Heterocyclic carboxylate compounds as glycolate oxidase inhibitors

Abstract

This invention relates generally to regulators of human glycolate oxidase, their use, and methods of manufacturing.

Description

Technical Field

[0001] This invention relates to compounds, compositions, and methods for treating primary type 1 hyperoxaluria and recurrent kidney stone formation. Specifically, this invention provides novel substituted heterocyclic carboxylic acid compounds, methods for their preparation, and their use as therapeutic or preventative agents. More specifically, this invention provides novel human glycolate oxidase inhibitors, pharmaceutical compositions containing such compounds, and methods for using these compounds to treat primary type 1 hyperoxaluria and recurrent kidney stone formation. Prior Technology

[0002] Kidney stones affect a large population. In the United States, the prevalence of kidney stones is 8.8%, with 10.6% in men and 7.1% in women. The disease also occurs in primary type 1 hyperoxaluria (PH1), which may be caused by a genetically deficient enzyme activity. Due to high glycolate oxidase activity, these patients may exhibit a significant increase in glyoxylate and oxalate production and calcium oxalate stone deposition. Medical procedures for removing kidney stones exist and are effective. However, the recurrence rate of kidney stones after these procedures may be high (e.g., exceeding 50%). Therefore, there is a need for agents that inhibit glycolate oxidase activity to treat PH1 patients and reduce the rate of recurrence of kidney stones in those with existing kidney stones. Summary of the Invention

[0003] This invention relates to novel substituted heterocyclic carboxylic acid compounds (including their stereoisomers, pharmaceutically acceptable salts, and prodrugs) that inhibit human glycolate oxidase activity, and the use of such compounds in the treatment of primary type 1 hyperoxaluria. The compounds of this invention can be used to treat recurrent kidney stone formation.

[0004] In one state sample, a compound having the structure of formula I is provided: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein A, R1 and R2 are as described herein.

[0005] In some embodiments, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of the present invention (e.g., a compound of Formula I or an additional formula described herein), and at least one pharmaceutically acceptable excipient. In some embodiments, pharmaceutical compositions are provided herein comprising a compound, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof.

[0006] Some embodiments provide a method of treating a disease or condition in a mammal (specifically, a human) using (or administering) a compound of Formula I or an additional formula described herein, the mammal being adapted for treatment by a human glycolate oxidase inhibitor.

[0007] Some embodiments provide a method of treating a disease or condition in a mammal (specifically, a human) using (or administering) a compound as described herein, the mammal being adapted for treatment by a human glycolate oxidase inhibitor. Simple Explanation of the Diagram

[0008] [picture] [1] Plasma concentration-time curves (mean ± SD, n=3) of Example 68 after oral administration of Example 2 at 5.0 mg / kg in SD rats are shown.

[0009] [picture] [2] Plasma concentration-time curves (mean ± SD, n=3) of Example 68 after intravenous infusion of 1.0 mg / kg over 30 minutes and PO administration of 5.0 mg / kg in SD rats are shown.

[0010] [picture] [3] Plasma concentration-time curves for Examples 168 and 175 in SD rats are shown.

[0011] [picture] [4] Plasma concentration-time curves for examples 168 and 175 in male Beagle dogs are shown. Implementation

[0012] [Cross-reference to related applications] [] This application claims the benefit of 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, pursuant to 35 USC § 119(e), each of which is incorporated herein by reference in its entirety.

[0013] [, Definition and general parameters , ] [] The following description illustrates exemplary methods, parameters, and the like. However, it should be understood that this description is not intended to limit the scope of the invention, but rather is provided as an example of exemplary embodiments.

[0014] As used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0015] A hyphen ("-") not between two letters or symbols is used to indicate the connection point of a substituent. For example, -C(O)NH₂ is connected via a carbon atom. A hyphen at the beginning or end of a chemical group is for convenience; the chemical group may be depicted with or without one or more hyphens without losing its general meaning. A wavy line drawn through a line in the structure indicates the connection point of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0016] The prefix "C uv" indicates that the following groups have 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 with quantity includes a stated value and has a meaning determined by the context (e.g., the degree of error associated with the measurement of a particular quantity). Furthermore, unless the context explicitly specifies otherwise, the singular forms "a" and "the" include a plural reference. Thus, for example, a reference to "compound" includes a plural of such compounds, and a reference to "analysis" includes reference to one or more analyses and their equivalents known to a person skilled in the art.

[0018] "alkyl" refers to a non-branched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, dibutyl, isobutyl, tributyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl group with a specific number of carbon atoms is named by its chemical name or identified by its molecular formula, it can encompass all positional isomers with that number of carbon atoms; therefore, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), dibutyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tributyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0019] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include vinyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0020] "Alynyl" refers to an alkyl group containing at least one carbon-carbon linkage and having 2 to 20 carbon atoms (i.e., C2-20 ynyl), 2 to 8 carbon atoms (i.e., C2-8 ynyl), 2 to 6 carbon atoms (i.e., C2-6 ynyl), or 2 to 4 carbon atoms (i.e., C2-4 ynyl). The term "ynyl" also includes other groups having one linkage and one double bond.

[0021] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, third butoxy, second butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0022] "Haloalkoxy" refers to an alkoxy group as defined above, in which one or more hydrogen atoms are replaced by halogens.

[0023] "Alkylthio" refers to the "alkyl-S-" group.

[0024] "Acryl" refers to the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl; each of which may be substituted as defined herein. Examples of acryl include methylacryl, acetylacryl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0025] "Acrylamide" refers to both the "C-acrylamide" group (referring to the group -C(O)NR yR z) and the "N-acrylamide" group (referring to the group -NR yC(O)R z), wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may be substituted as appropriate.

[0026] "Amino" refers to the group -NR yR z, where R y and R z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl or heteroaryl; each of which may be substituted as appropriate.

[0027] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) comprising a fused system. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, tyrosyl, and anthracene. However, aryl does not in any way encompass or overlap with heteroaryl groups as defined below. If one or more aryl groups are fused with a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused with a heterocyclic group, the resulting ring system is a heterocyclic group.

[0028] "Aminomethoxy" refers to both the "O-aminomethoxy" group (referring to the group -OC(O)NR yR z) and the "N-aminomethoxy" group (referring to the group -NR yC(O)OR z), wherein R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may be substituted as appropriate.

[0029] "Carboxy ester" refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may be substituted as defined herein.

[0030] "Cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl group having a single ring or multiple rings including fused, bridged, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclogroup having at least one double bond). As used herein, cycloalkyl groups have 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0031] "Imine" refers to the group -C(NR)R, where each R is an alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl, or heteroaryl group; each of which may be substituted as defined herein.

[0032] "Halogen" or "halogen group" includes fluorine, chlorine, bromine, and iodine. "Halogen alkyl" refers to a non-branched or branched alkyl group as defined above, wherein one or more hydrogen atoms are substituted with a halogen. For example, in cases where a group is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihalogen and trihalogen alkyl refer to alkyl groups substituted with two ("di") or three ("tri") halogen groups, which may (but are not required to) be the same halogen. Examples of halogen alkyl groups include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0033] "Heteroalkyl" means an alkyl group in which one or more of the carbon atoms (and any associated hydrogen atoms) are independently substituted with the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon atoms and heteroatoms. For example, one, two, or three carbon atoms may be independently substituted with the same or different heteroatom groups. Heteroatom groups include (but are not limited to) -NR-, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic, each of which may be substituted as appropriate. 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 substituted as appropriate. As used herein, heteroalkyl groups include 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, wherein one or more cyclic heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 cyclic carbon atoms (i.e., C1-20 heteroaryl), 3 to 12 cyclic carbon atoms (i.e., C3-12 heteroaryl), or 3 to 8 carbon cyclic atoms (i.e., C3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatom, independently selected from nitrogen, oxygen, and sulfur. Non-limiting examples of heteroaryl groups include (but are not limited to) aziryl, acridineyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodiazolyl, benzofuranyl, benzooxazolyl, benzothiadiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodialkyl, benzonaphthofuranyl, benzoxazolyl, and benzodiazolyl. Benzopiraniyl, Benzopiranione, Benzopirofurone, Benzopirethenyl (Benzopironthio), Benzopirazolyl, Benz[4,6]imidazo[1,2-a]pyridyl, Carbazole, Alpineyl, Dibenzofuranyl, Dibenzothienyl, Furanyl, Furanone, Isothiazolyl, Imidazolyl, Indazole, Indoleyl, Isoyindoleyl, Indoleline, Isoyindoleline, Isoquinolyl, Indoleyl alkyl, isozolyl, naphthidyl, acediazole, 2-side oxy-nitropyridine, acezolyl, oxygen 1-O-pyridyl, 1-O-pyrimidinyl, 1-O-pyridylpyridyl, 1-O-pyridylpyridyl, 1-O-pyridylpyridyl, 1-phenyl-1H-pyrrolyl, benzylayl, benzylaylthiayl, benzylaylpyridyl, phthalylpyridyl, pteridinyl, purine, pyrrolyl, pyrazolyl, pyridyl, pyridyl, pyridylpyridyl, pyrimidinyl, pyridylpyridyl, quinazolinyl, quinolinyl, quinolinyl Pyridyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazolyl, and phenylthio. Fused heteroaryl rings can be bonded via any ring in the fused system. Any aromatic ring having one or more fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of its connection to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not encompass or overlap with aryl groups as defined above.

[0035] "Heterocyclic group" refers to a saturated or unsaturated cycloalkyl group having one or more independent cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heterocyclic alkenyl groups (i.e., heterocyclic groups having at least one double bond), bridged heterocyclic groups, fused heterocyclic groups, and spirocyclic groups. A heterocyclic group can be a single ring or multiple rings, wherein the multiple rings can be fused, bridged, or spirocoupled. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of its connection (i.e., whether it is bonded via carbon atoms or heteroatoms). Furthermore, the term heterocyclic group is intended to cover any non-aromatic ring containing at least one heteroatom that can be fused with an aryl or heteroaryl ring, regardless of its connection to the rest of the molecule. As used herein, a heterocyclic group has 2 to 20 cyclic carbon atoms (i.e., C2-20 heterocyclic group), 2 to 12 cyclic carbon atoms (i.e., C2-12 heterocyclic group), 2 to 10 cyclic carbon atoms (i.e., C2-10 heterocyclic group), 2 to 8 cyclic carbon atoms (i.e., C2-8 heterocyclic group), 3 to 12 cyclic carbon atoms (i.e., C3-12 heterocyclic group), 3 to 8 cyclic carbon atoms (i.e., C3-8 heterocyclic group), or 3 to 6 cyclic carbon atoms (i.e., C3-6 heterocyclic group); 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 heteroatomum, independently selected from nitrogen, sulfur, or oxygen, and, where appropriate, one or more side oxygen groups. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperidinyl, oxadiol, diazonyl, acrylyl, and urinyl. As used herein, the term "bridged heterocyclic group" refers to a four- to ten-membered ring moiety having at least one heteroatom at two non-adjacent atoms of the heterocyclic group and one or more (e.g., one or two) four- to ten-membered ring moieties having at least one heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein, bridged heterocyclic groups include bicyclic and tricyclic ring systems. As also used herein, the term "spirocyclic group" refers to a ring system in which a three- to ten-membered heterocyclic group has one or more additional rings, wherein one or more additional rings are three- to ten-membered cycloalkyl groups or three- to ten-membered heterocyclic groups, wherein each atom of one or more additional rings is also an atom of a three- to ten-membered heterocyclic group. Examples of spiroheterocyclic rings include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. Examples of fused heterocyclic rings include (but are not limited to) 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridyl, indololinyl, and isoindololinyl (e.g., 2-methylisoquinolin-1(2H)-one), wherein the heterocyclic group may be linked via any ring bond of the fused system.

[0036] "Side oxygen group" refers to the group (=O) or (O).

[0037] "Sulfoyl" refers to the group -S(O)2R, where R is an alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl group. Examples of sulfonyl groups are methanesulfonyl, ethanesulfonyl, benzenesulfonyl, and toluenesulfonyl.

[0038] "alkylsulfonyl" refers to the group -S(O)2R, where R is an alkyl group.

[0039] "alkylsulfinyl" refers to the group -S(O)R, where R is an alkyl group.

[0040] "Thiol" refers to the group -SR, where R is alkyl, haloalkyl, heterocyclic, cycloalkyl, heteroaryl, or aryl.

[0041] Certain commonly used alternative chemical names may be used. For example, divalent groups such as "alkyl" and "aryl" may also be referred to as "alkylene" and "arylenyl," respectively. Furthermore, unless otherwise explicitly indicated, in cases where the combination of groups is referred to herein as a part (e.g., arylalkyl), the last group mentioned contains atoms that are connected to the rest of the molecule by that part.

[0042] The terms "depending on" or "depending on" mean that the event or situation described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. Furthermore, the term "depending on substitution" means that any one or more hydrogen atoms on a specified atom or group may be partially substituted with hydrogen atoms or may not be substituted.

[0043] Some compounds exist as tautomers. These tautomers exist in equilibrium with each other. For example, acetylamine-containing compounds can exist in equilibrium with their imine tautomers. Regardless of the tautomers exhibited or the equilibrium nature between them, those skilled in the art generally understand that a compound contains both its acetylamine and imine tautomers. Therefore, acetylamine-containing compounds should be understood to include their imine tautomers. Similarly, imine-containing compounds should be understood to include their acetylamine tautomers.

[0044] Any formula or structure given herein is intended to represent both the unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure described by the chemical formulas given herein, with the exception that one or more atoms are substituted with atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as (but not limited to) 2H (deuterium, D), 3H (tritium), 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, and 125I. The various isotopically labeled compounds of this invention are, for example, those compounds incorporating radioactive isotopes such as 3H, 13C, and 14C. Such isotopically labeled compounds can be used for metabolic studies; reaction kinetic studies; detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis; or for radiotherapy of patients.

[0045] This invention also includes "deuterated analogues" of Formula I compounds, wherein one to n hydrogen atoms attached to a carbon atom are deuterated, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased metabolic resistance and are therefore suitable for increasing the half-life of any Formula I compound when administered to mammals (specifically, humans). See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in this art, for example by using starting materials in which one or more hydrogen atoms have been deuterated.

[0046] The deuterium-labeled or substituted therapeutic compounds of this invention may possess modified DMPK (drug metabolism and pharmacokinetics) properties, which are related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (such as deuterium) can yield certain therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18F-labeled compounds are suitable for PET or SPECT studies. The isotopically labeled compounds of this invention and their prodrugs can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by performing the procedures disclosed in the examples and preparations described below. It should be understood that, in this context, deuterium is considered as a substituent in compounds of formula I.

[0047] The concentration of such heavier isotopes (especially deuterium) can be defined by an isotope enrichment factor. In the compounds of this invention, any atom not specifically designated as a particular isotope means any stable isotope of that atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen," it should be understood that that position has hydrogen in its natural abundance isotopic composition. Therefore, in the compounds of this invention, any atom specifically designated as deuterium (D) means deuterium. []

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

[0049] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and precursors of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials suitable for the preparation of pharmaceutical compositions for veterinary or human medical use.

[0050] The term "medically acceptable salt" for the given compounds refers to a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. "Medically acceptable salt" or "physiologically acceptable salt" includes, for example, salts formed with inorganic acids and salts formed with organic acids. Furthermore, if the compound described herein is obtained as an acid addition salt, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, specifically a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid, according to the known procedure for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include salts of acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. For example, salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include (but are not limited to) salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH₂(alkyl)); dialkylamines (i.e., HN(alkyl)₂); trialkylamines (i.e., N(alkyl)₃); substituted alkylamines (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); alkenylamines (i.e., NH₂(alkenyl)); dienylamines (i.e., HN(alkenyl)₂); trienylamines (i.e., N(alkenyl)₃); substituted alkenylamines (i.e., NH₂(substituted alkenyl)); di(substituted alkenyl)amines (i.e., HN(substituted alkenyl)). 2); tri(substituted alkenyl)amines (i.e., N(substituted alkenyl) 3); monocycloalkylamines, dicycloalkylamines, or tricycloalkylamines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂, N(cycloalkyl)₃); monoarylamines, diarylamines, or triarylamines (i.e., NH₂(aryl), HN(aryl)₂, N(aryl)₃); or mixtures of amines, etc. Specific examples of suitable amines, by way of example only, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperidine, piperidine, α-porphyrin, N-ethylpiperidine, and the like.

[0051] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the substitution does not exceed the normal valence of the specified atom. One or more substituents include (but are not limited to) alkyl, alkenyl, alkynyl, alkoxy, acetyl, amino, acetamyl, formamidinyl, aryl, azide, aminomethoxy, carboxyl, carboxyl ester, cyano, guanidinyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazyl, imino, serooxy, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Polymers or similar infinite structures obtained by defining substituents by an unlimited number of additional substituents (e.g., a substituted aryl group having a substituted alkyl group, which itself is substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended to be included herein. Unless otherwise stated, the maximum number of successive substitutions in the compounds described herein is three. For example, successive substitution of a substituted aryl group with two other substituted aryl groups is limited to a ((substituted aryl) substituted) aryl group. 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 modify chemical groups, the term "substituted" may describe other chemical groups as defined herein. Unless otherwise specified, in cases where a group is described as substituted as appropriate, any substituent in 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, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. In other embodiments, the one or more substituents may be further substituted with a halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is substituted. In other embodiments, the substituents may be further substituted with a halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group, each of which is unsubstituted.

[0052] In some embodiments, as used herein, the phrase "one or more" refers to one to five. In some embodiments, as used herein, the phrase "one or more" refers to one to three.

[0053] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutical acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, and the like. The use of such media and agents in pharmaceutically active substances is well known in the art. Unless any known media or agent is incompatible with the active ingredient, its use in therapeutic compositions is covered. Additional active ingredients may also be incorporated into the composition.

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

[0055] [, compound , ] [, , ] This document provides compounds that act as inhibitors of glycolate oxidase. In some embodiments, this document provides a compound of formula I: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is either N or CH; R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently -C≡C- or absent; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; Each Rb is independently hydrogen or C1-4 alkyl.

[0056] In some embodiments, when A is N, at least one of the following is true: 1) R1 is a fused tricyclic ring, substituted with one to three R3s, depending on the case; 2) R1 is a fused bicyclic compound substituted with at least one of the following R3 groups: cyano, -C≡CC 1-9 alkyl, -C 1-9 alkyl substituted with one to three R6 groups, -C≡CC 1-4 haloalkyl, -C≡C-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OC 1-4 alkyl, -O-phenyl, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is further substituted with one to three R6 groups as appropriate, and each L is independently -C≡C- or absent; 3) R1 is a substituted monocyclic ring substituted with at least one of the following R3: i) Cyano, -C≡CC 1-9 alkyl, -C≡CC 1-4 haloalkyl, -C≡C-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -C≡C-aryl, -C≡C-heteroaryl or -C≡C-heterocyclic, wherein each is further substituted with one to three R 6 groups as appropriate; ii) Monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclic, wherein each is further substituted with one to three cyano, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl groups, wherein each is substituted with one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl groups, as appropriate; iii) as appropriate, fused aryl, fused heteroaryl, or fused heterocyclic groups, wherein each is further substituted by one to three R6 substitutions as appropriate; or iv) Formula -L1-L2 substituent, wherein L1 is aryl, heteroaryl, or heterocyclic, each substituted with one to three R6 groups as appropriate; and L2 is phenyl, heterocyclic, or heteroaryl, each substituted with one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl groups as appropriate; or 4) R2 is -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4, or heteroaryl substituted with one to three R5, as appropriate.

[0057] In some embodiments, when A is CH, R1 is not a 10-membered heteroaryl group substituted with methoxy and methyl groups; or R1 is not a C6 aryl group substituted with 1 to 3 substituents independently selected from the following: cyano, halo, C1-4 alkyl, -OR7, C1-4 haloalkyl, and NR7R8, wherein R7 and R8 are each independently hydrogen or C1-4 alkyl; or R1 is not an unsubstituted C10 aryl group; or R1 is not an unsubstituted heterocyclic group.

[0058] In one state sample, a compound having the structure of formula I is provided: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is either N or CH; R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl group substituted with one to three R4 groups, or heteroaryl group substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently a single bond or -C≡C-; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2 group, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group.

[0059] In some embodiments, when R1 is phenyl, then R3 is aryl or heteroaryl, each of which is substituted by one to three R6 as appropriate.

[0060] In some embodiments, when R1 is a heteroaryl group, then R2 is not an unsubstituted C1-6 alkyl group.

[0061] In some embodiments, A is either N or CH; R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl group substituted with one to three R4 groups, or heteroaryl group substituted with one to three R5 groups, depending on the case; Each R 3 is independently a halogroup, -LC 1-9 alkyl, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-5 to 6-membered heteroaryl or -L-5 to 6-membered heterocyclic group, wherein each is substituted by one to three R 6 groups as appropriate, and each L is independently a monobonded or -C≡C-. Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2 group, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; and R7 and R8 are each independently hydrogen or C1-4 alkyl, or R7 and R8 together with the nitrogen atom to which they are attached form -(CH2)2-O-(CH2)2-.

[0062] Also provided is a compound of formula IIa: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl group substituted with one to three R4 groups, or heteroaryl group substituted with one to three R5 groups, depending on the case; Each R3 is independently cyano, halo, C1-9 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, -NR7R8, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, aryl, heteroaryl, or heterocyclic, wherein each is substituted by one to three R6 as appropriate, and each L is independently a single bond or -C≡C-; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2 group, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group.

[0063] In some embodiments, a compound of formula IIa is provided: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently -C≡C- or absent; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; Each Rb is independently hydrogen or C1-4 alkyl.

[0064] In some embodiments, for compounds of formula IIa, at least one of the following is true: 1) R1 is a fused tricyclic ring, substituted with one to three R3s, depending on the case; 2) R1 is a fused bicyclic compound substituted with at least one of the following R3 groups: cyano, -C≡CC 1-9 alkyl, -C 1-9 alkyl substituted with one to three R6 groups, -C≡CC 1-4 haloalkyl, -C≡C-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OC 1-4 alkyl, -O-phenyl, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is further substituted with one to three R6 groups as appropriate, and each L is independently -C≡C- or absent; 3) R1 is a substituted monocyclic ring substituted with at least one of the following R3: i) Cyano, -C≡CC 1-9 alkyl, -C≡CC 1-4 haloalkyl, -C≡C-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -C≡C-aryl, -C≡C-heteroaryl or -C≡C-heterocyclic, wherein each is further substituted with one to three R 6 groups as appropriate; ii) Monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclic, wherein each is further substituted with one to three cyano, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl groups, wherein each is substituted with one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl groups, as appropriate; iii) as appropriate, fused aryl, fused heteroaryl, or fused heterocyclic groups, wherein each is further substituted by one to three R6 substitutions as appropriate; or iv) Formula -L1-L2 substituent, wherein L1 is aryl, heteroaryl, or heterocyclic, each substituted with one to three R6 groups as appropriate; and L2 is phenyl, heterocyclic, or heteroaryl, each substituted with one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl groups as appropriate; or 4) R2 is -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4, or heteroaryl substituted with one to three R5, as appropriate.

[0065] Also provided is a compound of formula IIb: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently -C≡C- or absent; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; Each Rb is independently hydrogen or C1-4 alkyl.

[0066] In some embodiments, for compounds of formula IIb, R1 is not a 10-membered heteroaryl group substituted with methoxy and methyl; or R1 is not a C6 aryl group substituted with 1 to 3 substituents independently selected from: cyano, halo, C1-4 alkyl, -OR7, C1-4 haloalkyl and NR7R8, wherein R7 and R8 are each independently hydrogen or C1-4 alkyl; or R1 is not an unsubstituted C10 aryl group; or R1 is not an unsubstituted heterocyclic group.

[0067] In some embodiments, A is N. In some embodiments, A is CH.

[0068] In some embodiments, R1 is an aryl group substituted with one to three R3s, depending on the situation.

[0069] In some embodiments, R1 is a heteroaryl group substituted with one to three R3s, depending on the situation.

[0070] In some embodiments, R1 is a heterocyclic group substituted with one to three R3s, depending on the situation.

[0071] In some embodiments, R1 is a cycloalkyl group substituted with one to three R3s, depending on the case.

[0072] In some embodiments, R1 is Each n is independently 1, 2 or 3, and Y is CR 8R 9, C(O), O or NR 10; each of R 8 and R 9 is independently hydrogen, halogroup or C 1-4 alkyl; and R 10 is hydrogen or C 1-4 alkyl.

[0073] In some embodiments, L is a one-key (i.e., non-existent). In some embodiments, L is -C≡C-.

[0074] In some embodiments, each of R8 and R9 is a halogen group. In some embodiments, each of R8 and R9 is fluorine.

[0075] In some embodiments, each of R8 and R9 is hydrogen.

[0076] In some embodiments, R2 is hydrogen.

[0077] In some embodiments, R3 is a halogen, C1-9 alkyl, C1-4 haloalkyl, or -OR7.

[0078] In some embodiments, at least one R3 is a halogroup, a C1-9 alkyl group, or -OR7. In some embodiments, R3 is a halogroup, a C1-9 alkyl group, or -OR7.

[0079] In some embodiments, at least one R3 is fluorine, chlorine, bromine, methyl, tributyl, methoxy, or phenoxy.

[0080] In some embodiments, R3 is an aryl group substituted with one to three R6, depending on the situation.

[0081] In some embodiments, R3 is .

[0082] In some embodiments, at least one R3 is an aryl group substituted with a phenyl, heterocyclic, or heteroaryl group.

[0083] In some embodiments, at least one R3 is .

[0084] In some embodiments, R3 is .

[0085] In some embodiments, at least one R3 is a heteroaryl-substituted aryl group, which is substituted with a C1-4 alkyl group, a -C(O)OH group, or a C1-4 haloalkyl group.

[0086] In some embodiments, at least one R3 is .

[0087] In some embodiments, R3 is .

[0088] In some embodiments, at least one R3 is a heterocyclic group substituted with one to three R6, depending on the specific embodiment.

[0089] In some embodiments, at least one R3 is In some embodiments, R3 is .

[0090] In some embodiments, at least one R3 is a heteroaryl group substituted with one to three R6 groups, depending on the specific embodiment.

[0091] In some embodiments, at least one R3 is In some embodiments, R3 is .

[0092] In some embodiments, R2 is hydrogen, a C1-6 alkyl group substituted with one to three R4s as appropriate, or a cycloalkyl group; each R4 is independently -OC(O)Ra, -OC(O)ORa, -OP(O)(ORb)2 or a monocyclic heterocyclic group; the limitation is that only one R4 is a heterocyclic group; each Ra is independently a C1-6 alkyl group substituted with -NH2 or -OP(O)(ORb)2 as appropriate; and Rb is hydrogen.

[0093] In some embodiments, this document provides a compound of formula III: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R3 is independently aryl, heteroaryl, or heterocyclic, wherein each is substituted by one to three R6 groups, depending on the situation; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl, phenyl, or pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; and Each Rb is independently hydrogen or C1-4 alkyl.

[0094] In some embodiments, this document provides a compound of formula IV: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein: R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; and Each Rb is independently hydrogen or C1-4 alkyl.

[0095] In some embodiments, R2 is hydrogen, a C1-6 alkyl group substituted with one to three R4 substituted alkyl groups, or a cycloalkyl group. In some embodiments, R2 is hydrogen or a C1-6 alkyl group substituted with one R4 substituted alkyl group. In some embodiments, R2 is hydrogen. In some embodiments, R2 is a C1-6 alkyl group substituted with one to three R4 substituted alkyl groups. In some embodiments, R2 is a C1-6 alkyl group. In some embodiments, R2 is a C1-4 alkyl group.

[0096] In some embodiments, R2 is hydrogen, a C1-6 alkyl group substituted with one to three R4s as appropriate, or a cycloalkyl group; each R4 is independently -OC1-6 alkyl, -OC(O)Ra, -OC(O)ORa, -OP(O)(ORb)2 or a monocyclic heterocyclic group; each Ra is independently a C1-6 alkyl group substituted with -NH2 or -OP(O)(ORb)2 as appropriate; and Rb is hydrogen.

[0097] In some embodiments, each R4 is independently a -OC1-6 alkyl, -OC(O)Ra, -OC(O)ORa, -OP(O)(ORb)2 or a monocyclic heterocyclic group; wherein each Ra is independently a C1-6 alkyl substituted with -NH2 or -OP(O)(ORb)2 as appropriate, and Rb is hydrogen.

[0098] In some embodiments, each R4 is independently -OC(O)Ra, -OC(O)ORa, -OP(O)(ORb)2 or a monocyclic heterocyclic group; wherein each Ra is independently a C1-6 alkyl group substituted with -NH2 or -OP(O)(ORb)2 as appropriate, and Rb is hydrogen.

[0099] In some embodiments, a compound selected from Table 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, is provided. In some embodiments, the compound is selected from the compounds in Table 1: [surface] [1] []

[0100] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is provided. In some embodiments, the compound is selected from:

[0101] In some embodiments, a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is provided. In some embodiments, the compound is selected from: , R2 is as defined in this paper.

[0102] In some embodiments, R2 is a C1-6 alkyl group substituted with one to three R4 groups, depending on the specific embodiment. In some embodiments, R2 is a C1-6 alkyl group. In some embodiments, R2 is an ethyl group.

[0103] In some embodiments, the compounds are selected from: .

[0104] Generally, the specific compounds illustrated herein are named using ChemBioDraw Ultra. However, it should be understood that other names may be used to identify compounds with the same structure. Specifically, compounds may also be named using other nomenclature systems and symbols recognized in chemical techniques, including, for example, the Chemical Abstract Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). Other compounds or groups may be named using common names or systematic or unsystematic names.

[0105] In some embodiments, optical isomers, racemates, or other mixtures of the compounds described herein or their pharmaceutically acceptable salts or mixtures are provided. In such cases, a single enantiomer or diastereomer (i.e., the optically active form) may be obtained by asymmetric synthesis or by resolution. Resolution may be achieved, for example, by known methods, such as crystallization in the presence of a resolving agent, or by chromatography using, for example, a palmitic high-performance liquid chromatography (HPLC) column.

[0106] The compositions provided herein, including the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures, may include 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 expressly included herein, as each isomer is specifically and individually enumerated.

[0107] In some embodiments, chelates, non-covalent complexes, and mixtures thereof of the compounds described herein or their pharmaceutically acceptable salts are also provided. A "chelate" is formed by coordinating a compound to a metal ion at two (or more) sites. A "non-covalent complex" is formed by the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexes can occur via van der Waals interactions, hydrogen bonding, and electrostatic interactions (also known as ionic bonding).

[0108] In some embodiments, a prodrug of the compound described herein is provided. A "prodrug" means any compound that, when administered to a biological system, produces a drug substance or active ingredient through spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. Therefore, a prodrug is a covalently modified analogue or potential form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, diol moieties, and the like.

[0109] In some embodiments, a compound of formula I or IIa is provided, wherein R1 is ; Each R12 is independently hydrogen, C1-9 alkyl, C2-6 alkenyl, C2-6 ynyl, C3-15 cycloalkyl, aryl, heteroaryl, or heterocyclic; wherein any alkyl, alkenyl, ynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group is substituted by one to four Z1b groups as appropriate; and Each Z 1b is independently an alkyl group, thionyl group, hydroxyl group, halogen group, -NO 2, -N 3, cyano group, C1-9 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-15 cycloalkyl group, C1-8 haloalkyl group, aryl group, heteroaryl group, heterocyclic group, -O (C1-9 alkyl group), -O (C2-6 alkenyl group), -O (C2-6 alkynyl group), -O (C3-15 cycloalkyl group), -O (C1-8 haloalkyl group), -O (aryl group), -O (heteroaryl group), -O (heterocyclic group), -NH 2, -NH (C1-9 alkyl group), -NH (C2-6 alkenyl group), -NH (C2-6 alkynyl group), -NH (C3-15 cycloalkyl group), -NH (C1-8 haloalkyl group), -NH (aryl group), -NH (heteroaryl group), -NH (heterocyclic group), -N (C 1-9 alkyl) 2, -N(C 3-15 cycloalkyl) 2, -N(C 2-6 alkenyl) 2, -N(C 2-6 ynyl) 2, -N(C 3-15 cycloalkyl) 2, -N(C 1-8 haloalkyl) 2, -N(aryl) 2, -N(heteroaryl) 2, -N(heterocyclic) 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 ynyl), -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)(heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6 alkenyl), -C(O)(C 2-6 ynyl), -C(O)(C 3-15 cycloalkyl), -C(O)(C 1-8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclic), -C(O)O(C 1-9 alkyl), -C(O)O(C 2-6 alkenyl), -C(O)O(C 2-6 ynyl), -C(O)O(C 3-15 cycloalkyl), -C(O)O(C 1-8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclic), -C(O)NH 2, -C(O)NH(C 1-9 alkyl), -C(O)NH(C -2-6 alkenyl), -C(O)NH (C 2-6 ynyl), -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 (heterocyclic), -C(O)N (C 1-9 alkyl), -C(O)N (C 3-15 cycloalkyl), -C(O)N (C 2-6 alkenyl), -C(O)N (C 2-6 ynyl)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 (heterocyclic) 2. -NHC(O) (C 1-9 alkyl), -NHC(O) (C 2-6 alkenyl), -NHC(O) (C 2-6 ynyl), -NHC(O) (C 3-15 cycloalkyl), -NHC(O) (C 1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C 1-9 alkyl), -NHC(O)O (C 2-6 alkenyl), -NHC(O)O (C 2-6 ynyl), -NHC(O)O (C 2-6 ynyl) -3-15 cycloalkyl), -NHC(O)O (C 1-8 haloalkyl), -NHC(O)O (aryl), -NHC(O)O (heteroaryl), -NHC(O)O (heterocyclic), -NHC(O)NH (C 1-9 alkyl), -NHC(O)NH (C 2-6 alkenyl), -NHC(O)NH (C 2-6 alkynyl), -NHC(O)NH (C 3-15 cycloalkyl), -NHC(O)NH (C 1-8 haloalkyl), -NHC(O)NH (aryl), -NHC(O)NH (heteroaryl), -NHC(O)NH (heterocyclic), -SH, -S (C 1-9 alkyl), -S (C 2-6 alkenyl), -S (C 2-6 alkynyl), -S (C 3-15 cycloalkyl), -S (C 1-8 haloalkyl), -S (aryl), -S (heteroaryl), -S (heterocyclic), -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 ynyl), -S(O) (C 3-15 cycloalkyl), -S(O) (C 1-8 haloalkyl), -S(O) (aryl), -S(O) (heteroaryl), -S(O) (heterocyclic), -S(O) 2(C 1-9 alkyl), -S(O) 2(C 2-6 alkenyl), -S(O) 2(C 2-6 ynyl), -S(O) 2(C -3-15 cycloalkyl), -S(O)2 (C1-8 haloalkyl), -S(O)2 (aryl), -S(O)2 (heteroaryl), -S(O)2 (heterocyclic), -S(O)2NH (C1-9 alkyl) or -S(O)2N (C1-9 alkyl)2; Any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group may be derived from one to four halogen groups, C1-9 alkyl, C1-8 haloalkyl, -OH, -NH2, -NH (C1-9 alkyl), -NH (C3-15 cycloalkyl), -NH (C1-8 haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclic), -N (C1-9 alkyl), -N (C3-15 cycloalkyl), -NHC(O) (C3-15 cycloalkyl), -NHC(O) (C1-8 haloalkyl), -NHC(O) (aryl), -NHC(O) (heteroaryl), -NHC(O) (heterocyclic), -NHC(O)O (C1-9 alkyl), -NHC(O)O (C2-6 ynyl), -NHC(O)O (C3-15 cyclo ... 1-8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclic), -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(heterocyclic), -S(O) 2NH(C 1-9 alkyl), -S(O) 2N(C 1-9 alkyl), -O(C 3-15 cycloalkyl), -O(C 1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclic) or -O(C 1-9 alkyl) substitution.

[0110] In some embodiments, a compound of formula I or any sub-formula provided herein is provided, wherein R2 is .

[0111] Such substituents also include all individual stereoisomers and mixtures thereof, including (but not limited to) diametrical relationships at the phosphorus atom, such as those shown in the illustrative section above.

[0112] This article also provides in vivo metabolites of the compounds described herein. These products are primarily attributed to enzymatic processes that can occur, for example, by oxidation, reduction, hydrolysis, amination, esterification, and similar reactions of the administered compounds.

[0113] [, Therapeutic uses of compounds , ] [, , ] "Treatment / treating" is a method used to obtain a beneficial or desired outcome (including clinical outcomes). A beneficial or desired clinical outcome may include one or more of the following: a) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or alleviating the severity of the disease or condition); b) slowing or stopping the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., cancer metastasis)); and / or c) alleviating the disease, that is, the relief of clinical symptoms (e.g., improving the condition, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving quality of life, and / or prolonging survival).

[0114] "Prevention" means any treatment of a disease or condition that prevents the development of clinical symptoms. In some embodiments, compounds may be administered to individuals (including humans) who are at risk of a family history of the disease or condition or who have a family history of the disease or condition. Primary type 1 hyperoxaluria can lead to a need for kidney transplantation. Remission is likely to occur after transplantation. In some embodiments, the compounds disclosed herein are administered to the patient after transplantation for the purpose of preventing remission.

[0115] "Individual" means an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein are applicable to human therapeutics and / or veterinary applications. In some embodiments, the individual is a mammal. In one embodiment, the individual is a human.

[0116] The term "therapeutic effective amount" or "effective amount" for the compound described herein or its pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs means an amount sufficient, when administered to an individual, to achieve therapeutic effect and provide therapeutic benefits (such as improvement of symptoms or slowing of disease progression). For example, a therapeutic effective amount may be an amount sufficient to reduce symptoms of a disease or condition that responds to inhibition of glycolate oxidase activity. Therapeutic effective amounts may vary depending on the individual being treated and the disease or condition, the individual's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by someone generally skilled in this art.

[0117] The term "inhibition" indicates a reduction in the baseline activity of a biological activity or process. "Inhibition of glycolate oxidase activity" or variations thereof refers to a reduction in glycolate oxidase activity, as a direct or indirect response to the presence of the compound of this application relative to the activity of glycolate oxidase in the absence of the compound described herein. "Inhibition of glycolate oxidase" refers to a reduction in glycolate oxidase enzyme activity, as a direct or indirect response to the activity of glycolate oxidase in the absence of the compound described herein. In some embodiments, inhibition of glycolate oxidase enzymatic activity may be compared prior to treatment in the same individual or in other untreated individuals.

[0118] The methods described herein can be applied to in vivo or in vitro cell populations. "In vivo" means within a living individual, such as in an animal or human. In this context, the methods described herein can be used therapeutically within an individual. "In vitro" means outside a living individual. Examples of in vitro cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained using methods well known in this art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and their biopsies. In this context, the compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal timing and / or dose of glycolate oxidase inhibitors for a given indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental or clinical purposes to develop in vivo treatment protocols. Other in vitro applications that the compounds and compositions described herein may be suitable for are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine their safety or tolerable doses in humans or non-human individuals. Such properties may be examined using methods generally known to those skilled in the art.

[0119] The compounds disclosed herein are suitable for the treatment, prevention, diagnosis, or monitoring of glycolate oxidase-mediated diseases or conditions. Non-limiting examples of glycolate oxidase-mediated diseases or conditions include (but are not limited to) nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, type 1 hyperoxaluria, Bird's disease, glycolic aciduria, end-stage renal disease (ESRD), renal failure, failed kidney transplantation, and type 2 diabetes.

[0120] In some embodiments, the compounds disclosed herein are suitable for treating, preventing, diagnosing, or monitoring diseases or conditions mediated by oxalate, calcium oxalate, or glycolate oxidase. In some embodiments, the diseases or conditions are nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, type 1 hyperoxaluria, Burd's disease, glycolic aciduria, end-stage renal disease (ESRD), renal failure, failed kidney transplantation, and type 2 diabetes.

[0121] In other embodiments, methods are provided for alleviating symptoms of a disease or condition mediated by glycolate oxidase. In some embodiments, the method includes identifying a mammal having symptoms of a disease or condition mediated by glycolate oxidase and providing the mammal with a quantity of a compound as described herein that effectively improves the symptoms (i.e., reduces the severity of the symptoms).

[0122] In other embodiments, methods are provided for alleviating symptoms of a disease or condition mediated by oxalate, calcium oxalate, or glycolate oxidase. In some embodiments, the method includes identifying a mammal having symptoms of a disease or condition mediated by oxalate, calcium oxalate, or glycolate oxidase, and providing the mammal with a quantity of a compound as described herein that effectively improves the symptoms (i.e., reduces the severity of the symptoms).

[0123] In some embodiments, the disease or condition mediated by glycolate oxidase is kidney stone formation. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is kidney stone formation. In a particular embodiment, kidney stone formation is recurrent. In a particular embodiment, kidney stone formation is associated with primary type 1 hyperoxaluria.

[0124] In some embodiments, a disease or condition mediated by glycolate oxidase is kidney failure, which includes failure of one kidney or both kidneys. In some embodiments, a disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is kidney failure. In some embodiments, kidney failure is failure of one kidney or both kidneys.

[0125] In some embodiments, the disease or condition being prevented is kidney transplant failure.

[0126] In some embodiments, diseases or conditions mediated by glycolate oxidase are diabetes mellitus, including type 1 and type 2 diabetes mellitus, gestational diabetes mellitus, prediabetes mellitus, insulin resistance, metabolic syndrome, abnormal fasting glucose, and impaired glucose tolerance. In some embodiments, diseases or conditions mediated by oxalate or calcium oxalate or glycolate oxidase are diabetes mellitus. In some embodiments, diabetes mellitus is type 1 and type 2 diabetes mellitus, gestational diabetes mellitus, prediabetes mellitus, insulin resistance, metabolic syndrome, abnormal fasting glucose, and impaired glucose tolerance. Type 1 diabetes mellitus is also known as insulin-dependent diabetes mellitus (IDDM). Type 2 diabetes mellitus is also known as non-insulin-dependent diabetes mellitus (NIDDM).

[0127] 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.

[0128] Criteria applicable to assessing disease activity in individuals with primary type 1 hyperoxaluria can be found in Brooks et al. (2016) Am. J. Nephrol. 43, 4:293-303. Urine oxalate and calcium levels can be monitored.

[0129] The treatment methods disclosed in this invention can also be applied at any point in the disease process. In some embodiments, the method is applied to an individual with primary type 1 hyperoxaluria during a remission period (i.e., after kidney transplantation, when there is no active disease). In such embodiments, the method of the invention provides benefit by prolonging the remission period (e.g., prolonging the period without active disease) or by preventing, reducing, or delaying the onset of active disease. An example would be an increase in the time between kidney stone events. In other embodiments, the method can be applied to an individual with primary type 1 hyperoxaluria during a period of active disease. Such methods provide benefit by reducing the duration of the active disease period, reducing or improving one or more symptoms of primary type 1 hyperoxaluria, or treating primary type 1 hyperoxaluria. Such improvement could be a reduction in the size, number, or frequency of kidney stones.

[0130] In clinical practice, measures used to assess the efficacy of treatment for primary type 1 hyperoxaluria have been described and include, for example, the following: symptom control; calcium oxalate concentration in body fluids; renal function analysis; and improvement in quality of life.

[0131] In some embodiments, this document provides a method for treating primary type 1 hyperoxaluria, comprising administering to a patient in need a therapeutically effective amount of a compound as described herein, or a pharmaceutical composition as described herein, or a compound of formula I: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is either N or CH; R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently -C≡C- or absent; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; and Each Rb is independently hydrogen or C1-4 alkyl.

[0132] In some embodiments, when R1 is phenyl, R3 is aryl or heteroaryl, each of which is substituted with one to three R6 as appropriate; and when R1 is heteroaryl, R2 is not an unsubstituted C1-6 alkyl.

[0133] In some embodiments, this document provides a method for treating recurrent kidney stone formation, comprising administering to a patient in need a therapeutically effective amount of a compound as described herein, a pharmaceutical composition as described herein, or a compound of formula I: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is either N or CH; R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently -C≡C- or absent; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; and Each Rb is independently hydrogen or C1-4 alkyl.

[0134] In some embodiments, when R1 is phenyl, R3 is aryl or heteroaryl, each of which is substituted with one to three R6 as appropriate; and when R1 is heteroaryl, R2 is not an unsubstituted C1-6 alkyl.

[0135] In some embodiments, this document provides a method for inhibiting the production of glyoxylate and / or oxalate and / or inhibiting glycolate oxidase (GO), comprising administering to a patient in need a therapeutically effective amount of a compound as described herein, a pharmaceutical composition as described herein, or a compound of formula I: Or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein A is either N or CH; R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently -C≡C- or absent; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; and Each Rb is independently hydrogen or C1-4 alkyl.

[0136] In some embodiments, when R1 is phenyl, R3 is aryl or heteroaryl, each of which is substituted with one to three R6 as appropriate; and when R1 is heteroaryl, R2 is not an unsubstituted C1-6 alkyl.

[0137] In some embodiments, the use of compounds or pharmaceutical compositions as described herein is for the purpose of controlling or inhibiting the formation of recurrent kidney stones in patients in need of such control.

[0138] In some embodiments, the use of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof is for the purpose of controlling or inhibiting the formation of recurrent kidney stones in patients in need, wherein the compound of formula I: A is either N or CH; R1 is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic group, wherein each is substituted by one to three R3 groups as appropriate; R2 is hydrogen, -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl or cycloalkyl substituted with one to three R4 groups, or heteroaryl substituted with one to three R5 groups, depending on the case; Each R 3 is independently cyano, halo, -LC 1-9 alkyl, -LC 1-4 haloalkyl, -L-OC 1-4 haloalkyl, -NR 7R 8, -C(O)NR 7R 8, -S(O) 2NR 7R 8, -NR 7C(O)R 8, -OR 7, -L-aryl, -L-heteroaryl, or -L-heterocyclic, wherein each is substituted by one to three R 6 as appropriate, and each L is independently -C≡C- or absent; Each R4 is independently a halogroup, hydroxyl group, -OC 1-6 alkyl group, -NH 2, -NHC 1-6 alkyl group, -N(C 1-6 alkyl) 2, -OC(O)R a, -OC(O)OR a, -OP(O)(OR b) 2, or a monocyclic heterocyclic group; wherein each is substituted by one to three R5 groups as appropriate; the limiting condition is that only one R4 group is a heterocyclic group; Each R5 is independently a cyano, halo, C1-4 alkyl, hydroxyl, -OC1-4 alkyl, C1-4 haloalkyl, or -OC1-4 haloalkyl; Each R6 is independently cyano, halo, -C(O)R7, -C(O)OR7, -C(O)NR7R8, -S(O)2NR7R8, -NR7C(O)R8, -OR7, C1-4 alkyl, -OC1-4 alkyl, C1-4 haloalkyl, -OC1-4 haloalkyl, phenyl, heterocyclic, or heteroaryl; wherein each is substituted by one to three C1-4 alkyl, -C(O)OH, or C1-4 haloalkyl as appropriate; R7 and R8 are each independently hydrogen, C1-4 alkyl or phenyl, pyridyl, or R7 and R8 together with the nitrogen atom to which they are attached form a heterocyclic group; Each Ra is independently a C1-6 alkyl group substituted with -NH2, -NHC1-6 alkyl, -N(C1-6 alkyl)2, or -OP(O)(ORb)2, as appropriate; and Each Rb is independently hydrogen or C1-4 alkyl; The limiting conditions are that when R1 is phenyl, then R3 is aryl or heteroaryl, each of which is substituted by one to three R6 as appropriate; and when R1 is heteroaryl, then R2 is not an unsubstituted C1-6 alkyl.

[0139] [, Combination therapy , ] [, , ] In one embodiment, the compounds disclosed herein may be used in combination with one or more additional therapeutic agents or interventions that are in use and / or under development to treat primary type 1 hyperoxaluria. Examples of such therapeutic agents are calcium oxalate crystallization inhibitors, oxalate-degrading enzyme inhibitors, siRNA, oxazyme, and lumasiran. Examples of such therapeutic interventions are high fluid intake, dialysis, and kidney transplantation.

[0140] 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.

[0141] In some embodiments, the methods described herein further include administration of an additional therapeutic agent. In some embodiments, the use as described herein and the additional therapeutic agent are provided. In some embodiments, the additional therapeutic agent is a calcium oxalate crystallization inhibitor, an oxalate-degrading enzyme inhibitor, siRNA, oxalase, rumazir, nedosiran, oxabate, or reloxaliase. In some embodiments, the additional therapeutic agent is an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, eoaggliflozin, rupagliflozin, canagliflozin, tolagliflozin, ioggliflozin, empagliflozin, or potassium citrate.

[0142] [, Set , ] [, , ] This document also provides kits comprising compounds of formula I (or any other formula described herein) or their pharmaceutically acceptable salts, tautomers, prodrugs, or deuterated analogs, and suitable for packaging. In one embodiment, the kit further includes instructions for use. In one embodiment, the kit includes a label and / or instructions for use for the treatment of the indications (including diseases or conditions) described herein.

[0143] This article also provides articles comprising the compounds described herein or their pharmaceutically acceptable salts, tautomers, prodrugs, or deuterated analogs in suitable containers. Containers may be vials, wide-mouth bottles, ampoules, pre-loaded syringes, and intravenous bags.

[0144] [, Pharmaceutical Compositions and Dosage Modes , ] [, , ] The compounds described herein are typically administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions comprising one or more of the compounds described herein or their pharmaceutically acceptable salts, tautomers, prodrugs, or deuterated analogs, and one or more pharmaceutically acceptable mediators selected from carriers, adjuvants, and excipients are also provided herein. Suitable pharmaceutically acceptable mediators may include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in pharmaceutical technology. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th edition (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd edition (edited by GS Banker and CT Rhodes). []

[0145] The pharmaceutical composition may be administered in single or multiple doses. It may be administered by various methods, including, for example, rectally, buccally, intranasally, and transdermally. In some embodiments, the pharmaceutical composition may be administered via intra-arterial injection, intravenously, intraperitoneally, non-intestinal, intramuscular, subcutaneously, orally, topically, or as an inhalant. []

[0146] One mode of administration is non-enteral, such as by injection. Pharmaceutical compositions described herein may be administered by injection in forms including, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical mediators. []

[0147] Oral administration may be another route for administering the compounds described herein. Administration may be via, for example, capsules or enteric-coated tablets. In pharmaceutical compositions comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, the active ingredient is typically diluted with an excipient and / or sealed in a carrier, such as a capsule, sac, paper, or other container. When the excipient acts as a diluent, it may be in the form of a solid, semi-solid, or liquid material, serving as a medium, carrier, or carrier of the active ingredient. Thus, compositions may be in the form of: tablets, pills, powders, lozenges, sacs, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile encapsulated powders. []

[0148] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth gum, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. Formulas may also include: lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methylparaben and propylparaben; sweeteners; and flavoring agents. []

[0149] Compositions comprising at least one compound described herein or its pharmaceutically acceptable salt, tautomer, prodrug, or deuterated analogue can be formulated using procedures known in this art to provide rapid, sustained, or delayed release of the active ingredient after individual dosing. Controlled-release drug delivery systems for oral dosing include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation used in the methods disclosed herein employs a percutaneous delivery device (“patch”). Such percutaneous patches can be used to deliver the compounds described herein in controlled amounts via continuous or discontinuous infusion. The construction and use of percutaneous patches for drug delivery are well known in this art. Such patches can be constructed to deliver drugs continuously, pulsatilely, or on demand.

[0150] For the preparation of solid compositions (such as tablets), the main active ingredient may be mixed with a pharmaceutical excipient to form a solid preformed composition containing a homogeneous mixture of the compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof. When such preformed compositions are homogeneous, the active ingredient is uniformly dispersed throughout the composition, allowing the composition to be readily further divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0151] The tablets or pills of the compounds described herein may be coated or otherwise formulated to provide dosage forms that offer the advantages of prolonged action or protection from the acidic conditions of the stomach. For example, a tablet or pill may comprise an internal dose component and an external dose component, the latter being a coating on the former. The two components may be separated by an enteric coating layer, which prevents disintegration in the stomach and allows the internal component to enter the duodenum intact or delays release. Various materials may be used for such enteric coatings or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0152] Compositions for inhalation or inhalation may include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered via oral or nasal inhalation for local or systemic action. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized using an inert gas. The nebulized solution may be inhaled directly from a nebulizer, or the nebulizer may be connected to a mask holder or an intermittent positive pressure ventilation machine. The solution, suspension, or powder composition may be administered, preferably orally or nasally, from a device for delivering the preparation in a suitable manner.

[0153] [, Dosage , ] [, , ] The specific dosage of the compound of this application for any particular individual will depend on a variety of factors, including the activity of the specific compound used on the individual being treated, age, weight, general health condition, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity of the specific disease. For example, the dosage may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of individual body weight. Doses between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses between 0.5 and 60 mg / kg may be appropriate. Standardization based on individual weight is particularly suitable when adjusting dosages among individuals of wide range of body sizes, such as when using the drug in both children and adults, or when converting an effective dose in non-human individuals, such as dogs, into a dose suitable for human individuals.

[0154] The daily dose can also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of the compound of Formula I can be between about 1 mg and 4,000 mg, between about 2,000 and 4,000 mg / day, between about 1 and 2,000 mg / day, between about 1 and 1,000 mg / day, between about 10 and 500 mg / day, between about 20 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 15 and 150 mg / day.

[0155] When administered orally, the total daily dose for an individual human may be between 1 mg and 1,000 mg, between approximately 1,000 and 2,000 mg / day, between approximately 10 and 500 mg / day, between approximately 50 and 300 mg / day, between approximately 75 and 200 mg / day, or between approximately 100 and 150 mg / day.

[0156] The compounds or compositions thereof of this application may be administered once, twice, three or four times daily in any suitable manner as described above. Furthermore, compound administration or treatment may continue for multiple days; for example, a treatment cycle typically lasts at least 7, 14, or 28 days. Treatment cycles are well known in cancer chemotherapy and are often alternating with rest periods of approximately 1 to 28 days, typically about 7 or about 14 days, between cycles. In other embodiments, treatment cycles may also be continuous.

[0157] In one particular embodiment, the method comprises administering to an individual an initial daily dose of about 1 to 800 mg of the compound described herein, and incrementally increasing the dose until clinical efficacy is achieved. Increments 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.

[0158] [, Mode , ] [, I , ] [, Synthesis of compounds , ] [, , ] Compounds can be prepared using the methods disclosed herein and their conventional modifications (as will be apparent from the disclosure herein) and methods well known in this art. In addition to the teachings herein, conventional and well-known synthetic methods may also be used. The synthesis of typical compounds described herein can be performed as illustrated in the following examples. Reagents, if available, can be commercially purchased, for example from Sigma Aldrich or other chemical suppliers.

[0159] Universal synthesis Typical examples of the compounds described herein can be synthesized using the general reaction process described below. As will be apparent from the description herein, the general process can be altered by replacing the starting materials with other materials having similar structures, thereby producing correspondingly different products. Synthesis is subsequently described to provide several examples of how the starting materials can be modified to provide corresponding products. Given that the desired products with defined substituents are defined, the necessary starting materials can generally be determined by examination. Starting materials are typically obtained from commercial sources or synthesized using publicly available methods. For the synthesis of the compounds of the embodiments described in this invention, examination of the structure of the compound to be synthesized will provide identification of the various substituents. Given the examples herein, identification of the final product will generally make the identification of the necessary starting materials readily apparent through a simple examination process. Generally, the compounds described herein are typically stable and separable at room temperature and chamber pressure.

[0160] Synthesis reaction parameters The compounds of this invention can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that, unless otherwise stated, other process conditions may be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0161] Furthermore, it will be apparent to those skilled in this art that it may be necessary to know protecting groups to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting specific functional groups and for deprotecting specific functional groups, are well known in this art. For example, many protecting groups are described in TW Greene and GM Wuts (1999), Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0162] The starting materials used in the following reactions are commonly known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures described in standard reference texts or their obvious modifications, 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 Supplements (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).

[0163] The term "solvent" generally refers to a solvent that is inert under the reaction conditions described therein (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, diethyl ether, methanol, and the like). Unless otherwise stated, the solvent is an inert organic solvent, and the reaction can be carried out under an inert gas (preferably argon or nitrogen).

[0164] The term "appropriate amount (qs)" means adding enough to achieve the stated function (e.g., to bring the solution to the desired volume (i.e., 100%)).

[0165] exist [process] [1] In this context, A, R1, R2, R3 and R6 are defined as follows, each X is independently a halogen (e.g., chlorine, bromine or iodine), each R50 is independently an alkyl group or two R50s together form a ring (e.g., 4,4,5,5-tetramethyl-1,3,2-dioxoboron), and PG is a protecting group bonded to a heteroatom.

[0166] [] [process] [1] exist [process] [1] In this method, a properly protected compound is subjected to the presence of a catalyst (e.g., palladium, nickel, copper, etc.) to... [100'] and corresponding Acids (boronic acids) or esters

[0200] Compounds of formula I are prepared by coupling followed by removal of the protecting group. Alternatively, the appropriately protected compound can be coupled in the presence of a catalyst (e.g., palladium, nickel, copper, etc.).

[0400] Compounds with corresponding halogenated groups

[0500] Coupling to prepare compounds for the preparation of Formula I compounds as shown in Procedure 1

[0300] By means of a catalyst (e.g., palladium, nickel, copper, etc.) a properly protected compound [100'] and corresponding Acids or esters

[0600] Coupling to prepare compounds

[0400] . Various formulas used in the methods provided herein. [100']、

[0200] 、

[0500] and The compound of

[0600] can be purchased from commercial sources or synthesized by known methods.

[0167] In some embodiments, compounds

[0300] (where R2 is hydrogen) can be esterified under standard coupling conditions to form a compound.

[0300] , wherein R2 is as defined herein (e.g., -(CH2CH2O)1-9CH2CH2OCH3, C1-6 alkyl, cycloalkyl, or heteroaryl substituted with one to three R4, as appropriate).

[0168] Examples are provided below to illustrate specific embodiments of the invention. Those skilled in the art will understand that the techniques disclosed in the following examples represent techniques that work well in practicing the invention and can therefore be considered as specific patterns constituting its practice. However, according to the invention, those skilled in the art will understand that many changes can be made to the specific embodiments disclosed without departing from the spirit and scope of the invention and still obtaining the same or similar results.

[0169] [Intermediate substance] [3] [、] [4] [and] [6(] [and its methyl ester] [3'] [、] [4'] [and] [6')] [Of] [synthesis] []

[0170] [step] [1] A solution of trifluoromethanesulfonic anhydride (375 mL, 2.25 mol) in hexane (900 mL) was slowly added to a mixture of sodium azide (150.0 g, 2.25 mol) and tetrabutylammonium hydrogen sulfate (41.9 g, 123 mmol) in water (2.3 L) at 0 °C. After stirring the resulting mixture at 0 °C for 1 h, the organic soluble material was extracted with hexane (1.8 L), dried over sodium hydroxide pellets, and decanted. Ethyl 2-cyanoacetate was added to the solution. [1] Acetonitrile (1.1 L) and pyridine (300 mL, 4.0 mol) (150.0 g, 0.8 mol). The resulting mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in ethyl acetate / petroleum ether (1:6) to give impure ethyl 2-cyano-2-diazotate. [2](111 g, 99%).

[0171] [step] [2] Ethyl 2-cyano-2-diazoethyl acetate at 0°C [2] A solution of 111 g (795 mmol) in dimethyl ether (7 L) was bubbled with hydrogen bromide gas for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product ethyl 4-bromo-1H-1,2,3-triazol-5-carboxylate. [3](125 g), which was used directly in the next step without further purification.

[0172] [step] [3] At 0°C, the crude product ethyl 4-bromo-1H-1,2,3-triazol-5-carboxylate was extracted. [3] Sodium hydride (60%, 10.1 g, 275 mmol) was added to a solution of 50 g (227 mmol) in DMF (500 mL) and stirred under N2 for 30 min. Then, 2-(trimethylsilyl)ethoxymethyl chloride (40.5 g, 238 mmol) was added at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was quenched with 5% lithium chloride aqueous solution 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 column chromatography and dissolved in a hexane solution of ethyl acetate (2:5) to give a colorless oily mixture of isomers of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate. [4], 30 g, 38%): ES / MS m / z: C 11H 20BrN 3NaO 3Si (M+Na +) Calculated value: 372.04, Experimental value: 372.15.

[0173] A mixture of isomers of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate ( [4']) is also obtained from commercially available methyl 4-bromo-1H-1,2,3-triazol-5-carboxylate in a manner similar to that described above. [3']) Prepared as an oily substance: ES / MS m / z: C 10H 19BrN 3NaO 3Si (M+Na) Calculated value: 337.27, Experimental value: 336.53.

[0174] [step] [4] An isomer mixture (4.45 g, 129 mmol) of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate and 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)benzene [5] 85.0 g, 257 mmol) was added to a solution of 1,4-dimethylamine (800 mL) containing 2.0 M sodium carbonate aqueous solution (193 mL, 386 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.45 g, 12.9 mmol). The reaction mixture was stirred at 70 °C for 4 h under a N2 atmosphere. After cooling the reaction mixture to room temperature and diluting it with water, the product was extracted with ethyl acetate (3 × 1 L). The organic fraction was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silicone column chromatography and dissolved in ethyl acetate / petroleum ether (1:30) to give an oily mixture of isomers of ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate. [6], 25.5 g, 43%): ES / MS m / z: C 23H 36BN 3NaO 5Si (M+Na) Calculated value: 496.44, Experimental value: 496.45.

[0175] [Intermediate substance] [8] [Synthesis] []

[0176] [step] [1] To a mixture of isomers containing ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate ( [4], 25 g, 71.3 mmol) and 4,4'-bis(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)-1,1'-biphenyl ( [7] 45 g (110.8 mmol) of 1,4-dimethyl ether (500 mL) was mixed with 2.0 M Na₂CO₃ aqueous solution (106 mL, 215.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.2 g, 7.1 mmol). The reaction mixture was stirred overnight at 70 °C under a N₂ atmosphere. After cooling the reaction mixture to room temperature and diluting it with water, the product was extracted with ethyl acetate (3 × 500 mL). The organic fraction was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by silicone column chromatography and dissolved in ethyl acetate / petroleum ether (1:30) to give an oily mixture of isomers of ethyl 5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylic acid. [8], 11.5 g, 29%): ES / MS m / z: C 29H 41BN 3O 5Si (M+H) Calculated value: 550.29, Experimental value: 550.45.

[0177] [Intermediate substance]

[10] [Synthesis] []

[0178] [step] [1] To a mixture of isomers containing ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate) [6], 358 mg, 0.76 mmol) and 1,4-dibromobenzene ( [9] 1,4-dimethylamine (3 mL) was mixed with tetra(triphenylphosphine)palladium (0) (87 mg, 0.076 mmol) and 2.0 M Na₂CO₃ aqueous solution (1.13 mL). After purging the mixture with argon for 10 min, the reaction mixture was stirred at 110 °C for 40 min. After cooling the reaction mixture to room temperature and diluting 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 column chromatography and dissolved in hexane solution of 1-100% ethyl acetate to give an oily mixture of isomers of ethyl 5-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate (

[10] , 380 mg, 83%).

[0179] Synthesis of intermediates 11 and 12

[0180] [step] [1] An isomer mixture of ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (

[11] , 27 g, 49%) is a mixture of isomers similar to those used for ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate ( [3]) The procedure was to use p-methoxybenzyl chloride instead of 2-(trimethylsilyl)ethoxymethyl chloride to prepare an oily substance, the difference being that the reaction was carried out at room temperature for 8 h: ES / MS m / z: C 13H 14BrN 3NaO 3(M+H) Calculated value: 362.01, experimental value: 362.05.

[0181] [step] [2] An isomer mixture of ethyl 2-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-2H-1,2,3-triazol-4-carboxylic acid ester (

[12] ) is a mixture of isomers similar to those used for ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate) [6]) is prepared as an oily substance using the procedure.

[0182] [Intermediate substance]

[13] [Synthesis] []

[0183] [step] [1] An isomer mixture of ethyl 2-(4-methoxybenzyl)-5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)-2H-1,2,3-triazol-4-carboxylic acid (

[13] , 10.5 g, 26%) is similar to that used for ethyl 5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate ( [8]) The isomer mixture was prepared as an oil by a procedure: ES / MS m / z: C 31H 35BN 3O 5 (M+H) Calculated value: 540.27, experimental value: 540.55.

[0184] [Intermediate substance]

[15] [and]

[16] [Synthesis] []

[0185] [step] [1] 4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylic acid methyl ester (

[15] , 5.1 g, 59%) is similar to that used in the preparation of intermediates. [4] The procedure involves methyl 4-bromo-1H-pyrazole-5-carboxylate (

[14] , 5.0 g, 24.5 mmol) was prepared as an oil: 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 11H 20BrN 2O 3Si (M+H) calculated value: 335.04, molecular weight not detected.

[0186] [step] [2] 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylic acid methyl ester

[16] , 5.83 g, 38%) is similar to that used in the preparation of [6] The procedure was to use potassium carbonate instead of sodium carbonate to prepare an oily substance, the difference being that the reaction was carried out overnight at 110 °C: 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 23H 36BN 2O 5Si (M+H) calculated value: 459.25, molecular weight not detected.

[0187] [Intermediate substance]

[18] [Of] [synthesis] [] [] ethyl 3-bromo-1H-pyrazole-4-carboxylate (

[18] , 511 mg, 96%) is an intermediate similar to that used to prepare a mixture of two regioisomers.

[15] The procedure involves ethyl 3-bromo-1H-pyrazole-4-carboxylate (

[17] , 335 mg, 1.53 mmol) was prepared as an oil: ES / MS m / z: C 12H 22BrN 2O 3Si (M+H) Calculated value: 349.06, experimental value: 348.46.

[0188] [Intermediate substance]

[20] [Of] [synthesis] [] 4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-carboxylic acid methyl ester

[20] , 690 mg, 77%) is an intermediate similar to that used to prepare a mixture of two regioisomers.

[15] The procedure involves methyl 4-bromo-1H-imidazolium-5-carboxylate (

[19] , 335 mg, 1.53 mmol) was prepared as an oil: ES / MS m / z: C 12H 22BrN 2O 3Si (M+H) Calculated value: 335.04, Experimental value: 334.86.

[0189] [Suzuki Reaction] [(] [Suzuki reaction] [)] [Representative Procedure] [] Add a mixture of isomers of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate to a 5 mL microwave-safe vial. [4'], 46 mg, 0.14 mmol), 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxoboron(

[17] , 20 mg, 0.15 mmol), tetra(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol), 2 N potassium carbonate (0.14 mL) and dimethyl ether (2 mL). After purging with argon for 5 minutes, the resulting mixture was stirred at 110 °C for 1 h. After cooling, the reaction mixture was diluted with saturated NaHCO3, and the product was extracted with ethyl acetate, dried (MgSO4), concentrated and purified by silica gel column chromatography, and dissolved in hexane of ethyl acetate to give methyl 5-(o-tolyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate (

[18] ): Calculated value of ES / MS m / z: C 17H 26N 3O 3Si (M+H): 348.17, experimental value: 347.58.

[0190] [By] [HCl] [conduct] [SEM] [Representative Procedures for Removing Protection] [] Methyl 5-(o-tolyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate (

[18] 49 mg, 0.14 mmol) was added to a solution of tetrahydrofuran (1 mL) and methanol (1 mL) with 3 N HCl (0.21 mL) and the resulting mixture was stirred at 80 °C for 2 h, followed by overnight at 50 °C. The resulting reaction mixture was concentrated to obtain the crude product methyl 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylate (

[19] ): Calculated value of ES / MS m / z: C 11H 10N 3O 2(MH): 216.08, experimental value: 216.15.

[0191] [By] [TBAF] [conduct] [SEM] [Representative Procedures for Removing Protection] [] Ethyl 4-(4'-(1,1'-biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-carboxylic acid (

[20] ) was dissolved in 1N TBAF (5 equivalents) and the solution was heated to 60°C for 3 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, and the product was extracted with ethyl acetate, dried (MgSO4), concentrated and purified by silica gel column chromatography, and dissolved in hexane of ethyl acetate to give ethyl(4'-(5'-linylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid ethyl ester (

[21] ): Calculated value of ES / MS m / z: C 21H 23N 4O 5(M+H): 443.49, experimental value: 443.16.

[0192] [By] [TFA] [conduct] [PMB] [Representative Procedures for Removing Protection] [] [] Ethyl 1-(4-methoxybenzyl)-4-(4'-(5-methyl-1,3,4-thiadiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid (

[22] ) was dissolved in 1 mL of TFA and the mixture was heated to 40 °C for 80 minutes. After cooling, the reaction mixture was concentrated and diluted with saturated NaHCO3, and the product was then extracted with ethyl acetate, dried (MgSO4), concentrated and purified by silica gel column chromatography, and dissociated with ethyl acetate in hexane and 10% methanol / ethyl acetate to give ethyl 4-(4'-(5-methyl-1,3,4-thiadiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylate (

[23] ): Calculated value of ES / MS m / z:C 20H 18N 5O 2S (M+H): 392.45, experimental value: 392.16.

[0193] [Representative Procedures for Ester Hydrolysis] [] To the crude product methyl 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylate (

[21] 2 N NaOH (1 mL) was added to tetrahydrofuran (1 mL) and methanol (1 mL), and the resulting mixture was stirred at 80 °C for 2 h. After cooling the reaction mixture and neutralizing it with 1 N HCl, the solid was filtered off and purified by HPLC and lyophilized to give 4-(o-tolyl)-1H-1,2,3-triazol-5-carboxylic acid (

[24] ): Calculated value of ES / MS m / z: C 10H 8N 3O 2(MH): 202.08, experimental value: 201.97.

[0194] [Heterocyclic] [NH] [Of] [SEM] [Representative Procedures for Protection] [] 5-Bromo-1H-1,2,3-triazole was stirred in an ice bath while being added partically with 60% sodium hydride / mineral oil (410 mg, 10.25 mmol).

[25] 996.3 mg, 6.733 mmol) in a solution of DMF (20 mL). After 30 min, (2-(chloromethoxy)ethyl)trimethylsilane (1.25 mL, 7.063 mmol) was added to the reaction mixture and the resulting mixture was stirred in an ice bath for 1 h, followed by overnight at room temperature. After 19 h, the reaction mixture was diluted with saturated NH4Cl aqueous solution (~100 mL) and ethyl acetate (~100 mL) and the two layers were separated. After extraction of the aqueous fraction with ethyl acetate (× 1), the organic fraction was washed with water (~150 mL × 1), combined, dried (MgSO4), and concentrated. The residual oil was purified by silicone column chromatography and dissolved in a hexane solution of 0-30% ethyl acetate to obtain 726.0 mg (39%) of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (

[26] ): 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: Calculated value of C 11H 20BrN 2O 3Si (M+H): 335.04, molecular weight not detected.

[0195] [Preparation of Boron from Aryl Bromines] [acid] [Representative Procedures for Esters] [] 4-Bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (

[26] , 359 mg, 1.29 mmol), double ( (Base) diborone (

[27] A 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) in 1,4-dimethylamine (6 mL) was purged with Ar gas for 15 min in a 20 mL µW vial, and then heated at 110 °C for 1 h. 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 column chromatography, followed by dissolution with 0-40% ethyl acetate in hexane to yield 282 mg (67%) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (

[28] ): 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).

[0196] The following compounds were deprotected using a representative procedure similar to the Suzuki reaction, with the above-mentioned SEM or PMB removal and the use of the previously mentioned bromide intermediate. [4] (or) [4'])

[10] or

[15] with commercially available borate esters or using the previously mentioned borate ester intermediates. [6](or) [6']), [8]、

[12] 、

[13] and

[16] Prepared by hydrolysis with commercially available bromide esters: [Example] [1] [:] [4-(4'-] [chlorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [Second] [ester] [] 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: C₁₇H₁₃ClN₃O₂(MH) calculated value: 326.08, experimental value: 326.31.

[0197] [Example] [2] [:] [4-(4'-] [Aminomethoxy] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [Second] [ester] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₈H₁₇N₄O₃(M+H) calculated value: 337.13, experimental value: 337.03.

[0198] [Example] [3] [:] [4-(] [o-Tolyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴) δ 7.42–7.31 (m, 2H), 7.31–7.21 (m, 2H), 2.17 (s, 3H). ES / MS m / z: C₁₀H₁₀N₃O₂(M+H) calculated value: 204.08, experimental value: 347.58.

[0199] [Example] [4] [:] [4-(] [m-Toluyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁰H¹⁰N₃O₂(M+H) calculated value: 204.20, experimental value: 203.92.

[0200] [Example] [5] [:] [4-(] [p-Toluyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₀H₁₀N₃O₂(M+H) calculated value: 204.20, experimental value: 203.92.

[0201] [Example] [6] [:] [4-(3-)] [Ethylphenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹¹H¹²N₃O₂(M+H) calculated value: 218.09, experimental value: 217.97.

[0202] [Example] [7] [:] [4-(2-)] [Fluorophenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): δ 7.61–7.45 (m, 2H), 7.32–7.17 (m, 2H). ES / MS m / z: C₈H₇FN₃O₂(M+H) calculated value: 208.04, experimental value: 207.94.

[0203] Example 8: 4-(3-fluorophenyl)-1H-1,2,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, methanol-d⁴) 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: C₈H₇FN₃O₂(M+H) calculated value: 208.04, experimental value: 207.91.

[0204] [Example] [9] [:] [4-(4-)] [Chlorophenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): δ 7.89 - 7.81 (m, 2H), 7.51 - 7.42 (m, 2H). ES / MS m / z: C₉H₇ClN₃O₂(M+H) calculated value: 224.01, experimental value: 223.94.

[0205] [Example]

[10] [:] [4-(3-)] [Methoxyphenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₀H₈N₃O₃ (MH) calculated value: 218.20, experimental value: 217.98.

[0206] [Example]

[11] [:] [4-(4-)] [Methoxyphenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) δ 7.78 (d, J = 8.4 Hz, 2H), 7.06–6.98 (m, 2H), 3.85 (s, 3H). ES / MS m / z: C¹⁰H¹⁰N₃O₃(M+H) calculated value: 220.06, experimental value: 219.93.

[0207] [Example]

[12] [:] [4-(2,4'-] [Dichloro] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₀H₇N₄O₂(M+H) calculated value: 215.05, experimental value: 214.96.

[0208] [Example]

[13] [:] [4-(3-(] [Trifluoromethyl] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₀H₇F₃N₃O₂(M+H) calculated value: 258.07, experimental value: 257.97.

[0209] [Example]

[14] [:] [4-(3-(] [Third Butyl] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₃H₁₆N₃O₂(M+H) calculated value: 246.12, experimental value: 246.04.

[0210] [Example]

[15] [:] [4-(4-(] [Third Butyl] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): δ 7.78–7.70 (m, 2H), 7.55–7.47 (m, 2H), 1.36 (s, 9H). ES / MS m / z: C¹³H¹⁶N₃O₂(M+H) calculated value: 246.12, experimental value: 246.01.

[0211] [Example]

[16] [:] [4-(3-(] [Trifluoromethoxy] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 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: C₁₀H₇FN₃O₃(M+H) calculated value: 274.04, experimental value: 273.95.

[0212] [Example]

[17] [:] [5-(3-)] [chlorine] [-4-] [Fluorophenyl] [)-1-] [methyl] [-1H-1,2,3-] [Triazole] [-4-] [Formic acid] [] 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: Calculated value of C 10H 9ClFN 3O 2(MH): 254.63, experimental value: 254.04.

[0213] [Example]

[18] [:] [4-(3-)] [chlorine] [-4-] [Fluorophenyl] [)-1H-] [Pyrazole] [-3-] [Formic acid] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₀H₇ClFN₂O₂(M+H) Calculated value: 241.01, experimental value: 240.88.

[0214] [Example]

[19] [:] [4-(3,4-] [Dichlorophenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₉H₆Cl₂N₃O₂(M+H) calculated value: 257.98, experimental value: 257.95.

[0215] [Example]

[20] [:] [4-(3,5-] [Dichlorophenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) δ 7.95 (s, 2H), 7.52 (s, 1H). ES / MS m / z: C₉H₆Cl₂N₃O₂ (M+H) Calculated value: 257.98, experimental value: 257.92.

[0216] [Example] [twenty one] [:] [4-(3,5-] [Dichlorophenyl] [)-1H-] [Pyrazole] [-3-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶): δ 8.00 (s, ¹H), 7.68 (s, 2H), 7.58–7.44 (m, ¹H). ES / MS m / z: C₁₀H₅Cl₂N₂O₂ (MH) calculated: 254.98, experimental: 255.02.

[0217] [Example] [twenty two] [:] [4-(3-)] [chlorine] [-2-] [Fluorophenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₉H₆ClFN₃O₂(M+H) calculated value: 242.01, experimental value: 241.94.

[0218] Example 23: 5-(4-bromo-3-chlorophenyl)-1H-1,2,3-triazol-4-carboxylic acid [] ¹H NMR (400 MHz, methanol-d⁴): δ 8.04 (s, ¹H), 7.70–7.65 (m, 2H). ES / MS m / z: C₉H₄BrClN₃O₂ (MH) calculated value: 299.93, experimental value: 300.02.

[0219] Example 24: 4-(3,5-dichloro-4-fluorophenyl)-1H-1,2,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, methanol-d⁴) δ 8.09 (d, J = 6.4 Hz, 2H). ES / MS m / z: C₉H₄Cl₂FN₃O₂ (M+H) calculated value: 275.97, experimental value: 275.96.

[0220] [Example]

[25] [:] [4-(3-)] [Phenoxyphenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H¹²N₃O₃(M+H) calculated value: 282.08, experimental value: 282.01.

[0221] [Example]

[26] [:] [4-(4-)] [Phenoxyphenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H¹²N₃O₃(M+H) calculated value: 282.08, experimental value: 281.98.

[0222] [Example]

[27] [:] [4-([1,1'-] [Biphenyl] []-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H¹²N₃O₂(M+H) calculated value: 266.09, experimental value: 266.01.

[0223] [Example]

[28] [:] [4-([1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H¹²N₃O₂(M+H) calculated value: 266.09, experimental value: 265.96.

[0224] [Example]

[29] [:] [4-(2,2-] [difluorobenzo] [[d][1,3]] [dioxol] [-5-] [yl] [)-1H-1,2,3-] [triazole] [-5-] [carboxylic acid] [] [[ID=2"]] 1H NMR (400 MHz, methanol-d4) 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: Calculated for C10H6CF2N3O4(M+H): 270.02, Observed: 269.97.

[0225] Example 30: 4-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid 1H NMR (400 MHz, methanol-d4) δ 7.35 (d, J = 1.7 Hz, 2H), 6.95 - 6.86 (m, 1H), 6.02 (s, 2H). ES / MS m / z: Calculated for C10H6N3O4(M-H): 232.04, Observed: 232.00.

[0226] [Example]

[31] [:] [4-(4-(2,2-] [difluorobenzo] [[d][1,3]] [dioxol] [-5-] [yl] [)] [phenyl] [)-1H-1,2,3-] [triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁶H₈F₂N₃O₄ (MH) calculated value = 344.06; experimental value 344.04.

[0227] [Example]

[32] [:] [4-(2,3-] [Dihydrobenzox] [[b][1,4]] [Second] [𠯤] [-6-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹¹H¹⁰N³O₄(M+H) calculated value: 248.06, experimental value: 248.00.

[0228] [Example]

[33] [:] [4-(] [Naphthalene] [-2-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): δ 8.39 (s, ¹H), 7.98–7.86 (m, 4H), 7.59–7.49 (m, 2H). ES / MS m / z: C₈H₆ClFN₃O₂(M+H) calculated value: 242.01, experimental value: 239.97.

[0229] [Example]

[34] [:] [4-(] [Pyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₈H₇N₄O₂(M+H) calculated value: 191.05, experimental value: 191.01.

[0230] [Example]

[35] [:] [4-(] [Pyridine] [-3-] [base] [)-1H-] [Pyrazole] [-3-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₉H₇N₃O₂ (MH) calculated value: 190.05, experimental value: 190.02.

[0231] [Example]

[36] [:] [4-(] [Quinoline] [-7-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₂H₉N₄O₂(M+H) calculated value: 241.06, experimental value: 241.07.

[0232] [Example]

[37] [:] [4-(] [Isoquinoline] [-7-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₂H₈N₄O₂(M+H) calculated value: 241.06, experimental value: 241.05.

[0233] [Example]

[38] [:] [4-(6-)] [Phenynaphthalene] [-2-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁹H¹⁴N₃O₂(M+H) calculated value: 316.10, experimental value: 316.00.

[0234] [Example]

[39] [:] [4-(3-)] [Chloroisoquinoline] [-7-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₂H₈ClN₄O₂(M+H) calculated = 275.03; experimental value 275.05.

[0235] [Example]

[40] [:] [4-(3-)] [Methoxyisoquinoline] [-7-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 1H NMR (400 MHz, methanol-d4) 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).

[0236] [Example]

[41] [:] [4-(3-)] [Phenyloisoquinoline] [-7-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁸H¹³N₄O₂(M+H) calculated = 317.10; experimental value 317.09.

[0237] [Example]

[42] [:] [4-(4-(] [Naphthalene] [-1-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) δ 8.02 - 7.85 (m, 5H), 7.61 - 7.40 (m, 6H). ES / MS m / z: C₁₉H₁₄N₃O₂(M+H) calculated value = 316.11; experimental value 316.03.

[0238] [Example]

[43] [:] [4-(4-(] [Pyridine] [-2-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₄H₁¹N₄O₂(M+H) calculated value: 267.08, experimental value: 267.10.

[0239] [Example]

[44] [:] [4-(4-(] [Pyridine] [-3-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₄H₁₁N₄O₂(M+H) calculated value: 267.09, experimental value: 267.04.

[0240] [Example]

[45] [:] [4-(4-(] [Naphthalene] [-2-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₂N₃O₂ (MH) calculated value: 314.10, experimental value: 314.14.

[0241] [Example]

[46] [:] [4-(4-(6-)] [Chloronaphthalene] [-2-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) δ 8.31 (s, ¹H), 8.07–7.91 (m, ⁶H), 7.89 (s, ⁻¹H), 7.51 (dd, J = 8.7, 2.2 Hz, ¹H). ES / MS m / z: C₁₉H₁₃ClN₃O₂(M+H) calculated value: 350.06, experimental value: 350.00.

[0242] [Example]

[47] [:] [4-(4-(] [Isoquinoline] [-6-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₄H₁₁N₄O₂(M+H) calculated value: 267.09, experimental value: 267.04.

[0243] Example 48: 4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₇H₁₄N₅O₂(M+H) calculated value: 320.11, experimental value: 320.14.

[0244] [Example]

[49] [:] [4-(4'-] [chlorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H¹¹ClN₃O₂(M+H) calculated value: 300.05, experimental value: 299.97.

[0245] [Example]

[50] [:] [4-(3'-] [chlorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₁ClN₃O₂(M+H) calculated value: 300.05, experimental value: 299.98.

[0246] [Example]

[51] [:] [4-(4'-] [bromine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) δ 7.88 (s, 2H), 7.77 (d, J = 7.9 Hz, 2H), 7.72–7.60 (m, 4H). ES / MS m / z: C₁₅H₁₁BrN₃O₂(M+H) calculated value: 344.00, experimental value: 344.06.

[0247] [Example]

[52] [:] [4-(2,4'-] [Dichloro] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₅H₁₁BrN₃O₂(M+H) calculated value: 344.00, experimental value: 343.95.

[0248] [Example]

[53] [:] [4-(4'-] [methyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁶H¹⁴N₃O₂(M+H) calculated value: 280.10, experimental value: 279.96.

[0249] [Example]

[54] [:] [4-(4'-(] [Third Butyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁹H²⁰N³O₂(M+H) calculated value: 322.15, experimental value: 322.06.

[0250] [Example]

[55] [:] [4-(4'-(] [Trifluoromethoxy] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₆H₁₁F₃N₃O₃(M+H) calculated value: 350.08, experimental value: 350.00.

[0251] [Example]

[56] [:] [4-(4'-] [Methoxy] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁶H¹⁴N₃O₃(M+H) calculated value: 296.10, experimental value: 296.03.

[0252] [Example]

[57] [:] [4-(4'-] [fluorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H¹¹FN₃O₂(M+H) calculated value = 284.08; experimental value 284.31.

[0253] [Example]

[58] [:] [4-(3',4'-] [Dichloro] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₀Cl₂N₃O₂(M+H) calculated value: 334.02, experimental value: 334.08.

[0254] [Example]

[59] [:] [4-(4'-] [Cyano] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) δ 8.00 (d, J = 7.9 Hz, 2H), 7.93–7.77 (m, 6H). ES / MS m / z: C¹⁶H⁹N₄O₂ (MH) calculated value = 289.07; experimental value: 289.01.

[0255] [Example]

[60] [:] [4-(4'-] [chlorine] [-3'-] [fluorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H₈ClFN₃O₂ (MH) calculated value: 316.04, experimental value: 316.09.

[0256] [Example]

[61] [:] [4-(3'-] [chlorine] [-4'-] [fluorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₀ClFN₃O₂(M+H) calculated value: 318.04, experimental value: 317.97.

[0257] [Example]

[62] [:] [4-(3'-] [Phenoxy] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₂₁H₁₆N₃O₃(M+H) calculated value: 358.11, experimental value: 358.01.

[0258] [Example]

[63] [:] [4-(4'-] [Phenoxy] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₂₁H₁₆N₃O₃(M+H) calculated value: 358.11, experimental value: 357.98.

[0259] [Example]

[64] [:] [4-(4'-(] [Pyridine] [-2-] [kcalcium oxide] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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 20H 15N 4O 3(M+H) Calculated value: 359.11, Experimental value: 359.14.

[0260] [Example]

[65] [:] [4-(4'-] [acetyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₇H₁₄N₃O₃(M+H) calculated value = 308.10; experimental value 308.00.

[0261] [Example]

[66] [:] [4-(3'-] [Aminomethoxy] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₆H₁₃N₄O₃(M+H) calculated value: 309.09, experimental value: 309.09.

[0262] [Example]

[67] [:] [4-(3'-(] [Methylaminomethyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₇H₁₅N₄O₃(M+H) calculated value: 323.11, experimental value: 323.12.

[0263] [Example]

[68] [:] [4-(4'-] [Aminomethoxy] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): δ 7.98 (d, 4H), 7.77 (d, 4H). ES / MS m / z: C¹⁶H¹³N₄O₃(M+H) calculated value: 309.09, experimental value: 309.05.

[0264] [Example]

[69] [:] [4-(4'-(] [Methylaminomethyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁷H¹⁵N₄O₃(M+H) calculated value: 323.11, experimental value: 323.16.

[0265] [Example]

[70] [:] [4-(4'-(] [Dimethylaminomethyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): 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: C₁₈H₁₇N₄O₃(M+H) calculated value: 337.35, experimental value: 338.06.

[0266] [Example]

[71] [:] [4-(4'-] [Aminomethoxy] [-3'-] [chlorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₆H₁₂ClN₄O₃(M+H) Calculated value: 343.05, experimental value: 343.13.

[0267] Example 72: 4-(3'-aminosulfonyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁵H¹³N⁴O⁴S (MH) calculated value: 345.06, experimental value: 345.03.

[0268] [Example]

[73] [:] [4-(3'-(N,N-] [Dimethylaminesulfonyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): δ 8.06–7.97 (m, 4H), 7.85–7.69 (m, 4H), 2.74 (s, 6H). ES / MS m / z: C₁₇H₁₇N₄O₄S (M+H) calculated value: 373.09, experimental value: 373.11.

[0269] [Example]

[74] [:] [4-(3'-(] [piperidine] [-1-] [Sulfoyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₂₀H₂¹N₄O₄S (M+H) calculated value: 413.13, experimental value: 413.17.

[0270] [Example]

[75] [:] [4-(3'-(] [𠰌] [Pinylsulfonyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): 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: C₁₉H₁₉N₄O₅S (M+H) Calculated value: 415.10, experimental value: 415.11.

[0271] [Example]

[76] [:] [4-(4'-] [chlorine] [-3'-] [Aminosulfonyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₂ClN₄O₃S (M+H) Calculated value: 379.02, experimental value: 379.07.

[0272] [Example]

[77] [:] [4-(4'-] [Aminosulfonyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₁N₄O₄S (MH) calculated value: 343.06, experimental value: 342.31.

[0273] [Example]

[78] [:] [4-(4'-(N,N-] [Dimethylaminesulfonyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁷H¹⁷N⁴O⁴S (M+H) calculated value: 373.09, experimental value: 373.06.

[0274] [Example]

[79] [:] [4-(4'-(] [piperidine] [-1-] [Sulfoyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₂₀H₂¹N₄O₄S (M+H) calculated value: 413.13, experimental value: 413.10.

[0275] [Example]

[80] [:] [4-(4'-(] [𠰌] [Pinylsulfonyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₉H₁₉N₄O₅S (M+H) Calculated value: 415.11, experimental value: 415.07.

[0276] [Example]

[81] [:] [4-(3'-] [Acetamino] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): 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: C₁₇H₁₅N₄O₃(M+H) calculated value: 323.11, experimental value: 323.13.

[0277] [Example]

[82] [:] [4-(4'-] [Acetamino] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₇H₁₅N₄O₃(M+H) calculated value: 323.11, experimental value: 323.12.

[0278] [Example]

[83] [:] [4-(4'-(2-] [Side-oxypyrrolidine] [-1-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₇N₄O₃(M+H) Calculated value: 349.12, experimental value: 349.13.

[0279] [Example]

[84] [:] [4-(2,4'-] [Dichloro] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₉H₁₉N₄O₂(M+H) calculated value: 351.14, experimental value: 350.01.

[0280] [Example]

[85] [:] [4-(4'-] [chlorine] [-2'-] [methyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₆H₁₃ClN₃O₂(M+H) calculated value = 314.07; experimental value 314.01.

[0281] [Example]

[86] [:] [4-(9H-] [Fluorene] [-2-] [yl] [)-1H-1,2,3-] [Triazole] <00…[-5-] [Formic acid] [] 1H NMR (400 MHz, methanol-d4) δ 8.02 (s, 1H), 7.94 - 7.80 (m, 3H), 7.58 (dt, J = 7.3, 1.0 Hz, 1H), 7.43 - 7.29 (m, 2H), 3.97 (s, 2H). ES / MS m / z: Calculated value for C16H12N3O2(M+H): 278.09, Experimental value: 278.02.

[0282] [Example]

[87] [:] [4-(] [Dibenzofuran] [[b,d]] [Furan] [-3-] [yl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] <000…[[ID=…]] [[ID=…]] ​1H NMR (400 MHz, methanol-d4) 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: Calculated value for C15H10N3O3(M+H): 280.06, experimental value: 280.00.

[0283] [Example]

[88] [:] [4-(9H-] [carbazole] [-2-] [group] [)-1H-1,2,3-] [triazole] [-5-] [formic acid] [] 1H NMR (400 MHz, acetonitrile-d3) 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: Calculated value for C15H11N4O2(M+H) = 279.09; experimental value 279.01. ]

[0284] [Example]

[89] [:] [4-(9-] [side oxygen group] [-9H-] [fluorene] [-2-] [Base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 1H NMR (400 MHz, methanol-d4) 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: Calculated value for C16H10N3O3(M+H): 292.06, Experimental value: 292.08.

[0285] [Example]

[90] [:] [4-(9,9-] [Dimethyl] [-9H-] [Fluorene] [-2-] [Group] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 1H NMR (400 MHz, methanol-d4) 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: Calculated value for C18H16N3O2(M+H) = 306.12; Experimental value 306.06.

[0286] [Example]

[91] [:] [4-(4'-] [chlorine] [-3'-] [methyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₆H₁₁ClN₃O₂ (MH) calculated value: 312.06, experimental value: 312.08.

[0287] [Example]

[92] [:] [4-(4'-] [Aminomethoxy] [-3'-] [methyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₇H₁₅N₄O₃(M+H) calculated value: 323.11, experimental value: 323.10.

[0288] [Example]

[93] [:] [4-(4-(1-] [Side group] [-1,2,3,4-] [Tetrahydroisoquinoline] [-6-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁸H¹⁵N₄O₃(M+H) calculated value: 335.11, experimental value: 335.16.

[0289] [Example]

[94] [:] [4-(4-(1-] [Side group] [-1,2,3,4-] [Tetrahydroisoquinoline] [-6-] [base] [)] [Phenyl] [)-1H-] [Pyrazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₆N₃O₃(M+H) calculated value: 334.11, experimental value: 334.13.

[0290] [Example]

[95] [:] [4-(4-(3-] [methyl] [-1-] [Side group] [-1,2,3,4-] [Tetrahydroisoquinoline] [-6-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 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 19H 17N 4O 3(M+H) Calculated value: 349.13, experimental value: 349.10.

[0291] [Example]

[96] [:] [4-(4-(2-] [methyl] [-1-] [Side group] [-1,2,3,4-] [Tetrahydroisoquinoline] [-6-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₇N₄O₃(M+H) calculated value: 349.13, experimental value: 349.09.

[0292] [Example]

[97] [:] [4-(4-(1-] [Side-oxyisoindoline] [-5-] [base] [)] [Phenyl] [)-1H-1,2l4,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴): δ 8.00 (m, 3H), 7.94–7.77 (m, 4H), 4.55 (s, 2H). ES / MS m / z: C₁₇H₁₃N₄O₃(M+H) calculated value: 321.09, experimental value: 321.07.

[0293] Example 98: 4-(4-(3,3-dimethyl-1-sideoxyisoindoline-5-yl)phenyl)-1H-1,2l4,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, methanol-d⁴) δ 7.98 (d, J = 8.0 Hz, 2H), 7.90–7.76 (m, 5H), 1.60 (s, 6H). ES / MS m / z: C₁₉H₁₈N₄O₃(M+H) calculated value = 349.13; experimental value 349.13.

[0294] [Example]

[99] [:] [4-([1,1':3',1''-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₂¹H₁₆N₃O₂(M+H) calculated value: 342.12, experimental value: 342.01.

[0295] [Example]

[0100] [:] [4-([1,1':4',1''-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₂¹H₁₄N₃O₂ (MH) calculated value: 340.12, experimental value: 339.95.

[0296] [Example]

[0101] [:] [4-(4'-(] [Pyridine] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₂₀H₁₅N₄O₂(M+H) calculated value: 343.11, experimental value: 343.15.

[0297] [Example]

[0102] [:] [4-(4'-(] [Pyridine] [-3-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₂₀H₁₅N₄O₂(M+H) Calculated value: 343.12, Experimental value: 343.13.

[0298] [Example]

[0103] [:] [4-(4'-(] [Pyridine] [-4-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₂₀H₁₅N₄O₂(M+H) calculated value: 343.12, experimental value: 343.13.

[0299] [Example]

[0104] [:] [4-(4'-(] [Pyrimidine] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₉H₁₄N₅O₂(M+H) calculated value = 344.11; experimental value 344.03.

[0300] Example 105: 4-(4'-(1-methyl-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₈H₁₅N₆O₂(M+H) calculated value = 347.13; experimental value 347.14.

[0301] [Example]

[0106] [:] [4-(4'-(1-] [methyl] [-1H-1,2,4-] [Triazole] [-3-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C¹⁸H¹⁵N⁶O₂(M+H) calculated value: 347.12, experimental value: 347.10.

[0302] [Example]

[0107] [:] [4-(4'-(1-] [methyl] [-1H-] [Pyrazole] [-3-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₆N₅O₂(M+H) calculated value: 346.13, experimental value: 346.15.

[0303] [Example]

[0108] [:] [4-(4'-(] [Thiazole] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁸H¹³N⁴O₂S (M+H) calculated value: 349.07, experimental value: 349.03.

[0304] [Example]

[0109] [:] [4-(4'-(5-] [Methylthiazole] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶): δ 8.03 - 7.74 (m, 8H), 7.62 (s, 1H), 2.50 (s, 3H). ES / MS m / z: C₁₉H₁₅N₄O₂S (M+H) calculated value: 362.08, experimental value: 362.11.

[0305] [Example]

[0110] [:] [4-(4'-(5-(] [Trifluoromethyl] [)] [Thiazole] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₂F₃N₄O₂S (M+H) calculated value: 417.06, experimental value: 417.00.

[0306] [Example]

[0111] [:] [4-(4'-(5-] [methyl] [-1,3,4-] [Thiadiazole] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C¹⁸H¹²N⁵O₂S (MH) calculated value: 362.07, experimental value: 362.03.

[0307] [Example]

[0112] [:] [4-(4'-(] [Stamethasone] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₈H₁₃N₄O₃(M+H) calculated = 333.10; experimental value 333.00.

[0308] [Example]

[0113] [:] [4-(4'-(] [Isotoxorubicin] [-3-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₈H₁₃N₄O₃(M+H) calculated value = 333.10; experimental value 333.05.

[0309] [Example]

[0114] [:] [4-(4'-(4-)] [Methylthiazole] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₅N₄O₂S (M+H) calculated value: 363.09, experimental value: 363.08.

[0310] [Example]

[0115] [:] [4-(4'-(2-] [methyl] [-2H-1,2,3-] [Triazole] [-4-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C¹⁸H¹⁵N⁶O₂(M+H) calculated value: 347.13, experimental value: 347.02.

[0311] [Example]

[0116] [:] [4-(4'-(] [Thiazole] [-5-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) δ 9.10 (s, ¹H), 8.39 (s, ¹H), 7.81 (q, J = 8.4 Hz, 8H). ES / MS m / z: C₁₈H₁₃N₄O₂S (M+H) calculated value: 349.07, experimental value: 348.96.

[0312] [Example]

[0117] [:] [4-(4'-(1,5-] [Dimethyl] [-1H-] [Pyrazole] [-3-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₂₀H₁₈N₅O₂(M+H) calculated value: 360.15, experimental value: 360.16.

[0313] [Example]

[0118] [:] [4-(4'-(1,5-] [Dimethyl] [-1H-1,2,3-] [Triazole] [-4-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₇N₆O₂(M+H) calculated value: 361.14, experimental value: 361.13.

[0314] Example 119: 4-(4'-(1H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁸H¹⁴N⁵O₂(M+H) calculated value = 332.11; experimental value 332.14.

[0315] [Example]

[0120] [:] [4-(4'-(1H-1,2,3-] [Triazole] [-1-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₇H₁₃N₆O₂(M+H) calculated = 333.11; experimental value 333.11.

[0316] [Example]

[0121] [:] [4-(4'-(5-] [methyl] [-1H-1,2,3-] [Triazole] [-1-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁸H¹⁵N₆O₂(M+H) calculated value: 347.13, experimental value: 347.09.

[0317] Example 122: 4-(4'-(benzo[d]thiazolyl-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, DMSO-d⁶) 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: C₂₂H₁₅N₄O₂S (M+H) calculated value: 399.09, experimental value: 399.08.

[0318] [Example]

[0123] [:] [4,4'-([1,1'-] [Biphenyl] []-4,4'-] [Two Basics] [)] [pair] [(1H-1,2,3-] [Triazole] [-5-] [Formic acid] [)] [] 4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-1,2,3-triazol-5-carboxylic acid) is a series of ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-carboxylic acid (

[11] ) and ethyl 2-(4-methoxybenzyl)-5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-4-yl)-2H-1,2,3-triazol-4-carboxylate (

[13] ) Prepared by a general procedure similar to the Suzuki reaction, followed by PMB deprotection and ester hydrolysis: ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (s, 4H), 7.86 (d, J = 8.1 Hz, 4H). ES / MS m / z: C₁₈H₁₃N₆O₄(M+H) calculated value: 377.10, experimental value: 377.03.

[0319] [Example]

[0181] [:] [4-(4'-(5,6-] [Dihydrogen] [-4H-] [Cyclopenta] [[d]] [Thiazole] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₂¹H₁₇N₄O₂S (M+H) Calculated value: 389.11, experimental value: 389.11.

[0320] The following compounds were deprotected using a representative procedure similar to the Suzuki reaction and the aforementioned SEM or PMB method, followed by SEM protection of the heterocyclic NH followed by the use of the previously mentioned borate ester intermediate. [6] or [8] Prepared by ester hydrolysis with commercially available heterocyclic bromides: [Example]

[0124] [:] [4-(4'-(1H-)] [Pyrazole] [-4-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, DMSO-d⁶) δ 8.11 (s, 2H), 7.79 (d, J = 14.4 Hz, 4H), 7.72 (s, 4H). ES / MS m / z: C₁₈H₁₄N₅O₂(M+H) calculated value: 332.11, experimental value: 332.07.

[0321] Example 125: 4-(4'-(1H-pyrazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₈H₁₄N₅O₂(M+H) calculated value: 332.11, experimental value: 332.11.

[0322] [Example]

[0126] [:] [4-(4-(1H-)] [Benzoan] [[d]] [Imidazole] [-5-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 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: C¹⁶H¹²N₅O₃(M+H) calculated value: 306.09, experimental value: 306.14.

[0323] [Example]

[0127] [:] [4-(4'-(1H-1,2,3-] [Triazole] [-5-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) δ 7.96 (d, J = 7.6 Hz, 4H), 7.80 (d, J = 7.9 Hz, 5H). ES / MS m / z: C₁₆H₁₂N₅O₃(M+H) calculated value: 333.10, experimental value: 333.07.

[0324] [Example]

[0128] [:] [4-(4'-(1H-)] [Imidazole] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴) δ 7.29–7.05 (m, 4H), 6.95–6.62 (m, 6H). ES / MS m / z: C¹⁸H¹⁴N₅O₂(M+H) calculated value = 332.11; experimental value 332.12.

[0325] [Example]

[0129] [:] [4-(4'-(1H-)] [Imidazole] [-4-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴): 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: C¹⁸H¹⁴N⁵O₂(M+H) calculated value = 332.11; experimental value 332.12.

[0326] [Example]

[0130] [:] [4-(4'-(4-)] [methyl] [-1H-] [Pyrazole] [-3-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, DMSO-d⁶) 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: C₁₉H₁₆N₅O₂(M+H) calculated value = 346.13; experimental value 346.18.

[0327] The following compounds were deprotected using a representative procedure similar to the Suzuki reaction and by SEM with HCl, followed by conversion to The previously mentioned bromide intermediate is used after the borate ester. [4] or

[10] Prepared by ester hydrolysis with commercially available bromides: [Example]

[0131] [:] [4-(4'-(5-] [methyl] [-1H-1,2,3-] [Triazole] [-4-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, D₂O + NaHCO₃) δ 7.5 - 8.0 (m, 8H), 2.48 (s, 3H). ES / MS m / z: C₁₈H₁₅N₆O₂(M+H) Calculated value: 347.13, experimental value: 347.12.

[0328] [Example]

[0132] [:] [4-(6-)] [Chloronaphthalene] [-2-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₃H₉ClN₃O₂(M+H) Calculated value: 274.04, experimental value: 273.96.

[0329] [Example]

[0133] [:] [4-(] [phenanthren-] [-2-] [ylidene] [)-1H-1,2,3-] [triazole] [-5-] [carboxylic acid] [] 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 8.43 (s, 1H), 8.22 - 7.82 (m, 4H), 7.80 - 7.59 (m, 3H). ES / MS m / z: Calculated for C17H12N3O2(M+H) = 290.09; Observed 290.03.

[0330] [Example]

[0134] [:] [4-(7-] [amino] [-9H-] [fluoren-] [-2-] [ylidene] [)-1H-1,2,3-] [triazole] [-5-] [carboxylic acid] [] 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: C₁₆H₁₃N₄O₂(M+H) calculated value: 293.10, experimental value: 293.05.

[0331] [] [Example]

[0135] [:] [5-(3-)] [chlorine] [-4-] [Fluorophenyl] [)-1 , H , -1,2,3- ] [Triazole] [-4-] [Formic acid] []

[0332] [step] [1] 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 min, the reaction mixture was diluted with saturated NaHCO3, and the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography. The product was then dissociated with a hexane solution of ethyl acetate to give an isomeric mixture of methyl 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate: ES / MS m / z: C12H22BrN2OsSi (M+H) Calculated value: 349.05, Experimental value: 348.93.

[0333] [step] [2] [、] [step] [3] [and steps] [4] [] 4-(3-chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid is produced using a procedure similar to the Suzuki reaction, employing (3-chloro-4-fluorophenyl) The acid was then removed by SEM protection with HCl and followed by ester hydrolysis to prepare the following: ¹H NMR (400 MHz, methanol-d⁴) 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: C₁¹H₉ClFN₂O₂ (M+H) calculated value: 255.03, experimental value: 254.94.

[0334] [Example]

[0136] [:] [4-(3-)] [chlorine] [-4-] [Fluorophenyl] [)-3-] [methyl] [-1H-] [Pyrazole] [-5-] [Formic acid] []

[0335] [step] [1] 1-(3-chloro-4-fluorophenyl)ethyl-1-one was added dropwise to a stirred solution of potassium tert-butoxide (6.50 g, 57.9 mmol) in THF (30 mL) under N2 conditions.

[0301] A solution of methyl 3-(3-chloro-4-fluorophenyl)-3-sideoxypropionate (2.97 g, 44%) was prepared in dimethyl carbonate (4.9 mL, 58 mmol) and cooled in a water bath. After 90 min, the reaction mixture was cooled in an ice bath and then quenched with 2 M HCl. The mixture was then extracted with ethyl acetate, and the organic extract was dried (MgSO₄) and concentrated under vacuum. The crude residue was purified by silica gel column chromatography and dissolved in hexane with 0-40% ethyl acetate to give methyl 3-(3-chloro-4-fluorophenyl)-3-sideoxypropionate (2.97 g, 44%). Calculated value of LC / MS m / z: C₁₀H₉ClFO₃(M+H): 231.02, experimental value: 231.0.

[0336] [step] [2] A mixture of methyl 3-(3-chloro-4-fluorophenyl)-3-sideoxypropionate (537 mg, 2.33 mmol), p-methoxybenzyl azide (400 mg, 2.45 mmol), and potassium carbonate (1.36 g, 9.80 mmol) in dimethylformamide (5 mL) was stirred vigorously overnight at 80 °C. After the reaction mixture was cooled and diluted with water, the resulting solid was separated by filtration and further purified by silicone column chromatography, dissolving in a hexane solution of 0-50% ethyl acetate to give methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-carboxylate (400 mg, 43%) as a white solid. ES / MS m / z: C18H16ClFN3O3(M+H) Calculated value: 376.09, experimental value: 376.1.

[0337] [step] [3] [and steps] [4] [] 1M LiOH (1.0 mL, 1.0 mmol) was added to a solution of methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-carboxylate (75 mg, 0.20 mmol) in a 1:1 THF / methanol (2 mL) at room temperature. After stirring for 1 h, the reaction mixture was acidified with 2N HCl and the product was extracted with ethyl acetate (× 3). The combined organic extracts were dried (MgSO4) and concentrated under vacuum. The resulting residue was then dissolved in TFA and stirred at 65 °C for 2 h. After concentrating the reaction mixture under vacuum, the residue was purified by reverse-phase preparative HPLC to give 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-carboxylic acid: ¹H NMR (400 MHz, DMSO-d6) 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: C9H6ClFN3O2(M+H) calculated value: 242.01, experimental value: 242.0.

[0338] [] [Example]

[0137] [:] [4-] [Phenyl] [-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] 4-Phenyl-1H-1,2,3-triazol-5-carboxylic acid was prepared from acetophenone in a manner similar to that described in Example 136: ¹H NMR (400 MHz, DMSO-d6) δ 13.14 (br s, 1H), 7.79 (br s, 2H), 7.51–7.42 (m, 3H). ES / MS m / z: C 9H 8N 3O 2 (m+H) calculated: 190.06, experimental: 190.0.

[0339] Example 138: 4-(3-chlorophenyl)-1H-1,2,3-triazol-5-carboxylic acid 4-(3-chlorophenyl)-1H-1,2,3-triazol-5-carboxylic acid was prepared from 3-chlorophenylacetone in a manner similar to that described in Example 136: ¹H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.80 (br s, 1H), 7.54–7.48 (m, 2H). ES / MS m / z: C9H7ClN3O2 (M+H) calculated value: 224.02, experimental value 224.0.

[0340] [] [Example]

[0139] [:] [4-(] [Pyridine] [-2-] [base] [)-] [1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0341] [step] [1] In a 5 mL microwave-safe vial, an isomer mixture of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate (192 mg, 0.55 mmol), 2-(tributyltinyl)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 for 5 minutes, the resulting mixture was stirred at 110 °C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, and the product was then extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography. The product was then dissociated with a hexane solution of ethyl acetate to give ethyl 5-(pyridin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate: ES / MS m / z: C16H25N4O3Si (M+H) Calculated value: 349.16, Experimental value: 349.05.

[0342] [Step] 2 [and steps] 3 [] 4-(pyridin-2-yl)-1H-1,2,3-triazol-5-carboxylic acid was prepared by ester hydrolysis following a general procedure similar to SEM deprotection with HCl: ¹H NMR (400 MHz, DMSO-d6) 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: C8H7N4O2(M+H) calculated value: 191.05, experimental value: 190.99.

[0343] [Example]

[0140] [:] [4-(] [Pyridine] [-2-] [base] [)-] [1H-] [Pyrazole] [-5-] [Formic acid] [] 4-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid was prepared from 4-(tributyltinalkyl)pyridine in a manner similar to that of Example 141: ¹H NMR (400 MHz, methanol-d⁴) 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: C₈H₈N₃O₂(M+H) calculated value: 190.05, experimental value: 190.00.

[0344] [Example]

[0141] : [4-(] [Thiazole] [-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 4-(thiazol-4-yl)-1H-1,2,3-triazol-5-carboxylic acid was prepared from 4-(tributyltinyl)thiazole in a manner similar to that described in Example 141: ¹H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 8.65 (s, 1H), 3.15 (s, 1H). ES / MS m / z: C₆H₃N₄O₂S (MH) calculated value: 191.05, experimental value: 194.95.

[0345] [Example]

[0142] [and]

[0143] [:] [4-(3'-(] [Dimethylaminomethyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [and] [4-(3'-] [carboxyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0346] [step] [1] The isomer mixture of ethyl 5-(3'-(dimethylaminomethyl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate was prepared from 3-bromo-N,N-dimethylbenzylamine using a general procedure similar to the Suzuki reaction.

[0347] [step] [2] [and steps] [3] [] 4-(3'-(dimethylaminomethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid and 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid were prepared by a general procedure similar to SEM deprotection with HCl, followed by ester hydrolysis. Both compounds were separated by precipitation, followed by preparative HPLC purification.

[0348] [Example]

[0142] [:] [4-(3'-(] [Dimethylaminomethyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁶H¹²N³O₄(M+H) calculated value: 310.07, experimental value: 310.05.

[0349] [Example]

[0143] [:] [4-(3'-] [carboxyl] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₈H₁₇N₄O₃(M+H) Calculated value: 337.12, Experimental value: 337.17.

[0350] [Example]

[0144] [:] [4-(4-(1H-)] [Indazole] [-5-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] []

[0351] [step] [1] To a solution of 5-bromo-1H-indazole (100 mg, 0.49 mmol) in dichloromethane (2.0 mL), p-toluenesulfonic acid (9.0 mg, 0.049 mmol) and 3,4-dihydropiperanone (0.089 mL, 0.97 mmol) were added. After heating the mixture to 35 °C overnight, the reaction mixture was diluted with a saturated aqueous solution of NaHCO3, and the product was extracted with ethyl acetate (× 2). The combined organic layers were washed with water (× 1), dried (Na2SO4), and concentrated. The residue was purified by silicone column chromatography and dissociated with ethyl acetate in hexane to give 5-bromo-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole: ¹H NMR (400 MHz, acetonitrile-d³) 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, OH), 4.01–3.91 (m, 1H), 3.86–3.72 (m, 1H), 3.48 (dd, J = 1.9 Hz, 1H), 2.91 (t, J = 3.8 Hz, OH), 2.91 (m, 1H), 2.91 (t, J = 3.8 Hz, OH ... 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 12H 14BrN 2O (M+H) calculated value = 281.03; experimental value 280.75.

[0352] [step] [2] [、] [3] [and] [4] [] 4-(4-(1H-indazol-5-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid is produced from an intermediate via a general procedure similar to the Suzuki reaction. [6] and 5-bromo-1-(tetrahydro-2H-piperan-2-yl)-1H-indazole, and prepared by deprotection of PMB and THP by TFA followed by ester hydrolysis: 1H NMR (400 MHz, methanol-d4) 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: C15H11ClN3O2(M+H) calculated value: 300.05, experimental value: 300.00.

[0353] [Example]

[0145] [:] [4-(4-(1H-)] [Indazole] [-6-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 4-(4-(1H-indazole-6-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid was prepared from 6-bromo-1H-indazole using a procedure similar to that in Example 146: ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₆H₁₂N₅O₂(M+H) calculated = 306.10; experimental value 306.15.

[0354] [Example]

[0146] [:] [4-(4'-] [chlorine] [-3'-(] [𠰌] [Pinylsulfonyl] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0355] [Steps] [1] At 0°C, 220 mg, 3 mmol of 5-bromo-2-chlorobenzenesulfonyl chloride (366 mg, 10 mmol) was added to a solution of 5-bromo-2-chlorobenzenesulfonyl chloride in 3 mL of THF. After 10 minutes, the reaction mixture was diluted with ethyl acetate and washed with 1 N HCl (×2), water (×1), and saturated NaHCO3 (×1). The resulting organic fraction was dried (MgSO4) and concentrated. The residue was purified by silicone column chromatography and dissolved in hexane solution of 0-100% ethyl acetate to give 4-((5-bromo-2-chlorophenyl)sulfonyl) α-linole: 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).

[0356] [Steps] [2] [、] [3] [and] [4] [] 4-(4'-chloro-3'-(furinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid is produced from intermediates via a general procedure similar to the suzuki reaction. [6] and 4-((5-bromo-2-chlorophenyl)sulfonyl) iodine, and PMB deprotection followed by ester hydrolysis to prepare: 1H NMR (400 MHz, methanol-d4) 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: C19H18ClN4O5S (M+H) calculated value: 449.06, experimental value: 449.16.

[0357] [Example]

[0147] [:] [4-(3-)] [Bromophenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0358] [Steps] [1] The isomer mixture of methyl 5-(3-aminophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate was prepared using intermediates in a manner similar to the general procedure of the Suzuki reaction. [4'] and (3-aminophenyl) Preparation of acid: ES / MS m / z: C 16H 25N 4O 3Si (M+H) Calculated value: 347.17, experimental value: 348.96.

[0359] [Steps] [2] [:] [] Add 0.042 mL of tert-butyl nitrite (0.35 mmol) and copper(II) bromide (78 mg, 0.35 mmol) to a solution of methyl 4-(3-aminophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-5-carboxylate (102 mg, 0.29 mmol) in 3 mL of acetonitrile at 0 °C. After 30 minutes, the reaction mixture was diluted with saturated NaHCO3, and the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography. The product was then dissociated with a hexane solution of ethyl acetate to give a mixture of isomers of methyl 5-(3-bromophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate: 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).

[0360] [step] [3] [and steps] [4] 5-(4-Bromophenyl)-1H-1,2,3-triazol-4-carboxylic acid was prepared by ester hydrolysis following a general procedure similar to SEM deprotection with HCl: ¹H NMR (400 MHz, methanol-d⁴) 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: C₉H₇BrN₃O₂ (M+H) calculated value: 267.96, experimental value: 267.90.

[0361] [Example]

[0148] [:] [4-(2-)] [chlorine] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0362] [step] [1] [and] [2] [] The isomer mixture of methyl 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate is similar to [Example]

[0149] , [step] [1] [and] [2] The procedure was used to prepare 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)aniline: ES / MS m / z: C 16H 22BrClN 3O 3Si (M+H) Calculated value: 446.03, experimental value: 445.69.

[0363] [step] [3] [、] [step] [4] [and steps] [5] [] 4-(2-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid uses phenyl groups in a manner similar to the general procedure of the Suzuki reaction. The acid was prepared by SEM deprotection with HCl and ester hydrolysis: ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₁ClN₃O₂(M+H) calculated value: 300.05, experimental value: 300.00.

[0364] [Example]

[0149] [:] [4-(2,4'-] [Dichloro] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid is produced by a general procedure similar to the Suzuki reaction, consisting of an isomeric mixture of methyl 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylic acid and 4-chlorophenyl The acid was then prepared by a general procedure of SEM deprotection with HCl and ester hydrolysis: ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₀Cl₂N₃O₂ (M+H) calculated value: 334.01, experimental value: 333.97.

[0365] [Example]

[0150] [:] [4-(3-)] [chlorine] [-4-] [Fluorophenyl] [)-1-] [methyl] [-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] NaH (6 mg of 60% oil suspension) was added to a solution of 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazol-4-carboxylic acid (10 mg, 0.038 mmol) in 0.5 mL of DMF at 0 °C. After 10 min, iodomethane (7 µL, 0.11 mmol) was added at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min. After quenching the reactants by adding methanol, the product was purified by HPLC to obtain 5-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazol-4-carboxylic acid: 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: C10H6ClFN3O2(MH) calculated value: 254.01, experimental value: 253.96.

[0366] [Example]

[0151] [:] [4-(4'-(1-] [methyl] [-1H-1,2,3-] [Triazole] [-5-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0367] [step] [1] An oil suspension (48 mg, 1.2 mmol) containing 60% NaH was added to a solution of 4-(4-bromophenyl)-1H-1,2,3-triazole (242 mg, 1.05 mmol) in 2 mL DMF at 0 °C. After 10 min, iodomethane (71 µL, 1.1 mmol) was added at 0 °C, and the resulting mixture was stirred at 0 °C for 10 min. The reaction mixture was extracted with ethyl acetate and brine, the organic layer was concentrated and purified by silicone column chromatography, and dissociated with ethyl acetate and hexane to give 5-(4-bromophenyl)-1-methyl-1H-1,2,3-triazole: ES / MS m / z: C9H9BrN3(M+H) Calculated value: 237.99, experimental value: 238.09.

[0368] [step] [2] [、] [step] [3] [and steps] [4] [] 4-(4'-(1-methyl-1H-1,2,3-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid is produced by a general procedure similar to the Suzuki reaction from compounds...

[28] Subsequently, the ester was prepared by SEM deprotection with HCl and ester hydrolysis: ¹H NMR (400 MHz, DMSO-d₆) 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: C₁₈H₁₅N₆O₂(M+H) calculated value: 347.12, experimental value: 347.04.

[0369] [Example]

[0152] [:] [4-(4-(2,3,3-] [Trimethyl] [-1-] [Side-oxyisoindoline] [-5-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0370] [step] [1] Mineral oil (43 mg, 1.08 mmol) containing 60% sodium hydride 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 min, methyl iodoform (0.1 mL, 1.61 mmol) was added to the reaction mixture. The resulting solution was stirred at 0 °C for 1 h. The reaction mixture was diluted with ethyl acetate (~25 mL) and then washed with ~50% saturated NH4Cl solution. After extraction of the aqueous fraction with ethyl acetate (25 mL × 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silicone column chromatography and dissolved in 0-100% EA / hexane to give 5-bromo-2,3,3-trimethylisoindolin-1-one: ES / MS m / z: C 11H 13BrNO (M+H) Calculated value: 254.02, experimental value: 254.12.

[0371] [step] [2] [、] [step] [3] [and steps] [4] [] 4-(4-(2,3,3-trimethyl-1-sideoxyisoindoline-5-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid is produced from intermediates in a manner similar to the general procedure used for the Suzuki reaction. [6] and 5-bromo-2,3,3-trimethylisoindololin-1-one, after PMB protection removal, were prepared by ester hydrolysis: ¹H NMR (400 MHz, DMSO-d6) 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: C20H19N4O3(M+H) calculated value: 363.15, experimental value: 363.12.

[0372] Example 153: 4-(4-(3,3-dimethyl-1-sideoxy-2-(2,2,2-trifluoroethyl)isoindoline-5-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid 4-(4-(3,3-dimethyl-1-sideoxy-2-(2,2,2-trifluoroethyl)isoindoline-5-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid was prepared from 5-bromo-3,3-dimethylisoindoline-1-one using a procedure similar to that in Example 154 with 2,2,2-trifluoroethyl trifluoromethanesulfonate: 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 21H 18F 3N 4O 3(M+H) Calculated value: 431.13, experimental value: 431.15.

[0373] [Example]

[0154] [:] [4-(9-)] [methyl] [-9H-] [Carbazole] [-2-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0374] [step] [1] 5-(9H-carbazole-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylic acid ethyl ester is produced from an intermediate in a manner similar to the general procedure used for the Suzuki reaction. [4] and 2-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-9H-carbazole were used to prepare it.

[0375] [step] [2] Ethyl 5-(9H-carbazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazol-4-carboxylate (0.060 g; 0.068 mmol) in dimethylformamide (1 mL) was mixed with mineral oil (0.008 g; 0.21 mmol) containing 60% sodium hydride and stirred for 30 min, followed by the addition of MeI (0.009 mL; 0.13 mmol). The solution was stirred overnight at room temperature. Once complete, the mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH4Cl (1 mL). After extraction of the aqueous fraction with ethyl acetate (2 × 10 mL), the organic fraction was combined and washed with 5% LiCl (3 × 5 mL). Finally, the organic fraction was washed with water (5 mL), dried (Na₂SO₄), and concentrated to dryness. It was then purified by silica gel column chromatography and dissolved in ethyl acetate in hexane to obtain ethyl 5-(9-methyl-9H-carbazole-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylic acid: ES / MS m / z, C₂₄H₃¹N₄O₃Si (M+H) calculated value = 451.22, experimental value 450.90.

[0376] [step] [3] 4-(9-methyl-9H-carbazole-2-yl)-1H-1,2,3-triazol-5-carboxylic acid was prepared by ester hydrolysis following a procedure similar to the general procedure of SEM deprotection by TBAF: ¹H NMR (400 MHz, methanol-d⁴) 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 16H 11N 4O 2(MH) calculated value = 291.09; experimental value 291.11.

[0377] [Example]

[0155] [:] [4-(4-(6-(1H-1,2,3-] [Triazole] [-4-] [base] [)] [clatter] [𠯤] [-3-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] []

[0378] [] [step] [1] The isomer mixture of ethyl 5-(4-(6-bromopyridyl-3-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate is derived from intermediates [6] and 3,6-dibromopyridyl are used in a manner similar to the preparation of intermediates.

[10] The calculated value of ES / MS m / z: C 21H 27BrN 5O 3Si (M+H) was 504.11, and the experimental values ​​were 504.14 and 504.18.

[0379] [step] [2] [、] [step] [3] [and steps] [4] [] 4-(4-(6-(1H-1,2,3-triazol-4-yl)pyridyl-3-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid is produced by a general procedure similar to the Suzuki reaction from compounds...

[28] Subsequently, the ester was prepared by SEM deprotection with HCl and ester hydrolysis: ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₁N₈O₂(M+H) calculated value: 335.10, experimental value: 335.11.

[0380] [Example]

[0156] [:] [4-(4-(5-(1H-1,2,3-] [Triazole] [-4-] [base] [)] [Pyr] [𠯤] [-2-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [] 4-(4-(5-(1H-1,2,3-triazol-4-yl)pyridine-2-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid was prepared from 2,5-dibromopyridine using a procedure similar to that in Example 157: ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₅H₁₁N₈O₂(M+H) calculated value: 335.10, experimental value: 335.10.

[0381] [Example]

[0157] [:] [4-(3'-] [methyl] [-4'-(1H-1,2,3-] [Triazole] [-5-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0382] [Steps] [1] The isomer mixture of ethyl 5-(4-(6-bromodal-3-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate is composed of intermediates [6] and 1-bromo-4-iodo-2-toluene as analogous to intermediates in the preparation process

[10] The calculated value of ES / MS m / z: C 24H 31BrN 3O 3Si (M+H) was 516.11, and the experimental value was 516.02.

[0383] [step] [2] [、] [step] [3] [and steps] [4] [] 4-(3'-methyl-4'-(1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid is produced by a general procedure similar to the Suzuki reaction from compounds...

[28] Subsequently, the ester was prepared by SEM deprotection and ester hydrolysis with HCl: ¹H NMR (400 MHz, methanol-d⁴) 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: C¹⁸H¹⁵N⁶O₂S (M+H) calculated value: 347.12, experimental value: 347.15.

[0384] [Example]

[0158] [:] [4-(4'-] [chlorine] [-2-] [Cyano] [-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0385] [step] [1] 5-Bromo-2-iodobenzonitrile (1000 mg; 3.25 mmol) and (4-chlorophenyl) The 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 in a flask and purged with Ar for 5 min. The reaction mixture was then heated to 60 °C and held for 70 min. The reaction mixture was then diluted with water and extracted with ethyl acetate, filtered through diatomaceous earth / celite, and concentrated to dryness under reduced pressure. The crude reaction mixture was purified by rapid chromatography (0 to 100% ethyl acetate in hexane) to give 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carboxynitrile: 1H 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).

[0386] [step] [2] 4'-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-2-carboxylonitrile is prepared from 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carboxylonitrile using a procedure similar to that used in the preparation of borate esters.

[0387] [step] [3] [、] [4] [and] [5] [] 4-(4'-chloro-2-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid is produced by a general procedure similar to the Suzuki reaction from compounds... [4] and 4'-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-[1,1'-biphenyl]-2-carboxynitrile, which were then prepared by SEM deprotection and ester hydrolysis using TBAF: 1H NMR (400 MHz, methanol-d4) 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: C16H10ClN4O2(M+H) calculated = 325.05; experimental value 325.03.

[0388] [Example]

[0159] [:] [4-(4'-(1H-)] [Imidazole] [-1-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0389] [step] [1] Dipalladium (20 mg; 0.0039 mmol), 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-bidiphenyl (8 mg; 0.016 mmol), and tripotassium phosphate (83 mg, 0.39 mmol) were placed in a reaction vessel and the headspace was purged with nitrogen for 10 minutes. Separately, imidazole (16 mg; 0.23 mmol) and 5-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate (98 mg; 0.2 mmol) were dissolved in 5:1 (v / v) toluene-dimethylalkanes (3.0 mL) and purged with nitrogen for 10 minutes. The imidazole solution was added to the reaction vessel and the reaction was heated to 110°C until the reaction was complete. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH₄Cl (3 × 5 mL) solution. The aqueous layer was extracted with ethyl acetate (2 × 5 mL) and the combined organic fractions were washed with water (2 × 5 mL). Finally, the organic fraction was dried (Na₂SO₄) and concentrated to dryness, followed by purification by silica gel column chromatography and dissolution with ethyl acetate in hexane to give ethyl 5-(4'-(1H-imidazol-1-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate: ES / MS m / z: C₂₆H₃₂N₅O₃Si (M+H) Calculated value = 490.23; Experimental value 490.39.

[0390] [step] [2] [and] [3] 4-(4'-(1H-imidazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid was prepared by ester hydrolysis following a general procedure similar to SEM deprotection via TBAF: 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: C₁₈H₁₄N₅O₂(M+H) calculated = 332.11; experimental value 332.14.

[0391] [Example]

[0160] [:] [4-((4-] [Chlorophenyl] [)] [Ethyne group] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0392] [step] [1] Ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate (114 mg, 0.033 mmol), copper iodide (I) (19 mg, 0.0098 mmol), 1-chloro-4-acetylene (55 mg, 0.40 mmol), triethylamine (0.363 mL, 3 mmol), and dichlorobis(triphenylphosphine)palladium (II) (41 mg; 0.0065 mmol) in acetonitrile (3 mL) were purged with nitrogen for 10 min and heated to 60°C overnight. Additional copper iodide (I) and dichlorobis(triphenylphosphine)palladium (II) were added as needed to improve the desired product conversion. Once LC / MS was deemed sufficiently complete, the reactants were diluted with ethyl acetate (10 mL) and filtered through diatomaceous earth. The filtrate was washed with saturated NH4Cl (2 × 9 mL) and NaHCO3 (aqueous solution). The aqueous layer was extracted with ethyl acetate (1 × 10 mL). The combined organic compounds were washed with water (1 × 10 mL), dried (Na₂SO₄), and concentrated. They were then purified by silica gel column chromatography, dissociated with a hexane solution of 0-100% ethyl acetate, to give ethyl 5-((4-chlorophenyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate: ¹H NMR (400 MHz, acetonitrile-d₃) δ 7.64–7.56 (m, 1H), 7.52–7.45 (m, 1H), 5.98 (d, J = 9.7 Hz, 1H), 5.72 (s, OH), 4.51–4.37 (m, 1H), 3.75–3.58 (m, 1H), 2.14 (s, 2H), 2.11 (d, J = 1.2 Hz, 0H), 1.45 - 1.34 (m, 2H), 1.29 (s, 0H), 0.97 - 0.83 (m, 1H). ES / MS m / z, calculated value of C 19H 25ClN 3O 3Si (M+H) = 406.14; experimental value 406.86.

[0393] [step] [2] [and] [3] [] 4-((4-chlorophenyl)ethynyl)-1H-1,2,3-triazol-5-carboxylic acid was prepared by SEM deprotection using a standard procedure with TBAF followed by ester hydrolysis: ¹H NMR (400 MHz, methanol-d⁴) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H). ES / MS m / z: C₁₁H₇ClN₃O₂(M+H) calculated = 248.02; experimental value: 247.96.

[0394] [Example]

[0161] [:] [4-(1-(] [Oxygen] [-3-] [base] [)] [piperidine] [-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0395] [step] [1] In a microwave reaction flask, add an isomer mixture of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate ( [4], 285 mg, 0.814 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester (277 mg, 0.89 mmol), tetra(triphenylphosphine)palladium(O) (94 mg, 0.081 mmol), 2N potassium carbonate (1022 mL, 2 mmol) and 1,4-dimethylacetate (4 mL). After purging with argon for 5 minutes, the resulting mixture was stirred at 110 °C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, and the product was then extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography. The product was then dissolved in a hexane solution of ethyl acetate to give 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester: ES / MS m / z: C21H36N4O5Si (M+H) Calculated value: 453.25, Experimental value: 452.68.

[0396] [step] [2] A solution of 120 mg (0.27 mmol) of tert-butyl 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid in 1,4-dimethyl ether (2 mL) containing 4 N HCl was stirred overnight at room temperature. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography and dissolved in methanol / ethyl acetate to give impure ethyl 4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-1,2,3-triazol-5-carboxylic acid: ES / MS m / z: C 10H 15N 4O 2(M+H) Calculated value: 223.11, Experimental value: 223.01.

[0397] [step] [3] A mixture of ethyl 4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-1,2,3-triazol-5-carboxylate (22 mg, 0.01 mmol) and 10% palladium / carbon (20 mg) in ethanol (1 mL) was stirred for 2 h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give ethyl 4-(piperidin-4-yl)-1H-1,2,3-triazol-5-carboxylate: ES / MS m / z: C10H17N4O2(M+H) Calculated value: 225.13, Experimental value: 225.17.

[0398] [step] [4] Ethyl 4-(piperidin-4-yl)-1H-1,2,3-triazol-5-carboxylate (22 mg, 0.01 mmol) and 3-oxonone (35 mg, 0.05 mmol) in THF (1 mL) were supplemented with sodium triacetoxyborohydride (104 mg, 0.05 mmol), followed by 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 give ethyl 4-(1-(oxon-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-5-carboxylate: ES / MS m / z: C 13H 21N 4O 3(M+H) Calculated value: 281.15, Experimental value: 281.18.

[0399] [step] [5] [:] [] 4-(1-(oxo-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-5-carboxylic acid is prepared from ethyl 4-(1-(oxo-3-yl)piperidin-4-yl)-1H-1,2,3-triazol-5-carboxylic acid by a procedure similar to that of ester hydrolysis: ¹H NMR (400 MHz, methanol-d⁴): 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 11H 17N 4O 3(M+H) Calculated value: 253.12, Experimental value: 253.13.

[0400] [Example]

[0162] [:] [4-(4-(1-] [acetyl] [-1,2,3,6-] Tetrahydropyridine [-4-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0401] [step] [1] The isomer mixture of 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester is derived from intermediates

[11] and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester were prepared by a general procedure similar to the Suzuki reaction: ES / MS m / z: C 29H 35N 4O 5(M+H) Calculated value: 519.26, Experimental value: 518.98 and 518.96.

[0402] [step] [2] To a flask containing a mixture (128 mg, 0.25 mmol) of isomers of 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tributyl ester, 1,4-dimethyl alkylene (3 mL) containing 4 N HCl was added, and the mixture was stirred at room temperature for 15 min. After complete concentration of the solution, acetic anhydride (0.05 mL, 0.53 mmol) was added to the residue and dichloromethane (3 mL) containing pyridine (0.05 mL, 0.62 mmol) at 0 °C. After 30 min at 0 °C and 30 min at room temperature, the reaction mixture was diluted with ethyl acetate (~25 mL) and washed with saturated ammonium chloride aqueous solution (× 1), saturated sodium bicarbonate aqueous solution (× 1), and brine (× 1). After extraction of the aqueous fraction with ethyl acetate (~20 mL × 1), the organic fractions were combined, dried (MgSO₄), and concentrated. The residue was purified by silica gel column chromatography with a hexane solution of 50-100% ethyl acetate followed by dissolution with 0-20% methanol / ethyl acetate to give an isomer mixture of ethyl 5-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-carboxylic acid: ES / MS m / z: C₂₆H₂₉N₄O₄ (M+H) Calculated value: 461.22, Experimental values: 460.94 and 461.17.

[0403] [step] [3] [and steps] [4] [] 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid was prepared by a general procedure similar to PMB deprotection followed by ester hydrolysis: ¹H NMR (400 MHz, methanol-d4) δ 7.82 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 6.24 (s, 1H), 4.23 (dq, J = 5.8, 2.6 Hz, 2H), 3.81 (t, J = 5.8 Hz, 0.83H), 3.76 (t, J = 5.7 Hz, 1.17H), 2.66 (d, J = 6.6 Hz, 1.17H), 2.59 (s, 0.83H), 2.18 (s, 1.755H), 2.15 (s, 1.245H). ES / MS m / z: Calculated value of C 16H 17N 4O 3(M+H): 313.13, experimental value: 313.10.

[0404] [Example]

[0163] [:] [4-(4-(1-] [Ethylpiperidine] [-4-] [base] [)] [Phenyl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0405] [step] [1] To a flask containing an isomer mixture of ethyl 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazol-5-carboxylate (the product of step 2 in Example 164, 55 mg, 0.12 mmol), 20% palladium hydroxide / carbon (6.6 mg) and ethanol (4 mL) were added, and the resulting mixture was stirred at room temperature under a H₂ atmosphere for 3.5 h. The reaction mixture was diluted with methanol and dichloromethane, and then filtered through a diatomaceous earth mat. After washing the diatomaceous earth mat with ethanol, the filtrate was completely concentrated and co-evaporated with toluene (× 1) to obtain a crude isomer mixture of ethyl 5-(4-(1-acetylopirin-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-carboxylate: ES / MS m / z: C 26H 31N 4O 4 (M+H) Calculated value: 463.23, experimental values: 463.04 and 463.06.

[0406] [step] [2] [and steps] [3] [] 4-(4-(1-acetylopiridine-4-yl)phenyl)-1H-1,2,3-triazol-5-carboxylic acid was prepared by a general procedure similar to PMB deprotection followed by ester hydrolysis: ¹H NMR (400 MHz, methanol-d⁴) 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 16H 19N 4O 3(M+H) calculated value: 315.15, experimental value: 315.14.

[0407] [Example]

[0164] [:] [4-(4'-(] [Pyr] [𠯤] [-2-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0408] [Steps] [1] Pyridine (200 mg; 2 mmol), 4-bromo-phenyl A mixture of 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 ferric acetylpyruvate (iii) (440 mg, 1 mmol) in CH₂Cl₂ (10 mL) and water (10 mL) was stirred overnight at ambient temperature. The reaction mixture was diluted with CH₂Cl₂ (10 mL) and water (10 mL), and solid potassium carbonate was added until pH > 8. After separating the two layers, the aqueous fraction was extracted with dichloromethane (2 × 10 mL), and the combined organic fraction was dried (Na₂SO₄), concentrated, and purified by silica gel column chromatography. It was then dissolved in a hexane solution of 0-100% ethyl acetate to give 2-(4-bromophenyl)pyridine: 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). The calculated value of ES / MS m / z, C 10H 8BrN 2(m+H) is 234.99; the experimental value is 235.05.

[0409] [step] [2] [、] [3] [and] [4] [] 4-(4'-(pyridine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid is derived from 2-(4-bromophenyl)pyridine, using the representative procedure of the Suzuki reaction from intermediates. [6] It was synthesized by SEM deprotection with HCl and ester hydrolysis. ¹H NMR (400 MHz, DMSO-d6) 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 19H 14N 5O 2(M+H) calculated value = 344.11; experimental value 344.04.

[0410] [Example]

[0165] [:] [4-(4'-(1H-1,2,4-] [Triazole] [-5-] [base] [)-[1,1'-] [Biphenyl] []-4-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0411] [step] [1] The isomer mixture of 5-(4'-aminomethyl-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylic acid ethyl ester was prepared by a general procedure similar to the Suzuki reaction from 4-bromobenzylamine and intermediates. [6] The calculated value of ES / MS m / z:C24H30N4O4Si (M+H) was 467.2; the experimental value was 467.16.

[0412] [step] [2] Ethyl 5-(4'-aminomethoxy-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate (117 mg; 0.25 mmol) in THF (1 mL) was added to a solution of ethyl 5-(4'-(((dimethylamino)methylene)aminomethoxy)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate. The mixture was then heated to 60 °C until the starting material was exhausted and (E)-5-(4'-(((dimethylamino)methylene)aminomethoxy)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate was obtained. The material from this reaction was used directly for… [step] [3]: The calculated value of ES / MS m / z:C 27H 35N 5O 4Si (M+H) is 522.25; the experimental value is 522.11.

[0413] [step] [3] Towards [step] [2] The reaction mixture was added with hydrazine (39 µL; 1 mmol) and acetic acid (109 µL; 2.0 mmol) 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 × 5 mL). After extraction of the aqueous fraction with ethyl acetate (2 × 10 mL), the organic fractions were combined, washed with 1N HCl (5 mL) and water (5 mL), dried (Na2SO4), and concentrated to dryness. The crude product, ethyl 5-(4'-(1 H-1,2,4-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2 H-1,2,3-triazol-4-carboxylate, was used directly without further purification. [step] [4]: 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 25H 30N 6O 3Si (M+H) calculated value = 491.21; experimental value 491.25.

[0414] [step] [4] [and] [5] 4-(4'-(1H-1,2,4-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid was prepared by ester hydrolysis following a general procedure similar to the SEM deprotection with HCl: ¹H NMR (400 MHz, DMSO-d⁶) δ 8.49 (s, 1H), 8.15–8.08 (m, 2H), 7.96–7.81 (m, 6H). ES / MS m / z, C₁₇H₁₃N₆O₂(m+H) calculated 333.10; experimental 333.11.

[0415] Example 166: 4-(7-bromo-9H-furan-2-yl)-1H-1,2,3-triazol-5-carboxylic acid

[0416] [step] [1] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxoboron-2-yl)-9H-furo-2-amine is synthesized using a bis( (Base) diborone (

[27] ) to prepare.

[0417] [step] [2] The isomer mixture of ethyl 5-(7-amino-9-H-en-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate is derived from intermediates [4] and 7-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-9H-fu-2-amine were prepared by a general procedure similar to the Suzuki reaction: ES / MS m / z: C 24H 31N 4O 3Si (M+H) Calculated value: 451.22, experimental value: 451.33.

[0418] [step] [3] At 0 °C, tert-butyl nitrite (0.32 mL, 2.69 mmol) and copper(II) bromide (595 mg, 2.66 mmol) were added to a solution of ethyl 5-(7-amino-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (1.00 g, 2.22 mmol) in acetonitrile (12 mL). After 45 min, the reaction mixture was quenched with 1 M Na2S2O3 solution and the product was extracted with ethyl acetate. The extract was dried (MgSO4), concentrated and purified by silica gel column chromatography, eluting with hexane solution of 0 - 100% ethyl acetate to give a mixture of ethyl 5-(7-bromo-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate and the deamination by-product. The mixture was used in the next reaction without further purification.

[0419] [Step] [4] [and] [5] [ ] 4-(7-Bromo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a similar manner to the general procedure for SEM deprotection by HCl and ester hydrolysis: 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: Calculated for C16H11BrClN3O2(M+H): 355.92, found: 356.00.

[0420] [Example]

[0167] [:] [4-(7-] [chloro] [-9H-] [fluoren] [-2-] [yl] [)-1H-1,2,3-] [triazole] [-5-] [Formic acid] [] 4-(7-Chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (

[56] ) was prepared in a manner similar to the procedure of Step 3 of Example 168 using copper(II) chloride instead of copper(II) bromide, followed by the general procedure of SEM deprotection with HCl and ester hydrolysis: 1H NMR (400 MHz, methanol-d4) δ 8.03 (s, 1H), 7.94 - 7.81 (m, 3H), 7.60 (s, 1H), 7.39 (dd, J = 8.1, 1.9 Hz, 1H), 3.99 (s, 2H). ES / MS m / z: Calculated for C16H11ClN3O2(M+H): 312.05, found: 311.93.

[0421] [Example]

[0168] [:] [4-(7-(1H-1,2,3-] [Triazole] [-4-] [yl] [)-9H-] [Fluorene] [-2-] [yl] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] []

[0422] [Step] [1] Ethyl 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared in a manner similar to the representative procedure for the synthesis of boronic esters of aromatic bromides using bis( [ylidene)diboron (

[27] ) to prepare.

[0423] [step] [2] [、] [3] [and] [4] [] 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fumon-2-yl)-1H-1,2,3-triazol-5-carboxylic acid is produced via a general procedure similar to the Suzuki reaction, consisting of ethyl 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-9H-fumon-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylic acid and its borate ester.

[28] , then prepared by SEM deprotection with HCl and ester hydrolysis: ¹H NMR (400 MHz, methanol-d⁴) 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 18H 13N 6O 2(M+H) calculated value: 345.10, experimental value: 345.11.

[0424] [Example]

[0169] [:] [4-(9,9-] [Difluoride] [-7-(1H-1,2,3-] [Triazole] [-4-] [base] [)-9H-] [茀] [-2-] [基] [)-1H-1,2,3-] [三唑] [-5-] [甲酸] [] []

[0425] [] [步骤] [1] 4-(7-Bromo-9,9-difluoro-9H-fluoren-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 boronic ester

[28] in a manner similar to the general procedure of the Suzuki reaction: ES / MS m / z: Calculated value for C 21H 23BrF 2N 3OSi (M+H): 478.08, Experimental value: 477.76.

[0426] [步骤] [2] 4-(9,9-Difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole was prepared from 4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole in a manner similar to the representative procedure for the synthesis of boronic esters of aromatic bromides, using bis( radical) diboron (

[27] ): ES / MS m / z: Calculated value for C 27H 35BF 2N 3O 3Si (M+H): 526.25, Experimental value: 525.96.

[0427] <s [步骤] [3] [、步骤] [4] [And steps] [5] [] 4-(9,9-Difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid is prepared in a manner similar to the general procedure of the Suzuki reaction using the intermediate [4] and 4-(9,9-Difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole, followed by SEM deprotection and ester hydrolysis with HCl: 1H NMR (400 MHz, methanol-d4) δ 8.45 - 8.01 (m, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 8.13 - 8.01 (m, 2H), 7.85 (t, J = 7.0 Hz, 2H). ES / MS m / z: Calculated for C18H11F2N6O2(M+H): 381.09, Found: 38I.06.

[0428] [Examples]

[0170] [:] [4-(9,9-] [Difluoro] [-7-(1H-1,2,3-] [Triazole] [-4-] [yl] [)-9H-] [Fluorene] [-2-] [yl] [)-1H-] [Pyrazole] [-5-] [Formic acid] [] 4-(9,9-Difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-pyrazole-5-carboxylic acid is prepared from the intermediate in a manner similar to the general procedure of the Suzuki reaction

[15] And 4-(9,9-difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid, which was prepared by SEM deprotection and ester hydrolysis with HCl: 1H NMR (400 MHz, methanol-d4) 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: Calculated value for C19H12F2N5O2(M+H): 380.10, Experimental value: 380.11.

[0429] [Example]

[0171] [:] [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] [] []

[0430] [] <00, "05066"> [Steps] [1] Dissolve 2,7-dibromo-9,9-difluoro-9H-fluorene (2000 mg, 5.56 mmol), bis( [[ID=http: / / www.w3.org / 2001 / XMLSchema-instance" xmlns:xsi="http: / / www.w3.org / 2001 / XMLSchema-instance"> A mixture of diboron (5646 mg, 22.2 mmol), dichloro-1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloromethane (679 mg, 0.83 mmol), and potassium acetate (2903 mg, 29.6 mmol) in 1,4-dimethylamine (50 mL) was purged with argon for 15 min and then stirred at 80 °C for 16 h. The reaction mixture was completely concentrated, and the residue was dissolved in ethyl acetate (~300 mL) and washed with water (~250 mL × 2). After extraction of the aqueous fraction with ethyl acetate (~100 mL × 1), the organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified by silicone column chromatography and dissociated with hexane solution of 0-20% ethyl acetate to give 2,2'-(9,9-difluoro-9H-furo-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxoboron): 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). Massless.

[0431] [step] [2] The isomer mixture of ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)-9H-fu-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-carboxylate was obtained from an intermediate via a general procedure similar to the Suzuki reaction. [4] and 2,2'-(9,9-difluoro-9H-furo-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxoboron) were used to prepare the ES / MS m / z: C 30H 39BF 2N 3O 5Si (M+H) Calculated value: 598.27, experimental value: 597.81 and 597.67.

[0432] [step] [3] [、] [step] [4] [and steps] [5] [] 4-(7-(1,5-Dimethyl-1H-1,2,3-triazol-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 the Suzuki reaction using an isomeric mixture 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, followed by SEM deprotection with HCl and ester hydrolysis: 1H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 4.06 (s, 3H), 2.54 (s, 3H). ES / MS m / z: Calculated for C20H15F2N6O2(M+H): 409.12, found: 409.14.

[0433] [Example]

[0172] [:] [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] [] 4-(9,9-Difluoro-7-(2-methyl-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of the Suzuki reaction, using 4-bromo-2-methyl-2H-1,2,3-triazole and an isomeric mixture of ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate, followed by SEM deprotection with HCl and ester hydrolysis: 1H NMR (400 MHz, methanol-d4) 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: Calculated for C19H13F2N6O2(M+H): 395.11, Found: 395.03.

[0434] [Example]

[0173] [:] [4-(6-] [chloro] [-9H-] [fluorene] [-2-] [yl] [)-1H-1,2,3-] [triazole] [-5-] [carboxylic acid] []

[0435] [Step] [1] A mixture of 1-bromo-4-iodobenzene (1.00 g, 3.5 mmol), 4-chlorobenzonitrile (973 mg, 7.1 mmol), palladium(II) bis(acetonitrile)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. After 15 min, water (64 µL) was slowly added dropwise to the mixture while purging with argon. After 1 min, the flask was kept tightly sealed and heated to 140 °C for 90 h. After cooling, the reaction mixture was diluted with dichloromethane, filtered through a diatomaceous earth mat, and the resulting filtrate was concentrated. After dissolving the residue in an aqueous solution of dichloromethane and HCl, the insoluble material was filtered again through a diatomaceous earth mat to separate the two layers of the filtrate. The organic fraction was dried (MgSO4), concentrated, and purified by silicone column chromatography. It was then dissolved in hexane with 0-100% ethyl acetate to give 2-bromo-6-chloro-9-furon-9-one.

[0436] [step] [2] 1 M triethyllithium borohydride (0.34 mL) was added to a solution of 2-bromo-6-chloro-9-H-furan-9-one (33 mg, 0.11 mmol) in tetrahydrofuran (1 mL) at -78 °C. After 25 min, the reaction mixture was quenched with a saturated aqueous solution of NH₄Cl. After extraction of the product with ethyl acetate (× 4), the organic extracts were combined, washed with brine (× 1), dried (MgSO₄), and concentrated to give crude 2-bromo-6-chloro-9-H-furan-9-ol for the next step.

[0437] [step] [3] Triethylsilane (0.3 mL) and trifluoroacetic acid (0.3 mL) were added to crude 2-bromo-6-chloro-9-H-furon-9-ol, and the resulting mixture was stirred at room temperature for 1.7 h. After concentration, the residue was purified by silica gel column chromatography and dissolved in hexane solution of 0-100% ethyl acetate to give 2-bromo-6-chloro-9-furon.

[0438] [step] [4] 2-bromo-6-chloro-9-entaenia (27 mg, 0.095 mmol), bis( A mixture of 29 mg (0.11 mmol) of ferroxene (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (7.8 mg, 9.5 µmol) and potassium acetate (28 mg, 0.29 mmol) in dimethyl ether (1.5 mL) was placed in a microwave-safe reaction flask and purged with argon. After stirring the resulting mixture at 95 °C for 2.25 h and cooling, the mixture was diluted with water and extracted with ethyl acetate (× 4). The combined organic extracts were dried (MgSO4), concentrated, and purified by silica gel column chromatography, followed by dissolution with 0-100% ethyl acetate in hexane to give 2-(6-chloro-9H-furo-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron(II).

[0439] [step] [5] [,step] [6] [and steps] [7] 4-(6-chloro-9-sideoxy-9H-furan-2-yl)-1H-1,2,3-triazol-5-carboxylic acid is produced using an intermediate in a manner similar to the general procedure of the Suzuki reaction. [4] and 2-(6-chloro-9-H-furo-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboron, were subsequently deprotected by SEM and hydrolyzed by HCl: 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 16H 11ClN 3O 2(M+H) Calculated value: 312.05, Experimental value: 311.96.

[0440] Example 174: 4-(2-(piperidin-4-yl)-4'-(1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid []

[0441] [] [step] [1] 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-dioxoboron-2-yl)benzene ( [5] A mixture of 1.93 g (5.84 mmol) and tetra(triphenylphosphine)palladium(0) (168 mg, 0.15 mmol) in 2 M potassium carbonate (2.9 mL) and 1,4-dimethylamine (15 mL) was purged with Ar for 10 min in a 20 mL microwave flask and then stirred at 110 °C for 1.25 h. The reaction mixture was dissolved in ethyl acetate (~100 mL) and washed with ~50% saturated NaHCO3 (× 1) and water (× 1). After extraction of the aqueous fraction with ethyl acetate (~50 mL × 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography and dissolved in hexane solution of 0-100% ethyl acetate. Partially purified products were further purified by silicone column chromatography, dissociated with 0-20% ethyl acetate in hexane to obtain 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole: ES / MS m / z: C 20H 33BN 3O 3Si (M+H) Calculated value: 402.24, experimental value: 401.96.

[0442] [step] [2] A mixture of 5-bromo-2-iodobenzaldehyde (3.11 g, 10.00 mmol), diethyl malonate (6.45 g, 40.27 mmol), and potassium carbonate (5.57 g, 40.30 mmol) in DMF (20 mL) was stirred in an 85°C bath for 18 h. After cooling the reaction mixture and diluting it with water (100 mL), the product was extracted with ethyl acetate (100 mL × 4). After washing the extracts with water (100 mL × 1), the combined extracts were dried (Na₂SO₄) and concentrated.

[0443] After treating the residue with concentrated HCl (25 mL), the mixture was refluxed for 36 h. After cooling the resulting mixture in a freezer, the insoluble material was filtered and washed with water. The solid was dissolved in ethyl acetate (~100 mL), dried (MgSO4), and concentrated to give crude 3-(5-bromo-2-iodophenyl)glutaric acid: ES / MS m / z: C11H11BrIO4 (M+H) Calculated value: 412.89, experimental value: 412.58.

[0444] [step] [3] The mixture of crude 3-(5-bromo-2-iodophenyl)glutaric acid in acetic anhydride (~10 mL) was refluxed in a 155°C bath for 3 h. After concentrating the resulting solution, the residual syrup was co-evaporated with toluene (× 2) and dried under vacuum. The residue was dissolved in THF (50 mL) and stirred at room temperature, with 0.65 mL of 28% NH3 aqueous solution added three times at approximately 15 min intervals. The resulting mixture was stirred at room temperature for 7 h. The resulting suspension was completely concentrated, co-evaporated with toluene (× 2), and dried. The residue was refluxed with acetic anhydride (15 mL) in a 155°C bath for 4 h and then cooled. The solution was concentrated and the residue was purified by silicone column chromatography, followed by dissociation with 0-60% ethyl acetate in hexane to give 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione: ¹H NMR (400 MHz, DMSO-d6) 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).

[0445] [step] [4] THF (5 mL) containing 1.60 g (4.06 mmol) of 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione was stirred at 0 °C while THF (10.2 mL) containing a 1.0 M boranetetrahydrofuran complex solution was added dropwise. After refluxing the resulting mixture for 20 h, concentrated HCl (16 mL) was added to the mixture and the resulting solution was refluxed at 105 °C for 4.5 h. The solution was stirred in an ice bath while NaOH (solid) was added to neutralize the mixture. The resulting alkaline solution was diluted with some NaHCO3 solution and the product was extracted with ethyl acetate (~60 mL × 2). The extracts were washed with brine (× 1), combined, dried (Na2SO4), and concentrated to give 4-(5-bromo-2-iodophenyl)piperidine as an oil.

[0446] A solution of crude 4-(5-bromo-2-iodophenyl)piperidine in methanol (~25 mL) was stirred at 0 °C while Boc 2O (1078 mg, 4.939 mmol) and triethylamine (0.8 mL, 5.740 mmol) were added. After 2 h at 0 °C and overnight at room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate, followed by washing with water (× 2). The obtained organic fraction was dried (MgSO₄), concentrated, and purified by silica gel column chromatography, followed by dissociation with 0-10% EA / hexane to give tert-butyl 4-(5-bromo-2-iodophenyl)piperidine-1-carboxylic acid: 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).

[0447] [step] [5] A mixture of 4-(5-bromo-2-iodophenyl)piperidin-1-carboxylic acid tributyl ester (250 mg, 0.63 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboro-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (273 mg, 0.68 mmol), tetra(triphenylphosphine)palladium(0) (75 mg, 0.06 mmol) and 2 N potassium carbonate (0.6 mL) in dimethyl ether (6 mL) was purged with Ar gas for 10 min and stirred in a 110 °C bath for 1.5 h. After cooling, the mixture was diluted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography. It was then dissolved in a hexane solution of 0-50% ethyl acetate to give 4-(4-bromo-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylic acid tributyl ester: ES / MS m / z: C30H41BrN4NaO3Si (M+Na) Calculated value: 635.20, Experimental value: 635.14.

[0448] [step] [6] 4-(4-bromo-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidin-1-carboxylic acid tert-butyl ester (201 mg, 0.33 mmol), bis( (Base) diborone (

[27] A mixture of 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-dimethylamine (3 mL) was purged with Ar gas for 15 min in a microwave reaction flask, and then heated at 120 °C for 1.5 h. After cooling, the reaction mixture was diluted with ethyl acetate, dried (MgSO4), and concentrated. The residue was purified by silicone column chromatography and dissolved in hexane solution of 0-35% ethyl acetate to provide 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidin-1-carboxylic acid tributyl ester: ES / MS m / z: C 36H 53BN 4NaO 5Si (M+Na) Calculated value: 683.38, experimental value: 683.35.

[0449] [step] [7] [、] [step] [8] [and steps] [9] [] 4-(2-(Piperidin-4-yl)-4'-(1H-1,2,3-triazol-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 the Suzuki reaction using intermediate 4 and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(2-((2-trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate, followed by SEM deprotection with HCl and ester hydrolysis: 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: Calculated for C22H22N7O2(M+H): 416.18, Found: 416.14.

[0450] [Example]

[0175] [:] [4-(7-(1H-1,2,3-] [triazole] [-4-] [yl] [)-9, H , - ] [fluorene] [-2-] [yl] <00052​​​​​​​​​​​​​​​

[0451] [Step] [1] [, Step] [2] [, ] [Step] [3] [and Step] [4] Ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate was prepared in a manner similar to the procedures described herein, using intermediate

[11] and 2,7-dibromo-9H-fluorene, and then in a manner similar to the general procedure for PMB deprotection: 1H NMR (400 MHz, DMSO-d6) 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: Calculated for C20H17N6O2(M+H): 373.14, Found: 373.30.

[0452] [Example]

[0176] [:] [4-(7-(1H-1,2,3-] [triazole] [-4-] [yl] [)-9H-] [fluorene] [-2-] [yl] [)-1H-1,2,3-] [triazole] [-5-] [carboxylic acid] [2-] [ester] [Linyl ethyl ester] []

[0453] [step] [1] 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-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylate (18 g, 29.4 mmol) in MeOH (36 mL), THF (108 mL), and water (36 mL) under argon atmosphere at room temperature. The reaction mixture was heated to 60 °C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was diluted with water, acidified with 1 N HCl solution, and stirred for 10 min. 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-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylic acid: ES / MS m / z: C 34H 29N 6O 4(M+H). Calculated value: 585.23, experimental value: 585.41.

[0454] [, , ] [step] [2] 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-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylic acid (3.0 g, 5.14 mmol) in DMF (30 mL) under argon atmosphere, followed by the addition of 4-(2-chloroethyl)phospholine (1.53 g, 10.3 mmol). The mixture was heated to 50 °C and stirred for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by silicone column chromatography and dissolved in 80-100% ethyl acetate / petroleum ether to obtain 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylic acid 2-oxolinyl ethyl ester: ES / MS m / z: C 40H 40N 7O 5(M+H) Calculated value: 683.31, experimental value: 698.52.

[0455] [, , ] [step] [3] A mixture of ethyl 2-(quinolin-3-yl) 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate (3.0 g, 4.3 mmol) in TFA (30 mL) was heated at 80 °C for 16 h. After concentrating the reaction mixture under reduced pressure and neutralizing the crude residue with saturated NaHCO3 solution, the product was extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (neutralization method), and the pure eluate was lyophilized to obtain ethyl 2-(quinolin-3-yl) 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.14 (s, 1H), 8.05 (t, J = 8.4 Hz, 2H), 8.00 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 5.6 Hz, 2H), 4.08 (s, 2H), 3.49 (t, J = 4.6 Hz, 4H), 2.61 (t, J = 5.6 Hz, 2H), 2.49 - 2.33 (m, 4H). ES / MS m / z: Calculated for C24H24N7O3(M+H): 458.19, Found: 458.32.

[0456] [Example]

[0177] [:] [4-(7-(1H-1,2,3-] [Triazole] [-4-] [yl] [)-9H-] [Fluorene] [-2-]​​​​​​​​​​​​​​​[Linylpropyl ester] []

[0457] [step] [1] [and steps] [2] 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fumon-2-yl)-1H-1,2,3-triazol-5-carboxylic acid 3-pyrolinylpropyl ester is similar to [Example]

[0175] , [step] [2] [and steps] [3] The procedure was performed using 4-(3-chloropropyl)iodine and 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylic acid, followed by a general procedure similar to PMB deprotection: 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 25H 26N 7O 3(M+H) calculated value: 472.21, experimental value: 472.50.

[0458] [Example]

[0178] [:] [4-(7-(1H-1,2,3-] [Triazole] [-4-] [base] [)-9H-] [Fluorene] [-2-] [Group] [)-1H-1,2,3-] [Triazole] [-5-] [Formic acid] [2-((L-] [Valeryl group] [)] [Oxy group] [)] [Ethyl] [Ester] [] []

[0459] [] [Step] [1] At room temperature under argon, 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). After stirring the reaction mixture at room temperature for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and acidified with 1N HCl solution, followed by stirring for 10 min. 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: Calculated value for C 11H 10BrN 3NaO 3(M+H): 333.98, experimental value: 334.10.

[0460] [Step] [2] 4-Dimethylaminopyridine (0.33 g, 2.76 mmol) was added to a stirred solution of Boc-L-valine (3.0 g, 13.82 mmol), ethane-1,2-diol (1.11 g, 17.96 mmol), and dichloromethane (45 mL) under argon atmosphere at 0 °C. This was followed by the addition of dicyclohexylcarbodiimide (3.69 g, 17.96 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue was purified by silica gel column chromatography and dissociated with 0-30% ethyl acetate / petroleum ether to obtain 2-hydroxyethyl(tert-butoxycarbonyl)-L-valine (Boc-L-valine). [178-b]): 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).

[0461] [step] [3] At 0°C under argon atmosphere, 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-carboxylic acid ( [178-a], 2.55 g, 8.17 mmol), 2-hydroxyethyl (tert-butoxycarbonyl)-L-valine ( [178-b], 2.77 g, 10.62 mmol) was added to a stirred solution of dichloromethane (37.5 mL), 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 h. After concentrating the reaction mixture under reduced pressure, the residue was purified by silicone column chromatography and dissociated with 0-60% ethyl acetate / petroleum ether to obtain 2-(((tert-butoxycarbonyl)-L-valine)oxy)ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-carboxylic acid: ES / MS m / z: C23H32BrN4O7(M+H) Calculated value: 555.15, experimental value: 555.34.

[0462] [step] [4] 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fumon-2-yl)-2H-1,2,3-triazol-4-carboxylic acid 2-(((terbutoxycarbonyl)-L-valine)oxy)ethyl ester is prepared by a general procedure similar to the Suzuki reaction using 2-(4-methoxybenzyl)-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-9H-fumon-2-yl)-2H-1,2,3-triazole and 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-carboxylic acid 2-(((terbutoxycarbonyl)-L-valine)oxy)ethyl ester: ES / MS The calculated value of m / z: C 46H 49N 7NaO 8(M+Na) is 850.35, and the experimental value is 850.86.

[0463] [step] [5] A mixture of 2-((tert-Butoxycarbonyl)-L-valinyl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate (4.5 g, 5.44 mmol) in trifluoroacetic acid (45 mL) was stirred at 70 °C for 48 h. After concentrating the reaction mixture under reduced pressure, the residue was purified by preparative HPLC and the combined pure eluate fractions were lyophilized to obtain 2-((L-valinyl)oxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1H NMR (400 MHz, DMSO-d6) 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: Calculated for C25H26N7O4(M+H): 488.20, found: 488.39.

[0464] [Example]

[0179] [:] [4-(7-(1H-1,2,3-] [Triazole] [-4-] [yl] [)-9H-] [Fluorene] [-2-] [yl] [)-1H-1,2,3-] [Triazole] [-5-] [Carboxylic acid] [2-(] [Phosphonyloxy] [)] [Ethyl acetate] []

[0465] [step] [1] Triphenylphosphine (28.27 g, 107.91 mmol) was added to a stirred solution of diphenyl phosphate (117, 20 g, 71.94 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethanol-1-ol (15.22 g, 86.33 mmol) in THF (200 mL) at 0 °C under argon atmosphere, followed by the addition of diethyl aziridine (18.83 g, 107.91 mmol). The resulting mixture was stirred at room temperature for 5 h. After concentrating the reaction mixture under reduced pressure, the residue was purified by silicone column chromatography and dissociated with 0-10% ethyl acetate / petroleum ether to obtain (2-((tert-butyldimethylsilyl))oxy)ethyl)phenyl phosphate: ES / MS m / z: C 22H 34O 5PSi (M+H) Calculated value: 437.19, experimental value: 437.34.

[0466] [step] [2] Dowex-50W was added to a stirred solution of (2-((tert-butyldimethylsilyl))oxy)ethyl)phenyl phosphate (23 g, 52.75 mmol) in MeOH (230 mL) at room temperature under argon atmosphere. The mixture was stirred for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography, dissolved in 0-2% MeOH / dichloromethane, and centrifuged to obtain (2-hydroxyethyl)phenyl phosphate: ES / MS m / z: C16H20O5P (M+H) Calculated value: 323.10, experimental value: 323.24.

[0467] [step] [3] NET 3 (3.23 mL, 23.28 mmol) was added to a stirred solution of (2-hydroxyethyl) phenyl phosphate (5 g, 15.52 mmol) in dichloromethane (50 mL) at 0 °C under argon atmosphere, followed by the addition of MsCl (2.13 g, 18.63 mmol). After stirring the mixture at room temperature for 5 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure to obtain crude 2-((bis(phenyloxy)phosphatyl)oxy)ethyl methanesulfonate, which was used directly for the next step without any further purification: ES / MS m / z: C₁₇H₂₂O₇PS (M+H) calculated value: 401.08, experimental value: 401.27.

[0468] [step] [4] 2-((bis(benzyl)phosphatidyl)oxyethyl 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-triazol-4-yl)-9H-furan-2-yl)-2H-1,2,3-triazol-4-carboxylic acid (4 g, 6.84 mmol) and potassium carbonate (1.41 g, 10.26 mmol) in DMF (40 mL) at 0 °C under argon atmosphere. After stirring the mixture at 50 °C for 14 h, the reaction mixture was diluted with ice water and the product was extracted with ethyl acetate. The organic extract was dried (Na₂SO₄) and concentrated under reduced pressure. The crude residue was purified by silicone column chromatography and dissolved in 0-60% ethyl acetate / petroleum ether to obtain 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylic acid 2-((bis(benzyl)phosphatidyl)oxy)ethyl ester: ES / MS m / z: C 50H 46N 6O 8P (M+H) Calculated value: 889.31, experimental value: 889.77.

[0469] [step] [5] A mixture of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid 2-((bis(benzyloxy)phosphoryl)oxy)ethyl ester (11.5 g, 12.94 mmol) in trifluoroacetic acid (45 mL) was stirred at 70 °C for 20 h. After concentrating the reaction mixture under reduced pressure, the crude residue was purified by preparative HPLC to obtain 2-(phosphoryloxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1H 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: Calculated for C20H18N6O6P (M+H): 469.10, Found: 469.16.

[0470] [Example]

[0180] [:] [4-(7-(1H-1,2,3-] [Triazole] [-4-] [yl] [)-9H-] [Fluorene] [-2-] [yl] [)-1H-1,2,3-] [Triazole] [-5-] [Carboxylic acid] [(((2-(] [Phosphoryloxy] [)] [Ethoxy] [)] [Carbonyl] [)] [Oxy] [)] [Methyl] [Ester] [] []

[0471] [] [step] [1] Chloromethyl chloroformate (2.97 g, 23.29 mmol) was added to a stirred solution of (2-hydroxyethyl) phenyl phosphate (5 g, 15.52 mmol) and pyridine (2.5 mL, 31.04 mmol) in dichloromethane (100 mL) at 0 °C under argon atmosphere. After stirring the mixture at room temperature for 6 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure to obtain crude 2-((bis(phenyloxy)phosphatidyl)oxy)ethyl carbonate (chloromethyl ester), which was used directly for the next step without any further purification: ES / MS m / z: C₁₈H₂₁ClO₇P(M+H) calculated value: 415.07, experimental value: 415.31.

[0472] [step] [2] 2-((bis(benzyl)phosphatidyl)oxyethyl carbonate (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-triazol-4-yl)-9H-furan-2-yl)-2H-1,2,3-triazol-4-carboxylic acid (5.0 g, 8.56 mmol) and potassium carbonate (1.77 g, 12.84 mmol) in DMF (50 mL) at 0 °C under argon atmosphere. The mixture was stirred at 50 °C for 18 h. After diluting the reaction mixture with ice water, the product was extracted with ethyl acetate. The organic extract was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by silicone column chromatography and dissolved in 0-1% MeOH / dichloromethane to obtain 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylic acid (((2-((bis(benzyl)phosphatyl)oxy)ethoxy)carbonyl)oxy)methyl ester: ES / MS m / z: C 52H 48N 6O 11P (M+H) Calculated value: 963.31, experimental value: 963.39.

[0473] [step] [3] A mixture of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-furo-2-yl)-2H-1,2,3-triazol-4-carboxylic acid (((2-((bis(benzyl)phosphatyl)oxy)ethoxy)carbonyl)oxy)methyl ester (5.5 g, 5.71 mmol) in trifluoroacetic acid (55 mL) was stirred at 70 °C for 20 h. After concentrating the reaction mixture under reduced pressure, the crude residue was purified by preparative HPLC to obtain 4-(7-(1H-1,2,3-triazol-4-yl)-9H-furo-2-yl)-1H-1,2,3-triazol-5-carboxylic acid (((2-(phosphatoxy)ethoxy)carbonyl)oxy)methyl ester: 1H NMR (400 MHz, methanol-d4) 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 22H 20N 6O 9P (M+H) Calculated value: 543.10, experimental value: 543.40.

[0474] The following compounds were deprotected using a representative procedure similar to the Suzuki reaction, with the aforementioned SEM or PMB deprotection and the use of the previously mentioned bromide intermediate.

[18] or

[20] Prepared by ester hydrolysis with commercially available borate esters: [Example]

[0182] [:] [3-(3-)] [chlorine] [-] [4-] [Fluorophenyl] [)-1H-] [Pyrazole] [-4-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₀H₇ClFN₂O₂(M+H) Calculated value: 241.02, experimental value: 241.02.

[0475] [Example]

[0183] [:] [3-(3,5-] [Dichlorophenyl] [)-] [1H-] [Pyrazole] [-4-] [Formic acid] [] 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: C₁₀H₇Cl₂N₂O₂(M+H) calculated value: 256.99, experimental value: 257.03.

[0476] [Example]

[0184] [:] [4-(3-)] [chlorine] [-4-] [Fluorophenyl] [)-1H-] [Imidazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) 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: C₁₀H₇ClFN₂O₂(M+H) Calculated value: 241.02, experimental value: 240.94.

[0477] [Example]

[0185] [:] [4-(3,5-] [Dichlorophenyl] [)-1H-] [Imidazole] [-5-] [Formic acid] [] ¹H NMR (400 MHz, methanol-d⁴) δ 8.03 (s, 2H), 7.67 (s, 1H), 7.31 (s, 1H). ES / MS m / z: C₁₀H₇Cl₂N₂O₂ (M+H) Calculated value: 256.99, experimental value: 257.03.

[0478] [Bioanalysis] [] [Bioanalysis] [1] [:] [Biochemical Cell Analysis]

[0479] Material Glycolate oxidase (GO) was produced at Gilead using the HAO1 sequence by Jones et al., 2000 (J. Biol. Chem. 275: 12590-12597). The Amplex® Red hydrogen peroxide / peroxidase assay kit (catalog number A22188) was purchased from Thermo Fisher (Waltham, MA). Glycolic acid (catalog number 124737) and Tris 1M, pH 7.8 (catalog number T2569-1L) were from Sigma (St. Louis, MO), 10% Tween-20 (catalog number 51-12-02) was from SeraCare (Milford, MA), 2% BSA (catalog number BSA-1000) was from Rockland Immunochemicals (Pottstown, PA), and the black 384-well low-binding disk (catalog number 3860) was from Corning (Sunnyvale, CA).

[0480] method

[0481] [, 1. , ] [, GO , ] [, Biochemical analysis , ] [, , ] GO biochemical enzymatic reactions were performed in black 384-well low-binding discs with a total volume of 25 μL. The reaction mixture contained 5 nM GO, 100 μM hydroxyacetate, 0.1 U / mL HRP, 50 μM Amplex Red and buffer containing 50 mM Tris pH 7.8, 0.0025% Tween-20 and 0.02% BSA containing 1:3 serial dilutions of the test compound. Twenty-five nanoliters of 1000× test compounds were pre-spotted onto a 384-well low-binding disk by means of an Echo 555 liquid processor (Labcyte Inc., San Jose, CA), starting at a final concentration of 10 μM, followed by the addition of 5 microliters / well of 25 nM GO (5 nM final concentration of 5×) and incubated for 15 min. Ten microliters of 2.5 × 0.1 U / mL final concentration HRP was added to each well, followed by 10 μL of hydroxyacetate receptor at 2.5 × 100 μM final concentration and 2.5 × 50 μM final concentration of Amplex Red. The reaction was mixed and incubated at room temperature for 20 min, and the disks were subsequently read at 570 nm excitation and 585 nm emission by resorting to an EnVision disk reader (Perkin Elmer, San Jose, CA). The wells containing DMSO were used as negative control (such as 0% inhibition), while the wells without GO enzyme were used as positive control (such as 100% inhibition). % inhibition was calculated as 100% × (well-negative) / (positive-negative).

[0482] [ , 2. , ] [ , HRP , ] [ , Reverse , ] [ , Screening Analysis , ] [ , , ] The reverse screening analysis of HRP was performed in parallel with the biochemical analysis of GO to exclude compounds that can directly inhibit HRP but have no effect on inhibiting GO. Twenty-five nanoliters of the same set of 1000× test compounds were pre-pigmented onto a 384-well low-binding disk as described above in GO Biochemical Analysis, and subsequently in buffer containing 50 mM Tris pH 7.8, 0.0025% Tween, 0.02% BSA, 10 μL of 2.5×0.1 min U / mL was incubated at a final concentration of 5H U / mL. Then 15 μL of 1.67 × 50 μM final concentration of Ample Red and 1.67 × 10 μM final concentration of H The reaction was mixed and incubated at room temperature for 20 min. At the end of incubation, the disks were read with Envision at 570 nm excitation and 585 nm emission. The wells containing DMSO were used as negative control (such as 0% inhibition), while the wells without HR enzyme were used as positive control (such as 100% inhibition). Inhibition % was calculated as described above.

[0483] Analysis based on GO cells [ , 1. , ] [ , based on , ] [ , GO , ] [ , Analysis of transiently transfected cells , ] [ , , ]

[0484] ingredients HAO1 plastid DNA was generated by Lake Pharma (Belmont, CA) through PCR selection of HAO1 cDNA (Jones et al., 2000) into the pcDNA3.1 (+)-neomycin vector. FuGENE 6 transfection reagent (catalog number E2692) was purchased from Promega (Madison, WI). CHO-K1 cell line (catalog number ATCC CCL-61) and F-12K medium (catalog number 30-2004) were obtained from ATCC (Manassas, VA). OptiMEM I reduced serum medium (catalog number 31985-070) was obtained from Gibco / Life Technologies (Grand Island, NY). Fetal bovine serum (FBS) (catalog number SH30071.03) was obtained from HyClone (Logan, Utanh), and 100× penicillin / streptomycin / L-glutamic acid (catalog number 30-009-Cl) was obtained from Corning (Fremont, CA). 384-well black tissue culture dishes (catalog number 781086) were purchased from Greiner Bio-One (Monroe, NC).

[0485] method Transient transfection was performed by mixing three µl portions of FuGENE 6 reagent with one µg portion of HAO1 plasso DNA or vector control DNA in OptiMEM I reduced serum medium and incubating at room temperature for 15 min. The mixture was then mixed with CHO-K1 cells and dispersed in F-12K medium with 10% FBS at 45 μL / well containing 0.025 µg HAO1 plasso DNA, 0.075 µL FuGENE 6, and 4000 cells per cell. For GO expression, cells were incubated at 37°C for 48 h. The cell culture medium was then removed and replaced with 25 µL of a 1:3 serially diluted 1 µM test compound, and incubated at room temperature for 1 h. Next, 25 µl of reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) containing HRP (final concentration 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 min, followed by reading the discs using the EnVision disc reader as described above. Wells containing DMSO served as negative controls (0% inhibition), while wells containing vector control DNA transfection served as positive controls (e.g., 100% inhibition). Inhibition % was calculated as described above.

[0486] [, 2. , ] [, based on , ] [, GO , ] [, Analysis of stable pure cell lines , ] [, , ] Material The reagents and tissue culture media used for transient transfection are described in the transient transfection analysis section. Rabbit anti-HAO1 antibody (catalog number ab93137) was purchased from Abcam (Cambridge, MA), and anti-rabbit IgG (H+L), F(ab')2 fragment, and Alexa Fluor® 555 conjugate (catalog number #4413) were obtained from Cell Signaling Technology (Danvers, MA).

[0487] method [, 1) , ] [, CHO-K1-HAO1 , ] [, The generation of stable pure lines , ] [, , ] Stable pure GO lines were generated internally by transiently transfecting large quantities of GO plasso DNA into CHO-K1 cells and cultured for 48 hours as described above. Cells were then trypsinized, and 2000 cells / 200 μL were added to well A1, followed by serial 1:2 dilutions to A2 and then to A12 in ten 96-well tissue culture dishes. Cells from A1-A12 were further serially diluted 1:2 to H1-H12 and cultured for two weeks in F-12K medium supplemented with 500 µg / mL G418 and 10% FBS. Colony formation in each dish was monitored under a microscope. Twenty-eight single colonies were selected and amplified for GO performance testing.

[0488] [, Intracellular , ] [, GO , ] [, Immunocytochemistry of staining , ] [, , ] Intracellular GO staining was performed as follows: First, cells were fixed in 384-well plates at room temperature with 50 μL / well PBS containing 4% formaldehyde for 30 min, followed by washing three times with 80 μL / well washing buffer (PBS containing 0.05% Tween-20). Next, cells were infiltrated with 50 μL / well PBS containing 0.1% Triton for 30 min, washed three times, and then blocked with 50 μL / well PBS containing 3% BSA and 0.05% Tween-20 for 1 h. Cells were washed three times again, and 50 µL of rabbit anti-human GO (diluted 1:100 in PBS containing 1% BSA and 0.05% Tween-20) was added to each well and incubated overnight at 4°C. Cells were washed four times, incubated for 15 min between each wash, and then 40 µL of Alexa Fluor 555-bound anti-rabbit IgG (H+L) F(ab')2 fragment (1:250 dilution) and Hoechst (1:500 dilution in 1% BSA and 0.05% Tween-20) were added to each well. The plates were incubated at room temperature for 160 min and washed four times at the end of the incubation. Sixty μL of PBS was added to each well, and cell images were examined using an Arrayscan XTI HCS reader from Thermo Fisher Scientific (Waltham, MA).

[0489] [, 2) , ] [, Based on stable pure series , ] [, 2D2 GO , ] [, Analysis of enzyme activity in cells , ] [, , ] A 384-well tissue culture dish was pre-spotted at 25 nL per well for testing compounds, and subsequent reaction buffer containing 5000 cells / well / 25 microliters of pure line 2D2 (50 mM Tris pH 7.8, 0.0025% Tween and 0.02% BSA) was dispensed into all wells except tube column 22. In those wells a pure line 1A1 carrier control was added with 5000 cells / well / 25 microliters. The test compounds were incubated with cells at room temperature for 1 h, followed by the addition of 25 μL 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 hydroxyacetate and 50 μM Amplex Red. The reactants were mixed and incubated at room temperature for 20 min, and the fluorescence of the products tested for resorufin was measured as described above. The wells containing 2D2 and DMSO were used as negative controls (0% inhibition), while the wells containing the pure line of 1A1 carrier control were used as positive controls (such as 100% inhibition). The percent inhibition was calculated as described above ( Table 2 ). [table] [2.] [ , , ] [instance] [IC , 50 ,GO AR-384]。 [EC , 50 、GO CHO 】

K1 AR

[0490] Bioanalysis 2: Oral Bioavailability and PK Study The oral dose of Example 2 was reconstituted at 1.0 mg / mL in a sterile solution 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 animals weighed between 0.26 and 0.27 kg. For the oral administration group, the reconstituted dose was administered orally via tube feeding at a dose of 5.0 mL / kg (5.0 mg / kg). Non-in vitro pharmacokinetic analysis was performed on plasma concentration-time data. [surface] [3.] [animal] [animal] [weight] [(kg)] [Target] [concentration] [(mg / mL)] [Measurement] [concentration] [(mg / mL)] [Dose-volume] [(mL)] [dose] [(mg / kg)] [dose] [(nmol / kg)] 1 0.26 1.00 1.00 1.30 5.04 16344 2 0.26 1.00 1.00 1.30 4.96 16094 3 0.27 1.00 1.00 1.40 5.20 16881

[0491] Table 3 shows the mean plasma pharmacokinetic parameters (mean ± SD, n=3) of Example 2 after administration of PO at 5 mg / kg in SD rats. Table 4 shows the mean plasma pharmacokinetic parameters (mean ± SD, n=3) of Example 68 after administration of PO at 5 mg / kg in SD rats. As shown in Tables 4 and 5, the AUC inf of Example 2 was 1600 ± 280 nM·h and the Cmax was 2390 ± 246 nM. The AUC inf of Example 68 was 3250 ± 242 nM·h and the Cmax was 2270 ± 171 nM. The bioavailability of Example 68 was estimated to be 19.0% ± 1.4%. [surface] [4.] [PO] [Rat]

[0001]

[0002]

[0003] [average value] [SD] AUC 0-24h(nM·h) 1270 1550 1850 1560 288 AUC inf(nM·h) 1340 1570 1900 1600 280 C max(nM) 2540 2530 2110 2390 246 T max(hr) 0.25 0.25 0.50 0.33 0.14 F (%) NC NC NC NC NC [surface] [5.] [PO] [Rat]

[0001]

[0002]

[0003] [average value] [SD] AUC 0-24h(nM·h) 3150 3360 2930 3140 216 AUC inf(nM·h) 3320 3450 2980 3250 242 C max(nM) 2120 2220 2450 2270 171 T max(hr) 0.50 0.25 0.50 0.42 0.14 *F (%) 19.4 20.2 17.4 19.0 1.4 [*] Based on the IV exposure of Example 68 at 1.0 mg / kg in Table 7 below (AUC inf = 3420 nM·hr).

[0492] The apparent systemic clearance of Example 68 (CL = 0.95 ± 0.09 L / hr / kg) was lower than that of hepatic blood flow in rats (CL = 4.0 L / hr / kg). The volume of distribution (Vss = 0.44 ± 0.06 L / kg) was less than the volume of total body water (0.7 L / kg). The final t1 / 2 of Example 68 was 1.02 ± 0.06 hours, and the mean residence time (MRT) was 0.47 ± 0.02 hours. The oral bioavailability (%F) was estimated to be 2.3% ± 0.3%. See Tables 7 and 8 and Figure 2. [surface] [7.] Mean plasma pharmacokinetic parameters (mean ± SD, n=3) of Example 68 following a 30-minute IV infusion of 1 mg / kg in SD rats. [IV] [Rat] [] [A] [B] [C] [average value] [SD] [parameter] [] AUC last(nM·hr) 3680 3090 3450 3400 296 AUC inf(nM·hr) 3690 3110 3460 3420 295 C max(nM) 4940 5100 5350 5130 208 MRT (hr) 0.47 0.49 0.44 0.47 0.02 t 1 / 2 (hr) 1.01 1.08 0.96 1.02 0.06 V ss(L / kg) 0.41 0.51 0.41 0.44 0.06 CL (L / hr / kg) 0.87 1.04 0.93 0.95 0.09 [surface] [8.] Mean plasma pharmacokinetic parameters (mean ± SD, n=3) in SD rats following PO administration at 5 mg / kg. [Rat] [] [D] [E] [F] [average value] [SD] [parameter] [] AUC last(nM·hr) 429 334 396 386 48 AUC inf(nM·hr) 485 383 479 449 57 C max(nM) 90.4 65.0 182 113 61.7 T max(hr) 0.25 2.00 0.25 0.83 1.01 F (%) 2.5 1.9 2.3 2.3 0.3

[0493] Examples 168 or 175 were prepared in a sterile solution of 15% N-methyl-2-pyrrolidone, 55% PEG, and 30% water for oral or intravenous administration. Each administration group consisted of three fasted male SD rats or three fasted male beagle dogs. At administration, the rats weighed between 0.2 and 0.3 kg, and the dogs weighed between 10.72 and 10.82 kg. For oral administration, the prepared dose was administered orally via tube feeding at a dose of 5.0 mL / kg, which was either 5.0 mg / kg or 5.4 mg / kg. For intravenous administration, the prepared dose was 1.00 mg / kg. Non-in vitro pharmacokinetic analysis was performed on plasma concentration-time data. Data from these studies are shown in Figures 3 and 4.

Claims

1. A compound or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, wherein: , or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof.

2. A pharmaceutical composition comprising a compound as claimed in claim 1 or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, and a pharmaceutically acceptable carrier.

3. Use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as claimed in claim 2, for the preparation of a medicament for the treatment of primary type 1 hyperoxaluria.

4. Use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as claimed in claim 2, for the preparation of a medicament for the treatment of recurrent kidney stone formation.

5. Use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer, or mixture of stereoisomers thereof, or a pharmaceutical composition as claimed in claim 2, for the preparation of a medicament for inhibiting the production of glyoxylate and / or oxalate and / or inhibiting glycolate oxidase (GO).

6. The use as claimed in any of claims 3 to 5, wherein the drug further comprises an additional therapeutic agent selected from the group consisting of calcium oxalate crystallization inhibitors, oxalate degrading enzyme inhibitors, siRNA, oxazyme, lumasiran, nedosiran, oxabate, and reloxaliase, or is administered co-administered with an additional therapeutic agent selected from the group consisting of calcium oxalate crystallization inhibitors, oxalate degrading enzyme inhibitors, siRNA, oxazyme, lumasiran, nedosiran, oxabate, and reloxaliase.

7. The use as claimed in any of claims 3 to 5, wherein the drug further comprises an additional therapeutic agent of an SGLT2 inhibitor, or is administered co-administered with an additional therapeutic agent of an SGLT2 inhibitor.

8. As claimed in claim 7, wherein the SGL2 inhibitor is selected from the group consisting of dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, empagliflozin, and potassium citrate.

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