Heterocyclic carboxylate compounds as glycolate oxidase inhibitors

Abstract

To treat patients with primary hyperoxaluria type 1 (PH1) and reduce the recurrence rate of kidney stones in kidney stone formers, an agent that inhibits glycolic acid oxidase enzyme activity is provided. 【Solution means】 It is a compound of the following formula I. JPEG2026082935000269.jpg21170 (In the formula, A is N or CH; R 1 is alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with 1 to 3 R 3 ; R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, etc.; each R 3 is cyano, halo, -L-C 1~9 alkyl, etc.)

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefits under U.S. Provisional Patent Application No. 62 / 929,476 filed 1 November 2019 and U.S. Provisional Patent Application No. 63 / 093,094 filed 16 October 2020, both of which are incorporated by reference in their entirety with this application, in accordance with the provisions of 35 United States Code § 119(e).

[0002] This disclosure relates to compounds, compositions, and methods for the treatment of primary hyperoxaluria type 1 and recurrent kidney stone formers. This disclosure relates to novel substituted heterocyclic carboxylate compounds and methods for preparing them, as well as their use as therapeutic or prophylactic agents. Specifically, this disclosure provides novel inhibitors of human glycolate oxidase enzyme, pharmaceutical compositions containing such compounds, and methods for using these compounds for the treatment of primary hyperoxaluria type 1 and recurrent kidney stone formers. [Background technology]

[0003] Kidney stones affect a wide range of human populations. In the United States, the prevalence of kidney stones was 8.8% (10.6% in men and 7.1% in women). This condition also occurs in primary hyperoxaluria type 1 (PH1), which can be caused by genetically deficient enzyme activity. Due to elevated glycolate oxidase activity, these patients may show a significant increase in glyoxylic acid and oxalate production, as well as calcium oxalate stone deposition. Medical procedures to remove kidney stones exist and are effective. However, the recurrence rate of kidney stones after such procedures can be high (e.g., over 50%). [Overview of the project] [Problems that the invention aims to solve]

[0004] Therefore, there is a need for an agent that inhibits glycolate oxidase enzyme activity in order to treat PH1 patients and reduce the recurrence rate of kidney stones formed from kidney stones. [Means for solving the problem]

[0005] This disclosure relates to novel substituted heterocyclic carboxylate compounds (including their stereoisomers, pharmaceutically acceptable salts, and prodrugs) that inhibit human glycolate oxidase activity, and to the use of such compounds in the treatment of primary hyperoxaluria type 1. The compounds of this disclosure may be used to treat recurrent nephrolith formations.

[0006] In one embodiment, Equation I: [ka] Compounds having the structure of (A, R) or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof (wherein A, R) 1 , and R 2 (as described herein) is provided.

[0007] In certain embodiments, the Disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the Disclosure (for example, a compound of formula I or any additional formula described throughout) and at least one pharmaceutically acceptable excipient. In certain embodiments, the Specified Disclosure provides a pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, a tautomer, a stereoisomer, a mixture of stereoisomers, or a deuterated analog thereof.

[0008] Some embodiments provide methods for using (or administering) compounds of formula I or any additional formulas described throughout in mammals, particularly humans, in the treatment of a disease or condition, and which are applicable to treatment with inhibitors of human glycolate oxidase enzyme.

[0009] Some embodiments provide methods for using (or administering) the compounds described herein in the treatment of a disease or condition in mammals, particularly humans, and which are applicable to treatment with inhibitors of human glycolate oxidase enzyme. [Brief explanation of the drawing]

[0010] [Figure 1] The plasma concentration-time profiles (mean ± SD, n=3) for Example 2 and Example 68 after oral administration of 5.0 mg / kg of Example 2 in SD rats are shown. [Figure 2] The plasma concentration-time profiles (mean ± SD, n=3) of Example 68 after intravenous infusion of 1.0 mg / kg over 30 minutes and after administration of 5.0 mg / kg of polyoxygenated solution (PO) in SD rats are shown. [Figure 3] The plasma concentration-time profiles for Examples 168 and 175 in SD rats are shown. [Figure 4] The plasma concentration-time profiles for Examples 168 and 175 in male beagle dogs are shown. [Modes for carrying out the invention]

[0011] Definitions and general parameters The following description provides exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of this disclosure, but rather is provided as a description of exemplary embodiments.

[0012] As used herein, the following words, phrases, and symbols are intended to have the meanings set forth below, unless otherwise used in the context in which they are used.

[0013] A dash ("-") not between two letters or symbols is used to indicate a bond point to a substituent. For example, -C(O)NH2 is bonded via a carbon atom. Dashes before or after chemical groups are for convenience, and chemical groups can be depicted with or without one or more dashes without losing their usual meaning. A wavy line drawn through a line in a structure indicates a bond point of a group. Unless chemically or structurally required, direction is not suggested or implied by the order in which chemical groups are written or named.

[0014] Prefix “C” u~v " means that the following group has u to v carbon atoms. For example, "C 1~6 The term "alkyl" means that an alkyl group has 1 to 6 carbon atoms.

[0015] The modifier "approximately," used in relation to quantity, encompasses the stated value and has a contextually determined meaning (for example, including the degree of error associated with the measurement of that particular quantity). Furthermore, the singular forms "a" and "the" include plural references unless explicitly specified in the context. Therefore, for example, a reference to "compound" includes multiple such compounds, and a reference to "assay" includes one or more assays and their equivalents known to those skilled in the art.

[0016] "Alkyl" means an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a chain with 1 to 20 carbon atoms (i.e., C 1~20 Alkyl), 1 to 8 carbon atoms (i.e., C 1~8 Alkyl), 1 to 6 carbon atoms (i.e., C 1~6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1~4It has an alkyl group. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by its chemical name or identified by its molecular formula, all positional isomers having that number of carbons may be included. Thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), iso-butyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3), and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0017] "Alkenyl" means an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkenyl), 2 to 8 carbon atoms (i.e., C 2~8 alkenyl), 2 to 6 carbon atoms (i.e., C 2~6 alkenyl), or 2 to 4 carbon atoms (i.e., C 2~4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0018] "Alkynyl" means an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2~20 alkynyl), 2 to 8 carbon atoms (i.e., C 2~8 alkynyl), 2 to 6 carbon atoms (i.e., C 2~6 alkynyl), or 2 to 4 carbon atoms (i.e., C 2~4 alkynyl). The term "alkynyl" also includes groups having one triple bond and one double bond.

[0019] "Alkoxy" refers to an alkyl-O- group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0020] "Haloalkoxy" refers to an alkoxy group defined as having one or more hydrogen atoms replaced by halogens.

[0021] "Alkylthio" means "alkyl-S-" group.

[0022] "Acyl" means a -C(O)R group (wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl), each of which may be optionally substituted as defined herein. Examples of acyls include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, and benzoyl.

[0023] "Amide" is -C(O)NR y R z The group is called a "C-amide" group and -NR y C(O)R z The term "N-amide" means a group (where R y and R z (where is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl), and these may each be optionally substituted.

[0024] "Amino" means -NR y R z Base (here, R y and R z (wherein is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, or heteroaryl), each of which may be optionally substituted.

[0025] "Aryl" means an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) structure, including a condensed system. As used herein, aryl refers to a ring containing 6 to 20 carbon atoms (i.e., C 6~20 aryl), 6-12 carbon ring atoms (i.e., C 6~12 aryl), or 6 to 10 carbon ring atoms (i.e., C 6~10 It contains an aryl group. Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not include or overlap with any heteroaryl as defined below. When one or more aryl groups are fused with a heteroaryl, the resulting ring system is a heteroaryl. When one or more aryl groups are fused with a heterocyclyl, the resulting ring system is a heterocyclyl.

[0026] "Carbamoyl" is -OC(O)NR y R z The group "O-carbamoyl" and -NR are both meaning "group". y C(O)OR z The group that means "N-carbamoyl" (where R y and R z (where is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, or heteroaryl), and these may each be optionally substituted.

[0027] "Carboxyl ester" means both -OC(O)R and -C(O)OR (where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl), which may be optionally substituted as defined herein.

[0028] "Cycloalkyl" means saturated or partially unsaturated cyclic alkyl groups having monocyclic or polycyclic structures, including condensed, crosslinked, and spirocyclic systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to rings with 3 to 20 carbon atoms (i.e., C 3~20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3~12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3~10 Cycloalkyl), 3-8 ring carbon atoms (i.e., C 3~8 Cycloalkyl, or a ring of 3-6 carbon atoms (i.e., C 3~6 It has a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] "Imino" means a -C(NR)R group (where R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl), each of which may be optionally substituted as defined herein.

[0030] "Halogen" or "halo" includes fluoro, chloro, bromo, and iodine. "Haloalkyl" means an unbranched or branched alkyl group defined as having one or more hydrogen atoms replaced by halogens. For example, if a residue is substituted with two or more halogens, it may be referred to by using a prefix corresponding to the number of halogenated moieties. Dihaloalkyl and trihaloalkyl mean alkyl groups substituted with two ("di") or three ("tri") halo groups, which may not necessarily be the same halogen. Examples of haloalkyls include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0031] A "heteroalkyl" is an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced by the same or different heteroatomic 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 replaced by the same or different heteroatomic groups. Examples of heteroatomic groups, but not limited to, include -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc. (wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclyl), each of which may be optionally substituted. Examples of heteroalkyl groups include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3 (where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl), each of which may be optionally substituted. As used herein, a heteroalkyl group comprises 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms, and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0032] "Heteroaryl" means an aromatic group having a monocyclic, polycyclic, or polycondensed ring containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a ring containing 1 to 20 ring carbon atoms (i.e., C 1~20 Heteroaryls), 3 to 12 ring carbon atoms (i.e., C 3~12 Heteroaryls, or 3 to 8 carbon ring atoms (i.e., C 3~8The compound comprises a heteroaryl group and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, independently selected from nitrogen, oxygen, and sulfur. Non-exclusive examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranil, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, sinnolinil, dibenzofuranil, dibenzothiophenyl, furanil, furanonil, isothiazolyl, imidazolyl, and indazolyl. Examples include indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolidinyl, isoxazolyl, naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 1-oxidepyridinyl, 1-oxidepyrimidinyl, 1-oxidepyradinyl, 1-oxidepyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyridadinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl. A condensed heteroaryl ring can be bonded via any of the condensation systems. Any aromatic ring having one or more condensed rings containing at least one heteroatom is considered a heteroaryl, regardless of whether it is bonded to the rest of the molecule (i.e., via any one of the condensed rings). Heteroaryls do not encompass or overlap the aryls as defined above.

[0033] "Heterocyclyl" means a saturated or unsaturated cyclic alkyl group containing one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, condensed heterocyclyl groups, and spiroheterocyclyl groups. Heterocyclyls can be monocyclic or polycyclic, and polycyclics may be condensed, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl regardless of its bonding (i.e., bondable via carbon atoms or heteroatoms). Furthermore, the term heterocyclyl is intended to encompass any non-aromatic ring containing at least one heteroatom, and the ring may be condensed into an aryl ring or a heteroaryl ring regardless of its bonding to the rest of the molecule. As used herein, a heterocyclyl contains 2 to 20 ring carbon atoms (i.e., C 2~20 Heterocyclines), 2 to 12 ring carbon atoms (i.e., C 2~12 Heterocyclines), 2 to 10 ring carbon atoms (i.e., C 2~10 Heterocyclines), 2-8 ring carbon atoms (i.e., C 2~8 Heterocyclines), 3 to 12 ring carbon atoms (i.e., C 3~12 Heterocyclines), 3-8 ring carbon atoms (i.e., C 3~8 Heterocyclines), or ring carbon atoms with 3-6 atoms (i.e., C 3~6A heterocyclil has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, and optionally one or more oxo groups, which are independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclil groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanil, azetidinyl, and morpholinyl. As used herein, the term "bridged heterocyclil" means a 4 to 10-membered cyclic portion of a heterocyclil containing one or more (e.g., 1 or 2) 4 to 10-membered cyclic portions, each having at least one heteroatom independently selected from nitrogen, oxygen, and sulfur, to which two non-adjacent atoms are linked. As used herein, bridged heterocyclils include bicyclic and tricyclic ring systems. The term “spiroheterocyclyl” as used herein also refers to a ring system in which a 3- to 10-membered heterocyclyl has one or more additional rings, one or more of which are 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, and one or more single atoms of the additional rings are also atoms of the 3- to 10-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of condensed heterocyclyl rings, though not limited to them, include 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl, and isoindolinyl (e.g., 2-methylisoquinoline-1(2H)-one), where the heterocyclyl can be bonded via any of the rings in the condensation system.

[0034] "Oxo" means (=O) group or (O) group.

[0035] "Sulfonyl" refers to the -S(O)2R group (where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl). Examples of sulfonyl groups include methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0036] "Alkylsulfonyl" refers to the -S(O)2R group (where R is alkyl).

[0037] "Alkyl sulfinyl" refers to the -S(O)R group (where R is alkyl).

[0038] "Thiol" refers to an -SR group (wherein R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl).

[0039] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups and divalent "aryl" groups may also be referred to as "alkylene" or "alkylenyl" groups, or "arylene" or "aryrenyl" groups, respectively. Furthermore, unless otherwise explicitly indicated, when a combination of groups is referred herein as a single part, for example, an arylalkyl group, the last group listed contains an atom to which that part is bonded to the rest of the molecule.

[0040] The terms “optional” or “optionally” mean that the event or situation described thereafter may or may not occur, and that description includes the cases in which such event or situation occurs and the cases in which it does not occur. The term “optionally substituted” means that one or more hydrogen atoms on the specified atom or group may or may not be substituted for the non-hydrogen portion.

[0041] Some compounds exist as tautomers. Tautomers exist in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with an imido acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, it is understood by those skilled in the art that a compound contains both an amide and an imido acid tautomer. Therefore, an amide-containing compound is understood to contain its imido acid tautomer. Similarly, an imido acid-containing compound is understood to contain its amide tautomer.

[0042] Any formula or structure given herein is intended to represent the unlabeled and even isotopically labeled forms of a compound. An isotopically labeled compound has the structure depicted by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of this disclosure include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 I is one example. The various isotope-labeled compounds of this disclosure include, for example, 3 H, 13 C, 14 These compounds incorporate radioactive isotopes such as 13C. Such isotope-labeled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate distribution assays within tissues, or in radiation therapy for patients.

[0043] This disclosure also includes “deuterated analogs” of the compounds of formula I in which 1 to n hydrogens bonded to a carbon atom are replaced by deuterium (where n is the number of hydrogens in the molecule). Such compounds exhibit increased resistance to metabolism and are therefore useful for increasing the half-life of any of the compounds of formula I when administered to mammals, particularly 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 the art, for example, by using starting materials in which one or more hydrogens are replaced by deuterium.

[0044] The deuterium-labeled or substituted therapeutic compounds of this disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and / or improved therapeutic index. 18 1F-labeled compounds may be useful in PET or SPECT studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by following the procedures disclosed in the schemes or examples and preparations below, using readily available isotope-labeling reagents instead of non-isotopically labeled reagents. In this context, deuterium is understood to be a substituent of the compound of formula I.

[0045] The concentration of such heavier isotopes (specifically deuterium) can be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope represents one of the stable isotopes of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Therefore, in the compounds of this disclosure, any atom specifically designated as deuterium (D) represents deuterium.

[0046] In many cases, the compounds of this disclosure have the ability to form acid salts and / or base salts due to the presence of an amino group and / or a carboxyl group or a similar group.

[0047] Furthermore, pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided. "Pharmacologically acceptable" or "physiologically acceptable" means compounds, salts, compositions, formulations, and other materials useful for preparing pharmaceutical compositions suitable for veterinary or human medicinal use.

[0048] The term "pharmaceutically acceptable salt" of a given compound means a salt that retains the biological efficacy and properties of the given compound and is not biologically or otherwise undesirable. Examples of "pharmaceutically acceptable salts" or "physiologically acceptable salts" include salts with inorganic acids and salts with organic acids. In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, when the product is a free base, the addition salt, especially a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts will be apparent to those skilled in the art. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts derived from inorganic bases include salts of sodium, potassium, lithium, ammonium, calcium, and magnesium.Salts derived from organic bases are not limited to 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)), dialkenylamines (i.e., HN(alkenyl)2), and trialkenylamines (i.e., N( Examples of salts of primary, secondary, and tertiary amines include 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), mono, di, or tricycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono, di, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), and mixed amines. Specific examples of suitable amines, though these are merely examples, include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, and N-ethylpiperidine.

[0049] The term "substitution" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more non-hydrogen substituents, provided that the valence of the specified atom does not exceed its normal valence. Examples of one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amide, amidino, aryl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thion, or combinations thereof. Similar non-specific structures achieved by defining substituents that include polymers or an infinitely increasing number of substituents (e.g., substituted aryls having a substituted alkyl that is itself substituted with a substituted aryl group and further substituted with a substituted heteroalkyl group) are not intended to be included herein. Unless otherwise noted, the maximum number of consecutive substitutions in a compound described herein is three. For example, the sequential substitution of a substituted aryl group by two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definitions are 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 in relation to the modification of a chemical group, the term “substituted” may describe other chemical groups as defined herein. Unless otherwise specified, where a group is described as being optionally substituted, any substituent of the group is itself unsubstituted. For example, in some embodiments, the term “substituted alkyl” means alkyl groups having one or more substituents, including hydroxyl, halo, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted.In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0050] In certain embodiments, as used herein, the phrase "one or more" means one to five. In certain embodiments, as used herein, the phrase "one or more)" means one to three.

[0051] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes all solvents, dispersions, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in therapeutic compositions, provided that it is compatible with the active ingredient. Supplementary active ingredients can also be incorporated into compositions.

[0052] A "solvate" is 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.

[0053] compound This specification provides compounds that function as inhibitors of glycolate oxidase. In certain embodiments, this specification provides compounds of formula I: [ka] A compound of the same, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided, in which, A is either N or CH, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1 to 3 Rs 4 substituted C 1~6 alkyl, cycloalkyl, or 1 to 3 Rs 5 substituted heteroaryl, each R 3 is independently cyano, halo, -L-C 1~9 alkyl, -L-C 1~4 haloalkyl, -L-OC 1~4 haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 、-L-aryl, -L-heteroaryl, or -L-heterocyclyl, each of which is optionally substituted with 1 to 3 Rs 6 and each L is independently -C≡C- or absent, each R 4 is independently halo, hydroxy, -OC 1~6 alkyl, -NH2, -NHC 1~6 alkyl, -N(C 1~6 alkyl)2, -OC(O)R a 、-OC(O)OR a 、-OP(O)(OR b )2, or monocyclic heterocyclyl, each of which is optionally substituted with 1 to 3 Rs 5 provided that only one R 4 is heterocyclyl, each R 5 is independently cyano, halo, C 1~4 alkyl, hydroxy, -OC 1~4 alkyl, C 1~4 haloalkyl, or -OC 1~4 haloalkyl, each R 6 is independently cyano, halo, -C(O)R 7 、-C(O)OR<000-C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, Each R b These are, independently, hydrogen or C 1~4 It is alkyl.

[0054] In some embodiments, when A is N, at least one of the following is true: 1) R 1 This is 1 to 3 R 3 Is it a condensed tricyclic ring that has been arbitrarily substituted with, 2) R 1 This is cyano, -C≡CC 1~9 Alkyl, 1-3 R 6 -C replaced by 1~9 Alkyl, -C≡CC 1~4 Haloalkyl, -C≡C-OC 1~4 Haloalkyl, -NR 7 R 8-C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 -OC 1~4 At least one R selected from alkyl, -O-phenyl, -L-aryl, -L-heteroaryl, or -L-heterocyclyl 3 An arbitrarily substituted condensed bicyclic ring, each of which has 1 to 3 R 6 And if further arbitrarily substituted, and each L is independently -C≡C- or does not exist, 3) R 1 The following: i) Cyano, -C≡CC 1~9 Alkyl, -C≡CC 1~4 Haloalkyl, -C≡C-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 -C≡C-aryl, -C≡C-heteroaryl, or -C≡C-heterocyclyl, each of which contains 1 to 3 R 6 It is then arbitrarily replaced, ii) Monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each comprising 1 to 3 cyano-C(O)R 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Further substituted with haloalkyl, phenyl, heterocyclyl, or heteroaryl, each of which contains 1 to 3 C atoms. 1~4 Alkyl, -C(O)OH, or C 1~4Optionally substituted with a haloalkyl group, iii) an arbitrarily substituted condensed aryl, an arbitrarily substituted condensed heteroaryl, or an arbitrarily substituted condensed heterocyclyl, each having 1 to 3 R 6 It is further optionally replaced, or iv) Formula-L 1 -L 2 substituents, where L 1 These are aryl, heteroaryl, or heterocyclyl compounds, each containing 1 to 3 R 6 It is arbitrarily replaced by and L 2 These are phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 C atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, at least one R selected from 3 It is a substituted monocyclic ring that has been substituted with, or 4) R 2 is -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that has been arbitrarily substituted with, and.

[0055] In some embodiments, when A is CH, R 1 It is not a 10-membered heteroaryl substituted with methoxy and methyl, but R 1 cyano, halo, C 1~4 Alkyl, -OR 7 , C 1~4 Haloalkyl and NR 7 R 8 Not a C6 aryl substituted with 1 to 3 substituents independently selected from, where R 7 and R 8 Each of them independently consists of hydrogen or C 1~4 It is alkyl, R 1 is unsubstituted C 10 Not aryl, but R 1It is not an unsubstituted heterocyclyl either.

[0056] In one embodiment, Equation I: [ka] A compound having the structure of, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In the formula, A is either N or CH, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3 These are independently cyano, halo, and -LC. 1~9 Alkyl, -LC 1~4 Haloalkyl, -L-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 -L-aryl, -L-heteroaryl, or -L-heterocyclyl, each containing 1 to 3 R 6 It can be arbitrarily substituted, and each L is independently conjugated or -C≡C-, Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6Alkyl)2, or monocyclic heterocyclyl, each having 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline.

[0057] In a particular embodiment, R 1 When R is phenyl, 3 It is an aryl or heteroaryl compound, each containing 1 to 3 R 6 It is arbitrarily replaced.

[0058] In a particular embodiment, R 1 When R is a heteroaryl,2 is non-substituted C 1~6 It is not alkyl.

[0059] In a particular embodiment, A is either N or CH, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3 It is independently, Halo, -LC 1~9 Alkyl, -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 -L-5~6 member heteroaryl or -L-5~6 member heterocyclyl, each having 1~3 R 6 It is arbitrarily substituted, and each L is independently conjugated or -C≡C-, Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or monocyclic heterocyclyl, each having 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R6 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, and R 7 and R 8 Each of them independently consists of hydrogen or C 1~4 Alkyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form -(CH2)2-O-(CH2)2-.

[0060] Also, equation IIa: [ka] A compound of, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In the formula, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3 These are independently cyano, halo, and C. 1~9 Alkyl, C 1~4 Haloalkyl, -OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7aryl, heteroaryl, or heterocyclyl, each containing 1 to 3 R 6 It is arbitrarily substituted, and each L is independently conjugated or -C≡C-, Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or monocyclic heterocyclyl, each having 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline.

[0061] In a particular embodiment, formula IIa: [ka] A compound of, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In the formula, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3 These are independently cyano, halo, and -LC. 1~9 Alkyl, -LC 1~4 Haloalkyl, -L-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 -L-aryl, -L-heteroaryl, or -L-heterocyclyl, each containing 1 to 3 R 6 It is arbitrarily substituted, and each L is independently either -C≡C- or does not exist. Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each having 1 to 3 R5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, Each R b These are, independently, hydrogen or C 1~4 It is alkyl.

[0062] In some embodiments, with respect to compounds of formula IIa, at least one of the following is true: 1) R 1 This is 1 to 3 R 3 Is it a condensed tricyclic ring that has been arbitrarily substituted with, 2) R 1 This is cyano, -C≡CC 1~9 Alkyl, 1-3 R 6 -C replaced by 1~9 Alkyl, -C≡CC 1~4 Haloalkyl, -C≡C-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 -OC 1~4 At least one R selected from alkyl, -O-phenyl, -L-aryl, -L-heteroaryl, or -L-heterocyclyl 3 An arbitrarily substituted condensed bicyclic ring, each of which has 1 to 3 R 6 And it is further arbitrarily substituted, and each L is independently either -C≡C- or does not exist. 3) R 1 teeth, i) Cyano, -C≡CC 1~9 Alkyl, -C≡CC 1~4 Haloalkyl, -C≡C-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 -C≡C-aryl, -C≡C-heteroaryl, or -C≡C-heterocyclyl, each containing 1 to 3 R 6 It is then arbitrarily replaced, ii) Monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each comprising 1 to 3 cyano-C(O)R7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Further substituted with haloalkyl, phenyl, heterocyclyl, or heteroaryl, each of which contains 1 to 3 C atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, iii) an arbitrarily substituted condensed aryl, an arbitrarily substituted condensed heteroaryl, or an arbitrarily substituted condensed heterocyclyl, each having 1 to 3 R 6 It is further optionally replaced, or iv) Formula-L 1 -L 2 substituents, where L 1 These are aryl, heteroaryl, or heterocyclyl compounds, each containing 1 to 3 R 6 It is arbitrarily replaced by and L 2 These are phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 C atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 It was arbitrarily substituted with a haloalkyl group. at least one R selected from 3 It is a substituted monocyclic ring that has been substituted with, or 4) R 2 is -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that has been arbitrarily substituted with [the specified compound].

[0063] Also, equation IIb: [ka] A compound of, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In the formula, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3 These are independently cyano, halo, and -LC. 1~9 Alkyl, -LC 1~4 Haloalkyl, -L-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 -L-aryl, -L-heteroaryl, or -L-heterocyclyl, each containing 1 to 3 R 6 It is arbitrarily substituted, and each L is independently either -C≡C- or does not exist. Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each having 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, Each R b These are, independently, hydrogen or C 1~4 It is alkyl.

[0064] In some embodiments, with respect to compounds of formula IIb, R 1 It is not a 10-membered heteroaryl substituted with methoxy and methyl, but R 1 cyano, halo, C1~4 Alkyl, -OR 7 , C 1~4 Haloalkyl and NR 7 R 8 Not a C6 aryl substituted with 1 to 3 substituents independently selected from, where R 7 and R 8 Each of them independently consists of hydrogen or C 1~4 It is alkyl, R 1 is unsubstituted C 10 Not aryl, but R 1 It is not an unsubstituted heterocyclyl either.

[0065] In a particular embodiment, A is N. In a particular embodiment, A is CH.

[0066] In a particular embodiment, R 1 This is 1 to 3 R 3 This is the aryl that you want to replace with as you wish.

[0067] In a particular embodiment, R 1 This is 1 to 3 R 3 It is a heteroaryl compound that has been arbitrarily substituted with [the specified compound].

[0068] In a particular embodiment, R 1 This is 1 to 3 R 3 It is a heterocyclyl that has been arbitrarily substituted.

[0069] In a particular embodiment, R 1 This is 1 to 3 R 3 It is a cycloalkyl group that is optionally substituted with [a specific compound].

[0070] In a particular embodiment, R 1 teeth, [ka] And each n is independently 1, 2, or 3, and Y is CR 8 R 9 , C(O), O, or NR 10And R 8 and R 9 Each of these independently contains hydrogen, halo, or C. 1~4 It is alkyl, and R 10 is hydrogen or C 1~4 It is alkyl.

[0071] In certain embodiments, L is a bond (i.e., nonexistent). In certain embodiments, L is -C≡C-.

[0072] In a particular embodiment, R 8 and R 9 Each of these is a halo. In a particular embodiment, R 8 and R 9 Each of them is fluoro.

[0073] In a particular embodiment, R 8 and R 9 Each of them is hydrogen.

[0074] In a particular embodiment, R 2 It is hydrogen.

[0075] In a particular embodiment, R 3 Hello, C 1~9 Alkyl, C 1~4 Haloalkyl or -OR 7 That is the case.

[0076] In a particular embodiment, at least one R 3 Hello, C 1~9 Alkyl, or -OR 7 In a particular embodiment, R 3 Hello, C 1~9 Alkyl, or -OR 7 That is the case.

[0077] In a particular embodiment, at least one R 3 is fluoro, chloro, bromo, methyl, tert-butyl, methoxy, or phenoxy. In certain embodiments, R 3These are fluoro, chloro, bromo, methyl, tert-butyl, methoxy, or phenoxy.

[0078] In a particular embodiment, R 3 This is 1 to 3 R 6 This is an aryl that has been arbitrarily substituted.

[0079] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0080] In a particular embodiment, at least one R 3 is an aryl substituted with phenyl, heterocyclyl, or heteroaryl. In certain embodiments, R 3 This is an aryl compound substituted with phenyl, heterocyclyl, or heteroaryl.

[0081] In a particular embodiment, at least one R 3 teeth, [ka] That is the case.

[0082] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0083] In a particular embodiment, at least one R 3 is an aryl substituted with a heteroaryl, and that heteroaryl is C 1~4 Alkyl, -C(O)OH, or C 1~4 It is substituted with a haloalkyl group. In certain embodiments, R 3 is an aryl substituted with a heteroaryl, and that heteroaryl is C 1~4Alkyl, -C(O)OH, or C 1~4 It is substituted with a haloalkyl group.

[0084] In a particular embodiment, at least one R 3 teeth, [ka] That is the case.

[0085] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0086] In a particular embodiment, at least one R 3 This is 1 to 3 R 6 It is a heterocyclyl which is optionally substituted with R. In a particular embodiment, R 3 This is 1 to 3 R 6 It is a heterocyclyl that has been arbitrarily substituted.

[0087] In a particular embodiment, at least one R 3 teeth, [ka] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0088] In a particular embodiment, at least one R 3 This is 1 to 3 R 6 It is a heteroaryl which may be optionally substituted with R. In a particular embodiment, R 3 This is 1 to 3 R 6 It is a heteroaryl compound that has been arbitrarily substituted with [the specified compound].

[0089] In a particular embodiment, at least one R 3 teeth, [ka] In a particular embodiment, R 3 teeth, [ka] That is the case.

[0090] In a particular embodiment, R 2 It consists of hydrogen, 1 to 3 R atoms. 4 C arbitrarily replaced by 1~6 Alkyl or cycloalkyl, each R 4 -OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, provided that one R 4 Only heterocyclyl compounds are present, and each R a These are independently -NH2 or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and R b It is hydrogen.

[0091] In certain embodiments, this specification includes formula III: [ka] A compound of, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In the formula, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3These are independently aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 6 It is arbitrarily replaced with, Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each having 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, phenyl, or pyridyl, or R 7 and R 8These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and Each R b These are, independently, hydrogen or C 1~4 It is alkyl.

[0092] In certain embodiments, this specification includes formula IV: [ka] A compound of, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In the formula, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each having 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently Cyano, Halo, and C 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4It is a haloalkyl, Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and Each R b These are independently hydrogen or C 1~4 It is alkyl.

[0093] In a particular embodiment, R 2 It consists of hydrogen, 1 to 3 R atoms. 4 C arbitrarily replaced by 1~6 It is alkyl or cycloalkyl. In certain embodiments, R 2 is hydrogen or 1-3 R 4 C arbitrarily replaced by 1~6 It is alkyl. In a particular embodiment, R 2 is hydrogen or one R 4 C arbitrarily replaced by 1~6 It is alkyl. In a particular embodiment, R 2 is hydrogen. In a particular embodiment, R 2 This is 1 to 3 R 4 C arbitrarily replaced by 1~6 It is alkyl. In a particular embodiment, R 2 C 1~6 It is alkyl. In a particular embodiment, R 2 C 1~4 It is alkyl.

[0094] In a particular embodiment, R 2 It consists of hydrogen, 1 to 3 R atoms. 4 C arbitrarily replaced by 1~6 Alkyl or cycloalkyl, each R 4 It is independently, -OC 1~6 Alkyl, -OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each R aThese are independently -NH2 or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and R b It is hydrogen.

[0095] In a particular embodiment, each R 4 -OC 1~6 Alkyl, -OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each R a These are independently -NH2 or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and R b It is hydrogen.

[0096] In a particular embodiment, each R 4 -OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each R a These are independently -NH2 or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and R b It is hydrogen.

[0097] In certain embodiments, compounds selected from Table 1, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof are provided. In certain embodiments, compounds are selected from the compounds in Table 1.

[0098] [Table 1] JPEG2026082935000020.jpg219170JPEG2026082935000021.jpg224170JPEG2026082935 000022.jpg229170JPEG2026082935000023.jpg214170JPEG2026082935000024.jpg22917 0JPEG2026082935000025.jpg214170JPEG2026082935000026.jpg224170JPEG2026082935 000027.jpg224170JPEG2026082935000028.jpg209170JPEG2026082935000029.jpg61170

[0099] In certain embodiments, compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof are provided. In certain embodiments, compounds are selected from the following:

[0100] [Table 2]

[0101] In certain embodiments, compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof are provided. In certain embodiments, the compounds are [ka] (In the formula, R 2 (as defined herein) Selected from.

[0102] In a particular embodiment, R 2 This is 1 to 3 R 4 C arbitrarily replaced by 1~6 It is alkyl. In a particular embodiment, R 2 C 1~6 It is alkyl. In a particular embodiment, R 2 It is ethyl.

[0103] In a particular embodiment, the compound is [ka] Selected from.

[0104] Generally, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, it is understood that compounds with the same structure can be identified using other names. Specifically, compounds may also be named using other naming systems and symbols commonly recognized in the chemical art, 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 by common names, systematic names, or non-systematic names.

[0105] In certain embodiments, optical isomers, racemates, or other mixtures thereof of the compounds described herein, or pharmaceutically acceptable salts or mixtures thereof, are provided. In such circumstances, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be achieved, for example, by conventional methods such as crystallization in the presence of a resolving agent, or by chromatography using a chiral high-pressure liquid chromatography (HPLC) column.

[0106] Compositions provided herein, comprising the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof, may include racemic mixtures or mixtures containing an enantiomer-rich single enantiomer, or single diastereomers or mixtures of diastereomers. All such isomers of these compounds are expressly included herein as if all isomers were specifically and individually listed.

[0107] In certain embodiments, chelates, non-covalent complexes, and mixtures thereof of the compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof are also provided. A “chelate” is formed by the coordination of a compound to a metal ion at two (or more) points. A “non-covalent complex” is formed by the interaction of a compound with other molecules, in which case no covalent bond is formed between the compound and the molecules. For example, complexation can occur via van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).

[0108] In certain embodiments, prodrugs of the compounds described herein are provided. “Prodrug” means any compound that, when administered to a biological system, generates a drug substance or active ingredient as a result of spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. Thus, a prodrug is a covalently modified analog or latent form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, glycol moieties, and the like.

[0109] In a particular embodiment, R 1 but, [ka] A compound of formula I or IIa is provided. In the formula, Each R 12 These are, independently, hydrogen and C 1~9 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 A cycloalkyl, aryl, heteroaryl, or heterocyclyl, where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is each composed of 1 to 4 Z 1b It is arbitrarily substituted in the base, and, each Z 1bThese are independently oxo, thioxo, hydroxy, halo, -NO2, -N3, cyano, and C. 1~9 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~15 Cycloalkyl, C 1~8 Haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C) 1~9 Alkyl), -O(C 2~6 Alkenyl), -O(C 2~6 Alkinyl), -O(C 3~15 Cycloalkyl), -O(C 1~8 Haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1~9 Alkyl), -NH(C 2~6 Alkenyl), -NH(C 2~6 Alkinyl), -NH(C 3~15 Cycloalkyl), -NH(C 1~8 Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C 1~9 Alkyl)2,-N(C 3~15 Cycloalkyl)2,-N(C 2~6 Alkenyl)2,-N(C) 2~6 Alkinyl)2,-N(C) 3~15 Cycloalkyl)2,-N(C 1~8 Haloalkyl)2,-N(aryl)2,N(heteroaryl)2,N(heterocyclyl)2,-N(C 1~9 Alkyl)(C 3~15 Cycloalkyl), -N(C 1~9 Alkyl)(C 2~6 Alkenyl), -N(C 1~9 Alkyl)(C 2~6 Alkinyl), -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)(heterocyclyl), -C(O)(C1~9 Alkyl), -C(O)(C 2~6 Alkenyl), -C(O)(C 2~6 Alkinyl), --C(O)(C 3~15 Cycloalkyl), -C(O)(C 1~8 Haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C 1~9 Alkyl), -C(O)O(C 2~6 Alkenyl), -C(O)O(C 2~6 Alkinyl), -C(O)O(C 3~15 Cycloalkyl), -C(O)O(C 1~8 Haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C 1~9 Alkyl), -C(O)NH(C 2~6 Alkenyl), -C(O)NH(C 2~6 Alkinyl), -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(heterocyclyl), -C(O)N(C 1~9 Alkyl)2,-C(O)N(C 3~15 Cycloalkyl)2,-C(O)N(C 2~6 Alkenyl)2,-C(O)N(C) 2~6 Alkinyl)2,-C(O)N(C) 3~15 Cycloalkyl)2,-C(O)N(C 1~8 Haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclyl)2, -NHC(O)(C 1~9 Alkyl), -NHC(O)(C 2~6 Alkenyl), -NHC(O)(C 2~6 Alkinyl), --NHC(O)(C 3~15 Cycloalkyl), -NHC(O)(C 1~8 Haloalkyl))-NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C)1~9 Alkyl), -NHC(O)O(C 2~6 Alkenyl), -NHC(O)O(C 2~6 Alkinyl), -NHC(O)O(C 3~15 Cycloalkyl), -NHC(O)O(C 1~8 Haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1~9 Alkyl), -NHC(O)NH(C 2~6 Alkenyl), -NHC(O)NH(C 2~6 Alkinyl), -NHC(O)NH(C 3~15 Cycloalkyl), -NHC(O)NH(C 1~8 Haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C 1~9 Alkyl), -S(C 2~6 Alkenyl), -S(C 2~6 Alkinyl), -S(C 3~15 Cycloalkyl), -S(C 1~8 Haloalkyl), -S (aryl), -S (heteroaryl), -S (heterocyclyl), -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 Alkinyl), -S(O)(C 3~15 Cycloalkyl), -S(O)(C 1~8 Haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O)2(C) 1~9 Alkyl), -S(O)2(C 2~6 Alkenyl), -S(O)2(C 2~6 Alkinyl), -S(O)2(C 3~15 Cycloalkyl), -S(O)2(C1~8 Haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C) 1~9 Alkyl), or -S(O)2N(C 1~9 Alkyl)2, Here, alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl all have 1 to 4 halos, C 1~9 Alkyl, C 1~8 Haloalkyl, -OH, -NH2, -NH(C) 1~9 Alkyl), -NH(C 3~15 Cycloalkyl), -NH(C 1~8 Haloalkyl), -NH (aryl), -NH (heteroaryl), -NH (heterocyclyl), -N (C 1~9 Alkyl)2,-N(C 3~15 Cycloalkyl)2,-NHC(O)(C 3~15 Cycloalkyl), -NHC(O)(C 1~8 Haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C) 1~9 Alkyl), -NHC(O)O(C 2~6 Alkinyl), -NHC(O)O(C 3~15 Cycloalkyl), -NHC(O)O(C 1~8 Haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -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(heterocyclyl), -S(O)2NH(C) 1~9 Alkyl), -S(O)2N(C 1~9 Alkyl)2,-O(C 3~15 Cycloalkyl), -O(C 1~8Haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or -O(C 1~9 It can be optionally substituted with alkyl.

[0110] In a particular embodiment, R 2 but, [ka] Compounds of formula I or any of the subformulas provided herein are provided.

[0111] Such substituents also include, but are not limited to, all individual stereoisomers and mixtures thereof, including the chirality of the phosphorus atom, such as the exemplary moieties shown above.

[0112] Furthermore, this specification also provides in vivo metabolites of the compounds described herein. Such products may arise mainly from enzymatic processes, such as oxidation, reduction, hydrolysis, amidation, and esterification of the administered compounds.

[0113] Therapeutic use of compounds "Treatment" or "treating" refers to an approach to obtain a clinical outcome that includes a beneficial or desired result. A beneficial or desired clinical outcome may include one or more of the following: a) inhibiting the disease or condition (e.g., reducing one or more symptoms resulting from the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or stopping the onset of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing regression of clinical symptoms (e.g., restoring the disease state, providing partial or complete remission of the disease or condition, enhancing the effects of other medications, slowing the progression of the disease, improving quality of life, and / or extending survival).

[0114] "Prevention" or "preventing" means the treatment of any disease or condition in which the clinical symptoms of the disease or condition do not occur. In some embodiments, the compounds may be administered to subjects (including humans) who are at risk of or have a family history of the disease or condition. Primary hyperoxaluria type 1 may necessitate a kidney transplant. After transplantation, remission is highly likely. In certain embodiments, the compounds disclosed herein are administered to patients after transplantation for the purpose of preventing remission.

[0115] "Subject" means an animal, such as a mammal (including humans), that is the subject of treatment, observation, or experimentation. The methods described herein may be useful for human therapeutic and / or veterinary uses. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0116] The terms “therapeutic effective dose” or “effective dose” of any compound or pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog described herein mean an amount sufficient to provide a therapeutic benefit, such as the relief of symptoms or the slowing of disease progression, when administered to a subject. For example, a therapeutic effective dose may be an amount sufficient to reduce the symptoms of a disease or condition in response to the inhibition of glycolate oxidase activity. The therapeutic effective dose may vary depending on the subject, the disease or condition being treated, the subject’s weight and age, the severity of the disease or condition, and the method of administration, and this is readily determined by those skilled in the art.

[0117] The term "inhibition" means a decrease in baseline activity of a biological activity or process. "Inhibition of glycolate oxidase activity" or a variation thereof means a decrease in the activity of the glycolate oxidase enzyme as a direct or indirect reaction to the presence of the compound of the application, compared to the activity of glycolate oxidase in the absence of the compound of the application. "Glycolate oxidase inhibition" means a decrease in glycolate oxidase enzyme activity as a direct or indirect reaction to the presence of the compound of the application, compared to the activity of glycolate oxidase in the absence of the compound of the application. In some embodiments, inhibition of glycolate oxidase enzyme activity may be compared in the same subject before treatment or in other untreated subjects.

[0118] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living organism, such as an animal or a human. In this context, the methods described herein may be used therapeutically in an organism. “Ex vivo” means outside a living organism. Examples of ex vivo cell populations include biological samples, including in vitro cell cultures and fluid or tissue samples obtained from organisms. Such samples may be obtained by methods well known in the 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 may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine an optimal schedule and / or to set the dosage of a glycolate oxidase inhibitor for a given indication, cell type, organism, and other parameters. Information gathered from such use may be used experimentally or clinically to set protocols for in vivo treatment. Other ex vivo uses of the compounds and compositions described herein may be described below or will be apparent to those skilled in the art. Selected compounds may be further characterized to investigate safety or tolerable doses in human or non-human subjects. Such properties may be investigated using methods commonly known to those skilled in the art.

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

[0120] In certain embodiments, the compounds disclosed herein are useful for the treatment, prevention, diagnosis, or monitoring of diseases or conditions mediated by oxalic acid, calcium oxalate, or glycolate oxidase. In some embodiments, the diseases or conditions are nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, hyperoxaluria type 1, Bard's disease, glycoluria, end-stage renal disease (ESRD), renal failure, renal transplant failure, and type 2 diabetes mellitus.

[0121] In further embodiments, the method is provided for mitigating symptoms of a disease or disorder mediated by glycolate oxidase. In some embodiments, the method includes identifying a mammal having symptoms of a disease or disorder mediated by glycolate oxidase and providing the mammal with an amount of the compound described herein that is effective in reversing (i.e., reducing the severity) the symptoms.

[0122] In further embodiments, methods are provided for mitigating symptoms of diseases or disorders mediated by oxalic acid, calcium oxalate, or glycolate oxidase. In some embodiments, the methods include identifying a mammal having symptoms of a disease or disorder mediated by oxalic acid, calcium oxalate, or glycolate oxidase, and providing the mammal with an amount of the compound described herein that is effective in reversing (i.e., reducing the severity) 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, calcium oxalate, or glycolate oxidase is kidney stone formation. In certain embodiments, kidney stone formation is recurrent. In certain embodiments, kidney stone formation is associated with primary hyperoxaluria type 1.

[0124] In some embodiments, the disease or condition mediated by glycolate oxidase is renal failure, including single-kidney and bilateral renal failure. In some embodiments, the disease or condition mediated by oxalic acid, calcium oxalate, or glycolate oxidase is renal failure. In some embodiments, renal failure is failure of one kidney or both kidneys.

[0125] In some embodiments, the disease or condition to be prevented is renal transplant failure.

[0126] In some embodiments, the diseases or conditions mediated by glycolate oxidase are diabetes mellitus (including type 1 and type 2 diabetes mellitus), gestational diabetes mellitus, prediabetes, insulin resistance, metabolic syndrome, fasting blood glucose impairment, and glucose intolerance. In some embodiments, the diseases or conditions mediated by oxalic acid or calcium oxalate or glycolate oxidase are diabetes mellitus. In some embodiments, diabetes mellitus are type 1 and type 2 diabetes mellitus, gestational diabetes mellitus, prediabetes, insulin resistance, metabolic syndrome, fasting blood glucose impairment, or glucose intolerance. 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 oxalic acid, calcium oxalate, or glycolate oxidase is bladder stone formation.

[0128] Useful criteria for assessing disease activity in subjects with primary hyperoxaluria type 1 can be found in Brooks et al. (2016) Am.J.Nephrol. 43,4:293-303. Urinary oxalate and calcium levels are monitorable.

[0129] The therapeutic methods disclosed herein are also applicable at any point in the disease course. In certain embodiments, the method is applied to subjects with primary hyperoxaluria type 1 (i.e., inactive disease after kidney transplantation) during a period of remission. In such embodiments, the method provides benefits by extending the period of remission (e.g., extending the period of inactive disease) or by preventing, reducing, or delaying the onset of active disease. An example would be an increase in the time between kidney stone incidents. In other embodiments, the method may be applied to subjects with primary hyperoxaluria type 1 during an active disease period. Such methods provide benefits by reducing the duration of active disease, by reducing or reversing one or more symptoms of primary hyperoxaluria type 1, or by treating primary hyperoxaluria type 1. Such reversal may be a reduction in the size, number, or frequency of kidney stones.

[0130] Measures for determining the efficacy of primary hyperoxaluria type 1 treatment in clinical practice are described and include, for example, symptom suppression, calcium oxalate concentration in body fluids, renal function assays, and improvement in quality of life.

[0131] In certain embodiments, this specification provides a therapeutically effective amount of the compound or pharmaceutical composition or formula I described herein to a patient as needed. [ka] A method for treating primary hyperoxaluria type 1 is provided, comprising administering the compound or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. A is either N or CH, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9CH2CH2OCH3, 1 to 3 Rs 4 C optionally substituted with 1~6 alkyl, cycloalkyl, or heteroaryl optionally substituted with 1 to 3 Rs 5 and each R is independently cyano, halo, -L-C 3 alkyl, -L-C 1~9 haloalkyl, -L-OC 1~4 haloalkyl, -NR 1~4 R 7 -C(O)NR 8 R 7 -S(O)2NR 8 R 7 -NR 8 C(O)R 7 -OR 8 -L-aryl, -L-heteroaryl, or -L-heterocyclyl, each of which is optionally substituted with 1 to 3 Rs 7 and each L is independently -C≡C- or absent 6 and each R is independently halo, hydroxy, -OC 4 alkyl, -NH2, -NHC 1~6 alkyl, -N(C 1~6 alkyl)2, -OC(O)R 1~6 -OC(O)OR a -OP(O)(OR a )2, or monocyclic heterocyclyl, each of which is optionally substituted with 1 to 3 Rs b provided that only one R 5 is heterocyclyl 4 and each R is independently cyano, halo, C 5 alkyl, hydroxy, -OC<00009{08}>alkyl, C 1~4 haloalkyl, or -OC 1~4 haloalkyl 1~4 and each R is independently cyano, halo, -C(O)R 6 -C(O)OR 7 -C(O)NR 7 R 7 R 8-S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and Each R b These are, independently, hydrogen or C 1~4 It is alkyl.

[0132] In a particular embodiment, R 1 When R is phenyl, 3 It is an aryl or heteroaryl compound, each containing 1 to 3 R 6 It is arbitrarily replaced by and R 1 When R is a heteroaryl, 2 is non-substituted C 1~6 It is not alkyl.

[0133] In certain embodiments, this specification provides a therapeutically effective amount of the compound described herein, the pharmaceutical composition described herein, or Formula I: [ka] A method for treating recurrent renal stone formation is provided, which comprises administering a compound of formula or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. In the formula, A is N or CH, R 1 is alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one to three R 3 ; R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, C 4 alkyl optionally substituted with one to three R 1~6 , cycloalkyl, or heteroaryl optionally substituted with one to three R 5 ; each R 3 is independently cyano, halo, -L-C 1~9 alkyl, -L-C 1~4 haloalkyl, -L-OC 1~4 haloalkyl, -NR 7 R 8 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-aryl, -L-heteroaryl, or -L-heterocyclyl, each of which is optionally substituted with one to three R 6 ; and each L is independently -C≡C- or absent; each R 4 is independently halo, hydroxy, -OC 1~6 alkyl, -NH2, -NHC 1~6 alkyl, -N(C 1~6 alkyl)2, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclyl, each of which is optionally substituted with one to three R 5It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and Each R b These are, independently, hydrogen or C 1~4 It is alkyl.

[0134] In a particular embodiment, R 1When R is phenyl, 3 It is an aryl or heteroaryl compound, each containing 1 to 3 R 6 It is arbitrarily replaced by and R 1 When R is a heteroaryl, 2 is non-substituted C 1~6 It is not alkyl.

[0135] In certain embodiments, this specification provides a therapeutically effective amount of the compound described herein, the pharmaceutical composition described herein, or Formula I: [ka] A method is provided for inhibiting the production of glyoxylic acid and / or oxalic acid, and / or glycolate oxidase (GO), comprising administering a compound or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof. A is either N or CH, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3 These are independently cyano, halo, and -LC. 1~9 Alkyl, -LC 1~4 Haloalkyl, -L-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7-L-aryl, -L-heteroaryl, or -L-heterocyclyl, each containing 1 to 3 R 6 It is arbitrarily substituted, and each L is independently either -C≡C- or does not exist. Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocycline, each having 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R8 These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and Each R b These are, independently, hydrogen or C 1~4 It is alkyl.

[0136] In some embodiments, R 1 When R is phenyl, 3 It is an aryl or heteroaryl compound, each containing 1 to 3 R 6 It is arbitrarily replaced by and R 1 When R is a heteroaryl, 2 is non-substituted C 1~6 It is not alkyl.

[0137] In certain embodiments, the use of the compounds or pharmaceutical compositions described herein is for the purpose of suppressing or inhibiting the formation of recurrent kidney stone formations in patients who require it.

[0138] In certain embodiments, the use of the compound of formula I or its pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterated analogs is for the purpose of suppressing or inhibiting the formation of recurrent kidney stone formations in patients who require it. Formula I: [ka] Among the compounds, A is either N or CH, R 1 These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R 3 It is arbitrarily replaced with, R 2 is hydrogen, -(CH2CH2O) 1~9CH2CH2OCH3, 1-3 R 4 C arbitrarily replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It is a heteroaryl compound that is arbitrarily substituted with, Each R 3 These are independently cyano, halo, and -LC. 1~9 Alkyl, -LC 1~4 Haloalkyl, -L-OC 1~4 Haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 -L-aryl, -L-heteroaryl, or -L-heterocyclyl, each containing 1 to 3 R 6 It is arbitrarily substituted, and each L is independently either -C≡C- or does not exist. Each R 4 These are independently halo, hydroxyl, and -OC. 1~6 Alkyl, -NH2, -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2,-OC(O)R a -OC(O)OR a , -OP(O)(OR b )2, or monocyclic heterocyclines, each containing 1 to 3 R 5 It is arbitrarily replaced by, however, one R 4 Only heterocyclyls, Each R 5 These are independently cyano, halo, and C. 1~4 Alkyl, hydroxy, -OC 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is a haloalkyl, Each R 6 These are independently cyano, halo, and -C(O)R. 7 , -C(O)OR 7 -C(O)NR 7 R 8 -S(O)2NR7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1~4 Alkyl, -OC 1~4 Alkyl, C 1~4 Haloalkyl, -OC 1~4 They are haloalkyl, phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 carbon atoms. 1~4 Alkyl, -C(O)OH, or C 1~4 Optionally substituted with a haloalkyl group, R 7 and R 8 These are, independently, hydrogen and C 1~4 Alkyl, or phenyl, pyridyl, or R 7 and R 8 These, together with the nitrogen atom to which they are bonded, form a heterocycline. Each R a These are independently -NH2 and -NHC 1~6 Alkyl, -N(C 1~6 Alkyl)2, or -OP(O)(OR b )C arbitrarily substituted in 2 1~6 It is alkyl, and Each R b These are, independently, hydrogen or C 1~4 It is alkyl, However, R 1 When R is phenyl, 3 It is an aryl or heteroaryl compound, each containing 1 to 3 R 6 It is arbitrarily replaced by and R 1 When R is a heteroaryl, 2 is non-substituted C 1~6 It is not 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 used and / or developed to treat primary hyperoxaluria type 1. Examples of such therapeutic agents include calcium oxalate crystallization inhibitors, oxalate degrading enzyme inhibitors, siRNAs, oxazymes, and lumasiranes. Examples of such therapeutic interventions include 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, ipragliflozin, empagliflozin, and potassium citrate.

[0141] In some embodiments, the methods described herein further include administering an additional therapeutic agent. In some embodiments, the uses described herein are provided in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a calcium oxalate crystallization inhibitor, an oxalate degrading enzyme inhibitor, siRNA, oxazyme, lumasilan, nedosilan, oxybate, or reloxaliase. In some embodiments, the additional therapeutic agent is an SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, erzgliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, ipragliflozin, empagliflozin, or potassium citrate.

[0142] kit This specification also provides kits comprising a compound of formula I (or any other formula described herein) or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further includes instructions for use. In one embodiment, the kit comprises a compound of formula I (or any other formula described herein) or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterated analog thereof, and a label and / or instructions for the use of the compound in the treatment of indications (including diseases or conditions) described herein.

[0143] This specification also provides products comprising the compounds described herein or pharmaceutically acceptable salts, tautomers, prodrugs, or deuterated analogs thereof in a suitable container. The container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

[0144] <Pharmaceutical composition and administration mode> The compounds provided herein are typically administered in the form of pharmaceutical compositions. Therefore, this specification also provides 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 media selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable media 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 methods well known in the pharmaceutical art. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985) and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GSBanker & CTRhodes, Eds.).

[0145] The pharmaceutical composition may be administered as a single or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectally, buccally, nasally, and transdermally. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0146] One mode of administration is parenteral, such as by injection. Forms into which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oily suspensions or emulsions (including sesame oil, corn oil, barley oil, or peanut oil), as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical media.

[0147] Oral administration may be another route of administration of the compounds described herein. Administration may be, for example, via capsules or enteric-coated tablets. In the manufacture of a pharmaceutical composition comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient acts as a diluent, it may be in the form of a solid, semi-solid, or liquid material and acts as a medium, carrier, or medium for the active ingredient. Therefore, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments containing up to 10% by weight of the active compound, for example, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0148] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may also contain lubricants, such as talc, magnesium stearate, and mineral oil, humectants, emulsifiers and suspending agents, preservatives, such as methyl and propyl hydroxybenzoates, sweeteners, and flavoring agents.

[0149] Compositions comprising at least one of the compounds described herein or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterated analog thereof can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by utilizing procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are given in U.S. Patents No. 3,845,770, No. 4,326,525, No. 4,902,514, and No. 5,616,345. Other formulations for use in the manner disclosed herein employ transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous injection of the compounds described herein in controlled doses. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. Such patches may be constructed for continuous, pulsating, or on-demand delivery of pharmaceutical agents.

[0150] When preparing solid compositions such as tablets, the main active ingredient may be mixed with pharmaceutical excipients to form a solid pre-formulation composition containing the compound described herein or a homogeneous mixture thereof of a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog. When this pre-formulation composition is referred to as homogeneous, the active ingredient may be uniformly dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit formulations, such as tablets, pills, and capsules.

[0151] Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a formulation that offers the benefit of a prolonged effect or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an internally administered component and an externally administered component, the latter in the form of an envelope covering the former. The two components can be separated by an enteric coating that resists disintegration in the stomach and allows the internal component to pass through the duodenum intact or its release to be delayed. Various materials can be used for such enteric coatings or coatings, including several 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 in pharmaceutically acceptable aqueous solvents or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, compositions are administered orally or via nasal respiratory routes for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, which may be attached to a face mask tent or an intermittent positive pressure respirator. Solutions, suspensions, or powder compositions may preferably be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0153] dose The specific dose level of the compound of this application for any particular subject will depend on a variety of factors, including the activity of the specific compound used, the age, weight, overall health, sex, diet, timing of administration, route of administration, and excretion rate of the subject receiving treatment, the combination of drugs, and the severity of the specific disease. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of the subject's body weight. Doses of approximately 0.1 to 150 mg / kg may be appropriate. In some embodiments, approximately 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing by subject's body weight is particularly useful when adjusting doses between subjects of significantly different body sizes, such as when using the drug in both children and adult humans, or when converting effective doses in non-human subjects such as dogs to doses suitable for human subjects.

[0154] The daily dose may 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 may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

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

[0156] The compound or composition thereof may be administered once, twice, three times, or four times daily using any of the preferred modes described above. Administration or treatment with the compound may also be continued over a period of time. For example, treatment would typically last at least 7, 14, or 28 days in a single treatment cycle. Treatment cycles are well-known in cancer chemotherapy and frequently alternate with rest periods of approximately 1 to 28 days, usually about 7 or 14 days, between cycles. Treatment cycles may also be continuous in other embodiments.

[0157] In certain embodiments, the method comprises administering a subject an initial daily dose of about 1 to 800 mg of the compound described herein, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased once daily, every other day, twice a week, or once a week.

[0158] Synthesis of the compound of formula I The compounds may be prepared using the methods disclosed herein and their routine modifications, which will become apparent given the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well known synthetic methods may be used. The synthesis of typical compounds described herein may be achieved as described in the following examples. Reagents may be purchased from Sigma Aldrich or other chemical suppliers, where available.

[0159] general synthesis Typical embodiments of the compounds described herein can be synthesized using the general reaction scheme described below. It will become apparent from the description herein that the general scheme can be modified to yield correspondingly different products by substituting the starting materials with other materials having similar structures. The description of the synthesis continues to provide numerous examples of how the starting materials can be modified to provide corresponding products. Given a desired product with defined substituents, the required starting materials can generally be determined by investigation. The starting materials are typically obtained from suppliers or synthesized using publicly available methods. When synthesizing the compounds of the embodiments described herein, an investigation of the structure of the compound to be synthesized will provide the identity of each substituent. The identity of the final product will generally be determined by a simple investigation process, considering the examples herein, which will reveal the identity of the required starting materials. Generally, the compounds described herein are typically stable and isolateable at room temperature and room pressure.

[0160] <Synthesis reaction parameters> The compounds of this disclosure can be prepared, for example, from readily available starting materials using the general methods and procedures described below. Given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reagents, solvent, pressure, etc.), it will be understood that other process conditions are also usable unless otherwise specified. Optimal reaction conditions may vary depending on the specific reagents or solvents used, but such conditions can be determined by routine optimization procedures for those skilled in the art.

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

[0162] The starting materials for the reactions described below are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce, or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures or obvious modifications thereof described in standard references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0163] The term "solvent" generally refers to an inert solvent under the conditions of the reaction described in relation to it (e.g., benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, etc.). Unless otherwise specified, the solvent is an inert organic solvent, and the reaction may be carried out under an inert gas, preferably argon or nitrogen.

[0164] The term "qs" means adding a sufficient amount to achieve the specified function, for example, to bring the solution to the desired volume (i.e., 100%).

[0165] In Scheme 1, A, R 1 , R 2 , R 3 , and R 6 As defined herein, each X is independently a halo (e.g., chloro, bromo, or iodine), and each R 50 These are independently alkyl or two R 50 These groups together form a ring (for example, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane), and PG is a protecting group bonded to the heteroatom. [ka]

[0166] In Scheme 1, the compound of formula I is prepared by coupling a well-protected compound 100' with the corresponding boronic acid or its ester 200 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.) and then deprotecting it. Compound 300 for use in the preparation of the compound of formula I shown in Scheme 1 is also prepared by coupling a well-protected compound 400 with the corresponding halo-substituted compound 500 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.). Compound 400 is prepared by coupling a well-protected compound 100' with the corresponding boronic acid or its ester 600 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.). The various compounds of formulas 100', 200, 500, and 600 for use in the methods provided herein are available from suppliers or can be synthesized by known methods.

[0167] In some embodiments, R 2 Compound 300, in which hydrogen is R 2 As defined herein (for example, -(CH2CH2O) 1~9 CH2CH2OCH3, 1-3 R 4 C is arbitrarily replaced by 1~6 Alkyl, cycloalkyl, or 1-3 R 5 It can be esterified via standard coupling conditions to form compound 300, which is a heteroaryl compound (which can be optionally substituted). [Examples]

[0168] The following embodiments are included to demonstrate specific embodiments of the Disclosure. Those skilled in the art should recognize that the techniques disclosed in the following embodiments represent techniques that function well in the practical application of the Disclosure and can therefore be considered to constitute specific practical modes thereof. However, those skilled in the art should recognize that many modifications can be made to the specific embodiments disclosed in light of the Disclosure, and that the same or similar results can still be obtained without departing from the spirit and scope of the Disclosure.

[0169] Synthesis of intermediates 3, 4, and 6 (and their methyl esters 3', 4', and 6') [ka]

[0170] Process 1 A mixture of sodium azide (150.0 g, 2.25 mol) and tetrabutylammonium bisulfate (41.9 g, 123 mmol) in water (2.3 L) was gradually added at 0°C to a solution of trifluic anhydride (375 mL, 2.25 mol) in hexane (900 mL). The resulting mixture was stirred at 0°C for 1 hour, after which the organic soluble material was extracted with hexane (1.8 L), dried on a sodium hydroxide pellet, and decanted. Ethyl 2-cyanoacetate 1 (150.0 g, 0.8 mol) in acetonitrile (1.1 L) and pyridine (300 mL, 4.0 mol) was added to the solution. The resulting mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was purified by ethyl acetate-containing petroleum ether (1:6) elution silica gel column chromatography to obtain impure ethyl 2-cyano-2-diazoacetate 2 (111 g, 99%).

[0171] Process 2 A solution of ethyl 2-cyano-2-diazoacetate 2 (111 g, 795 mmol) in dioxane (7 L) was bubbling with hydrogen bromide gas at 0°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain crude ethyl 4-bromo-1H-1,2,3-triazole-5-carboxylate 3 (125 g), which was used directly in the next step without further purification.

[0172] Process 3 To a solution of crude ethyl 4-bromo-1H-1,2,3-triazole-5-carboxylate 3 (50 g, 227 mmol) in DMF (500 mL), sodium hydride (60%, 10.1 g, 275 mmol) was added at 0°C, and the mixture was stirred under N2 for 30 minutes. Then, 2-(trimethylsilyl)ethoxymethyl chloride (40.5 g, 238 mmol) was added at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was quenched with 5% aqueous lithium chloride 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 using ethyl acetate-containing hexane (2:5) elution to obtain a colorless oil mixture of isomers of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4, 30 g, 38%): ES / MS m / z: C 11 H 20 BrN3NaO3Si(M+Na + Calculated value for ): 372.04, measured value: 372.15.

[0173] A mixture of isomers of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4') was also prepared as an oil from commercially available methyl 4-bromo-1H-1,2,3-triazole-5-carboxylate (3') in a manner similar to the above procedure:ES / MS m / z:C 10 H 19 Calculated value for BrN3NaO3Si(M+Na): 337.27, measured value: 336.53.

[0174] Process 4 A mixture of isomers of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4, 45 g, 129 mmol) and a solution of 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (5, 85.0 g, 257 mmol) were mixed with 2.0 M aqueous sodium carbonate (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 hours under an N2 atmosphere. After cooling the reaction mixture to room temperature and diluting it with water, the product was extracted with ethyl acetate (3 × 1 L). The organic fraction was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-containing petroleum ether (1:30) to obtain an isomer mixture (6, 25.5 g, 43%) of ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as oil: ES / MS m / z:C 23 H 36 Calculated value for BN3NaO5Si(M+Na): 496.44, measured value: 496.45.

[0175] Synthesis of Intermediate 8 [ka]

[0176] Process 1 A mixture of isomers of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4, 25 g, 71.3 mmol) and 4,4'-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1'-biphenyl (7, 45 g, 110.8 mmol) was added to 1,4-dioxane (500 mL), to which 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) were added. The reaction mixture was stirred overnight at 70°C under an N2 atmosphere. After cooling the reaction mixture to room temperature and diluting it with water, the product was extracted with ethyl acetate (3 × 500 mL). The organic fraction was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with ethyl acetate-containing petroleum ether (1:30) to obtain an isomer mixture (8, 11.5 g, 29%) of ethyl 5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as oil: ES / MS m / z:C 29 H 41 Calculated value for BN3O5Si(M+H): 550.29, measured value: 550.45.

[0177] Synthesis of intermediate 10 [ka]

[0178] Process 1 A mixture of isomers of ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (6, 358 mg, 0.76 mmol) and 1,4-dibromobenzene (9, 178 mg, 0.76 mmol) was added to 1,4-dioxane (3 mL), to which tetrakis(triphenylphosphine)palladium (0) (87 mg, 0.076 mmol) and 2.0 M Na2CO3 aqueous solution (1.13 mL) were added. The mixture was purged with argon gas for 10 minutes, and the reaction mixture was stirred at 110 °C for 40 minutes. The reaction mixture was cooled to room temperature and diluted with saturated NaHCO3, after which the product was extracted with ethyl acetate, washed, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane elution containing 1-100% ethyl acetate to obtain an isomer mixture of ethyl 5-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate as an oil (10, 380 mg, 83%).

[0179] Synthesis of intermediates 11 and 12 [ka]

[0180] Process 1 An isomer mixture of ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (11, 27 g, 49%) was prepared using para-methoxybenzyl chloride instead of 2-(trimethylsilyl)ethoxymethyl chloride, in a manner similar to the procedure for the isomer mixture of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (3), except that the reaction was carried out at room temperature for 8 hours. ES / MS m / z:C 13 H 14Calculated value for BrN3NaO3(M+H): 362.01, measured value: 362.05.

[0181] Process 2 A mixture of isomers of ethyl 2-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate) (12) was prepared as an oil in a manner similar to the procedure for the mixture of isomers of ethyl 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole-4-carboxylate (6).

[0182] Synthesis of intermediate 13 [ka]

[0183] Process 1 A mixture of isomers of ethyl 2-(4-methoxybenzyl)-5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate) (13, 10.5 g, 26%) was prepared as an oil in a manner similar to the procedure for the mixture of isomers of ethyl 5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-2H-1,2,3-triazole-4-carboxylate (8). ES / MS m / z:C 31 H 35 Calculated value for BN3O5(M+H): 540.27, measured value: 540.55.

[0184] Synthesis of intermediates 15 and 16 [ka]

[0185] Process 1 Methyl-4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (15, 5.1 g, 59%) was prepared as an oil from methyl-4-bromo-1H-pyrazole-5-carboxylate (14, 5.0 g, 24.5 mmol): 1 ¹H NMR (400MHz, chloroform-d): δ 7.56 (s, 1H), 5.81 (s, 2H), 3.96 (s, 3H), 3.54 (t, J=8.0Hz, 2H), 0.88 (t, J=8.0Hz, 2H), 0.04 (s, 9H). ES / MS m / z: C 11 H 20 Calculated value for BrN2O3Si(M+H): 335.04; molecular weight was not detected.

[0186] Process 2 Except for carrying out the reaction overnight at 110°C, potassium carbonate was used instead of sodium carbonate to prepare methyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (16, 5.83 g, 38%) as an oil, in a manner similar to the preparation procedure in 6: 1 H NMR (400MHz, chloroform-d) δ7.82(d,J=8.4Hz,2H),7.60(s,1H),7.40(d,J=8.4Hz,2H),5.85(s ,2H),3.77(s,3H),3.60(t,J=7.2Hz,2H),1.32(s,12H),0.89(t,J=7.2Hz,2H),0.04(s,9H). ES / MS m / z:C 23 H 36 Calculated value for BN2O5Si(M+H): 459.25; molecular weight was not detected.

[0187] Synthesis of intermediate 18 [ka]

[0188] Ethyl-3-bromo-1H-pyrazole-4-carboxylate (18, 511 mg, 96%) was prepared as an oil from ethyl-3-bromo-1H-pyrazole-4-carboxylate (17, 335 mg, 1.53 mmol) in a manner similar to the preparation procedure for intermediate 15 as a mixture of two positional isomers: ES / MS m / z:C 12 H 22 Calculated value for BrN2O3Si(M+H): 349.06, measured value: 348.46.

[0189] Synthesis of intermediate 20 [ka]

[0190] Methyl-4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (20, 690 mg, 77%) was prepared as an oil from methyl-4-bromo-1H-imidazole-5-carboxylate (19, 335 mg, 1.53 mmol) in a manner similar to the preparation procedure for intermediate 15 as a mixture of two positional isomers: ES / MS m / z:C 12 H 22 Calculated value for BrN2O3Si(M+H): 335.04, measured value: 334.86.

[0191] Typical procedure for the Suzuki reaction [ka]

[0192] A mixture of isomers of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4', 46 mg, 0.14 mmol), 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxaborolane (17, 20 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol), 2N potassium carbonate (0.14 mL), and dioxane (2 mL) were added to a 5 mL microwave vial. After purging with argon gas for 5 minutes, the resulting mixture was stirred at 110°C for 1 hour. After cooling, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography using ethyl acetate-containing hexane elution to obtain methyl 5-(o-tolyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (18): ES / MS m / z: C 17 H 26 Calculated value for N3O3Si(M+H): 348.17, measured value: 347.58.

[0193] Typical procedure for SEM deprotection using HCl [ka]

[0194] To a solution of methyl 5-(o-tolyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (18, 49 mg, 0.14 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL), 3N HCl (0.21 mL) was added, and the resulting mixture was stirred at 80°C for 2 hours, and then at 50°C overnight. The resulting reaction mixture was concentrated to obtain crude methyl 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylate (19):ES / MS m / z:C 11 H 10 Calculated value for N3O2(MH): 216.08, measured value: 216.15.

[0195] Typical procedure for SEM deprotection using TBAF [ka]

[0196] Ethyl 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-5-carboxylate (20) was dissolved in 1N TBAF (5 eq.), and the solution was heated at 60°C for 3 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography with ethyl acetate-containing hexane elution to obtain ethyl 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate (21): ES / MS m / z: C 21 H 23 Calculated value for N4O5(M+H): 443.49, measured value: 443.16.

[0197] Typical Procedure for PMB Deprotection using TFA [ka]

[0198] Ethyl 1-(4-methoxybenzyl)-4-(4'-(5-methyl-1,3,4-thiadiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate (22) was dissolved in 1 mL of TFA, and the mixture was heated at 40°C for 80 minutes. After cooling, the reaction mixture was concentrated and diluted with saturated NaHCO3, and the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography of ethyl acetate-containing hexane and ethyl acetate-containing 10% methanol-containing elutions to obtain ethyl 4-(4'-(5-methyl-1,3,4-thiadiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate (23):ES / MS m / z:C 20 H 18 Calculated value for N5O2S(M+H): 392.45, measured value: 392.16.

[0199] Typical procedure for ester hydrolysis [ka]

[0200] Crude methyl 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylate (21) in tetrahydrofuran (1 mL) and methanol (1 mL) was mixed with 2N NaOH (1 mL), and the resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled and neutralized with 1N HCl, the solid was filtered, the solid was purified by HPLC, and then freeze-dried to obtain 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylic acid (24). ES / MS m / z:ES / MS m / z:C 10 Calculated value for H8N3O2(MH): 202.08, measured value: 201.97.

[0201] Typical procedure for SEM protection of heterocyclic NH groups [ka]

[0202] A solution of 5-bromo-1H-1,2,3-triazole (25 mg, 996.3 mg, 6.733 mmol) in DMF (20 mL) was stirred in an ice bath while gradually adding 60% sodium hydride (410 mg, 10.25 mmol) from mineral oil. After 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (1.25 mL, 7.063 mmol) was added to the reaction mixture, and the resulting mixture was stirred in an ice bath for 1 hour, followed by overnight at room temperature. After 19 hours, the reaction mixture was diluted with saturated aqueous solution of NH4Cl (approximately 100 mL) and ethyl acetate (approximately 100 mL), and the two layers were separated. The aqueous fraction was extracted with ethyl acetate (×1), and the organic fraction was washed with water (approximately 150 mL × 1), combined, dried (MgSO4), and concentrated. The residual oil was purified by column chromatography using silica gel eluted from hexane containing 0-30% ethyl acetate to obtain 726.0 mg (39%) of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (26): 1 ¹H NMR (400MHz, chloroform-d): δ 7.63 (s,1H), 5.63 (s,2H), 3.72-3.60 (m,2H), 0.99-0.86 (m,2H), -0.02 (s,9H). ES / MS m / z:C 11 H 20 Calculated value for BrN2O3Si(M+H): 335.04; molecular weight was not detected.

[0203] Typical procedure for the preparation of boronate esters from aryl bromides [ka]

[0204] A mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (26, 359 mg, 1.29 mmol), bis(pinacolato)diborone (27, 362 mg, 1.43 mmol), dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium(II)dichloromethane (116 mg, 0.14 mmol), and potassium acetate (384 mg, 3.92 mmol) in 1,4-dioxane (6 mL) in a 20 mL μW vial was purged with Ar gas for 15 minutes, and the mixture was heated at 110 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (approximately 60 mL), treated with Na₂SO₄, and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography using hexane elution containing 0-40% ethyl acetate to obtain 282 mg (67%) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (28): 1 ¹H NMR (400 MHz, chloroform-d): δ 7.99 (s, 1H), 5.74 (s, 2H), 3.70-3.56 (m, 2H), 1.37 (s, 12H), 0.96-0.85 (m, 2H), -0.04 (s, 9H).

[0205] The following compounds were prepared using either commercially available boronate along with the bromide intermediates 4 (or 4'), 10, or 15 described above, or commercially available bromide along with the boronate intermediates 6 (or 6'), 8, 12, 13, and 16 described above, in a manner similar to the Suzuki reaction, the SEM or PMB deprotection described above, and the typical ester hydrolysis procedure:

[0206] Example 1: Ethyl 4-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate [ka] 1H NMR(400MHz,chloroform-d)δ7.95(dd,J=8.3,6.7Hz,2H),7.65(dd,J=8.2,5.5Hz,2H),7.60-7.49(m, 2H),7.43(dd,J=8.5,1.9Hz,2H),5.90(s,1H),4.45(qd,J=7.2,4.8Hz,2H),1.41(t,J=7.1Hz,3H). ES / MS m / z:C 17 H 13 Calculated value for ClN3O2(MH): 326.08, measured value: 326.31.

[0207] Example 2: Ethyl 4-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate [ka] 1 H NMR (400MHz, methanol-d4) δ7.99-7.91(m,2H),7.88(d,J=8.1Hz,2H),7.72(dd,J=8.4,1.8Hz,4H),4.38(q,J=7.2Hz,2H),1.35(t,J=7.1Hz,3H). ES / MS m / z:C 18 H 17 Calculated value for N4O3(M+H): 337.13, measured value: 337.03.

[0208] Example 3: 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.42-7.31 (m, 2H), 7.31-7.21 (m, 2H), 2.17 (s, 3H). ES / MS m / z: C 10 H 10 Calculated value for N3O2(M+H): 204.08, measured value: 347.58.

[0209] Example 4: 4-(m-tolyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.65-7.55 (m, 2H), 7.34 (t, J=7.6Hz, 1H), 7.27 (d, J=7.7Hz, 1H), 2.40 (s, 3H). ES / MS m / z: C 10 H 10 Calculated value for N3O2(M+H): 204.20, measured value: 203.92.

[0210] Example 5: 4-(p-tolyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.81 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 2.36 (s, 3H). ES / MS m / z:C 10 H 10 Calculated value for N3O2(M+H): 204.20, measured value: 203.92.

[0211] Example 6: 4-(3-ethylphenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.68-7.56(m,2H),7.42-7.28(m,2H),2.71(q,J=7.6Hz,2H),1.27(t,J=7.6Hz,3H). ES / MS m / z:C 11 H 12 Calculated value for N3O2(M+H): 218.09, measured value: 217.97.

[0212] Example 7: 4-(2-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400 MHz, methanol-d4): δ 7.61-7.45 (m, 2H), 7.32-7.17 (m, 2H). ES / MS m / z: Calculated value for C9H7FN3O2 (M+H): 208.04, Measured value: 207.94.

[0213] Example 8: 4-(3-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.74-7.66 (m, 2H), 7.46 (td, J=8.1, 5.9Hz, 1H), 7.16 (td, J=8.6, 2.5Hz, 1H). ES / MS m / z: Calculated value for C9H7FN3O2 (M+H): 208.04, Measured value: 207.91.

[0214] Example 9: 4-(4-chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400 MHz, methanol-d4): δ 7.89-7.81 (m, 2H), 7.51-7.42 (m, 2H). ES / MS m / z: Calculated value for C9H7ClN3O2 (M+H): 224.01, Measured value: 223.94.

[0215] Example 10: 4-(3-methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.45 (d, J=2.5Hz, 1H), 7.37 (d, J=7.1Hz, 2H), 7.06-6.98 (m, 1H), 3.84 (s, 3H). ES / MS m / z: C 10Calculated value for H8N3O3(MH): 218.20, measured value: 217.98.

[0216] Example 11: 4-(4-methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.78(d,J=8.4Hz,2H),7.06-6.98(m,2H),3.85(s,3H). ES / MS m / z:C 10 H 10 Calculated value for N3O3(M+H): 220.06, measured value: 219.93.

[0217] Example 12: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.34 (s, 1H), 8.24 (d, J=8.0Hz, 1H), 7.78 (dt, J=7.8, 1.4Hz, 1H), 7.64 (t, J=7.9Hz, 1H). ES / MS m / z: C 10 Calculated value for H7N4O2(M+H): 215.05, measured value: 214.96.

[0218] Example 13: 4-(3-(trifluoromethyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.24(t,J=1.7Hz,1H),8.15(d,J=7.9Hz,1H),7.74(d,J=7.8Hz,1H),7.66(t,J=7.8Hz,1H). ES / MS m / z:C 10Calculated value for H7F3N3O2(M+H): 258.07, measured value: 257.97.

[0219] Example 14: 4-(3-(tert-butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.90 (t, J=1.9Hz, 1H), 7.59 (dt, J=7.6, 1.4Hz, 1H), 7.51 (ddd, J=7.9, 2.0, 1.1Hz, 1H), 7.39 (t, J=7.8Hz, 1H), 1.36 (s, 9H). ES / MS m / z: C 13 H 16 Calculated value for N3O2(M+H): 246.12, measured value: 246.04.

[0220] Example 15: 4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.78-7.70 (m, 2H), 7.55-7.47 (m, 2H), 1.36 (s, 9H). ES / MS m / z: C 13 H 16 Calculated value for N3O2(M+H): 246.12, measured value: 246.01.

[0221] Example 16: 4-(3-(trifluoromethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.89 (d, J = 7.8 Hz, 2H), 7.55 (td, J = 7.9, 7.4, 1.0 Hz, 1H), 7.39-7.31 (m, 1H). ES / MS m / z:C 10Calculated value for H7FN3O3(M+H): 274.04, measured value: 273.95.

[0222] Example 17: 5-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid [ka] 1 ¹H NMR (400MHz, chloroform-d): δ 8.00 (dd, J=7.1, 2.2Hz, 1H), 7.83 (ddd, J=8.7, 4.6, 2.2Hz, 1H), 7.21 (t, J=8.7Hz, 1H), 4.32 (s, 3H). ES / MS m / z:C 10 Calculated value for H9ClFN3O2(MH): 254.63, measured value: 254.04.

[0223] Example 18: 4-(3-chloro-4-fluorophenyl)-1H-pyrazole-3-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.80 (s, 1H), 7.71 (dd, J=7.2, 2.2Hz, 1H), 7.50 (ddd, J=8.6, 4.6, 2.2Hz, 1H), 7.22 (dd, J=9.2, 8.6Hz, 1H). ES / MS m / z: C 10 Calculated value for H7ClFN2O2(M+H): 241.01, measured value: 240.88.

[0224] Example 19: 4-(3,4-dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1¹H NMR (400MHz, methanol-d4): δ 8.13 (d, J=2.1Hz, 1H), 7.85 (dd, J=8.4, 2.1Hz, 1H), 7.61 (d, J=8.5Hz, 1H). ES / MS m / z: Calculated value for C9H6Cl2N3O2(M+H): 257.98, Measured value: 257.95.

[0225] Example 20: 4-(3,5-dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.95 (s, 2H), 7.52 (s, 1H). ES / MS m / z: Calculated value for C9H6Cl2N3O2 (M+H): 257.98, Measured value: 257.92.

[0226] Example 21: 4-(3,5-dichlorophenyl)-1H-pyrazole-3-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6): δ8.00 (s, 1H), 7.68 (s, 2H), 7.58-7.44 (m, 1H). ES / MS m / z:C 10 H5Cl 2N2 Calculated value for O2(MH): 254.98, measured value: 255.02.

[0227] Example 22: 4-(3-chloro-2-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1¹H NMR (400MHz, methanol-d4): δ 7.59 (ddd, J=8.6, 7.0, 1.7Hz, 1H), 7.50 (ddd, J=7.9, 6.3, 1.7Hz, 1H), 7.27 (td, J=7.9, 1.2Hz, 1H). ES / MS m / z: Calculated value for C9H6ClFN3O2(M+H): 242.01, Measured value: 241.94.

[0228] Example 23: 5-(4-bromo-3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.04 (s, 1H), 7.70-7.65 (m, 2H). ES / MS m / z: Calculated value for C9H4BrClN3O2(MH): 299.93, Measured value: 300.02.

[0229] Example 24: 4-(3,5-dichloro-4-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.09 (d, J=6.4Hz, 2H). ES / MS m / z: Calculated value for C9H4Cl2FN3O2(M+H): 275.97, Measured value: 275.96.

[0230] Example 25: 4-(3-phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.57 (ddd, J=7.7, 1.6, 1.0Hz, 1H), 7.52-7.40 (m, 2H), 7.40-7.31 (m, 2H), 7.18-7.08 (m, 1H), 7.08-6.99 (m, 3H). ES / MS m / z:C 15H 12 Calculated value for N3O3(M+H): 282.08, measured value: 282.01.

[0231] Example 26: 4-(4-phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.83 (d, J=8.4Hz, 2H), 7.44-7.34 (m, 2H), 7.21-7.12 (m, 1H), 7.10-7.01 (m, 4H). ES / MS m / z: C 15 H 12 Calculated value for N3O3(M+H): 282.08, measured value: 281.98.

[0232] Example 27: 4-([1,1'-biphenyl]-3-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.03(t,J=1.8Hz,1H),7.71(dt,J=7.7,1.4Hz,1H),7 .67-7.54(m,3H),7.46(t,J=7.8Hz,1H),7.41-7.32(m,2H),7.31-7.22(m,1H). ES / MS m / z:C 15 H 12 Calculated value for N3O2(M+H): 266.09, measured value: 266.01.

[0233] Example 28: 4-([1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ7.92(d,J=8.0Hz,2H),7.77-7.64(m,4H),7.51-7.41(m,2H),7.41-7.32(m,1H). ES / MS m / z:C 15 H 12 Calculated value for N3O2(M+H): 266.09, measured value: 265.96.

[0234] Example 29: 4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.79 (dd, J=1.7, 0.5Hz, 1H), 7.72 (dd, J=8.4, 1.7Hz, 1H), 7.29 (d, J=8.4Hz, 1H). ES / MS m / z:C 10 Calculated value for H6CF2N3O4(M+H): 270.02, measured value: 269.97.

[0235] Example 30: 4-(benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 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:C 10 Calculated value for H6N3O4(MH): 232.04, measured value: 232.00.

[0236] Example 31: 4-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1¹H NMR (400MHz, methanol-d4): δ 7.46-7.35 (m, 3H), 7.32 (dt, J=8.4, 1.6Hz, 1H), 7.19 (dd, J=8.4, 1.3Hz, 1H), 6.89-6.81 (m, 2H). ES / MS m / z: C 16 The calculated value for H8F2N3O4(MH) was 344.06, while the measured value was 344.04.

[0237] Example 32: 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.39 (s, 1H), 7.31 (d, J=7.1Hz, 1H), 6.90 (d, J=8.5Hz, 1H), 4.32-4.24 (s, 4H). ES / MS m / z: C 11 H 10 Calculated value for N3O4(M+H): 248.06, measured value: 248.00.

[0238] Example 33: 4-(naphthalene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.39 (s, 1H), 7.98-7.86 (m, 4H), 7.59-7.49 (m, 2H). ES / MS m / z: Calculated value for C9H6ClFN3O2 (M+H): 242.01, Measured value: 239.97.

[0239] Example 34: 4-(pyridine-3-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1¹H NMR (400MHz, methanol-d4): δ 9.61-9.53 (m, 1H), 9.24 (dt, J=8.2, 1.7Hz, 1H), 8.89 (dt, J=5.7, 1.2Hz, 1H), 8.18 (ddd, J=8.2, 5.8, 0.8Hz, 1H). ES / MS m / z: Calculated value for C8H7N4O2 (M+H): 191.05, Measured value: 191.01.

[0240] Example 35: 4-(pyridine-3-yl)-1H-pyrazole-3-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 9.40 (d, J=1.9Hz, 1H), 9.00 (ddd, J=8.2, 2.0, 1.5Hz, 1H), 8.79 (ddd, J=5.6, 1.4, 0.7Hz, 1H), 8.35 (s, 1H), 8.03 (ddd, J=8.2, 5.7, 0.8Hz, 1H). ES / MS m / z: Calculated value for C9H7N3O2(MH): 190.05, Measured value: 190.02.

[0241] Example 36: 4-(quinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ9.05-8.98 (m, 1H), 8.62-8.52 (m, 1H), 8.11 (d, J = 11.3Hz, 1H), 7.69-7.48 (m, 4H). ES / MS m / z:C 12 Calculated value for H9N4O2(M+H): 241.06, measured value: 241.07.

[0242] Example 37: 4-(isoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1¹H NMR (400MHz, methanol-d4): δ 9.80 (s, 1H), 9.11 (s, 1H), 8.74 (d, J=9.3Hz, 1H), 8.60 (d, J=6.6Hz, 1H), 8.47 (d, J=6.6Hz, 1H), 8.36 (d, J=8.8Hz, 1H). ES / MS m / z: C 12 Calculated value for H8N4O2(M+H): 241.06, measured value: 241.05.

[0243] Example 38: 4-(6-phenylnaphthalene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.43(s,1H),8.15(s,1H),8.02(d,J=8.4Hz,2H),7.95(s,1 H),7.89-7.81(m,1H),7.81-7.74(m,2H),7.49(t,J=7.7Hz,2H),7.43-7.34(m,1H). ES / MS m / z:C 19 H 14 Calculated value for N3O2(M+H): 316.10, measured value: 316.00.

[0244] Example 39: 4-(3-chloroisoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 9.17 (s, 1H), 8.70 (s, 1H), 8.29 (dd, J=8.6, 1.7Hz, 1H), 8.12-7.86 (m, 2H). ES / MS m / z: C 12 The calculated value for H8ClN4O2(M+H) was 275.03, while the measured value was 275.05.

[0245] Example 40: 4-(3-methoxyisoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ9.06(d,J=0.9Hz,1H),8.40-8.35(m,1H),8.12(dd,J=8.7,1.9Hz,1H),7.94(d,J=8.8Hz,1H),7.19(s,1H),4.04(s,3H).

[0246] Example 41: 4-(3-phenylisoquinoline-7-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ9.55(s,1H),8.86(s,1H),8.45(d,J=15.6Hz,2H),8.20(d,J=8.5Hz,1H),8.07(d,J=7.7Hz,2H),7.64-7.51(m,3H). ES / MS m / z:C 18 H 13 For N4O2(M+H), the value is 317.10, and the measured value is 317.09.

[0247] Example 42: 4-(4-(naphthalene-1-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400 MHz, methanol-d4) δ 8.02-7.85 (m, 5H), 7.61-7.40 (m, 6H). ES / MS m / z: C 19 H 14 The calculated value for N3O2(M+H) was 316.11, while the measured value was 316.03.

[0248] Example 43: 4-(4-(pyridine-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR(400MHz,DMSO-d6)δ8.69(dt,J=4.7,1.5Hz,1H),8.19(d,J=12.8Hz,2H),8 .03(d,J=8.0Hz,1H),7.90(td,J=7.7,1.9Hz,3H),7.38(dd,J=7.6,4.9Hz,1H). ES / MS m / z:C 14 H 11 Calculated value for N4O2(M+H): 267.08, measured value: 267.10.

[0249] Example 44: 4-(4-(pyridine-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ9.17(d,J=2.1Hz,1H),8.88-8.76(m,2H),8.11(d,J=8.4Hz,2H),8.06(dd,J=8.2,5.6Hz,1H),7.91(d,J=8.5Hz,2H). ES / MS m / z:C 14 H 11 Calculated value for N4O2(M+H): 267.09, measured value: 267.04.

[0250] Example 45: 4-(4-(naphthalene-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 8.09-7.99 (m, 2H), 7.93 (tt, J = 8.6, 4.4Hz, 6H), 7.54 (tt, J = 6.9, 5.4Hz, 2H). ES / MS m / z:C 19 H 12 Calculated value for N3O2(MH): 314.10, measured value: 314.14.

[0251] Example 46: 4-(4-(6-chloronaphthalene-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.31 (s, 1H), 8.07-7.91 (m, 6H), 7.89 (s, 2H), 7.51 (dd, J = 8.7, 2.2Hz, 1H). ES / MS m / z:C 19 H 13 Calculated value for ClN3O2(M+H): 350.06, measured value: 350.00.

[0252] Example 47: 4-(4-(isoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ9.51(s,1H),8.59(d,J=6.0Hz,1H),8.48(d,J=2.1Hz ,1H),8.36(d,J=8.5Hz,1H),8.21(d,J=8.7Hz,1H),8.08(s,1H),8.02(s,4H). ES / MS m / z:C 14 H 11 Calculated value for N4O2(M+H): 267.09, measured value: 267.04.

[0253] Example 48: 4-(4-(1-methyl-1H-benzo[d]imidazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 8.00 (s, 1H), 7.85 (t, J = 15.5Hz, 4H), 7.70 (s, 2H), 3.88 (s, 3H). ES / MS m / z:C 17 H 14Calculated value for N5O2(M+H): 320.11, measured value: 320.14.

[0254] Example 49: 4-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.94 (d, J=8.0Hz, 1H), 7.76-7.71 (m, 1H), 7.71-7.65 (m, 2H), 7.65-7.55 (m, 1H), 7.61-7.58 (m, 1H), 7.55-7.42 (m, 2H). ES / MS m / z:C 15 H 11 Calculated value for ClN3O2(M+H): 300.05, measured value: 299.97.

[0255] Example 50: 4-(3'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.02-7.90(m,2H),7.76-7.66(m,3H),7.65-7.59(m,1H),7.45(t,J=7.9Hz,1H),7.38(ddd,J=8.0,2.1,1.1Hz,1H). ES / MS m / z:C 15 H 11 Calculated value for ClN3O2(M+H): 300.05, measured value: 299.98.

[0256] Example 51: 4-(4'-bromo-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, DMSO-d6) δ7.88 (s, 2H), 7.77 (d, J = 7.9Hz, 2H), 7.72-7.60 (m, 4H). ES / MS m / z:C 15 H 11 Calculated value for BrN3O2(M+H): 344.00, measured value: 344.06.

[0257] Example 52: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.92(t,J=1.9Hz,2H),7.84-7.69(m,3H),7.58(dt,J=7.9,1.4Hz,1H),7.44(t,J=7.9Hz,2H). ES / MS m / z:C 15 H 11 Calculated value for BrN3O2(M+H): 344.00, measured value: 343.95.

[0258] Example 53: 4-(4'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.90(d,J=8.0Hz,2H),7.71(d,J=8.1Hz,2H),7.61-7.53(m,2H),7.31-7.24(m,2H),2.38(s,3H). ES / MS m / z:C 16 H 14 Calculated value for N3O2(M+H): 280.10, measured value: 279.96.

[0259] Example 54: 4-(4'-(tert-butyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.90(d,J=8.1Hz,2H),7.73(d,J=8.1Hz,2H),7.66-7.58(m,2H),7.55-7.46(m,2H),1.36(s,9H). ES / MS m / z:C 19 H 20 Calculated value for N3O2(M+H): 322.15, measured value: 322.06.

[0260] Example 55: 4-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.95(d,J=8.1Hz,2H),7.78(d,J=8.8Hz,2H),7.75(d,J=8.0Hz,2H),7.41-7.34(m,2H). ES / MS m / z:C 16 H 11 Calculated value for F3N3O3(M+H): 350.08, measured value: 350.00.

[0261] Example 56: 4-(4'-Methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.89(d,J=8.0Hz,2H),7.69(d,J=8.1Hz,2H),7.62(d,J=8.8Hz,2H),7.02(d,J=8.8Hz,2H),3.84(s,3H). ES / MS m / z:C 16 H 14 Calculated value for N3O3(M+H): 296.10, measured value: 296.03.

[0262] Example 57: 4-(4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.57-7.48(m,2H), 7.43-7.36(m,2H), 7.14-7.05(m,2H), 6.87-6.80(m,2H). ES / MS m / z:C 15 H 11 The calculated value for FN3O2(M+H) was 284.08, while the measured value was 284.31.

[0263] Example 58: 4-(3',4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.96(d,J=7.9Hz,2H),7.87(d,J=1.7Hz,1H),7.75(d,J=8.0Hz,2H),7.68-7.58(m,2H). ES / MS m / z:C 15 H 10 Calculated value for Cl2N3O2(M+H): 334.02, measured value: 334.08.

[0264] Example 59: 4-(4'-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.00 (d, J=7.9Hz, 2H), 7.93-7.77 (m, 6H). ES / MS m / z:C 16 The calculated value for H9N4O2(MH) was 289.07, while the measured value was 289.01.

[0265] Example 60: 4-(4'-chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 7.96 (d, J=8.1Hz, 1H), 7.75 (d, J=8.2Hz, 1H), 7.69-7.48 (m, 5H). ES / MS m / z: C 15 Calculated value for H8ClFN3O2(MH): 316.04, measured value: 316.09.

[0266] Example 61: 4-(3'-chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.95(d,J=8.3Hz,2H),7.81(dd,J=7.0,2.3Hz,1H),7.72(d,J=8.2Hz,2H),7.65(ddd,J=8.6,4.5,2.3Hz,1H),7.34(t,J=8.9Hz,1H). ES / MS m / z:C 15 H 10 Calculated value for ClFN3O2(M+H): 318.04, measured value: 317.97.

[0267] Example 62: 4-(3'-phenoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ7.91(d,J=7.9Hz,2H),7.68(d,J=8.2Hz,2H),7.49-7.42(m,2H),7.41-7 .31(m,2H),7.29(dt,J=2.4,1.0Hz,1H),7.17-7.08(m,1H),7.06-7.00(m,2H),7.00-6.95(m,1H). ES / MS m / z:C 21 H 16 Calculated value for N3O3(M+H): 358.11, measured value: 358.01.

[0268] Example 63: 4-(4'-phenoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.91(d,J=8.0Hz,2H),7.78-7.63(m,4H),7.37(dd,J=8.5,7.3Hz,2H),7.12(d,J=7.4Hz,1H),7.09-6.97(m,4H). ES / MS m / z:C 21 H 16 Calculated value for N3O3(M+H): 358.11, measured value: 357.98.

[0269] Example 64: 4-(4'-(pyridine-2-yloxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.16(ddd,J=5.0,2.0,0.9Hz,1H),7.93(d,J=7.8Hz,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=7.2,5.0,1.0Hz,1H),6.99(dt,J=8.3,0.9Hz,1H). ES / MS m / z:C20 H 15 Calculated value for N4O3(M+H): 359.11, measured value: 359.14.

[0270] Example 65: 4-(4'-acetyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.14-8.07 (m, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 11.8, 8.3 Hz, 4H), 2.65 (s, 3H). ES / MS m / z:C 17 H 14 The calculated value for N3O3(M+H) is 308.10, and the measured value is 308.00.

[0271] Example 66: 4-(3'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.21(t,J=1.9Hz,1H),8.01-7.93(m,2H),7.89(dd,J=7.8,1.9Hz,2H),7.83-7.74(m,2H),7.58(t,J=7.8Hz,1H). ES / MS m / z:C 16 H 13 Calculated value for N4O3(M+H): 309.09, measured value: 309.09.

[0272] Example 67: 4-(3'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ8.14 (t, J = 1.8 Hz, 1H), 8.01-7.91 (m, 2H), 7.91-7.74 (m, 4H), 7.56 (t, J = 7.8Hz, 1H), 2.95 (s, 3H). ES / MS m / z:C 17 H 15 Calculated value for N4O3(M+H): 323.11, measured value: 323.12.

[0273] Example 68: 4-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400 MHz, methanol-d4): δ 7.98 (d, 4H), 7.77 (d, 4H). ES / MS m / z: C 16 H 13 Calculated value for N4O3(M+H): 309.09, measured value: 309.05.

[0274] Example 69: 4-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.97(d,J=8.0Hz,2H),7.95-7.87(m,2H),7.84-7.72(m,4H),2.95(s,3H). ES / MS m / z:C 17 H 15 Calculated value for N4O3(M+H): 323.11, measured value: 323.16.

[0275] Example 70: 4-(4'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4): δ8.03-7.92(m,2H), 7.87-7.74(m,4H), 7.60-7.47(m,2H), 3.13(s,3H), 3.06(s,3H). ES / MS m / z:C 18 H 17 Calculated value for N4O3(M+H): 337.35, measured value: 338.06.

[0276] Example 71: 4-(4'-carbamoyl-3'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.97(d,J=8.0Hz,2H),7.86-7.74(m,3H),7.70(dd,J=8.1,1.7Hz,1H),7.62(d,J=8.1Hz,1H). ES / MS m / z:C 16 H 12 Calculated value for ClN4O3(M+H): 343.05, measured value: 343.13.

[0277] Example 72: 4-(3'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.22(t,J=1.8Hz,1H),7.99(d,J=8.0Hz,2H),7.91(dtt,J=8.5,3.6,1.8Hz,2H),7.84-7.73(m,2H),7.65(t,J=7.9Hz,1H). ES / MS m / z:C 15 H 13 Calculated value for N4O4S(MH): 345.06, measured value: 345.03.

[0278] Example 73: 4-(3'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 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: C 17 H 17 Calculated value for N4O4S(M+H): 373.09, measured value: 373.11.

[0279] Example 74: 4-(3'-(piperidine-1-ylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR(400MHz,DMSO-d6)δ8.09(d,J=6.6Hz,1H),7.96(s,2H),7.93-7.79(m,3H),7.77(d ,J=6.6Hz,2H),2.95(t,J=5.5Hz,4H),1.56(dt,J=10.7,5.9Hz,4H),1.42-1.30(m,2H). ES / MS m / z:C 20 H 21 Calculated value for N4O4S(M+H): 413.13, measured value: 413.17.

[0280] Example 75: 4-(3'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4): δ8.08-7.96(m,4H), 7.86-7.65(m,4H), 3.78-3.65(m,4H), 3.07-2.95(m,4H). ES / MS m / z:C19 H 19 Calculated value for N4O5S(M+H): 415.10, measured value: 415.11.

[0281] Example 76: 4-(4'-chloro-3'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.35(d,J=2.3Hz,1H),7.98(d,J=8.1Hz,2H),7.90-7.83(m,1H),7.82-7.72(m,2H),7.71-7.62(m,1H). ES / MS m / z:C 15 H 12 Calculated value for ClN4O3S(M+H): 379.02, measured value: 379.07.

[0282] Example 77: 4-(4'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.99(d,J=8.2Hz,4H),7.86(d,J=8.2Hz,2H),7.80(d,J=8.1Hz,2H). ES / MS m / z:C 15 H 11 Calculated value for N4O4S(MH): 343.06, measured value: 342.31.

[0283] Example 78: 4-(4'-(N,N-dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ8.01(d,J=8.2Hz,2H),7.96-7.93(m,2H),7.91-7.86(m,2H),7.83(dd,J=7.6,5.6Hz,2H),2.73(s,6H). ES / MS m / z:C 17 H 17 Calculated value for N4O4S(M+H): 373.09, measured value: 373.06.

[0284] Example 79: 4-(4'-(piperidine-1-ylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR(400MHz,DMSO-d6)δ8.01(d,J=8.2Hz,2H),7.97-7.85(m,4H),7.82(d,J=8. 3Hz, 2H), 2.94 (t, J = 5.5Hz, 4H), 1.56 (p, J = 6.2, 5.4Hz, 4H), 1.45-1.32 (m, 2H). ES / MS m / z:C 20 H 21 Calculated value for N4O4S(M+H): 413.13, measured value: 413.10.

[0285] Example 80: 4-(4'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.05-7.93(m,4H), 7.93-7.76(m,4H), 3.78-3.65(m,4H), 3.07-2.96(m,4H). ES / MS m / z:C 19 H 19 Calculated value for N4O5S(M+H): 415.11, measured value: 415.07.

[0286] Example 81: 4-(3'-acetamido-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4): δ8.06-7.85(m,3H), 7.77-7.68(m,2H), 7.60-7.51(m,1H), 7.47-7.32(m,2H), 2.15(s,3H). ES / MS m / z:C 17 H 15 Calculated value for N4O3(M+H): 323.11, measured value: 323.13.

[0287] Example 82: 4-(4'-acetamido-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ10.03(s,1H),7.85(s,2H),7.73(d,J=8.1Hz,2H),7.68(s,4H),2.05(s,3H). ES / MS m / z:C 17 H 15 Calculated value for N4O3(M+H): 323.11, measured value: 323.12.

[0288] Example 83: 4-(4'-(2-oxopyrrolidine-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.76 (m, 8H), 3.87 (t, J = 7.0Hz, 2H), 2.52 (d, J = 8.0Hz, 2H), 2.07 (p, J = 7.6Hz, 2H). ES / MS m / z:C 19 H 17Calculated value for N4O3(M+H): 349.12, measured value: 349.13.

[0289] Example 84: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.88(d,J=8.0Hz,2H),7.69(d,J=8.1Hz,2H),7.61( d,J=8.7Hz,2H),7.06(d,J=8.8Hz,2H),3.93-3.81(m,4H),3.23-3.16(m,4H). ES / MS m / z:C 19 H 19 Calculated value for N4O2(M+H): 351.14, measured value: 350.01.

[0290] Example 85: 4-(4'-chloro-2'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.94-7.87(m,2H),7.44-7.37(m,2H),7.32(d,J=2.0Hz,1H),7.29-7.18(m,2H),2.27(s,3H). ES / MS m / z:C 16 H 13 The calculated value for ClN3O2(M+H) was 314.07, while the measured value was 314.01.

[0291] Example 86: 4-(9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1¹H NMR (400MHz, methanol-d4): δ 8.02 (s, 1H), 7.94-7.80 (m, 3H), 7.58 (dt, J=7.3, 1.0Hz, 1H), 7.43-7.29 (m, 2H), 3.97 (s, 2H). ES / MS m / z: C 16 H 12 Calculated value for N3O2(M+H): 278.09, measured value: 278.02.

[0292] Example 87: 4-(dibenzo[b,d]furan-3-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.16(dd,J=1.3,0.6Hz,1H),8.14-8.04(m,2H),7.87(d,J=8.0Hz,1H),7 .61(dt,J=8.3,0.9Hz,1H),7.52(ddd,J=8.4,7.3,1.3Hz,1H),7.39(ddd,J=7.7,7.2,1.0Hz,1H). ES / MS m / z:C 15 H 10 Calculated value for N3O3(M+H): 280.06, measured value: 280.00.

[0293] Example 88: 4-(9H-carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, acetonitrile-d3): δ 6.77 (dd, J=18.7, 8.0Hz, 2H), 6.64 (s, 1H), 6.23 (s, 1H), 6.12 (d, J=8.1Hz, 1H), 6.05 (t, J=7.6Hz, 1H), 5.83 (t, J=7.4Hz, 1H). ES / MS m / z:C 15 H 11 The calculated value for N4O2(M+H) was 279.09, while the measured value was 279.01.

[0294] Example 89: 4-(9-oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.11(d,J=13.5Hz,2H),7.77(dd,J=14.9,7.6Hz,2H),7.69-7.53(m,2H),7.39(t,J=7.3Hz,1H). ES / MS m / z:C 16 H 10 Calculated value for N3O3(M+H): 292.06, measured value: 292.08.

[0295] Example 90: 4-(9,9-dimethyl-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.96(d,J=1.5Hz,1H),7.88-7.76(m,3H),7.50(dd,J=5.8,2.9Hz,1H),7.39-7.29(m,2H),1.51(s,6H). ES / MS m / z:C 18 H 16 The calculated value for N3O2(M+H) was 306.12, while the measured value was 306.06.

[0296] Example 91: 4-(4'-chloro-3'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.12(d,J=7.9Hz,2H),6.91(d,J=8.2Hz,2H),6.81(d,J=2.3Hz,1H),6.72-6.52(m,3H),1.64(s,3H). ES / MS m / z:C 16 H 11Calculated value for ClN3O2(MH): 312.06, measured value: 312.08.

[0297] Example 92: 4-(4'-carbamoyl-3'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.95(d,J=7.7Hz,2H),7.75(d,J=8.1Hz,2H),7.62-7.45(m,3H),2.53(s,3H). ES / MS m / z:C 17 H 15 Calculated value for N4O3(M+H): 323.11, measured value: 323.10.

[0298] Example 93: 4-(4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.01(t,J=7.3Hz,2H),7.79(d,J=8.0Hz,3H),7.74-7.63(m,2H),3.55(t,J=6.7Hz,2H),3.08(t,J=6.6Hz,2H). ES / MS m / z:C 18 H 15 Calculated value for N4O3(M+H): 335.11, measured value: 335.16.

[0299] Example 94: 4-(4-(1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-pyrazole-5-carboxylic acid [ka] 1H NMR (400MHz, DMSO-d6) δ7.89(d,J=8.1Hz,2H),7.77-7.56(m,5H),3.40(dt,J=7.2,3.6Hz,2H),2.97(t,J=6.6Hz,2H). ES / MS m / z:C 19 H 16 Calculated value for N3O3(M+H): 334.11, measured value: 334.13.

[0300] Example 95: 4-(4-(3-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.01(d,J=8.1Hz,1H),7.99-7.93(m,2H),7.82-7.75(m,2H),7.69(dd,J=8.1,1.8Hz,1H),7.62(d,J=1. 7Hz,1H), 3.84(dqd,J=12.9,6.5,4.6Hz,1H),3.11(dd,J=15.8,4.5Hz,1H),2.84(dd,J=15.7,10.1Hz,1H),1.33(d,J=6.5Hz,3H). ES / MS m / z:C 19 H 17 Calculated value for N4O3(M+H): 349.13, measured value: 349.10.

[0301] Example 96: 4-(4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR(400MHz,DMSO-d6)δ13.14(s,1H),7.96(d,J=8.1Hz,1H),7.85(m,4H),7.72(dd,J=8 .2,1.8Hz,1H),7.69(s,2H),3.59(t,J=6.6Hz,2H),3.07(t,J=6.6Hz,2H),3.05(s,3H). ES / MS m / z:C 19 H 17 Calculated value for N4O3(M+H): 349.13, measured value: 349.09.

[0302] Example 97: 4-(4-(1-oxoisoindorin-5-yl)phenyl)-1H-1,2l4,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4): δ8.00 (m, 3H), 7.94-7.77 (m, 4H), 4.55 (s, 2H). ES / MS m / z:C 17 H 13 Calculated value for N4O3(M+H): 321.09, measured value: 321.07.

[0303] Example 98: 4-(4-(3,3-dimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2l4,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.98 (d, J=8.0Hz, 2H), 7.90-7.76 (m, 5H), 1.60 (s, 6H). ES / MS m / z:C 19 H 18 The calculated value for N4O3(M+H) is 349.13, and the measured value is 349.13.

[0304] Example 99: 4-([1,1':3',1''-terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR(400MHz,DMSO-d6)δ8.06-7.83(m,5H),7.81-7.76(m,2H),7.73-7.62(m ,2H),7.57(t,J=7.7Hz,1H),7.48(dd,J=8.4,6.9Hz,2H),7.43-7.30(m,1H). ES / MS m / z:C 21 H 16 Calculated value for N3O2(M+H): 342.12, measured value: 342.01.

[0305] Example 100: 4-([1,1':4',1''-terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.97-7.63 (m, 10H), 7.48 (t, J = 7.6Hz, 2H), 7.46-7.25 (m, 2H). ES / MS m / z:C 21 H 14 Calculated value for N3O2(MH): 340.12, measured value: 339.95.

[0306] Example 101: 4-(4'-(pyridine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.83(d,J=5.3Hz,1H),8.62(s,2H),8.41(d,J=9.3Hz,1H),8.17-7.93(m,6H),7.87(d,J=9.7Hz,2H). ES / MS m / z:C 20 H 15 Calculated value for N4O2(M+H): 343.11, measured value: 343.15.

[0307] Example 102: 4-(4'-(pyridine-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ9.04(s,1H),8.67(d,J=5.0Hz,1H),8.56-8.50(m,1H),7.99(d,J=8.1Hz,2H),7.94-7.86(m,4H),7.83(d,J=8.1Hz,3H). ES / MS m / z:C 20 H 15 Calculated value for N4O2(M+H): 343.12, measured value: 343.13.

[0308] Example 103: 4-(4'-(pyridine-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.79(d,J=6.1Hz,2H),8.30-8.23(m,2H),8.07(d,J=8 .2Hz,2H),8.02(d,J=8.0Hz,2H),7.97(d,J=8.3Hz,2H),7.86(d,J=8.3Hz,2H). ES / MS m / z:C 20 H 15 Calculated value for N4O2(M+H): 343.12, measured value: 343.13.

[0309] Example 104: 4-(4'-(pyrimidine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ8.87(d,J=4.8Hz,2H),8.52(d,J=8.5Hz,2H),7.98(s,2H),7.85(dd,J=8.2,6.4Hz,4H),7.37(t,J=4.9Hz,1H). ES / MS m / z:C 19 H 14 The calculated value for N5O2(M+H) was 344.11, while the measured value was 344.03.

[0310] Example 105: 4-(4'-(1-methyl-1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.33 (s, 1H), 7.95 (dd, J = 14.0, 8.3Hz, 4H), 7.79 (d, J = 8.2Hz, 4H), 4.18 (s, 3H). ES / MS m / z:C 18 H 15 The calculated value for N6O2(M+H) was 347.13, while the measured value was 347.14.

[0311] Example 106: 4-(4'-(1-methyl-1H-1,2,4-triazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.53 (s, 1H), 8.14-8.04 (m, 2H), 7.84 (d, J = 8.7Hz, 6H), 3.93 (s, 3H). ES / MS m / z:C 18 H 15 Calculated value for N6O2(M+H): 347.12, measured value: 347.10.

[0312] Example 107: 4-(4'-(1-methyl-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.96-7.87(m,4H),7.83(d,J=8.0Hz,2H),7.78(d,J=8.3Hz,2H),7.76(d,J=2.2Hz,1H),6.76(d,J=2.3Hz,1H),3.91(s,3H). ES / MS m / z:C 19 H 16 Calculated value for N5O2(M+H): 346.13, measured value: 346.15.

[0313] Example 108: 4-(4'-(thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.07(d,J=8.4Hz,2H),7.97(d,J=7.7Hz,2H),7.89(d,J=3.3Hz,1H),7.83(t,J=8.7Hz,4H),7.63(d,J=3.3Hz,1H). ES / MS m / z:C 18 H 13 Calculated value for N4O2S(M+H): 349.07, measured value: 349.03.

[0314] Example 109: 4-(4'-(5-methylthiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6): δ8.03-7.74 (m, 8H), 7.62 (s, 1H), 2.50 (s, 3H). ES / MS m / z:C19 H 15 Calculated value for N4O2S(M+H): 362.08, measured value: 362.11.

[0315] Example 110: 4-(4'-(5-(trifluoromethyl)thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.58 (s, 1H), 8.15 (d, J = 8.0Hz, 2H), 7.97 (d, J = 8.0Hz, 2H), 7.94-7.85 (m, 4H). ES / MS m / z:C 19 H 12 Calculated value for F3N4O2S(M+H): 417.06, measured value: 417.00.

[0316] Example 111: 4-(4'-(5-methyl-1,3,4-thiadiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=6.5Hz,1H),8.00(d,J=16.3Hz,2H),7.96-7.89(m,3H),7.85(d,J=8.3Hz,2H),2.78(s,3H). ES / MS m / z:C 18 H 12 Calculated value for N5O2S(MH): 362.07, measured value: 362.03.

[0317] Example 112: 4-(4'-(oxazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ8.13(s,1H), δ8.09-7.91(m,4H), δ7.91-7.77(m,3H), δ7.39-7.28(s,2H). ES / MS m / z:C 18 H 13 The calculated value for N4O3(M+H) was 333.10, while the measured value was 333.00.

[0318] Example 113: 4-(4'-(isoxazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, J = 1.7 Hz, 1H), 8.07-7.97 (m, 3H), 7.93-7.86 (m, 5H), 7.24-7.19 (m, 1H). ES / MS m / z:C 18 H 13 The calculated value for N4O3(M+H) was 333.10, while the measured value was 333.05.

[0319] Example 114: 4-(4'-(4-methylthiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=8.4Hz,2H),7.95(d,J=8.0Hz,2H),7.87(t,J=7.9Hz,4H),7.36(d,J=1.2Hz,1H),3.33(s,3H). ES / MS m / z:C 19 H 15 Calculated value for N4O2S(M+H): 363.09, measured value: 363.08.

[0320] Example 115: 4-(4'-(2-methyl-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.30 (s, 1H), 7.95 (t, J = 7.0Hz, 4H), 7.90-7.80 (m, 4H), 4.22 (s, 3H). ES / MS m / z:C 18 H 15 Calculated value for N6O2(M+H): 347.13, measured value: 347.02.

[0321] Example 116: 4-(4'-(thiazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.39 (s, 1H), 7.81 (q, J = 8.4Hz, 8H). ES / MS m / z:C 18 H 13 Calculated value for N4O2S(M+H): 349.07, measured value: 348.96.

[0322] Example 117: 4-(4'-(1,5-dimethyl-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=8.1Hz,2H),7.88-7.79(m,4H),7.76(d,J=8.2Hz,2H),6.54(s,1H),3.78(s,3H),2.30(s,3H). ES / MS m / z:C 20 H 18Calculated value for N5O2(M+H): 360.15, measured value: 360.16.

[0323] Example 118: 4-(4'-(1,5-dimethyl-1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ13.13(s,1H),7.95-7.90(m,1H),7.89-7.75(m,8H),4.00(s,3H),2.51(s,3H). ES / MS m / z:C 19 H 17 Calculated value for N6O2(M+H): 361.14, measured value: 361.13.

[0324] Example 119: 4-(4'-(1H-pyrazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.28(d,J=2.4Hz,1H),7.96(d,J=7.8Hz,2H),7.91-7.62(m,6H),6.56(d,J=2.4Hz,2H). ES / MS m / z:C 18 H 14 The calculated value for N5O2(M+H) was 332.11, while the measured value was 332.14.

[0325] Example 120: 4-(4'-(1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ8.59(s,1H),8.07(s,2H),8.01-7.85(m,5H),7.79(d,J=8.2Hz,2H). ES / MS m / z:C 17 H 13 The calculated value for N6O2(M+H) is 333.11, and the measured value is 333.11.

[0326] Example 121: 4-(4'-(5-methyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.01(d,J=8.0Hz,2H),7.97-7.90(m,2H),7.83(d,J=8.2Hz,2H),7.70-7.61(m,3H),2.42(d,J=0.9Hz,3H). ES / MS m / z:C 18 H 15 Calculated value for N6O2(M+H): 347.13, measured value: 347.09.

[0327] Example 122: 4-(4'-(benzo[d]thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR(400MHz,DMSO-d6)δ8.20(d,J=8.2Hz,2H),8.16(d,J=8.0Hz,1H),8.08(d,J=8.1Hz,1H) ,7.96(d,J=8.2Hz,5H),7.88(d,J=8.3Hz,2H),7.55(t,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H). ES / MS m / z:C 22 H 15 Calculated value for N4O2S(M+H): 399.09, measured value: 399.08.

[0328] Example 123: 4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-1,2,3-triazole-5-carboxylic acid) [ka] 4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-1,2,3-triazole-5-carboxylic acid) was prepared from ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (11) and ethyl 2-(4-methoxybenzyl)-5-(4'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-4-yl)-2H-1,2,3-triazole-4-carboxylate (13) in a manner similar to the general procedure of the Suzuki reaction, followed by PMB deprotection and ester hydrolysis: 1 H NMR (400MHz, DMSO-d6) δ7.95 (s, 4H), 7.86 (d, J = 8.1Hz, 4H). ES / MS m / z:C 18 H 13 Calculated value for N6O4(M+H): 377.10, measured value: 377.03.

[0329] Example 181: 4-(4'-(5,6-dihydro-4H-cyclopenta[d]thiazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.99(d,J=8.1Hz,2H),7.86(m,6H),3.17(s,2H),2.96(s,2H),2.89-2.78(m,2H). ES / MS m / z:C 21 H 17 Calculated value for N4O2S(M+H): 389.11, measured value: 389.11.

[0330] After SEM protection of the heterocyclic NH group, the following compound was prepared by subsequent ester hydrolysis using the commercially available bromide-containing heterocyclic group and the boronate intermediate 6 or 8 described above, in a manner similar to the typical Suzuki reaction and SEM or PMB deprotection procedures described above: Example 124: 4-(4'-(1H-pyrazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 2H), 7.79 (d, J = 14.4Hz, 4H), 7.72 (s, 4H). ES / MS m / z:C 18 H 14 Calculated value for N5O2(M+H): 332.11, measured value: 332.07.

[0331] Example 125: 4-(4'-(1H-pyrazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ7.99-7.86(m,4H),7.88-7.74(m,4H),7.72(d,J=2.2Hz,1H),6.76(t,J=2.3Hz,1H). ES / MS m / z:C 18 H 14 Calculated value for N5O2(M+H): 332.11, measured value: 332.11.

[0332] Example 126: 4-(4-(1H-benzo[d]imidazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ9.31(s,1H), 8.09(dd,J=1.6,0.8Hz,1H),8.03(d,J=1.8Hz,1H),8.02-7.89(m,3H),7.88-7.79(m,2H). ES / MS m / z:C 16 H 12 Calculated value for N5O3(M+H): 306.09, measured value: 306.14.

[0333] Example 127: 4-(4'-(1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.96(d,J=7.6Hz,4H),7.80(d,J=7.9Hz,5H). ES / MS m / z:C 16 H 12 Calculated value for N5O3(M+H): 333.10, measured value: 333.07.

[0334] Example 128: 4-(4'-(1H-imidazole-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400 MHz, methanol-d4) δ 7.29-7.05 (m, 4H), 6.95-6.62 (m, 6H). ES / MS m / z: C 18 H 14 The calculated value for N5O2(M+H) was 332.11, while the measured value was 332.12.

[0335] Example 129: 4-(4'-(1H-imidazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 9.02 (d, J=1.4Hz, 1H), 8.10-7.95 (m, 3H), 7.85 (dt, J=24.3, 8.3Hz, 6H). ES / MS m / z: C 18 H 14 The calculated value for N5O2(M+H) was 332.11, while the measured value was 332.12.

[0336] Example 130: 4-(4'-(4-methyl-1H-pyrazole-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ12.98(s,2H),7.82(d,J=8.1Hz,4H),7.75(d,J=8.1Hz,2H),7.51(s,1H),2.23(d,J=0.7Hz,3H). ES / MS m / z:C 19 H 16 The calculated value for N5O2(M+H) was 346.13, while the measured value was 346.18.

[0337] After conversion to pinacol boronate, the following compounds were prepared using either bromide intermediate 4 or 10 described above, along with a commercially available bromide, in a manner similar to the typical Suzuki reaction, SEM deprotection with HCl, followed by ester hydrolysis: Example 131: 4-(4'-(5-methyl-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid [ka] 1 H NMR (400MHz,D2O+NaHCO3)δ7.5-8.0(m,8H),2.48(s,3H). ES / MS m / z:C 18 H 15 Calculated value for N6O2(M+H): 347.13, measured value: 347.12.

[0338] Example 132: 4-(6-chloronaphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.45 (m, 1H), 7.92 (dd, J=13.0, 8.2Hz, 4H), 7.50 (d, J=8.7Hz, 1H). ES / MS m / z: C 13 Calculated value for H9ClN3O2(M+H): 274.04, measured value: 273.96.

[0339] Example 133: 4-(phenanthren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, DMSO-d6) δ8.88 (s, 2H), 8.43 (s, 1H), 8.22-7.82 (m, 4H), 7.80-7.59 (m, 3H). ES / MS m / z:C 17 H 12 The calculated value for N3O2(M+H) was 290.09, while the measured value was 290.03.

[0340] Example 134: 4-(7-amino-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ8.07(s,1H),7.97(dd,J=14.0,8.1Hz,2H),7.88(d,J=7.9Hz,1H),7.55(s,1H),7.36(d,J=8.3Hz,1H),4.05(s,2H). ES / MS m / z:C 16 H 13 Calculated value for N4O2(M+H): 293.10, measured value: 293.05.

[0341] Example 135: 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid [ka]

[0342] Process 1 A solution of methyl 4-bromo-3-methyl-1H-pyrazole-5-carboxylate (275 mg, 1.255 mmol) in DMF was mixed with sodium hydride (60% suspension, 1.38 mmol), followed by SEM-Cl (0.233 mL, 1.31 mmol) at 0°C. After 10 minutes, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography using ethyl acetate-containing hexane elution to obtain a mixture of isomers of methyl 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate: ES / MS m / z: C 12 H 22 Calculated value for BrN2OsSi(M+H): 349.05, measured value: 348.93.

[0343] Steps 2, 3, and 4 4-(3-chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid was prepared using (3-chloro-4-fluorophenyl)boronic acid in a manner similar to the general procedure of the Suzuki reaction followed by SEM deprotection with HCl and ester hydrolysis: 1 ¹H NMR (400MHz, methanol-d4): δ 7.43 (ddd, J=7.2, 1.9, 0.5Hz, 1H), 7.31-7.19 (m, 2H), 2.22 (s, 3H). ES / MS m / z: C 11 Calculated value for H9ClFN2O2(M+H): 255.03, measured value: 254.94.

[0344] Example 136: 4-(3-chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid [ka]

[0345] Process 1 A solution of 1-(3-chloro-4-fluorophenyl)ethane-1-one (301 g, 5.00 g, 29.0 mmol) in dimethyl carbonate (4.9 mL, 58 mmol) was added dropwise under N2 to a stirred solution of potassium tert-butoxide (6.50 g, 57.9 mmol) in THF (30 mL), and the mixture was cooled in a water bath. After 90 minutes, the reaction mixture was cooled in an ice bath and then quenched with 2 M HCl. The mixture was then extracted with ethyl acetate, the organic extract was dried (MgSO4), and concentrated under vacuum. The resulting crude residue was purified by silica gel column chromatography with 0-40% ethyl acetate elution via hexane to obtain methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropanoate (2.97 g, 44%). LC / MS m / z:C 10 Calculated value for H9ClFO3(M+H): 231.02, measured value: 231.0.

[0346] Process 2 A mixture of methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropanoate (537 mg, 2.33 mmol), p-methoxybenzyl azide (400 mg, 2.45 mmol), and potassium carbonate (1.36 g, 9.80 mmol) in dimethyl sulfoxide (5 mL) was vigorously stirred overnight at 80°C. After the reaction, the mixture was cooled and diluted with water. The resulting solid was isolated by filtration and further purified by silica gel column chromatography using hexane elution containing 0-50% ethyl acetate to obtain methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, 43%) as a white solid: ES / MS m / z:C 18 H 16Calculated value for ClFN3O3(M+H): 376.09, measured value: 376.1.

[0347] Steps 3 and 4 To a solution of methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (75 mg, 0.20 mmol) in 1:1 THF / methanol (2 mL), 1 M LiOH (1.0 mL, 1.0 mmol) was added at room temperature. After stirring for 1 hour, the reaction mixture was acidified with 2N HCl, and the product was extracted with ethyl acetate (×3). The combined organic extract was dried (MgSO4) and concentrated under vacuum. The resulting residue was then dissolved in TFA and stirred at 65°C for 2 hours. After the reaction, the mixture was concentrated under vacuum, and the residue was purified by reverse-phase preparative HPLC to obtain 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid. 1 ¹H NMR (400MHz, DMSO-d6): δ 13.33 (br s, 1H), 8.07 (br s, 1H), 7.84 (br s, 1H), 7.54 (br t, J=8.0Hz, 1H). ES / MS m / z: Calculated value for C9H6ClFN3O2 (M+H): 242.01, Measured value: 242.0.

[0348] Example 137: 4-phenyl-1H-1,2,3-triazole-5-carboxylic acid [ka] 4-phenyl-1H-1,2,3-triazole-5-carboxylic acid was prepared from acetophenone using a method similar to that of Example 136: 1 ¹H NMR (400MHz, DMSO-d6): δ 13.14 (br s, 1H), 7.79 (br s, 2H), 7.51-7.42 (m, 3H). ES / MS m / z: Calculated value for C9H8N3O2 (m+H): 190.06, Measured value: 190.0.

[0349] Example 138: 4-(3-chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 4-(3-chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 3-chloroacetophenone using a method similar to that of Example 136: 1 ¹H NMR (400MHz, DMSO-d6): δ 7.92 (s, 1H), 7.80 (br s, 1H), 7.54-7.48 (m, 2H). ES / MS m / z: Calculated value for C9H7ClN3O2 (M+H): 224.02, Measured value: 224.0.

[0350] Example 139: 4-(pyridine-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0351] Process 1 A mixture of isomers of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (192 mg, 0.55 mmol), 2-(tributylstannyl)pyridine (222 mg, 0.193 mL, 0.60 mmol), tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.055 mmol), and toluene (2 mL) were added to a 5 mL microwave vial. After purging with argon gas for 5 minutes, the resulting mixture was stirred at 110°C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography using ethyl acetate-containing hexane elution to obtain ethyl 5-(pyridine-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 16 H 25 Calculated value for N4O3Si(M+H): 349.16, measured value: 349.05.

[0352] Steps 2 and 3 4-(pyridine-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared by SEM deprotection with HCl, followed by a procedure similar to the general procedure for ester hydrolysis: 1 ¹H NMR (400MHz, DMSO-d6): δ 8.78 (d, J=5.2Hz, 1H), 8.41 (d, J=8.0Hz, 1H), 8.25 (t, J=8.0Hz, 1H), 7.69 (dd, J=7.4, 5.4Hz, 1H). ES / MS m / z: Calculated value for C8H7N4O2 (M+H): 191.05, Measured value: 190.99.

[0353] Example 140: 4-(pyridine-2-yl)-1H-pyrazole-5-carboxylic acid [ka] 4-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid was prepared from 4-(tributylstannyl)pyridine using a method similar to that of Example 141: 1 ¹H NMR (400MHz, methanol-d4): δ 8.85-8.78 (m, 1H), 8.70 (s, 1H), 8.54 (td, J=8.0, 1.6Hz, 1H), 8.43 (dt, J=8.4, 1.0Hz, 1H), 7.89 (ddd, J=7.3, 5.9, 1.2Hz, 1H). ES / MS m / z: Calculated value for C9H8N3O2 (M+H): 190.05, Measured value: 190.00.

[0354] Example 141: 4-(thiazole-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 4-(thiazole-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 4-(tributylstannyl)thiazole using a method similar to that of Example 141: 1¹H NMR (400MHz, DMSO-d6): δ 9.32 (s,1H), 8.65 (s,1H), 3.15 (s,1H). ES / MS m / z: Calculated value for C6H3N4O2S(MH): 191.05, Measured value: 194.95.

[0355] Examples 142 and 143: 4-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid and 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0356] Process 1 A mixture of isomers of ethyl 5-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate) was prepared from 3-bromo-N,N-dimethylbenzamide using a procedure similar to the general Suzuki reaction:

[0357] Steps 2 and 3 4-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid and 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid were prepared using a procedure similar to the general procedure for ester hydrolysis, followed by SEM deprotection with HCl. The two compounds were separated by precipitation and subsequent preparative HPLC purification.

[0358] Example 142: 4-(3'-(dimethylcarbamoyl)-[1,1'-biphenyl]4-yl)-1H-1,2,3-triazole 5-carboxylic acid [ka] 1H NMR (400MHz, methanol-d4) δ8.33 (t, J = 1.7 Hz, 1H), 8.10-7.87 (m, 3H), 7.87-7.71 (m, 2H), 7.59 (t, J = 7.9Hz, 2H). ES / MS m / z:C 16 H 12 Calculated value for N3O4(M+H): 310.07, measured value: 310.05.

[0359] Example 143: 4-(3'-carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 1 H NMR (400MHz, methanol-d4) δ7.96(d,J=8.4Hz,2H),7.86-7.72(m,4H),7.57(td,J=7.7,0.6Hz,1H),7.44(dt,J=7.6,1.3Hz,1H),3.14(s,3H),3.06(s,3H). ES / MS m / z:C 18 H 17 Calculated value for N4O3(M+H): 337.12, measured value: 337.17.

[0360] Example 144: 4-(4-(1H-indazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0361] Process 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-dihydropyran (0.089 mL, 0.97 mmol) were added. The mixture was heated overnight at 35°C, and the reaction mixture was diluted with aqueous saturated NaHCO3. The product was then extracted with ethyl acetate (×2). The combined organic layer was washed with water (×1), dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography using ethyl acetate-containing hexane elution to obtain 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: 1 H NMR(400MHz,acetonitrile-d3)δ8.03-7.93(m,2H),7.62(dt,J=8.9,0.8Hz,1H),7.52 (dd,J=8.9,1.9Hz,1H),5.77(dd,J=9.8,2.6Hz,1H),4.89(t,J=3.8Hz,0H),4.01- 3.91(m,1H),3.86-3.72(m,1H),3.48(dd,J=11.0,6.0Hz,0H),2.47(dddd,J=13.7 ,12.2,9.7,4.0Hz,1H),2.17-1.97(m,2H),1.87-1.60(m,3H),1.64-1.48(m,1H). ES / MS m / z:C 12 H 14 The calculated value for BrN2O(M+H) was 281.03, while the measured value was 280.75.

[0362] Steps 2, 3, and 4 4-(4-(1H-indazole-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using intermediates 6 and 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole in a manner similar to the general procedure of the Suzuki reaction, followed by PMB and THP deprotection with TFA, and then ester hydrolysis: 1 ¹H NMR (400MHz, methanol-d4): δ 8.10-8.05 (m, 1H), 7.89 (d, J=8.0Hz, 1H), 7.50-7.35 (m, 6H). ES / MS m / z: C 15 H11 Calculated value for ClN3O2(M+H): 300.05, measured value: 300.00.

[0363] Example 145: 4-(4-(1H-indazole-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 4-(4-(1H-indazole-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 6-bromo-1H-indazole in a manner similar to that of Example 146: 1 H NMR (400MHz, methanol-d4) δ8.10-7.92(m,3H),7.81(d,J=8.4Hz,1H),7.75(s,1H),7.65(d,J=8.2Hz,2H),7.46(d,J=8.7Hz,2H). ES / MS m / z:C 16 H 12 The calculated value for N5O2(M+H) was 306.10, while the measured value was 306.15.

[0364] Example 146: 4-(4'-chloro-3'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0365] Process 1 Morpholine (220 mg, 3 mmol) was added at 0°C to a solution of 5-bromo-2-chlorobenzenesulfonyl chloride (366 mg, 10 mmol) in THF (3 mL). After 10 minutes, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl (×2), water (×1), and saturated NaHCO3 (×1). The resulting organic fraction was dried (MgSO4) and concentrated. The residue was purified by hexane-eluted silica gel column chromatography containing 0-100% ethyl acetate to obtain 4-(5-bromo-2-chlorophenyl)(sulfonyl)morpholine. 1¹H 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).

[0366] Steps 2, 3, and 4 Using intermediate 6 and 4-((5-bromo-2-chlorophenyl)sulfonyl)morpholine, 4-(4'-chloro-3'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of the Suzuki reaction and PMB deprotection followed by ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ8.30(d,J=2.3Hz,1H),8.07-7.91(m,3H),7.76(dd,J=16.0,8.2Hz,3H),3.75-3.65(m,4H),3.29(m,4H):ES / MS m / z:C 19 H 18 Calculated value for ClN4O5S(M+H): 449.06, measured value: 449.16.

[0367] Example 147: 4-(3-bromophenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0368] Process 1 An isomer mixture of methyl 5-(3-aminophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared using intermediate 4' and (3-aminophenyl)boronic acid in a manner similar to the general procedure of the Suzuki reaction: ES / MS m / z:C 16 H 25 Calculated value for N4O3Si(M+H): 347.17, measured value: 348.96.

[0369] Step 2: To a solution of methyl 4-(3-aminophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-5-carboxylate (102 mg, 0.29 mmol) in 3 mL of acetonitrile, tert-butyl nitride (0.042 mL, 0.35 mmol) and copper(II) bromide (78 mg, 0.35 mmol) were added at 0°C. After 30 minutes, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography using ethyl acetate-containing hexane elution to obtain a mixture of isomers of methyl 5-(3-bromophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 ¹H NMR (400 MHz, chloroform-d): δ 8.12-7.30 (m, 4H), 6.18-5.76 (m, 2H), 3.98 (d, 3H), 3.78-3.684 (m, 2H), 0.95 (m, 2H), 0.00 (d, 9H).

[0370] Steps 3 and 4 5-(4-bromophenyl)-1H-1,2,3-triazole-4-carboxylic acid was prepared by SEM deprotection with HCl, followed by a procedure similar to the general procedure for ester hydrolysis: 1 ¹H NMR (400MHz, methanol-d4): δ 8.07 (s, 1H), 7.85 (d, J=7.8Hz, 1H), 7.63-7.56 (m, 1H), 7.38 (t, J=7.9Hz, 1H). ES / MS m / z: Calculated value for C9H7BrN3O2(M+H): 267.96, Measured value: 267.90.

[0371] Example 148: 4-(2-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0372] Steps 1 and 2 Using 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, an isomer mixture of methyl 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared in a manner similar to steps 1 and 2 of Example 149: ES / MS m / z:C 16 H 22 Calculated value for BrClN3O3Si(M+H): 446.03, measured value: 445.69.

[0373] Steps 3, 4, and 5 4-(2-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using phenylboronic acid in a manner similar to the general procedure of the Suzuki reaction, SEM deprotection with HCl, and ester hydrolysis: 1 ¹H NMR (400MHz, methanol-d4): δ 8.10-8.05 (m, 1H), 7.89 (d, J=8.0Hz, 1H), 7.50-7.35 (m, 6H). ES / MS m / z: C 15 H 11 Calculated value for ClN3O2(M+H): 300.05, measured value: 300.00.

[0374] Example 149: 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from an isomer mixture of methyl 5-(4-bromo3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate and 4-chlorophenylboronic acid by a procedure similar to the general Suzuki reaction, followed by general SEM deprotection with HCl and ester hydrolysis: 1H NMR (400MHz, methanol-d4) δ8.00 (d, J=1.7Hz, 1H), 7.81 (dd, J=8.0, 1.8Hz, 1H), 7.37 (m, 5H). ES / MS m / z:C 15 H 10 Calculated value for Cl2N3O2(M+H): 334.01, measured value: 333.97.

[0375] Example 150: 4-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid [ka] To a solution of 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (10 mg, 0.038 mmol) in 0.5 mL of DMF, NaH (60% oily suspension, 6 mg) was added at 0°C. After 10 minutes at 0°C, iodomethane (7 μL, 0.11 mmol) was added, and the resulting mixture was stirred at 0°C for 10 minutes. After quenching the reaction with methanol, the product was purified by HPLC to give 5-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid. 1 ¹H NMR (400MHz, chloroform-d): δ 7.99 (dd, J=7.1, 2.2Hz, 1H), 7.82 (ddd, J=8.6, 4.6, 2.2Hz, 1H), 7.20 (t, J=8.7Hz, 1H), 4.31 (s, 3H). ES / MS m / z:C 10 Calculated value for H6ClFN3O2(MH): 254.01, measured value: 253.96.

[0376] Example 151: 4-(4'-(1-methyl-1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0377] Process 1 To a solution of 4-(4-bromophenyl)-1H-1,2,3-triazole (242 mg, 1.05 mmol) in 2 mL of DMF, 60% NaH oil suspension (48 mg, 1.2 mmol) was added at 0°C. After 10 minutes at 0°C, iodomethane (71 μL, 1.1 mmol) was added, and the resulting mixture was stirred at 0°C for 10 minutes. The reaction mixture was extracted using ethyl acetate together with brine, the organic layer was concentrated, and then purified by silica gel column chromatography eluted with ethyl acetate and hexane to give 5-(4-bromophenyl)-1-methyl-1H-1,2,3-triazole: ES / MS m / z: Calculated value relative to C9H9BrN3(M+H): 237.99, Measured value: 238.09.

[0378] Steps 2, 3, and 4 Using compound 28, 4-(4'-(1-methyl-1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of the Suzuki reaction followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.09(s,2H),7.97-7.88(m,2H),7.81(dt,J=13.6,5.3Hz,4H),4.20(s,3H). ES / MS m / z:C 18 H 15 Calculated value for N6O2(M+H): 347.12, measured value: 347.04.

[0379] Example 152: 4-(4-(2,3,3-trimethyl-1-oxoisoindorin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0380] Process 1 To a solution of 5-bromo-3,3-dimethylisoindorin-1-one (205 mg, 0.85 mmol) in N,N-dimethylformamide (2 mL), 60% sodium hydride (43 mg, 1.08 mmol) in mineral oil was added at 0°C. After 15 minutes, iodomethane (0.1 mL, 1.61 mmol) was added to the reaction mixture. The resulting solution was stirred at 0°C for 1 hour. The reaction mixture was diluted with ethyl acetate (approximately 25 mL) and washed with approximately 50% saturated NH4Cl solution. The aqueous fraction was extracted with ethyl acetate (25 mL x 1), and the organic fraction was combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography using hexane elution with 0-100% EA to obtain 5-bromo-2,3,3-trimethylisoindorin-1-one: ES / MS m / z: C 11 H 13 Calculated value for BrNO(M+H): 254.02, measured value: 254.12.

[0381] Steps 2, 3, and 4 Using intermediates 6 and 5-bromo-2,3,3-trimethylisoindorin-1-one, 4-(4-(2,3,3-trimethyl-1-oxoisoindorin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for the Suzuki reaction and PMB deprotection, followed by ester hydrolysis: 1 H NMR(400MHz,DMSO-d6)δ8.10(d,J=1.5Hz,1H),8.00(s,2H),7.89(dd,J=7.7,5.6Hz ,2H),7.83(dd,J=7.9,1.6Hz,1H),7.73(d,J=7.9Hz,1H),2.95(s,3H),1.50(s,6H). ES / MS m / z:C 20 H 19 Calculated value for N4O3(M+H): 363.15, measured value: 363.12.

[0382] Example 153: 4-(4-(3,3-dimethyl-1-oxo-2-(2,2,2-trifluoroethyl)isoindorin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] Using 2,2,2-trifluoroethyltrifluoromethanesulfonate, 4-(4-(3,3-dimethyl-1-oxo-2-(2,2,2-trifluoroethyl)isoindorin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 5-bromo-3,3-dimethylisoindorin-1-one in a manner similar to the procedure of Example 154: 1 H NMR (400MHz, DMSO-d6) δ8.11(d,J=19.7Hz,3H),8.00-7.83(m,3H),7.79(d,J=7.9Hz,1H),4.34(q,J=9.6Hz,2H),1.58(s,6H). ES / MS m / z:C 21 H 18 Calculated value for F3N4O3(M+H): 431.13, measured value: 431.15.

[0383] Example 154: 4-(9-methyl-9H-carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0384] Process 1 Using intermediate 4 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole, ethyl 5-(9H-carbazole-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared in a manner similar to the general procedure for the Suzuki reaction.

[0385] Process 2 To a solution of ethyl 5-(9H carbazole 2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-4-carboxylate (0.060 g, 0.068 mmol) in dimethylformamide (1 mL), 60% sodium hydride (0.008 g, 0.21 mmol) in mineral oil was added and the mixture was stirred for 30 minutes, after which MeI (0.009 mL, 0.13 mmol) was added. The solution was stirred overnight at room temperature. After completion, the mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH4Cl (1 mL). The aqueous fraction was extracted with ethyl acetate (2 × 10 mL), and then 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), concentrated to dryness, and then purified by silica gel column chromatography using ethyl acetate-containing hexane elution to obtain ethyl 5-(9-methyl-9H-carbazol-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z C 24 H 31 The calculated value for N4O3Si(M+H) is 451.22, and the measured value is 450.90.

[0386] Process 3 4-(9-methyl-9H-carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using a procedure similar to the general procedure for ester hydrolysis, followed by SEM deprotection with TBAF: 1 H NMR (400MHz, methanol-d4) δ8.21-8.09(m,2H),8.06(d,J=1.3Hz,1H),7.65(d,J= 8.0Hz, 1H), 7.56-7.45 (m, 2H), 7.23 (ddd, J=7.9, 6.6, 1.6Hz, 1H), 3.92 (s, 3H). ES / MS m / z:C 16 H 11 The calculated value for N4O2(MH) was 291.09, while the measured value was 291.11.

[0387] Example 155: 4-(4-(6-(1H-1,2,3-triazole-4-yl)pyridazin-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0388] Process 1 A mixture of isomers of ethyl 5-(4-(6-bromopyridazin-3-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from intermediates 6 and 3,6-dibromopyridazine using a method similar to that used for preparing intermediate 10: ES / MS m / z:C 21 H 27 Calculated value for BrN5O3Si(M+H): 504.11, measured values: 504.14 and 504.18.

[0389] Steps 2, 3, and 4 Using compound 28, 4-(4-(6-(1H-1,2,3-triazole-4-yl)pyridazin-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of the Suzuki reaction followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ8.53(s,1H), 8.43(d,J=9.0Hz,1H),8.28(d,J=8.9Hz,1H),8.24-8.15(m,2H),8.12-8.03(m,2H). ES / MS m / z:C 15 H 11 Calculated value for N8O2(M+H): 335.10, measured value: 335.11.

[0390] Example 156: 4-(4-(5-(1H-1,2,3-triazole-4-yl)pyrazine-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 4-(4-(5-(1H-1,2,3-triazole-4-yl)pyrazine-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 2,5-dibromopyrazine in a manner similar to that of Example 157: 1 H NMR (400MHz, methanol-d4) δ9.30 (s, 1H), 9.22 (d, J = 1.5 Hz, 1 H), 8.26 (d, J = 8.2 Hz, 2 H), 8.06 (d, J = 7.7 Hz, 3 H). ES / MS m / z:C 15 H 11 Calculated value for N8O2(M+H): 335.10, measured value: 335.10.

[0391] Example 157: 4-(3'-methyl-4'-(1H-1,2,3-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid [ka]

[0392] Process 1 A mixture of isomers of ethyl 5-(4-(6-bromopyridazin-3-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from intermediate 6 and 1-bromo-4-iodo-2-methylbenzene using a method similar to that used for preparing intermediate 10: ES / MS m / z:C 24 H 31 Calculated value for BrN3O3Si(M+H): 516.11, measured value: 516.02.

[0393] Steps 2, 3, and 4 4-(3'-methyl-4'-(1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using compound 28 in a manner similar to the general procedure of Suzuki reaction followed by SEM deprotection with HCl and ester hydrolysis: 1H NMR (400MHz, methanol-d4) δ7.97(d,J=8.0Hz,3H),7.77(d,J=8.3Hz,2H),7.73-7.53(m,3H),2.54(s,3H). ES / MS m / z:C 18 H 15 Calculated value for N6O2S(M+H): 347.12, measured value: 347.15.

[0394] Example 158: 4-(4'-chloro-2-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0395] Process 1 5-Bromo-2-iodobenzonitrile (1000 mg, 3.25 mmol), (4-chlorophenyl)boronic acid (559 mg, 3.57 mmol), triphenylphosphine (26 mg, 0.097 mmol), palladium acetate (36 mg, 0.162 mmol), potassium phosphate (1347 mg, 9.74 mmol), toluene (4 mL), and water (2 mL) were combined in a flask and purged with Ar for 5 minutes. The reaction system was then heated to 60°C for 70 minutes. The reaction mixture was then diluted with water, extracted with ethyl acetate, filtered through diatomaceous earth / Celite, and then concentrated to dryness under reduced pressure. The crude reaction mixture was purified by flash chromatography (0-100% ethyl acetate / hexane) to give 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carbonitrile: 1 ¹H NMR (400MHz, chloroform-d): δ 7.89 (d, J=2.1Hz, 1H), 7.77 (dd, J=8.4, 2.1Hz, 1H), 7.47 (s, 4H), 7.36 (d, J=8.4Hz, 1H).

[0396] Process 2 Using a method similar to the typical procedure for boronate ester preparation, 4'-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-carbonitrile was prepared from 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carbonitrile.

[0397] Steps 3, 4, and 5 4-(4'-chloro-2-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using compound 4 and 4'-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-carbonitrile in a manner similar to the general procedure of Suzuki reaction followed by SEM deprotection with TBAF and ester hydrolysis: 1 ¹H NMR (400MHz, methanol-d4): δ 8.46 (s, 1H), 8.30 (d, J=8.2Hz, 1H), 7.72-7.59 (m, 3H), 7.58-7.50 (m, 2H). ES / MS m / z: C 16 H 10 The calculated value for ClN4O2(M+H) was 325.05, while the measured value was 325.03.

[0398] Example 159: 4-(4'-(1H-imidazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0399] Process 1 Tris(benzylideneacetone)dipalladium (20 mg, 0.0039 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (8 mg, 0.016 mmol), and tripotassium phosphate (83 mg, 0.39 mmol) were charged into a reaction vessel, and the headspace was purged with nitrogen gas for 10 minutes. Separately, imidazole (16 mg, 0.23 mmol) and ethyl 5-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (98 mg, 0.2 mmol) were dissolved in 5:1 (v / v) toluene-dioxane (3.0 mL), and the mixture was purged with nitrogen gas for 10 minutes. The imidazole solution was added to the reaction vessel, and the reaction system 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). The aqueous layer was extracted with ethyl acetate (2 × 5 mL), and the combined organic fraction was washed with water (2 × 5 mL). Finally, the organic fraction was dried (Na2SO4), concentrated to dryness, and then purified by silica gel column chromatography using hexane elution with ethyl acetate to obtain ethyl 5-(4'-(1H-imidazole-1-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate:ES / MS m / z:C 26 H 32 The calculated value for N5O3Si(M+H) was 490.23, while the measured value was 490.39.

[0400] Steps 2 and 3 4-(4'-(1H-imidazole-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using a procedure similar to the general procedure for ester hydrolysis, followed by SEM deprotection with TBAF: 1H NMR (400MHz, methanol-d4) δ9.48 (s, 3H), 8.145 (t, 1H) 8.00 (dd, J = 12.2, 8.5 Hz, 3H), 7.83 (dd, J = 8.4, 6.2 Hz, 4H). ES / MS m / z:C 18 H 14 The calculated value for N5O2(M+H) was 332.11, while the measured value was 332.14.

[0401] Example 160: 4-((4-chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0402] Process 1 A mixture of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (114 mg, 0.033 mmol), copper(I) iodide (19 mg, 0.0098 mmol), 1-chloro-4-ethynylbenzene (55 mg, 0.40 mmol), triethylamine (0.363 mL, 3 mmol), and dichlorobis(triphenylphosphine)palladium(II) (41 mg, 0.0065 mmol) in acetonitrile (3 mL) was purged with N2 for 10 minutes and heated overnight at 60°C. If necessary, more copper(I) iodide and dichlorobis(triphenylphosphine)palladium(II) were added to improve conversion to the desired product. Once the reaction was deemed complete by LC / MS, the reaction system was diluted with ethyl acetate (10 mL) and filtered through Celite. 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 matter was washed with water (1 × 10 mL), dried (Na2SO4), concentrated, and then purified by silica gel column chromatography with hexane elution containing 0-100% ethyl acetate to give ethyl 5-((4-chlorophenyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate:1 ¹H NMR (400MHz, acetonitrile-d3) δ 7.64-7.56 (m,1H), 7.52-7.45 (m,1H), 5.98 (d,J=9.7Hz,1H), 5.72 (s,0H), 4.51-4.37 (m,1H), 3.75-3.58 (m,1H), 2.14 (s,2H), 2.11 (d,J=1.2Hz,0H), 1.45-1.34 (m,2H), 1.29 (s,0H), 0.97-0.83 (m,1H). ES / MS m / z C 19 H 25 The calculated value for ClN3O3Si(M+H) was 406.14, while the measured value was 406.86.

[0403] Steps 2 and 3 4-((4-chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using a standard procedure for SEM deprotection with TBAF followed by ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ7.57(d,J=8.4Hz,2H),7.43(d,J =8.4Hz,2H), ES / MS m / z:C 11 The calculated value for H7ClN3O2(M+H) is 248.02, while the measured value is 247.96.

[0404] Example 161: 4-(1-(oxetan-3-yl)piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0405] Process 1 A mixture of isomers of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4, 285 mg, 0.814 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (277 mg, 0.89 mmol), tetrakis(triphenylphosphine)palladium (0) (94 mg, 0.081 mmol), 2N potassium carbonate (1022 mL, 2 mmol), and 1,4-dioxane (4 mL) were added to a microwave reaction vial. After purging with argon gas for 5 minutes, the resulting mixture was stirred at 110°C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography using ethyl acetate-containing hexane elution to obtain tert-butyl 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl-3,6-dihydropyridine-1(2H)-carboxylate: ES / MS m / z: C 21 H 36 Calculated value for N4O5Si(M+H): 453.25, measured value: 452.68.

[0406] Process 2 A solution of tert-butyl 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl-3,6-dihydropyridine-1(2H)-carboxylate (120 mg, 0.27 mmol) in 1,4-dioxane (2 mL) containing 4N HCl was stirred overnight at rt. After concentrating the reaction mixture, the residue was purified by silica gel column chromatography using methanol-containing ethyl acetate elution to obtain impure ethyl 4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 10 H 15Calculated value for N4O2(M+H): 223.11, measured value: 223.01.

[0407] Process 3 A mixture of ethyl 4-(1,2,3,6-tetrahydropyridine-4-yl)-1H-1,2,3-triazole-5-carboxylate (22 mg, 0.01 mmol) and 10% palladium-supported carbon (20 mg) (1 mL) in ethanol was stirred under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to obtain ethyl 4-(piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 10 H 17 Calculated value for N4O2(M+H): 225.13, measured value: 225.17.

[0408] Process 4 To a suspension of ethyl 4-(piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylate (22 mg, 0.01 mmol) and 3-oxetanone (35 mg, 0.05 mmol) in THF (1 mL), sodium triacetoxyborohydride (104 mg, 0.05 mmol), followed by one drop of acetic acid, was added. The reaction mixture was stirred overnight at room temperature. After concentrating the reaction mixture, the residue was purified by preparative HPLC to obtain ethyl 4-(1-(oxetan-3-yl)piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylate:ES / MS m / z:C 13 H 21 Calculated value for N4O3(M+H): 281.15, measured value: 281.18.

[0409] Step 5: 4-(1-(oxetan-3-yl)piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylate was prepared from ethyl 4-(1-(oxetan-3-yl)piperidine-4-yl)-1H-1,2,3-triazole-5-carboxylic acid using a method similar to the general procedure for ester hydrolysis: 1H NMR (400MHz, methanol-d4): δ4.89(m,4H), 4.17-4.01(m,1H), 3.80(m,1H), 3.72-3.42(m,3H), 3.26-3.05(m,1H), 2.37-2.02(m,4H). ES / MS m / z:C 11 H 17 Calculated value for N4O3(M+H): 253.12, measured value: 253.13.

[0410] Example 162: 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0411] Process 1 A mixture of isomers of tert-butyl 4-(4,(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate was prepared from intermediate 11 and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate using a method similar to the general procedure of the Suzuki reaction: ES / MS m / z:C 29 H 35 Calculated value for N4O5(M+H): 519.26, measured value: 518.98 and 518.96.

[0412] Process 2 A flask containing an isomer mixture of tert-butyl 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (128 mg, 0.25 mmol) was mixed with 1,4-dioxane containing 4N HCl (3 mL), and the resulting mixture was stirred at room temperature for 15 minutes. After the solution was completely concentrated, the residue in dichloromethane (3 mL) and pyridine (0.05 mL, 0.62 mmol) were mixed with anhydrous acetic acid (0.05 mL, 0.53 mmol) at 0°C. After 30 minutes at 0°C and 30 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (approximately 25 mL) and washed with saturated aqueous ammonium chloride (×1), saturated aqueous sodium bicarbonate (×1), and brine (×1). The aqueous fraction was extracted with ethyl acetate (approximately 20 mL x 1), then combined with the organic fraction, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography using hexane elution with 50-100% ethyl acetate, followed by ethyl acetate elution with 0-20% methanol, to obtain a mixture of isomers of ethyl 5-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 26 H 29 Calculated value for N4O4(M+H): 461.22, measured values: 460.94 and 461.17.

[0413] Steps 3 and 4 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of PMB deprotection followed by ester hydrolysis: 1H NMR (400MHz, methanol-d4) δ7.82(d,J=8.2Hz,2H),7.54(d,J=8.1Hz,2H),6.24(s,1H),4.23(dq,J=5.8,2.6Hz,2H),3.81(t,J =5.8Hz,0.83H),3.76(t,J=5.7Hz,1.17H),2.66(d,J=6.6Hz,1.17H),2.59(s,0.83H),2.18(s,1.755H),2.15(s,1.245H). ES / MS m / z:C 16 H 17 Calculated value for N4O3(M+H): 313.13, measured value: 313.10.

[0414] Example 163: 4-(4-(1-acetylpiperidine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0415] Process 1 A flask containing an isomer mixture of ethyl 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (product from Step 2 of Example 164, 55 mg, 0.12 mmol) was mixed with 20% palladium hydroxide-supported carbon (6.6 mg) and ethanol (4 mL). The resulting mixture was stirred at room temperature under an H2 atmosphere for 3.5 hours. The reaction mixture was diluted with methanol and dichloromethane and filtered through a Celite pad. After washing the Celite pad with ethanol, the filtrate was completely concentrated and co-evaporated with toluene (×1) to obtain a crude isomer mixture of ethyl 5-(4-(1-acetylpiperidine-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate:ES / MS m / z:C 26 H 31 Calculated value for N4O4(M+H): 463.23, measured values: 463.04 and 463.06.

[0416] Steps 2 and 3 4-(4-(1-acetylpiperidine-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using a method similar to the general procedure of PMB deprotection followed by ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ7.80-7.70(m,2H),7.41-7.30(m,2H),4.68(ddt,J=13.2,4.4,2.2Hz,1H),4.15-3.95(m,1H),3.25(dt,J=13.0,2 .9Hz,1H),2.89(tt,J=12.1,3.6Hz,1H),2.73(td,J=13.0,2.7Hz,1H),2.14(s,3H),1.92(ddt,J=17.2,14.8,2.9Hz,2H),1.73 and 1.62(two qd,J=12.5,4.1Hz,2H). ES / MS m / z:C 16 H 19 Calculated value for N4O3(M+H): 315.15, measured value: 315.14.

[0417] Example 164: 4-(4'-(pyrazine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0418] Process 1 A mixture of pyrazine (200 mg, 2 mmol), 4-bromophenylboronic acid (552 mg, 3 mmol), trifluoroacetic acid (0.191 mL, 2 mmol), tetrabutylammonium bromide (40 mg, 0.125 mmol), potassium persulfate (2.0 g, 7 mmol), and iron(III) acetylacetonate (440 mg, 1 mmol) in CH2Cl2 (10 ml) and water (10 ml) 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 the pH > 8. After separating the two layers, the aqueous fraction was extracted with dichloromethane (2 × 10 mL), the combined organic fraction was dried (Na2SO4), concentrated, and purified by silica gel column chromatography with hexane elution containing 0-100% ethyl acetate to give 2-(4-bromophenyl)pyrazine. 1 ¹H NMR (400MHz, chloroform-d): δ 9.01 (d, J=1.5Hz, 1H), 8.63 (dd, J=2.5, 1.5Hz, 1H), 8.53 (d, J=2.5Hz, 1H), 7.94-7.86 (m, 2H), 7.69-7.61 (m, 2H). ES / MS m / z C 10 The calculated value for H8BrN2(m+H) was 234.99, while the measured value was 235.05.

[0419] Steps 2, 3, and 4 Using intermediate 6, 4-(4'-(pyrazine-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was synthesized from 2-(4-bromophenyl)pyrazine using a typical procedure for the Suzuki reaction, SEM deprotection with HCl, and ester hydrolysis. 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),9.32(d,J=1.6Hz,1H),8.73(dd,J=2.5,1.5Hz,1H),8.62(d,J=2.5Hz,1H),8.30-8.23(m,2H),7.96-7.86(m,6H). ES / MS m / z:C 19 H 14 The calculated value for N5O2(M+H) was 344.11, while the measured value was 344.04.

[0420] Example 165: 4-(4'-(1H-1,2,4-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazol-5-carboxylic acid [ka]

[0421] Process 1 A mixture of isomers of ethyl 5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from 4-bromobenzamide and intermediate 6 using a procedure similar to the general Suzuki reaction: ES / MS m / z:C 24 H 30 The calculated value for N4O4Si(M+H) is 467.2, and the measured value is 467.16.

[0422] Process 2 To a solution of ethyl 5-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (117 mg, 0.25 mmol) in THF (1 mL), t-butoxybis(dimethylamino)methane (Bredereck's reagent, 62 μL, 0.30 mmol) was added. The mixture was then heated to 60°C until the starting material was consumed and ethyl(E)-5-(4'-(((dimethylamino)methylene)carbamoyl)-[1,1'-biphenyl]4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate appeared. The material from this reaction was used directly in step 3: ES / MS m / z: C 27 H 35 The calculated value for N5O4Si(M+H) is 522.25, and the measured value is 522.11.

[0423] Process 3 Hydrazine (39 μL, 1 mmol) and acetic acid (109 μL, 2.0 mmol) were added to the reaction mixture from step 2 and heated to 60°C. After completion by LC / MS, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 (2 × 5 mL). The aqueous fraction was extracted with ethyl acetate (2 × 10 mL), and the organic fraction was combined and washed with 1N HCl (5 mL) and water (5 mL), dried (Na2SO4), and concentrated to dryness. Without further purification, the crude product ethyl 5-(4'-(1H-1,2,4-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was used directly in step 4: 1 H NMR (400MHz, chloroform-d) δ8.36(s,1H),8.18(d,J=8.0Hz,1H),7.94(dd,J=26.9,8.1Hz,1H),7. 70(ddd,J=21.3,12.8,7.8Hz,3H),7.58(t,J=7.2Hz,0H),7.53-7.45(m,0H),6.05(s,0H),5.7 7(s,1H),4.50-4.36(m,1H),4.12(q,J=7.1Hz,2H),3.81-3.72(m,1H),3.70-3.61(m,0H),2.1 1(s,1H),2.04(s,3H),1.45-1.31(m,2H),1.25(t,J=7.1Hz,4H),0.95(dt,J=15.9,8.3Hz,1H). ES / MS m / z:C 25 H 30 The calculated value for N6O3Si(M+H) is 491.21, and the measured value is 491.25.

[0424] Steps 4 and 5 4-(4'-(1H-1,2,4-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared by a procedure similar to the general procedure for ester hydrolysis, followed by SEM deprotection with HCl: 1H NMR (400MHz, DMSO-d6) δ8.49 (s, 1H), 8.15-8.08 (m, 2H), 7.96-7.81 (m, 6H). ES / MS m / z C 17 H 13 The calculated value for N6O2(m+H) is 333.10, and the measured value is 333.11.

[0425] Example 166: 4-(7-bromo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0426] Process 1 Using bis(pinacolato)diborone (27), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-amine was prepared from aromatic bromides in a manner similar to the typical procedure for boronate synthesis:

[0427] Process 2 An isomer mixture of ethyl 5-(7-amino-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from the intermediates 4 and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-amine using a procedure similar to the general Suzuki reaction: ES / MS m / z:C 24 H 31 Calculated value for N4O3Si(M+H): 451.22, measured value: 451.33.

[0428] Process 3 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), t-butyl nitride (0.32 mL, 2.69 mmol) and cupric bromide (595 mg, 2.66 mmol) were added at 0°C. After 45 minutes, the reaction mixture was quenched with a 1 M Na2S2O3 solution, and the product was extracted with ethyl acetate. The extract was dried (MgSO4), concentrated, and purified by silica gel column chromatography with hexane elution containing 0-100% ethyl acetate to obtain a mixture of the desired ethyl 5-(7-bromo-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate, along with deamination byproducts. The mixture was used in the next reaction without further purification.

[0429] Steps 4 and 5 4-(7-bromo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using a method similar to the general procedure for SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, 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, 1.8Hz, 1H), 3.98 (s, 2H). ES / MS m / z:C 16 H 11 Calculated value for BrClN3O2(M+H): 355.92, measured value: 356.00.

[0430] Example 167: 4-(7-chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] 4-(7-chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (56) was prepared using copper(II) chloride instead of copper(II) bromide, following a procedure similar to that of Step 3 in Example 168, followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ 8.03 (s, 1H), 7.94-7.81 (m, 3H), 7.60 (s, 1H), 7.39 (dd, J = 8.1, 1.9Hz, 1H), 3.99 (s, 2H). ES / MS m / z:C 16 H 11 Calculated value for ClN3O2(M+H): 312.05, measured value: 311.93.

[0431] Example 168: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5-carboxylic acid [ka]

[0432] Process 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 from aromatic bromides using bis(pinacorato)diborone (27) in a manner similar to the typical procedure for boronate synthesis.

[0433] Steps 2, 3, and 4 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 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 and boronate 28 by a procedure similar to the general Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ7.80-7.70(m,2H),7.41-7.30(m,2H),4.68(ddt,J=13.2,4.4,2.2Hz,1H),4.15-3.95(m,1H),3.25(dt,J=13.0,2.9Hz,1H), 2.89(tt,J=12.1,3.6Hz,1H),2.73(td,J=13.0,2.7Hz,1H),2.14(s,3H),1 .92 (ddt, J=17.2, 14.8, 2.9Hz, 2H), 1.73 and 1.62 (2qd, J=12.5, 4.1Hz, 2H). ES / MS m / z:C 18 H 13 Calculated value for N6O2(M+H): 345.10, measured value: 345.11.

[0434] Example 169: 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0435] Process 1 4-(7-bromo-9,9-difluoro-7-iodo-9H-fluorene)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole was prepared from 2-bromo-9,9-difluoro-9H-fluorene-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole from 2-bromo-9,9-difluoro-7-iodo-9H-fluorene and boronate 28 using a method similar to the general procedure of the Suzuki reaction: ES / MS m / z:C 21 H 23Calculated value for BrF2N3OSi(M+H): 478.08, measured value: 477.76.

[0436] Process 2 Using bis(pinacolato)diborone (27), 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 typical procedure for boronate synthesis from aromatic bromides: ES / MS m / z:C 27 H 35 Calculated value for BF2N3O3Si(M+H): 526.25, measured value: 525.96.

[0437] Steps 5, 6, and 7 Using intermediates 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, 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared by a procedure similar to the general Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 ¹H NMR (400MHz, 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=7.0Hz, 2H). ES / MS m / z:C 18 H 11 Calculated value for F2N6O2(M+H): 381.09, measured value: 381.06.

[0438] Example 170: 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-pyrazole-5-carboxylic acid [ka] From intermediate 15 and 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid, 4-(9,9-difluoro-7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-pyrazole-5-carboxylic acid was prepared by a procedure similar to the general Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ8.27(s,1H),8.11(d,J=1.7Hz,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=7.9Hz,1H),7.77-7.70(m,2H). ES / MS m / z:C 19 H 12 Calculated value for F2N5O2(M+H): 380.10, measured value: 380.11.

[0439] Example 171: 4-(7-(1,5-dimethyl-1H-1,2,3-triazole-4-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0440] Process 1 A mixture of 2,7-dibromo-9,9-difluoro-9H-fluorene (2000 mg, 5.56 mmol), bis(pinacolato)diborone (5646 mg, 22.2 mmol), dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium(II)dichloromethane (679 mg, 0.83 mmol), and potassium acetate (2903 mg, 29.6 mmol) in 1,4-dioxane (50 mL) was purged with argon gas for 15 minutes and then stirred at 80°C for 16 hours. The reaction mixture was completely concentrated, the residue was dissolved in ethyl acetate (approximately 300 mL), and washed with water (approximately 250 mL x 2). The aq. fraction was extracted with ethyl acetate (approximately 100 mL x 1), the organic fractions were combined and dried (Na2SO4), and then concentrated. The residue was purified by silica gel column chromatography using hexane elution with 0-20% ethyl acetate to obtain 2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane): 1 H NMR (400MHz, chloroform-d) δ8.08(dt,J=2.0,0.9Hz,2H),7.95-7.89(m,2H),7.60(dd,J=7.5,0.9Hz,2H),1.36(s,24H). Mass data unavailable.

[0441] Process 2 From intermediate 4 and 2,2'-(9,9-difluoro-9H-fluoren-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane), an isomer mixture of ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-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 general procedure of the Suzuki reaction: ES / MS m / z:C 30 H 39 Calculated value for BF2N3O5Si(M+H): 598.27, measured values: 597.81 and 597.67.

[0442] Steps 3, 4, and 5 Using an isomer 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-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate), 4-(7-(1,5-dimethyl-1H-1,2,3-triazole-4-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared by a procedure similar to the general Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ8.20(s,1H),8.11(d,J=7.8Hz,1H),7.94(s,1H),7.88(d,J=8.1Hz,1H),7.85(d,J=8.6Hz,2H),4.06(s,3H),2.54(s,3H). ES / MS m / z:C 20 H 15 Calculated value for F2N6O2(M+H): 409.12, measured value: 409.14.

[0443] Example 172: 4-(9,9-difluoro-7-(2-methyl-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka] Using an isomer mixture of 4-bromo-2-methyl-2H-1,2,3-triazole and ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate), 4-(9,9-difluoro-7-(2-methyl-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared by a procedure similar to the general Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ8.19(s,1H),8.11(s,3H),8.03(d,J=7.9Hz,1H),7.83(d,J=8.0Hz,2H),4.24(s,3H). ES / MS m / z:C 19 H 13 Calculated value for F2N6O2(M+H): 395.11, measured value: 395.03.

[0444] Example 173: 4-(6-chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0445] Process 1 A mixture of 1-bromo-4-iodobenzene (1.00 g, 3.5 mmol), 4-chlorobenzonitrile (973 mg, 7.1 mmol), bis(acetonitrile)palladium(II) chloride (92 mg, 0.35 mmol), and silver(I) oxide (901 mg, 3.9 mmol) in trifluoroacetic acid (35 mL) and dimethylacetamide (1.75 mL) was purged with argon gas. After 15 minutes, water (64 μL) was gradually added dropwise to the mixture while argon purging was performed. After 1 minute, the flask was kept airtight and heated at 140°C for 90 hours. After cooling, the reaction mixture was diluted with dichloromethane, filtered through a Celite pad, and the resulting filtrate was concentrated. The residue was dissolved in dichloromethane and aq.HCl, and the insoluble material was filtered off again through a Celite pad, separating the two layers of the filtrate. The organic fraction was dried (MgSO4), concentrated, and purified by silica gel column chromatography with hexane elution containing 0-100% ethyl acetate to obtain 2-bromo-6-chloro-9H-fluoren-9-one.

[0446] Process 2 To a solution of 2-bromo-6-chloro-9H-fluoren-9-one (33 mg, 0.11 mmol) in tetrahydrofuran (1 mL), 1 M lithium triethyl borohydride (0.34 mL) was added at -78°C. After 25 minutes, the reaction mixture was quenched with saturated NH4Cl aqueous solution. The product was extracted with ethyl acetate (×4), the organic extracts were washed with brine (×1), dried (MgSO4), and concentrated to obtain crude 2-bromo-6-chloro-9H-fluoren-9-ol, which was used in the next step.

[0447] Process 3 Crude 2-bromo-6-chloro-9H-fluoren-9-ol was mixed with triethyl silin (0.3 mL) and trifluoroacetic acid (0.3 mL), and the resulting mixture was stirred at room temperature for 1.7 hours. After concentration, the residue was purified by silica gel column chromatography using hexane elution containing 0-100% ethyl acetate to obtain 2-bromo-6-chloro-9H-fluorene.

[0448] Process 4 A mixture of 2-bromo-6-chloro-9H-fluorene (27 mg, 0.095 mmol), bis(pinacolato)diborone (29 mg, 0.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.8 mg, 9.5 μmol), and potassium acetate (28 mg, 0.29 mmol) in dioxane (1.5 mL) was placed in a microwave reaction vial and purged with argon gas. The resulting mixture was stirred at 95°C for 2.25 hours and cooled. After the mixture was diluted with water, the product was extracted with ethyl acetate (×4). The combined organic extracts were dried (MgSO4), concentrated, and purified by silica gel column chromatography with hexane elution containing 0-100% ethyl acetate to obtain 2-(6-chloro-9H-fluoren-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[0449] Steps 5, 6, and 7 4-(6-chloro-9-oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using intermediate 4 and 2-(6-chloro-9H-fluoren-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to the general procedure of the Suzuki reaction followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400MHz, methanol-d4) δ8.05(s,1H),7.94(d,J=8.0Hz,1H),7.92-7.84(m,2H),7.57(d,J=8.0Hz,1H),7.33(dd,J=8.0,2.0Hz,1H),3.98(s,2H). ES / MS m / z:C 16 H 11 Calculated value for ClN3O2(M+H): 312.05, measured value: 311.96.

[0450] Example 174: 4-(2-(piperidine-4-yl)-4'-(1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid [ka]

[0451] Process 1 A mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (28, 403 mg, 1.45 mmol), 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (5, 1.93 g, 5.84 mmol), and palladium(0)tetrakis(triphenylphosphine) (168 mg, 0.15 mmol) in 2M potassium carbonate (2.9 mL) and 1,4-dioxane (15 mL) in a 20 mL microwave reaction vial was purged with Ar for 10 minutes and then stirred in a 110°C bath for 1.25 hours. The reaction mixture was dissolved in ethyl acetate (approximately 100 mL) and washed with approximately 50% saturated NaHCO3 (×1) and water (×1). The aq. fraction was extracted with ethyl acetate (approximately 50 mL x 1), then the organic fraction was combined and dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography with hexane elution containing 0-100% ethyl acetate. The partially purified product was further purified by silica gel column chromatography with hexane elution containing 0-20% ethyl acetate to obtain 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole: ES / MS m / z: C 20 H 33 Calculated value for BN3O3Si(M+H): 402.24, measured value: 401.96.

[0452] Process 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 a bath at 85°C for 18 hours. The reaction mixture was cooled and diluted with water (100 mL), and the product was extracted with ethyl acetate (100 mL x 4). After washing the extract with water (100 mL x 1), the combined extract was dried (Na2SO4) and concentrated. The residue was treated with concentrated HCl (25 mL), and the mixture was refluxed for 36 hours. After cooling the resulting mixture in a refrigerator, the insoluble material was filtered and washed with water. The solids were dissolved in ethyl acetate (approximately 100 mL), dried (MgSO4), and concentrated to obtain crude 3-(5-bromo-2-iodophenyl)pentanedioic acid: ES / MS m / z: C 11 H 11 Calculated value for BrIO4(M+H): 412.89, measured value: 412.58.

[0453] Process 3 The above crude 3-(5-bromo-2-iodophenyl)pentanedioic acid mixture in acetic anhydride (approximately 10 mL) was refluxed in a 155°C bath for 3 hours. After concentrating the resulting solution, the residual syrup was co-evaporated with toluene (x2) and dried in vacuum. The residue was dissolved in THF (50 mL) and stirred at room temperature, during which 28% NH3 aqueous solution (0.65 mL each) was added three times at intervals of approximately 15 minutes. The resulting mixture was stirred at room temperature for 7 hours. The resulting suspension was completely concentrated, co-evaporated with toluene (x2), and dried. The residue was refluxed in a 155°C bath with acetic anhydride (15 mL) for 4 hours and then cooled. The solution was concentrated, and the residue was purified by silica gel column chromatography using hexane elution with 0-60% ethyl acetate to obtain 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione. 1H NMR(400MHz,DMSO-d6)δ10.98(s,1H),7.82(d,J=8.4Hz,1H),7.55(d,J=2.4Hz,1H),7.25(dd,J= 8.4,2.4Hz,1H),3.52(tt,J=12.0,4.1Hz,1H),2.90-2.78(m,2H),2.63(dd,J=16.7,4.1Hz,2H).

[0454] Process 4 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione (1.60 g, 4.06 mmol) in THF (5 mL) was stirred at 0°C while adding a 1.0 M boranetetrahydrofuran complex solution dropwise in THF (10.2 mL). The resulting mixture was refluxed for 20 hours, then c.HCl (16 mL) was added to the mixture, and the resulting solution was refluxed in a 105°C bath for 4.5 hours. The solution was stirred in an ice bath while neutralizing the mixture with the addition of NaOH (solid). The resulting basic solution was diluted with some NaHCO3 solution, and the product was extracted with ethyl acetate (approximately 60 mL x 2). The extract was washed with brine (x 1), dried together (Na2SO4), and concentrated to obtain 4-(5-bromo-2-iodophenyl)piperidine as an oil.

[0455] The crude 4-(5-bromo-2-iodophenyl)piperidine solution in methanol (approximately 25 mL) was stirred while adding Boc2O (1078 mg, 4.939 mmol) and triethylamine (0.8 mL, 5.740 mmol). After 2 hours at 0°C and overnight at room temperature, the reaction mixture was concentrated, the residue was dissolved in ethyl acetate, and washed with water (×2). The resulting organic fraction was dried (MgSO4), concentrated, and purified by silica gel column chromatography with hexane elution containing 0-10% EA to obtain tert-butyl 4-(5-bromo-2-iodophenyl)piperidine-1-carboxylate. 1H NMR (400MHz, chloroform-d) δ7.68(d,J=8.4Hz,1H),7.27(d,J=2.4Hz,1H),7.05(dd,J=8.4,2.4Hz,1H) ,4.27(s,2H),2.94-2.85(tt,J=3.4,12.9Hz,1H),2.82(s,2H),1.84(d,J=12.9Hz,2H),1.51(dd,J =3.8,12.9Hz,2H),1.48(s,9H).

[0456] Process 5 A mixture of tert-butyl 4-(5-bromo-2-iodophenyl)piperidine-1-carboxylate (250 mg, 0.63 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (273 mg, 0.68 mmol), tetrakis(triphenylphosphine)palladium (0) (75 mg, 0.06 mmol), and 2N potassium carbonate (0.6 mL) in dioxane (6 mL) was purged with Ar gas for 10 minutes and then stirred in a bath at 110 °C for 1.5 hours. After cooling, the mixture was diluted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography with hexane elution containing 0-50% ethyl acetate to obtain tert-butyl 4-(4-bromo-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate: ES / MS m / z:C 30 H 41 Calculated value for BrN4NaO3Si(M+Na): 635.20, measured value: 635.14.

[0457] Process 6 A mixture of tert-butyl 4-(4-bromo-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate (201 mg, 0.33 mmol), bis(pinacolato)diborone (27 mg, 0.66 mmol), dichloro-1,1'-bis(diphenylphosphino)ferrocenepalladium(II)dichloromethane (116 mg, 0.03 mmol), and potassium acetate (102 mg, 1.04 mmol) in 1,4-dioxane (3 mL) in a microwave reaction vial was purged with Ar gas for 15 minutes, and then the mixture was heated at 120°C for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography using hexane elution containing 0-35% ethyl acetate to provide 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-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate: ES / MS m / z:C 36 H 53 Calculated value for BN4NaO5Si(M+Na): 683.38, measured value: 683.35.

[0458] Steps 7, 8, and 9 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-triazole-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate were used in a procedure similar to the general Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis to prepare 4-(2-(piperidine-4-yl)-4'-(1H-1,2,3-triazole-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid: 1H NMR (400MHz, methanol-d4) δ8.23(s,1H),7.99(d,J=1.8Hz,1H),7.98-7.91(m,2H),7.78(dd,J=8.0,1.7Hz,1H),7.49-7.41(m,2H),7.3 6(d,J=7.9Hz,1H),3.41(dd,J=12.8,3.2Hz,2H),3.21-3.03(m,1H),2.93(ddd,J=16.6,8.6,5.2Hz,2H),2.03(tt,J=8.6,3.4Hz,4H). ES / MS m / z:C 22 H 22 Calculated value for N7O2(M+H): 416.18, measured value: 416.14.

[0459] Example 175: Ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5-carboxylate [ka]

[0460] Process 1, Process 2, Process 3, and Process 4 Using intermediate 11 and 2,7-dibromo-9H-fluorene, ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluorene-2-yl)-1H-1,2,3-triazol-5-carboxylate was prepared in a manner similar to the procedure described herein, followed by a manner similar to the general procedure for PMB deprotection: 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.14(s,1H),8.07-8.02(m,3H),7.95(d,J=8 .0Hz,1H),7.82(m,1H),4.32(q,J=7.0Hz,2H),4.08(s,2H),1.28(t,J=7.0Hz,3H). ES / MS m / z:C 20 H 17 Calculated value for N6O2(M+H): 373.14, measured value: 373.30.

[0461] Example 176: 2-Morpholinoethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5-carboxylate [ka]

[0462] Process 1 To a stirred solution of ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate (18 g, 29.4 mmol) in MeOH (36 mL), THF (108 mL), and water (36 mL), lithium hydroxide monohydrate (3.7 g, 88.18 mmol) was added under argon at room temperature. The reaction mixture was heated to 60 °C and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was diluted with water, acidified with 1 N HCl solution, and stirred for 10 minutes. The precipitated solid was filtered, the solid was washed with water, and then dried under vacuum to obtain 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid:ES / MS m / z:C 34 H 29 Calculated value for N6O4(M+H): 585.23, measured value: 585.41.

[0463] Process 2 To a stirred solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (3.0 g, 5.14 mmol) in DMF (30 mL), potassium carbonate (1.41 g, 10.3 mmol), followed by 4-(2-chloroethyl)morpholine (1.53 g, 10.3 mmol), was added under argon at room temperature. The mixture was heated to 50 °C and stirred for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether elution with 80-100% ethyl acetate to obtain 2-morpholinoethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z:C 40 H 40 Calculated value for N7O5(M+H): 683.31, measured value: 698.52.

[0464] Process 3 A mixture of 2-morpholinoethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-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 hours. The reaction mixture was concentrated under reduced pressure, and the crude residue was neutralized with saturated aqueous NaHCO3. The product was extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by Prep-HPLC (neutral method), and the pure fraction was freeze-dried to obtain 2-morpholinoethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1H NMR(400MHz,DMSO-d6)δ8.41(s,1H),8.14(s,1H),8.05(t,J=8.4Hz,2H),8.00(s,1H),7.95(d,J=8.4Hz,1H),7.81(d ,J=8.4Hz,1H),4.38(t,J=5.6Hz,2H),4.08(s,2H),3.49(t,J=4.6Hz,4H),2.61(t,J=5.6Hz,2H),2.49-2.33(m,4H). ES / MS m / z:C 24 H 24 Calculated value for N7O3(M+H): 458.19, measured value: 458.32.

[0465] Example 177: 3-Morpholinopropyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5-carboxylate [ka]

[0466] Steps 1 and 2 3-morpholinopropyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate was prepared using 4-(3-chloropropyl)morpholine and 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid in a manner similar to the procedure of steps 2 and 3 of Example 175, followed by a manner similar to the general procedure for PMB deprotection: 1H NMR(400MHz,DMSO-d6)δ15.18(s,1H),8.42(s,1H),8.14(s,1H),8.04(m,2H),7.98(s,1H),7.95(d,J=8.0Hz,1H),7.77 (d,J=8.0Hz,1H),4.27(t,J=6.2Hz,2H),4.08(s,2H),3.42(t,J=4.4Hz,4H),2.22-2.18(m,6H),1.77(qn,J=6.7Hz,2H). ES / MS m / z:C 25 H 26 Calculated value for N7O3(M+H): 472.21, measured value: 472.50.

[0467] Example 178: 2-((L-valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5-carboxylate [ka]

[0468] Process 1 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), lithium hydroxide monohydrate (1.85 g, 44.24 mmol) was added under argon at room temperature. After the reaction, the mixture was stirred at room temperature for 5 hours, and the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, acidified with 1 N HCl solution, and then stirred for 10 minutes. The precipitated solid was filtered, washed with water, and dried under vacuum to obtain 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid (178-a):ES / MS m / z:C 11 H 10 Calculated value for BrN3NaO3(M+H): 333.98, measured value: 334.10.

[0469] Process 2 To a stirred solution of Boc-L-valine (3.0 g, 13.82 mmol) and ethane-1,2-diol (1.11 g, 17.96 mmol) in dichloromethane (45 mL), 4-dimethylaminopyridine (0.33 g, 2.76 mmol) was added under argon at 0°C, followed by a solution of dicyclohexylcarbodiimide (3.69 g, 17.96 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue was purified by silica gel column chromatography eluting 0-30% ethyl acetate-containing petroleum ether to obtain 2-hydroxyethyl (tert-butoxycarbonyl)-L-valine (178-b): 1 H NMR(400MHz,DMSO-d6)δ7.11(d,2ZH),4.77(t,J=5.4Hz,1H),4.06(m,2H),3.87(dd,J=7.8 and 6.0Hz,1H),3.56(appt q,J=5.2Hz,2H),2.50(m,1H),2.01(m,1H),1.39(s,9H),0.87(d,J=6.6Hz,6H).

[0470] Process 3 To a stirred solution of 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid (178-a, 2.55 g, 8.17 mmol) and 2-hydroxyethyl (tert-butoxycarbonyl)-L-valinate (178-b, 2.77 g, 10.62 mmol) in dichloromethane (37.5 mL), 4-dimethylaminopyridine (0.2 g, 1.63 mmol) was added, followed by a solution of dicyclohexylcarbodiimide (2.18 g, 10.62 mmol) in dichloromethane (12.5 mL) at 0°C under argon. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using petroleum ether elution containing 0-60% ethyl acetate to obtain 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z:C 23 H 32Calculated value for BrN4O7(M+H): 555.15, measured value: 555.34.

[0471] Process 4 2-(4-methoxybenzyl)-4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole and 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate were prepared using a method similar to the general procedure of the Suzuki reaction: ES / MS m / z:C 46 H 49 Calculated value for N7NaO8(M+Na): 850.35, measured value: 850.86.

[0472] Process 5 A mixture of 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-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 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by prep-HPLC, and the combined pure fraction was freeze-dried to obtain 2-((L-valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.28(s,3H),8.14(s,1H),8.07-8.03(m,3H),7.96(d,J=8.0Hz,1H),7.83(d,J=6.0Hz,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=6.8Hz,1H),0.86(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H). ES / MS m / z:C 25 H 26 Calculated value for N7O4(M+H): 488.20, measured value: 488.39.

[0473] Example 179: 2-(phosphonooxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5-carboxylate [ka]

[0474] Process 1 Dibenzyl hydrocarbon phosphate (117, 20 g, 71.94 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethane-1-ol (15.22 g, 86.33 mmol) were stirred in THF (200 mL). Triphenylphosphine (28.27 g, 107.91 mmol), followed by diethyl azadicarboxylate (18.83 g, 107.91 mmol), were added under argon at 0°C. The resulting mixture was stirred at rt for 5 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography eluting 0-10% ethyl acetate-containing petroleum ether to obtain dibenzyl(2-((tert-butyldimethylsilyl)oxy)ethyl) phosphate: ES / MS m / z: C 22 H 34 Calculated value for O5PSi(M+H): 437.19, measured value: 437.34.

[0475] Process 2 Dowex-50W was added to a stirred solution of dibenzyl (2-((tert-butyldimethylsilyl)oxy)ethyl) phosphate (23 g, 52.75 mmol) in MeOH (230 mL) under argon at room temperature. The mixture was stirred for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel column chromatography using 0-2% MeOH-containing dichloromethane elution to obtain dibenzyl (2-hydroxyethyl) phosphate: ES / MS m / z: C 16 H 20 Calculated value for O5P(M+H): 323.10, measured value: 323.24.

[0476] Process 3 To a stirred solution of dibenzyl(2-hydroxyethyl) phosphate (5 g, 15.52 mmol) in dichloromethane (50 mL), NEt3 (3.23 mL, 23.28 mmol), followed by MsCl (2.13 g, 18.63 mmol), was added under argon at 0°C. After stirring the mixture at room temperature for 5 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to obtain crude 2-((bis(benzyloxy)phosphoryl)oxy)ethylmethanesulfonate, which was used directly in the next step without any further purification: ES / MS m / z:C 17 H 22 Calculated value for O7PS(M+H): 401.08, measured value: 401.27.

[0477] Process 4 2-((bis(benzyloxy)phosphoryl)oxy)ethylmethanesulfonate (3.28 g, 8.21 mmol) was added to a stirred mixture of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (4 g, 6.84 mmol) and potassium carbonate (1.41 g, 10.26 mmol) in DMF (40 mL) under argon at 0°C. The mixture was stirred at 50°C for 14 hours, and the reaction mixture was diluted with ice water. The product was extracted with ethyl acetate. The organic extract was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using petroleum ether elution containing 0-60% ethyl acetate to obtain 2-((bis(benzyloxy)phosphoryl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate:ES / MS m / z:C 50 H 46 Calculated value for N6O8P(M+H): 889.31, measured value: 889.77.

[0478] Process 5 A mixture of 2-((bis(benzyloxy)phosphoryl)oxy)ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate (11.5 g, 12.94 mmol) in trifluoroacetic acid (45 mL) was stirred at 70°C for 20 hours. After concentrating the reaction mixture under reduced pressure, the crude residue was purified by Prep-HPLC to obtain 2-(phosphonooxy)ethyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1H NMR (400MHz, DMSO-d6) δ8.39(s,1H),8.19(s,1H),8.11(s,1H),8.01-7.97(m,3H),7.92(d,J=7.3Hz,1H),4.36(m,2H),4.06(s,2H),4.03(m,2H). ES / MS m / z:C 20 H 18 Calculated value for N6O6P(M+H): 469.10, measured value: 469.16.

[0479] Example 180: (((2-(phosphonooxy)ethoxy)carbonyl)oxy)methyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazol-5-carboxylate [ka]

[0480] Process 1 To a stirred solution of dibenzyl(2-hydroxyethyl) phosphate (5 g, 15.52 mmol) and pyridine (2.5 mL, 31.04 mmol) in dichloromethane (100 mL), chloromethyl carbonochloride (2.97 g, 23.29 mmol) was added under argon at 0°C. After stirring the mixture at room temperature for 6 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to obtain crude 2-((bis(benzyloxy)phosphoryl)oxy)ethyl(chloromethyl) carbonate, which was used directly in the next step without any further purification: ES / MS m / z:C 18 H 21 Calculated value for ClO7P(M+H): 415.07, measured value: 415.31.

[0481] Process 2 2-((bis(benzyloxy)phosphoryl)oxy)ethyl(chloromethyl) carbonate (0.25 g, 10.27 mmol) was added to a stirred solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (5.0 g, 8.56 mmol) and potassium carbonate (1.77 g, 12.84 mmol) in DMF (50 mL) under argon at 0°C. The mixture was stirred at 50°C for 18 hours. After diluting the reaction mixture with ice water, the product was extracted with ethyl acetate. The organic extract was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 0-1% MeOH-containing dichloromethane elution to obtain (((2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)carbonyl)oxy)methyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate:ES / MS m / z:C 52 H 48 N6O 11 Calculated value for P(M+H): 963.31, measured value: 963.39.

[0482] Process 3 A mixture of (((2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)carbonyl)oxy)methyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate (5.5 g, 5.71 mmol) in trifluoroacetic acid (55 mL) was stirred at 70°C for 20 hours. After concentrating the reaction mixture under reduced pressure, the crude residue was purified by Prep-HPLC to obtain (((2-(phosphonooxy)ethoxy)carbonyl)oxy)methyl 4-(7-(1H-1,2,3-triazole-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1H NMR (400MHz, methanol-d4) δ8.42(s,1H),8.15(s,1H),8.06(t,J=8.0Hz,2H),8.00(s,1H),7.95 (d,J=8.0Hz,1H),7.80(d,J=8.0Hz,1H),5.94(s,2H),4.32(m,2H),4.08(s,2H),4.01(m,2H). ES / MS m / z:C 22 H 20 Calculated value for N6O9P(M+H): 543.10, measured value: 543.40.

[0483] Using commercially available boronate along with either bromide intermediate 18 or 20 as described above, the following compounds were prepared in a manner similar to the typical Suzuki reaction, SEM or PMB deprotection, and ester hydrolysis procedures described above: Example 182: 3-(3-chloro-4-fluorophenyl)-1H-pyrazole-4-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.17 (s, 1H), 7.90 (dd, J=7.2, 2.2Hz, 1H), 7.71 (ddd, J=8.6, 4.6, 2.2Hz, 1H), 7.29 (t, J=8.9Hz, 1H). ES / MS m / z: C 10 Calculated value for H7ClFN2O2(M+H): 241.02, measured value: 241.02.

[0484] Example 183: 3-(3,5-dichlorophenyl)-1H-pyrazole-4-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.21 (s, 1H), 7.77 (d, J=2.0Hz, 2H), 7.47 (t, J=2.0Hz, 1H). ES / MS m / z: C 10 H7C l2 Calculated value for N2O2(M+H): 256.99, measured value: 257.03.

[0485] Example 184: 4-(3-chloro-4-fluorophenyl)-1H-imidazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): 8.12 (dd, J=7.4, 2.2Hz, 1H), 7.90 (ddd, J=8.6, 4.7, 2.2Hz, 1H), 7.68 (s, 1H), 7.20 (dd, J=9.2, 8.7Hz, 1H). ES / MS m / z:C 10 Calculated value for H7ClFN2O2(M+H): 241.02, measured value: 240.94.

[0486] Example 185: 4-(3,5-dichlorophenyl)-1H-imidazole-5-carboxylic acid [ka] 1 ¹H NMR (400MHz, methanol-d4): δ 8.03 (s, 2H), 7.67 (s, 1H), 7.31 (s, 1H). ES / MS m / z: C 10 Calculated value for H7Cl2N2O2(M+H): 256.99, measured value: 257.03.

[0487] Biological assays Biological Assay 1: Biochemical Cell Assay material Glycolate oxidase (GO) was generated in Gilead using the HAO1 sequence according to 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 No. 124737) and Tris 1M, pH 7.8 (catalog No. T2569-1L) were manufactured by Sigma (St. Louis, MO), 10% Tween-20 (catalog No. 51-12-02) was manufactured by SeraCare (Milford, MA), 2% BSA (catalog No. BSA-1000) was manufactured by Rockland Immunochemicals (Pottstown, PA), and the black 384-well low-binding plate (catalog No. 3860) was manufactured by Corning (Sunnyvale, CA).

[0488] method 1. GO biochemical assay The GO biochemical enzymatic reaction was carried out in a black 384-well low-binding plate with a total volume of 25 μL. The reaction mixture contained 5 nM GO, 100 μM glycolic acid, 0.1 U / mL HRP, 50 μM Amplex Red, and 1:3 sequentially diluted test compounds in a buffer containing 50 mM Tris pH 7.8, 0.0025% Tween-20, and 0.02% BSA. 25 nanoliters of the 1000X test compound were initially pre-spotted onto the 384-well low-binding plate at a final concentration of 10 μM using an Echo 555 Liquid Handler (Labcyte Inc., San Jose, CA), followed by the addition of 5 μL / well of 25 nM GO (5X at a final concentration of 5 nM) and incubation for 15 minutes. 10 microliters of 2.5X 0.1 U / mL final concentration HRP were added to each well, followed by 10 μL of 2.5X 100 μM final concentration glycolate substrate and 2.5X 50 μM final concentration Amplex Red. The reaction system was mixed and incubated at room temperature for 20 minutes, after which the plate was read using an EnVision plate reader (Perkin Elmer, San Jose, CA) with 570 nm excitation and 585 nm emission. Wells containing DMSO were used as negative controls (0% inhibition), while wells without GO enzyme were used as positive controls (100% inhibition). Percentage inhibition was calculated as 100% × (well - negative) / (positive - negative).

[0489] 2. HRP counter screen assay To eliminate compounds that did not affect GO inhibition but may directly inhibit HRP, an HRP counterscreen assay was performed in parallel with the GO biochemical assay. As described in the GO biochemical assay above, 25 nanoliters of the same set of 1000X test compounds were pre-spotted onto a 384-well low-binding plate. Subsequently, 10 μL of 2.5X 0.1 U / mL HRP at a final concentration was added to a buffer containing 50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA, and incubated for 15 minutes. Then, 15 μL of 1.67X 50 μM Amplex Red and 1.67X 10 μM H2O2 at a final concentration were added to each well. The reaction system was mixed and incubated at room temperature for 20 minutes. At the end of incubation, the plate was read by Envision with 570 nm excitation and 585 nm emission. Wells containing DMSO were used as negative controls (0% inhibition), while wells without HR enzyme were used as positive controls (100% inhibition). Percentage inhibition was calculated as described above.

[0490] GO cell-based assay 1. GO transient transfection cell-based assay material HAO1 plasmid DNA was generated by PCR cloning of HAO1 cDNA (Jones et al., 2000) into a pcDNA3.1(+)-neomycin vector by LakePharma (Belmont, CA). FuGENE6 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 serum-reduced medium (catalog number 31985-070) was manufactured by Gibco / Life Technologies (Grand Island, NY). Fetal bovine serum (FBS) (catalog number SH30071.03) was manufactured by HyClone (Logan, Utanh), and 100X penicillin / streptomycin / L-glutamine (catalog number 30-009-Cl) was manufactured by Corning (Fremont, CA). 384-well black tissue culture plates (catalog No. 781086) were purchased from Greiner Bio-One (Monroe, NC).

[0491] method Transient transfection was performed in OptiMEM I serum-reduced medium by mixing 3 μl portions of FuGENE6 reagent with 1 μg portion of HAO1 plasmid DNA or vector control DNA, and incubated at room temperature for 15 minutes. The mixture was mixed with CHO-K1 cells and dispensed in 45 μL / wells of F-12K medium plus 10% FBS containing 0.025 μg HAO1 plasmid DNA, 0.075 μL FuGENE6, and 4000 cells. Cells were incubated in a 37°C incubator for 48 hours to express GO. The cell culture medium was then removed and replaced with 25 μL of 1:3 serially diluted test compound at a starting concentration of 1 μM, and incubated at room temperature for 1 hour. Next, 25 μl of reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) containing HRP (final concentration 0.1 U / mL), 300 μM glycolic acid, and 50 μM Amplex Red was added to each well. The reaction system was mixed and incubated at room temperature for 20 minutes, after which the plate was read using an EnVision plate reader as described above. The wells containing DMSO were used as negative controls (0% inhibition), while the wells containing vector control DNA transfection were used as positive controls (100% inhibition). Percentage inhibition was calculated as described above.

[0492] 2. GO stable clone cell-based assay material Reagents and tissue culture media for transient transfection are described in the section on transient transfection assays. 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).

[0493] method 1) Generation of stable CHO-K1-HAO1 clones Stable GO clones were generated in-house by performing bulk transient transfection of GO plasmid DNA into CHO-K1 cells as described above and incubated for 48 hours. The cells were then trypsinized, and 2000 cells / 200 μl were added to well A1 of a 1096-well tissue culture plate, followed by 1:2 serial dilutions to A2 and so on, up to A12. Cells from A1-A12 were further 1:2 serial dilutions to H1-H12 and cultured for 2 weeks in F-12K medium with 10% FBS supplemented with 500 μg / mL G418. Each plate was monitored under a microscope for colony formation. 28 single colonies were isolated and expanded to test GO expression.

[0494] Immunocytochemistry for intracellular GO staining Intracellular GO staining was performed by first fixing cells in a 384-well plate with 50 μL / well of 4% formaldehyde-containing PBS at room temperature for 30 minutes, followed by three washes with 80 μL / well of wash buffer (PBS containing 0.05% Tween-20). The cells were then permeabilized with 50 μL / well of 0.1% Triton-containing PBS for 30 minutes, washed three times, and blocked with 50 μL / well of 3% BSA-containing PBS (containing 0.05% Tween-20) for 1 hour. The cells were washed three times again, and 50 μL of rabbit anti-human GO in a 1:100 dilution in PBS containing 1% BSA and 0.05% Tween-20 was added to each well and incubated overnight at 4°C. The cells were washed four times, with a 15-minute incubation between each wash. Subsequently, 40 μL of 1:250 dilution of Alexa Fluor555 conjugate anti-rabbit IgG(H+L)F(ab')2 fragment and 1:500 dilution of Hoechst were added to each well in 1% BSA and 0.05% Tween-20. The plates were incubated at room temperature for 160 minutes and washed four times at the end of incubation. 60 microliters of PBS were added to each well, and cell images were examined using an Arrayscan XTI HCS reader from Thermo Fisher Scientific (Waltham, MA).

[0495] 2) Stable clone 2D2GO enzyme-active cell-based assay 25 nL of the test compound / well was pre-spotted into a 384-well tissue culture plate, followed by dispensing 5000 cells / well / 25 μL of reaction buffer containing clone 2D2 (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) into all wells, except for column 22, which contained 5000 cells / well / 25 μL of clone 1A1 vector control. The test compound was incubated with the cells at room temperature for 1 hour, followed by the addition of 25 μL of reaction buffer containing HRP (final concentration 0.1 U / mL), 160 μM glycolic acid, and 50 μM Amplex Red (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA). The reaction system was mixed and incubated at room temperature for 20 minutes, and the fluorescence of the product resolphin was measured as described above. Wells containing 2D2 and DMSO were used as negative controls (0% inhibition), while wells containing 1A1 vector control clones were used as positive controls (100% inhibition). Percentage inhibition was calculated as described above (Table 2).

[0496] [Table 3] JPEG2026082935000242.jpg249170JPEG2026082935000243.jpg249170JPEG2026082935000244.jpg249170JPEG2026082935000245.jpg168170

[0497] Biological assay 2: Oral bioavailability and PK test The oral dose in Example 2 was formulated at 1.0 mg / mL in a sterile solution of 50% water, 37.5% PEG300, and 12.5% ​​DMSO. The treatment group consisted of three fasting male Sprague Dolly rats. At the time of administration, the animals weighed 0.26–0.27 kg. In the oral administration group, the prescribed dose was 5.0 mL / kg per 5.0 mg / kg via oral gastric tube administration. Non-compartmental pharmacokinetic analysis was performed on plasma concentration-time data.

[0498] [Table 4]

[0499] Table 3 shows the mean plasma pharmacokinetic parameters of Example 2 after PO administration at 5 mg / kg in SD rats (mean ± SD, n=3). Table 4 shows the mean plasma pharmacokinetic parameters of Example 68 after PO administration at 5 mg / kg in SD rats (mean ± SD, n=3). As shown in Tables 4 and 5, the AUC of Example 2 inf It is 1600±280 nM·h, and C max The AUC of Example 68 was 2390 ± 246 nM. inf It is 3250±242 nM·h, and C max The concentration was 2270 ± 171 nM. The bioavailability of Example 68 was estimated to be 19.0% ± 1.4%.

[0500] [Table 5]

[0501] [Table 6]

[0502] The apparent whole-body clearance (CL = 0.95 ± 0.09 L / hr / kg) in Example 68 was lower than that of hepatic blood flow in rats (CL = 4.0 L / hr / kg). (V) ss The value (=0.44±0.06 L / kg) was less than the total volume of body water (0.7 L / kg). (Terminal t of Example 68) 1 / 2 The average retention time (MRT) was 1.02 ± 0.06 hours, and the mean dwell time (MRT) was 0.47 ± 0.02 hours. The oral bioavailability (%F) was estimated to be 2.3% ± 0.3%. See Tables 7, 8, and Figure 2.

[0503] [Table 7]

[0504] [Table 8]

[0505] Examples 168 or 175 were formulated for oral or intravenous administration in a sterile solution of 15% N-methyl-2-pyrrolidone, 55% PEG, and 30% water. The treatment groups consisted of three fasted male SD rats or three fasted male beagle dogs. At the time of administration, the rats weighed 0.2–0.3 kg and the dogs weighed 10.72–10.82 kg. In the oral administration group, the prescribed dose was 5.0 mg / kg or 5.4 mg / kg administered via oral gastric tube at a dose of 5.0 mL / kg. In the intravenous administration group, the prescribed dose was 1.00 mg / kg. Non-compartmental pharmacokinetic analysis was performed on plasma concentration-time data. Data from these studies are shown in Figures 3 and 4.

Claims

1. Compound of formula I: 【Chemistry 1】 Alternatively, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is either N or CH; R １ These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which has 1 to 3 R ３ It is arbitrarily replaced by; R ２ is hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , C alkyl, cycloalkyl optionally substituted with 1 to 3 R ４ ; or heteroaryl optionally substituted with 1 to 3 R １～６ ; and ５ is heteroaryl optionally substituted with 1 to 3 R Each R ３ These are independently cyano, halo, and -L-C １～９ Alkyl, -L-C １～４ Haloalkyl, -L-OC １～４ Haloalkyl, -NR ７ R ８ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ -L-aryl, -L-heteroaryl, or -L-heterocyclyl, each of which contains 1 to 3 R ６ It is arbitrarily substituted, and each L is independently either -C≡C- or does not exist; Each R ４ These are independently halo, hydroxyl, and -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocyclines, each having 1 to 3 R ５ It is arbitrarily substituted, provided that one R ４ Only heterocyclyls are; Each R ５ These are independently cyano, halo, and C. １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; Each R ６ These are independently cyano, halo, and -C(O)R. ７ , -C(O)OR ７ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ , C １～４ Alkyl, -OC １～４ Alkyl, C １～４ Haloalkyl, -OC １～４ The elements are haloalkyl, phenyl, heterocyclyl, or heteroaryl; each of which contains 1 to 3 C atoms. １～４ Alkyl, -C(O)OH, or C １～４ Optionally substituted with a haloalkyl group; R ７ and R ８ These are, independently, hydrogen and C １～４ Alkyl, phenyl, pyridyl, or R ７ and R ８ They, together with the nitrogen atom to which they are bonded, form a heterocycline; Each R ａ It is independently, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; Each R ｂ These are, independently, hydrogen or C １～４ It is alkyl; However, when A is N, then: 1) R １ This is 1 to 3 R ３ It is a condensed tricyclic ring arbitrarily substituted with; 2) R １ is cyano, -C≡C-C １～９ alkyl, 1 to 3 R ６ substituted -C １～９ alkyl, -C≡C-C １～４ haloalkyl, -C≡C-OC １～４ haloalkyl, -NR ７ R ８ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -O-C １～４ alkyl, -O-phenyl, -L-aryl, -L-heteroaryl, or -L-heterocyclyl, and each L is independently -C≡C- or absent; ３ is an optionally substituted fused bicyclic ring substituted with at least 1 R ６ and each of which is further optionally substituted with 1 to 3 R 3) R １ is a substituted monocyclic ring and is as follows: i) Cyano, -C ≡ C - C １～９ Alkyl, -C≡C-C １～４ Haloalkyl, -C≡C-OC １～４ Haloalkyl, -NR ７ R ８ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ -C≡C-aryl, -C≡C-heteroaryl, or -C≡C-heterocyclyl, each of which contains 1 to 3 R ６ It is further arbitrarily replaced; ii) Monocyclic aryl, monocyclic heteroaryl, or monocyclic heterocyclyl, each comprising 1 to 3 cyano-C(O)R ７ , -C(O)OR ７ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , C １～４ Alkyl, -OC １～４ Alkyl, C １～４ Further substituted with haloalkyl, phenyl, heterocyclyl, or heteroaryl, each of which contains 1 to 3 C atoms. １～４ It is optionally substituted with alkyl, -C(O)OH, or 1-4 haloalkyl groups; iii) Any substituted condensed aryl, any substituted condensed heteroaryl, or any substituted condensed heterocyclyl, each having 1 to 3 R ６ It is further arbitrarily replaced by; or, iv) Formula-L １ -L ２ substituents, where L １ These are aryl, heteroaryl, or heterocyclyl compounds, each containing 1 to 3 R ６ It is arbitrarily replaced by and L ２ These are phenyl, heterocyclyl, or heteroaryl compounds, each containing 1 to 3 C atoms. １～４ Alkyl, -C(O)OH, or C １～４ Optionally substituted with a haloalkyl group; at least one R selected from ３ Replaced by; or 4) R ２ is, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C replaced by １～６ Alkyl, cycloalkyl, or 1 to 3 R ５ It is a heteroaryl compound arbitrarily substituted with; At least one of the following applies: However, when A is CH, R １ R is not a 10-membered heteroaryl substituted with methoxy and methyl. １ cyano, halo, C １～４ Alkyl, -OR ７ , C １～４ Haloalkyl and NR ７ R ８ C is arbitrarily substituted with 1 to 3 substituents independently selected from the above. ６ Not Ariel, but here, R ７ and R ８ Each of them independently consists of hydrogen or C １～４ It is alkyl; also, R １ is unsubstituted C １０ Not Ariel; R １ It is a compound that is neither an unsubstituted heterocyclyl nor a compound.

2. The compound according to claim 1: A is either N or CH; R １ However, the compound is an alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which has 1 to 3 R ３ It is arbitrarily replaced with; R ２ However, hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl, or 1 to 3 R ５ It is a heteroaryl that is arbitrarily substituted with; Each R ３ However, independently, Haro, -L-C １～９ Alkyl, -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ -L-5 to 6-membered heteroaryl or -L-5 to 6-membered heterocycline, where each is 1 to 3 R ６ It is arbitrarily substituted, and each L is independently conjugated or -C≡C-; Each R ４ However, independently, halo, hydroxy, -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or monocyclic heterocyclines, each having 1 to 3 R ５ It is arbitrarily replaced by; here, one R ４ Only heterocyclyls are; Each R ５ However, independently, Cyano, Halo, C １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; Each R ６ However, independently, Cyano, Halo, C １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; and R ７ and R ８ However, each independently, hydrogen or C １～４ Alkyl, or R ７ and R ８ However, together with the nitrogen atom to which they are bonded, they form - (CH ２ ) ２ -O-(CH ２ ) ２ A compound that forms a -.

3. Compounds of formula IIa: 【Chemistry 2】 Alternatively, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, where R １ and R ２ A compound as defined in claim 1.

4. Compounds of formula IIb: 【Transformation 3】 Alternatively, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, where R １ and R ２ A compound as defined in claim 1.

5. R １ However, 1 to 3 R ３ A compound according to any one of the preceding paragraphs, wherein the aryl is optionally substituted with the aryl compound.

6. R １ However, 1 to 3 R ３ The compound according to any one of claims 1 to 4, wherein the heteroaryl is optionally substituted with .

7. R １ However, 1 to 3 R ３ The compound according to any one of claims 1 to 4, which is a heterocyclyl optionally substituted with .

8. R １ However, 1 to 3 R ３ The compound according to any one of claims 1 to 4, wherein the compound is a cycloalkyl group optionally substituted with .

9. R １ but, 【Chemistry 4】 And each n is independently 1, 2, or 3, and Y is CR ８ R ９ , C(O), O, or NR １０ And R ８ and R ９ Each of these independently produces hydrogen, halo, or C. １～４ It is alkyl, and R １０ However, hydrogen or C １～４ A compound according to any one of claims 1 to 4, wherein it is alkyl.

10. at least one R ３ But, hello, C １～９ Alkyl, or -OR ７ The compound described in any one of the preceding paragraphs.

11. at least one R ３ The compound according to any one of claims 1 to 9, wherein the compound is fluoro, chloro, bromo, methyl, tert-butyl, methoxy, or phenoxy.

12. at least one R ３ The compound according to any one of claims 1 to 9, wherein the compound is an aryl substituted with phenyl, heterocyclyl, or heteroaryl.

13. at least one R ３ but, 【Transformation 5】 The compound according to any one of claims 1 to 9.

14. at least one R ３ However, it is an aryl substituted with a heteroaryl, and that heteroaryl is C １～４ , alkyl-C(O)OH, or C １～４ A compound according to any one of claims 1 to 9, which is substituted with a haloalkyl group.

15. at least one R ３ but, 【Transformation 6】 The compound according to any one of claims 1 to 9.

16. at least one R ３ However, 1 to 3 R ６ The compound according to any one of claims 1 to 9, which is a heterocyclyl optionally substituted with .

17. at least one R ３ but, 【Transformation 7】 The compound according to any one of claims 1 to 9.

18. at least one R ３ However, 1 to 3 R ６ The compound according to any one of claims 1 to 9, wherein the heteroaryl is optionally substituted with .

19. at least one R ３ but, 【Transformation 8】 The compound according to any one of claims 1 to 9.

20. A compound according to any one of claims 1 to 19: R ２ However, hydrogen, 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl or cycloalkyl; Each R ４ However, independently, -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or a monocyclic heterocycline; provided that one R ４ Only heterocyclyls are; Each R ａ However, it became independent, -NH ２ OR -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; and, A compound in which Rb is hydrogen.

21. Compounds of formula III: 【Chemistry 9】 Or, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: R ２ is hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl, cycloalkyl, or 1 to 3 R ５ It is a heteroaryl that is arbitrarily substituted with; Each R ３ These are independently aryl, heteroaryl, or heterocyclyl, each of which contains 1 to 3 R ６ It is arbitrarily replaced by; Each R ４ These are independently halo, hydroxyl, and -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocyclines; where each of them has 1 to 3 R ５ It is arbitrarily replaced by; however, one R ４ Only heterocyclyls are; Each R ５ These are independently cyano, halo, and C. １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; Each R ６ These are independently cyano, halo, and -C(O)R. ７ , -C(O)OR ７ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ , C １～４ Alkyl, -OC １～４ Alkyl, C １～４ Haloalkyl, -OC １～４ The elements are haloalkyl, phenyl, heterocyclyl, or heteroaryl; each of which contains 1 to 3 C atoms. １～４ Alkyl, -C(O)OH, or C １～４ Optionally substituted with a haloalkyl group; R ７ and R ８ These are, independently, hydrogen and C １～４ Alkyl, phenyl, or pyridyl, or R ７ and R ８ They, together with the nitrogen atom to which they are bonded, form a heterocycline; Each R ａ It is independently, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; and, Each R ｂ These are, independently, hydrogen or C １～４ A compound that is alkyl.

22. Compounds of formula IV: 【Chemistry 10】 Or, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein: R ２ is hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl, cycloalkyl, or 1 to 3 R ５ It is a heteroaryl compound that is arbitrarily substituted with, Each R ４ These are independently halo, hydroxyl, and -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocyclines; where each of them has 1 to 3 R ５ It is arbitrarily replaced by; however, one R ４ Only heterocyclyls are; Each R ５ These are independently cyano, halo, and C. １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; Each R ａ It is independently, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; and, Each R ｂ These are, independently, hydrogen or C １～４ A compound that is alkyl.

23. The compound according to claim 22: R ２ However, hydrogen, 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl or cycloalkyl; Each R ４ However, independently, -OC １～６ Alkyl, -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocycline; Each R ａ However, it became independent, -NH ２ OR -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; and, A compound in which Rb is hydrogen.

24. below: 【Chemistry 11】 【change】 A compound selected from the following.

25. A compound selected from Table 1.

26. A compound selected from the following: 【Chemistry 12】 Here, R ２ A compound as defined in claim 1.

27. The compound according to claim 26, wherein the compound is as follows: 【Chemistry 13】 A compound selected from among them.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof.

29. A method for treating primary hyperoxaluria type 1, comprising providing to a patient in need a therapeutically effective amount of the compound described in any one of claims 1 to 27, or the pharmaceutical composition described in claim 28, or the compound of formula I: 【Chemistry 14】 Alternatively, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is either N or CH; R １ These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which has 1 to 3 R ３ It is arbitrarily replaced by; R ２ is hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl, cycloalkyl, or 1 to 3 R ５ It is a heteroaryl that is arbitrarily substituted with; Each R ３ These are independently cyano, halo, and -L-C １～９ Alkyl, -L-C １～４ Haloalkyl, -L-OC １～４ Haloalkyl, -NR ７ R ８ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ -L-aryl, -L-heteroaryl, or -L-heterocyclyl, where each of them has 1 to 3 R ６ It may be arbitrarily substituted, and each L is independently either -C≡C- or does not exist; Each R ４ These are independently halo, hydroxyl, and -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocyclines; where each of them has 1 to 3 R ５ It is arbitrarily replaced by; however, one R ４ Only heterocyclyls are; Each R ５ These are independently cyano, halo, and C. １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; Each R ６ These are independently cyano, halo, and -C(O)R. ７ , -C(O)OR ７ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ , C １～４ Alkyl, -OC １～４ Alkyl, C １～４ Haloalkyl, -OC １～４ The elements are haloalkyl, phenyl, heterocyclyl, or heteroaryl; each of which contains 1 to 3 C atoms. １～４ Alkyl, -C(O)OH, or C １～４ Optionally substituted with a haloalkyl group; R ７ and R ８ These are, independently, hydrogen and C １～４ Alkyl, phenyl, pyridyl, or R ７ and R ８ They, together with the nitrogen atom to which they are bonded, form a heterocycline; Each R ａ It is independently, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; Each R ｂ These are, independently, hydrogen or C １～４ It is alkyl; However, R １ When R is phenyl, ３ is an aryl or heteroaryl compound, each containing 1 to 3 R ６ It may be arbitrarily substituted with; and, R １ When R is a heteroaryl, ２ is non-substituted C １～６ Not alkyl, A treatment method for primary hyperoxaluria type 1, including the administration of [a specific drug].

30. A method for treating recurrent kidney stone formation, comprising: a therapeutically effective amount of any one of claims 1 to 27, the pharmaceutical composition according to claim 28, or a compound of formula I, to a patient in need: 【Chemistry 15】 Alternatively, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is either N or CH; R １ These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which has 1 to 3 R ３ It is arbitrarily replaced by; R ２ is hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl, cycloalkyl, or 1 to 3 R ５ It is a heteroaryl that is arbitrarily substituted with; Each R ３ These are independently cyano, halo, and -L-C １～９ Alkyl, -L-C １～４ Haloalkyl, -L-OC １～４ Haloalkyl, -NR ７ R ８ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ -L-aryl, -L-heteroaryl, or -L-heterocyclyl, where each of them has 1 to 3 R ６ It may be arbitrarily substituted, and each L is independently either -C≡C- or does not exist; Each R ４ These are independently halo, hydroxyl, and -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocyclines; where each of them has 1 to 3 R ５ It is arbitrarily replaced by; however, one R ４ Only heterocyclyls are; Each R ５ These are independently cyano, halo, and C. １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl, Each R ６ These are independently cyano, halo, and -C(O)R. ７ , -C(O)OR ７ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ , C １～４ Alkyl, -OC １～４ Alkyl, C １～４ Haloalkyl, -OC １～４ The elements are haloalkyl, phenyl, heterocyclyl, or heteroaryl; each of which contains 1 to 3 C atoms. １～４ Alkyl, -C(O)OH, or C １～４ Optionally substituted with a haloalkyl group; R ７ and R ８ These are, independently, hydrogen and C １～４ Alkyl, phenyl, pyridyl, or R ７ and R ８ They, together with the nitrogen atom to which they are bonded, form a heterocycline; Each R ａ It is independently, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; and, Each R ｂ These are, independently, hydrogen or C １～４ It is alkyl; However, R １ When R is phenyl, ３ is an aryl or heteroaryl compound, each containing 1 to 3 R ６ It is arbitrarily replaced by; and, R １ When R is a heteroaryl, ２ is non-substituted C １～６ Not alkyl, A method for treating recurrent kidney stone formation, including the administration of [a specific drug / method].

31. A method for inhibiting the production of glyoxylic acid and / or oxalic acid and / or glycolate oxidase (GO), wherein a therapeutically effective amount of the compound according to any one of claims 1 to 27, the pharmaceutical composition according to claim 28, or the compound of formula I is given to a patient in need: 【Chemistry 16】 Alternatively, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is either N or CH; R １ These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which has 1 to 3 R ３ It is arbitrarily replaced by; R ２ is hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl, cycloalkyl, or 1 to 3 R ５ It is a heteroaryl that is arbitrarily substituted with; Each R ３ These are independently cyano, halo, and -L-C １～９ Alkyl, -L-C １～４ Haloalkyl, -L-OC １～４ Haloalkyl, -NR ７ R ８ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ -L-aryl, -L-heteroaryl, or -L-heterocyclyl, where each of them has 1 to 3 R ６ It is arbitrarily substituted, and each L is independently either -C≡C- or does not exist; Each R ４ These are independently halo, hydroxyl, and -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocyclines; where each of them has 1 to 3 R ５ It is arbitrarily replaced by; however, one R ４ Only heterocyclyls are; Each R ５ These are independently cyano, halo, and C. １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; Each R ６ These are independently cyano, halo, and -C(O)R. ７ , -C(O)OR ７ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ , C １～４ Alkyl, -OC １～４ Alkyl, C １～４ Haloalkyl, -OC １～４ The elements are haloalkyl, phenyl, heterocyclyl, or heteroaryl; each of which contains 1 to 3 C atoms. １～４ Alkyl, -C(O)OH, or C １～４ Optionally substituted with a haloalkyl group; R ７ and R ８ These are, independently, hydrogen and C １～４ Alkyl, phenyl, pyridyl, or R ７ and R ８ They, together with the nitrogen atom to which they are bonded, form a heterocycline; Each R ａ It is independently, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; and, Each R ｂ These are, independently, hydrogen or C １～４ It is alkyl; However, R １ When R is phenyl, ３ is an aryl or heteroaryl compound, each containing 1 to 3 R ６ It is arbitrarily replaced by; and, R １ When R is a heteroaryl, ２ is non-substituted C １～６ Not alkyl, A method for inhibiting the production of glyoxylic acid and / or oxalic acid, and / or a method for inhibiting glycolate oxidase (GO), comprising administering a substance.

32. Use of a compound according to any one of claims 1 to 27 or a pharmaceutical composition according to claim 28 for suppressing or inhibiting the formation of recurrent kidney stone formations in patients who require it.

33. A compound of formula I for suppressing or inhibiting the formation of recurrent kidney stone formations in patients who require it: 【Chemistry 17】 Alternatively, a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof, wherein A is either N or CH; R １ These are alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which has 1 to 3 R ３ It is arbitrarily replaced by; R ２ is hydrogen, -(CH ２ CH ２ O) １～９ CH ２ CH ２ OCH ３ , 1 to 3 R ４ C arbitrarily substituted with １～６ Alkyl, cycloalkyl, or 1 to 3 R ５ It is a heteroaryl that is arbitrarily substituted with; Each R ３ These are independently cyano, halo, and -L-C １～９ Alkyl, -L-C １～４ Haloalkyl, -L-OC １～４ Haloalkyl, -NR ７ R ８ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ -L-aryl, -L-heteroaryl, or -L-heterocyclyl, where each of them has 1 to 3 R ６ It may be arbitrarily substituted, and each L is independently either -C≡C- or does not exist; Each R ４ These are independently halo, hydroxyl, and -OC １～６ Alkyl, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , -OC(O)R ａ , -OC(O)OR ａ , -OP(O)(OR ｂ ) ２ , or monocyclic heterocyclines; where each of them has 1 to 3 R ５ It is arbitrarily replaced by; however, one R ４ Only heterocyclyls are; Each R ５ These are independently cyano, halo, and C. １～４ Alkyl, hydroxy, -OC １～４ Alkyl, C １～４ Haloalkyl or -OC １～４ It is a haloalkyl; Each R ６ These are independently cyano, halo, and -C(O)R. ７ , -C(O)OR ７ , -C(O)NR ７ R ８ , -S(O) ２ NR ７ R ８ , -NR ７ C(O)R ８ , -OR ７ , C １～４ Alkyl, -OC １～４ Alkyl, C １～４ Haloalkyl, -OC １～４ The elements are haloalkyl, phenyl, heterocyclyl, or heteroaryl; each of which contains 1 to 3 C atoms. １～４ Alkyl, -C(O)OH, or C １～４ Optionally substituted with a haloalkyl group; R ７ and R ８ These are, independently, hydrogen and C １～４ Alkyl, phenyl, pyridyl, or R ７ and R ８ They, together with the nitrogen atom to which they are bonded, form a heterocycline; Each R ａ It is independently, -NH ２ , - NHC １～６ Alkyl, -N(C) １～６ Alkyl) ２ , or -OP(O)(OR ｂ ) ２ C arbitrarily substituted with １～６ It is alkyl; and, Each R ｂ These are, independently, hydrogen or C １～４ It is alkyl; However, R １ When R is phenyl, ３ is an aryl or heteroaryl compound, each containing 1 to 3 R ６ It is arbitrarily replaced by; and, R １ When R is a heteroaryl, ２ is non-substituted C １～６ Use of compounds other than alkyl groups.

34. The method according to any one of claims 29 to 31, further comprising administering an additional therapeutic agent.

35. The use according to claim 32 or 33 in combination with an additional therapeutic agent.

36. The method according to claim 34 or the use according to claim 35, wherein the additional therapeutic agent is a calcium oxalate crystallization inhibitor, an oxalate degrading enzyme inhibitor, siRNA, oxazyme, lumasilan, nedosilan, oxybate, or reloxaliase.

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

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

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