to control or inhibit the formation of recurrent kidney stone-forming agents in patients requiring such use.

[0309] In certain embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterium analogue thereof is intended to control or inhibit the formation of recurrent kidney stone-forming agents in patients requiring it:

[0310]

[0311] A is N or CH;

[0312] R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclil, wherein each is 1 to 3 R 3 Arbitrarily replaced with;

[0313] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with;

[0314] Each R 3 It independently consists of cyano, halo, and -LC 1-9 Alkyl, -LC 1-4 Haloalkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclil, where each is 1 to 3 R 6 It is arbitrarily substituted with, and each L is independently -C≡C- or absent;

[0315] Each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where each is 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is a heterocyclile;

[0316] Each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl;

[0317] Each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; wherein, each is 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl;

[0318] R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded;

[0319] Each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl;

[0320] Each R b is independently hydrogen or C 1-4 It is alkyl;

[0321] However, R 1In the case of this phenyl, R 3 It is an aryl or heteroaryl, and each of these has 1 to 3 R 6 Arbitrarily substituted by; R 1 In the case of this heteroaryl, R 2 is unsubstituted C 1-6 It is not an alkyl.

[0322] Combination therapy

[0323] In one embodiment, the compound disclosed herein may be used in combination with one or more additional therapeutic agents or interventions used or / or developed to treat primary hyperoxaluria type 1. Examples of such therapeutic agents are calcium oxalate crystallization inhibitors, oxalate degradase inhibitors, SiRNA, oxazyme, and lumasiran. Examples of such therapeutic interventions are high fluid intake, dialysis, and kidney transplantation.

[0324] In some embodiments, the compounds disclosed herein may be used in combination with SGLT2 inhibitors. Non-limiting examples of SGLT2 inhibitors include dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, empagliflozin, and potassium citrate.

[0325] In some embodiments, the method described herein comprises administering an additional therapeutic agent. In some embodiments, the use described herein is provided in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a calcium oxalate crystallization inhibitor, an oxalate degradase inhibitor, SiRNA, oxazim, lumasiran, nedosiran, oxabate, or reloxaliase. In some embodiments, the additional therapeutic agent is an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, ertugliflozin, luceogliflozin, canagliflozin, topogliflozin, ipragliflozin, empagliflozin, and potassium citrate.

[0326] Kit

[0327] In the present invention, a kit is also provided comprising a compound of formula (I) (or any other formula described herein), or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterium analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one embodiment, the kit comprises a compound of formula (I) (or any other formula described herein), or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterium analog thereof, and a label and / or instructions for the use of the compound in the treatment of symptoms, including the disease or condition described herein.

[0328] In this invention, manufactured articles comprising the compound described herein or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterium analog thereof in a suitable container are also provided. The container may be a vial, jar, ampoule, pre-loaded syringe, and intravenous bag.

[0329] Pharmaceutical composition and method of administration

[0330] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, the present invention provides a pharmaceutical composition comprising one or more of the compounds described herein or their pharmaceutically acceptable salts, tautomers, prodrugs, or deuterium analogs, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents including sterile liquid solutions and various organic solvents, permeability enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. Reference Examples [Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & CT Rhodes, Eds.)].

[0331] The pharmaceutical composition may be administered as a single dose or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectal, oral, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0332] One method of administration is parenteral, e.g., by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, e.g., sesame oil, corn oil, cottonseed oil, or peanut oil, as well as aqueous or oily suspensions or emulsions or sterile aqueous solutions with elixir, mannitol, or dextrose, and similar pharmaceutical vehicles.

[0333] Oral administration may be another route for administering the compounds described herein. Administration may be made, for example, through capsules or enteric-coated tablets. In preparing a pharmaceutical composition comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterium analog thereof, the active ingredient is generally diluted by an excipient and / or encapsulated in a carrier which may be in the form of a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it may be in the form of a vehicle, a carrier, or a solid, semi-solid, or liquid material acting as a medium for the active ingredient. Accordingly, the composition may be in the form of tablets, pills, powders, lozenges, sachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), for example, ointments containing up to 10 weight percent of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0334] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulation may additionally include lubricants, e.g., talc, magnesium stearate, and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives, e.g., methyl and propylhydroxybenzoate; sweeteners; and flavoring agents.

[0335] A composition comprising at least one of the compounds described herein, or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterium analog thereof, may be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject using procedures known in the art. A controlled-release drug delivery system for oral administration comprises an osmotic pump system and a dissolution system containing a polymer-coated reservoir or a drug-polymer matrix formulation. Examples of controlled-release systems are given in U.S. Patents No. 3,845,770; No. 4,326,525; No. 4,902,514; and No. 5,616,345. Another formulation for use in the methods disclosed herein utilizes a transdermal delivery device (“patch”). Such a transdermal patch may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The composition and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. Such patches may be configured for continuous, pulsed, or on-demand delivery of pharmaceutical agents.

[0336] To prepare a solid composition, e.g., a tablet, the main active ingredient may be mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing the compound described herein or a homogeneous mixture of the pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterium analogs thereof. When these pre-formulation compositions are referred to as homogeneous, the active ingredient is evenly dispersed throughout the composition, allowing the composition to be easily subdivided into equally effective unit dosage forms, e.g., tablets, pills, and capsules.

[0337] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form that offers the benefit of delayed action or protection from the acidic conditions of the stomach. For example, the tablets or pills may contain an internal and an external dosage component, the latter in the form of an envelope above the former. The two components may be separated by an enteric layer that withstands disintegration in the stomach and acts to allow the internal component to pass intact into the duodenum or delay release. Various materials may be used for such an enteric layer or coating, and such materials include a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0338] Compositions for inhalation or insufflation may comprise solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, compositions are administered via oral or nasal breathing routes for local or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized by the use of an inert gas. The atomized solution may be inhaled directly from a nebulizer, or the nebulizer may be attached to a facemask tent or an intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0339] administration

[0340] The specific dosage level of the compound of the present application for any particular subject will depend on various factors including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration, and elimination rate, drug combination, and the severity of the specific disease in the subject being treated. For example, the dosage is expressed as the number of milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). A dosage of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, a dosage of about 0.1 to 100 mg / kg may be appropriate. In other embodiments, a dosage of 0.5 to 60 mg / kg may be appropriate. Standardization based on the subject's body weight is particularly useful when adjusting the dosage among subjects of widely different sizes, such as when using the drug in both children and adults, or when converting an effective dosage in a non-human subject, e.g., a dog, to a dosage suitable for a human subject.

[0341] The daily dose may also be described as the total amount of the compound described herein administered per dose or daily. The daily dose of the compound of formula (I) may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0342] When administered orally, the total daily dose for human subjects may be 1 mg to 1,000 mg, about 1,000-2,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day.

[0343] The compound of the present application or its composition may be administered once, twice, three, or four times daily using any suitable method described above. Additionally, administration or treatment with the compound may continue for several days; for example, generally, treatment will continue for at least 7, 14, or 28 days for one treatment cycle. Treatment cycles are well known in cancer chemotherapy and are frequently alternated between cycles with rest periods of about 1 to 28 days, generally about 7 or about 14 days. In other embodiments, treatment cycles may also be continuous.

[0344] In a specific embodiment, the method comprises administering an additional daily dose of about 1 to 800 mg of the compound described herein to a subject and incrementally increasing the dose until clinical efficacy is achieved. Increases of about 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.

[0345] Synthesis of the compound of chemical formula (I)

[0346] Compounds may be prepared using the methods disclosed herein and conventional variations thereof, which will become apparent when considering the disclosure herein and methods well known in the art. Conventional and well-known synthesis methods may be additionally utilized in accordance with the teachings herein. The synthesis of typical compounds described herein may be achieved as described in the following examples. Where available, reagents may be commercially purchased, for example, from Sigma Aldrich or other chemical suppliers.

[0347] General synthesis

[0348] Typical embodiments of the compounds described herein can be synthesized using the general reaction scheme described below. It will be clear from the description herein that the general scheme can be modified by substituting the starting materials with other materials having similar structures to produce correspondingly different products. The description of the synthesis follows to provide various examples of how the starting materials can be varied to provide the corresponding products. When considering the desired product in which substituents are defined, the required starting materials can generally be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using disclosed methods. To synthesize the compounds that are embodiments described in this disclosure, an inspection of the structure of the compound to be synthesized will provide the identity of each substituent. The identity of the final product will generally be clarified by a simple inspection process, considering the examples in this disclosure. In general, the compounds described herein are typically stable and separable at room temperature and atmospheric pressure.

[0349] Synthesis reaction parameters

[0350] The compounds of the present disclosure may be prepared from readily available starting materials, for example, by using the general methods and procedures described below. It will be apparent that other process conditions may also be used, unless otherwise noted, provided that typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, and pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by a person skilled in the art through ordinary optimization procedures.

[0351] Additionally, as is obvious to those skilled in the art, conventional protecting groups may be necessary to prevent a specific functional group from undergoing an unwanted reaction. Not only protecting groups suitable for various functional groups, but also conditions suitable for protecting and deprotecting specific functional groups are well known in the art. For example, various protecting groups are described in the literature [TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York] and the references cited therein.

[0352] 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 starting materials are available for purchase from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures described in standard reference literature, 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)), or by obvious variations thereof.

[0353] The term “solvent” generally refers to a solvent that is inert under the conditions of the reaction described with it (e.g., benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, and methanol, etc.). Unless otherwise specified, the solvent is an inert organic solvent, and the reaction may be carried out under an inert gas, preferably argon or nitrogen.

[0354] The term "qs" means adding an amount sufficient to achieve the mentioned function, for example, to make the solution the desired volume (i.e., 100%).

[0355] Diagram 1 In, A, R 1 , R 2 , R 3 and R 6 ... as defined herein, each X is independently a halo (e.g., chloro, bromo, or iodo), and each R 50 is independently alkyl, or two R 50 Together they form a ring (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxaborolane), and PG is a protecting group bonded to a heteroatom.

[0356] Diagram 1

[0357]

[0358] Diagram 1 In this case, the compound of formula (I) is a compound that is appropriately protected in the presence of a catalyst (e.g., palladium, nickel, copper, etc.) 100' ) corresponding boronic acid or ester ( 200 It is manufactured by coupling with ) and then performing deprotection. A compound ( 300 ) is also a suitably protected compound (e.g., palladium, nickel, copper, etc.) in the presence of a catalyst (e.g., palladium, nickel, copper, etc.) 400 ) a compound substituted with a corresponding hal ( 500 It is manufactured by coupling with ). Compound ( 400 ) is a compound that is appropriately protected in the presence of a catalyst (e.g., palladium, nickel, copper, etc.) 100' ) corresponding boronic acid or ester ( 600 It is manufactured by coupling with ). Chemical formula for use in the method provided herein ( 100', 200, 500 and 600Various compounds of ) can be purchased from commercial sources or synthesized by known methods.

[0359] In some specific examples, R 2 A compound in which hydrogen ( 300 ) is esterified, R 2 as defined herein (e.g., -(CH2CH2O) through standard coupling conditions) 1-9 CH2CH2OCH3, 1 to 3 R 4 Arbitrarily replaced with C 1-6 Alkyl, cycloalkyl, or 1 to 3 R 4 (heteroaryl compound arbitrarily substituted with ) 300 It can form ).

[0360] Examples

[0361] The following examples are incorporated to demonstrate specific embodiments of the present disclosure. It will be recognized by those skilled in the art that the technology disclosed in the following examples represents a technology that works well in the practice of the present disclosure and, accordingly, may be considered to constitute a specific method for practicing the present disclosure. However, those skilled in the art will recognize that, with consideration of the present disclosure, many variations may be made in the specific embodiments disclosed and the same or similar results may be obtained without departing from the spirit and scope of the present disclosure.

[0362] Synthesis of intermediates 3, 4, and 6 (and their methyl esters 3', 4', and 6')

[0363]

[0364] Step 1

[0365] To a mixture of sodium azide (150.0 g, 2.25 mol) and tetrabutylammonium bisulfate (41.9 g, 123 mmol) in water (2.3 L), a solution of triflic acid anhydride (375 mL, 2.25 mol) in hexane (900 mL) was slowly added at 0°C. After stirring the resulting mixture for 1 hour (h) at 0°C, the organically soluble material was extracted with hexane (1.8 L), dried on a sodium hydroxide pellet, and drained. To the solution, ethyl 2-cyanoacetate in acetonitrile (1.1 L), 1 (150.0 g, 0.8 mol) and pyridine (300 mL, 4.0 mol) were added. The resulting mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with ethyl acetate (1:6) in petroleum ether to obtain impurity-containing ethyl 2-cyano-2-diazoacetate, 2 (111 g, 99%) was obtained.

[0366] Step 2

[0367] Ethyl 2-cyano-2-diazoacetate in dioxane (7 L), 2 A solution of (111 g, 795 mmol) was bubbled with hydrogen bromide gas at 0°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude ethyl 4-bromo-1H-1,2,3-triazole-5-carboxylate, 3 (125 g) was obtained and used directly for the next step without further purification.

[0368] Step 3

[0369] Unpurified ethyl 4-bromo-1H-1,2,3-triazole-5-carboxylate in DMF (500 mL), 3Sodium hydride (60%, 10.1 g, 275 mmol) was added to a solution of (50 g, 227 mmol) at 0°C and stirred under N2 for 30 minutes, after which 2-(trimethylsilyl)ethoxymethyl chloride (40.5 g, 238 mmol) was added at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was quenched with 5% aqueous lithium chloride, and the product was extracted with ethyl acetate. The organic fraction was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with ethyl acetate in hexane (2:5) to obtain ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate ( 4 A mixture of , 30 g, 38%) was obtained as a colorless oil: ES / MS m / z: C 11 H 20 BrN3NaO3Si(M+Na + Calculated value for ): 372.04, Measured value: 372.15.

[0370] Methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate( 4' A mixture of isomers of ) is also commercially available methyl 4-bromo-1H-1,2,3-triazole-5-carboxylate ( 3' It was prepared as oil from ) in a manner similar to the above procedure: ES / MS m / z: C 10 H 19 Calculated value for BrN3NaO3Si(M+Na): 337.27, measured value: 336.53.

[0371] Step 4

[0372] Ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate in 1,4-dioxane (800 mL) 4, 45 g, 129 mmol) and 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene ( 5 To a solution of an isomer mixture of 85.0 g (257 mmol), 2.0 M aqueous sodium carbonate (193 mL, 386 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.45 g, 12.9 mmol) were added. The reaction mixture was stirred at 70°C for 4 hours under an N2 atmosphere. The reaction mixture was cooled to room temperature and diluted with water, after which the product was extracted with ethyl acetate (3 x 1 L). The organic fraction was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by silica gel chromatography in which ethyl acetate (1:30) in petroleum ether is eluted, and ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate ( 6 A mixture of isomers (25.5 g, 43%) was obtained as an oil: ES / MS m / z: C 23 H 36 Calculated value for BN3NaO5Si(M+Na): 496.44, Measured value: 496.45.

[0373] Synthesis of Intermediate 8

[0374]

[0375] Step 1

[0376] Ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate in 1,4-dioxane (500 mL) 4 , 25 g, 71.3 mmol) and 4,4'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1'-biphenyl( 7To a mixture of isomers (45 g, 110.8 mmol), 2.0 M aqueous Na2CO3 (106 mL, 215.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.2 g, 7.1 mmol) were added. The reaction mixture was stirred overnight at 70°C under an N2 atmosphere. After cooling the reaction mixture to room temperature and diluting it with water, the product was extracted with ethyl acetate (3 x 500 mL). The organic fraction was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue is purified by silica gel chromatography in which the residue is eluted with ethyl acetate (1:30) in petroleum ether, and ethyl 5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate ( 8 An isomer mixture of , 11.5 g, 29%) was obtained as an oil: ES / MS m / z: C 29 H 41 Calculated value for BN3O5Si(M+H): 550.29, Measured value: 550.45.

[0377] Synthesis of Intermediate 10

[0378]

[0379] Step 1

[0380] Ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (in 3 mL of 1,4-dioxane) 6 , 358 mg, 0.76 mmol) and 1,4-dibromobenzene ( 9Tetrakis(triphenylphosphine)palladium (0) (87 mg, 0.076 mmol) and 2.0 M aqueous Na2CO3 (1.13 mL) were added to a mixture of isomers of , 178 mg, 0.76 mmol). After purging the mixture with argon gas for 10 minutes, the reaction mixture was stirred at 110°C for 40 minutes. After cooling the reaction mixture to room temperature and diluting it with saturated NaHCO3, the product was extracted with ethyl acetate, washed, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 1-100% ethyl acetate in hexane, and ethyl 5-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate( 10 A mixture of isomers of , 380 mg, 83%) was obtained as oil.

[0381] Synthesis of intermediates 11 and 12

[0382]

[0383] Step 1

[0384] Ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate( 11 A mixture of isomers of , 27 g, 49%), using para-methoxybenzyl chloride instead of 2-(trimethylsilyl)ethoxymethyl chloride, except that the reaction was carried out at room temperature for 8 hours, ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate ( 3 It was prepared as an oil in a manner similar to the procedure for the isomer mixture of ): ES / MS m / z: C 13 H 14 Calculated value for BrN3NaO3(M+H): 362.01, Measured value: 362.05.

[0385] Step 2

[0386] Ethyl 2-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole-4-carboxylate( 12 A mixture of isomers of ) ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate( 6 It was prepared as an oil in a manner similar to the procedure for isomer mixtures of ).

[0387] Synthesis of Intermediate 13

[0388]

[0389] Step 1

[0390] Ethyl 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( 13 A mixture of isomers of , 10.5 g, 26%), ethyl 5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate( 8 It was prepared as an oil in a manner similar to the procedure for the isomer mixture of ): ES / MS m / z: C 31 H 35 Calculated value for BN3O5(M+H): 540.27, Measured value: 540.55.

[0391] Synthesis of intermediates 15 and 16

[0392]

[0393] Step 1

[0394] Methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-carboxylate( 15 , 5.1 g, 59%) as an intermediate4 Methyl-4-bromo-1H-pyrazole-5-carboxylate (in a manner similar to the procedure for manufacturing 14 It was prepared as an oil from , 5.0 g, 24.5 mmol): 1 ¹H NMR(400 MHz, chloroform- d ) 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: C 11 H 20 Calculated value for BrN2O3Si(M+H): 335.04, molecular weight was not detected.

[0395] Step 2

[0396] methyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-carboxylate( 16 , 5.83 g, 38%), using potassium carbonate instead of sodium carbonate, except that the reaction was carried out overnight at 110°C. 6 In the manufacture of It was manufactured as oil in a manner similar to the procedure for the following: 1 ¹H NMR(400 MHz, chloroform- d ) δ 7.82(d, J = 8.4 Hz, 2H), 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: C 23 H 36 Calculated value for BN2O5Si(M+H): 459.25, molecular weight was not detected.

[0397] Synthesis of Intermediate 18

[0398]

[0399] Ethyl-3-bromo-1H-pyrazol-4-carboxylate ( 18 , 511 mg, 96%) as an intermediate as a mixture of two positional isomers 15 Ethyl 3-bromo-1H-pyrazole-4-carboxylate (in a manner similar to the procedure for manufacturing 17 It was prepared as an oil from , 335 mg, 1.53 mmol): ES / MS m / z: C 12 H 22 Calculated value for BrN2O3Si(M+H): 349.06, measured value: 348.46.

[0400] Synthesis of intermediate 20

[0401]

[0402] Methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate( 20 , 690 mg, 77%) as an intermediate as a mixture of two positional isomers 15 Methyl 4-bromo-1H-imidazole-5-carboxylate (in a manner similar to the procedure for manufacturing 19 It was prepared as an oil from , 335 mg, 1.53 mmol): ES / MS m / z: C 12 H 22 Calculated value for BrN2O3Si(M+H): 335.04, Measured value: 334.86.

[0403] Representative procedure of the Suzuki reaction

[0404]

[0405] In a 5 mL microwave vial, methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2 H -1,2,3-triazole-4-carboxylate( 4'A mixture of isomers of , 46 mg, 0.14 mmol), 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxaborolane ( 17 , 20 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol), 2 N potassium carbonate (0.14 mL), and dioxane (2 mL) were added. After purging with argon gas for 5 minutes, the resulting mixture was stirred at 110°C for 1 hour. After cooling, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain methyl 5-(o-tolyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2 H -1,2,3-triazole-4-carboxylate( 18 ) obtained: ES / MS m / z: C 17 H 26 Calculated value for N3O3Si(M+H): 348.17, Measured value: 347.58.

[0406] Representative procedure for SEM deprotection by HCl

[0407]

[0408] Methyl 5-(o-tolyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2 in tetrahydrofuran (1 mL) and methanol (1 mL) H -1,2,3-triazole-4-carboxylate( 18 3 N HCl (0.21 mL) was added to a solution of , 49 mg, 0.14 mmol), and the resulting mixture was stirred at 80°C for 2 hours, followed by stirring overnight at 50°C. The resulting reaction mixture was concentrated to obtain unpurified methyl 4-(o-tolyl)-1 H -1,2,3-triazole-5-carboxylate( 19 ) obtained: ES / MS m / z: C 11 H 10 N3O2( Calculated value for MH: 216.08, Measured value: 216.15.

[0409] Representative procedure for SEM deprotection by TBAF

[0410]

[0411] Ethyl 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-5-carboxylate( 20 ) was dissolved in 1N TBAF (5 eq.) and the solution was heated at 60°C for 3 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain ethyl 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate( 21 ) obtained: ES / MS m / z: C 21 H 23 N4O 5( Calculated value for M+H: 443.49, Measured value: 443.16.

[0412] Representative procedure for PMB deprotection by TFA

[0413]

[0414] Ethyl 1-(4-methoxybenzyl)-4-(4'-(5-methyl-1,3,4-thiadiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate( 22) was dissolved in 1 mL of TFA, and the mixture was heated at 40°C for 80 minutes. After cooling, the reaction mixture was concentrated and diluted with saturated NaHCO3, after which the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel chromatography by elution with ethyl acetate in hexane and 10% methanol in ethyl acetate, to obtain ethyl 4-(4'-(5-methyl-1,3,4-thiadiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate( 23 ) obtained: ES / MS m / z: C 20 H 18 Calculated value for N5O2S(M+H): 392.45, Measured value: 392.16.

[0415] Representative procedures of ester hydrolysis

[0416]

[0417] Unpurified methyl 4-(o-tolyl)-1 in tetrahydrofuran (1 mL) and methanol (1 mL) H -1,2,3-triazole-5-carboxylate( 21 The mixture was stirred at 80°C for 2 hours. After cooling the reaction mixture and neutralizing it with 1 N HCl, the solid was filtered, purified by HPLC, and freeze-dried to obtain 4-(o-tolyl)-1 H -1,2,3-triazole-5-carboxylic acid ( 24 ) obtained: ES / MS m / z: ES / MS m / z: C 10 H8N3O 2( Calculated value for MH: 202.08, Measured value: 201.97.

[0418] Representative procedure for SEM protection of heterocyclic NH

[0419]

[0420] 5-bromo-1H-1,2,3-triazole in DMF (20 mL) 25A solution of (996.3 mg, 6.733 mmol) was stirred in an ice bath, at which time 60% sodium hydride in mineral oil (410 mg, 10.25 mmol) was added as a fraction. After 30 minutes, (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 hour, followed by stirring overnight at room temperature. After 19 hours, the reaction mixture was diluted with a saturated aqueous solution of NH4Cl (~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 (MgSO4), and concentrated. The residual oil was purified by silica gel chromatography eluted with 0-30% ethyl acetate in hexane, and 726.0 mg (39%) of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole ( 26 obtained ) 1 ¹H NMR(400 MHz, chloroform- 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: C 11 H 20 Calculated value for BrN2O3Si(M+H): 335.04, molecular weight was not detected.

[0421] Representative procedure for the preparation of boronate esters from aryl bromide

[0422]

[0423] 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (in 6 mL of 1,4-dioxane in a 20 mL μW vial 26 , 359 mg, 1.29 mmol), bis(pinacoleto)diborane( 27A mixture of , 362 mg, 1.43 mmol), dichloro-1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloromethane (116 mg, 0.14 mmol), and potassium acetate (384 mg, 3.92 mmol) was purged with Ar gas for 15 minutes, after which the mixture was heated at 110°C for 1 hour. The reaction mixture was diluted with ethyl acetate (~60 mL), treated with Na2SO4, and filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatography eluted with 0-40% ethyl acetate in hexane to obtain 282 mg (67%) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole( 28 obtained ) 1 ¹H 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).

[0424] The following compounds, the Suzuki reaction, the aforementioned SEM or PMB deprotection, and the aforementioned bromide intermediate together with a commercially available boronate, 4 (or 4' ), 10 , or 15 Using the aforementioned boronate intermediate together with commercially available boronates 6 (or 6' ), 8, 12, 13, and 16 It was prepared in a manner similar to the typical procedure for ester hydrolysis using:

[0425] Example 1: Ethyl 4-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate

[0426]

[0427] 1 ¹H NMR(400 MHz, chloroform-d ) δ 7.95 (dd, J = 8.3, 6.7 Hz, 2H), 7.65 (dd, J = 8.2, 5.5 Hz, 2H), 7.60 - 7.49 (m, 2H), 7.43 (dd, J = 8.5, 1.9 Hz, 2H), 5.90 (s, 1H), 4.45 (qd, J = 7.2, 4.8 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ES / MS m / z: C 17 H 13 Calculated value for ClN3O2(MH): 326.08, Measured value: 326.31.

[0428] Example 2: Ethyl 4-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate

[0429]

[0430] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.99 - 7.91(m, 2H), 7.88(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: C 18 H 17 Calculated value for N4O3(M+H): 337.13, Measured value: 337.03.

[0431] Example 3: 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0432]

[0433] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.42 - 7.31(m, 2H), 7.31 - 7.21(m, 2H), 2.17(s, 3H). ES / MS m / z: C 10 H 10 Calculated value for N3O2(M+H): 204.08, Measured value: 347.58.

[0434] Example 4: 4-(m-tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0435]

[0436] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 10 H 10 N3O 2( Calculated value for M+H: 204.20, Measured value: 203.92.

[0437] Example 5: 4-(p-tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0438]

[0439] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 10 H 10 Calculated value for N3O2(M+H): 204.20, Measured value: 203.92.

[0440] Example 6: 4-(3-ethylphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0441]

[0442] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 11 H 12 Calculated value for N3O2(M+H): 218.09, Measured value: 217.97

[0443] Example 7: 4-(2-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0444]

[0445] 1 1H NMR(400 MHz, methanol- d 4 ): δ 7.61 - 7.45(m, 2H), 7.32 - 7.17(m, 2H). ES / MS m / z: Calculated value for C9H7FN3O2(M+H): 208.04, Measured value: 207.94.

[0446] Example 8: 4-(3-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0447]

[0448] 1 1H NMR(400 MHz, methanol- d 4 ) 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 value for C9H7FN3O2(M+H): 208.04, Measured value: 207.91.

[0449] Example 9: 4-(4-chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0450]

[0451] 1 1H NMR(400 MHz, methanol- d 4 ): δ 7.89 - 7.81(m, 2H), 7.51 - 7.42(m, 2H). ES / MS m / z: Calculated value for C9H7ClN3O2(M+H): 224.01, Measured value: 223.94.

[0452] Example 10: 4-(3-methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0453]

[0454] 1 1H NMR(400 MHz, methanol- d 4) 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). ES / MS m / z: C 10 Calculated value for H8N3O3(MH): 218.20, Measured value: 217.98.

[0455] Example 11: 4-(4-methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0456]

[0457] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.78(d, J = 8.4 Hz, 2H), 7.06 - 6.98(m, 2H), 3.85(s, 3H). ES / MS m / z: C 10 H 10 Calculated value for N3O3(M+H): 220.06, Measured value: 219.93.

[0458] Example 12: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0459]

[0460] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 10 Calculated value for H7N4O2(M+H): 215.05, Measured value: 214.96.

[0461] Example 13: 4-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0462]

[0463] 1 1H NMR(400 MHz, methanol- d 4) 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: C 10 Calculated value for H7F3N3O2(M+H): 258.07, Measured value: 257.97

[0464] Example 14: 4-(3-(tert-butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0465]

[0466] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 13 H 16 Calculated value for N3O2(M+H): 246.12, Measured value: 246.04.

[0467] Example 15: 4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0468]

[0469] 1 1H NMR(400 MHz, methanol- d 4 ): δ 7.78 - 7.70 (m, 2H), 7.55 - 7.47 (m, 2H), 1.36 (s, 9H). ES / MS m / z: C 13 H 16 Calculated value for N3O2(M+H): 246.12, Measured value: 246.01.

[0470] Example 16: 4-(3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0471]

[0472] 1 1H NMR(400 MHz, methanol- d4 ) 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, 1H). ES / MS m / z: C 10 Calculated value for H7FN3O3(M+H): 274.04, Measured value: 273.95.

[0473] Example 17: 5-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid

[0474]

[0475] 1 ¹H 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: C 10 Calculated value for H9ClFN3O2(MH): 254.63, Measured value: 254.04.

[0476] Example 18: 4-(3-chloro-4-fluorophenyl)-1H-pyrazole-3-carboxylic acid

[0477]

[0478] 1H NMR (400 MHz, methanol- d 4 ) 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: C 10 Calculated value for H7ClFN2O2(M+H): 241.01, Measured value: 240.88.

[0479] Example 19: 4-(3,4-dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0480]

[0481] 1 1H NMR(400 MHz, methanol- d 4) 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 value for C9H6Cl2N3O2(M+H): 257.98, Measured value: 257.95.

[0482] Example 20: 4-(3,5-dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0483]

[0484] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.95(s, 2H), 7.52(s, 1H). ES / MS m / z: Calculated value for C9H6Cl2N3O2(M+H): 257.98, Measured value: 257.92.

[0485] Example 21: 4-(3,5-dichlorophenyl)-1H-pyrazole-3-carboxylic acid

[0486]

[0487] 1 ¹H NMR(400 MHz, DMSO- d 6 ): δ 8.00(s, 1H), 7.68(s, 2H), 7.58 - 7.44(m, 1H). ES / MS m / z: C 10 Calculated value for H5Cl2N2O2(MH): 254.98, Measured value: 255.02.

[0488] Example 22: 4-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0489]

[0490] 1 1H NMR(400 MHz, methanol- d 4) 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 value for C9H6ClFN3O2(M+H): 242.01, Measured value: 241.94.

[0491] Example 23: 5-(4-bromo-3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0492]

[0493] 1 1H NMR(400 MHz, methanol- d 4 ): δ 8.04(s, 1H), 7.70 - 7.65(m, 2H). ES / MS m / z: Calculated value for C9H4BrClN3O2(MH): 299.93, Found value: 300.02.

[0494] Example 24: 4-(3,5-dichloro-4-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0495]

[0496] 1 1H NMR(400 MHz, methanol- d 4 ) δ 8.09(d, J = 6.4 Hz, 2H). ES / MS m / z: Calculated value for C9H4Cl2FN3O2(M+H): 275.97, Measured value: 275.96.

[0497] Example 25: 4-(3-phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0498]

[0499] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 12Calculated value for N3O3(M+H): 282.08, Measured value: 282.01

[0500] Example 26: 4-(4-phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0501]

[0502] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 12 Calculated value for N3O3(M+H): 282.08, Measured value: 281.98.

[0503] Example 27: 4-([1,1'-biphenyl]-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0504]

[0505] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 12 Calculated value for N3O2(M+H): 266.09, Measured value: 266.01.

[0506] Example 28: 4-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0507]

[0508] 1 1H NMR(400 MHz, methanol- d 4) δ 7.92 (d, J = 8.0 Hz, 2H), 7.77 - 7.64 (m, 4H), 7.51 - 7.41 (m, 2H), 7.41 - 7.32 (m, 1H). ES / MS m / z: C 15 H 12 Calculated value for N3O2(M+H): 266.09, Measured value: 265.96.

[0509] Example 29: 4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0510]

[0511] 1 1H NMR(400 MHz, methanol- d 4 ) 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, 1H). ES / MS m / z: C 10 Calculated value for H6CF2N3O4(M+H): 270.02, Measured value: 269.97.

[0512] Example 30: 4-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0513]

[0514] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.35(d, J = 1.7 Hz, 2H), 6.95 - 6.86(m, 1H), 6.02(s, 2H). ES / MS m / z: C 10 Calculated value for H6N3O4(MH): 232.04, Measured value: 232.00.

[0515] Example 31: 4-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0516]

[0517] 1 1H NMR(400 MHz, methanol- d 4) δ 7.46 - 7.35 (m, 3H), 7.32 (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: C 16 Calculated value for H8F2N3O4(MH) = 344.06; Measured value 344.04

[0518] Example 32: 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0519]

[0520] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 11 H 10 Calculated value for N3O4(M+H): 248.06, Measured value: 248.00.

[0521] Example 33: 4-(naphthalene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0522]

[0523] 1 1H NMR(400 MHz, methanol- d 4 ): δ 8.39(s, 1H), 7.98 - 7.86(m, 4H), 7.59 - 7.49(m, 2H). ES / MS m / z: Calculated value for C9H6ClFN3O2(M+H): 242.01, Measured value: 239.97.

[0524] Example 34: 4-(pyridine-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0525]

[0526] 1 1H NMR(400 MHz, methanol- d 4) 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 value for C8H7N4O2(M+H): 191.05, Measured value: 191.01

[0527] Example 35: 4-(pyridine-3-yl)-1H-pyrazole-3-carboxylic acid

[0528]

[0529] 1 1H NMR(400 MHz, methanol- d 4 ) 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 value for C9H7N3O2(MH): 190.05, Measured value: 190.02.

[0530] Example 36: 4-(quinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0531]

[0532] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 12 Calculated value for H9N4O2(M+H): 241.06, Measured value: 241.07.

[0533] Example 37: 4-(isoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0534]

[0535] 1 1H NMR(400 MHz, methanol-d 4 ) 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: C 12 Calculated value for H8N4O2(M+H): 241.06, Measured value: 241.05.

[0536] Example 38: 4-(6-phenylnaphthalene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0537]

[0538] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 19 H 14 Calculated value for N3O2(M+H): 316.10, Measured value: 316.00.

[0539] Example 39: 4-(3-chloroisoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0540]

[0541] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 12 Calculated value for H8ClN4O2(M+H) = 275.03; measured value 275.05.

[0542] Example 40: 4-(3-methoxyisoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0543]

[0544] 1 1H NMR(400 MHz, methanol- d 4 ) 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(d, J = 8.8 Hz, 1H), 7.19(s, 1H), 4.04(s, 3H).

[0545] Example 41: 4-(3-phenylisoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0546]

[0547] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H 13 Calculated value for N4O2(M+H) = 317.10; measured value 317.09.

[0548] Example 42: 4-(4-(naphthalene-1-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0549]

[0550] 1 1H NMR(400 MHz, methanol- d 4 ) δ 8.02 - 7.85 (m, 5H), 7.61 - 7.40 (m, 6H). ES / MS m / z: C 19 H 14 Calculated value for N3O2(M+H) = 316.11; measured value 316.03.

[0551] Example 43: 4-(4-(pyridine-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0552]

[0553] 1 ¹H NMR(400 MHz, DMSO-d 6 ) 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: C 14 H 11 Calculated value for N4O2(M+H): 267.08, Measured value: 267.10.

[0554] Example 44: 4-(4-(pyridine-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0555]

[0556] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 14 H 11 Calculated value for N4O2(M+H): 267.09, Measured value: 267.04.

[0557] Example 45: 4-(4-(naphthalene-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0558]

[0559] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 12 Calculated value for N3O2(MH): 314.10, Measured value: 314.14.

[0560] Example 46: 4-(4-(6-chloronaphthalene-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0561]

[0562] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 13 Calculated value for ClN3O2(M+H): 350.06, Measured value: 350.00.

[0563] Example 47: 4-(4-(isoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0564]

[0565] 1 1H NMR(400 MHz, methanol- d 4 ) δ 9.51(s, 1H), 8.59(d, J = 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: C 14 H 11 Calculated value for N4O2(M+H): 267.09, Measured value: 267.04.

[0566] Example 48: 4-(4-(1-methyl-1H-benzo[d]imidazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0567]

[0568] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 17 H 14 Calculated value for N5O2(M+H): 320.11, Measured value: 320.14.

[0569] Example 49: 4-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0570]

[0571] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 11 Calculated value for ClN3O2(M+H): 300.05, Measured value: 299.97.

[0572] Example 50: 4-(3'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0573]

[0574] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 11 Calculated value for ClN3O2(M+H): 300.05, Measured value: 299.98.

[0575] Example 51: 4-(4'-bromo-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0576]

[0577] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 7.88(s, 2H), 7.77(d, J = 7.9 Hz, 2H), 7.72 - 7.60(m, 4H). ES / MS m / z: C 15 H 11Calculated value for BrN3O2(M+H): 344.00, Measured value: 344.06.

[0578] Example 52: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0579]

[0580] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 15 H 11 Calculated value for BrN3O2(M+H): 344.00, Measured value: 343.95.

[0581] Example 53: 4-(4'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0582]

[0583] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.90 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.61 - 7.53 (m, 2H), 7.31 - 7.24 (m, 2H), 2.38 (s, 3H).ES / MS m / z: C 16 H 14 Calculated value for N3O2(M+H): 280.10, Measured value: 279.96.

[0584] Example 54: 4-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0585]

[0586] 1 1H NMR(400 MHz, methanol- d 4) 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: C 19 H 20 Calculated value for N3O2(M+H): 322.15, Measured value: 322.06.

[0587] Example 55: 4-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0588]

[0589] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 11 Calculated value for F3N3O3(M+H): 350.08, Measured value: 350.00.

[0590] Example 56: 4-(4'-methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0591]

[0592] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 14 Calculated value for N3O3(M+H): 296.10, Measured value: 296.03.

[0593] Example 57: 4-(4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0594]

[0595] 11H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 11 Calculated value for FN3O2(M+H) = 284.08; measured value 284.31.

[0596] Example 58: 4-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0597]

[0598] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.96 (d, J = 7.9 Hz, 2H), 7.87 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.68 - 7.58 (m, 2H). ES / MS m / z: C 15 H 10 Calculated value for Cl2N3O2(M+H): 334.02, Measured value: 334.08.

[0599] Example 59: 4-(4'-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0600]

[0602] 1 1H NMR(400 MHz, methanol- d 4 ) δ 8.00 (d, J = 7.9 Hz, 2H), 7.93 - 7.77 (m, 6H). ES / MS m / z: C 16 Calculated value for H9N4O2(MH) = 289.07; Measured value: 289.01.

[0603] Example 60: 4-(4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0604]

[0605] 1 1H NMR(400 MHz, methanol- d 4) 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: C 15 Calculated value for H8ClFN3O2(MH): 316.04, Measured value: 316.09.

[0606] Example 61: 4-(3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0607]

[0608] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 10 Calculated value for ClFN3O2(M+H): 318.04, Measured value: 317.97.

[0609] Example 62: 4-(3'-phenoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0610]

[0611] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 21 H 16 Calculated value for N3O3(M+H): 358.11, Measured value: 358.01.

[0612] Example 63: 4-(4'-phenoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0613]

[0614] 1 1H NMR(400 MHz, methanol- d 4 ) 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 (m, 4H). ES / MS m / z: C 21 H 16 Calculated value for N3O3(M+H): 358.11, Measured value: 357.98.

[0615] Example 64: 4-(4'-(pyridine-2-yloxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0616]

[0617] 1 1H NMR(400 MHz, methanol- d 4 ) 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, 0.9 Hz, 1H). ES / MS m / z: C 20 H 15 Calculated value for N4O3(M+H): 359.11, Measured value: 359.14.

[0618] Example 65: 4-(4'-acetyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0619]

[0620] 1 1H NMR(400 MHz, methanol- d 4) δ 8.14 - 8.07(m, 2H), 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: C 17 H 14 Calculated value for N3O3(M+H) = 308.10; measured value 308.00.

[0621] Example 66: 4-(3'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0622]

[0623] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 13 Calculated value for N4O3(M+H): 309.09, Measured value: 309.09.

[0624] Example 67: 4-(3'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0625]

[0626] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 17 H 15 Calculated value for N4O3(M+H): 323.11, Measured value: 323.12.

[0627] Example 68: 4-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0628]

[0629] 11H NMR(400 MHz, methanol- d 4 ): δ 7.98(d, 4H), 7.77(d, 4H). ES / MS m / z: C 16 H 13 Calculated value for N4O3(M+H): 309.09, Measured value: 309.05.

[0630] Example 69: 4-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0631]

[0632] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.97(d, J = 8.0 Hz, 2H), 7.95 - 7.87(m, 2H), 7.84 - 7.72(m, 4H), 2.95(s, 3H). ES / MS m / z: C 17 H 15 Calculated value for N4O3(M+H): 323.11, Measured value: 323.16.

[0633] Example 70: 4-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0634]

[0635] 1 1H NMR(400 MHz, methanol- d 4 ): δ 8.03 - 7.92 (m, 2H), 7.87 - 7.74 (m, 4H), 7.60 - 7.47 (m, 2H), 3.13 (s, 3H), 3.06 (s, 3H). ES / MS m / z: C 18 H 17 Calculated value for N4O3(M+H): 337.35, Measured value: 338.06.

[0636] Example 71: 4-(4'-carbamoyl-3'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0637]

[0638] 1 1H NMR(400 MHz, methanol- d 4) 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: C 16 H 12 Calculated value for ClN4O3(M+H): 343.05, Measured value: 343.13.

[0639] Example 72: 4-(3'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0640]

[0641] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 13 Calculated value for N4O4S(MH): 345.06, Measured value: 345.03.

[0642] Example 73: 4-(3'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0643]

[0644] 1 1H NMR(400 MHz, methanol- d 4 ): δ 8.06 - 7.97 (m, 4H), 7.85 - 7.69 (m, 4H), 2.74 (s, 6H). ES / MS m / z: C 17 H 17 N4O4S Calculated value for (M+H): 373.09, Measured value: 373.11.

[0645] Example 74: 4-(3'-(piperidine-1-ylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0646]

[0647] 1¹H NMR(400 MHz, DMSO- d 6 ) 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: C 20 H 21 Calculated value for N4O4S(M+H): 413.13, Measured value: 413.17.

[0648] Example 75: 4-(3'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0649]

[0650] 1 1H NMR(400 MHz, methanol- d 4 ): 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: C 19 H 19 Calculated value for N4O5S (M+H): 415.10, Measured value: 415.11.

[0651] Example 76: 4-(4'-chloro-3'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0652]

[0653] 1 1H NMR(400 MHz, methanol- d 4 ) 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, 1H). ES / MS m / z: C 15 H 12 Calculated value for ClN4O3S (M+H): 379.02, Measured value: 379.07.

[0654] Example 77: 4-(4'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0655]

[0656] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 11 Calculated value for N4O4S(MH): 343.06, Measured value: 342.31.

[0657] Example 78: 4-(4'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0658]

[0659] 1 1H NMR(400 MHz, methanol- d 4 ) δ 8.01(d, J = 8.2 Hz, 2H), 7.96 - 7.93(m, 2H), 7.91 - 7.86(m, 2H), 7.83(dd, J = 7.6, 5.6 Hz, 2H), 2.73(s, 6H). ES / MS m / z: C 17 H 17 N4O4S Calculated value for (M+H): 373.09, Measured value: 373.06.

[0660] Example 79: 4-(4'-(piperidine-1-ylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0661]

[0662] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 20 H21 Calculated value for N4O4S(M+H): 413.13, Measured value: 413.10.

[0663] Example 80: 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0664]

[0665] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 19 H 19 Calculated value for N4O5S(M+H): 415.11, Measured value: 415.07.

[0666] Example 81: 4-(3'-acetamido-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0667]

[0668] 1 1H NMR(400 MHz, methanol- d 4 ): 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: C 17 H 15 Calculated value for N4O3(M+H): 323.11, Measured value: 323.13.

[0669] Example 82: 4-(4'-acetamido-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0670]

[0671] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 17 H 15Calculated value for N4O3(M+H): 323.11, Measured value: 323.12.

[0672] Example 83: 4-(4'-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0673]

[0674] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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, 2H). ES / MS m / z: C 19 H 17 Calculated value for N4O3(M+H): 349.12, Measured value: 349.13.

[0675] Example 84: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0676]

[0677] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 19 H 19 Calculated value for N4O2(M+H): 351.14, Measured value: 350.01.

[0678] Example 85: 4-(4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0679]

[0680] 1 1H NMR(400 MHz, methanol- d 4) δ 7.94 - 7.87(m, 2H), 7.44 - 7.37(m, 2H), 7.32(d, J = 2.0 Hz, 1H), 7.29 - 7.18(m, 2H), 2.27(s, 3H). ES / MS m / z: C 16 H 13 Calculated value for ClN3O2(M+H) = 314.07; measured value 314.01.

[0681] Example 86: 4-(9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0682]

[0683] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 12 Calculated value for N3O2(M+H): 278.09, Measured value: 278.02.

[0684] Example 87: 4-(dibenzo[b,d]furan-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0685]

[0686] 1 1H NMR(400 MHz, methanol- d 4 ) 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, J = 8.3, 0.9 Hz, 1H), 7.52 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.39(ddd, J = 7.7, 7.2, 1.0 Hz, 1H). ES / MS m / z: C 15 H 10 Calculated value for N3O3(M+H): 280.06, Measured value: 280.00.

[0687] Example 88: 4-(9H-carbazole-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0688]

[0689] 1 ¹H NMR(400 MHz, acetonitrile- d 3 ) 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). ES / MS m / z: C 15 H 11 Calculated value for N4O2(M+H) = 279.09; measured value, 279.01.

[0690] Example 89: 4-(9-oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0691]

[0692] 1 1H NMR(400 MHz, methanol- d 4 ) δ 8.11 (d, J = 13.5 Hz, 2H), 7.77 (dd, J = 14.9, 7.6 Hz, 2H), 7.69 - 7.53 (m, 2H), 7.39 (t, J = 7.3 Hz, 1H). ES / MS m / z: C 16 H 10 Calculated value for N3O3(M+H): 292.06, Measured value: 292.08.

[0693] Example 90: 4-(9,9-dimethyl-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0694]

[0695] 1 1H NMR(400 MHz, methanol- d 4 ) 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 (m, 2H), 1.51 (s, 6H). ES / MS m / z: C 18 H16 Calculated value for N3O2(M+H) = 306.12; measured value 306.06.

[0696] Example 91: 4-(4'-chloro-3'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0697]

[0698] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 16 H 11 Calculated value for ClN3O2(MH): 312.06, Measured value: 312.08.

[0699] Example 92: 4-(4'-carbamoyl-3'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0700]

[0701] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 17 H 15 Calculated value for N4O3(M+H): 323.11, Measured value: 323.10.

[0702] Example 93: 4-(4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0703]

[0704] 1 1H NMR(400 MHz, methanol- d 4) 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: C 18 H 15 Calculated value for N4O3(M+H): 335.11, Measured value: 335.16.

[0705] Example 94: 4-(4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-pyrazole-5-carboxylic acid

[0706]

[0707] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 16 Calculated value for N3O3(M+H): 334.11, Measured value: 334.13.

[0708] Example 95: 4-(4-(3-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0709]

[0710] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 19 H 17Calculated value for N4O3(M+H): 349.13, Measured value: 349.10.

[0711] Example 96: 4-(4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0712]

[0713] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 17 Calculated value for N4O3(M+H): 349.13, Measured value: 349.09.

[0714] Example 97: 4-(4-(1-oxoisoindolin-5-yl)phenyl)-1H-1,2l4,3-triazole-5-carboxylic acid

[0715]

[0716] 1 1H NMR(400 MHz, methanol- d 4 ): δ 8.00(m, 3H), 7.94 - 7.77(m, 4H), 4.55(s, 2H). ES / MS m / z: C 17 H 13 Calculated value for N4O3(M+H): 321.09, Measured value: 321.07.

[0717] Example 98: 4-(4-(3,3-dimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2l4,3-triazole-5-carboxylic acid

[0718]

[0719] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.98 (d, J = 8.0 Hz, 2H), 7.90 - 7.76 (m, 5H), 1.60 (s, 6H). ES / MS m / z: C 19 H 18Calculated value for N4O3(M+H) = 349.13; Measured value 349.13

[0720] Example 99: 4-([1,1':3',1''-terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0721]

[0722] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 21 H 16 Calculated value for N3O2(M+H): 342.12, Measured value: 342.01.

[0723] Example 100: 4-([1,1':4',1''-terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0724]

[0725] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 21 H 14 Calculated value for N3O2(MH): 340.12, Measured value: 339.95.

[0726] Example 101: 4-(4'-(pyridine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0727]

[0728] 1 1H NMR(400 MHz, methanol- d 4) 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), 7.87(d, J = 9.7 Hz, 2H). ES / MS m / z: C 20 H 15 Calculated value for N4O2(M+H): 343.11, Measured value: 343.15.

[0729] Example 102: 4-(4'-(pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0730]

[0731] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 20 H 15 N4O 2( Calculated value for M+H): 343.12, Measured value: 343.13.

[0732] Example 103: 4-(4'-(pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0733]

[0734] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 20 H 15 Calculated value for N4O2(M+H): 343.12, Measured value: 343.13.

[0735] Example 104: 4-(4'-(pyrimidine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0736]

[0737] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 19 H 14 Calculated value for N5O2(M+H) = 344.11; Measured value 344.03

[0738] Example 105: 4-(4'-(1-methyl-1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0739]

[0740] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H 15 Calculated value for N6O2(M+H) = 347.13; measured value 347.14.

[0741] Example 106: 4-(4'-(1-methyl-1H-1,2,4-triazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0742]

[0743] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 18 H 15 Calculated value for N6O2(M+H): 347.12, Measured value: 347.10.

[0744] Example 107: 4-(4'-(1-methyl-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0745]

[0746] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 16 Calculated value for N5O2(M+H): 346.13, Measured value: 346.15.

[0747] Example 108: 4-(4'-(thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0748]

[0749] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H 13 Calculated value for N4O2S(M+H): 349.07, Measured value: 349.03.

[0750] Example 109: 4-(4'-(5-methylthiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0751]

[0752] 1 ¹H NMR(400 MHz, DMSO- d 6 ): δ 8.03 - 7.74(m, 8H), 7.62(s, 1H), 2.50(s, 3H). ES / MS m / z: C 19 H 15Calculated value for N4O2S(M+H): 362.08, Measured value: 362.11.

[0753] Example 110: 4-(4'-(5-(trifluoromethyl)thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0754]

[0755] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 12 Calculated value for F3N4O2S(M+H): 417.06, Measured value: 417.00.

[0756] Example 111: 4-(4'-(5-methyl-1,3,4-thiadiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0757]

[0758] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 18 H 12 Calculated value for N5O2S(MH): 362.07, Measured value: 362.03.

[0759] Example 112: 4-(4'-(oxazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0760]

[0761] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H13 Calculated value for N4O3(M+H) = 333.10; measured value 333.00.

[0762] Example 113: 4-(4'-(isoxazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0763]

[0764] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 18 H 13 Calculated value for N4O3(M+H) = 333.10; measured value 333.05.

[0765] Example 114: 4-(4'-(4-methylthiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0766]

[0767] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 15 Calculated value for N4O2S(M+H): 363.09, Measured value: 363.08.

[0768] Example 115: 4-(4'-(2-methyl-2H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0769]

[0770] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 18H 15 Calculated value for N6O2(M+H): 347.13, Measured value: 347.02.

[0771] Example 116: 4-(4'-(thiazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0772]

[0773] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 9.10(s, 1H), 8.39(s, 1H), 7.81(q, J = 8.4 Hz, 8H). ES / MS m / z: C 18 H 13 Calculated value for N4O2S(M+H): 349.07, Measured value: 348.96.

[0774] Example 117: 4-(4'-(1,5-dimethyl-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0775]

[0776] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 20 H 18 Calculated value for N5O2(M+H): 360.15, Measured value: 360.16.

[0777] Example 118: 4-(4'-(1,5-dimethyl-1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0778]

[0779] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 17Calculated value for N6O2(M+H): 361.14, Measured value: 361.13.

[0780] Example 119: 4-(4'-(1H-pyrazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0781]

[0782] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H 14 Calculated value for N5O2(M+H) = 332.11; measured value 332.14.

[0783] Example 120: 4-(4'-(1H-1,2,3-triazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0784]

[0785] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 17 H 13 Calculated value for N6O2(M+H) = 333.11; measured value 333.11.

[0786] Example 121: 4-(4'-(5-methyl-1H-1,2,3-triazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0787]

[0788] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H15 Calculated value for N6O2(M+H): 347.13, Measured value: 347.09.

[0789] Example 122: 4-(4'-(benzo[d]thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0790]

[0791] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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, 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: C 22 H 15 Calculated value for N4O2S(M+H): 399.09, Measured value: 399.08.

[0792] Example 123: 4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-1,2,3-triazole-5-carboxylic acid)

[0793]

[0794] 4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-1,2,3-triazole-5-carboxylic acid) was prepared from ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (11) and ethyl 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 (13) in a manner similar to PMB deprotection and ester hydrolysis following the general procedure of the Suzuki reaction: 1 ¹H NMR (400 MHz, DMSO- d 6 ) δ 7.95 (s, 4H), 7.86 (d, J = 8.1 Hz, 4H). ES / MS m / z: C 18 H 13Calculated value for N6O4(M+H): 377.10, Measured value: 377.03.

[0795] Example 181: 4-(4'-(5,6-dihydro-4H-cyclopenta[d]thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0796]

[0797] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 21 H 17 Calculated value for N4O2S(M+H): 389.11, Measured value: 389.11.

[0798] The above compounds, along with the aforementioned boronate intermediate, together with a commercially available bromide-containing heterocyclic after SEM protection of heterocyclic NH following the Suzuki reaction and SEM or PMB deprotection described above, 6 or 8 It was prepared in a manner similar to the typical procedure for ester hydrolysis using:

[0799] Example 124: 4-(4'-(1H-pyrazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0800]

[0801] 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 8.11(s, 2H), 7.79(d, J = 14.4 Hz, 4H), 7.72(s, 4H). ES / MS m / z: C 18 H 14 Calculated value for N5O2(M+H): 332.11, Measured value: 332.07.

[0802] Example 125: 4-(4'-(1H-pyrazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0803]

[0804] 1¹H NMR(400 MHz, DMSO- d 6 ) 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: C 18 H 14 Calculated value for N5O2(M+H): 332.11, Measured value: 332.11.

[0805] Example 126: 4-(4-(1H-benzo[d]imidazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0806]

[0807] 1 1H NMR(400 MHz, methanol- d4 ) 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, 3H), 7.88 - 7.79(m, 2H). ES / MS m / z: C 16 H 12 Calculated value for N5O3(M+H): 306.09, Measured value: 306.14.

[0808] Example 127: 4-(4'-(1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0809]

[0810] 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.96 (d, J = 7.6 Hz, 4H), 7.80 (d, J = 7.9 Hz, 5H). ES / MS m / z:C 16 H 12 Calculated value for N5O3(M+H): 333.10, Measured value: 333.07.

[0811] Example 128: 4-(4'-(1H-imidazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0812]

[0813] 1 1H NMR(400 MHz, methanol- d4) δ 7.29 - 7.05 (m, 4H), 6.95 - 6.62 (m, 6H). ES / MS m / z: C 18 H 14 Calculated value for N5O2(M+H) = 332.11; measured value 332.12.

[0814] Example 129: 4-(4'-(1H-imidazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0815]

[0816] 1 1H NMR(400 MHz, methanol- d 4 ): δ 9.02 (d, J = 1.4 Hz, 1H), 8.10-7.95 (m, 3H), 7.85 (dt, J = 24.3, 8.3 Hz, 6H). ES / MS m / z: C 18 H 14 Calculated value for N5O2(M+H) = 332.11; Measured value 332.12

[0817] Example 130: 4-(4'-(4-methyl-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0818]

[0819] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 16 Calculated value for N5O2(M+H) = 346.13; measured value 346.18.

[0820] The aforementioned bromide intermediate, together with a commercially available bromide after conversion to pinacol boronate, following the Suzuki reaction and SEM deprotection by HCl of the following compounds, 4 or 10 It was prepared in a manner similar to the typical procedure for ester hydrolysis using:

[0821] Example 131: 4-(4'-(5-methyl-1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0822]

[0823] 1 H NMR (400 MHz, D2O + NaHCO3) δ 7.5 - 8.0 (m, 8H), 2.48 (s, 3H). ES / MS m / z: C 18 H 15 Calculated value for N6O2(M+H): 347.13, Measured value: 347.12.

[0824] Example 132: 4-(6-chloronaphthalene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0825]

[0826] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 13 Calculated value for H9ClN3O2(M+H): 274.04, Measured value: 273.96.

[0827] Example 133: 4-(phenanthrene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0828]

[0829] 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 17 H 12 Calculated value for N3O2(M+H) = 290.09; measured value, 290.03.

[0830] Example 134: 4-(7-amino-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0831]

[0832] 1 1H NMR(400 MHz, methanol- d4 ) 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: C 16 H 13 Calculated value for N4O2(M+H): 293.10, Measured value: 293.05.

[0833] Example 135: 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0834]

[0835] Step 1

[0836] Sodium hydride (60% suspension, 1.38 mmol) was added to a solution of methyl 4-bromo-3-methyl-1H-pyrazole-5-carboxylate (275 mg, 1.255 mmol) in DMF at 0°C, followed by the addition of SEM-Cl (0.233 mL, 1.31 mmol). After 10 minutes, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain a mixture of isomers of methyl 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate: ES / MS m / z: C 12 H 22 BrN2O s Calculated value for Si (M+H): 349.05, Measured value: 348.93.

[0837] Step 2, Step 3, and Step 4

[0838] 4-(3-chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection with HCl and ester hydrolysis following a Suzuki reaction using (3-chloro-4-fluorophenyl)boronic acid: 11H NMR(400 MHz, methanol- d 4 ) δ 7.43(ddd, J = 7.2, 1.9, 0.5 Hz, 1H), 7.31 - 7.19(m, 2H), 2.22(s, 3H). ES / MS m / z: C 11 Calculated value for H9ClFN2O2(M+H): 255.03, Measured value: 254.94.

[0839] Example 136: 4-(3-chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0840]

[0841] Step 1

[0842] A solution of 1-(3-chloro-4-fluorophenyl)ethane-1-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 THF (30 mL) under N2, and cooled in a water bath. After 90 minutes, the reaction mixture was cooled in an ice bath and then quenched with 2 M HCl. Subsequently, the mixture was extracted with ethyl acetate, the organic extract was dried (MgSO4), and concentrated under vacuum. The resulting crude residue was purified by silica gel chromatography eluted with 0-40% ethyl acetate in hexane to obtain methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropanoate (2.97 g, 44%). LC / MS m / z: C 10 Calculated value for H9ClFO3(M+H): 231.02, Measured value: 231.0.

[0843] Step 2

[0844] 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 vigorously stirred overnight at 80 °C. After cooling the reaction mixture and diluting it with water, the resulting solid was separated by filtration and subsequently further purified by silica gel chromatography eluted with 0-50% ethyl acetate in hexane to obtain methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, 43%) as a white solid: ES / MS m / z: C 18 H 16 Calculated value for ClFN3O3(M+H): 376.09, Measured value: 376.1.

[0845] Step 3 and Step 4

[0846] 1 M LiOH (1.0 mL, 1.0 mmol) was added at room temperature to a solution of methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (75 mg, 0.20 mmol) in 1:1 THF / methanol (2 mL). After stirring for 1 hour, the reaction mixture was acidified with 2 N HCl, and the product was extracted with ethyl acetate (x 3). The combined organic extract was dried (MgSO4) and concentrated under vacuum. The resulting residue was dissolved in TFA and stirred at 65°C for 2 hours. After concentrating the reaction mixture under vacuum, the residue was purified by reverse-phase preparative HPLC to obtain 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid: 1 ¹H NMR(400 MHz, DMSO- d 6) 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 value for C9H6ClFN3O2(M+H): 242.01, found value 242.0.

[0847] Example 137: 4-phenyl-1H-1,2,3-triazole-5-carboxylic acid

[0848]

[0849] 4-phenyl-1H-1,2,3-triazole-5-carboxylic acid was prepared from acetophenone in a manner similar to the procedure in Example 136: 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 13.14(br s, 1H), 7.79(br s, 2H), 7.51 - 7.42(m, 3H). ES / MS m / z: Calculated value for C9H8N3O2(M+H): 190.06, Measured value 190.0.

[0850] Example 138: 4-(3-chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0851]

[0852] 4-(3-chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 3-chloroacetophenone in a manner similar to the procedure in Example 136: 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 7.92(s, 1H), 7.80(br s, 1H), 7.54 - 7.48(m, 2H). ES / MS m / z: Calculated value for C9H7ClN3O2(M+H): 224.02, found value 224.0.

[0853] Example 139: 4-(pyridine-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0854]

[0855] Step 1

[0856] In a 5 mL microwave vial, an isomer mixture of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (192 mg, 0.55 mmol), 2-(tributylstanyl)pyridine (222 mg, 0.193 mL, 0.60 mmol), tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.055 mmol), and toluene (2 mL) were added. 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 NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain ethyl 5-(pyridine-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 16 H 25 Calculated value for N4O3Si(M+H): 349.16, Measured value: 349.05.

[0857] Step 2 and Step 3

[0858] 4-(pyridine-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for ester hydrolysis following SEM deprotection with HCl: 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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 value for C8H7N4O2(M+H): 191.05, Measured value: 190.99.

[0859] Example 140: 4-(pyridine-2-yl)-1H-pyrazole-5-carboxylic acid

[0860]

[0861] 4-(pyridine-2-yl)-1H-pyrazole-5-carboxylic acid was prepared from 4-(tributylstanyl)pyridine in a manner similar to the procedure of Example 141: 1 1H NMR(400 MHz, methanol- d 4 ) 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 value for C9H8N3O2(M+H): 190.05, Measured value: 190.00.

[0862] Example 141: 4-(thiazole-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0863]

[0864] 4-(thiazole-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 4-(tributylstanyl)thiazole in a manner similar to the procedure of Example 141: 1 ¹H NMR(400 MHz, DMSO- d 6 ): δ 9.32(s, 1H), 8.65(s, 1H), 3.15(s, 1H). ES / MS m / z: Calculated value for C6H3N4O2S(MH): 191.05, Measured value: 194.95.

[0865] Examples 142 and 143: 4-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid and 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0866]

[0867] Step 1

[0868] An isomer mixture of ethyl 5-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from 3-bromo-N,N-dimethylbenzamide in a manner similar to the general procedure of the Suzuki reaction:

[0869] Step 2 and Step 3

[0870] 4-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid and 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid were prepared following SEM deprotection with HCl in a manner similar to the general procedure for ester hydrolysis. The two compounds were separated by precipitation followed by precipitation and HPLC purification:

[0871] Example 142: 4-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0872]

[0873] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 12 Calculated value for N3O4(M+H): 310.07, Measured value: 310.05.

[0874] Example 143: 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0875]

[0876] 1 1H NMR(400 MHz, methanol- d 4) δ 7.96 (d, J = 8.4 Hz, 2H), 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: C 18 H 17 Calculated value for N4O3(M+H): 337.12, Measured value: 337.17.

[0877] Example 144: 4-(4-(1H-indazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0878]

[0879] Step 1

[0880] p-toluenesulfonic acid (9.0 mg, 0.049 mmol) and 3,4-dihydropyran (0.089 mL, 0.97 mmol) were added to a solution of 5-bromo-1H-indazole (100 mg, 0.49 mmol) in dichloromethane (2.0 mL). After heating the mixture at 35°C overnight, the reaction mixture was diluted with a saturated aqueous solution of NaHCO3, and the product was extracted with ethyl acetate (x 2). The combined organic layer was washed with water (x 1), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: 1 ¹H NMR(400 MHz, acetonitrile- d 3 ) δ 8.03 - 7.93(m, 2H), 7.62(dt, J = 8.9, 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, 0H), 4.01 - 3.91(m, 1H), 3.86 - 3.72(m, 1H), 3.48(dd, J = 11.0, 6.0 Hz, 0H), 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: C 12 H 14 Calculated value for BrN2O(M+H) = 281.03; measured value 280.75.

[0881] Steps 2, 3, and 4

[0882] 4-(4-(1H-indazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of ester hydrolysis, following a Suzuki reaction with intermediate 6 and 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole, and deprotection of PMB and THP by TFA: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 11 Calculated value for ClN3O2(M+H): 300.05, Measured value: 300.00.

[0883] Example 145: 4-(4-(1H-indazole-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0884]

[0885] 4-(4-(1H-indazole-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 6-bromo-1H-indazole in a manner similar to the procedure in Example 146: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 12 Calculated value for N5O2(M+H) = 306.10; Measured value 306.15

[0886] Example 146: 4-(4'-chloro-3'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0887]

[0888] Step 1

[0889] Morpholine (220 mg, 3 mmol) was added to a solution of 5-bromo-2-chlorobenzenesulfonyl chloride (366 mg, 10 mmol) in THF (3 mL) at 0°C, and after 10 minutes, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (x 2), water (x 1), and saturated NaHCO3 (x 1). The resulting organic fraction was dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane to obtain 4-((5-bromo-2-chlorophenyl)sulfonyl)morpholine: 1 ¹H NMR(400 MHz, chloroform- d ): δ 7.60(s, 1H), 7.60(d, 1H), 7.29(d, 1H), 3.70(m, 4H), 3.28(m, 4H).

[0890] Steps 2, 3, and 4

[0891] 4-(4'-chloro-3'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of ester hydrolysis, following a Suzuki reaction with intermediate 6 and 4-((5-bromo-2-chlorophenyl)sulfonyl)morpholine, and PMB deprotection: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 19 H 18 Calculated value for ClN4O5S(M+H): 449.06, Measured value: 449.16.

[0892] Example 147: 4-(3-bromophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0893]

[0894] Step 1

[0895] A mixture of isomers of methyl 5-(3-aminophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as an intermediate 4' and was prepared in a manner similar to the general procedure of the Suzuki reaction using (3-aminophenyl)boronic acid: ES / MS m / z: C 16 H 25 Calculated value for N4O3Si(M+H): 347.17, Measured value: 348.96.

[0896] Step 2:

[0897] To a solution of methyl 4-(3-aminophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-5-carboxylate (102 mg, 0.29 mmol) in 3 mL of acetonitrile, tertiary-butyl nitrite (0.042 mL, 0.35 mmol) and copper(II) bromide (78 mg, 0.35 mmol) were added at 0°C. After 30 minutes, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by chromatography on silica gel with ethyl acetate in hexane to obtain a mixture of isomers of methyl 5-(3-bromophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 ¹H NMR(400 MHz, chloroform- d ): δ 8.12-7.30 (m, 4H), 6.18-5.76 (m, 2H), 3.98 (d, 3H), 3.78-3.684 (m, 2H), 0.95 (m, 2H), 0.00 (d, 9H).

[0898] Step 3 and Step 4

[0899] 5-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxylic acid was prepared in a manner similar to the general procedure for ester hydrolysis following SEM deprotection with HCl: 1 1H NMR(400 MHz, methanol- d 4 ) 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 value for C9H7BrN3O2(M+H): 267.96, Measured value: 267.90.

[0900] Example 148: 4-(2-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0901]

[0902] Steps 1 and 2

[0903] An isomer mixture of methyl 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared in a manner similar to the procedure in Example 149, steps 1 and 2 using 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: ES / MS m / z: C 16 H 22 Calculated value for BrClN3O3Si(M+H): 446.03, Measured value: 445.69.

[0904] Step 3, Step 4, and Step 5

[0905] 4-(2-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of the Suzuki reaction using phenylboronic acid, SEM deprotection with HCl, and ester hydrolysis: 1 1H NMR(400 MHz, methanol- d 4) 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: C 15 H 11 Calculated value for ClN3O2(M+H): 300.05, Measured value: 300.00.

[0906] Example 149: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0907]

[0908] 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for SEM deprotection with HCl and ester hydrolysis, following the general procedure for the Suzuki reaction from a mixture of isomers of methyl 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate and 4-chlorophenylboronic acid. 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 15 H 10 Calculated value for Cl2N3O2(M+H): 334.01, Measured value: 333.97.

[0909] Example 150: 4-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0910]

[0911] NaH (60% oil suspension, 6 mg) was added to a solution of 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (10 mg, 0.038 mmol) in 0.5 mL DMF at 0°C. After 10 minutes at 0°C, iodomethane (7 μL, 0.11 mmol) was added, and the resulting mixture was stirred at 0°C for 10 minutes. After quenching the reaction by adding methanol, the product was purified by HPLC to obtain 5-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid: 1 ¹H 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: C 10 Calculated value for H6ClFN3O2(MH): 254.01, Measured value: 253.96.

[0912] Example 151: 4-(4'-(1-methyl-1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0913]

[0914] Step 1

[0915] 60% NaH in an oil suspension (48 mg, 1.2 mmol) was added to a solution of 4-(4-bromophenyl)-1H-1,2,3-triazole (242 mg, 1.05 mmol) in 2 mL of DMF at 0°C. After 10 minutes at 0°C, iodomethane (71 μL, 1.1 mmol) was added, and the resulting mixture was stirred at 0°C for 10 minutes. The reaction mixture was extracted with ethyl acetate in brine, the organic layer was concentrated, and purified by chromatography on silica gel eluted with ethyl acetate in hexane to obtain 5-(4-bromophenyl)-1-methyl-1H-1,2,3-triazole: ES / MS m / z: Calculated value for C9H9BrN3(M+H): 237.99, Found value: 238.09.

[0916] Step 2, Step 3, and Step 4

[0917] 4-(4'-(1-methyl-1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid compound 28 Following the Suzuki reaction, it was prepared in a manner similar to the general procedure for SEM deprotection and ester hydrolysis with HCl: 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 18 H 15 Calculated value for N6O2(M+H): 347.12, Measured value: 347.04.

[0918] Example 152: 4-(4-(2,3,3-trimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0919]

[0920] Step 1

[0921] 60% sodium hydride in mineral oil (43 mg, 1.08 mmol) was added to a solution of 5-bromo-3,3-dimethylisoindolin-1-one (205 mg, 0.85 mmol) in N,N-dimethylformamide (2 mL) at 0°C. After 15 minutes, 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 with ethyl acetate (~25 mL) and then washed with a ~50% saturated NH4Cl solution. After extracting the aqueous fraction with ethyl acetate (25 mL x 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluted with 0-100% EA in hexane to obtain 5-bromo-2,3,3-trimethylisoindolin-1-one: ES / MS m / z: C 11 H 13 Calculated value for BrNO(M+H): 254.02, Measured value: 254.12.

[0922] Step 2, Step 3, and Step 4

[0923] 4-(4-(2,3,3-trimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid as an intermediate 6 and Suzuki reaction with 5-bromo-2,3,3-trimethylisoindolin-1-one, and following PMB deprotection, was prepared in a manner similar to the general procedure for ester hydrolysis: 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 20 H 19Calculated value for N4O3(M+H): 363.15, Measured value: 363.12.

[0924] Example 153: 4-(4-(3,3-dimethyl-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0925]

[0926] 4-(4-(3,3-dimethyl-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 5-bromo-3,3-dimethylisoindolin-1-one in a manner similar to the procedure in Example 154 using 2,2,2-trifluoroethyl trifluoromethanesulfonate: 1 ¹H NMR(400 MHz, DMSO- d6 ) δ 8.11 (d, J = 19.7 Hz, 3H), 8.00 - 7.83 (m, 3H), 7.79 (d, J = 7.9 Hz, 1H), 4.34 (q, J = 9.6 Hz, 2H), 1.58 (s, 6H). ES / MS m / z: C 21 H 18 Calculated value for F3N4O3(M+H): 431.13, Measured value: 431.15.

[0927] Example 154: 4-(9-methyl-9H-carbazole-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0928]

[0929] Step 1

[0930] Ethyl 5-(9H-carbazole-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared in a manner similar to the general procedure for the Suzuki reaction using intermediate 4 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole.

[0931] Step 2

[0932] 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 minutes, after which MeI (0.009 mL; 0.13 mmol) was added. The solution was stirred overnight at room temperature. When completed, the mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH4Cl (1 mL). After extracting the aqueous fraction 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 (Na2SO4), concentrated, and then purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain ethyl 5-(9-methyl-9H-carbazole-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z C 24 H 31 Calculated value for N4O3Si(M+H) = 451.22, measured value: 450.90.

[0933] Step 3

[0934] 4-(9-methyl-9H-carbazole-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for ester hydrolysis following SEM deprotection by TBAF: 1 1H NMR(400 MHz, methanol- d 4) 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, J = 7.9, 6.6, 1.6 Hz, 1H), 3.92(s, 3H). ES / MS m / z: C 16 H 11 Calculated value for N4O2(MH) = 291.09; measured value 291.11.

[0935] Example 155: 4-(4-(6-(1H-1,2,3-triazole-4-yl)pyridazine-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0936]

[0937] Step 1

[0938] A mixture of isomers of ethyl 5-(4-(6-bromopyridazine-3-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as an intermediate 10 Intermediate in a manner similar to the procedure for manufacturing 6 and was prepared from 3,6-dibromopyridazine: ES / MS m / z: C 21 H 27 Calculated value for BrN5O3Si(M+H): 504.11, found value: 504.14 and 504.18.

[0939] Step 2, Step 3, and Step 4

[0940] 4-(4-(6-(1H-1,2,3-triazole-4-yl)pyridazine-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection with HCl and ester hydrolysis following the Suzuki reaction with compound 28: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C15 H 11 Calculated value for N8O2(M+H): 335.10, Measured value: 335.11.

[0941] Example 156: 4-(4-(5-(1H-1,2,3-triazole-4-yl)pyrazine-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0942]

[0943] 4-(4-(5-(1H-1,2,3-triazole-4-yl)pyrazine-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 2,5-dibromopyrazine in a manner similar to the procedure in Example 157: 1 1H NMR(400 MHz, methanol- d 4 ) 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 = 7.7 Hz, 3H). ES / MS m / z: C 15 H 11 Calculated value for N8O2(M+H): 335.10, Measured value: 335.10.

[0944] Example 157: 4-(3'-methyl-4'-(1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0945]

[0946] Step 1

[0947] A mixture of isomers of ethyl 5-(4-(6-bromopyridazine-3-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate in a manner similar to the procedure for the preparation of intermediate 10 6 and was prepared from 1-bromo-4-iodo-2-methylbenzene: ES / MS m / z: C 24 H 31 Calculated value for BrN3O3Si(M+H): 516.11, measured value: 516.02.

[0948] Step 2, Step 3, and Step 4

[0949] 4-(3'-methyl-4'-(1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection with HCl and ester hydrolysis following the Suzuki reaction with compound 28: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H 15 Calculated value for N6O2S(M+H): 347.12, Measured value: 347.15.

[0950] Example 158: 4-(4'-chloro-2-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0952]

[0953] Step 1

[0954] 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) were combined into a flask and purged with Ar for 5 minutes. Subsequently, the reaction was heated at 60 °C for 70 minutes. Then, the reaction mixture was diluted with water and extracted with ethyl acetate, filtered through diatomaceous earth / celite, and concentrated to a dry state under reduced pressure. The unpurified reaction mixture was purified by flash chromatography (0 to 100% ethyl acetate / hexane) to obtain 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carbonitrile: 1¹H NMR(400 MHz, chloroform- d ) δ 7.89(d, J = 2.1 Hz, 1H), 7.77(dd, J = 8.4, 2.1 Hz, 1H), 7.47(s, 4H), 7.36(d, J = 8.4 Hz, 1H).

[0955] Step 2

[0956] 4'-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-carbonitrile was prepared from 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carbonitrile in a manner similar to the typical procedure for preparing boronate esters.

[0957] Steps 3, 4, and 5

[0958] 4-(4'-chloro-2-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid compound 4 and following the Suzuki reaction with 4'-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-carbonitrile, it was prepared in a manner similar to the general procedure of SEM deprotection and ester hydrolysis by TBAF: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 10 Calculated value for ClN4O2(M+H) = 325.05; measured value 325.03.

[0959] Example 159: 4-(4'-(1H-imidazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0960]

[0961] Step 1

[0962] Tris(benzylideneacetone) dipalladium (20 mg; 0.0039 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (8 mg; 0.016 mmol), and potassium phosphate tribasic (83 mg, 0.39 mmol) were charged into a 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-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (98 mg; 0.2 mmol) were dissolved in 5:1 (v / v) toluene-dioxane (3.0 mL) and purged with nitrogen gas for 10 minutes. The imidazole solution was added to a reaction vessel, and the reaction mixture was heated to 110 °C until the reaction was complete. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH4Cl (3 x 5 mL). The aqueous layer was extracted with ethyl acetate (2 x 5 mL), and the combined organic fraction was washed with water (2 x 5 mL). Finally, the organic fraction was dried (Na2SO4), concentrated in a dry state, and purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain ethyl 5-(4'-(1H-imidazole-1-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 26 H 32 Calculated value for N5O3Si (M+H) = 490.23; measured value 490.39.

[0963] Steps 2 and 3

[0964] 4-(4'-(1H-imidazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for ester hydrolysis following SEM deprotection by TBAF:1 1H NMR(400 MHz, methanol- d4 ) 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: C 18 H 14 Calculated value for N5O2(M+H) = 332.11; measured value 332.14.

[0965] Example 160: 4-((4-chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid

[0966]

[0967] Step 1

[0968] A mixture of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (114 mg, 0.033 mmol), copper(I) iodide (19 mg, 0.0098 mmol), 1-chloro-4-ethynylbenzene (55 mg, 0.40 mmol), triethylamine (0.363 mL, 3 mmol), and dichlorobis(triphenyl-phosphine)palladium(II) (41 mg; 0.0065 mmol) in acetonitrile (3 mL) was purged with N2 for 10 minutes and heated overnight at 60°C. More copper(I) iodide and dichlorobis(triphenyl-phosphine)palladium(II) were added as needed to improve the conversion to the desired product. Once determined to be sufficiently complete by LC / MS, the reaction was diluted with ethyl acetate (10 mL) and filtered through Celite. The filtrate was washed with saturated NH4Cl (2 x 9 mL) and NaHCO3(aq). The aqueous layer was extracted with ethyl acetate (1 x 10 mL). The combined organic matter was washed with water (1 x 10 mL), dried (Na2SO4), concentrated, and then purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane to obtain ethyl 5-((4-chlorophenyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 ¹H NMR(400 MHz, acetonitrile- d 3 ) δ 7.64 - 7.56(m, 1H), 7.52 - 7.45(m, 1H), 5.98(d, J = 9.7 Hz, 1H), 5.72(s, 0H), 4.51 - 4.37(m, 1H), 3.75 - 3.58(m, 1H), 2.14(s, 2H), 2.11(d, J = 1.2 Hz, 0H), 1.45 - 1.34(m, 2H), 1.29(s, 0H), 0.97 - 0.83(m, 1H). ES / MS m / z C 19 H 25Calculated value for ClN3O3Si(M+H) = 406.14; measured value 406.86.

[0969] Steps 2 and 3

[0970] 4-((4-chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using a standard procedure for ester hydrolysis following SEM deprotection by TBAF: 1 1H NMR(400 MHz, methanol- d 4 ) δ 7.57(d, J = 8.4 Hz, 2H), 7.43(d, J = 8.4 Hz, 2H),. ES / MS m / z: C 11 Calculated value for H7ClN3O2(M+H) = 248.02; Measured value: 247.96.

[0971] Example 161: 4-(1-(oxetane-3-yl)piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0972]

[0973] Step 1

[0974] In a microwave reaction vial, ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate ( 4A mixture of isomers of , 285 mg, 0.814 mmol), tertiary-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (277 mg, 0.89 mmol), tetrakis(triphenylphosphine)palladium (0) (94 mg, 0.081 mmol), 2N potassium carbonate (1022 mL, 2 mmol), and 1,4-dioxane (4 mL) were added. 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 NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with ethyl acetate in hexane to obtain tert-butyl 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate: ES / MS m / z: C 21 H 36 Calculated value for N4O5Si(M+H): 453.25, Measured value: 452.68.

[0975] Step 2

[0976] A solution of tertiary-butyl 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (120 mg, 0.27 mmol) in 4 N HCl in 1,4-dioxane (2 mL) was stirred overnight at room temperature. After concentrating the reaction mixture, the residue was purified by silica gel chromatography eluted with methanol in ethyl acetate to obtain impurity-containing ethyl 4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 10 H 15Calculated value for N4O2(M+H): 223.11, Measured value: 223.01.

[0977] Step 3

[0978] A mixture of ethyl 4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-1,2,3-triazole-5-carboxylate (22 mg, 0.01 mmol) and 10% carbonaceous palladium (20 mg) in ethanol (1 mL) was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC to obtain ethyl 4-(piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 10 H 15 Calculated value for N4O2(M+H): 225.13, Measured value: 225.17.

[0979] Step 4

[0980] Sodium triacetoxyborohydride (104 mg, 0.05 mmol) was added to a suspension of ethyl 4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate (22 mg, 0.01 mmol) and 3-oxetanone (35 mg, 0.05 mmol) in THF (1 mL), followed by the addition of one drop of acetic acid. The reaction mixture was stirred overnight at room temperature. After concentrating the reaction mixture, the residue was purified by preparative HPLC to obtain ethyl 4-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 13 H 21 Calculated value for N4O3(M+H): 281.15, Measured value: 281.18.

[0981] Step 5:

[0982] 4-(1-(oxetane-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from ethyl 4-(1-(oxetane-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate in a manner similar to the general procedure of ester hydrolysis: 1 1H NMR(400 MHz, methanol- d 4 ): 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: C 11 H 17 Calculated value for N4O3(M+H): 253.12, Measured value: 253.13.

[0983] Example 162: 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0984]

[0985] Step 1

[0986] A mixture of isomers of tert-butyl 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate as an intermediate in a manner similar to the general procedure of the Suzuki reaction 11 and was prepared from tertiary-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate: ES / MS m / z: C 29 H 35 Calculated value for N4O5(M+H): 519.26, measured value: 518.98 and 518.96.

[0987] Step 2

[0988] To a flask containing a mixture of isomers of tert-butyl 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (128 mg, 0.25 mmol), 4 N HCl in 1,4-dioxane (3 mL) was added, and the resulting mixture was stirred at room temperature for 15 minutes. After the solution was completely concentrated, acetic anhydride (0.05 mL, 0.53 mmol) was added to the residue in dichloromethane (3 mL) and pyridine (0.05 mL, 0.62 mmol) at 0°C. After 30 minutes at 0°C and 30 minutes 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 (x 1). After extracting the aqueous fraction with ethyl acetate (~20 mL x 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by chromatography on silica gel eluted with 50-100% ethyl acetate in hexane followed by 0-20% methanol in ethyl acetate to obtain a mixture of isomers of ethyl 5-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 26 H 29 Calculated value for N4O4(M+H): 461.22, measured value: 460.94 and 461.17.

[0989] Step 3 and Step 4

[0990] 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared following PMB deprotection in a manner similar to the general procedure for ester hydrolysis: 1 1H NMR(400 MHz, methanol- d 4) 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: C 16 H 17 Calculated value for N4O3(M+H): 313.13, Measured value: 313.10.

[0991] Example 163: 4-(4-(1-acetylpiperidine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0992]

[0993] Step 1

[0994] To a flask containing a mixture of isomers of ethyl 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (product of Step 2 of Example 164, 55 mg, 0.12 mmol), 20% palladium hydroxide (6.6 mg) and ethanol (4 mL) were added, and the resulting mixture was stirred at room temperature under an H2 atmosphere for 3.5 hours. After diluting the reaction mixture with methanol and dichloromethane, it was filtered through a Celite pad. After washing the Celite pad with ethanol, the filtrate was fully concentrated and co-evaporated with toluene (x 1) to obtain a mixture of crude isomers of ethyl 5-(4-(1-acetylpiperidin-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 26 H 31 Calculated value for N4O4(M+H): 463.23, measured value: 463.04 and 463.06.

[0995] Step 2 and Step 3

[0996] 4-(4-(1-acetylpiperidine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared following PMB deprotection in a manner similar to the general procedure for ester hydrolysis: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 19 Calculated value for N4O3(M+H): 315.15, Measured value: 315.14.

[0997] Example 164: 4-(4'-(pyrazine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0998]

[0999] Step 1

[1000] 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) acetylacetate (440 mg, 1 mmol) in CH2Cl2 (10 ml) and water (10 ml) was stirred overnight at ambient temperature. The reaction mixture was CH2Cl 2(It was diluted with 10 ml of aqueous solution and 10 ml of water, and solid potassium carbonate was added to the pH > 8. After separating the two layers, the aqueous fraction was extracted with dichloromethane (2 x 10 mL), the combined organic fraction was dried (Na2SO4), concentrated, and purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane to obtain 2-(4-bromophenyl)pyrazine: 1 ¹H 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). ES / MS m / z C 10 H8BrN 2( Calculated value for M+H = 234.99; measured value, 235.05.

[1001] Steps 2, 3, and 4

[1002] 4-(4'-(pyrazine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was synthesized from 2-(4-bromophenyl)pyrazine using a representative procedure for the Suzuki reaction with intermediate 6, SEM deprotection with HCl, and ester hydrolysis. 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 19 H 14 N5O 2( Calculated value for M+H = 344.11; measured value 344.04.

[1003] Example 165: 4-(4'-(1H-1,2,4-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1004]

[1005] Step 1

[1006] A mixture of isomers of ethyl 5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as 4-bromobenzamide and intermediate 6 It was prepared from in a manner similar to the general procedure of the Suzuki reaction: ES / MS m / z: C 24 H 30 Calculated value for N4O4Si (M+H) = 467.2; measured value 467.16.

[1007] Step 2

[1008] t-butoxybis(dimethylamino)methane (Bredereck's Reagent; 62 μL; 0.30 mmol) was added to a solution of ethyl 5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (117 mg; 0.25 mmol) in THF (1 mL). The mixture was then heated to 60°C until the starting material was consumed and ethyl(E)-5-(4'-(((dimethylamino)methylene)carbamoyl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate appeared. The material from this reaction was used directly in Step 3: ES / MS m / z: C 27 H 35 Calculated value for N5O4Si(M+H) = 522.25; measured value 522.11.

[1009] Step 3

[1010] Hydrazine (39 μL; 1 mmol) and acetic acid (109 μL; 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 NaHCO3 (2 x 5 mL). After extracting the aqueous fraction with ethyl acetate (2 x 10 mL), the organic fractions were combined, washed with 1N HCl (5 mL) and water (5 mL), dried (Na2SO4), and concentrated in a dry state. The unpurified product, ethyl 5-(4'-(1H-1,2,4-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate, was used directly in step 4 without further purification: 1 ¹H 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, 0H), 7.53 - 7.45 (m, 0H), 6.05 (s, 0H), 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, 0H), 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: C 25 H 30 Calculated value for N6O3Si(M+H) = 491.21; measured value 491.25.

[1011] Steps 4 and 5

[1012] 4-(4'-(1H-1,2,4-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for ester hydrolysis following SEM deprotection with HCl: 1 ¹H NMR(400 MHz, DMSO- d 6 ) δ 8.49(s, 1H), 8.15 - 8.08(m, 2H), 7.96 - 7.81(m, 6H). ES / MS m / z C 17 H 13 Calculated value for N6O2(m+H) 333.10; measured value 333.11.

[1013] Example 166: 4-(7-bromo-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1014]

[1015] Step 1

[1016] 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-amine was prepared using bis(pinacoleto)diborane (27) in a manner similar to the typical procedure for synthesizing boronates from aromatic bromides:

[1017] Step 2

[1018] A mixture of isomers of ethyl 5-(7-amino-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as an intermediate in a manner similar to the general procedure of the Suzuki reaction 4 and was prepared from 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-amine: ES / MS m / z: C 24 H 31 Calculated value for N4O3Si(M+H): 451.22, Measured value: 451.33.

[1019] Step 3

[1020] To a solution of ethyl 5-(7-amino-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (1.00 g, 2.22 mmol) in acetonitrile (12 mL), t-butyl nitrite (0.32 mL, 2.69 mmol) and copper bromide (595 mg, 2.66 mmol) were added at 0°C. After 45 minutes, the reaction mixture was quenched with a 1 M Na2S2O3 solution, and the product was extracted with ethyl acetate. The extract was dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane to obtain a mixture of the desired ethyl 5-(7-bromo-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate along with the deamination byproduct. The mixture was used for the following reaction without further purification.

[1021] Steps 4 and 5

[1022] 4-(7-bromo-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for SEM deprotection and ester hydrolysis by HCl: 1 1H NMR(400 MHz, methanol- d4 ) 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: C 16 H 11 Calculated value for BrClN3O2(M+H): 355.92, Measured value: 356.00.

[1023] Example 167: 4-(7-chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1024]

[1025] 4-(7-chloro-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid( 56 ) was prepared in a manner similar to the general procedure of SEM deprotection and ester hydrolysis with HCl, following the procedure of Step 3 of Example 168 using copper(II) chloride instead of copper(II) bromide: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 16 H 11 Calculated value for ClN3O2(M+H): 312.05, Measured value: 311.93

[1026] Example 168: 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1027]

[1028] Step 1

[1029] Ethyl 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate bis(pinacoleto)diborane 27 It was prepared in a manner similar to the typical procedure for the synthesis of boronates from aromatic bromides using ).

[1030] Steps 2, 3, and 4

[1031] 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from ethyl 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate and benzolonate 28 in a manner similar to Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H 13 Calculated value for N6O2(M+H): 345.10, Measured value: 345.11.

[1032] Example 169: 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1033]

[1034] Step 1

[1035] 4-(7-bromo-9,9-difluoro-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole was prepared from 2-bromo-9,9-difluoro-7-iodo-9H-fluorene and boronate 28 in a manner similar to the general procedure of the Suzuki reaction: ES / MS m / z: C 21 H 23Calculated value for BrF2N3OSi(M+H): 478.08, measured value: 477.76.

[1036] Step 2

[1037] 4-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole bis(pinacoleto)diboran( 27 It was prepared from 4-(7-bromo-9,9-difluoro-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole in a manner similar to the representative procedure for the synthesis of boronates from aromatic bromides using ): ES / MS m / z: C 27 H 35 Calculated value for BF2N3O3Si(M+H): 526.25, Measured value: 525.96.

[1038] Step 5, Step 6, and Step 7

[1039] 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid as an intermediate 4 and was prepared in a manner similar to the general procedure of SEM deprotection with HCl and ester hydrolysis following a Suzuki reaction using 4-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 18 H 11 Calculated value for F2N6O2(M+H): 381.09, Measured value: 381.06.

[1040] Example 170: 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-pyrazol-5-carboxylic acid

[1041]

[1042] 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-pyrazol-5-carboxylic acid as an intermediate 15 and from 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid, following the Suzuki reaction, it was prepared in a manner similar to the general procedure of SEM deprotection with HCl and ester hydrolysis: 1 1H NMR(400 MHz, methanol- d 4 ) δ 8.27(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: C 19 H 12 Calculated value for F2N5O2(M+H): 380.10, Measured value: 380.11.

[1043] Example 171: 4-(7-(1,5-dimethyl-1H-1,2,3-triazole-4-yl)-9,9-difluoro-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1044]

[1045] Step 1

[1046] A mixture of 2,7-dibromo-9,9-difluoro-9H-fluorene (2000 mg, 5.56 mmol), bis(pinacoleto)diborane (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) was purged with argon gas for 15 minutes and stirred at 80°C for 16 hours. The reaction mixture was fully concentrated, the residue was dissolved in ethyl acetate (~300 mL), and washed with water (~250 mL x 2). After extracting the aqueous fraction with ethyl acetate (~100 mL x 1), the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography eluted with 0-20% ethyl acetate in hexane to obtain 2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane): 1 ¹H 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). Mass spectrometry not performed.

[1047] Step 2

[1048] A mixture of isomers of ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as an intermediate 4 and was prepared from 2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in a manner similar to the general procedure of the Suzuki reaction: ES / MSm / z:C30 H 39 Calculated value for BF2N3O5Si (M+H): 598.27, found value: 597.81 and 597.67.

[1049] Step 3, Step 4, and Step 5

[1050] 4-(7-(1,5-dimethyl-1H-1,2,3-triazole-4-yl)-9,9-difluoro-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection with HCl and ester hydrolysis, following a Suzuki reaction using a mixture of isomers of 4-bromo-1,5-dimethyl-1H-1,2,3-triazole and ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 20 H 15 Calculated value for F2N6O2(M+H): 409.12, Measured value: 409.14.

[1051] Example 172: 4-(9,9-difluoro-7-(2-methyl-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1052]

[1053] 4-(9,9-difluoro-7-(2-methyl-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection with HCl and ester hydrolysis, following a Suzuki reaction using a mixture of isomers of 4-bromo-2-methyl-2H-1,2,3-triazole and ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 1H NMR(400 MHz, methanol- d 4 ) δ 8.19(s, 1H), 8.11(s, 3H), 8.03(d, J = 7.9 Hz, 1H), 7.83(d, J = 8.0 Hz, 2H), 4.24(s, 3H). ES / MS m / z: C 19 H 13 Calculated value for F2N6O2(M+H): 395.11, Measured value: 395.03.

[1054] Example 173: 4-(6-chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1055]

[1056] Step 1

[1057] A mixture of 1-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(I) oxide (901 mg, 3.9 mmol) in trifluoroacetic acid (35 mL) and dimethylacetamide (1.75 mL) was purged with argon gas. After 15 minutes, water (64 μL) was slowly added dropwise to the mixture during argon purging. After 1 minute, the flask was held tight and heated to 140°C for 90 hours. After cooling, the reaction mixture was diluted with dichloromethane, filtered through a Celite pad, and the resulting filtrate was concentrated. The residue was dissolved in dichloromethane and aqueous HCl, the insoluble material was filtered again through a Celite pad, and the two layers of the filtrate were separated. The organic fraction was dried (MgSO4), concentrated, and purified by chromatography on a silica gel with 0-100% ethyl acetate in hexane to obtain 2-bromo-6-chloro-9H-fluoren-9-one.

[1058] Step 2

[1059] 1 M lithium triethylborohydride (0.34 mL) was added to a solution of 2-bromo-6-chloro-9H-fluoren-9-ol (33 mg, 0.11 mmol) in tetrahydrofuran (1 mL) at -78 °C. After 25 minutes, the reaction mixture was quenched with saturated aqueous NH4Cl. After extracting the product with ethyl acetate (x 4), the organic extracts were combined, washed with brine (x 1), dried (MgSO4), and concentrated to obtain unpurified 2-bromo-6-chloro-9H-fluoren-9-ol, which was used for the next step.

[1060] Step 3

[1061] Triethylsilin (0.3 mL) and trifluoroacetic acid (0.3 mL) were added to unpurified 2-bromo-6-chloro-9H-fluorene-9-ol, and the resulting mixture was stirred at room temperature for 1.7 hours. After concentration, the residue was purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane to obtain 2-bromo-6-chloro-9H-fluorene.

[1062] Step 4

[1063] A mixture of 2-bromo-6-chloro-9H-fluorene (27 mg, 0.095 mmol), bis(pinacoleto)diborane (29 mg, 0.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.8 mg, 9.5 μmol), and potassium acetate (28 mg, 0.29 mmol) in dioxane (1.5 mL) was placed in a microwave reaction vial and purged with argon gas. The resulting mixture was stirred at 95°C for 2.25 hours and, after cooling, the mixture was diluted by molar and the product was extracted with ethyl acetate (x 4). The combined organic extract was dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane to obtain 2-(6-chloro-9H-fluorene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[1064] Steps 5, 6, and 7

[1065] 4-(6-chloro-9-oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid as an intermediate 4 and following the Suzuki reaction using 2-(6-chloro-9H-fluorene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, it was prepared in a manner similar to the general procedure of SEM deprotection and ester hydrolysis with HCl: 1 1H NMR(400 MHz, methanol- d4 ) 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: C 16 H 11 Calculated value for ClN3O2(M+H): 312.05, Measured value: 311.96.

[1066] Example 174: 4-(2-(piperidine-4-yl)-4'-(1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1067]

[1068]

[1069] Step 1

[1070] A mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (28, 403 mg, 1.45 mmol), 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (5, 1.93 g, 5.84 mmol), and palladium (0) tetrakis(triphenylphosphine) (168 mg, 0.15 mmol) in 2 M potassium carbonate (2.9 mL) and 1,4-dioxane (15 mL) in a 20 mL microwave reaction vial was purged with Ar for 10 minutes, and then stirred in a 110°C bath for 1.25 hours. The reaction mixture was dissolved in ethyl acetate (~100 mL) and washed with ~50% saturated NaHCO3 (x 1) and water (x 1). After extracting the aqueous fraction with ethyl acetate (~50 mL x 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluted with 0-100% ethyl acetate in hexane. The partially purified product was further purified by silica gel chromatography eluted with 0-20% ethyl acetate in hexane to obtain 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole: ES / MS m / z: C 20 H 33 Calculated value for BN3O3Si(M+H): 402.24, measured value: 401.96.

[1071] Step 2

[1072] 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 in an 85°C bath for 18 hours. After cooling the reaction mixture and diluting it with water (100 mL), the product was extracted with ethyl acetate (100 mL x 4). After washing the extract with water (100 mL x 1), the combined extract was dried (Na2SO4) and concentrated.

[1073] After treating the residue with concentrated HCl (25 mL), the mixture was refluxed for 36 hours. After cooling the resulting mixture in a refrigerator, the insoluble material was filtered and washed with water. The solids were dissolved in ethyl acetate (~100 mL), dried (MgSO4), and concentrated to obtain crude 3-(5-bromo-2-iodophenyl)pentanedioic acid: ES / MS m / z: C 11 H 11 Calculated value for BrIO4(M+H): 412.89, Measured value: 412.58.

[1074] Step 3

[1075] The mixture of the above-mentioned unpurified 3-(5-bromo-2-iodophenyl)pentanedioic acid in acetic anhydride (~10 mL) was refluxed in a 155°C bath for 3 hours. After concentrating the resulting solution, the residual syrup was co-evaporated with toluene (x 2) and dried under vacuum. The residue was dissolved in THF (50 mL) and stirred at room temperature, while adding 28% NH3 aqueous solution (0.65 mL each) three times at approximately 15-minute intervals. The resulting mixture was stirred at room temperature for 7 hours. 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 155°C bath for 4 hours and cooled. The solution was concentrated and purified by silica gel chromatography eluted with 0-60% ethyl acetate in hexane to obtain 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione: 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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 Hz, 1H), 2.90 - 2.78(m, 2H), 2.63(dd, J = 16.7, 4.1 Hz, 2H).

[1076] Step 4

[1077] 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione (1.60 g, 4.06 mmol) in THF (5 mL) was stirred at 0°C, and a 1.0 M borane tetrahydrofuran complex solution in THF (10.2 mL) was added dropwise. After refluxing the resulting mixture for 20 hours, concentrated HCl (16 mL) was added to the mixture, and the resulting solution was refluxed in a 105°C bath for 4.5 hours. The solution was stirred in an ice bath, and NaOH (solid) was added to neutralize the mixture. The resulting basic solution was diluted with a small amount of NaHCO3 solution, and the product was extracted with ethyl acetate (~60 mL x 2). The extracts were washed with brine (x 1), combined, dried (Na2SO4), and concentrated to obtain 4-(5-bromo-2-iodophenyl)piperidine as oil.

[1078] A solution of unpurified 4-(5-bromo-2-iodophenyl)piperidine in methanol (~25 mL) was stirred at 0°C, at which point Boc2O (1078 mg, 4.939 mmol) and triethylamine (0.8 mL, 5.740 mmol) were added. After 2 hours at 0°C and overnight at room temperature, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and then washed with water (x 2). The resulting organic fraction was dried (MgSO4), concentrated, and purified by silica gel chromatography eluted with 0-10% EA in hexane to obtain tertiary-butyl 4-(5-bromo-2-iodophenyl)piperidine-1-carboxylate: 1 ¹H 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).

[1079] Step 5

[1080] A mixture of tert-butyl 4-(5-bromo-2-iodophenyl)piperidine-1-carboxylate (250 mg, 0.63 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-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 minutes and stirred in a 110°C bath for 1.5 hours. After cooling, the mixture was diluted with ethyl acetate, dried (MgSO4), concentrated, and purified by chromatography on silica gel eluted with 0-50% ethyl acetate in hexane to obtain tertiary-butyl 4-(4-bromo-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate: ES / MS m / z: C 30 H 41 Calculated value for BrN4NaO3Si(M+Na): 635.20, Measured value: 635.14.

[1081] Step 6

[1082] A mixture of tert-butyl 4-(4-bromo-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate (201 mg, 0.33 mmol), bis(pinacoleto)diborane (27 mg, 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 minutes, and then the mixture was heated at 120°C for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, dried (MgSO4), and concentrated. The residue was purified by silica gel chromatography eluted with 0-35% ethyl acetate in hexane to obtain tertiary-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate: ES / MS m / z: C 36 H 53 Calculated value for BN4NaO5Si(M+Na): 683.38, Measured value: 683.35.

[1083] Step 7, Step 8, and Step 9

[1084] 4-(2-(piperidine-4-yl)-4'-(1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid as an intermediate 4and following the Suzuki reaction using tertiary-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate, it was prepared in a manner similar to the general procedure of SEM deprotection and ester hydrolysis with HCl: 1 1H NMR(400 MHz, methanol- d4 ) δ 8.23(s, 1H), 7.99(d, J = 1.8 Hz, 1H), 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: C 22 H 22 Calculated value for N7O2(M+H): 416.18, Measured value: 416.14.

[1085] Example 175: Ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1086]

[1087] Step 1, Step 2, Step 3, and Step 4

[1088] Ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate as an intermediate 11 and was prepared in a manner similar to the procedure described herein using 2,7-dibromo-9H-fluorene, followed by a manner similar to the general procedure for PMB deprotection: 1 ¹H NMR(400 MHz, DMSO- d 6) 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), 1.28(t, J = 7.0 Hz, 3H). ES / MS m / z: C 20 H 17 Calculated value for N6O2(M+H): 373.14, Measured value: 373.30.

[1089] Example 176: 2-morpholinoethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1090]

[1091] Step 1

[1092] Lithium hydroxide monohydrate (3.7 g, 88.18 mmol) was added to a stirred solution of ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate (18 g, 29.4 mmol) in MeOH (36 mL), THF (108 mL), and water (36 mL) at room temperature under argon. The reaction mixture was heated to 60°C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain an unpurified product, which was diluted with water, acidified with a 1 N HCl solution, and stirred for 10 minutes. The precipitated solid was filtered, washed with water, and dried under vacuum to obtain 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylic acid: ES / MS m / z: C 34 H 29 Calculated value for N6O4(M+H): 585.23, Measured value: 585.41.

[1093] Step 2

[1094] Potassium carbonate (1.41 g, 10.3 mmol) was added to a stirred solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-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, followed by the addition of 4-(2-chloroethyl)morpholine (1.53 g, 10.3 mmol). The mixture was heated to 50°C and stirred for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 80-100% ethyl acetate in PET-ether to obtain 2-morpholinoethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 40 H 40 Calculated value for N7O5(M+H): 683.31, Measured value: 698.52.

[1095] Step 3

[1096] A mixture of 2-morpholinoethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate (3.0 g, 4.3 mmol) in TFA (30 mL) was heated at 80°C for 16 hours. The reaction mixture was concentrated under reduced pressure, the unpurified residue was neutralized with a saturated solution of NaHCO3, and the product was extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC (neutral method), and the pure fraction was freeze-dried to obtain 2-morpholinoethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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: C 24 H 24 Calculated value for N7O3(M+H): 458.19, Measured value: 458.32.

[1097] Example 177: 3-Morpolinopropyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1098]

[1099] Step 1 and Step 2

[1100] 3-morpholinopropyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate was prepared in a manner similar to the general procedure for PMB deprotection, following steps 2 and 3 of Example 175 using 4-(3-chloropropyl)morpholine and 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylic acid: 1 ¹H NMR(400 MHz, DMSO- d 6 ) 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 = 6.7 Hz, 2H). ES / MS m / z: C 25 H 26 Calculated value for N7O3(M+H): 472.21, Measured value: 472.50.

[1101] Example 178: 2-((L-valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1102]

[1103] Step 1

[1104] Lithium hydroxide monohydrate (1.85 g, 44.24 mmol) was added to a stirred solution of ethyl 5-bromo-2-(4-methoxybenzyl)-2H-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. After stirring the reaction mixture at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, acidified with a 1N HCl solution, and stirred for 10 minutes. The precipitated solid was filtered, washed with water, and dried under vacuum to obtain 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid (178-a): ES / MS m / z: C 11 H 10 Calculated value for BrN3NaO3(M+H): 333.98, Measured value: 334.10.

[1105] Step 2

[1106] 4-dimethylaminopyridine (0.33 g, 2.76 mmol) was added to a stirred solution of Boc-L-valine (3.0 g, 13.82 mmol) and ethane-1,2-diol (1.11 g, 17.96 mmol) in dichloromethane (45 mL) at 0 °C under argon, followed by the addition of a solution of dicyclohexylcarbodiimide (3.69 g, 17.96 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting unrefined residue was purified by silica gel chromatography eluted with 0-30% ethyl acetate in PET-ether to obtain 2-hydroxyethyl(tert-butoxycarbonyl)-L-valineate (178-b): 1 ¹H NMR(400 MHz, DMSO- d 6) 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).

[1107] Step 3

[1108] 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid in dichloromethane (37.5 mL) at 0°C under argon ( 178-a , 2.55 g, 8.17 mmol), 2-hydroxyethyl(tert-butoxycarbonyl)-L-valinate( 178-b To a stirred solution of 2.77 g (10.62 mmol), 4-dimethylaminopyridine (0.2 g, 1.63 mmol) was added, followed by the addition of a solution of dicyclohexylcarbodiimide (2.18 g, 10.62 mmol) in dichloromethane (12.5 mL). The mixture was stirred at room temperature for 16 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel chromatography eluted with 0-60% ethyl acetate in PET ether to obtain 2-(((tertiary-butoxycarbonyl)-L-valyl)oxy)ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 23 H 32 Calculated value for BrN4O7(M+H): 555.15, Measured value: 555.34.

[1109] Step 4

[1110] 2-(((tertiary-butoxycarbonyl)-L-valyl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate using 2-(4-methoxybenzyl)-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole and 2-(((tertiary-butoxycarbonyl)-L-valyl)oxy)ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate Prepared in a manner similar to the general procedure of the Suzuki reaction: ES / MS m / z: C 46 H 49 Calculated value for N7NaO8(M+Na): 850.35, Measured value: 850.86.

[1111] Step 5

[1112] A mixture of 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-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, and the combined modest fraction was freeze-dried to obtain 2-((L-valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1 ¹H NMR(400 MHz, DMSO- d 6) 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), 4.08(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: C 25 H 26 Calculated value for N7O4(M+H): 488.20, Measured value: 488.39.

[1113] Example 179: 2-(phosphonooxy)ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1114]

[1115] Step 1

[1116] Triphenylphosphine (28.27 g, 107.91 mmol) was added to a stirred solution of dibenzyl hydrogen phosphate (117 g, 20 g, 71.94 mmol) and 2-((tertiary-butyldimethylsilyl)oxy)ethanol-1-ol (15.22 g, 86.33 mmol) in THF (200 mL) under argon at 0°C, followed by the addition of diethyl azadicarboxylate (18.83 g, 107.91 mmol). The resulting mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel chromatography eluted with 0-10% ethyl acetate in PET-ether to obtain dibenzyl(2-((tert-butyldimethylsilyl)oxy)ethyl) phosphate: ES / MS m / z: C 22 H 34 Calculated value for O5PSi(M+H): 437.19, Measured value: 437.34.

[1117] Step 2

[1118] Dowex-50W was added 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. The mixture was stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel chromatography eluted with 0-2% MeOH in dichloromethane to obtain dibenzyl(2-hydroxyethyl)phosphate: ES / MS m / z: C 16 H 20 Calculated value for O5P(M+H): 323.10, Measured value: 323.24.

[1119] Step 3

[1120] NET3 (3.23 mL, 23.28 mmol) was added to a stirred solution of dibenzyl(2-hydroxyethyl) phosphate (5 g, 15.52 mmol) in dichloromethane (50 mL) at 0 °C under argon, followed by the addition of MsCl (2.13 g, 18.63 mmol). After stirring the mixture at room temperature for 5 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to obtain unpurified 2-((bis(benzyloxy)phosphoryl)oxy)ethyl methanesulfonate, which was used directly in the following step without any further purification: ES / MS m / z: C 17 H 22 Calculated value for O7PS(M+H): 401.08, Measured value: 401.27.

[1121] Step 4

[1122] 2-((bis(benzyloxybenzyl)phosphoryl)oxy)ethyl methanesulfonate (3.28 g, 8.21 mmol) was added to a stirred mixture of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (4 g, 6.84 mmol) and potassium carbonate (1.41 g, 10.26 mmol) in DMF (40 mL) under argon at 0°C. After stirring the mixture at 50°C for 14 hours, 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 unrefined residue was purified by silica gel chromatography eluted with 0-60% ethyl acetate in PET-ether to obtain 2-((bis(benzyloxy)phosphoryl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 50 H 46 Calculated value for N6O8P(M+H): 889.31, Measured value: 889.77.

[1123] Step 5

[1124] A mixture of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate (11.5 g, 12.94 mmol) in trifluoroacetic acid (45 mL) was stirred at 70°C for 20 hours. After concentrating the reaction mixture under reduced pressure, the unrefined residue was purified by Prep-HPLC to obtain 2-(phosphonooxy)ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1¹H NMR(400 MHz, DMSO- d6 ) 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: C 20 H 18 Calculated value for N6O6P(M+H): 469.10, Measured value: 469.16.

[1125] Example 180: (((2-(phosphonooxy)ethoxy)carbonyl)oxy)methyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1126]

[1127] Step 1

[1128] Chloromethyl carbonochloridate (2.97 g, 23.29 mmol) was added to a stirred solution of dibenzyl(2-hydroxyethyl) phosphate (5 g, 15.52 mmol) and pyridine (2.5 mL, 31.04 mmol) in dichloromethane (100 mL) at 0 °C under argon. After stirring the mixture at room temperature for 6 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to obtain unpurified 2-((bis(benzyloxy)phosphoryl)oxy)ethyl(chloromethyl) carbonate, which was used directly in the next step without any further purification: ES / MS m / z: C 18 H 21 Calculated value for ClO7P(M+H): 415.07, Measured value: 415.31.

[1129] Step 2

[1130] 2-((bis(benzyloxybenzyl)phosphoryl)oxy)ethyl(chloromethyl) carbonate (0.25 g, 10.27 mmol) was added to a stirred solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-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) under argon at 0°C. The mixture was stirred at 50°C for 18 hours. After diluting the reaction mixture with ice water, the product was extracted with ethyl acetate. The organic extract was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 0-1% 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-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 52 H 48 N6O 11 Calculated value for P(M+H): 963.31, Measured value: 963.39.

[1131] Step 3

[1132] A mixture of (((2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)carbonyl)oxy)methyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-2H-1,2,3-triazole-4-carboxylate (5.5 g, 5.71 mmol) in trifluoroacetic acid (55 mL) was stirred at 70°C for 20 hours. After concentrating the reaction mixture under reduced pressure, the unrefined residue was purified by Prep-HPLC to obtain (((2-(phosphonooxy)ethoxy)carbonyl)oxy)methyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 22 H 20 Calculated value for N6O9P(M+H): 543.10, Measured value: 543.40.

[1133] The following compounds are the aforementioned bromide intermediates with the commercially available boronates, the Suzuki reaction, SEM, or PMB deprotection described above, and commercially available boronates, 18 or 20 It was prepared in a manner similar to the typical procedure for ester hydrolysis using:

[1134] Example 182: 3-(3-chloro-4-fluorophenyl)-1H-pyrazole-4-carboxylic acid

[1135]

[1136] 1 1H NMR(400 MHz, methanol- d 4) 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: C 10 Calculated value for H7ClFN2O2(M+H): 241.02, Measured value: 241.02.

[1137] Example 183: 3-(3,5-dichlorophenyl)-1H-pyrazole-4-carboxylic acid

[1138]

[1139] 1 ¹H NMR(400 MHz, methanol-d4) 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: C 10 Calculated value for H7ClFN2O2(M+H): 256.99, Measured value: 257.03.

[1140] Example 184: 4-(3-chloro-4-fluorophenyl)-1H-imidazole-5-carboxylic acid

[1141]

[1142] 1 1H NMR(400 MHz, methanol- d 4 ) 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: C 10 Calculated value for H7ClFN2O2(M+H): 241.02, Measured value: 240.94.

[1143] Example 185: 4-(3,5-dichlorophenyl)-1H-imidazole-5-carboxylic acid

[1144]

[1145] 1 1H NMR(400 MHz, methanol- d 4) δ 8.03(s, 2H), 7.67(s, 1H), 7.31(s, 1H). ES / MS m / z: C 10 Calculated value for H7Cl2N2O2(M+H): 256.99, Measured value: 257.03.

[1146] Biological analysis

[1147] Biological Analysis 1: Biochemical Cell Analysis

[1148] ingredient

[1149] Glycolate oxidase (GO) was generated in Gilead using the HAO1 sequence according to the literature [Jones et al., 2000 (J. Biol. Chem. 275: 12590-12597)]. The Amplex® Red Hydrogen Peroxide / Peroxidase Assay Kit (Catalog no. A22188) was purchased from Thermo Fisher (Waltham, MA). Glycolic acid (Catlog No. 124737) and Tris 1M, pH 7.8 (Catalog no. T2569-1L) were purchased from Sigma (St. Louis, MO), 10% Tween-20 (Catalog no. 51-12-02) was purchased from SeraCare (Milford, MA), 2% BSA (Catalog no. BSA-1000) was purchased from Rockland Immunochemicals (Pottstown, PA), and Black 384-well low binding plates (Catalog no. 3860) were purchased from Corning (Sunnyvale, CA).

[1150] method

[1151] 1. GO Biochemical Analysis

[1152] The GO biochemical enzymatic reaction was performed in a black 384-well low binding plate at a total volume of 25 μL. The reaction mixture contained 5 nM GO, 100 μM glycolate, 0.1 U / mL HRP, 50 μM Amplex Red, and a 1:3 series of diluted test compounds in a buffer containing 50 mM Tris pH 7.8, 0.0025% Tween-20, and 0.02% BSA. 25 nanoliters of the 1000X test compound were pre-spotted onto a 384-well low-binding plate using an Echo 555 Liquid Handler (Labcyte Inc., San Jose, CA) with a starting final concentration of 10 μM, then 5 μL / well of 25 nM GO (5X with a final concentration of 5 nM) was added and incubated for 15 minutes. 10 microliters of 2.5X HRP with a final concentration of 0.1 U / mL were added to each well, followed by the addition of 10 μL of 2.5X glycolate substrate with a final concentration of 100 μM and 2.5X Amplex Red with a final concentration of 50 μM. The reaction mixtures were mixed and incubated at room temperature for 20 minutes, after which the plates were read using an EnVision plate reader (Perkin Elmer, San Jose, CA) with excitation at 570 nm and emission at 585 nm. Wells containing DMSO were used as negative controls (0% inhibition rate), while wells without the GO enzyme were used as positive controls (100% inhibition rate). The % inhibition rate was calculated as 100% x (well-negative) / (positive-negative).

[1153] 2. HRP counter screen assay

[1154] HRP counterscreen analysis was performed simultaneously with GO biochemical analysis to exclude compounds capable of directly inhibiting HRP but ineffective in inhibiting GO. 25 nanoliters of the same set of 1000X test compounds were pre-spotted onto a 384-well low-binding plate as described above for GO biochemical analysis, and then 10 μL of 2.5X 0.1 U / mL final concentration HRP in a buffer containing 50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA was added and incubated for 15 minutes. Subsequently, 15 μL of 1.67X 50 μM final concentration Amplex Red and 1.67X 10 μM final concentration H2O2 were added to each well. The reactants were mixed and incubated at room temperature for 20 minutes. At the end of the incubation, the plates were read by Envision with an excitation of 570 nm and an emission of 585 nm. Wells containing DMSO were used as negative controls (as 0% inhibition), while wells without the HR enzyme were used as positive controls (as 100% inhibition). The % inhibition rate was calculated as described above.

[1155] GO cell-based analysis

[1156] 1. GO Transient Transfected Cell-Based Analysis

[1157] ingredient

[1158] HAO1 plasmid DNA was generated by PCR cloning of HAO1 cDNA (Jones et al., 2000) into the pcDNA3.1(+)-neomycin vector by LakePharma (Belmont, CA). FuGENE 6 transfection reagent (Catalog no. E2692) was purchased from Promega (Madison, WI). CHO-K1 cell line (Catalog no. ATCC CCL-61) and F-12K medium (Catalog No. 30-2004) were obtained from ATCC (Manassas, VA). OptiMEM I reduced serum medium (Catalog No. 31985-070) was obtained from Gibco / Life Technologies (Grand Island, NY). Fetal Bovine Serum (FBS) (Catalog no. SH30071.03) was obtained from HyClone (Logan, Utanh), and 100X penicillin / streptomycin / L-glutamine (Catalog no. 30-009-Cl) was obtained from Corning (Fremont, CA). 384-well black tissue culture plates (Catalog No. 781086) were purchased from Greiner Bio-One (Monroe, NC).

[1159] method

[1160] Transient transfection was performed by mixing 3 parts of FuGENE 6 reagent (μl) with 1 part of HAO1 plasmid DNA or vector control DNA (μg) in OptiMEM I reduced fluorescence medium, and incubated at room temperature for 15 minutes. The mixture was mixed with CHO-K1 cells and dispensed into 45 μL / wells containing 0.025 μg HAO1 plasmid DNA, 0.075 μL FuGENE 6, and 4000 cells in F-12K medium plus 10% FBS. To express GO, cells were incubated in a 37°C incubator for 48 hours. Subsequently, the cell culture medium was removed and replaced with 25 μL of a 1:3 series of diluted test compounds at a starting concentration of 1 μM, and incubated at room temperature for 1 hour. 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 μM glycolate, and 50 μM Amplex Red was added to each well. The reaction mixture was mixed and incubated at room temperature for 20 minutes, after which the plate was read using an EnVision plate reader as described above. Wells containing DMSO were used as negative controls (0% inhibition rate), while wells transfected with vector-prepared DNA were used as positive controls (100% inhibition rate). The % inhibition rate was calculated as described above.

[1161] 2. GO stable clone cell-based analysis

[1162] ingredient

[1163] The reagents and tissue culture media for transient hematological infection were described in the transient transfection analysis section. Rabbit anti-HAO1 antibody (Catalog No. ab93137) was purchased from Abcam (Cambridge, MA), and anti-rabbit IgG (H+L), F(ab')2 fragment, and Alexa Fluor® 555 Conjugate (Catalog No. 4413) were obtained from Cell Signaling Technology (Danvers, MA).

[1164] method

[1165] 1) Creation of a stable clone of CHO-K1-HAO1

[1166] GO stable clones were generated in a house by performing bulk transient transfection of GO plasmid DNA into CHO-K1 cells and incubated for 48 hours as described above. Subsequently, the cells were trypsinized, and 2000 cells / 200 μl were added to well A1, followed by a series of 1:2 dilutions to A2 and all intermediate to A12 for 10 96-well tissue culture plates. Cells in A1-A12 were further diluted in a series of 1:2 to H1-H12 and incubated for 2 weeks in F-12K medium containing 10% FBS supplemented with 500 μg / mL G418. Each plate was monitored under a microscope for colony formation. Twenty-eight single colonies were selected and expanded to test GO expression.

[1167] Immunocytochemistry for intracellular GO staining

[1168] Intracellular GO staining was performed by first fixing cells with 4% formaldehyde in 50 μl / well PBS in a 384-well plate at room temperature for 30 minutes, followed by washing three times with 80 μl / well wash buffer (PBS containing 0.05% Tween-20). Subsequently, cells were permeable with 0.1% Triton in 50 μl / well PBS, washed three times, and blocked for 1 hour with 3% BSA in 50 μl / well PBS containing 0.05% Tween-20. Cells were washed three more times, 50 μl of rabbit anti-human GO was added to each well as a 1:100 dilution in PBS containing 1% BSA and 0.05% Tween-20, and incubated overnight at 4°C. Cells were washed four times with 15 minutes of incubation between each wash, and then 40 μL of Alexa Fluor 555 conjugated anti-rabbit IgG(H+L) F(ab')2 fragment at a 1:250 dilution in 1% BSA and 0.05% Tween-20 and Hoechst at a 1:500 dilution were added to each well.

[1169] Cells were washed four times, with 15 minutes of incubation between each wash, followed by the addition of 40 μL of Alexa Fluor 555 conjugated anti-rabbit IgG(H+L) F(ab') fragment in 1% BSA and 0.05% Tween-20 dilutions and a 1:500 dilution to each well. The plates were incubated at room temperature for 160 minutes and washed four times at the end of the incubation. 60 ml of PBS was added to each well, and cell images were examined using an Arrayscan XTI HCS reader from Thermo Fisher Scientific (Waltham, MA).

[1170] 2) Stable clone 2D2 GO enzyme-activated cell-based analysis

[1171] 384-well tissue culture plates were pre-spotted with 25 nL of the test compound per well, and then 5000 cells / well / 25 μL of clone 2D2 in reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) was dispensed into all wells except column 22, which contained 5000 cells / well / 25 μL of clone 1A1 vector control. The test compound was incubated with the cells at room temperature for 1 hour, and then 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), 160 μM glycolate, and 50 μM Amplex Red was added. The reactants were mixed and incubated at room temperature for 20 minutes, and the fluorescence of the product resorufin was measured as described above. Wells containing 2D2 and DMSO were used as negative controls (0% inhibition rate), while wells containing the 1A1 vector control clone were used as positive controls (100% inhibition rate). The inhibition percentages were calculated as described above (Table 2).

[1172] Table 2:

[1173]

[1174]

[1175]

[1176]

[1177]

[1178] Biological Analysis 2: Oral Bioavailability and PK Study

[1179] The oral formulation of Example 2 was formulated in a sterile solution of 1.0 mg / mL of 50% water, 37.5% PEG 300, and 12.5% ​​DMSO. The administration group consisted of three fasted male Sprague Dawley rats. At the time of administration, the body weight of the animals was 0.26 to 0.27 kg. For the oral administration group, the formulated formulation was administered via oral gastrointestinal administration of 5.0 mL / kg for a dose of 5.0 mg / kg. Non-compartmental pharmacokinetic analysis was performed on plasma concentration-time data.

[1180] Table 3:

[1181]

[1182] Table 3 shows the mean plasma pharmacokinetic parameters of Example 2 after PO administration of 5 mg / kg of Example 2 in SD rats (mean ± SD, n=3). Table 4 shows the mean plasma pharmacokinetic parameters of Example 68 after PO administration of 5 mg / kg of Example 2 in SD rats (mean ± SD, n=3). As shown in Tables 4 and 5, the AUC of Example 2 inf was 1600 ± 280 nM·h, and C max It was 2390 ± 246 nM. Example 68 AUC inf was 3250 ± 242 nM·h, and C max It was 2270 ± 171 nM. The bioavailability of Example 68 was calculated to be 19.0% ± 1.4%.

[1183] Table 4:

[1184]

[1185] Table 5:

[1186]

[1187] IV exposure (AUC) of Example 68 at 1.0 mg / kg from Table 7 belowinf Based on = 3420 nM·hr).

[1188] Apparent systemic clearance for Example 68 (CL = 0.95 ± 0.09 L / hr / kg) was slow compared to hepatic blood flow in rats (CL = 4.0 L / hr / kg). Distribution volume (V ss = 0.44 ± 0.06 L / kg) was smaller than the volume of whole water (0.7 L / kg). The final t of Example 68 1 / 2 It was 1.02 ± 0.06 hr, and the mean retention time (MRT) was 0.47 ± 0.02 hr. The oral bioavailability (%F) was calculated to be 2.3% ± 0.3%. See Tables 7 and 8 and Figure 2.

[1189] Table 7: Mean plasma pharmacokinetic parameters of Example 68 after 30-minute IV infusion of 1 mg / kg in SD rats (mean ± SD, n=3).

[1190]

[1191] Table 8: Mean plasma pharmacokinetic parameters of Example 68 after administration of 5 mg / kg PO in SD rats (mean ± SD, n=3).

[1192]

[1193] Example 168 or Example 175 was formulated in a sterile solution of 15% N-methyl-2-pyrrolidone, 55% PEG, and 30% water for oral or intravenous administration. The administration group consisted of three fasted male SD rats or three fasted male Beagle dogs. At the time of administration, the rats had a body weight of 0.2 to 0.3 kg, and the dogs had a body weight of 10.72 to 10.82 kg. For the oral administration group, the formulated dosage was administered via oral gastrogastric administration of 5.0 mL / kg for doses of 5.0 mg / kg or 5.4 mg / kg. For the intravenous administration group, the formulated dosage was 1.00 mg / kg. Non-compartmental pharmacokinetic analysis was performed on plasma concentration-time data. Data from these studies are shown in Figures 3 and 4.

Claims

Claim 1 Compound of formula (III), or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterium analogs thereof: In the above equation, R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with; and each R 3 is independently an aryl, heteroaryl, or heterocyclil, where, each R 3 1 to 3 R 6 Arbitrarily substituted with; each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where, each R 4 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is heterocyclile; and each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl; and each R 6 is independently cyano, halo, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 It is a haloalkyl, phenyl, heterocyclyl, or heteroaryl; where, each R 6 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 Optionally substituted with a haloalkyl; R 7 and R 8 Each independently hydrogen, C 1-4 Alkyl, phenyl, or pyridyl, or R 7 and R 8 They form heterocyclines together with the nitrogen atoms to which they are bonded; and each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl; and each R b is independently hydrogen or C 1-4 It is an alkyl. Claim 2 Compound of formula (IV), or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterium analogs thereof: In the above equation, R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, 1 to 3 R 4 C arbitrarily substituted as 1-6 Alkyl, cycloalkyl, or 1 to 3 R 5 It is a heteroaryl arbitrarily substituted with; and each R 4 is independently halo, hydroxy, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; where, each R 4 1 to 3 R 5 arbitrarily substituted with; provided that only one R 4 is heterocyclile; and each R 5 is independently cyano, halo, C 1-4 Alkyl, hydroxy, -OC 1-4 Alkyl, C 1-4 haloalkyl, or -OC 1-4 It is a haloalkyl; and each R a -NH2, -NHC independently 1-6 Alkyl, -N(C 1-6 Alkyl)2, or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl; and each R b is independently hydrogen or C 1-4 It is an alkyl. Claim 3 In claim 2, R 2 is hydrogen, 1 to 3 R 4 C arbitrarily substituted as 1-6 alkyl, or cycloalkyl; and each R 4 -OC independently 1-6 Alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclile; and each R a is independently -NH2 or -OP(O)(OR b C arbitrarily substituted with )2 1-6 It is alkyl; R b is a compound that is hydrogen. Claim 4 Compounds selected from the following compounds: . Claim 5 Compound having the following structure: or its pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterium analogs. Claim 6 Compound having the following structure: or its pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterium analogs. Claim 7 delete Claim 8 delete Claim 9 delete Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete Claim 32 delete Claim 33 delete Claim 34 delete Claim 35 delete Claim 36 delete Claim 37 delete Claim 38 delete Claim 39 delete Claim 40 delete

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