Heterocyclic carboxylic acid ester compounds as glycolate oxidase inhibitors

Abstract

The present disclosure relates generally to modulators of human glycolate oxidase and methods of use and preparation thereof. Formula I # imgabs0 #

Description

[0001] This patent application is a divisional application; the filing date of its original application is October 27, 2020, the application number is 202080090874.4, and the invention title is "Heterocyclic Carboxylate Compounds as Glycolic Acid Oxidase Inhibitors". The original application is an international application, with the international application number PCT / US2020 / 057575, the international filing date of October 27, 2020, and the entry date into the Chinese national phase of June 30, 2022.

[0002] Cross-reference to related applications

[0003] Under 35 U.S.C. § 119(e), this application claims the benefit of U.S. Provisional Application No. 62 / 929,476 filed on November 1, 2019 and No. 63 / 093,094 filed on October 16, 2020, each of which is hereby incorporated by reference in its entirety. Technical field

[0004] This disclosure relates to compounds, compositions, and methods for treating primary hyperoxaluria type 1 and recurrent kidney stone formers. This disclosure relates to novel substituted heterocyclic carboxylate compounds and methods for their preparation, as well as their use as therapeutic or prophylactic agents. In particular, this disclosure provides novel inhibitors of human glycolic acid oxidase, pharmaceutical compositions containing such compounds, and methods of using these compounds to treat primary hyperoxaluria type 1 and recurrent kidney stone formers. Background art

[0005] Kidney stones affect a large number of people. In the United States, the prevalence of kidney stones is 8.8%, 10.6% in men, and 7.1% in women. The disease also occurs in primary hyperoxaluria type 1 (PH1), which may be caused by genetically defective enzyme activity. Due to the high activity of glycolic acid oxidase, those patients exhibit a significant increase in glyoxylate and oxalate production and calcium oxalate stone deposition. Medical procedures for removing kidney stones exist and are effective. However, after these procedures, the recurrence rate of kidney stones can be high (e.g., over 50%). Therefore, there is a need for drugs that inhibit glycolic acid oxidase activity to treat PH1 patients and reduce the recurrence rate of kidney stones in kidney stone formers. Summary of the invention

[0006] This disclosure relates to novel substituted heterocyclic carboxylate compounds that inhibit human glycolic acid oxidase activity, including their stereoisomers, pharmaceutically acceptable salts, and prodrugs, and the use of such compounds in the treatment of primary hyperoxaluria type 1. The compounds of this disclosure can be used to treat recurrent kidney stone formers.

[0007] On the one hand, a compound having the structure of Formula I is provided:

[0008]

[0009] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein A, R 1 and R 2 are as described herein.

[0010] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of Formula I or a compound of other formulas described throughout) and at least one pharmaceutically acceptable excipient. In certain embodiments, provided herein is a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof.

[0011] Some embodiments provide a method of using (or administering) a compound of Formula I or a compound of other formulas described throughout in the treatment of a disease or disorder in a mammal (particularly a human) that is treatable by a human glycollate oxidase inhibitor.

[0012] Some embodiments provide a method of using (or administering) a compound described herein in the treatment of a disease or disorder in a mammal (particularly a human) that is treatable by a human glycollate oxidase inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] Figure 1 Shows the plasma concentration-time curves of Example 2 and Example 68 after oral administration of Example 2 at a dose of 5.0 mg / kg in SD rats (mean ± SD, n = 3).

[0014] Figure 2 Shows the plasma concentration-time curve of Example 68 after intravenous infusion at 1.0 mg / kg for 30 minutes and an oral dose of 5.0 mg / kg in SD rats (mean ± SD, n = 3).

[0015] Figure 3 Shows the plasma concentration-time curves of Example 168 and Example 175 in SD rats.

[0016] Figure 4 Shows the plasma concentration-time curves of Example 168 and Example 175 in male beagle dogs. DETAILED DESCRIPTION

[0017] Definitions and General Parameters

[0018] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the present disclosure, but rather is provided as a description of exemplary embodiments.

[0019] As used in this specification, unless the context in which they are used otherwise indicates, the following words, phrases, and symbols generally have the meanings set forth below.

[0020] A dash (“-”) that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes at the front or end of a chemical group are for convenience; a chemical group may be depicted with one or more dashes or without dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or named does not indicate or imply directionality.

[0021] The prefix “C u-v ” indicates that the following group has u to v carbon atoms. For example, “C 1-6 alkyl” indicates that the alkyl group has 1 - 6 carbon atoms.

[0022] The modifier “about” when used in conjunction with a quantity includes the recited value and has the meaning ascribed by the context (e.g., includes the degree of error associated with a particular quantity of measurement). In addition, unless the context clearly dictates otherwise, the singular forms “a” and “the” include plural references. Thus, for example, a reference to “the compound” includes a plurality of such compounds, and a reference to “the assay” includes reference to one or more assays known to those of ordinary skill in the art and their equivalents.

[0023] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 - 20 carbon atoms (i.e., C 1-20 alkyl), 1 - 8 carbon atoms (i.e., C 1-8 alkyl), 1 - 6 carbon atoms (i.e., C 1-6 alkyl), or 1 - 4 carbon atoms (i.e., C 1-4Alkyl). Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by chemical name or determined by molecular formula, it may include all positional isomers having that number of carbon atoms; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0024] "Alkenyl" refers to an alkyl group having at least one carbon-carbon double bond and having 2 - 20 carbon atoms (i.e., C 2-20 alkenyl), 2 - 8 carbon atoms (i.e., C 2-8 alkenyl), 2 - 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 - 4 carbon atoms (i.e., C 2-4 alkenyl). Examples of alkenyl include vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0025] "Alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond and having 2 - 20 carbon atoms (i.e., C 2-20 alkynyl), an alkyl group having 2 - 8 carbon atoms (i.e., C 2-8 alkynyl), an alkyl group having 2 - 6 carbon atoms (i.e., C 2-6 alkynyl), or an alkyl group having 2 - 4 carbon atoms (i.e., C 2-4 alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0026] "Alkoxy" refers to the "alkyl-O-" group. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0027] "Halogenated alkoxy" refers to the alkoxy as defined above, in which one or more hydrogen atoms are replaced by a halogen element.

[0028] "Alkylthio" refers to the "alkyl-S-" group.

[0029] "Acyl" means a -C(O)R group, where R is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of them may optionally be substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0030] "Amido" means a "C-amido" group (referring to the group -C(O)NR y R z ) and an "N-amido" group (referring to the group -NR y C(O)R z ), where R y and R z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of them may optionally be substituted.

[0031] "Amino" means the group -NR y R z , where R y and R z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl or heteroaryl; each of them may optionally be substituted.

[0032] "Aryl" means an aromatic carbocyclic group having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) structure, including a fused system. As used herein, aryl has 6-20 ring carbon atoms (i.e., C 6-20 aryl), 6-12 carbocyclic atoms (i.e., C 6-12 aryl) or 6-10 carbocyclic atoms (i.e., C 6-10 aryl). Examples of aryl include phenyl, naphthyl, fluorenyl and anthracenyl. However, aryl does not in any way include or overlap with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is heteroaryl. If one or more aryl groups are fused to a heterocyclic group, the resulting ring system is heterocyclic.

[0033] "Carbamoyl" means an "O-carbamoyl" group (referring to the -O-C(O)NR y R z group) and an "N-carbamoyl" group (referring to the -NR y C(O)OR z group), where R y and R zindependently selected from hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of them may optionally be substituted.

[0034] "Carboxylate ester" means -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; as defined herein, each of them may optionally be substituted.

[0035] "Cycloalkyl" means a saturated or partially unsaturated cyclic alkyl having a single ring or multiple rings, including fused systems, bridged ring systems and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond). The cycloalkyl used herein has 3 - 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 - 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 - 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 - 8 ring carbon atoms (i.e., C 3-8 cycloalkyl) or 3 - 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0036] "Imino" means a -C(NR)R group, where each R is alkyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; as defined herein, each of them may optionally be substituted.

[0037] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" means an unbranched or branched alkyl as defined above, in which one or more hydrogen atoms are replaced by a halogen element. For example, when a residue is substituted by more than one halogen element, the residue can be referred to by using a prefix corresponding to the number of the attached halogen element moieties. Dihaloalkyl and trihaloalkyl mean an alkyl substituted by two ("di") or three ("tri") halogen element groups, which may or may not be the same halogen element. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0038] "Heteroalkyl" means an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes unbranched or branched saturated chains having carbon and heteroatoms. For example, 1, 2 or 3 carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O)2-, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclic group, each of which may optionally be substituted. Examples of heteroalkyl include -OCH3, -CH2OCH3, -SCH3, -CH2SCH3, -NRCH3, and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which may optionally be substituted. As used herein, heteroalkyl includes 1 - 10 carbon atoms, 1 - 8 carbon atoms or 1 - 4 carbon atoms; and 1 - 3 heteroatoms, 1 - 2 heteroatoms or 1 heteroatom.

[0039] "Heteroaryl" means an aromatic group having a monocyclic, polycyclic or polyfused ring, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 - 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 - 12 ring carbon atoms (i.e., C 3-12 heteroaryl) or 3 - 8 carbocyclic atoms (i.e., C 3-8heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, which is independently selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxane, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, dibenzo-p-dioxin, chromenyl, chromenone, benzofuranyl, benzofuranone, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanone, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl. The fused heteroaryl ring can be attached through any ring of the fused system. Any aromatic ring having a single or multiple fused rings and containing at least one heteroatom is considered a heteroaryl, regardless of the connection to the rest of the molecule (i.e., through any of the fused rings). Heteroaryl does not include or overlap with aryl as defined above.

[0040] "heterocyclic group" means a saturated or unsaturated cycloalkyl having one or more ring heteroatoms, which is independently selected from nitrogen, oxygen and sulfur. The term "heterocyclic group" includes heterocyclenyl (i.e., a heterocyclic group having at least one double bond), bridged heterocyclic group, fused heterocyclic group and spiro heterocyclic group. The heterocyclic group can be monocyclic or polycyclic, where the polycyclic can be a fused ring, a bridged ring or a spiro ring. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of the connection (i.e., it can be attached through a carbon atom or a heteroatom). In addition, the term heterocyclic group is intended to include any non-aromatic ring containing at least one heteroatom, which can be fused to an aromatic ring or a heteroaryl ring, regardless of the connection to the rest of the molecule. As used herein, the heterocyclic group has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8(heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 (heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 (heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C 3-6 (heterocyclic group); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, the ring heteroatom being independently selected from nitrogen, sulfur or oxygen, and optionally one or more oxo groups. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. As used herein, the term "bridged heterocyclic group" refers to a four- to ten-membered ring moiety connected at two non-adjacent atoms of the heterocyclic group, wherein one or more (e.g., 1 or 2) four- to ten-membered ring moieties have at least one heteroatom, and each heteroatom is independently selected from nitrogen, oxygen and sulfur. As used herein, bridged heterocyclic groups include bicyclic and tricyclic systems. Also used herein, the term "spiro heterocyclic group" refers to a ring system in which a three- to ten-membered heterocyclic group has one or more additional rings, wherein one or more of the additional rings are three- to ten-membered cycloalkyl or three- to ten-membered heterocyclic groups, and a single atom of one or more of the additional rings is also an atom of the three- to ten-membered heterocyclic group. Examples of spiro heterocyclic rings include bicyclic and tricyclic 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 fused heterocyclic rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl (e.g., 2-methylisoquinolin-1(2H)-one), wherein the heterocyclic group can be attached through any ring of the fused system.

[0041] "Oxo" means the (=O) or (O) group.

[0042] "Sulfonyl" means -S(O)2R group, where R is alkyl, haloalkyl, heterocyclic group, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl groups are mesyl, ethylsulfonyl, benzenesulfonyl and toluenesulfonyl.

[0043] "Alkylsulfonyl" means -S(O)2R group, where R is alkyl.

[0044] "Alkylsulfinyl" means -S(O)R group, where R is alkyl.

[0045] "Thiol" means -SR group, where R is alkyl, haloalkyl, heterocyclic group, cycloalkyl, heteroaryl or aryl.

[0046] Certain common alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkyl enyl" groups, "arylene" groups or "arylenyl" groups, respectively. In addition, unless otherwise expressly stated, when groups are combined and referred to as a moiety herein (e.g., arylalkyl), the last-mentioned group contains the atom through which the moiety is attached to the remainder of the molecule.

[0047] The term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. In addition, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may or may not be replaced by a moiety other than hydrogen.

[0048] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, a compound containing an amide can exist in equilibrium with an imino acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art understands that these compounds contain both the amide tautomer and the imino acid tautomer. Thus, a compound containing an amide is understood to include its imino acid tautomers. Similarly, a compound containing an imino acid should be understood to include its amide tautomers.

[0049] Any formula or structure given herein is also intended to represent both the unlabeled form and the isotopically labeled form 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 the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as (but not limited to) 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. Various isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes such as 3 H, 13 C and 14Those of C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetics studies, detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution, or for radioactive treatment of patients.

[0050] The present disclosure also includes “deuterated analogs” of the compounds of Formula I, wherein 1 to n hydrogens attached to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and thus can be used to increase the half-life of any compound of Formula I when administered to a mammal, particularly a human. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods known in the art, e.g., by using starting materials in which one or more hydrogens are replaced by deuterium.

[0051] The deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure can have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Replacement with a heavier isotope, such as deuterium, can provide certain therapeutic advantages that result from greater metabolic stability, e.g., increased in vivo half-life, reduced dose requirements, and / or improvement of the therapeutic index. 18 Fluorine-labeled compounds can be used in PET or SPECT studies. The isotopically labeled compounds and prodrugs of the present disclosure can generally be prepared by carrying out the protocols or examples described below and the procedures disclosed in the preparations, by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents. It should be understood that deuterium is considered a substituent in the compounds of Formula I herein.

[0052] The concentration of such heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise indicated, when a position is specifically designated as “H” or “hydrogen,” that position is understood to contain hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0053] In many cases, the compounds of the present disclosure form acid addition salts and / or base addition salts due to the presence of amino and / or carboxyl groups or groups similar thereto.

[0054] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0055] The "pharmaceutically acceptable salts" of a given compound refer to salts that retain the biological effectiveness and properties of the given compound and are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Additionally, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by basifying the acid salt solution. Conversely, if the product is a free base, the addition salts (especially pharmaceutically acceptable addition salts) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Similarly, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), bis(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tris(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), bis(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tris(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), monocyclic alkylamines, bicyclic alkylamines, or tricyclic alkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), monoarylamines, diarylamines, or triarylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tris(isopropyl)amine, tris(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0056] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, acylamino, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate ester, cyano, guanidino, halogen, haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclic, hydroxy, hydrazino, imino, oxo, nitro, alkanesulfinyl, sulfonic acid, alkanesulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indeterminate structures obtained by defining substituents with an unlimited number of additional substituents (e.g., a substituted aryl having a substituted alkyl, which itself is substituted by a substituted aryl, which is further substituted by a substituted heteroalkyl, etc.) are not intended to be included in the present application. Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitutions of a substituted aryl with two other substituted aryls are limited to ((substituted aryl) substituted aryl). Similarly, the above definition is not intended to include non-permissible substitution patterns (e.g., a methyl group substituted by 5 fluorines or a heteroaryl having two adjacent oxygen ring atoms). Such non-permissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" can describe other chemical groups as defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituent of that group is itself unsubstituted. For example, in some embodiments, the term "substituted alkyl" means an alkyl having one or more substituents, which substituents include hydroxy, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, one or more of the substituents may be further substituted by halogen, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted by halogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclic, aryl, or heteroaryl, each of which is unsubstituted.

[0057] In certain embodiments, as used herein, the phrase "one or more" means from one to five. In certain embodiments, as used herein, the phrase "one or more" means from one to three.

[0058] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0059] "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.

[0060] Compound

[0061] Compounds are provided herein that are used as glycolic acid oxidase inhibitors. In certain embodiments, compounds of Formula I are provided:

[0062]

[0063] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein

[0064] A is N or CH;

[0065] R 1 is an alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group, each of which is optionally substituted by 1 - 3 R 3 substituents;

[0066] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted by 1 - 3 R 1-6 substituents, cycloalkyl or heteroaryl optionally substituted by 1 - 3 R 5 substituents;

[0067] Each R 3 is independently cyano, halogen, -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-heterocyclic group, each of which is optionally substituted by 1 - 3 R 6 substituents, and each L is independently -C≡C- or L is absent;

[0068] Each R 4 is independently halogen, hydroxy, -OC 1-6 alkyl, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2, -OC(O)Ra 、 -OC(O)OR a 、 -OP(O)(OR b )2 or a monocyclic heterocyclic group; each of which is optionally substituted by 1 - 3 R 5 ; provided that only one R 4 is a heterocyclic group;

[0069] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0070] Each R 6 is independently cyano, halogen, -C(O)R 7 、 -C(O)OR 7 、 -C(O)NR 7 R 8 、 -S(O)2NR 7 R 8 、 -NR 7 C(O)R 8 、 -OR 7 、 C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0071] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0072] Each R a is independently C 1-6 alkyl optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C b )2 or -OP(O)(OR 1-6 )2;

[0073] Each R b is independently hydrogen or C 1-4 alkyl.

[0074] In some embodiments, when A is N, at least one of the following holds:

[0075] 1) R 1 is a fused tricyclic optionally substituted with 1 - 3 R 3 substituents;

[0076] 2) R 1 is a fused bicyclic optionally substituted and substituted with at least one R 3 substituent, where R 3 is selected from cyano, -C≡C-C 1-9 alkyl, -C substituted with 1 - 3 R 6 alkyl, -C≡C-C 1-9 haloalkyl, -C≡C-OC 1-4 haloalkyl, -NR 1-4 R 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-O-C 1-4 alkyl, -O-phenyl, -L-aryl, -L-heteroaryl or -L-heterocyclic, where each is also optionally substituted with 1 - 3 R 6 substituents, and each L is independently -C≡C- or L is absent;

[0077] 3) R 1 is a substituted monocyclic substituted with at least one R selected from the following: 3 substituents:

[0078] 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)2NR 7 R 8 、-NR 7 C(O)R 8 、-C≡C-aryl, -C≡

[0079] C-heteroaryl or -C≡C-heterocyclic, where each is also optionally substituted with 1 - 3 R 6 substituents;

[0080] ii) a monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclic group, each of which is further substituted with 1 - 3 of the following groups: 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 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted with 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0082] iii) an optionally substituted fused aryl, optionally substituted fused heteroaryl or optionally substituted fused heterocyclic group, each of which is further optionally substituted with 1 - 3 R 6 substituents; or

[0083] iv) a substituent of the formula -L 1 -L 2 , where L 1 is an aryl, heteroaryl or heterocyclic group, each of which is optionally substituted with 1 - 3 R 6 substituents; and L 2 is a phenyl, heterocyclic group or heteroaryl, each of which is optionally substituted with 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl; or

[0084] 4) R 2 is -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl substituted with 1 - 3 R 1-6 substituents, cycloalkyl or heteroaryl optionally substituted with 1 - 3 R 5 substituents; and

[0085] In some embodiments, when A is CH, R 1 is not a 10 - membered heteroaryl substituted with methoxy and methyl; or R 1 is not a C6 aryl optionally substituted with 1 - 3 substituents independently selected from cyano, halogen, C 1-4 alkyl, -OR 7 , C 1-4 haloalkyl and NR 7 R 8 , where R 7 and R8 Each is independently hydrogen or C 1-4 alkyl; or R 1 is not unsubstituted C 10 aryl; or R 1 is not unsubstituted heterocyclic group.

[0086] On the one hand, a compound having the structure of Formula I is provided:

[0087]

[0088] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein

[0089] A is N or CH;

[0090] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group, each of which is optionally substituted by 1 - 3 R 3 substituents;

[0091] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted by 1 - 3 R 1-6 or heteroaryl optionally substituted by 1 - 3 R 5 substituents;

[0092] Each R 3 is independently cyano, halogen, -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-heterocyclic group, each of which is optionally substituted by 1 - 3 R 6 substituents, and each L is independently a bond or -C≡C-;

[0093] Each R 4 is independently halogen, hydroxy, -OC 1-6 alkyl, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or monocyclic heterocyclic group; each of which is optionally substituted by 1 - 3 R5 Substituted; provided that only one R 4 is a heterocyclic group;

[0094] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0095] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0096] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group.

[0097] In certain embodiments, when R 1 is phenyl, then R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 - 3 R 6 substituents.

[0098] In certain embodiments, when R 1 is heteroaryl, then R 2 is not unsubstituted C 1-6 alkyl.

[0099] In certain embodiments,

[0100] A is N or CH;

[0101] R 1is an alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group, each of which is optionally substituted by 1-3 R 3 substituted;

[0102] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 [[ID=1l]]alkyl optionally substituted by 1-3 R 1-6 or heteroaryl optionally substituted by 1-3 R 5 substituted;

[0103] Each R 3 is independently halogen, -L-C 1-9 alkyl, -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , -L-5-6 membered heteroaryl or -L-5-6 membered heterocyclic group, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently a bond or -C≡C-;

[0104] Each R 4 is independently halogen, hydroxy, -OC 1-6 alkyl, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or monocyclic heterocyclic group; each of which is optionally substituted by 1-3 R 5 substituted; provided that only one R 4 is a heterocyclic group;

[0105] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0106] Each R 6 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl; and

[0107] R 7 and R 8 are each independently hydrogen or C 1-4 alkyl, or R 7 and R8 Together with the nitrogen atom to which they are attached, form -(CH2)2-O-(CH2)2-.

[0108] There is also provided a compound of formula IIa:

[0109]

[0110] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein

[0111] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic, each of which is optionally substituted by 1 - 3 R 3 substituents;

[0112] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted by 1 - 3 R 1-6 substituents, or heteroaryl optionally substituted by 1 - 3 R 5 substituents;

[0113] Each R 3 is independently cyano, halogen, C 1-9 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, -NR 7 R 8 -C(O)NR 7 R 8 -S(O)2NR 7 R 8 -NR 7 C(O)R 8 -OR 7 , aryl, heteroaryl or heterocyclic, each of which is optionally substituted by 1 - 3 R 6 substituents, and each L is independently a bond or -C≡C-;

[0114] Each R 4 is independently halogen, hydroxy, -OC 1-6 alkyl, -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or monocyclic heterocyclic; each of which is optionally substituted by 1 - 3 R 5 substituents; provided that only one R 4 is heterocyclic;

[0115] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0116] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0117] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group.

[0118] In certain embodiments, there is provided a compound of formula IIa:

[0119]

[0120] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein

[0121] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group, each of which is optionally substituted by 1 - 3 R 3 ;

[0122] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted by 1 - 3 R 1-6 , cycloalkyl or heteroaryl optionally substituted by 1 - 3 R 5 ;

[0123] Each R 3 is independently cyano, halogen, -L-C1-9 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-heterocyclic group, each of which is optionally substituted by 1 - 3 R 6 substituents, and each L is independently -C≡C- or L is absent;

[0124] Each R 4 is independently halogen, 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 heterocyclic group; each of which is optionally substituted by 1 - 3 R 5 substituents; provided that only one R 4 is a heterocyclic group;

[0125] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0126] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4Alkyl, -C(O)OH or C 1-4 substituted with haloalkyl;

[0127] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0128] Each R a is independently optionally substituted with -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or -OP(O)(OR b )2 substituted C 1-6 alkyl;

[0129] Each R b is independently hydrogen or C 1-4 alkyl.

[0130] In some embodiments, for the compound of Formula IIa, at least one of the following holds:

[0131] 1) R 1 is a fused tricyclic optionally substituted with 1 - 3 R 3 ;

[0132] 2) R 1 is a fused bicyclic optionally substituted, which is substituted with at least one R 3 , R 3 selected from cyano, -C≡C-C 1-9 alkyl, -C substituted with 1 - 3 R 6 alkyl, -C≡C-C 1-9 haloalkyl, -C≡C-OC 1-4 haloalkyl, -NR 1-4 R 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-O-C 1-4 alkyl, -O-phenyl, -L-aryl, -L-heteroaryl or -L-heterocyclic group, each of which is also optionally substituted with 1 - 3 R 6 and each L is independently -C≡C- or L is absent;

[0133] 3) R 1is a substituted monocyclic ring, which is R selected from at least one of the following 3 Substituted:

[0134] 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)2NR 7 R 8 、-NR 7 C(O)R 8 、-C≡C-aryl, -C≡

[0135] C-heteroaryl or -C≡C-heterocyclic group, each of which is also optionally substituted by 1-3 R 6 Substituted;

[0136] ii) monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclic group, each of which is also substituted by 1-3 of the following groups: 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 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl substituted;

[0138] iii) optionally substituted fused aryl, optionally substituted fused heteroaryl or optionally substituted fused heterocyclic group, each of which is also optionally substituted by 1-3 R 6 Substituted; or

[0139] iv) a substituent of the formula -L 1 -L 2 wherein L 1 is aryl, heteroaryl or heterocyclic group, each of which is optionally substituted by 1-3 R 6 Substituted; and L 2 is phenyl, heterocyclic group or heteroaryl, each of which is optionally substituted by 1-3 C 1-4 alkyl, -C(O)OH or C 1-4Halogenoalkyl substitution; or

[0140] 4) R 2 is -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl, cycloalkyl or heteroaryl optionally substituted by 1 - 3 R 1-6 ; 5

[0141] There is also provided a compound of formula IIb:

[0142]

[0143] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein

[0144] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group, each of which is optionally substituted by 1 - 3 R 3 ;

[0145] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl, cycloalkyl or heteroaryl optionally substituted by 1 - 3 R 1-6 ; 5

[0146] Each R 3 is independently cyano, halogen, -L-C 1-9 alkyl, -L-C 1-4 halogenoalkyl, -L-OC 1-4 halogenoalkyl, -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-heterocyclic group, each of which is optionally substituted by 1 - 3 R 6 and each L is independently -C≡C- or L is absent;

[0147] Each R 4 is independently halogen, 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 a monocyclic heterocyclic group; each of which is optionally substituted by 1 - 3 R 5 ; provided that only one R 4 is a heterocyclic group;

[0148] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0149] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0150] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0151] Each R a is independently optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or -OP(O)(OR b )2 substituted C 1-6 alkyl;

[0152] Each R b is independently hydrogen or C 1-4 alkyl.

[0153] In some embodiments, for the compound of formula IIb, R 1 is not a 10-membered heteroaryl substituted with methoxy and methyl; or R 1 is not a C6 aryl optionally substituted with 1-3 substituents independently selected from cyano, halogen, C 1-4 alkyl, -OR 7 , C 1-4 haloalkyl, and NR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen or C 1-4 alkyl; or R 1 is not an unsubstituted C 10 aryl; or R 1 is not an unsubstituted heterocyclic group.

[0154] In certain embodiments, A is N. In certain embodiments, A is CH.

[0155] In certain embodiments, R 1 is an aryl optionally substituted with 1-3 R 3 substituents.

[0156] In certain embodiments, R 1 is a heteroaryl optionally substituted with 1-3 R 3 substituents.

[0157] In certain embodiments, R 1 is a heterocyclic group optionally substituted with 1-3 R 3 substituents.

[0158] In certain embodiments, R 1 is a cycloalkyl optionally substituted with 1-3 R 3 substituents.

[0159] In certain embodiments, R 1 is Each n is independently 1, 2, or 3, Y is CR 8 R 9 , C(O), O, or NR 10 ; R 8 and R 9 are each independently hydrogen, halogen, or C 1-4 alkyl; and R 10 is hydrogen or C 1-4 alkyl.

[0160] In certain embodiments, L is a bond (i.e., absent). In certain embodiments, L is -C≡C-.

[0161] In certain embodiments, R 8 and R 9 are each a halogen. In certain embodiments, R 8 and R 9 are each fluorine.

[0162] In certain embodiments, R 8 and R 9 are each hydrogen.

[0163] In certain embodiments, R 2 is hydrogen.

[0164] In certain embodiments, R 3 is a halogen, C 1-9 alkyl, C 1-4 haloalkyl, or -OR 7 .

[0165] In certain embodiments, at least one R 3 is a halogen, C 1-9 alkyl, or -OR 7 . In certain embodiments, R 3 is a halogen, C 1-9 alkyl, or -OR 7 .

[0166] In certain embodiments, at least one R 3 is fluorine, chlorine, bromine, methyl, tert-butyl, methoxy, or phenoxy. In certain embodiments, R 3 is fluorine, chlorine, bromine, methyl, tert-butyl, methoxy, or phenoxy.

[0167] In certain embodiments, R 3 is an aryl optionally substituted with 1-3 R 6 .

[0168] In certain embodiments, R 3 is

[0169] In certain embodiments, at least one R 3 is an aryl substituted with a phenyl, heterocyclic group, or heteroaryl. In certain embodiments, R 3 is an aryl substituted with a phenyl, heterocyclic group, or heteroaryl.

[0170] In certain embodiments, at least one R 3 is

[0171] In certain embodiments, R 3 is

[0172] In certain embodiments, at least one R 3 is an aryl substituted with a heteroaryl, the heteroaryl being substituted with C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl. In certain embodiments, R 3 is an aryl substituted with a heteroaryl, the heteroaryl being substituted with C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl.

[0173] In certain embodiments, at least one R 3 is

[0174] In certain embodiments, R 3 is

[0175] In certain embodiments, at least one R 3 is a heterocyclic group optionally substituted with 1-3 R 6 groups. In certain embodiments, R 3 is a heterocyclic group optionally substituted with 1-3 R 6 groups.

[0176] In certain embodiments, at least one R 3 is In certain embodiments, R 3 is

[0177] In certain embodiments, at least one R 3 is a heteroaryl optionally substituted with 1-3 R 6 groups. In certain embodiments, R 3 is a heteroaryl optionally substituted with 1-3 R 6 groups.

[0178] In certain embodiments, at least one R 3 is In certain embodiments, R 3 is

[0179] In certain embodiments, R 2 is hydrogen, C 4 optionally substituted with 1-3 R 1-6alkyl, or cycloalkyl; each R 4 is independently -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2 or a monocyclic heterocyclic group; provided that only one R 4 is a heterocyclic group; each R a is independently C b alkyl optionally substituted with -NH2 or -OP(O)(OR 1-6 )2; and R b is hydrogen. <>

[0180] In certain embodiments, provided herein are compounds of Formula III: <>

[0181] <> <> <>

[0182] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein: <>

[0183] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted with 1 - 3 R 1-6 groups, cycloalkyl or heteroaryl optionally substituted with 1 - 3 R 5 groups; <>

[0184] Each R 3 is independently aryl, heteroaryl or heterocyclic group, each of which is optionally substituted with 1 - 3 R 6 groups; <>

[0185] Each R 4 is independently halogen, 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 a monocyclic heterocyclic group; each of which is optionally substituted with 1 - 3 R 5 groups; provided that only one R 4 is a heterocyclic group; <>

[0186] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0187] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0188] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl, phenyl or pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0189] Each R a is independently C 1-6 alkyl optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C b alkyl)2 or -OP(O)(OR 1-6 )2; and

[0190] Each R b is independently hydrogen or C 1-4 alkyl.

[0191] In certain embodiments, provided herein are compounds of Formula IV:

[0192]

[0193] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein:

[0194] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted by 1 - 3 R 1-6 , cycloalkyl or C 5Substituted heteroaryl;

[0195] Each R 4 is independently halogen, 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 heterocyclic group; each of which is optionally substituted by 1 - 3 R 5 ; provided that only one R 4 is a heterocyclic group;

[0196] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0197] Each R a is independently C 1-6 alkyl optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C b alkyl)2 or -OP(O)(OR 1-6 )2; and

[0198] Each R b is independently hydrogen or C 1-4 alkyl.

[0199] In certain embodiments, R 2 is hydrogen, C 4 alkyl optionally substituted by 1 - 3 R 1-6 , or cycloalkyl. In certain embodiments, R 2 is hydrogen or C 4 alkyl optionally substituted by 1 - 3 R 1-6 . In certain embodiments, R 2 is hydrogen or C 4 alkyl optionally substituted by 1 R 1-6 . In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is C 4 alkyl optionally substituted by 1 - 3 R 1-6 . In certain embodiments, R 2 is C 1-6 alkyl. In certain embodiments, R 2 is C 1-4 alkyl.

[0200] In certain embodiments, R 2 is hydrogen, optionally C 4 alkyl substituted with 1 - 3 R 1-6 groups, or cycloalkyl; each R 4 is independently -OC 1-6 alkyl, -OC(O)R a group, -OC(O)OR a , -OP(O)(OR b )2 or monocyclic heterocyclic group; each R a is independently C b alkyl optionally substituted with -NH2 or -OP(O)(OR 1-6 )2; and R b is hydrogen.

[0201] In certain embodiments, each R 4 is independently -OC 1-6 alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2 or monocyclic heterocyclic group; wherein each R a is independently C b alkyl optionally substituted with -NH2 or -OP(O)(OR 1-6 )2, and R b is hydrogen.

[0202] In certain embodiments, each R 4 is independently -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2 or monocyclic heterocyclic group; wherein each R a is independently C b alkyl optionally substituted with -NH2 or -OP(O)(OR 1-6 )2, and R b is hydrogen.

[0203] In certain embodiments, there is provided a compound selected from those in Table 1 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof. In certain embodiments, the compound is selected from the compounds in Table 1:

[0204] Table 1

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216] In certain embodiments, there is provided a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. In certain embodiments, the compound is selected from:

[0217]

[0218] In certain embodiments, there is provided a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. In certain embodiments, the compound is selected from:

[0219]

[0220] wherein R 2 is as defined herein.

[0221] In certain embodiments, R 2 is C 4 alkyl optionally substituted with 1 - 3 R 1-6 In certain embodiments, R 2 is C 1-6 alkyl. In certain embodiments, R 2 is ethyl.

[0222] In certain embodiments, the compound is selected from:

[0223]

[0224]

[0225] Generally, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, it should be understood that other names may be used to identify compounds of the same structure. In particular, compounds may also be named using other naming systems and notations commonly recognized in the chemical art, including, for example, Chemical Abstracts 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.

[0226] In certain embodiments, provided are optical isomers, racemates, or other mixtures of the compounds described herein or pharmaceutically acceptable salts or mixtures thereof. In these cases, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be accomplished by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, such as using a chiral high performance liquid chromatography (HPLC) column.

[0227] Compositions provided herein that comprise the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof may include racemic mixtures, or mixtures containing an enantiomer in enantiomeric excess or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually listed.

[0228] In certain embodiments, also provided are 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. A "chelate" is formed by coordination of a compound with a metal ion at two (or more) points. A "non-covalent complex" is formed by the interaction of a compound with another molecule, wherein no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonds).

[0229] In certain embodiments, provided are prodrugs of the compounds described herein. A "prodrug" refers to any compound that, when administered to a biological system, gives rise to a drug or active ingredient due to spontaneous chemical reactions, enzyme-catalyzed chemical reactions, photolysis, and / or metabolic chemical reactions. Thus, a prodrug is a covalently modified analog or potential form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, diol moieties, and the like.

[0230] In certain embodiments, provided are compounds of Formula I or compounds of Formula IIa, wherein R 1 is

[0231]

[0232] where each R 12 is independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl or heterocyclic group; where any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1 - 4 Z 1b groups; and

[0233] each Z 1b is independently oxo, thioxo, hydroxy, halogen, -NO2, -N3, cyano, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, heterocyclic group, -O(C 1-9 alkyl), -O(C 2-6 alkenyl), -O(C 2-6 alkynyl), -O(C 3-15 cycloalkyl), -O(C 1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclic group), -NH2, -NH(C 1-9 alkyl), -NH(C 2-6 alkenyl), -NH(C 2-6 alkynyl), -NH(C 3-15 cycloalkyl), -NH(C 1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclic group), -N(C 1-9 alkyl)2, -N(C 3-15 cycloalkyl)2, -N(C 2-6 alkenyl)2, -N(C 2-6 alkynyl)2, -N(C 3-15 cycloalkyl)2, -N(C 1-8 haloalkyl)2, -N(aryl)2, -N(heteroaryl)2, -N(heterocyclic group)2, -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 2-6 alkenyl), -N(C 1-9 alkyl)(C 2-6 alkynyl), -N(C 1-9 alkyl)(C 3-15 cycloalkyl), -N(C 1-9 alkyl)(C 1-8 haloalkyl), -N(C 1-9(alkyl)(aryl), -N(C 1-9 (alkyl)(heteroaryl), -N(C 1-9 (alkyl)(heterocyclic), -C(O)(C 1-9 (alkyl), -C(O)(C 2-6 (alkenyl), -C(O)(C 2-6 (alkynyl), -C(O)(C 3-15 (cycloalkyl), -C(O)(C 1-8 (haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclic), -C(O)O(C 1-9 (alkyl), -C(O)O(C 2-6 (alkenyl), -C(O)O(C 2-6 (alkynyl), -C(O)O(C 3-15 (cycloalkyl), -C(O)O(C 1-8 (haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclic), -C(O)NH2, -C(O)NH(C 1-9 (alkyl), -C(O)NH(C 2-6 (alkenyl), -C(O)NH(C 2-6 (alkynyl), -C(O)NH(C 3-15 (cycloalkyl), -C(O)NH(C 1-8 (haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O)NH(heterocyclic), -C(O)N(C 1-9 (alkyl)2, -C(O)N(C 3-15 (cycloalkyl)2, -C(O)N(C 2-6 (alkenyl)2, -C(O)N(C 2-6 (alkynyl)2, -C(O)N(C 3-15 (cycloalkyl)2, -C(O)N(C 1-8 (haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclic)2, -NHC(O)(C 1-9 (alkyl), -NHC(O)(C 2-6 (alkenyl), -NHC(O)(C 2-6 (alkynyl), -NHC(O)(C 3-15 (cycloalkyl), -NHC(O)(C 1-8 (haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclic), -NHC(O)O(C 1-9 (alkyl), -NHC(O)O(C 2-6 (alkenyl), -NHC(O)O(C2-6 (alkynyl), -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(heterocyclic group), -NHC(O)NH(C 1-9 (alkyl), -NHC(O)NH(C 2-6 (alkenyl), -NHC(O)NH(C 2-6 (alkynyl), -NHC(O)NH(C 3-15 (cycloalkyl), -NHC(O)NH(C 1-8 (haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclic group), -SH, -S(C 1-9 (alkyl), -S(C 2-6 (alkenyl), -S(C 2-6 (alkynyl), -S(C 3-15 (cycloalkyl), -S(C 1-8 (haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclic group), -NHS(O)(C 1-9 (alkyl), -N(C 1-9 (alkyl)(S(O)(C 1-9 (alkyl), -S(O)N(C 1-9 (alkyl)2, -S(O)(C 1-9 (alkyl), -S(O)(NH)(C 1-9 (alkyl), -S(O)(C 2-6 (alkenyl), -S(O)(C 2-6 (alkynyl), -S(O)(C 3-15 (cycloalkyl), -S(O)(C 1-8 (haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclic group), -S(O)2(C 1-9 (alkyl), -S(O)2(C 2-6 (alkenyl), -S(O)2(C 2-6 (alkynyl), -S(O)2(C 3-15 (cycloalkyl), -S(O)2(C 1-8 (haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclic group), -S(O)2NH(C 1-9 (alkyl) or -S(O)2N(C 1-9 (alkyl)2;

[0234] wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1-4 of the following groups: halogen, C1-9 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(heterocyclic), -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)(heterocyclic), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 2-6 alkynyl), -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(heterocyclic), -NHC(O)NH(C 1-9 alkyl), -S(O)(NH)(C 1-9 alkyl), -S(O)2(C 1-9 alkyl), -S(O)2(C 3-15 cycloalkyl), -S(O)2(C 1-8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclic), -S(O)2NH(C 1-9 alkyl), -S(O)2N(C 1-9 alkyl)2, -O(C 3-15 cycloalkyl), -O(C 1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclic) or O(C 1-9 alkyl).

[0235] In certain embodiments, there is provided a compound of formula I or any of the sub-formulas provided herein, wherein R 2 is

[0236] Such substituents also include all individual stereoisomers and mixtures thereof, including but not limited to chirality at a phosphorus atom, such as in the exemplary moieties shown above.

[0237] The present invention also provides in vivo metabolites of the compounds described herein. These products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compound, mainly due to enzymatic processes.

[0238] Therapeutic uses of the compounds

[0239] "Treatment" or "treating" is a method of obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and / or alleviating the degree of the disease or disorder); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder, and / or preventing or delaying the spread of the disease or disorder (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing the clinical symptoms to subside (e.g., improving the disease state, providing partial or complete remission of the disease or disorder, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or prolonging the survival time).

[0240] "Prevention" or "preventing" refers to any treatment of a disease or disorder such that the clinical symptoms of the disease or disorder do not develop. In some embodiments, the compounds can be administered to a subject (including a human) at risk of a disease or disorder or having a family history of a disease or disorder. Primary hyperoxaluria type 1 can lead to the need for a kidney transplant. Remission is likely after transplantation. In certain embodiments, the compounds disclosed herein are administered to a patient after transplantation to prevent remission.

[0241] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein can be used for human treatment and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0242] The "therapeutically effective amount" or "effective amount" of the compounds described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof, refers to an amount that is sufficient to effect treatment when administered to a subject to provide a therapeutic benefit (e.g., improvement of symptoms or slowing of disease progression). For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or disorder responsive to inhibition of glycolic acid oxidase activity. The therapeutically effective amount can vary depending on the subject, the disease or disorder being treated, the weight and age of the subject, the severity of the disease or disorder, and the mode of administration, which can be readily determined by one of ordinary skill in the art.

[0243] The term "inhibition" means a decrease in the baseline activity of a biological activity or process. "Inhibiting the activity of glycolate oxidase" or variants thereof means a decrease in the activity of glycolate oxidase as a direct or indirect response to the presence of the compounds of the present application, relative to the activity of glycolate oxidase in the absence of the compounds of the present application. "Inhibiting glycolate oxidase" means a decrease in the activity of glycolate oxidase as a direct or indirect response to the presence of the compounds described herein, relative to the activity of glycolate oxidase in the absence of the compounds described herein. In some embodiments, the inhibition of glycolate oxidase activity can be compared in the same subject before treatment or in other untreated subjects.

[0244] The methods described herein can be applied to cell populations in vivo or in vitro. "In vivo" means within a living organism, such as in an animal or human. In this context, the methods described herein can be used therapeutically in an individual. "In vitro" means outside of a living organism. Examples of in vitro cell populations include cell cultures in vitro and biological samples, including fluid or tissue samples obtained from an individual. These samples can 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 biopsy samples. In this context, the compounds and compositions described herein can be used for various purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used in vitro to determine the optimal regimen and / or dose for administering a glycolate oxidase inhibitor for a given indication, cell type, individual, and other parameters. Information collected from such uses can be used for experimental purposes or clinically to develop in vivo treatment regimens. Other in vitro uses for which the compounds and compositions described herein may be suitable are described hereinafter or will be apparent to those skilled in the art. The selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. These properties can be examined using methods well known to those skilled in the art.

[0245] The compounds disclosed herein can be used to treat, prevent, diagnose, or monitor diseases or disorders mediated by glycolate oxidase. Non-limiting examples of diseases or disorders mediated by glycolate oxidase include, but are not limited to, nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, primary hyperoxaluria type 1, hyperoxaluria, glycolic aciduria, end-stage renal disease (ESRD), renal failure, renal transplant failure, and type II diabetes.

[0246] In certain embodiments, the compounds disclosed herein can be used to treat, prevent, diagnose, or monitor diseases or disorders mediated by oxalate or calcium oxalate or glycolate oxidase. In some embodiments, the disease or disorder is nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, primary hyperoxaluria type 1, hyperoxaluria, glycolic aciduria, end-stage renal disease (ESRD), renal failure, renal transplant failure, and type II diabetes.

[0247] In further embodiments, methods of alleviating the symptoms of a disease or disorder mediated by glycolate oxidase are provided. In some embodiments, the method includes identifying a mammal having symptoms of a disease or disorder mediated by glycolate oxidase and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., reduce the severity of) the symptoms.

[0248] In further embodiments, methods of alleviating the symptoms of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase are provided. In some embodiments, the method includes identifying a mammal having symptoms of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase and providing to the mammal an amount of a compound as described herein effective to ameliorate (i.e., reduce the severity of) the symptoms.

[0249] In some embodiments, the disease or disorder mediated by glycolate oxidase is kidney stone formation. In some embodiments, the disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase is kidney stone formation. In certain embodiments, the kidney stone formation is recurrent. In certain embodiments, the kidney stone formation is associated with primary hyperoxaluria type 1.

[0250] In some embodiments, the disease or disorder mediated by glycolate oxidase is renal failure, including failure of a single kidney and failure of both kidneys. In some embodiments, the disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase is renal failure. In some embodiments, the renal failure is failure of a single kidney or both kidneys.

[0251] In some embodiments, the disease or disorder to be prevented is renal transplant failure.

[0252] In some embodiments, the disease or disorder mediated by glycolate oxidase is diabetes, including type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glucose, and impaired glucose tolerance. In some embodiments, the disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase is diabetes. In some embodiments, the diabetes is type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glucose, or impaired glucose tolerance. Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM). Type 2 diabetes is also known as non-insulin-dependent diabetes mellitus (NIDDM).

[0253] In some embodiments, the disease or disorder mediated by glycolate oxidase is bladder stone formation. In some embodiments, the disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase is bladder stone formation.

[0254] 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. The oxalate and calcium content in urine can be monitored.

[0255] The presently disclosed methods of treatment can also be applied at any point during the disease process. In certain embodiments, the method is applied to subjects with primary hyperoxaluria type 1 during a remission period (i.e., non-active disease, after renal transplantation). In such embodiments, the methods of the invention provide a benefit by prolonging the remission period (e.g., prolonging the non-active disease period) or by preventing, reducing, or delaying the onset of active disease. An example is an increase in the interval between kidney stone events. In other embodiments, the method can be applied to subjects with primary hyperoxaluria type 1 during an active disease period. Such methods provide a benefit by shortening the duration of the active disease period, alleviating or improving one or more symptoms of primary hyperoxaluria type 1, or treating primary hyperoxaluria type 1. Such improvement can be a reduction in the size, number, or frequency of kidney stones.

[0256] Measurements for determining the treatment efficacy of primary hyperoxaluria type 1 in clinical practice have been described and include, for example: symptom control; calcium oxalate concentration in body fluids; renal function determination; and improvement in quality of life.

[0257] In certain embodiments, provided herein is a method of treating primary hyperoxaluria type 1, comprising administering to a patient in need a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein or a compound of formula I:

[0258]

[0259] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein

[0260] A is N or CH;

[0261] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group, each of which is optionally substituted by 1 - 3 R 3 substituents;

[0262] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted by 1 - 3 R 1-6 substituents, cycloalkyl or heteroaryl optionally substituted by 1 - 3 R 5 substituents;

[0263] Each R 3 is independently cyano, halogen, -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-heterocyclic group, each of which is optionally substituted by 1 - 3 R 6 substituents, and each L is independently -C≡C- or L is absent;

[0264] Each R 4 is independently halogen, 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 heterocyclic group; each of which is optionally substituted by 1 - 3 R 5 substituents; provided that only one R 4 is a heterocyclic group;

[0265] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C1-4 haloalkyl or -OC 1-4 haloalkyl;

[0266] each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0267] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0268] each R a is independently C 1-6 alkyl optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C b alkyl)2 or -OP(O)(OR 1-6 )2; and

[0269] each R b is independently hydrogen or C 1-4 alkyl.

[0270] In certain embodiments, when R 1 is phenyl, then R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 - 3 R 6 ; and when R 1 is heteroaryl, then R 2 is not unsubstituted C 1-6 alkyl.

[0271] In certain embodiments, provided herein is a method of treating recurrent kidney stone formers, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, a pharmaceutical composition described herein, or a compound of Formula I:

[0272]

[0273] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein

[0274] A is N or CH;

[0275] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, each of which is optionally substituted with 1 - 3 R 3 substituents;

[0276] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted with 1 - 3 R 1-6 substituents, cycloalkyl, or heteroaryl optionally substituted with 1 - 3 R 5 substituents;

[0277] Each R 3 is independently cyano, halogen, -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-heterocycloalkyl, each of which is optionally substituted with 1 - 3 R 6 substituents, and each L is independently -C≡C- or L is absent;

[0278] Each R 4 is independently halogen, 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 heterocycloalkyl; each of which is optionally substituted with 1 - 3 R5 Substituted; provided that only one R 4 is a heterocyclic group;

[0279] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0280] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0281] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0282] Each R a is independently optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or -OP(O)(OR b )2-substituted C 1-6 alkyl; and

[0283] Each R b is independently hydrogen or C 1-4 alkyl.

[0284] In certain embodiments, when R 1 is phenyl, then R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 - 3 R 6 ; and when R 1When it is a heteroaryl, then R 2 is not unsubstituted C 1-6 alkyl.

[0285] In certain embodiments, provided herein are methods of inhibiting glyoxylate and / or oxalate production and / or inhibiting glycolate oxidase (GO), comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, a pharmaceutical composition described herein, or a compound of formula I:

[0286]

[0287] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, wherein

[0288] A is N or CH;

[0289] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic, each of which is optionally substituted by 1-3 R 3 substituents;

[0290] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted by 1-3 R 1-6 substituents, cycloalkyl, or heteroaryl optionally substituted by 1-3 R 5 substituents;

[0291] Each R 3 is independently cyano, halogen, -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-heterocyclic, each of which is optionally substituted by 1-3 R 6 substituents, and each L is independently -C≡C- or L is absent;

[0292] Each R 4 is independently halogen, 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 a monocyclic heterocyclic group; each of which is optionally substituted by 1 - 3 R 5 ; provided that only one R 4 is a heterocyclic group;

[0293] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0294] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic group or heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0295] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0296] Each R a is independently C 1-6 alkyl optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C b )2 or -OP(O)(OR 1-6 )2; and

[0297] Each R b is independently hydrogen or C 1-4 alkyl.

[0298] In some embodiments, when R 1 is phenyl, then R 3 is aryl or heteroaryl, each optionally substituted with 1 - 3 R 6 ; and when R 1 is heteroaryl, then R 2 is not unsubstituted C 1-6 alkyl.

[0299] In certain embodiments, the use of the compounds described herein or the pharmaceutical compositions described herein is to control or inhibit the production of recurrent nephrolithiasis formers in a patient in need thereof.

[0300] In certain embodiments, the use of a compound of formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof is to control or inhibit the production of recurrent nephrolithiasis formers in a patient in need thereof, wherein the compound of formula I:

[0301]

[0302] A is N or CH;

[0303] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclic group, each optionally substituted with 1 - 3 R 3 ;

[0304] R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl optionally substituted with 1 - 3 R 1-6 , cycloalkyl or heteroaryl optionally substituted with 1 - 3 R 5 ;

[0305] Each R 3 is independently cyano, halogen, -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-heterocyclic group, each optionally substituted with 1 - 3 R 6 and each L is independently -C≡C- or L is absent;

[0306] Each R 4 is independently halogen, 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 a monocyclic heterocyclic group; each of which is optionally substituted by 1 - 3 R 5 ; provided that only one R 4 is a heterocyclic group;

[0307] Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl or -OC 1-4 haloalkyl;

[0308] Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, a heterocyclic group or a heteroaryl; each of which is optionally substituted by 1 - 3 C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl;

[0309] R 7 and R 8 are each independently hydrogen, C 1-4 alkyl or phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which they are attached form a heterocyclic group;

[0310] Each R a is independently C optionally substituted by -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or -OP(O)(OR b )2 substituted1-6 alkyl; and

[0311] each R b is independently hydrogen or C 1-4 alkyl;

[0312] when R 1 is phenyl, then R 3 is aryl or heteroaryl, each of which is optionally substituted with 1 - 3 R 6 substituents; and when R 1 is heteroaryl, then R 2 is not unsubstituted C 1-6 alkyl.

[0313] Combination therapy

[0314] In one embodiment, the compounds disclosed herein can be used in combination with one or more additional therapeutic agents or interventions that are currently in use and / or being developed for the treatment of primary hyperoxaluria type 1. Examples of such therapeutic agents are calcium oxalate crystal inhibitors, oxalate - degrading enzyme inhibitors, siRNA, oxazyme, and lumasiran. Examples of such therapeutic interventions are high fluid intake, dialysis, and kidney transplantation.

[0315] In some embodiments, the compounds disclosed herein can be used in combination with SGLT2 inhibitors. Non - limiting examples of SGL 2 inhibitors include dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, empagliflozin, and potassium citrate.

[0316] In some embodiments, the methods described herein further include administering an additional therapeutic agent. In some embodiments, uses in combination with an additional therapeutic agent as described herein are provided. In some embodiments, the additional therapeutic agent is a calcium oxalate crystal inhibitor, an oxalate-degrading enzyme inhibitor, an SiRNA, oxazyme, lumasiran, nedosiran, oxa bate, or reloxaliase. In some embodiments, the additional therapeutic agent is an SGLT2 inhibitor. In some embodiments, the SGL2 inhibitor is dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, ipragliflozi n, empagliflozin, or potassium citrate.

[0317] Kit

[0318] Also provided herein is a kit that includes a compound of Formula I (or any other formula described herein) or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterated analogue thereof, and a suitable package. In one embodiment, the kit further includes instructions for use. In one aspect, the kit includes a compound of Formula I (or any other formula described herein) or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterated analogue thereof, and a label and / or instructions for treating an indication (including a disease or disorder) described herein using the compound.

[0319] Also provided herein is an article of manufacture that includes a compound described herein or a pharmaceutically acceptable salt, tautomer, prodrug, or deuterated analogue thereof in a suitable container. The container can be a vial, jar, ampule, prefilled syringe, and intravenous bag.

[0320] Pharmaceutical Compositions and Modes of Administration

[0321] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, the present invention also provides pharmaceutical compositions comprising one or more of the compounds described herein or pharmaceutically acceptable salts, tautomers, prodrugs or deuterated analogs thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants. These compositions are prepared in a manner 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. (G.S. Banker & C.T. Rhodes, Eds.).

[0322] The pharmaceutical compositions can be administered in single or multiple doses. The pharmaceutical compositions can be administered by a variety of methods including, for example, rectal, oral, intranasal and transdermal routes. In certain embodiments, the pharmaceutical compositions can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or as an inhalant.

[0323] One mode of administration is parenteral administration, such as by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oleaginous suspensions or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, and elixirs, mannitol, dextrose or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0324] Oral administration can be another route of administration of the compounds described herein. The administration can be, for example, by capsules or enteric-coated tablets. In preparing a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analogue thereof, the active ingredient is usually diluted with excipients and / or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material, as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments e.g. containing up to 10 wt% of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0325] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents.

[0326] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, prodrug or deuterated analogue thereof can be formulated so as to provide for rapid, sustained or delayed release of the active ingredient after administration to a subject by procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing a reservoir or a drug-polymer matrix formulation with a polymeric coating. Examples of controlled-release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in a controlled amount. The construction and use of transdermal patches for delivering agents are well known in the art. Such patches can be configured for continuous, pulsatile or on-demand delivery of the agent.

[0327] To prepare solid compositions such as tablets, the primary active ingredient can be mixed with pharmaceutical excipients to form a solid preformulation composition that contains a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogue thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition such that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0328] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form with the advantage of extended action or to protect them from the effects of gastric acid conditions. For example, a tablet or pill can include an inner dosage component and an outer dosage component, the latter being in an encapsulated form over the former. These two components can be separated by an enteric layer that is used to resist disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to be released in a delayed manner. A variety of materials can be used for such enteric layers or coatings, and such materials include a variety of polymeric acids and mixtures of polymeric acids with such materials (such as shellac, cetyl alcohol, and cellulose acetate).

[0329] Compositions for inhalation or insufflation can include solutions and suspensions, as well as powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered by the oral or nasal respiratory route to achieve a local or systemic effect. In other embodiments, the composition in a pharmaceutically acceptable solvent can be atomized by using an inert gas. The atomized solution can be inhaled directly from the atomizing device, or the atomizing device can be connected to a face mask tent or an intermittent positive pressure breathing machine. The solution, suspension, or powder composition can be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.

[0330] Dosage

[0331] For any particular subject, the specific dosage level of the compounds of the present application will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, route of administration and rate of excretion, drug combination, and the severity of the particular disease being treated in the subject. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). A dosage between about 0.1 and 150 mg / kg may be suitable. In some embodiments, a dosage between about 0.1 and 100 mg / kg may be suitable. In other embodiments, a dosage between 0.5 and 60 mg / kg may be suitable. Normalization according to the subject's body weight is particularly useful when adjusting dosages between individuals of widely differing sizes, such as when using a drug in children and adults, or when converting an effective dosage in a non-human subject (e.g., a dog) to a dosage suitable for a human subject.

[0332] The daily dosage can also be described as a unit dosage or the total amount of the compound described herein administered per day. The daily dosage of the compound of Formula I can be between about 1 mg - 4,000 mg, between about 2,000 - 4,000 mg / day, between about 1 - 2,000 mg / day, between about 1 - 1,000 mg / day, between about 10 - 500 mg / day, between about 20 - 500 mg / day, between about 50 - 300 mg / day, between about 75 - 200 mg / day, or between about 15 - 150 mg / day.

[0333] When administered orally, the total daily dosage for a human subject can be between 1 mg - 1,000 mg, between about 1,000 - 2,000 mg / day, between about 10 - 500 mg / day, between about 50 - 300 mg / day, between about 75 - 200 mg / day, or between about 100 - 150 mg / day.

[0334] The compounds or their compositions of the present application can be administered once, twice, three times, or four times a day using any of the above suitable means. In addition, the administration or treatment with the compound can continue for several days; for example, for one treatment cycle, the treatment typically continues for at least 7 days, 14 days, or 28 days. Treatment cycles are well known in cancer chemotherapy and treatment cycles are often alternated with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. In other embodiments, the treatment cycle can also be continuous.

[0335] In a particular embodiment, the method includes administering an initial daily dosage of about 1 to 800 mg of the compound described herein to a subject and increasing the dosage in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dosage. The dosage can be increased daily, every other day, twice a week, or once a week.

[0336] Synthesis of Compounds of Formula I

[0337] The compounds can be prepared using the methods disclosed herein and their conventional modifications, which will be apparent in view of the disclosure herein and methods known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can be used. The synthesis of the exemplary compounds described herein can be accomplished as described in the following examples. If available, the reagents can be obtained from, for example, Sigma Aldrich or other chemical suppliers.

[0338] General Synthesis

[0339] Exemplary embodiments of the compounds described herein can be synthesized using the following general reaction scheme. In view of the description herein, it will be apparent that the general scheme can be varied by substituting other materials having similar structures for the starting materials to obtain correspondingly different products. The following description of the synthesis provides many examples of how the starting materials can be varied to provide the corresponding products. Given the desired product defining the substituents, the necessary starting materials can generally be determined by inspection. The starting materials are generally obtained from commercial sources or synthesized using published methods. For synthesizing the compounds of the embodiments described in the present disclosure, examining the structure of the compound to be synthesized will provide the identity of each substituent. In view of the examples herein, the identity of the final product will generally show the identity of the necessary starting materials by simple inspection methods. Generally, the compounds described herein are usually stable and separable at room temperature and room pressure.

[0340] Synthesis Reaction Parameters

[0341] The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions can also be used unless otherwise specified. The optimal reaction conditions can vary with the specific reactants or solvents used, but these conditions can be determined by those skilled in the art through routine optimization procedures.

[0342] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent unwanted reactions of certain functional groups. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in T.W. Greene and G.M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York and the references cited therein.

[0343] The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemice or Sigma (St. Louis, Missouri, USA). Others can be prepared by methods described in standard reference works or obvious modifications thereof, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0344] The term "solvent" generally refers to a solvent that is inert under the reaction conditions described in conjunction with it (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, etc.). Unless otherwise stated, the solvent is an inert organic solvent and the reaction can be carried out under an inert gas, preferably argon or nitrogen.

[0345] The term "q.s." means that an amount sufficient to effect the stated function is added, for example, to bring a solution to the desired volume (i.e., 100%).

[0346] In Scheme 1, A, R 1 、R 2 、R 3 and R 6As defined herein, each X is independently a halogen (e.g., chlorine, bromine or iodine), and each R 50 is independently an alkyl or two Rs 50 together form a ring (e.g., 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolane), and PG is a protecting group bonded to a heteroatom.

[0347] Scheme 1

[0348]

[0349] In Scheme 1, the compound of formula I is prepared by coupling a suitably protected compound 100' with the corresponding boric acid or ester 200 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.), followed by deprotection. As shown in Scheme 1, the compound 300 for preparing the compound of formula I is also prepared by coupling a suitably protected compound 400 with the corresponding halo - compound 500 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.). The compound 400 is prepared by coupling a suitably protected compound 100' with the corresponding boric acid or ester 600 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.). The various compounds of formula 100', 200, 500 and 600 used in the methods provided herein are commercially available or can be synthesized by known methods.

[0350] In some embodiments, the compound 300 in which R 2 is hydrogen can be esterified under standard coupling conditions to form the compound 300 in which R 2 is as defined herein (e.g., -(CH2CH2O) 1-9 CH2CH2OCH3, optionally substituted C 4 alkyl, cycloalkyl, or heteroaryl optionally substituted by 1 - 3 Rs 1-6 5 5 substituted).

[0351] Examples

[0352] The following examples are included to illustrate specific embodiments of the present disclosure. Those skilled in the art should understand that the techniques disclosed in the following examples represent techniques that work well in the practice of the present disclosure and thus can be considered to constitute specific modes of its practice. However, based on the present disclosure, those skilled in the art should understand that many changes can be made to the disclosed specific embodiments without departing from the spirit and scope of the invention and still obtain the same or similar results.

[0353] Synthesis of Intermediates 3, 4 and 6 (and their methyl esters 3', 4' and 6')

[0354]

[0355] Step 1

[0356] At 0 °C, a solution of trifluoromethanesulfonic anhydride (375 mL, 2.25 mol) in hexane (900 mL) was slowly added to a mixture of sodium azide (150.0 g, 2.25 mol) and tetrabutylammonium hydrogensulfate (41.9 g, 123 mmol) in water (2.3 L). After stirring the resulting mixture at 0 °C for 1 h, the organic-soluble material was extracted with hexane (1.8 L), dried over sodium hydroxide pellets and decanted. To this solution was added a solution of ethyl 2-cyanoacetate, 1 (150.0 g, 0.8 mol) in acetonitrile (1.1 L) and pyridine (300 mL, 4.0 mol). The resulting mixture was stirred at room temperature for 2 days and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of ethyl acetate (1:6), to give impure ethyl 2-cyano-2-diazoacetate, 2 (111 g, 99%).

[0357] Step 2

[0358] Hydrogen bromide gas was bubbled through a solution of ethyl 2-cyano-2-diazoacetate, 2 (111 g, 795 mmol) in dioxane (7 L) at 0 °C for 3 h. The reaction mixture was concentrated under reduced pressure to give 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.

[0359] Step 3

[0360] At 0 °C, sodium hydride (60%, 10.1 g, 275 mmol) was added to a solution of crude ethyl 4-bromo-1H-1,2,3-triazole-5-carboxylate, 3 (50 g, 227 mmol) in DMF (500 mL) and the mixture was stirred under N2 for 30 min, then 2-(trimethylsilyl)ethoxymethyl chloride (40.5 g, 238 mmol) was added at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was quenched with 5% 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, eluting with a hexane solution of ethyl acetate (2:5), to give a mixture of isomers of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4, 30 g, 38%) as a colorless oil: ES / MS m / z: C 11 H 20 BrN3NaO3Si (M+Na + ) calculated: 372.04, found: 372.15.

[0361] In a manner similar to the above method, a mixture of isomers of methyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (4') was prepared from commercially available methyl 4-bromo-1H-1,2,3-triazole-5-carboxylate (3') as an oily substance: ES / MS m / z: C 10 H 19 BrN3NaO3Si (M+Na) calculated: 337.27, found: 336.53.

[0362] Step 4

[0363] To a solution of 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 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (5, 85.0 g, 257 mmol) in 1,4-dioxane (800 mL) was added aqueous 2.0 M sodium carbonate solution (193 mL, 386 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.45 g, 12.9 mmol). The reaction mixture was stirred at 70 °C under a N2 atmosphere for 4 h. After cooling the reaction mixture to room temperature and diluting with water, the product was extracted with ethyl acetate (3 × 1 L). The organic fractions were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of ethyl acetate (1:30), to give 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, 25.5 g, 43%) as an oily substance: ES / MS m / z: C 23 H 36 BN3NaO5Si (M+Na) calculated: 496.44, found: 496.45.

[0364] Synthesis of Intermediate 8

[0365]

[0366] Step 1

[0367] To a solution of 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) in 1,4-dioxane (500 mL) was added 2.0 M aqueous Na2CO3 solution (106 mL, 215.9 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.2 g, 7.1 mmol). The reaction mixture was stirred overnight at 70 °C under a N2 atmosphere. After the reaction mixture was cooled to room temperature and diluted with water, the product was extracted with ethyl acetate (3 × 500 mL). The organic fractions were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of ethyl acetate (1:30), to give a mixture of isomers 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 (8, 11.5 g, 29%) as an oil: ES / MS m / z: C 29 H 41 BN3O5Si (M+H) calcd: 550.29, found: 550.45.

[0368] Synthesis of Intermediate 10

[0369]

[0370] Step 1

[0371] To a solution of 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) in 1,4-dioxane (3 mL) was added tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.076 mmol) and 2.0 M aqueous Na2CO3 solution (1.13 mL). After purging the mixture with argon for 10 minutes, the reaction mixture was stirred at 110 °C for 40 minutes. After cooling the reaction mixture to room temperature, it was diluted with saturated NaHCO3, the product was extracted with ethyl acetate, washed, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a hexane solution of 1%-100% ethyl acetate, to give a mixture of isomers of ethyl 5-(4'-bromo-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (10, 380 mg, 83%) as an oil.

[0372] Synthesis of Intermediate 11 and Intermediate 12

[0373]

[0374] Step 1

[0375] A mixture of isomers of ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (11, 27 g, 49%) as an oil was prepared in a manner similar to the method for the mixture of isomers of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (3), using 4-methoxybenzyl chloride instead of 2-(trimethylsilyl)ethoxymethyl chloride, but the reaction was carried out at room temperature for 8 hours: ES / MS m / z: C 13 H 14 BrN3NaO3 (M+H) calculated: 362.01, found: 362.05.

[0376] Step 2

[0377] In a manner similar to the method for the isomer mixture 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), an isomer mixture of ethyl 2-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole-4-carboxylate (12) was prepared as an oil.

[0378] Synthesis of Intermediate 13

[0379]

[0380] Step 1

[0381] An isomer mixture of 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, 10.5 g, 26%) was prepared as an oil in a manner similar to the method for the isomeric mixture 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 (8): ES / MS m / z: C 31 H 35 BN3O5(M+H) Calcd: 540.27, Found: 540.55.

[0382] Synthesis of Intermediates 15 and 16

[0383]

[0384] Step 1

[0385] 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) in a manner similar to the method for preparing Intermediate 4: 1 H NMR (400 MHz, chloroform-d) δ 7.56 (s, 1H), 5.81 (s, 2H), 3.96 (s, 3H), 3.54 (t, J = 8.0 Hz, 2H), 0.88 (t, J = 8.0 Hz, 2H), 0.04 (s, 9H). ES / MS m / z: C 11 H20 Calculated for BrN2O3Si(M+H): 335.04, molecular weight not detected.

[0386] Step 2

[0387] Using potassium carbonate instead of sodium carbonate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-

[0388] ((trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-

[0389] carboxylic acid methyl ester (16, 5.83 g, 38%) was obtained as an oil, except that the reaction was carried out at 110 °C overnight: 1 H NMR (400 MHz, chloroform-d) δ 7.82 (d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 5.85 (s, 2H), 3.77 (s, 3H), 3.60 (t, J = 7.2 Hz, 2H), 1.32 (s, 12H), 0.89 (t, J = 7.2 Hz, 2H), 0.04 (s, 9H). ES / MS m / z: C 23 H 36 Calculated for HBN2O5Si(M+H): 459.25, molecular weight not detected.

[0390] Synthesis of Intermediate 18

[0391]

[0392] 3-Bromo-1H-pyrazole-4-carboxylic acid ethyl ester (18, 511 mg, 96%) was prepared as an oil, as a mixture of two regioisomers, in a similar manner to the preparation of Intermediate 15 from ethyl 3-bromo-1H-pyrazole-4-carboxylate (17, 335 mg, 1.53 mmol): ES / MS m / z: C 12 H 22 Calculated for BrN2O3Si(M+H): 349.06, found: 348.46.

[0393] Synthesis of Intermediate 20

[0394]

[0395] In a manner similar to the method for preparing Intermediate 15, methyl 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylate (20, 690 mg, 77%) was prepared from methyl 4-bromo-1H-imidazole-5-carboxylate (19, 335 mg, 1.53 mmol) as an oil, as a mixture of two regioisomers: ES / MS m / z: C 12 H 22 BrN2O3Si (M+H) Calcd: 335.04, Found: 334.86.

[0396] Representative procedure for the Suzuki reaction

[0397]

[0398] Into a 5 mL microwave vial was added 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). After purging with argon for 5 minutes, the resulting mixture was stirred at 110 °C for 1 h. After cooling, the reaction mixture was diluted with saturated NaHCO3, and then the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate to afford 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 N3O3Si (M+H) Calcd: 348.17, Found: 347.58.

[0399] Representative procedure for SEM deprotection by HCl

[0400]

[0401] 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) was added 3N HCl (0.21 mL), and the resulting mixture was stirred at 80 °C for 2 h and then at 50 °C overnight. The resulting reaction mixture was concentrated to give crude methyl 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylate (19): ES / MS m / z: C 11 H 10 N3O2 (M-H) Calcd: 216.08, Found: 216.15.

[0402] Representative procedure for SEM deprotection by TBAF

[0403]

[0404] 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 to 60 °C for 3 h. After cooling, the reaction mixture was diluted with saturated NaHCO3, and the product was then extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate to give 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 N4O5 (M+H) Calcd: 443.49, Found: 443.16.

[0405] Representative procedure for PMB deprotection by TFA

[0406]

[0407] 1-(4-Methoxybenzyl)-4-(4'-(5-methyl-1,3,4-thiadiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-

[0408] Ethyl 4-(4'-(5-methyl-1,3,4-thiadiazol-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 to 40 °C for 80 minutes. After cooling, the reaction mixture was concentrated, diluted with saturated NaHCO3, and the product was then extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with hexane solution of ethyl acetate and ethyl acetate solution of 10% methanol to obtain ethyl 4-(4'-(5-methyl-1,3,4-thiadiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate (23): ES / MS m / z: C 20 H 18 N5O2S (M + H) calculated: 392.45, found: 392.16.

[0409] Representative procedure for ester hydrolysis

[0410]

[0411] To a solution of crude methyl 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylate (21) in tetrahydrofuran (1 mL) and methanol (1 mL) was added 2N NaOH (1 mL), and the resulting mixture was stirred at 80 °C for 2 hours. After cooling the reaction mixture and neutralizing with 1N HCl, the solid was filtered and the solid was purified by HPLC and 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 H8N3O2 (M - H) calculated: 202.08, found: 201.97.

[0412] Representative procedure for SEM protection of heterocyclic N-H

[0413]

[0414] Stir a solution of 5-bromo-1H-1,2,3-triazole (25,996.3 mg, 6.733 mmol) in DMF (20 mL) in an ice bath, and add portionwise a mineral oil solution of 60% sodium hydride (410 mg, 10.25 mmol). After 30 minutes, add (2-(chloromethoxy)ethyl)trimethylsilane (1.25 mL, 7.063 mmol) to the reaction mixture. Stir the resulting mixture in an ice bath for 1 hour and then overnight at room temperature. After 19 hours, dilute the reaction mixture with saturated NH4Cl solution (~100 mL) and ethyl acetate (~100 mL), and separate the two layers. The aqueous fraction is extracted with ethyl acetate (x1), and the organic fraction is washed with water (~150 mL x1). Combine, dry (MgSO4), and concentrate. Purify the residual oil by silica gel column chromatography, eluting with a 0%-30% ethyl acetate in hexanes solution to give 726.0 mg (39%) of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (26): 1 H NMR (400 MHz, chloroform-d) δ 7.63 (s, 1H), 5.63 (s, 2H), 3.72 - 3.60 (m, 2H), 0.99 - 0.86 (m, 2H), -0.02 (s, 9H). ES / MS m / z: C 11 H 20 BrN2O3Si (M + H) calculated: 335.04, molecular weight not detected.

[0415] Representative procedure for the preparation of boronic esters from aryl bromides

[0416]

[0417] A mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (26, 359 mg, 1.29 mmol), bis(pinacolato)diboron (27, 362 mg, 1.43 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane (116 mg, 0.14 mmol), and potassium acetate (384 mg, 3.92 mmol) in 1,4-dioxane (6 mL) was purged with Ar gas for 15 minutes and then the mixture was heated at 110 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (~60 mL), treated with Na2SO4, and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography, eluting with a hexane solution of 0%-40% ethyl acetate, to give 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 H NMR (400 MHz, chloroform-d) δ 7.99 (s, 1H), 5.74 (s, 2H), 3.70 - 3.56 (m, 2H), 1.37 (s, 12H), 0.96 - 0.85 (m, 2H), -0.04 (s, 9H).

[0418] The following compounds were prepared in a manner similar to the representative procedures of the Suzuki reaction, the above-mentioned SEM or PMB deprotection, and ester hydrolysis, using the previously mentioned bromide intermediates 4 (or 4'), 10, or 15 with commercially available boronic esters, or using the previously mentioned boronic ester intermediates 6 (or 6'), 8, 12, 13, and 16 with commercially available bromides:

[0419] Example 1: Ethyl 4-(4'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate

[0420]

[0421] 1 H NMR (400 MHz, chloroform-d) δ 7.95 (dd, J = 8.3, 6.7 Hz, 2H), 7.65 (dd, J = 8.2, 5.5 Hz, 2H), 7.60 - 7.49 (m, 2H), 7.43 (dd, J = 8.5, 1.9 Hz, 2H), 5.90 (s, 1H), 4.45 (qd, J = 7.2, 4.8 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H). ES / MS m / z: C 17 H 13Calculated value of ClN3O2(M-H): 326.08, measured value: 326.31.

[0422] Example 2: Ethyl 4-(4'-carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate

[0423]

[0424] 1 H NMR (400 MHz, methanol-d4) δ 7.99 - 7.91 (m, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.72 (dd, J = 8.4, 1.8 Hz, 4H), 4.38 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). ES / MS m / z: C 18 H 17 Calculated value of C

[0425] Example 3: 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0426]

[0427] 1 H NMR (400 MHz, methanol-d4) δ 7.42 - 7.31 (m, 2H), 7.31 - 7.21 (m, 2H), 2.17 (s, 3H). ES / MS m / z: C 10 H 10 Calculated value of N3O2(M+H): 204.08, measured value: 347.58.

[0428] Example 4: 4-(m-tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0429]

[0430] 1 H NMR (400 MHz, methanol-d4) δ 7.65 - 7.55 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 2.40 (s, 3H). ES / MS m / z: C 10 H 10 Calculated value of N3O2(M+H): 204.20, measured value: 203.92.

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

[0432]

[0433] 1 1H NMR (400 MHz, methanol-d4) δ 7.81 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 2.36 (s, 3H). ES / MS m / z: C 10 H 10 N3O2 (M+H) Calcd: 204.20, Found: 203.92.

[0434] Example 6: 4-(3-Ethylphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0435]

[0436] 1 1H NMR (400 MHz, methanol-d4) δ 7.68 - 7.56 (m, 2H), 7.42 - 7.28 (m, 2H), 2.71 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). ES / MS m / z: C 11 H 12 N3O2 (M+H) Calcd: 218.09, Found: 217.97

[0437] Example 7: 4-(2-Fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0438]

[0439] 1 1H NMR (400 MHz, methanol-d4): δ 7.61 - 7.45 (m, 2H), 7.32 - 7.17 (m, 2H). ES / MS m / z: C9H7FN3O2 (M+H) Calcd: 208.04, Found: 207.94.

[0440] Example 8: 4-(3-Fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0441]

[0442] 1 1H NMR (400 MHz, methanol-d4) δ 7.74 - 7.66 (m, 2H), 7.46 (td, J = 8.1, 5.9 Hz, 1H), 7.16 (td, J = 8.6, 2.5 Hz, 1H). ES / MS m / z: C9H7FN3O2 (M+H) Calcd: 208.04, Found: 207.91.

[0443] Example 9: 4-(4-Chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0444]

[0445] 1 H NMR (400 MHz, methanol-d4): δ 7.89 - 7.81 (m, 2H), 7.51 - 7.42 (m, 2H). ES / MS m / z: C9H7ClN3O2 (M + H) calculated: 224.01, found: 223.94.

[0446] Example 10: 4-(3-Methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0447]

[0448] 1 H NMR (400 MHz, methanol-d4) δ 7.45 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 7.1 Hz, 2H), 7.06 - 6.98 (m, 1H), 3.84 (s, 3H). ES / MS m / z: C 10 H8N3O3 (M - H) calculated: 218.20, found: 217.98.

[0449] Example 11: 4-(4-Methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0450]

[0451] 1 H NMR (400 MHz, methanol-d4) δ 7.78 (d, J = 8.4 Hz, 2H), 7.06 - 6.98 (m, 2H), 3.85 (s, 3H). ES / MS m / z: C 10 H 10 N3O3 (M + H) calculated: 220.06, found: 219.93.

[0452] Example 12: 4-(2,4'-Dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0453]

[0454] 11H NMR (400 MHz, methanol-d4) δ 8.34 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.78 (dt, J = 7.8, 1.4 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H). ES / MS m / z: C 10 For C

[0455] Example 13: 4-(3-(Trifluoromethyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0456]

[0457] 1 1H NMR (400 MHz, methanol-d4) δ 8.24 (t, J = 1.7 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H). ES / MS m / z: C 10 For C

[0458] Example 14: 4-(3-Tert-butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0459]

[0460] 1 1H NMR (400 MHz, methanol-d4) δ 7.90 (t, J = 1.9 Hz, 1H), 7.59 (dt, J = 7.6, 1.4 Hz, 1H), 7.51 (ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 1.36 (s, 9H). ES / MS m / z: C 13 H 16 For C

[0461] Example 15: 4-(4-Tert-butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0462]

[0463] 1 1H NMR (400 MHz, methanol-d4): δ 7.78 - 7.70 (m, 2H), 7.55 - 7.47 (m, 2H), 1.36 (s, 9H). ES / MS m / z: C 13 H16 Calculated value of N3O2(M+H): 246.12, measured value: 246.01.

[0464] Example 16: 4-(3-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0465]

[0466] 1 H NMR (400 MHz, methanol-d4) δ 7.89 (d, J = 7.8 Hz, 2H), 7.55 (td, J = 7.9, 7.4, 1.0 Hz, 1H), 7.39 - 7.31 (m, 1H). ES / MS m / z: C 10 Calculated value of H7FN3O3(M+H): 274.04, measured value: 273.95.

[0467] Example 17: 5-(3-Chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid

[0468]

[0469] 1 H NMR (400 MHz, chloroform-d) δ 8.00 (dd, J = 7.1, 2.2 Hz, 1H), 7.83 (ddd, J = 8.7, 4.6, 2.2 Hz, 1H), 7.21 (t, J = 8.7 Hz, 1H), 4.32 (s, 3H). ES / MS m / z: C 10 Calculated value of H9ClFN3O2(M-H): 254.63, measured value: 254.04.

[0470] Example 18: 4-(3-Chloro-4-fluorophenyl)-1H-pyrazole-3-carboxylic acid

[0471]

[0472] 1 H NMR (400 MHz, methanol-d4) δ 7.80 (s, 1H), 7.71 (dd, J = 7.2, 2.2 Hz, 1H), 7.50 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.22 (dd, J = 9.2, 8.6 Hz, 1H). ES / MS m / z: C 10 Calculated value of H7ClFN2O2(M+H): 241.01, measured value: 240.88.

[0473] Example 19: 4-(3,4-Dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0474]

[0475] 1 1H NMR (400 MHz, methanol-d4) δ 8.13 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 8.4, 2.1 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H). ES / MS m / z: C9H6Cl2N3O2 (M+H) calculated: 257.98, found: 257.95.

[0476] Example 20: 4-(3,5-Dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0477]

[0478] 1 1H NMR (400 MHz, methanol-d4) δ 7.95 (s, 2H), 7.52 (s, 1H). ES / MS m / z: C9H6Cl2N3O2 (M+H) calculated: 257.98, found: 257.92.

[0479] Example 21: 4-(3,5-Dichlorophenyl)-1H-pyrazole-3-carboxylic acid

[0480]

[0481] 1 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 1H), 7.68 (s, 2H), 7.58 - 7.44 (m, 1H). ES / MS m / z: C 10 H5Cl2N2O2 (M-H) calculated: 254.98, found: 255.02.

[0482] Example 22: 4-(3-Chloro-2-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0483]

[0484] 1 1H NMR (400 MHz, methanol-d4) δ 7.59 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H), 7.50 (ddd, J = 7.9, 6.3, 1.7 Hz, 1H), 7.27 (td, J = 7.9, 1.2 Hz, 1H). ES / MS m / z: C9H6ClFN3O2 (M+H) calculated: 242.01, found: 241.94.

[0485] Example 23: 5-(4-Bromo-3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0486]

[0487] 1 H NMR (400 MHz, methanol-d4): δ 8.04 (s, 1H), 7.70 - 7.65 (m, 2H). ES / MS m / z: C9H4BrClN3O2 (M - H) calculated: 299.93, found: 300.02.

[0488] Example 24: 4-(3,5-Dichloro-4-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0489]

[0490] 1 H NMR (400 MHz, methanol-d4) δ 8.09 (d, J = 6.4 Hz, 2H). ES / MS m / z: C9H4Cl2FN3O2 (M + H) calculated: 275.97, found: 275.96.

[0491] Example 25: 4-(3-Phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0492]

[0493] 1 H NMR (400 MHz, methanol-d4) δ 7.57 (ddd, J = 7.7, 1.6, 1.0 Hz, 1H), 7.52 - 7.40 (m, 2H), 7.40 - 7.31 (m, 2H), 7.18 - 7.08 (m, 1H), 7.08 - 6.99 (m, 3H). ES / MS m / z: C 15 H 12 N3O3 (M + H) calculated: 282.08, found: 282.01.

[0494] Example 26: 4-(4-Phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0495]

[0496] 1 H NMR (400 MHz, methanol-d4) δ 7.83 (d, J = 8.4 Hz, 2H), 7.44 - 7.34 (m, 2H), 7.21 - 7.12 (m, 1H), 7.10 - 7.01 (m, 4H). ES / MS m / z: C15 H 12 Calculated value of N3O3(M + H): 282.08, measured value: 281.98.

[0497] Example 27: 4-([1,1'-Biphenyl]-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0498]

[0499] 1 H NMR (400 MHz, methanol-d4) δ 8.03 (t, J = 1.8 Hz, 1H), 7.71 (dt, J = 7.7, 1.4 Hz, 1H), 7.67 - 7.54 (m, 3H), 7.46 (t, J = 7.8 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.31 - 7.22 (m, 1H). ES / MS m / z: C 15 H 12 Calculated value of N3O2(M + H): 266.09, measured value: 266.01.

[0500] Example 28: 4-([1,1'-Biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0501]

[0502] 1 H NMR (400 MHz, methanol-d4) δ 7.92 (d, J = 8.0 Hz, 2H), 7.77 - 7.64 (m, 4H), 7.51 - 7.41 (m, 2H), 7.41 - 7.32 (m, 1H). ES / MS m / z: C 15 H 12 Calculated value of N3O2(M + H): 266.09, measured value: 265.96.

[0503] Example 29: 4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0504]

[0505] 1 H NMR (400 MHz, methanol-d4) δ 7.79 (dd, J = 1.7, 0.5 Hz, 1H), 7.72 (dd, J = 8.4, 1.7 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H). ES / MS m / z: C 10 Calculated value of H6CF2N3O4(M + H): 270.02, measured value: 269.97.

[0506] Example 30: 4-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0507]

[0508] 1 H 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 H6N3O4 (M - H) calculated: 232.04, found: 232.00.

[0509] Example 31: 4-(4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazole-

[0510] 5-carboxylic acid

[0511]

[0512] 1 H NMR (400 MHz, methanol-d4) δ 7.46 - 7.35 (m, 3H), 7.32 (dt, J = 8.4, 1.6 Hz, 1H), 7.19 (dd, J = 8.4, 1.3 Hz, 1H), 6.89 - 6.81 (m, 2H). ES / MS m / z: C 16 H8F2N3O4 (M - H) calculated = 344.06; found 344.04

[0513] Example 32: 4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0514]

[0515] 1 H NMR (400 MHz, methanol-d4) δ 7.39 (s, 1H), 7.31 (d, J = 7.1 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.32 - 4.24 (s, 4H). ES / MS m / z: C 11 H 10 N3O4 (M + H) calculated: 248.06, found: 248.00.

[0516] Example 33: 4-(Naphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0517]

[0518] 1 1H NMR (400 MHz, methanol-d4): δ 8.39 (s, 1H), 7.98 - 7.86 (m, 4H), 7.59 - 7.49 (m, 2H). ES / MS m / z: Calculated for C9H6ClFN3O2 (M + H): 242.01, Found: 239.97.

[0519] Example 34: 4-(Pyridin-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0520]

[0521] 1 1H NMR (400 MHz, methanol-d4) δ 9.61 - 9.53 (m, 1H), 9.24 (dt, J = 8.2, 1.7 Hz, 1H), 8.89 (dt, J = 5.7, 1.2 Hz, 1H), 8.18 (ddd, J = 8.2, 5.8, 0.8 Hz, 1H). ES / MS m / z: Calculated for C8H7N4O2 (M + H): 191.05, Found: 191.01

[0522] Example 35: 4-(Pyridin-3-yl)-1H-pyrazole-3-carboxylic acid

[0523]

[0524] 1 1H NMR (400 MHz, methanol-d4) δ 9.40 (d, J = 1.9 Hz, 1H), 9.00 (ddd, J = 8.2, 2.0, 1.5 Hz, 1H), 8.79 (ddd, J = 5.6, 1.4, 0.7 Hz, 1H), 8.35 (s, 1H), 8.03 (ddd, J = 8.2, 5.7, 0.8 Hz, 1H). ES / MS m / z: Calculated for C9H7N3O2 (M - H): 190.05, Found: 190.02.

[0525] Example 36: 4-(Quinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0526]

[0527] 11H NMR (400 MHz, DMSO-d6) δ 9.05 - 8.98 (m, 1H), 8.62 - 8.52 (m, 1H), 8.11 (d, J = 11.3 Hz, 1H), 7.69 - 7.48 (m, 4H). ES / MS m / z: C 12 For C12H9N4O2 (M + H), calculated: 241.06, found: 241.07.

[0528] Example 37: 4-(Isoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0529]

[0530] 1 1H NMR (400 MHz, methanol-d4) δ 9.80 (s, 1H), 9.11 (s, 1H), 8.74 (d, J = 9.3 Hz, 1H), 8.60 (d, J = 6.6 Hz, 1H), 8.47 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H). ES / MS m / z: C 12 For C12H8N4O2 (M + H), calculated: 241.06, found: 241.05.

[0531] Example 38: 4-(6-Phenylnaphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0532]

[0533] 1 1H NMR (400 MHz, methanol-d4) δ 8.43 (s, 1H), 8.15 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.95 (s, 1H), 7.89 - 7.81 (m, 1H), 7.81 - 7.74 (m, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.43 - 7.34 (m, 1H). ES / MS m / z: C 19 H 14 For C19H13N3O2 (M + H), calculated: 316.10, found: 316.00.

[0534] Example 39: 4-(3-Chloroisoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0535]

[0536] 11H NMR (400 MHz, methanol-d4) δ 9.17 (s, 1H), 8.70 (s, 1H), 8.29 (dd, J = 8.6, 1.7 Hz, 1H), 8.12 - 7.86 (m, 2H). ES / MS m / z: C 12 H8ClN4O2 (M+H) calculated = 275.03; found 275.05.

[0537] Example 40: 4-(3-Methoxyisoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0538]

[0539] 1 1H NMR (400 MHz, methanol-d4) δ 9.06 (d, J = 0.9 Hz, 1H), 8.40 - 8.35 (m, 1H), 8.12 (dd, J = 8.7, 1.9 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 4.04 (s, 3H).

[0540] Example 41: 4-(3-Phenylisoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0541]

[0542] 1 1H NMR (400 MHz, methanol-d4) δ 9.55 (s, 1H), 8.86 (s, 1H), 8.45 (d, J = 15.6 Hz, 2H), 8.20 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 7.7 Hz, 2H), 7.64 - 7.51 (m, 3H). ES / MS m / z: C 18 H 13 N4O2 (M+H) calculated = 317.10; found 317.09.

[0543] Example 42: 4-(4-(Naphthalen-1-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0544]

[0545] 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 N3O2 (M+H) calculated = 316.11; found 316.03.

[0546] Example 43: 4-(4-(Pyridin-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0547]

[0548] 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (dt, J = 4.7, 1.5 Hz, 1H), 8.19 (d, J = 12.8 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H), 7.90 (td, J = 7.7, 1.9 Hz, 3H), 7.38 (dd, J = 7.6, 4.9 Hz, 1H). ES / MS m / z: C 14 H 11 Calculated for C13H9N4O2 (M+H): 267.08, Found: 267.10.

[0549] Example 44: 4-(4-(Pyridin-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0550]

[0551] 1 H NMR (400 MHz, methanol-d4) δ 9.17 (d, J = 2.1 Hz, 1H), 8.88 - 8.76 (m, 2H), 8.11 (d, J = 8.4 Hz, 2H), 8.06 (dd, J = 8.2, 5.6 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H). ES / MS m / z: C 14 H 11 Calculated for C13H9N4O2 (M+H): 267.09, Found: 267.04.

[0552] Example 45: 4-(4-(Naphthalen-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0553]

[0554] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.09 - 7.99 (m, 2H), 7.93 (tt, J = 8.6, 4.4 Hz, 6H), 7.54 (tt, J = 6.9, 5.4 Hz, 2H). ES / MS m / z: C 19 H 12 Calculated for C18H11N3O2 (M-H): 314.10, Found: 314.14.

[0555] Example 46: 4-(4-(6-Chloronaphthalen-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0556]

[0557] 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.07 - 7.91 (m, 6H), 7.89 (s, 2H), 7.51 (dd, J = 8.7, 2.2 Hz, 1H). ES / MS m / z: C 19 H 13 ClN3O2 (M + H) calculated: 350.06, found: 350.00.

[0558] Example 47: 4-(4-(Isoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0559]

[0560] 1 H NMR (400 MHz, methanol-d4) δ 9.51 (s, 1H), 8.59 (d, J = 6.0 Hz, 1H), 8.48 (d, J = 2.1 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.08 (s, 1H), 8.02 (s, 4H). ES / MS m / z: C 14 H 11 N4O2 (M + H) calculated: 267.09, found: 267.04.

[0561] Example 48: 4-(4-(1-Methyl-1H-benzo[d]imidazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0562]

[0563] 1 H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.00 (s, 1H), 7.85 (t, J = 15.5 Hz, 4H), 7.70 (s, 2H), 3.88 (s, 3H). ES / MS m / z: C 17 H 14 N5O2 (M + H) calculated: 320.11, found: 320.14.

[0564] Example 49: 4-(4'-Chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0565]

[0566] 1 1H NMR (400 MHz, methanol-d4) δ 7.94 (d, J = 8.0 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.71 - 7.65 (m, 2H), 7.65 - 7.55 (m, 1H), 7.61 - 7.58 (m, 1H), 7.55 - 7.42 (m, 2H). ES / MS m / z: C 15 H 11 Calculated for ClN3O2(M + H): 300.05, found: 299.97.

[0567] Example 50: 4-(3'-Chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0568]

[0569] 1 1H NMR (400 MHz, methanol-d4) δ 8.02 - 7.90 (m, 2H), 7.76 - 7.66 (m, 3H), 7.65 - 7.59 (m, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.38 (ddd, J = 8.0, 2.1, 1.1 Hz, 1H). ES / MS m / z: C 15 H 11 Calculated for ClN3O2(M + H): 300.05, found: 299.98.

[0570] Example 51: 4-(4'-Bromo-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0571]

[0572] 1 1H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 2H), 7.77 (d, J = 7.9 Hz, 2H), 7.72 - 7.60 (m, 4H). ES / MS m / z: C 15 H 11 Calculated for BrN3O2(M + H): 344.00, found: 344.06.

[0573] Example 52: 4-(2,4'-Dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0574]

[0575] 1 1H NMR (400 MHz, DMSO-d6) δ 7.92 (t, J = 1.9 Hz, 2H), 7.84 - 7.69 (m, 3H), 7.58 (dt, J = 7.9, 1.4 Hz, 1H), 7.44 (t, J = 7.9 Hz, 2H). ES / MS m / z: C 15 H 11 BrN3O2 (M + H) calculated: 344.00, found: 343.95.

[0576] Example 53: 4-(4'-Methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0577]

[0578] 1 1H NMR (400 MHz, methanol-d4) δ 7.90 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.1 Hz, 2H), 7.61 - 7.53 (m, 2H), 7.31 - 7.24 (m, 2H), 2.38 (s, 3H). ES / MS m / z: C 16 H 14 N3O2 (M + H) calculated: 280.10, found: 279.96.

[0579] Example 54: 4-(4'-(tert-Butyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0580]

[0581] 1 1H NMR (400 MHz, methanol-d4) δ 7.90 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.66 - 7.58 (m, 2H), 7.55 - 7.46 (m, 2H), 1.36 (s, 9H). ES / MS m / z: C 19 H 20 N3O2 (M + H) calculated: 322.15, found: 322.06.

[0582] Example 55: 4-(4'-(Trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0583]

[0584] 11H NMR (400 MHz, methanol-d4) δ 7.95 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.41 - 7.34 (m, 2H). ES / MS m / z: C 16 H 11 F3N3O3 (M+H) Calcd: 350.08, Found: 350.00.

[0585] Example 56: 4-(4'-Methoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0586]

[0587] 1 1H NMR (400 MHz, methanol-d4) δ 7.89 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H). ES / MS m / z: C 16 H 14 N3O3 (M+H) Calcd: 296.10, Found: 296.03.

[0588] Example 57: 4-(4'-Fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0589]

[0590] 1 1H NMR (400 MHz, methanol-d4) δ 7.57 - 7.48 (m, 2H), 7.43 - 7.36 (m, 2H), 7.14 - 7.05 (m, 2H), 6.87 - 6.80 (m, 2H). ES / MS m / z: C 15 H 11 FN3O2 (M+H) Calcd = 284.08; Found 284.31.

[0591] Example 58: 4-(3',4'-Dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0592]

[0593] 11H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 7.9 Hz, 2H), 7.87 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.68 - 7.58 (m, 2H). ES / MS m / z: C 15 H 10 Calculated for Cl2N3O2(M + H): 334.02, found: 334.08.

[0594] Example 59: 4-(4'-Cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0595]

[0596] 1 1H NMR (400 MHz, methanol-d4) δ 8.00 (d, J = 7.9 Hz, 2H), 7.93 - 7.77 (m, 6H). ES / MS m / z: C 16 Calculated for C9H9N4O2(M - H) = 289.07, found: 289.01.

[0597] Example 60: 4-(4'-Chloro-3'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0598]

[0599] 1 1H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.69 - 7.48 (m, 5H). ES / MS m / z: C 15 Calculated for C8H8ClFN3O2(M - H): 316.04, found: 316.09.

[0600] Example 61: 4-(3'-Chloro-4'-fluoro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0601]

[0602] 11H NMR (400 MHz, methanol-d4) δ 7.95 (d, J = 8.3 Hz, 2H), 7.81 (dd, J = 7.0, 2.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.65 (ddd, J = 8.6, 4.5, 2.3 Hz, 1H), 7.34 (t, J = 8.9 Hz, 1H). ES / MS m / z: C 15 H 10 ClFN3O2 (M+H) Calculated: 318.04, Found: 317.97.

[0603] Example 62: 4-(3'-phenoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0604]

[0605] 1 1H NMR (400 MHz, methanol-d4) δ 7.91 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 8.2 Hz, 2H), 7.49 - 7.42 (m, 2H), 7.41 - 7.31 (m, 2H), 7.29 (dt, J = 2.4, 1.0 Hz, 1H), 7.17 - 7.08 (m, 1H), 7.06 - 7.00 (m, 2H), 7.00 - 6.95 (m, 1H). ES / MS m / z: C 21 H 16 N3O3 (M+H) Calculated: 358.11, Found: 358.01.

[0606] Example 63: 4-(4'-phenoxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0607]

[0608] 1 1H NMR (400 MHz, methanol-d4) δ 7.91 (d, J = 8.0 Hz, 2H), 7.78 - 7.63 (m, 4H), 7.37 (dd, J = 8.5, 7.3 Hz, 2H), 7.12 (d, J = 7.4 Hz, 1H), 7.09 - 6.97 (m, 4H). ES / MS m / z: C 21 H 16 N3O3 (M+H) Calculated: 358.11, Found: 357.98.

[0609] Example 64: 4-(4'-(pyridin-2-yloxy)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0610]

[0611] 1 1H NMR (400 MHz, methanol-d4) δ 8.16 (ddd, J = 5.0, 2.0, 0.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7.84 (ddd, J = 8.3, 7.2, 2.0 Hz, 1H), 7.77 - 7.68 (m, 4H), 7.27 - 7.19 (m, 2H), 7.14 (ddd, J = 7.2, 5.0, 1.0 Hz, 1H), 6.99 (dt, J = 8.3, 0.9 Hz, 1H). ES / MS m / z: C 20 H 15 Calculated for C18H11N4O3 (M+H): 359.11, found: 359.14.

[0612] Example 65: 4-(4'-Acetyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0613]

[0614] 1 1H NMR (400 MHz, methanol-d4) δ 8.14 - 8.07 (m, 2H), 7.98 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 11.8, 8.3 Hz, 4H), 2.65 (s, 3H). ES / MS m / z: C 17 H 14 Calculated for C16H12N3O3 (M+H) = 308.10; found 308.00.

[0615] Example 66: 4-(3'-Carbamoyl-[]1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0616]

[0617] 1 1H NMR (400 MHz, methanol-d4) δ 8.21 (t, J = 1.9 Hz, 1H), 8.01 - 7.93 (m, 2H), 7.89 (dd, J = 7.8, 1.9 Hz, 2H), 7.83 - 7.74 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H). ES / MS m / z: C 16 H 13 Calculated for C17H12N4O3 (M+H): 309.09, found: 309.09.

[0618] Example 67: 4-(3'-(Methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0619]

[0620] 1 H NMR (400 MHz, methanol-d4) δ 8.14 (t, J = 1.8 Hz, 1H), 8.01 - 7.91 (m, 2H), 7.91 - 7.74 (m, 4H), 7.56 (t, J = 7.8 Hz, 1H), 2.95 (s, 3H). ES / MS m / z: C 17 H 15 Calculated for C

[0621] Example 68: 4-(4'-Carbamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0622]

[0623] 1 H NMR (400 MHz, methanol-d4): δ 7.98 (d, 4H), 7.77 (d, 4H). ES / MS m / z: C 16 H 13 Calculated for C

[0624] Example 69: 4-(4'-(Methylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0625]

[0626] 1 H NMR (400 MHz, methanol-d4) δ 7.97 (d, J = 8.0 Hz, 2H), 7.95 - 7.87 (m, 2H), 7.84 - 7.72 (m, 4H), 2.95 (s, 3H). ES / MS m / z: C 17 H 15 Calculated for C

[0627] Example 70: 4-(4'-(Dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0628]

[0629] 1 1H NMR (400 MHz, methanol-d4): δ 8.03 - 7.92 (m, 2H), 7.87 - 7.74 (m, 4H), 7.60 - 7.47 (m, 2H), 3.13 (s, 3H), 3.06 (s, 3H). ES / MS m / z: C 18 H 17 Calculated for C₁₅H₁₁N₄O₃ (M+H): 337.35, found: 338.06.

[0630] Example 71: 4-(4'-Carbamoyl-3'-chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0631]

[0632] 1 1H NMR (400 MHz, methanol-d4) δ 7.97 (d, J = 8.0 Hz, 2H), 7.86 - 7.74 (m, 3H), 7.70 (dd, J = 8.1, 1.7 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H). ES / MS m / z: C 16 H 12 Calculated for C₁₅H₁₀ClN₄O₃ (M+H): 343.05, found: 343.13.

[0633] Example 72: 4-(3'-Sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0634]

[0635] 1 1H NMR (400 MHz, methanol-d4) δ 8.22 (t, J = 1.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.91 (dtt, J = 8.5, 3.6, 1.8 Hz, 2H), 7.84 - 7.73 (m, 2H), 7.65 (t, J = 7.9 Hz, 1H). ES / MS m / z: C 15 H 13 Calculated for C₁₅H₁₁N₄O₄S (M-H): 345.06, found: 345.03.

[0636] Example 73: 4-(3'-(N,N-Dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0637]

[0638] 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 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.6 Hz, 1H), 7.96 (s, 2H), 7.93 - 7.79 (m, 3H), 7.77 (d, J = 6.6 Hz, 2H), 2.95 (t, J = 5.5 Hz, 4H), 1.56 (dt, J = 10.7, 5.9 Hz, 4H), 1.42 - 1.30 (m, 2H). ES / MS m / z: C 20 H 21 1H NMR (400 MHz, methanol-d4): δ 8.08 - 7.96 (m, 4H), 7.86 - 7.65 (m, 4H), 3.78 - 3.65 (m, 4H), 3.07 - 2.95 (m, 4H). ES / MS m / z: C 19 H 19 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.6 Hz, 1H), 7.96 (s, 2H), 7.93 - 7.79 (m, 3H), 7.77 (d, J = 6.6 Hz, 2H), 2.95 (t, J = 5.5 Hz, 4H), 1.56 (dt, J = 10.7, 5.9 Hz, 4H), 1.42 - 1.30 (m, 2H). ES / MS m / z: C 1

[0639] Example 74: 4-(3'-(Piperidine-1-ylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0640]

[0641] 1 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.6 Hz, 1H), 7.96 (s, 2H), 7.93 - 7.79 (m, 3H), 7.77 (d, J = 6.6 Hz, 2H), 2.95 (t, J = 5.5 Hz, 4H), 1.56 (dt, J = 10.7, 5.9 Hz, 4H), 1.42 - 1.30 (m, 2H). ES / MS m / z: C 20 H 21 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J = 6.6 Hz, 1H), 7.96 (s, 2H), 7.93 - 7.79 (m, 3H), 7.77 (d, J = 6.6 Hz, 2H), 2.95 (t, J = 5.5 Hz, 4H), 1.56 (dt, J = 10.7, 5.9 Hz, 4H), 1.42 - 1.30 (m, 2H). ES / MS m / z: C

[0642] Example 75: 4-(3'-(Morpholinylsulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0643]

[0644] 1 1H NMR (400 MHz, methanol-d4): δ 8.08 - 7.96 (m, 4H), 7.86 - 7.65 (m, 4H), 3.78 - 3.65 (m, 4H), 3.07 - 2.95 (m, 4H). ES / MS m / z: C 19 H 19 1H NMR (400 MHz, methanol-d4): δ 8.08 - 7.96 (m, 4H), 7.86 - 7.65 (m, 4H), 3.78 - 3.65 (m, 4H), 3.07 - 2.95 (m, 4H). ES / MS m / z: C

[0645] Example 76: 4-(4'-Chloro-3'-sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0646]

[0647] 1 N4O4S(M + H) calculated value: 373.09, found value: 373.11. N4O4S(M + H) calculated value: 413.13, found value: 413.17. N4O5S(M + H) calculated value: 415.10, found value: 415.11.1H NMR (400 MHz, methanol-d4) δ 8.35 (d, J = 2.3 Hz, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.90 - 7.83 (m, 1H), 7.82 - 7.72 (m, 2H), 7.71 - 7.62 (m, 1H). ES / MS m / z: C 15 H 12 ClN4O3S (M+H) Calculated: 379.02, Found: 379.07.

[0648] Example 77: 4-(4'-Sulfamoyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0649]

[0650] 1 1H NMR (400 MHz, methanol-d4) δ 7.99 (d, J = 8.2 Hz, 4H), 7.86 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H). ES / MS m / z: C 15 H 11 N4O4S (M-H) Calculated: 343.06, Found: 342.31.

[0651] Example 78: 4-(4'-(N,N-Dimethylsulfamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0652]

[0653] 1 1H NMR (400 MHz, methanol-d4) δ 8.01 (d, J = 8.2 Hz, 2H), 7.96 - 7.93 (m, 2H), 7.91 - 7.86 (m, 2H), 7.83 (dd, J = 7.6, 5.6 Hz, 2H), 2.73 (s, 6H). ES / MS m / z: C 17 H 17 N4O4S (M+H) Calculated: 373.09, Found: 373.06.

[0654] Example 79: 4-(4'-(Piperidin-1-ylsulfamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0655]

[0656] 11H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 8.2 Hz, 2H), 7.97 - 7.85 (m, 4H), 7.82 (d, J = 8.3 Hz, 2H), 2.94 (t, J = 5.5 Hz, 4H), 1.56 (p, J = 6.2, 5.4 Hz, 4H), 1.45 - 1.32 (m, 2H). ES / MS m / z: C 20 H 21 Calculated for C 20 H 21 N4O4S (M + H): 413.13, found: 413.10.

[0657] Example 80: 4-(4'-(Morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0658]

[0659] 1 1H NMR (400 MHz, methanol-d4) δ 8.05 - 7.93 (m, 4H), 7.93 - 7.76 (m, 4H), 3.78 - 3.65 (m, 4H), 3.07 - 2.96 (m, 4H). ES / MS m / z: C 19 H 19 Calculated for C 19 H 19 N4O5S (M + H): 415.11, found: 415.07.

[0660] Example 81: 4-(3'-Acetamido-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0661]

[0662] 1 1H NMR (400 MHz, methanol-d4): δ 8.06 - 7.85 (m, 3H), 7.77 - 7.68 (m, 2H), 7.60 - 7.51 (m, 1H), 7.47 - 7.32 (m, 2H), 2.15 (s, 3H). ES / MS m / z: C 17 H 15 Calculated for C 17 H 15 N4O3 (M + H): 323.11, found: 323.13.

[0663] Example 82: 4-(4'-Acetamido-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0664]

[0665] 11H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.85 (s, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.68 (s, 4H), 2.05 (s, 3H). ES / MS m / z: C 17 H 15 N4O3 (M+H) Calcd: 323.11, Found: 323.12.

[0666] Example 83: 4-(4'-(2-Oxopyrrolidin-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0667]

[0668] 1 1H NMR (400 MHz, DMSO-d6) δ 7.76 (m, 8H), 3.87 (t, J = 7.0 Hz, 2H), 2.52 (d, J = 8.0 Hz, 2H), 2.07 (p, J = 7.6 Hz, 2H). ES / MS m / z: C 19 H 17 N4O3 (M+H) Calcd: 349.12, Found: 349.13.

[0669] Example 84: 4-(2,4'-Dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0670]

[0671] 1 1H NMR (400 MHz, methanol-d4) δ 7.88 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.1 Hz, 2H), 7.61 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 3.93 - 3.81 (m, 4H), 3.23 - 3.16 (m, 4H). ES / MS m / z: C 19 H 19 N4O2 (M+H) Calcd: 351.14, Found: 350.01.

[0672] Example 85: 4-(4'-Chloro-2'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0673]

[0674] 11H NMR (400 MHz, methanol-d4) δ 7.94 - 7.87 (m, 2H), 7.44 - 7.37 (m, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.29 - 7.18 (m, 2H), 2.27 (s, 3H). ES / MS m / z: C 16 H 13 N3O2 (M + H) Calcd = 314.07; Found 314.01.

[0675] Example 86: 4-(9H-Fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0676]

[0677] 1 1H NMR (400 MHz, methanol-d4) δ 8.02 (s, 1H), 7.94 - 7.80 (m, 3H), 7.58 (dt, J = 7.3, 1.0 Hz, 1H), 7.43 - 7.29 (m, 2H), 3.97 (s, 2H). ES / MS m / z: C 16 H 12 N3O2 (M + H) Calcd: 278.09, Found: 278.02.

[0678] Example 87: 4-(Dibenzo[b,d]furan-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0679]

[0680] 1 1H NMR (400 MHz, methanol-d4) δ 8.16 (dd, J = 1.3, 0.6 Hz, 1H), 8.14 - 8.04 (m, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.61 (dt, J = 8.3, 0.9 Hz, 1H), 7.52 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.39 (ddd, J = 7.7, 7.2, 1.0 Hz, 1H). ES / MS m / z: C 15 H 10 N3O3 (M + H) Calcd: 280.06, Found: 280.00.

[0681] Example 88: 4-(9H-Carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0682]

[0683] 11H NMR (400 MHz, acetonitrile-d3) δ 6.77 (dd, J = 18.7, 8.0 Hz, 2H), 6.64 (s, 1H), 6.23 (s, 1H), 6.12 (d, J = 8.1 Hz, 1H), 6.05 (t, J = 7.6 Hz, 1H), 5.83 (t, J = 7.4 Hz, 1H). ES / MS m / z: C 15 H 11 N4O2 (M+H) Calcd = 279.09; Found 279.01.

[0684] Example 89: 4-(9-oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0685]

[0686] 1 1H NMR (400 MHz, methanol-d4) δ 8.11 (d, J = 13.5 Hz, 2H), 7.77 (dd, J = 14.9, 7.6 Hz, 2H), 7.69 - 7.53 (m, 2H), 7.39 (t, J = 7.3 Hz, 1H). ES / MS m / z: C 16 H 10 N3O3 (M+H) Calcd: 292.06, Found: 292.08.

[0687] Example 90: 4-(9,9-dimethyl-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0688]

[0689] 1 1H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 1.5 Hz, 1H), 7.88 - 7.76 (m, 3H), 7.50 (dd, J = 5.8, 2.9 Hz, 1H), 7.39 - 7.29 (m, 2H), 1.51 (s, 6H). ES / MS m / z: C 18 H 16 N3O2 (M+H) Calcd = 306.12; Found 306.06.

[0690] Example 91: 4-(4'-chloro-3'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0691]

[0692] 11H NMR (400 MHz, DMSO-d6) δ 7.12 (d, J = 7.9 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 6.81 (d, J = 2.3 Hz, 1H), 6.72 - 6.52 (m, 3H), 1.64 (s, 3H). ES / MS m / z: C 16 H 11 ClN3O2 (M - H) Calculated: 312.06, Found: 312.08.

[0693] Example 92: 4-(4'-Carbamoyl-3'-methyl-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0694]

[0695] 1 1H NMR (400 MHz, methanol-d4) δ 7.95 (d, J = 7.7 Hz, 2H), 7.75 (d, J = 8.1 Hz, 2H), 7.62 - 7.45 (m, 3H), 2.53 (s, 3H). ES / MS m / z: C 17 H 15 N4O3 (M + H) Calculated: 323.11, Found: 323.10.

[0696] Example 93: 4-(4-(1-Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0697]

[0698] 1 1H NMR (400 MHz, methanol-d4) δ 8.01 (t, J = 7.3 Hz, 2H), 7.79 (d, J = 8.0 Hz, 3H), 7.74 - 7.63 (m, 2H), 3.55 (t, J = 6.7 Hz, 2H), 3.08 (t, J = 6.6 Hz, 2H). ES / MS m / z: C 18 H 15 N4O3 (M + H) Calculated: 335.11, Found: 335.16.

[0699] Example 94: 4-(4-(1-Oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-pyrazole-5-carboxylic acid

[0700]

[0701] 11H NMR (400 MHz, DMSO-d6) δ 7.89 (d, J = 8.1 Hz, 2H), 7.77 - 7.56 (m, 5H), 3.40 (dt, J = 7.2, 3.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H). ES / MS m / z: C 19 H 16 Calculated for C 19 H 16 N3O3 (M+H): 334.11, Found: 334.13.

[0702] Example 95: 4-(4-(3-Methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-

[0703] 5-carboxylic acid

[0704]

[0705] 1 1H NMR (400 MHz, methanol-d4) δ 8.01 (d, J = 8.1 Hz, 1H), 7.99 - 7.93 (m, 2H), 7.82 - 7.75 (m, 2H), 7.69 (dd, J = 8.1, 1.8 Hz, 1H), 7.62 (d, J = 1.7 Hz, 1H), 3.84 (dqd, J = 12.9, 6.5, 4.6 Hz, 1H), 3.11 (dd, J = 15.8, 4.5 Hz, 1H), 2.84 (dd, J = 15.7, 10.1 Hz, 1H), 1.33 (d, J = 6.5 Hz, 3H). ES / MS m / z: C 19 H 17 Calculated for C 19 H 17 N4O3 (M+H): 349.13, Found: 349.10. Example 96: 4-(4-(2-Methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-

[0706] 5-carboxylic acid

[0707]

[0708] 1 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.85 (m, 4H), 7.72 (dd, J = 8.2, 1.8 Hz, 1H), 7.69 (s, 2H), 3.59 (t, J = 6.6 Hz, 2H), 3.07 (t, J = 6.6 Hz, 2H), 3.05 (s, 3H). ES / MS m / z: C 19 H 17Calculated value of N4O3(M+H): 349.13, measured value: 349.09.

[0709] Example 97: 4-(4-(1-oxoisoindolin-5-yl)phenyl)-1H-1,2,4,3-triazole-5-carboxylic acid

[0710]

[0711] 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 of N4O3(M+H): 321.09, measured value: 321.07.

[0712] Example 98: 4-(4-(3,3-dimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2,4,3-triazole-5-carboxylic acid

[0713]

[0714] 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 Calculated value of N4O3(M+H) = 349.13; measured value 349.13.

[0715] Example 99: 4-([1,1':3',1”-terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0716]

[0717] 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 of N3O2(M+H): 342.12, measured value: 342.01.

[0718] Example 100: 4-([1,1':4',1''-Terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0719]

[0720] 1 H NMR (400 MHz, DMSO-d6) δ 7.97 - 7.63 (m, 10H), 7.48 (t, J = 7.6 Hz, 2H), 7.46 - 7.25 (m, 2H). ES / MS m / z: C 21 H 14 N3O2 (M - H) Calculated: 340.12, Found: 339.95.

[0721] Example 101: 4-(4'-(Pyridin-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0722]

[0723] 1 H NMR (400 MHz, methanol-d4) δ 8.83 (d, J = 5.3 Hz, 1H), 8.62 (s, 2H), 8.41 (d, J = 9.3 Hz, 1H), 8.17 - 7.93 (m, 6H), 7.87 (d, J = 9.7 Hz, 2H). ES / MS m / z: C 20 H 15 N4O2 (M + H) Calculated: 343.11, Found: 343.15.

[0724] Example 102: 4-(4'-(Pyridin-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0725]

[0726] 1 H NMR (400 MHz, methanol-d4) δ 9.04 (s, 1H), 8.67 (d, J = 5.0 Hz, 1H), 8.56 - 8.50 (m, 1H), 7.99 (d, J = 8.1 Hz, 2H), 7.94 - 7.86 (m, 4H), 7.83 (d, J = 8.1 Hz, 3H). ES / MS m / z: C 20 H 15 N4O2 (M + H) Calculated: 343.12, Found: 343.13.

[0727] Example 103: 4-(4'-(Pyridin-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0728]

[0729] 1 H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 6.1 Hz, 2H), 8.30 - 8.23 (m, 2H), 8.07 (d, J = 8.2 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H). ES / MS m / z: C 20 H 15 N4O2 (M+H) calculated value: 343.12, measured value: 343.13.

[0730] Example 104: 4-(4'-(Pyrimidin-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0731]

[0732] 1 H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 4.8 Hz, 2H), 8.52 (d, J = 8.5 Hz, 2H), 7.98 (s, 2H), 7.85 (dd, J = 8.2, 6.4 Hz, 4H), 7.37 (t, J = 4.9 Hz, 1H). ES / MS m / z: C 19 H 14 N5O2 (M+H) calculated value = 344.11; measured value 344.03.

[0733] Example 105: 4-(4'-(1-Methyl-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-

[0734] 5-carboxylic acid

[0735]

[0736] 1 H NMR (400 MHz, methanol-d4) δ 8.33 (s, 1H), 7.95 (dd, J = 14.0, 8.3 Hz, 4H), 7.79 (d, J = 8.2 Hz, 4H), 4.18 (s, 3H). ES / MS m / z: C 18 H 15Calculated value of N6O2(M+H) = 347.13; measured value 347.14.

[0737] Example 106: 4-(4'-(1-Methyl-1H-1,2,4-triazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-

[0738] 5-carboxylic acid

[0739]

[0740] 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.14 - 8.04 (m, 2H), 7.84 (d, J = 8.7 Hz, 6H), 3.93 (s, 3H). ES / MS m / z: C 18 H 15 Calculated value of C H N6O2(M+H): 347.12, measured value: 347.10.

[0741] Example 107: 4-(4'-(1-Methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0742]

[0743] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 - 7.87 (m, 4H), 7.83 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 2.2 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 3.91 (s, 3H). ES / MS m / z: C 19 [[ID=;29]]H 16 Calculated value of C H N5O2(M+H): 346.13, measured value: 346.15.

[0744] Example 108: 4-(4'-(Thiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0745]

[0746] 11H NMR (400 MHz, methanol-d4) δ 8.07 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 7.7 Hz, 2H), 7.89 (d, J = 3.3 Hz, 1H), 7.83 (t, J = 8.7 Hz, 4H), 7.63 (d, J = 3.3 Hz, 1H). ES / MS m / z: C 18 H 13 N4O2S (M + H) calculated: 349.07, found: 349.03.

[0747] Example 109: 4-(4'-(5-Methylthiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0748]

[0749] 1 1H NMR (400 MHz, DMSO-d6): δ 8.03 - 7.74 (m, 8H), 7.62 (s, 1H), 2.50 (s, 3H). ES / MS m / z: C 19 H 15 N4O2S (M + H) calculated: 362.08, found: 362.11.

[0750] Example 110: 4-(4'-(5-(Trifluoromethyl)thiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0751]

[0752] 1 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.15 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H), 7.94 - 7.85 (m, 4H). ES / MS m / z: C 19 H 12 F3N4O2S (M + H) calculated: 417.06, found: 417.00.

[0753] Example 111: 4-(4'-(5-Methyl-1,3,4-thiadiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-

[0754] carboxylic acid

[0755]

[0756] 11H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 6.5 Hz, 1H), 8.00 (d, J = 16.3 Hz, 2H), 7.96 - 7.89 (m, 3H), 7.85 (d, J = 8.3 Hz, 2H), 2.78 (s, 3H). ES / MS m / z: C 18 H 12 N5O2S (M - H) Calculated: 362.07, Found: 362.03.

[0757] Example 112: 4-(4'-(Oxazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0758]

[0759] 1 1H NMR (400 MHz, methanol-d4) δ 8.13 (s, 1H), δ 8.09 - 7.91 (m, 4H), δ 7.91 - 7.77 (m, 3H), δ 7.39 - 7.28 (s, 2H). ES / MS m / z: C 18 H 13 N4O3 (M + H) Calculated = 333.10; Found 333.00.

[0760] Example 113: 4-(4'-(Isoxazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0761]

[0762] 1 1H NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 1.7 Hz, 1H), 8.07 - 7.97 (m, 3H), 7.93 - 7.86 (m, 5H), 7.24 - 7.19 (m, 1H). ES / MS m / z: C 18 H 13 N4O3 (M + H) Calculated = 333.10; Found 333.05.

[0763] Example 114: 4-(4'-(4-Methylthiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0764]

[0765] 11H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.0 Hz, 2H), 7.87 (t, J = 7.9 Hz, 4H), 7.36 (d, J = 1.2 Hz, 1H), 3.33 (s, 3H). ES / MS m / z: C 19 H 15 N4O2S (M+H) Calculated: 363.09, Found: 363.08.

[0766] Example 115: 4-(4'-(2-Methyl-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-

[0767] 5-carboxylic acid

[0768]

[0769] 1 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.95 (t, J = 7.0 Hz, 4H), 7.90 - 7.80 (m, 4H), 4.22 (s, 3H). ES / MS m / z: C 18 H 15 N6O2 (M+H) Calculated: 347.13, Found: 347.02.

[0770] Example 116: 4-(4'-(Thiazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0771]

[0772] 1 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.39 (s, 1H), 7.81 (q, J = 8.4 Hz, 8H). ES / MS m / z: C 18 H 13 N4O2S (M+H) Calculated: 349.07, Found: 348.96.

[0773] Example 117: 4-(4'-(1,5-Dimethyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-

[0774] carboxylic acid

[0775]

[0776] 11H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 8.1 Hz, 2H), 7.88 - 7.79 (m, 4H), 7.76 (d, J = 8.2 Hz, 2H), 6.54 (s, 1H), 3.78 (s, 3H), 2.30 (s, 3H). ES / MS m / z: C 20 H 18 Calculated for C19H15N5O2 (M+H): 360.15, found: 360.16.

[0777] Example 118: 4-(4'-(1,5-Dimethyl-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-

[0778] triazole-5-carboxylic acid

[0779]

[0780] 1 1H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 7.95 - 7.90 (m, 1H), 7.89 - 7.75 (m, 8H), 4.00 (s, 3H), 2.51 (s, 3H). ES / MS m / z: C 19 H 17 Calculated for C20H16N6O2 (M+H): 361.14, found: 361.13.

[0781] Example 119: 4-(4'-(1H-Pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0782]

[0783] 1 1H NMR (400 MHz, methanol-d4) δ 8.28 (d, J = 2.4 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H), 7.91 - 7.62 (m, 6H), 6.56 (d, J = 2.4 Hz, 2H). ES / MS m / z: C 18 H 14 Calculated for C18H13N5O2 (M+H) = 332.11; found 332.14.

[0784] Example 120: 4-(4'-(1H-1,2,3-Triazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0785]

[0786] 1 1H NMR (400 MHz, methanol-d4) δ 8.59 (s, 1H), 8.07 (s, 2H), 8.01 - 7.85 (m, 5H), 7.79 (d, J = 8.2 Hz, 2H). ES / MS m / z: C 17 H 13 N6O2 (M+H) Calcd = 333.11; Found 333.11.

[0787] Example 121: 4-(4'-(5-Methyl-1H-1,2,3-triazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-

[0788] 5-carboxylic acid

[0789]

[0790] 1 1H NMR (400 MHz, methanol-d4) δ 8.01 (d, J = 8.0 Hz, 2H), 7.97 - 7.90 (m, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.70 - 7.61 (m, 3H), 2.42 (d, J = 0.9 Hz, 3H). ES / MS m / z: C 18 H 15 N6O2 (M+H) Calcd: 347.13, Found: 347.09.

[0791] Example 122: 4-(4'-(Benzothiazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0792]

[0793] 1 1H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.2 Hz, 5H), 7.88 (d, J = 8.3 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H). ES / MS m / z: C 22 H 15 N4O2S (M+H) Calcd: 399.09, Found: 399.08.

[0794] Example 123: 4,4'-([1,1'-Biphenyl]-4,4'-diyl)bis(1H-1,2,3-triazole-5-carboxylic acid)

[0795]

[0796] 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 HNMR (400 MHz, DMSO-d6) δ 7.95 (s, 4H), 7.86 (d, J = 8.1 Hz, 4H). ES / MS m / z: C 18 H 13 N6O4 (M+H) Calcd: 377.10, Found: 377.03.

[0797] Example 181: 4-(4'-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-[1,1'-biphenyl]-4-yl)-

[0798] 1H-1,2,3-triazole-5-carboxylic acid

[0799]

[0800] 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, J = 8.1 Hz, 2H), 7.86 (m, 6H), 3.17 (s, 2H), 2.96 (s, 2H), 2.89 - 2.78 (m, 2H). ES / MS m / z: C 21 H 17 N4O2S (M+H) Calcd: 389.11, Found: 389.11.

[0801] The following compounds were prepared in a manner similar to the representative procedures of the Suzuki reaction and SEM or PMB deprotection described above, and then, after SEM protection of the heterocyclic N-H, ester hydrolysis was carried out with the commercially available heterocyclic bromide using the boronate intermediates 6 or 8 mentioned above:

[0802] Example 124: 4-(4'-(1H-Pyrazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0803]

[0804] 1 1H NMR (400 MHz, DMSO-d6) δ 8.11 (s, 2H), 7.79 (d, J = 14.4 Hz, 4H), 7.72 (s, 4H). ES / MS m / z: C 18 H 14 N5O2 (M+H) Calcd: 332.11, Found: 332.07.

[0805] Example 125: 4-(4'-(1H-Pyrazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0806]

[0807] 1 1H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.86 (m, 4H), 7.88 - 7.74 (m, 4H), 7.72 (d, J = 2.2 Hz, 1H), 6.76 (t, J = 2.3 Hz, 1H). ES / MS m / z: C 18 H 14 N5O2 (M+H) Calcd: 332.11, Found: 332.11.

[0808] Example 126: 4-(4-(1H-Benzimidazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0809]

[0810] 1 1H NMR (400 MHz, methanol-d4) δ 9.31 (s, 1H), 8.09 (dd, J = 1.6, 0.8 Hz, 1H), 8.03 (d, J = 1.8 Hz, 1H), 8.02 - 7.89 (m, 3H), 7.88 - 7.79 (m, 2H). ES / MS m / z: C 16 H 12 N5O3 (M+H) Calcd: 306.09, Found: 306.14.

[0811] Example 127: 4-(4'-(1H-1,2,3-Triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0812]

[0813] 11H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 7.6 Hz, 4H), 7.80 (d, J = 7.9 Hz, 5H). ES / MS m / z: C 16 H 12 N5O3 (M+H) calculated: 333.10, found: 333.07.

[0814] Example 128: 4-(4'-(1H-Imidazol-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0815]

[0816] 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 N5O2 (M+H) calculated = 332.11; found 332.12.

[0817] Example 129: 4-(4'-(1H-Imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0818]

[0819] 1 1H NMR (400 MHz, methanol-d4): δ 9.02 (d, J = 1.4 Hz, 1H), 8.10 - 7.95 (m, 3H), 7.85 (dt, J = 24.3, 8.3 Hz, 6H). ES / MS m / z: C 18 H 14 N5O2 (M+H) calculated = 332.11; found 332.12.

[0820] Example 130: 4-(4'-(4-Methyl-1H-pyrazol-3-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0821]

[0822] 1 1H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 2H), 7.82 (d, J = 8.1 Hz, 4H), 7.75 (d, J = 8.1 Hz, 2H), 7.51 (s, 1H), 2.23 (d, J = 0.7 Hz, 3H). ES / MS m / z: C 19 H16 Calculated value of N5O2(M+H) = 346.13; Measured value 346.18.

[0823] The following compounds were prepared by representative procedures similar to the Suzuki reaction and SEM deprotection via HCl, and then using the aforementioned bromide intermediates 4 or 10, after conversion to pinacol borate esters, ester hydrolysis was carried out with commercially available bromides:

[0824] Example 131: 4-(4'-(5-Methyl-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-

[0825] 5-carboxylic acid

[0826]

[0827] 1 1H NMR (400 MHz, D2O + NaHCO3) δ 7.5 - 8.0 (m, 8H), 2.48 (s, 3H). ES / MS m / z: C 18 H 15 Calculated value of C1H6N6O2(M+H): 347.13, Measured value: 347.12.

[0828] Example 132: 4-(6-Chloronaphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0829]

[0830] 1 1H NMR (400 MHz, methanol-d4) δ 8.45 (m, 1H) 7.92 (dd, J = 13.0, 8.2 Hz, 4H), 7.50 (d, J = 8.7 Hz, 1H). ES / MS m / z: C 13 Calculated value of C9H9ClN3O2(M+H): 274.04, Measured value: 273.96.

[0831] Example 133: 4-(Phenanthren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0832]

[0833] 1 1H NMR (400 MHz, DMSO-d6) δ 8.88 (s, 2H), 8.43 (s, 1H), 8.22 - 7.82 (m, 4H), 7.80 - 7.59 (m, 3H). ES / MS m / z: C 17 H 12Calculated value of N3O2(M+H) = 290.09; measured value 290.03.

[0834] Example 134: 4-(7-Amino-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0835]

[0836] 1 H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 7.97 (dd, J = 14.0, 8.1 Hz, 2H), 7.88 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.36 (d, J = 8.3 Hz, 1H), 4.05 (s, 2H). ES / MS m / z: C 16 H 13 Calculated value of C H N4O2(M+H): 293.10, measured value: 293.05.

[0837] Example 135: 5-(3-Chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0838]

[0839] Step 1

[0840] To a solution of methyl 4-bromo-3-methyl-1H-pyrazole-5-carboxylate (275 mg, 1.255 mmol) in DMF was added sodium hydride (60% suspension, 1.38 mmol) at 0 °C, and then SEM-Cl (0.233 mL, 1.31 mmol) was added. After 10 minutes, the reaction mixture was diluted with saturated NaHCO3, and the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate to obtain a mixture of isomers of methyl 4-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate: ES / MS m / z: C 12 H 22 BrN2O s Calculated value of Si(M+H): 349.05, measured value: 348.93.

[0841] Steps 2, 3 and 4

[0842] 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 for the Suzuki reaction, and then SEM deprotection and ester hydrolysis were carried out with HCl: 11H NMR (400 MHz, methanol-d4) δ 7.43 (ddd, J = 7.2, 1.9, 0.5 Hz, 1H), 7.31 - 7.19 (m, 2H), 2.22 (s, 3H). ES / MS m / z: C 11 H9ClFN2O2 (M + H) calculated: 255.03, found: 254.94.

[0843] Example 136: 4-(3-Chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0844]

[0845] Step 1

[0846] Under N2, a solution of 1-(3-chloro-4-fluorophenyl)ethan-1-one (301, 5.00 g, 29.0 mmol) in dimethyl carbonate (4.9 mL, 58 mmol) was added dropwise to a stirred solution of potassium tert-butoxide (6.50 g, 57.9 mmol) in THF (30 mL) and cooled in a water bath. After 90 minutes, the reaction mixture was cooled in an ice bath and then quenched with 2 M HCl. The mixture was then extracted with ethyl acetate, the organic extract was dried (MgSO4) and concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography, eluting with a hexane solution of 0% - 40% ethyl acetate to give methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropionate (2.97 g, 44%). LC / MS m / z: C 10 H9ClFO3 (M + H) calculated: 231.02, found: 231.0.

[0847] Step 2 A solution of a mixture of methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropionate (537 mg, 2.33 mmol), p-methoxybenzyl azide (400 mg, 2.45 mmol) and potassium carbonate (1.36 g, 9.80 mmol) in dimethyl sulfoxide (5 mL) was stirred vigorously at 80 °C overnight. The reaction mixture was then cooled and diluted with water, and the resulting solid was separated by filtration and further purified by silica gel column chromatography, eluting with a hexane solution of 0% - 50% ethyl acetate to give methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (400 mg, 43%), as a white solid: ES / MS m / z: C 18 H 16 ClFN3O3 (M + H) calculated: 376.09, found 376.1.

[0848] Steps 3 and 4

[0849] At room temperature, 1 M LiOH (1.0 mL, 1.0 mmol) was added to a 1:1 THF / methanol (2 mL) solution of methyl 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (75 mg, 0.20 mmol). After stirring for 1 h, the reaction mixture was acidified with 2 N HCl and the product was extracted with ethyl acetate (x3). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in TFA and stirred at 65 °C for 2 h. After concentrating the reaction mixture in vacuo, the residue was purified by reverse-phase preparative HPLC to give 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid: 1 1H NMR (400 MHz, DMSO-d6) δ 13.33 (br s, 1H), 8.07 (br s, 1H), 7.84 (br s, 1H), 7.54 (br t, J = 8.0 Hz, 1H). ES / MS m / z: calcd for C9H6ClFN3O2 (M+H) 242.01, found 242.0.

[0850] Example 137: 4-Phenyl-1H-1,2,3-triazole-5-carboxylic acid

[0851]

[0852] 4-Phenyl-1H-1,2,3-triazole-5-carboxylic acid was prepared from acetophenone in a manner similar to the procedure in Example 136: 1 1H NMR (400 MHz, DMSO-d6) δ 13.14 (br s, 1H), 7.79 (br s, 2H), 7.51 - 7.42 (m, 3H). ES / MS m / z: calcd for C9H8N3O2 (M+H) 190.06, found 190.0.

[0853] Example 138: 4-(3-Chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0854]

[0855] 4-(3-Chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 3-chloroacetophenone in a manner similar to the procedure in Example 136: 1 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 1H), 7.80 (br s, 1H), 7.54 - 7.48 (m, 2H). ES / MS m / z: calcd for C9H7ClN3O2 (M+H) 224.02, found 224.0.

[0856] Example 139: 4-(Pyridin-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0857]

[0858] Step 1

[0859] In a 5 mL microwave vial, 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) was added. After purging with argon for 5 minutes, the resulting mixture was stirred at 110 °C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, and then the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate, to give ethyl 5-(pyridin-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 16 H 25 N4O3Si(M+H) calculated: 349.16, found: 349.05.

[0860] Steps 2 and 3

[0861] 4-(Pyridin-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of deprotection of SEM by HCl followed by ester hydrolysis: 1 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.25 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 7.4, 5.4 Hz, 1H). ES / MS m / z: C8H7N4O2(M+H) calculated: 191.05, found: 190.99.

[0862] Example 140: 4-(Pyridin-2-yl)-1H-pyrazole-5-carboxylic acid

[0863]

[0864] 4-(Pyridin-2-yl)-1H-pyrazole-5-carboxylic acid was prepared from 4-(tributylstannyl)pyridine in a manner similar to the procedure of Example 141: 11H NMR (400 MHz, methanol-d4) δ 8.85 - 8.78 (m, 1H), 8.70 (s, 1H), 8.54 (td, J = 8.0, 1.6 Hz, 1H), 8.43 (dt, J = 8.4, 1.0 Hz, 1H), 7.89 (ddd, J = 7.3, 5.9, 1.2 Hz, 1H). ES / MS m / z: C9H8N3O2 (M + H) calculated: 190.05, found: 190.00.

[0865] Example 141: 4-(Thiazol-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0866]

[0867] 4-(Thiazol-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to Example 141 from 4-(tributylstannyl)thiazole: 1 1H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 8.65 (s, 1H), 3.15 (s, 1H). ES / MS m / z: C6H3N4O2S (M - H) calculated: 191.05, found: 194.95.

[0868] 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

[0869]

[0870] Step 1

[0871] 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 in a manner similar to the general procedure of the Suzuki reaction:

[0872] Steps 2 and 3

[0873] 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 in a manner similar to the general procedure of deprotecting SEM with HCl followed by ester hydrolysis. The two compounds were separated by precipitation and subsequently purified by preparative HPLC:

[0874] Example 142: 4-(3'-(Dimethylcarbamoyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0875]

[0876] 1 1H NMR (400 MHz, methanol-d4) δ 8.33 (t, J = 1.7 Hz, 1H), 8.10 - 7.87 (m, 3H), 7.87 - 7.71 (m, 2H), 7.59 (t, J = 7.9 Hz, 2H). ES / MS m / z: C 16 H 12 N3O4 (M + H) calcd: 310.07, found: 310.05.

[0877] Example 143: 4-(3'-Carboxy-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0878]

[0879] 1 1H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 8.4 Hz, 2H), 7.86 - 7.72 (m, 4H), 7.57 (td, J = 7.7, 0.6 Hz, 1H), 7.44 (dt, J = 7.6, 1.3 Hz, 1H), 3.14 (s, 3H), 3.06 (s, 3H). ES / MS m / z: C 18 H 17 N4O3 (M + H) calcd: 337.12, found: 337.17.

[0880] Example 144: 4-(4-(1H-Indazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0881]

[0882] Step 1

[0883] To a solution of 5-bromo-1H-indazole (100 mg, 0.49 mmol) in dichloromethane (2.0 mL) were added p-toluenesulfonic acid (9.0 mg, 0.049 mmol) and 3,4-dihydropyran (0.089 mL, 0.97 mmol). After heating the mixture at 35 °C overnight, the reaction mixture was diluted with saturated aqueous NaHCO3 and the product was extracted with ethyl acetate (x2). The combined organic layers were washed with water (x1), dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate, to give 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: 1 H NMR (400 MHz, acetonitrile-d3) δ 8.03 - 7.93 (m, 2H), 7.62 (dt, J = 8.9, 0.8 Hz, 1H), 7.52 (dd, J = 8.9, 1.9 Hz, 1H), 5.77 (dd, J = 9.8, 2.6 Hz, 1H), 4.89 (t, J = 3.8 Hz, 0H), 4.01 - 3.91 (m, 1H), 3.86 - 3.72 (m, 1H), 3.48 (dd, J = 11.0, 6.0 Hz, 0H), 2.47 (dddd, J = 13.7, 12.2, 9.7, 4.0 Hz, 1H), 2.17 - 1.97 (m, 2H), 1.87 - 1.60 (m, 3H), 1.64 - 1.48 (m, 1H). ES / MS m / z: C 12 H 14 BrN2O (M + H) calculated = 281.03; found 280.75.

[0884] Steps 2, 3 and 4

[0885] Using intermediate 6 and 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole, in a manner analogous to the general procedure for the Suzuki reaction, and with PMB and THP deprotection by TFA followed by ester hydrolysis, 4-(4-(1H-indazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared: 1 H NMR (400 MHz, methanol-d4) δ 8.10 - 8.05 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.50 - 7.35 (m, 6H). ES / MS m / z: C 15 H 11 ClN3O2 (M + H) calculated: 300.05, found: 300.00.

[0886] Example 145: 4-(4-(1H-indazol-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0887]

[0888] 4-(4-(1H-Indazol-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 6-bromo-1H-indazole in a manner similar to the procedure in Example 146: 1 H NMR (400 MHz, methanol-d4) δ 8.10 - 7.92 (m, 3H), 7.81 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H). ES / MS m / z: C 16 H 12 N5O2 (M + H) calcd = 306.10; found 306.15.

[0889] Example 146: 4-(4'-Chloro-3'-(morpholinosulfonyl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-

[0890] 5-carboxylic acid

[0891]

[0892] Step 1

[0893] At 0 °C, morpholine (220 mg, 3 mmol) was added 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 (x2), water (x1), and saturated NaHCO3 (x1). The resulting organic fraction was dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate to give 4-((5-bromo-2-chlorophenyl)sulfonyl)morpholine: 1 H 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).

[0894] Steps 2, 3, and 4

[0895] 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 for the Suzuki reaction, followed by PMB deprotection and then ester hydrolysis: 11H NMR (400 MHz, methanol-d4) δ 8.30 (d, J = 2.3 Hz, 1H), 8.07 - 7.91 (m, 3H), 7.76 (dd, J = 16.0, 8.2 Hz, 3H), 3.75 - 3.65 (m, 4H), 3.29 (m, 4H): ES / MS m / z: C 19 H 18 ClN4O5S (M+H) Calcd: 449.06, Found: 449.16.

[0896] Example 147: 4-(3-Bromophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0897]

[0898] Step 1

[0899] In a manner similar to the general procedure for the Suzuki reaction, a mixture of isomers 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: ES / MS m / z: C 16 H 25 N4O3Si (M+H) Calcd: 347.17, Found: 348.96.

[0900] Step 2:

[0901] At 0 °C, tert-butyl nitrite (0.042 mL, 0.35 mmol)) and copper(II) bromide (78 mg, 0.35 mmol) were added to a 3 mL acetonitrile solution of methyl 4-(3-aminophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-5-carboxylate (102 mg, 0.29 mmol). After 30 minutes, the reaction mixture was diluted with saturated NaHCO3, and the product was then extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate to give a mixture of isomers of methyl 5-(3-bromophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-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).

[0902] Steps 3 and 4

[0903] 5-(4-Bromophenyl)-1H-1,2,3-triazole-4-carboxylic acid was prepared in a general method similar to SEM deprotection by HCl followed by ester hydrolysis: 1 1H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H). ES / MS m / z: C9H7BrN3O2 (M+H) calculated: 267.96, found: 267.90.

[0904] Example 148: 4-(2-Chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0905]

[0906] Steps 1 and 2

[0907] A mixture of isomers of methyl 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared using 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in a method similar to Steps 1 and 2 of Example 149: ES / MS m / z: C 16 H 22 BrClN3O3Si (M+H) calculated: 446.03, found: 445.69.

[0908] Steps 3, 4 and 5

[0909] 4-(2-Chloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using phenylboronic acid in a general procedure similar to the Suzuki reaction, followed by SEM deprotection by HCl and ester hydrolysis: 1 1H NMR (400 MHz, methanol-d4) δ 8.10 - 8.05 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.50 - 7.35 (m, 6H). ES / MS m / z: C 15 H 11 ClN3O2 (M+H) calculated: 300.05, found: 300.00.

[0910] Example 149: 4-(2,4'-Dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0911]

[0912] A mixture of isomers of methyl 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate and 4-chlorophenylboronic acid were used in a manner similar to the general procedure for the Suzuki reaction, and then 4-(2,4'-dichloro-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared by the general method of SEM deprotection and ester hydrolysis with HCl: 1 1H NMR (400 MHz, methanol-d4) δ 8.00 (d, J = 1.7 Hz, 1H), 7.81 (dd, J = 8.0, 1.8 Hz, 1H), 7.37 (m, 5H). ES / MS m / z: C 15 H 10 Cl2N3O2 (M+H) calculated: 334.01, found: 333.97.

[0913] Example 150: 4-(3-Chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0914]

[0915] At 0 °C, NaH (60% oil suspension, 6 mg) was added to a 0.5 mL DMF solution of 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (10 mg, 0.038 mmol). After 10 minutes at 0 °C, iodomethane (7 μL, 0.11 mmol) was added and the resulting mixture was stirred at 0 °C for 10 minutes. After quenching the reaction by adding methanol, the product was purified by HPLC to give 5-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid: 1 1H NMR (400 MHz, chloroform-d) δ 7.99 (dd, J = 7.1, 2.2 Hz, 1H), 7.82 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.7 Hz, 1H), 4.31 (s, 3H). ES / MS m / z: C 10 H6ClFN3O2 (M-H) calculated: 254.01, found: 253.96.

[0916] Example 151: 4-(4'-(1-Methyl-1H-1,2,3-triazole-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-

[0917] 5-carboxylic acid

[0918]

[0919] Step 1

[0920] At 0 °C, an oil suspension of 60% NaH (48 mg, 1.2 mmol) was added to a 2 mL DMF solution of 4-(4-bromophenyl)-1H-1,2,3-triazole (242 mg, 1.05 mmol). After 10 minutes at 0 °C, iodomethane (71 μL, 1.1 mmol) was added and the resulting mixture was stirred at 0 °C for 10 minutes. The reaction mixture was extracted with ethyl acetate and brine, the organic layer was concentrated, and purified by silica gel column chromatography, eluting with ethyl acetate and hexane to give 5-(4-bromophenyl)-1-methyl-1H-1,2,3-triazole: ES / MS m / z: C9H9BrN3(M+H) calculated: 237.99, found: 238.09.

[0921] Steps 2, 3 and 4

[0922] 4-(4'-(1-Methyl-1H-1,2,3-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from Compound 28 in a manner analogous to the general procedure for the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 1H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.09 (s, 2H), 7.97 - 7.88 (m, 2H), 7.81 (dt, J = 13.6, 5.3 Hz, 4H), 4.20 (s, 3H). ES / MS m / z: C 18 1 15 7H6O2(M+H) calculated: 347.12, found: 347.04. Example 152: 4-(4-(2,3,3-Trimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0923]

[0924] Step 1

[0925] At 0 °C, to a solution of 5-bromo-3,3-dimethylisoindolin-1-one (205 mg, 0.85 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride (60% in mineral oil, 43 mg, 1.08 mmol). After 15 minutes, iodomethane (0.1 mL, 1.61 mmol) was added to the reaction mixture. The resulting solution was stirred at 0 °C for 1 hour. The reaction mixture was diluted with ethyl acetate (~25 mL) and then washed with ~50% saturated NH4Cl solution. After extraction of the aqueous fraction with ethyl acetate (25 mL×1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% EA, to give 5-bromo-2,3,3-trimethylisoindolin-1-one: ES / MS m / z: C 11 H 13 BrNO (M+H) calculated: 254.02, found: 254.12.

[0926] Steps 2, 3, and 4

[0927] 4-(4-(2,3,3-Trimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from Intermediate 6 and 5-bromo-2,3,3-trimethylisoindolin-1-one in a manner analogous to the general procedure for the Suzuki reaction, followed by PMB deprotection and then ester hydrolysis: 1 H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 1.5 Hz, 1H), 8.00 (s, 2H), 7.89 (dd, J = 7.7, 5.6 Hz, 2H), 7.83 (dd, J = 7.9, 1.6 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 2.95 (s, 3H), 1.50 (s, 6H). ES / MS m / z: C 20 H 19 N4O3 (M+H) calculated: 363.15, found: 363.12.

[0928] Example 153: 4-(4-(3,3-Dimethyl-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)phenyl)-

[0929] 1H-1,2,3-triazole-5-carboxylic acid

[0930]

[0931] In a similar manner to Example 154, 4-(4-(3,3-dimethyl-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 5-bromo-3,3-dimethylisoindolin-1-one using 2,2,2-trifluoroethyl trifluoromethanesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 19.7 Hz, 3H), 8.00 - 7.83 (m, 3H), 7.79 (d, J = 7.9 Hz, 1H), 4.34 (q, J = 9.6 Hz, 2H), 1.58 (s, 6H). ES / MS m / z: C 21 H 18 F3N4O3 (M+H) calculated: 431.13, found: 431.15.

[0932] Example 154: 4-(9-methyl-9H-carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0933]

[0934] Step 1

[0935] 5-(9H-carbazol-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester was prepared using Intermediate 4 and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole in a manner similar to the general procedure of the Suzuki reaction.

[0936] Step 2

[0937] To a solution of ethyl 5-(9H-carbazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-4-carboxylate (0.060 g; 0.068 mmol) in dimethylformamide (1 mL) was added 60% sodium hydride in mineral oil (0.008 g; 0.21 mmol), and the mixture was stirred for 30 minutes. Then MeI (0.009 mL; 0.13 mmol) was added. The solution was stirred overnight at room temperature. Once completed, the mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH4Cl (1 mL). After extracting the aqueous fraction with ethyl acetate (2 x 10 mL), the organic fractions were combined and washed with 5% LiCl (3 x 5 mL). Finally, the organic fraction was washed with water (5 mL), dried (Na2SO4), concentrated to dryness, and then purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate, to give 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 N4O3Si (M+H) calcd = 451.22, found 450.90.

[0938] Step 3

[0939] 4-(9-Methyl-9H-carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for SEM deprotection with TBAF, followed by ester hydrolysis: 1 H NMR (400 MHz, methanol-d4) δ 8.21 - 8.09 (m, 2H), 8.06 (d, J = 1.3 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.56 - 7.45 (m, 2H), 7.23 (ddd, J = 7.9, 6.6, 1.6 Hz, 1H), 3.92 (s, 3H). ES / MS m / z: C 16 H 11 N4O2 (M-H) calcd = 291.09, found 291.11.

[0940] Example 155: 4-(4-(6-(1H-1,2,3-triazol-4-yl)pyridazin-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0941]

[0942] Step 1

[0943] In a manner similar to the procedure for preparing Intermediate 10, an isomeric mixture 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 3,6-dibromopyridazine: ES / MS m / z: C 21 H 27 BrN5O3Si (M+H) calculated: 504.11, found: 504.14 and 504.18.

[0944] Steps 2, 3 and 4

[0945] 4-(4-(6-(1H-1,2,3-Triazol-4-yl)pyridazin-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from Compound 28 in a manner similar to the general procedure for the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 8.43 (d, J = 9.0 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.24 - 8.15 (m, 2H), 8.12 - 8.03 (m, 2H). ES / MS m / z: C 15 H 11 N8O2 (M+H) calculated: 335.10, found: 335.11.

[0946] Example 156: 4-(4-(5-(1H-1,2,3-Triazol-4-yl)pyrazin-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0947]

[0948] 4-(4-(5-(1H-1,2,3-Triazol-4-yl)pyrazin-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 2,5-dibromopyrazine in a manner similar to the procedure in Example 157: 1 H NMR (400 MHz, methanol-d4) δ 9.30 (s, 1H), 9.22 (d, J = 1.5 Hz, 1H), 8.26 (d, J = 8.2 Hz, 2H), 8.06 (d, J = 7.7 Hz, 3H). ES / MS m / z: C 15 H 11 N8O2 (M+H) calculated: 335.10, found: 335.10.

[0949] Example 157: 4-(3'-Methyl-4'-(1H-1,2,3-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole

[0950] -5-carboxylic acid

[0951]

[0952] Step 1

[0953] In a manner similar to the procedure for preparing Intermediate 10, an isomeric mixture 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: ES / MS m / z: C 24 H 31 BrN3O3Si(M+H) Calcd: 516.11, Found: 516.02.

[0954] Steps 2, 3 and 4

[0955] 4-(3'-Methyl-4'-(1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from Compound 28 in a manner similar to the general procedure for the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis: 1 H NMR (400 MHz, methanol-d4) δ 7.97 (d, J = 8.0 Hz, 3H), 7.77 (d, J = 8.3 Hz, 2H), 7.73 - 7.53 (m, 3H), 2.54 (s, 3H). ES / MS m / z: C 18 H 15 N6O2S(M+H) Calcd: 347.12, Found: 347.15.

[0956] Example 158: 4-(4'-Chloro-2-cyano-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0957]

[0958] Step 1

[0959] 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(II) 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 was then heated to 60 °C for 70 minutes. The reaction mixture was then diluted with water and extracted with ethyl acetate, then filtered through celite / Celite, and then concentrated to dryness under reduced pressure. The crude reaction mixture was purified by flash chromatography (0% to 100% ethyl acetate / hexanes) to afford 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carbonitrile: 1 1H NMR (400 MHz, chloroform-d) δ 7.89 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.1 Hz, 1H), 7.47 (s, 4H), 7.36 (d, J = 8.4 Hz, 1H).

[0960] Step 2

[0961] 4'-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1'-biphenyl]-2-carbonitrile was prepared from 4-bromo-4'-chloro-[1,1'-biphenyl]-2-carbonitrile in a manner analogous to the representative procedure for boronate preparation.

[0962] Steps 3, 4 and 5

[0963] 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 analogous to the general procedure for the Suzuki reaction, followed by SEM deprotection with TBAF and ester hydrolysis. 1 1H NMR (400 MHz, methanol-d4) δ 8.46 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.72 - 7.59 (m, 3H), 7.58 - 7.50 (m, 2H). ES / MS m / z: C 16 H 10 ClN4O2 (M+H) calcd = 325.05; found 325.03.

[0964] Example 159: 4-(4'-(1H-Imidazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0965]

[0966] Step 1

[0967] Add tris(benzylideneacetone)dipalladium(0) (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) to a reaction vessel and purge the headspace with nitrogen for 10 minutes. Separately, dissolve 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) in toluene-dioxane (3.0 mL) in a 5:1 (v / v) ratio and purge with nitrogen for 10 minutes. Add the imidazole solution to the reaction vessel and heat the reaction to 110 °C until the reaction is complete. Dilute the reaction mixture with ethyl acetate (10 mL) and wash with saturated NH4Cl (3 x 5 mL). Extract the aqueous layer with ethyl acetate (2 x 5 mL) and wash the combined organic fractions with water (2 x 5 mL). Finally, dry the organic fraction (Na2SO4), concentrate to dryness, and then purify by silica column chromatography, eluting with a hexane solution of ethyl acetate to obtain ethyl 5-(4'-(1H-imidazol-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 N5O3Si (M+H) calcd = 490.23; found: 430.39.

[0968] Steps 2 and 3

[0969] Prepare 4-(4'-(1H-imidazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid in a manner analogous to the general procedure for SEM deprotection with TBAF followed by ester hydrolysis: 1 1H NMR (400 MHz, methanol-d4) δ 9.48 (s, 3H), 8.145 (t, 1H) 8.00 (dd, J = 12.2, 8.5 Hz, 3H), 7.83 (dd, J = 8.4, 6.2 Hz, 4H). ES / MS m / z: C 18 H 14 N5O2 (M+H) calcd = 332.11; found 332.14.

[0970] Example 160: 4-((4-chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid

[0971]

[0972] Step 1

[0973] A solution of 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 at 60 °C overnight. Additional copper(I) iodide and dichlorobis(triphenylphosphine)palladium(II) were added as needed to improve the conversion to the desired product. Once judged that the LC / MS was sufficiently complete, the reaction mixture was diluted with ethyl acetate (10 mL) and filtered through Celite. The filtrate was washed with saturated NH4Cl (2 x 9 mL) and NaHCO3 (aqueous solution). The aqueous layer was extracted with ethyl acetate (1 x 10 mL). The combined organic layers were washed with water (1 x 10 mL), dried (Na2SO4), concentrated, and then purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate to give ethyl 5-((4-chlorophenyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 1H NMR (400 MHz, acetonitrile-d3) δ 7.64 - 7.56 (m, 1H), 7.52 - 7.45 (m, 1H), 5.98 (d, J = 9.7 Hz, 1H), 5.72 (s, 0H), 4.51 - 4.37 (m, 1H), 3.75 - 3.58 (m, 1H), 2.14 (s, 2H), 2.11 (d, J = 1.2 Hz, 0H), 1.45 - 1.34 (m, 2H), 1.29 (s, 0H), 0.97 - 0.83 (m, 1H). ES / MS M / z C 19 1 25 ClN3O3Si (M+H) calculated = 406.14; found 406.86.

[0974] Steps 2 and 3

[0975] Using the general procedure for SEM deprotection with TBAF, followed by ester hydrolysis, 4-((4-chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared: 11H NMR (400 MHz, methanol-d4) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H). ES / MS m / z: C 11 1H7ClN3O2 (M+H) calculated = 248.02; found: 247.96.

[0976] Example 161: 4-(1-(Oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0977]

[0978] Step 1

[0979] In a microwave reaction vial, 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) was added. After purging with argon for 5 minutes, the resulting mixture was stirred at 110 °C for 2 hours. After cooling, the reaction mixture was diluted with saturated NaHCO3, and the product was then extracted with ethyl acetate, dried (MgSO4), concentrated and purified by silica gel column chromatography, eluting with a hexane solution of ethyl acetate to give tert-butyl 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate: ES / MS m / z: C 21 1H 36 1N4O5Si (M+H) calculated: 453.25, found: 452.68.

[0980] Step 2

[0981] tert-Butyl 4-(5-(ethoxycarbonyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (120 mg, 0.27 mmol) was stirred overnight at room temperature in a solution of 4N HCl in 1,4-dioxane (2 mL). After concentration of the reaction mixture, the residue was purified by silica gel column chromatography, eluting with ethyl acetate solution in methanol, to give impure ethyl 4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 10 H 15 Calculated for N4O2(M+H): 223.11, found: 223.01.

[0982] Step 3

[0983] A solution of a mixture of ethyl 4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-1,2,3-triazole-5-carboxylate (22 mg, 0.01 mmol) and 10% palladium on carbon (20 mg) in ethanol (1 mL) was stirred under a hydrogen atmosphere for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give ethyl 4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 10 H 17 Calculated for N4O2(M+H): 225.13, found: 225.17.

[0984] Step 4

[0985] Sodium triacetoxyborohydride (104 mg, 0.05 mmol) was added to a suspension of ethyl 4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate (22 mg, 0.01 mmol) and 3-oxetanone (35 mg, 0.05 mmol) in THF (1 mL), and then acetic acid was added dropwise. The reaction mixture was stirred at room temperature overnight. After concentration of the reaction mixture, the residue was purified by preparative HPLC to give ethyl 4-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate: ES / MS m / z: C 13 H 21 Calculated for N4O3(M+H): 281.15, found: 281.18.

[0986] Step 5:

[0987] 4-(1-(Oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from ethyl 4-(1-(oxetan-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate in a manner similar to the general procedure for ester hydrolysis: 1 H NMR (400 MHz, methanol-d4): δ 4.89 (m, 4H), 4.17 - 4.01 (m, 1H), 3.80 (m, 1H), 3.72 - 3.42 (m, 3H), 3.26 - 3.05 (m, 1H), 2.37 - 2.02 (m, 4H). ES / MS m / z: C 11 H 17 N4O3(M + H) calculated: 253.12, found: 253.13.

[0988] Example 162: 4-(4-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0989]

[0990] Step 1

[0991] A mixture of isomers of tert-butyl 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-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 in a manner similar to the general procedure for the Suzuki reaction: ES / MS m / z: C 29 H 35 N4O5(M + H) calculated: 519.26, found: 518.98 and 518.96.

[0992] Step 2

[0993] To a flask containing a mixture of isomers of tert-butyl 4-(4-(5-(ethoxycarbonyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (128 mg, 0.25 mmol) was added a 1,4-dioxane solution of 4N HCl (3 mL), and the resulting mixture was stirred at room temperature for 15 minutes. After the solution was completely concentrated, at 0 °C, acetic anhydride (0.05 mL, 0.53 mmol) was added to a solution of the residue and pyridine (0.05 mL, 0.62 mmol) in dichloromethane (3 mL). After 30 minutes at 0 °C and 30 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (~25 mL) and washed with saturated aqueous ammonium chloride (x1), saturated aqueous sodium bicarbonate (x1), and brine (x1). After the aqueous fraction was extracted with ethyl acetate (~20 mL×1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography, eluting with a hexane solution of 50%-100% ethyl acetate, and then with an ethyl acetate solution of 0%-20% methanol, to give a mixture of isomers of ethyl 5-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 26 H 29 Calculated for C23H25N4O4 (M+H): 461.22, found: 460.94 and 461.17.

[0994] Steps 3 and 4

[0995] 4-(4-(1-Acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for PMB deprotection, followed by ester hydrolysis: 1 1H NMR (400 MHz, methanol-d4) δ 7.82 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.1 Hz, 2H), 6.24 (s, 1H), 4.23 (dq, J = 5.8, 2.6 Hz, 2H), 3.81 (t, J = 5.8 Hz, 0.83H), 3.76 (t, J = 5.7 Hz, 1.17H), 2.66 (d, J = 6.6 Hz, 1.17H), 2.59 (s, 0.83H), 2.18 (s, 1.755H), 2.15 (s, 1.245H). ES / MS m / z: C 16 H 17 Calculated for C15H17N4O3 (M+H): 313.13, found: 313.10.

[0996] Example 163: 4-(4-(1-Acetylpiperidin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0997]

[0998] Step 1

[0999] To a flask containing a mixture of isomers of ethyl 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-5-carboxylate (product of Step 2 of Example 164, 55 mg, 0.12 mmol), 20% palladium on carbon (6.6 mg) and ethanol (4 mL) were added, and the resulting mixture was stirred at room temperature under a H2 atmosphere for 3.5 h. Before filtration through a Celite pad, the reaction mixture was diluted with methanol and dichloromethane. After the Celite pad was washed with ethanol, the filtrate was concentrated completely and co-evaporated with toluene (x1) to give a crude mixture of isomers of ethyl 5-(4-(1-acetylpiperidin-4-yl)phenyl)-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 26 H 31 N4O4(M+H) calculated: 463.23, found: 463.04 and 463.06.

[1000] Steps 2 and 3

[1001] 4-(4-(1-Acetylpiperidin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for PMB deprotection, followed by ester hydrolysis: 1 H NMR (400 MHz, methanol-d4) δ 7.80 - 7.70 (m, 2H), 7.41 - 7.30 (m, 2H), 4.68 (ddt, J = 13.2, 4.4, 2.2 Hz, 1H), 4.15 - 3.95 (m, 1H), 3.25 (dt, J = 13.0, 2.9 Hz, 1H), 2.89 (tt, J = 12.1, 3.6 Hz, 1H), 2.73 (td, J = 13.0, 2.7 Hz, 1H), 2.14 (s, 3H), 1.92 (ddt, J = 17.2, 14.8, 2.9 Hz, 2H), 1.73 and 1.62 (two qd, J = 12.5, 4.1 Hz, 2H). ES / MS m / z: C 16 H 19 N4O3(M+H) calculated: 315.15, found: 315.14.

[1002] Example 164: 4-(4'-(Pyrazin-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1003]

[1004] Step 1

[1005] A solution of a mixture of pyrazine (200 mg; 2 mmol), 4-bromo-phenylboronic 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 pH > 8. After separating the two layers, the aqueous fraction was extracted with dichloromethane (2 × 10 ml), the combined organic fractions were dried (Na2SO4), concentrated and purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate to give 2-(4-bromophenyl)pyrazine: 1 1H NMR (400 MHz, chloroform-d) δ 9.01 (d, J = 1.5 Hz, 1H), 8.63 (dd, J = 2.5, 1.5 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H), 7.94 - 7.86 (m, 2H), 7.69 - 7.61 (m, 2H). ES / MS m / z C 10 1H8BrN2 (M+H) calculated = 234.99; found 235.05.

[1006] Steps 2, 3 and 4

[1007] 4-(4'-(Pyrazin-2-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was synthesized from 2-(4-bromophenyl)pyrazine using a representative procedure for the Suzuki reaction, SEM deprotection with HCl, and ester hydrolysis with the intermediate 6. 1 1H NMR (400 MHz, DMSO-d6) δ 13.21 (s, 1H), 9.32 (d, J = 1.6 Hz, 1H), 8.73 (dd, J = 2.5, 1.5 Hz, 1H), 8.62 (d, J = 2.5 Hz, 1H), 8.30 - 8.23 (m, 2H), 7.96 - 7.86 (m, 6H). ES / MS m / z: C 19 1H 14 1N5O2 (M+H) calculated = 344.11; found 344.04.

[1008] Example 165: 4-(4'-(1H-1,2,4-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1009]

[1010] Step 1

[1011] In a manner similar to the general procedure of the Suzuki reaction, an isomeric mixture 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: ES / MS m / z: C 24 H 30 N4O4Si(M+H) calculated value = 467.2; found 467.16.

[1012] Step 2

[1013] 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) was added tert-butoxybis(dimethylamino)methane (Bredereck's reagent; 62 μL; 0.30 mmol). The mixture was then heated to 60 °C until the starting material was exhausted, 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 N5O4Si(M+H) calculated value = 522.25; found 522.11.

[1014] Step 3

[1015] Hydrazine (39 μL; 1 mmol) and acetic acid (109 μL; 2.0 mmol) were added to the reaction mixture from Step 2 and heated to 60 °C. Once completed by LC / MS, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 (2 × 5 mL). After extraction of the aqueous fraction with ethyl acetate (2 x 10 mL), the organic fractions were combined, washed with 1N HCl (5 mL) and water (5 mL), dried (Na2SO4), and concentrated to dryness. The crude product, ethyl 5-(4'-(1H-1,2,4-triazol-5-yl)-[1,1'-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate, was used directly in Step 4 without further purification: 1 H NMR (400 MHz, chloroform-d) δ 8.36 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.94 (dd, J = 26.9, 8.1 Hz, 1H), 7.70 (ddd, J = 21.3, 12.8, 7.8 Hz, 3H), 7.58 (t, J = 7.2 Hz, 0H), 7.53 - 7.45 (m, 0H), 6.05 (s, 0H), 5.77 (s, 1H), 4.50 - 4.36 (m, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.81 - 3.72 (m, 1H), 3.70 - 3.61 (m, 0H), 2.11 (s, 1H), 2.04 (s, 3H), 1.45 - 1.31 (m, 2H), 1.25 Hz (t, J = 7.1 Hz, 4H), 0.95 (dt, J = 15.9, 8.3 Hz, 1H). ES / MS m / z: C 25 H 30 N6O3Si (M + H) calculated = 491.21; found 491.25.

[1016] Steps 4 and 5

[1017] 4-(4'-(1H-1,2,4-Triazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared following a general procedure similar to the SEM deprotection with HCl followed by ester hydrolysis: 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.15 - 8.08 (m, 2H), 7.96 - 7.81 (m, 6H). ES / MS m / z C 17 H 13 N6O2 (M + H) calculated 333.10; found 333.11.

[1018] Example 166: 4-(7-Bromo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1019]

[1020] Step 1

[1021] 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-amine was prepared in a manner similar to the representative procedure for the synthesis of boronic acid esters from aromatic bromides using bis(pinacolato)diboron (27):

[1022] Step 2

[1023] A mixture of isomers of ethyl 5-(7-amino-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from intermediate 4 and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-amine in a manner similar to the general procedure for the Suzuki reaction: ES / MS m / z: C 24 H 31 N4O3Si (M+H) calculated: 451.22, found: 451.33.

[1024] Step 3

[1025] At 0 °C, tert-butyl nitrite (0.32 mL, 2.69 mmol) and copper(II) bromide (595 mg, 2.66 mmol) were added to a solution of ethyl 5-(7-amino-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (1.00 g, 2.22 mmol) in acetonitrile (12 mL). After 45 minutes, the reaction mixture was quenched with 1 M Na2S2O3 solution and the product was extracted with ethyl acetate. The extract was dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate, to give 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 and the deamination byproduct. The mixture was used in the next reaction without further purification.

[1026] Steps 4 and 5

[1027] 4-(7-Bromo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for SEM deprotection with HCl and ester hydrolysis: 11H NMR (400 MHz, methanol-d4) δ 8.03 (s, 1H), 7.94 - 7.82 (m, 2H), 7.81 - 7.71 (m, 2H), 7.54 (dd, J = 8.1, 1.8 Hz, 1H), 3.98 (s, 2H). ES / MS m / z: C 16 H 11 Calculated for BrClN3O2 (M+H): 355.92, found: 356.00.

[1028] Example 167: 4-(7-Chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1029]

[1030] 4-(7-Chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (56) was prepared in a manner analogous to the procedure of Step 3 of Example 168, using copper(II) chloride instead of copper(II) bromide, followed by the general procedure of SEM deprotection and ester hydrolysis with HCl: 1 1H NMR (400 MHz, methanol-d4) δ 8.03 (s, 1H), 7.94 - 7.81 (m, 3H), 7.60 (s, 1H), 7.39 (dd, J = 8.1, 1.9 Hz, 1H), 3.99 (s, 2H). ES / MS m / z: C 16 H 11 Calculated for ClN3O2 (M+H): 312.05, found: 311.93.

[1031] Example 168: 4-(7-(1H-1,2,3-Triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1032]

[1033] Step 1

[1034] Ethyl 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared in a manner analogous to the representative procedure for the synthesis of boronic esters from aromatic bromides using bis(pinacolato)diboron (27).

[1035] Steps 2, 3, and 4

[1036] 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 boronic ester 28 were used in a manner similar to the general procedure of the Suzuki reaction, and then SEM deprotection was carried out with HCl and ester hydrolysis to prepare 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid: 1 H NMR (400 MHz, methanol-d4) δ 7.80 - 7.70 (m, 2H), 7.41 - 7.30 (m, 2H), 4.68 (ddt, J = 13.2, 4.4, 2.2 Hz, 1H), 4.15 - 3.95 (m, 1H), 3.25 (dt, J = 13.0, 2.9 Hz, 1H), 2.89 (tt, J = 12.1, 3.6 Hz, 1H), 2.73 (td, J = 13.0, 2.7 Hz, 1H), 2.14 (s, 3H), 1.92 (ddt, J = 17.2, 14.8, 2.9 Hz, 2H), 1.73 and 1.62 (two qd, J = 12.5, 4.1 Hz, 2H). ES / MS m / z: C 18 H 13 N6O2 (M+H) calculated: 345.10, found: 345.11.

[1037] Example 169: 4-(9,9-Difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-

[1038] carboxylic acid

[1039]

[1040] Step 1

[1041] 4-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole was prepared from 2-bromo-9,9-difluoro-7-iodo-9H-fluorene and boronic ester 28 in a manner similar to the general procedure of the Suzuki reaction: ES / MS m / z: C 21 H 23 BrF2N3OSi (M+H) calculated: 478.08, found: 477.76.

[1042] Step 2

[1043] In a manner similar to the representative procedure for the synthesis of boronic acid esters from aromatic bromides using bis(pinacolato)diboron (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: ES / MS m / z: C 27 H 35 BF2N3O3Si (M+H) Calcd: 526.25, Found: 525.96.

[1044] Steps 5, 6, and 7

[1045] Using the intermediate 4 and 4-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole in a general procedure similar to the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis, 4-(9,9-difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared: 1 1H NMR (400 MHz, methanol-d4) δ 8.45 - 8.01 (m, 1H), 8.19 (s, 1H), 8.15 (s, 1H), 8.13 - 8.01 (m, 2H), 7.85 (t, J = 7.0 Hz, 2H). ES / MS m / z: C 18 H 11 F2N6O2 (M+H) Calcd: 381.09, Found: 381.06.

[1046] Example 170: 4-(9,9-Difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-pyrazole-5-carboxylic acid

[1047]

[1048] Using the intermediate 15 and 4-(9,9-difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid in a general method similar to the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis, 4-(9,9-difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-pyrazole-5-carboxylic acid was prepared:1 1H NMR (400 MHz, methanol-d4) δ 8.27 (s, 1H), 8.11 (d, J = 1.7 Hz, 1H), 8.03 (dd, J = 7.9, 1.5 Hz, 1H), 7.89 (s, 1H), 7.88 - 7.84 (m, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.77 - 7.70 (m, 2H). ES / MS m / z: C 19 H 12 F2N5O2 (M+H) Calcd: 380.10, Found: 380.11.

[1049] Example 171: 4-(7-(1,5-Dimethyl-1H-1,2,3-triazol-4-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-

[1050] 1,2,3-triazole-5-carboxylic acid

[1051]

[1052] Step 1

[1053] A mixture of 2,7-dibromo-9,9-difluoro-9H-fluorene (2000 mg, 5.56 mmol), bis(pinacolato)diboron (5646 mg, 22.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane (679 mg, 0.83 mmol) and potassium acetate (2903 mg, 29.6 mmol) in 1,4-dioxane (50 mL) was purged with argon for 15 minutes and then stirred at 80 °C for 16 hours. The reaction mixture was concentrated completely, the residue was dissolved in ethyl acetate (~300 mL), and washed with water (~250 mL × 2). After extracting the aqueous fraction with ethyl acetate (~100 mL × 1), the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography, eluting with a hexane solution of 0% - 20% ethyl acetate to give 2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane): 1 1H NMR (400 MHz, chloroform-d) δ 8.08 (dt, J = 2.0, 0.9 Hz, 2H), 7.95 - 7.89 (m, 2H), 7.60 (dd, J = 7.5, 0.9 Hz, 2H), 1.36 (s, 24H), no mass.

[1054] Step 2

[1055] In a manner similar to the general procedure of the Suzuki reaction, an isomer mixture of ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from intermediate 4 and 2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane): ES / MS m / z: C 30 H 39 BF2N3O5Si (M+H) Calcd: 598.27, Found: 597.81 and 597.67.

[1056] Steps 3, 4 and 5

[1057] Using 4-bromo-1,5-dimethyl-1H-1,2,3-triazole and the isomer mixture of ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate, in a manner similar to the general procedure of the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis, 4-(7-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared: 1 1H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 7.94 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 4.06 (s, 3H), 2.54 (s, 3H). ES / MS m / z: C 20 H 15 F2N6O2 (M+H) Calcd: 409.12, Found: 409.14.

[1058] Example 172: 4-(9,9-Difluoro-7-(2-methyl-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-

[1059] triazole-5-carboxylic acid

[1060]

[1061] Using a mixture of isomers of 4-bromo-2-methyl-2H-1,2,3-triazole and ethyl 5-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate, in a manner similar to the general procedure of the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis, 4-(9,9-difluoro-7-(2-methyl-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared: 1 1H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 8.11 (s, 3H), 8.03 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H), 4.24 (s, 3H). ES / MS m / z: C 19 H 13 F2N6O2 (M + H) calculated: 395.11, found: 395.03.

[1062] Example 173: 4-(6-chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1063]

[1064] Step 1

[1065] A solution 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. After 15 minutes, water (64 μL) was slowly added dropwise to the mixture while purging with argon. After 1 minute, the flask was kept tight and heated to 140 °C for 90 hours. After cooling, the reaction mixture was diluted with dichloromethane, filtered through a Celite pad, and the resulting filtrate was concentrated. The residue was dissolved in dichloromethane and aqueous HCl, and the insoluble material was filtered out again through a Celite pad, and the two layers of filtrate were separated. The organic fraction was dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate to give 2-bromo-6-chloro-9H-fluoren-9-one.

[1066] Step 2

[1067] At -78 °C, 1 M lithium triethylborohydride (0.34 mL) was added to a solution of 2-bromo-6-chloro-9H-fluoren-9-one (33 mg, 0.11 mmol) in tetrahydrofuran (1 mL). After 25 minutes, the reaction mixture was quenched with saturated aqueous NH4Cl. The product was extracted with ethyl acetate (x4), the combined organic extracts were washed with brine (x1), dried (MgSO4), and concentrated to give crude 2-bromo-6-chloro-9H-fluoren-9-ol for use in the next step.

[1068] Step 3

[1069] Triethylsilane (0.3 mL) and trifluoroacetic acid (0.3 mL) were added to the crude 2-bromo-6-chloro-9H-fluoren-9-ol, and the resulting mixture was stirred at room temperature for 1.7 h. After concentration, the residue was purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate to give 2-bromo-6-chloro-9H-fluorene.

[1070] Step 4

[1071] A solution of a mixture of 2-bromo-6-chloro-9H-fluorene (27 mg, 0.095 mmol), bis(pinacolato)diboron (29 mg, 0.11 mmol), [1,1'-(bis(diphenylphosphino)ferrocene)palladium(II) dichloride (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 vessel and purged with argon. After the resulting mixture was stirred at 95 °C for 2.25 h and cooled, the mixture was diluted with water and the product was extracted with ethyl acetate (x4). The combined organic extracts were dried (MgSO4) and concentrated, and purified by silica gel column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate to give 2-(6-chloro-9H-fluoren-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[1072] Steps 5, 6, and 7

[1073] 4-(6-Chloro-9-oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for the Suzuki reaction, using intermediate 4 and 2-(6-chloro-9H-fluoren-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, followed by SEM deprotection with HCl and ester hydrolysis: 11H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.92 - 7.84 (m, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.0, 2.0 Hz, 1H), 3.98 (s, 2H). ES / MS m / z: C 16 H 11 ClN3O2 (M+H) Calcd: 312.05, Found: 311.96.

[1074] Example 174: 4-(2-(Piperidin-4-yl)-4'-(1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-

[1075] 1,2,3-triazole-5-carboxylic acid

[1076]

[1077] Step 1

[1078] A solution 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 tetrakis(triphenylphosphine)palladium(0) (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 (∼100 mL) and washed with ∼50% saturated NaHCO3 (x1) and water (x1). After extracting the aqueous fraction with ethyl acetate (∼50 mL×1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica column chromatography, eluting with a hexane solution of 0%-100% ethyl acetate. The partially purified product was further purified by silica column chromatography, eluting with a hexane solution of 0%-20% ethyl acetate to give 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 BN3O3Si (M+H) Calcd: 402.24, Found: 401.96.

[1079] Step 2

[1080] A solution of a mixture of 5-bromo-2-iodobenzaldehyde (3.11 g, 10.00 mmol), diethyl malonate (6.45 g, 40.27 mmol) and potassium carbonate (5.57 g, 40.30 mmol) in DMF (20 mL) was stirred in an 85 °C bath for 18 h. After cooling the reaction mixture and diluting it with water (100 mL), the product was extracted with ethyl acetate (100 mL × 4). After the extract was washed with water (100 mL × 1), the combined extracts were dried (Na2SO4) and concentrated.

[1081] After the residue was treated with concentrated hydrochloric acid (25 mL), the mixture was refluxed for 36 h. After the resulting mixture was cooled in a refrigerator, the insoluble material was filtered off and washed with water. The solid was dissolved in ethyl acetate (~100 mL), dried (MgSO4), and concentrated to give crude 3-(5-bromo-2-iodophenyl)glutaric acid: ES / MS m / z: C 11 H 11 BrIO4 (M + H) calculated value: 412.89, found value: 412.58.

[1082] Step 3

[1083] A solution of the above crude 3-(5-bromo-2-iodophenyl)glutaric acid in acetic anhydride (~10 mL) was refluxed in a 155 °C bath for 3 h. After concentrating the resulting solution, the remaining slurry was co-evaporated with toluene (x2) and dried in vacuo. The residue was dissolved in THF (50 mL) and stirred at room temperature. 28% aqueous NH3 solution (0.65 mL each time) was added three times at intervals of about 15 minutes. The resulting mixture was stirred at room temperature for 7 h. The resulting suspension was completely concentrated, co-evaporated with toluene (x2), and dried. The residue was refluxed with acetic anhydride (15 mL) in a 155 °C bath for 4 h and cooled. The solution was concentrated and the residue was purified by silica gel column chromatography, eluting with a hexane solution of 0%-60% ethyl acetate to give 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione: 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 8.4, 2.4 Hz, 1H), 3.52 (tt, J = 12.0, 4.1 Hz, 1H), 2.90 - 2.78 (m, 2H), 2.63 (dd, J = 16.7, 4.1 Hz, 2H).

[1084] Step 4

[1085] Stir a solution of 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione (1.60 g, 4.06 mmol) in THF (5 mL) at 0 °C while dropwise adding a solution of 1.0 M borane tetrahydrofuran complex in THF (10.2 mL). After refluxing the resulting mixture for 20 h, add c.HCl (16 mL) to the mixture and reflux the resulting solution in a 105 °C bath for 4.5 h. Stir the solution in an ice bath while adding NaOH (solid) to neutralize the mixture. Dilute the resulting basic solution with NaHCO3 and extract the product with ethyl acetate (~60 mL × 2). Wash the extracts with brine (x1), combine, dry (Na2SO4), and concentrate to give 4-(5-bromo-2-iodophenyl)piperidine as an oil.

[1086] At 0 °C, stir a methanol solution (~25 mL) of crude 4-(5-bromo-2-iodophenyl)piperidine while adding Boc2O (1078 mg, 4.939 mmol) and triethylamine (0.8 mL, 5.740 mmol). After 2 h at 0 °C and overnight at room temperature. Concentrate the reaction mixture, dissolve the residue in ethyl acetate, and then wash with water (x2). Dry the resulting organic fraction (MgSO4), concentrate, and purify by silica gel column chromatography, eluting with a 0%-10% EA in hexanes solution to give tert-butyl 4-(5-bromo-2-iodophenyl)piperidine-1-carboxylate: 1 H NMR (400 MHz, chloroform-d) δ 7.68 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 8.4, 2.4 Hz, 1H), 4.27 (s, 2H), 2.94 - 2.85 (tt, J = 3.4, 12.9 Hz, 1H), 2.82 (s, 2H), 1.84 (d, J = 12.9 Hz, 2H), 1.51 (dd, J = 3.8, 12.9 Hz, 2H), 1.48 (s, 9H).

[1087] Step 5

[1088] A solution of 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 stirred in an 110 °C bath for 1.5 hours. After cooling, the mixture was diluted with ethyl acetate, dried (MgSO4), concentrated and purified by silica gel column chromatography, eluting with a hexane solution of 0%-50% ethyl acetate to give tert-butyl 4-(4-bromo-4'-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate: ES / MS m / z: C 30 H 41 BrN4NaO3Si (M+Na) Calcd: 635.20, Found: 635.14.

[1089] Step 6

[1090] A mixture of tert-butyl 4-(4-bromo-4'-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate (201 mg, 0.33 mmol), bis(pinacolato)diboron (27, 27 mg, 0.66 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane (116 mg, 0.03 mmol) and potassium acetate (102 mg, 1.04 mmol) in 1,4-dioxane (3 mL) in a microwave reaction vessel 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, eluting with a hexane solution of 0%-35% ethyl acetate to give tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate: ES / MS m / z: C 36 H 53 BN4NaO5Si (M+Na) Calcd: 683.38, Found: 683.35.

[1091] Steps 7, 8, and 9

[1092] Using intermediate 4 and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4'-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-2-yl)piperidine-1-carboxylate, in a manner similar to the general procedure for the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis, to prepare 4-(2-(piperidin-4-yl)-4'-(1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid; 1 H NMR (400 MHz, methanol-d4) δ 8.23 (s, 1H), 7.99 (d, J = 1.8 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.49 - 7.41 (m, 2H), 7.36 (d, J = 7.9 Hz, 1H), 3.41 (dd, J = 12.8, 3.2 Hz, 2H), 3.21 - 3.03 (m, 1H), 2.93 (ddd, J = 16.6, 8.6, 5.2 Hz, 2H), 2.03 (tt, J = 8.6, 3.4 Hz, 4H). ES / MS m / z: C 22 H 22 N7O2 (M + H) calculated: 416.18, found: 416.14.

[1093] Example 175: Ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1094]

[1095] Steps 1, 2, 3, and 4

[1096] In a manner similar to the method described herein, using intermediate 11 and 2,7-dibromo-9H-fluorene, and subsequently in a manner similar to the general procedure for PMB deprotection, to prepare ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 11H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.14 (s, 1H), 8.07 - 8.02 (m, 3H), 7.95 (d, J = 8.0 Hz, 1H), 7.82 (m, 1H), 4.32 (q, J = 7.0 Hz, 2H), 4.08 (s, 2H), 1.28 (t, J = 7.0 Hz, 3H). ES / MS m / z: C 20 H 17 Calculated for C19H15N6O2 (M+H): 373.14, found: 373.30.

[1097] Example 176: 2-Morpholinoethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1098]

[1099] Step 1

[1100] At room temperature and under argon, lithium hydroxide monohydrate (3.7 g, 88.18 mmol) was added to a stirred solution of ethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-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). The reaction mixture was heated to 60 °C and stirred for 5 h. The reaction mixture was concentrated under reduced pressure to give the crude product, diluted with water, acidified with 1 N HCl solution and stirred for 10 min. The precipitated solid was filtered, washed with water and dried in vacuo to give 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid: ES / MS m / z: C 34 H 29 Calculated for C29H23N6O4 (M+H): 585.23, found: 585.41.

[1101] Step 2

[1102] At room temperature and under argon, potassium carbonate (1.41 g, 10.3 mmol) was added to a stirred solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (3.0 g, 5.14 mmol) in DMF (30 mL), and then 4-(2-chloroethyl)morpholine (1.53 g, 10.3 mmol) was added. The mixture was heated to 50 °C and stirred for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of 80%-100% ethyl acetate, to give 2-morpholinoethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate: ES / MS m / z: C 40 H 40 Calculated for C 40 H 40 N7O5 (M+H): 683.31, found: 698.52.

[1103] Step 3

[1104] A mixture of a solution of 2-morpholinoethyl 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate (3.0 g, 4.3 mmol) in TFA (30 mL) was heated at 80 °C for 16 h. The reaction mixture was then concentrated under reduced pressure, and the crude residue was neutralized with saturated NaHCO3 solution; the product was extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by preparative HPLC (neutral method), and the pure fractions were lyophilized to give 2-morpholinoethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1 1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 8.14 (s, 1H), 8.05 (t, J = 8.4 Hz, 2H), 8.00 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 5.6 Hz, 2H), 4.08 (s, 2H), 3.49 (t, J = 4.6 Hz, 4H), 2.61 (t, J = 5.6 Hz, 2H), 2.49 - 2.33 (m, 4H). ES / MS m / z: C 24 H 24Calculated value of N7O3(M+H): 458.19, measured value: 458.32.

[1105] Example 177: 3-Morpholinopropyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1106]

[1107] Steps 1 and 2

[1108] In a method similar to the procedures of Steps 2 and 3 of Example 175, 4-(3-chloropropyl)morpholine and 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid were used, and then 3-morpholinopropyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate was prepared in a method similar to the general procedure for PMB deprotection: 1 HNMR(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 of H N7O3(M+H): 472.21, measured value: 472.50.

[1109] Example 178: 2-((L-

[1110] valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1111]

[1112] Step 1

[1113] At room temperature and under argon, 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. After the reaction mixture was stirred at room temperature for 5 h, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and acidified with 1N HCl solution, then stirred for 10 min. The precipitated solid was filtered, washed with water and dried in vacuo to give 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid (178-a): ES / MS m / z: C 11 H 10 BrN3NaO3 (M+H) calcd: 333.98, found: 334.10.

[1114] Step 2

[1115] At 0 °C and under argon, 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, followed by a solution of dicyclohexylcarbodiimide (3.69 g, 17.96 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure and the resulting crude residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of 0%-30% ethyl acetate to give (tert-butoxycarbonyl)-L-valine 2-hydroxyethyl ester (178-b): 1 H NMR (400 MHz, DMSO-d6) δ 7.11 (d, 2ZH), 4.77 (t, J = 5.4 Hz, 1H), 4.06 (m, 2H), 3.87 (dd, J = 7.8 and 6.0 Hz, 1H), 3.56 (appt q, J = 5.2 Hz, 2H), 2.50 (m, 1H), 2.01 (m, 1H), 1.39 (s, 9H), 0.87 (d, J = 6.6 Hz, 6H).

[1116] Step 3

[1117] At 0 °C and under argon, 4-dimethylaminopyridine (0.2 g, 1.63 mmol) was added 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 (tert-butoxycarbonyl)-L-valine 2-hydroxyethyl ester (178-b, 2.77 g, 10.62 mmol) in dichloromethane (37.5 mL), and then a solution of dicyclohexylcarbodiimide (2.18 g, 10.62 mmol) in dichloromethane (12.5 mL) was added. The mixture was stirred at room temperature for 16 h. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of 0%-60% ethyl acetate, to give 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl ester: ES / MS m / z: C 23 H 32 Calculated for BrN4O7(M + H): 555.15, found: 555.34.

[1118] Step 4

[1119] In a manner analogous to the general procedure for the Suzuki reaction, 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl ester was prepared using 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 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid 2-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl ester: ES / MS m / z: C 46 H 49 Calculated for N7NaO8(M + Na): 850.35, found: 850.86.

[1120] Step 5

[1121] A mixture of 2-((((tert-butoxycarbonyl)-L-valyl)oxy)ethyl) 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylate (4.5 g, 5.44 mmol) in trifluoroacetic acid (45 mL) was stirred at 70 °C for 48 h. After the reaction mixture was concentrated under reduced pressure, the residue was purified by preparative HPLC, and the combined pure fractions were lyophilized to give 2-((L-valyl)oxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate: 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.28 (s, 3H), 8.14 (s, 1H), 8.07 - 8.03 (m, 3H), 7.96 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 6.0 Hz, 1H), 4.56 (m, 1H), 4.55 (m, 2H), 4.43 (m, 1H), 4.08 (s, 2H), 3.92 (m, 1H), 2.05 (h, J = 6.8 Hz, 1H), 0.86 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.8 Hz, 3H). ES / MS m / z: C 25 H 26 alculated for C25H27N7O4 (M+H): 488.20, found: 488.39.

[1122] Example 179: 2-(Phosphonyloxy)ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1123]

[1124] Step 1

[1125] Under argon at 0 °C, to a stirred solution of dibenzyl hydrogen phosphate (117, 20 g, 71.94 mmol) and 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (15.22 g, 86.33 mmol) in THF (200 mL) was added triphenylphosphine (28.27 g, 107.91 mmol), followed by diethyl azodicarboxylate (18.83 g, 107.91 mmol). The resulting mixture was stirred at room temperature for 5 h. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of 0%-10% ethyl acetate, to give dibenzyl (2-((tert-butyldimethylsilyl)oxy)ethyl) phosphate: ES / MS m / z: C 22 H34 Calculated value of O5PSi(M+H): 437.19, measured value: 437.34.

[1126] Step 2

[1127] At room temperature and under argon, Dowex-50W was added to a stirred solution of bis(benzyloxy)(2-((tert-butyldimethylsilyl)oxy)ethyl)phosphonate (23 g, 52.75 mmol) in MeOH (230 mL). The mixture was stirred for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a crude compound. The crude compound was purified by silica gel column chromatography, eluting with a dichloromethane solution of 0%-2% MeOH, to give bis(benzyloxy)(2-hydroxyethyl)phosphonate: ES / MS m / z: C 16 H 20 Calculated value of H O5P(M+H): 323.10, measured value: 323.24.

[1128] Step 3

[1129] At 0 °C and under argon, NEt3 (3.23 mL, 23.28 mmol) was added to a stirred solution of bis(benzyloxy)(2-hydroxyethyl)phosphonate (5 g, 15.52 mmol) in dichloromethane (50 mL), followed by MsCl (2.13 g, 18.63 mmol). After stirring the mixture at room temperature for 5 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to give crude 2-((bis(benzyloxy)phosphoryl)oxy)ethyl methanesulfonate, which was used directly in the next step without any further purification: ES / MS m / z: C 17 H 22 Calculated value of H O7PS(M+H): 401.08, measured value: 401.27.

[1130] Step 4

[1131] At 0 °C under argon, to a stirred mixture of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (4 g, 6.84 mmol) and potassium carbonate (1.41 g, 10.26 mmol) in DMF (40 mL) was added 2-((bis(benzyloxy)phosphoryl)oxy)ethyl methanesulfonate (3.28 g, 8.21 mmol). After stirring the mixture at 50 °C for 14 h, the reaction mixture was diluted with ice water and the product was extracted with ethyl acetate. The organic extract was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluting with a petroleum ether solution of 0%-60% ethyl acetate, to give 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid 2-((bis(benzyloxy)phosphoryl)oxy)ethyl: ES / MS m / z: C 50 H 46 N6O8P (M+H) Calcd: 889.31, Found: 889.77.

[1132] Step 5

[1133] A solution mixture of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid 2-((bis(benzyloxy)phosphoryl)oxy)ethyl (11.5 g, 12.94 mmol) in trifluoroacetic acid (45 mL) was stirred at 70 °C for 20 h. After the reaction mixture was concentrated under reduced pressure, the crude residue was purified by preparative HPLC to afford 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2-(phosphoryloxy)ethyl: 1 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 8.01 - 7.97 (m, 3H), 7.92 (d, J = 7.3 Hz, 1H), 4.36 (m, 2H), 4.06 (s, 2H), 4.03 (m, 2H). ES / MS m / z: C 20 H 18 N6O6P (M+H) Calcd: 469.10, Found: 469.16. Example 180: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (((2-

[1134] ((Phosphonyloxy)ethoxy)carbonyl)oxy)methyl ester

[1135]

[1136] Step 1

[1137] At 0 °C under argon, to a stirred solution of dibenzyl (2-hydroxyethyl)phosphonate (5 g, 15.52 mmol) and pyridine (2.5 mL, 31.04 mmol) in dichloromethane (100 mL), chloroformyl chloride (2.97 g, 23.29 mmol) was added. 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 give 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 ClO7P (M+H) calculated: 415.07, found: 415.31.

[1138] Step 2

[1139] At 0 °C under argon, to a stirred solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (5.0 g, 8.56 mmol) and potassium carbonate (1.77 g, 12.84 mmol) in DMF (50 mL) was added 2-((bis(benzyloxy)phosphoryl)oxy)ethyl (chloromethyl) carbonate (25 g, 10.27 mmol). 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, eluting with a dichloromethane solution of 0%-1% MeOH, to give 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (((2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)carbonyl)oxy)methyl ester: ES / MS m / z: C 52 H 48 N6O 11 P (M+H) calculated: 963.31, found: 963.39.

[1140] Step 3

[1141] A mixture of a solution of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid (((2-((bis(benzyloxy)phosphoryl)oxy)ethoxy)carbonyl)oxy)methyl ester (5.5 g, 5.71 mmol) in trifluoroacetic acid (55 mL) was stirred at 70 °C for 20 h. After the reaction mixture was concentrated under reduced pressure, the crude residue was purified by preparative HPLC to give methyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (((2-(phosphoryloxy)ethoxy)carbonyl)oxy)methyl ester: 1 H NMR (400 MHz, methanol-d4) δ 8.42 (s, 1H), 8.15 (s, 1H), 8.06 (t, J = 8.0 Hz, 2H), 8.00 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H), 4.32 (m, 2H), 4.08 (s, 2H), 4.01 (m, 2H). ES / MS m / z: C 22 H 20 N6O9P (M+H) calcd: 543.10, found: 543.40.

[1142] In a manner analogous to the representative procedure for the Suzuki reaction, the above SEM or PMB deprotection, as well as ester hydrolysis, were carried out using the aforementioned bromide intermediates 18 or 20 and commercially available boronic esters to prepare the following compounds:

[1143] Example 182: 3-(3-chloro-4-fluorophenyl)-1H-pyrazole-4-carboxylic acid

[1144]

[1145] 1 H NMR (400 MHz, methanol-d4) δ 8.17 (s, 1H), 7.90 (dd, J = 7.2, 2.2 Hz, 1H), 7.71 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.29 (t, J = 8.9 Hz, 1H). ES / MS m / z: C 10 H7ClFN2O2 (M+H) calcd: 241.02, found: 241.02.

[1146] Example 183: 3-(3,5-dichlorophenyl)-1H-pyrazole-4-carboxylic acid

[1147]

[1148] 1 1H NMR (400 MHz, methanol-d4) δ 8.21 (s, 1H), 7.77 (d, J = 2.0 Hz, 2H), 7.47 (t, J = 2.0 Hz, 1H). ES / MS m / z: C 10 H7Cl2N2O2 (M+H) Calculated: 256.99, Found: 257.03.

[1149] Example 184: 4-(3-Chloro-4-fluorophenyl)-1H-imidazole-5-carboxylic acid

[1150]

[1151] 1 1H NMR (400 MHz, methanol-d4) 8.12 (dd, J = 7.4, 2.2 Hz, 1H), 7.90 (ddd, J = 8.6, 4.7, 2.2 Hz, 1H), 7.68 (s, 1H), 7.20 (dd, J = 9.2, 8.7 Hz, 1H). ES / MS m / z: C 10 H7ClFN2O2 (M+H) Calculated: 241.02, Found: 240.94.

[1152] Example 185: 4-(3,5-Dichlorophenyl)-1H-imidazole-5-carboxylic acid

[1153]

[1154] 1 1H NMR (400 MHz, methanol-d4) δ 8.03 (s, 2H), 7.67 (s, 1H), 7.31 (s, 1H). ES / MS m / z: C 10 H7Cl2N2O2 (M+H) Calculated: 256.99, Found: 257.03.

[1155] Biological assays

[1156] Biological assay 1: Biochemical cell assay

[1157] Materials

[1158] Glycolate oxidase (GO) was generated at Gilead using the HAO1 sequence according to Jones et al., 2000 (J. Biol. Chem. 275:12590-12597). The Red Hydrogen Peroxide / Peroxidase Detection Kit (Catalog No. A22188) was purchased from Thermo Fisher (Waltham, Massachusetts). Glycolic acid (Catalog No. 124737) and Tris 1M, pH 7.8 (Catalog No. T2569-1L) were from Sigma (St. Louis, Missouri), 10% Tween-20 (Catalog No. 51-12-02) was from SeraCare (Milford, Massachusetts), 2% BSA (Catalog No. BSA-1000) was from Rockland Immunochemicals (Pottstown, Pennsylvania), and black 384-well low-binding plates (Catalog No. 3860) were from Corning (Sunnyvale, California).

[1159] Method

[1160] 1. GO Biochemical Assay

[1161] The GO biochemical enzymatic reaction was carried out in black 384-well low-binding plates 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 a 1:3 serial dilution of the test compound, which was in a buffer containing 50 mM Tris pH 7.8, 0.0025% Tween-20, and 0.02% BSA. 25 nL of 1000X test compound was pre-spotted on the 384-well low-binding plate using an Echo 555 liquid handler (Labcyte Inc., San Jose, California) at an initial concentration of 10 μM, followed by the addition of 5 μL / well of 25 nM GO (5X 5 nM final concentration) and incubation for 15 minutes. 10 μL of 2.5X 0.1 U / mL final concentration of HRP was added to each well, then 10 μL of 2.5X 100 μM final concentration of glycolic acid substrate and 2.5X 50 μM final concentration of Amplex Red were added. The reaction mixture was incubated at room temperature for 20 minutes, and then read using an EnVision plate reader (Perkin Elmer, San Jose, California) at 570 nm excitation and 585 nm emission. Wells containing DMSO were used as negative controls (as 0% inhibition), and wells without the GO enzyme were used as positive controls (as 100% inhibition). The percent inhibition was calculated as: 100% x (well - negative) / (positive - negative).

[1162] 2. HRP Counter Screen Assay

[1163] The HRP rescreening assay was performed in parallel with the GO biochemical assay to exclude compounds that might directly inhibit HRP but have no effect on inhibiting GO. 25 nL of the same set of 1000X test compounds was pre-spotted onto a 384-well low-binding plate as described above in the GO biochemical assay. Subsequently, 10 μL of 2.5X HRP at a final concentration of 0.1 U / mL was added, which was in 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 Amplex Red at a final concentration of 50 μM and 1.67X H2O2 at a final concentration of 10 μM were added to each well. The reaction mixture was mixed and incubated at room temperature for 20 minutes. At the end of the incubation, the plate was read using an Envision plate reader with excitation at 570 nm and emission at 585 nm. Wells containing DMSO were used as negative controls (as 0% inhibition), while wells without the HR enzyme were used as positive controls (as 100% inhibition). The percent inhibition was calculated as described above.

[1164] GO cell-based assay

[1165] 1. GO transient transfection cell-based assay

[1166] Materials

[1167] The HAO1 plasmid DNA was generated by Lake Pharma (Belmont, CA) by cloning the HAO1 cDNA (Jones et al., 2000) into the pcDNA3.1(+)-neomycin vector by PCR. The FuGENE 6 transfection reagent (catalog number E2692) was purchased from Promega (Madison, WI). The CHO-K1 cell line (catalog number ATCC CCL-61) and F-12K medium (catalog number 30-2004) were purchased from ATCC (Manassas, VA). OptiMEM I reduced-serum medium (catalog number 31985-070) was purchased from Gibco / Life Technologies (Grand Island, NY). Fetal bovine serum (FBS) (catalog number SH30071.03) was purchased from HyClone (Logan, UT), and 100X penicillin / streptomycin / L-glutamine (catalog number 30-009-Cl) was purchased from Corning (Fremont, CA). The 384-well black tissue culture plate (catalog number 781086) was purchased from Greiner Bio-one (Monroe, NC). <F

[1168] Methods

[1169] Transient transfection was performed by mixing 3 parts of FuGENE 6 reagent (μl) with one part of HAO1 plasmid DNA or vector control DNA (μg) in OptiMEM I reduced serum medium and incubating for 15 minutes at room temperature. The mixture was then mixed with CHO-K1 cells and dispensed at 45 μL / well, containing 0.025 μg of HAO1 plasmid DNA, 0.075 μL of FuGENE 6, and 4,000 cells, and placed in F-12K medium supplemented with 10% FBS. The cells were cultured in a 37 °C incubator for 48 hours to allow GO expression. The cell medium was then removed and replaced with 25 μL of serially diluted test compound (starting concentration of 1 μM) in a 1:3 dilution and incubated for 1 hour at room temperature. Then, 25 μl of reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) containing HRP (final concentration of 0.1 U / mL), 300 μM glyoxylic acid, and 50 μM Amplex Red were added to each well. The reaction mixture was mixed and incubated for 20 minutes at room temperature, and then read using an EnVision plate reader as described above. Wells containing DMSO were used as negative controls (0% inhibition), while wells transfected with vector control DNA were used as positive controls (100% inhibition). The inhibition rate % was calculated as described above.

[1170] 2. Detection Based on GO Stable Clone Cells

[1171] Materials

[1172] The reagents and tissue culture medium for transient transfection were described in the transient transfection assay section. Rabbit anti-HAO1 antibody (catalog number ab93137) was purchased from Abcam (Cambridge, Massachusetts), and anti-rabbit IgG (H+L), F(ab')2 fragment, Alexa 555 conjugate (catalog number #4413) was purchased from Cell Signaling Technology (Danvers, Massachusetts).

[1173] Methods

[1174] 1) Generation of CHO-K1-HAO1 Stable Clones

[1175] GO plasmid DNA was transiently transfected into CHO-K1 cells in batches and cultured for 48 hours as described above to generate stable clones of GO internally. The cells were then treated with trypsin, and 2000 cells / 200 μl were added to well A1, followed by serial 1:2 dilution to well A2 and continuously diluted to well A12 for 10 96-well tissue culture plates. The cells in A1 - A12 were further serially diluted 1:2 to H1 - H12 and cultured in F-12K medium containing 10% FBS supplemented with 500 μg / mL G418 for two weeks. Colony formation of each plate was monitored under a microscope. Twenty-eight single colonies were picked and amplified to test GO expression.

[1176] Immunocytochemistry for intracellular GO staining

[1177] Intracellular GO staining was performed by first fixing the cells with 50 μL / well of 4% formaldehyde in PBS solution in a 384-well plate for 30 minutes at room temperature, then washing 3 times with 80 μL / well of wash buffer (PBS with 0.05% Tween-20). Then, the cells were permeabilized with 50 μL / well of 0.1% Triton in PBS solution for 30 minutes, washed 3 times, and blocked with 50 μL / well of 3% BSA in PBS solution containing 0.05% Tween-20 for 1 hour. The cells were washed 3 times again, and 50 μL of a solution of rabbit anti-human GO diluted 1:100 in PBS containing 1% BSA and 0.05% Tween-20 was added to each well and cultured overnight at 4°C. The cells were washed 4 times, with 15 minutes of incubation between each wash, and then 40 μL of Alexa Fluor 555-conjugated anti-rabbit IgG (H+L) F(ab')2 fragment diluted 1:250 and Hoechst diluted 1:500 (diluted in 1% BSA and 0.05% Tween-20) were added to each well. The plate was incubated at room temperature for 160 minutes and washed four times after the incubation. Sixty microliters of PBS was added to each well, and the cell images were examined by an ArrayScan XTIHCS reader from Thermo Fisher Scientific (Waltham, Massachusetts).

[1178] 2) Detection of cells with stable clone 2D2 GO enzyme activity

[1179] Pre-spot 25 nL of the test compound into each well of a 384-well tissue culture plate, then dispense 5000 cells / well / 25 μL of clone 2D2 in reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) into all wells except the 22nd column. Add 5000 cells / well / 25 μL of clone 1A1 vector control to the wells of the 22nd column. Incubate the test compound with the cells at room temperature for 1 hour, then add 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), 160 μM glycolic acid, and 50 μM Amplex Red. Mix the reaction and incubate at room temperature for 20 minutes, and measure the fluorescence of the product resorufin as described above. Wells with 2D2 and DMSO are used as negative controls (0% inhibition), while wells with the 1A1 vector control clone are used as positive controls (100% inhibition). Calculate the percentage of inhibition as described above (Table 2).

[1180] Table 2

[1181]

[1182]

[1183]

[1184]

[1185] Biological Assay 2: Oral Bioavailability and PK Studies

[1186] Formulate the oral dose of Example 2 at 1.0 mg / mL in a sterile solution of 50% water, 37.5% PEG 300, and 12.5% DMSO. The dosing group consists of three fasted male Sprague Dawley rats. At the time of dosing, the weight of the animals is between 0.26 and 0.27 kg. For the oral dosing group, the formulated dose is administered by oral gavage at 5.0 mL / kg, for a dose of 5.0 mg / kg. Perform non-compartmental pharmacokinetic analysis on the plasma concentration-time data.

[1187] Table 3

[1188]

[1189] Table 3 shows the mean plasma pharmacokinetic parameters (mean ± SD, n = 3) of Example 2 after oral (PO) administration to SD rats at a dose of 5 mg / kg of Example 2. Table 4 shows the mean plasma pharmacokinetic parameters (mean ± SD, n = 3) of Example 68 after oral administration to SD rats at a dose of 5 mg / kg of Example 2. As shown in Tables 4 and 5, the AUC of Example 2 inf was 1600 ± 280 nM·h, and the C max was 2390 ± 246 nM. The AUC of Example 68 inf was 3250 ± 242 nM·h, and the C max was 2270 ± 171 nM. The bioavailability of Example 68 was estimated to be 19.0% ± 1.4%

[1190] Table 4

[1191]

[1192] Table 5

[1193]

[1194] *From Table 7 below, based on the intravenous (IV) exposure (AUC inf = 3420 nM·hr) of Example 68 at 1.0 mg / kg.

[1195] Relative to the rat hepatic blood flow (CL = 4.0 L / hr / kg), the apparent systemic clearance of Example 68 (CL = 0.95 ± 0.09 L / hr / kg) was lower. The volume of distribution (V ss = 0.44 ± 0.06 L / kg) was less than the volume of total body water (0.7 L / kg). The terminal t 1 / 2 of Example 68 was 1.02 ± 0.06 hours, and the mean residence time (MRT) was 0.47 ± 0.02 hours. The estimated oral bioavailability (%F) was 2.3% ± 0.3%. See Tables 7, 8, and Figure 2 .

[1196] Table 7. Mean plasma pharmacokinetic parameters (mean ± SD, n = 3) of Example 68 after intravenous infusion for 30 minutes at 1 mg / kg in SD rats

[1197]

[1198] Table 8. Mean plasma pharmacokinetic parameters (mean ± SD, n = 3) of Example 68 after an oral dose of 5 mg / kg in SD rats

[1199]

[1200] Example 168 or Example 175 was formulated in a sterile solution of 15% N-methyl-2-pyrrolidone, 55% PEG, and 30% water for oral or intravenous administration. The dosing group consisted of three fasted male SD rats or three fasted male beagle dogs. At the time of dosing, the body weights of the rats were between 0.2 and 0.3 kg, and the body weights of the dogs were between 10.72 and 10.82 kg. For the oral dosing group, the formulated dose was administered at 5.0 mL / kg by oral gavage, at a dose of 5.0 mg / kg or 5.4 mg / kg. For the intravenous dosing group, the formulated dose was 1.00 mg / kg. Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data. The data from these studies are shown in Figure 3 and Figure 4 .

Claims

1. A method for treating patients with recurrent kidney stone formation, comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula III: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein: R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl, cycloalkyl, or heteroaryl optionally substituted with one to three R 1-6 groups; 5 ​ Each R 3 is independently aryl, heteroaryl, or heterocyclic group, wherein each R 3 is optionally substituted with one to three R 6 substituents; Each R 4 is independently halogen, 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 a monocyclic heterocyclic group; each of which is optionally substituted by one to three R 5 ; provided that only one R 4 is a heterocyclic group; Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl, or -OC 1-4 haloalkyl; Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic or heteroaryl; each of which is optionally substituted by one to three C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl; R 7 and R 8 each independently is hydrogen, C 1-4 alkyl, phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which it is attached forms a heterocyclic group; Each R a is independently optionally -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or -OP(O)(OR b )2 substituted C 1-6 alkyl; and Each R b is independently hydrogen or C 1-4 alkyl.

2. The method of claim 1, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising a compound of formula III and a pharmaceutically acceptable excipient.

3. A method for treating patients with recurrent kidney stone formation, comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula IV: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein: R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, C 4 alkyl, cycloalkyl, or heteroaryl optionally substituted with one to three R 1-6 groups; 5 ​ Each R 4 is independently halogen, 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 heterocyclic group; each of which is optionally substituted with one to three R 5 ; provided that only one R 4 is a heterocyclic group; Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl, or -OC 1-4 haloalkyl; Each R a is independently optionally -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or -OP(O)(OR b )2 substituted C 1-6 alkyl; and Each R b is independently hydrogen or C 1-4 alkyl.

4. The method of claim 3, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising a compound of formula IV and a pharmaceutically acceptable excipient.

5. The method of claim 3, wherein R 2 is hydrogen, C 4 alkyl, or cycloalkyl, optionally substituted with one to three R 1-6 groups; Each R 4 is independently -OC 1-6 alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocyclic group; Each R a is independently optionally C alkyl substituted with -NH2 or -OP(O)(OR b )2; and 1-6 alkyl; and R b is hydrogen.

6. The method of claim 4, wherein R 2 is hydrogen, C 4 alkyl, optionally substituted with one to three R 1-6 groups, or cycloalkyl; Each R 4 is independently -OC 1-6 alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocyclic group; Each R a is independently optionally C b alkyl substituted by -NH2 or -OP(O)(OR 1-6 )2; and R b is hydrogen.

7. A method for treating patients with recurrent kidney stone formation, comprising administering to a patient in need thereof a therapeutically effective dose of a compound selected from:

8. The method of claim 7, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable excipient.

9. A method for treating patients with recurrent kidney stone formation, comprising administering to a patient in need thereof a therapeutically effective dose of a compound having the following structure: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof.

10. The method of claim 9, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable excipient.

11. A method for treating patients with recurrent kidney stone formation, comprising administering to a patient in need thereof a therapeutically effective dose of a compound having the following structure: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof.

12. The method of claim 11, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable excipient.

13. A method for inhibiting the production of glyoxylic acid and / or oxalate and / or inhibiting glycolate oxidase (GO) in a patient, comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula III: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein: R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, a C 4 alkyl, cycloalkyl, or a heteroaryl optionally 1-6 substituted with one to three R 5 groups; Each R 3 is independently aryl, heteroaryl, or heterocyclic group, wherein each R 3 is optionally substituted with one to three R 6 substituents; Each R 4 is independently halogen, 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 a monocyclic heterocyclic group; each of which is optionally substituted with one to three R 5 ; provided that only one R 4 is a heterocyclic group; Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl, or -OC 1-4 haloalkyl; Each R 6 is independently cyano, halogen, -C(O)R 7 , -C(O)OR 7 , -C(O)NR 7 R 8 , -S(O)2NR 7 R 8 , -NR 7 C(O)R 8 , -OR 7 , C 1-4 alkyl, -OC 1-4 alkyl, C 1-4 haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclic or heteroaryl; where each is optionally substituted by one to three C 1-4 alkyl, -C(O)OH or C 1-4 haloalkyl; R 7 and R 8 each independently is hydrogen, C 1-4 alkyl, phenyl, pyridyl, or R 7 and R 8 together with the nitrogen atom to which it is attached forms a heterocyclic group; Each R a is independently optionally -NH2, -NHC 1-6 alkyl, -N(C 1-6 alkyl)2 or -OP(O)(OR b )2 substituted C 1-6 alkyl; and Each R b is independently hydrogen or C 1-4 alkyl.

14. The method of claim 13, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising a compound of formula III and a pharmaceutically acceptable excipient.

15. A method for inhibiting the production of glyoxylic acid and / or oxalate in a patient and / or inhibiting glycolate oxidase (GO), comprising administering to a patient in need thereof a therapeutically effective dose of a compound of formula IV: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein: R 2 is hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, a C 4 alkyl, cycloalkyl, or a heteroaryl 1-6 optionally substituted with one to three R 5 groups; Each R 4 is independently halogen, 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 heterocyclic group; each of which is optionally substituted by one to three R 5 ; provided that only one R 4 is a heterocyclic group; Each R 5 is independently cyano, halogen, C 1-4 alkyl, hydroxy, -OC 1-4 alkyl, C 1-4 haloalkyl, or -OC 1-4 haloalkyl; Each R a is independently optionally a C 1-6 alkyl group substituted by -NH2, -NHC 1-6 alkyl, -N(C b alkyl)2 or -OP(O)(OR 1-6 )2; and Each R b is independently hydrogen or a C 1-4 alkyl group.

16. The method of claim 15, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising a compound of formula IV and a pharmaceutically acceptable excipient.

17. The method of claim 15, wherein R 2 is hydrogen, C 4 alkyl, or cycloalkyl, optionally substituted with one to three R 1-6 groups; Each R 4 is independently -OC 1-6 alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocyclic group; Each R a is independently optionally C alkyl substituted with -NH2 or -OP(O)(OR b )2; and 1-6 alkyl; and R b is hydrogen.

18. The method of claim 17, wherein R 2 is hydrogen, C 4 alkyl, or cycloalkyl, optionally substituted with one to three R 1-6 groups; Each R 4 is independently -OC 1-6 alkyl, -OC(O)R a , -OC(O)OR a , -OP(O)(OR b )2, or a monocyclic heterocyclic group; Each R a is independently optionally C alkyl substituted by -NH2 or -OP(O)(OR b )2; and 1-6 alkyl; and R b is hydrogen.

19. A method for inhibiting the production of glyoxylic acid and / or oxalate in a patient and / or inhibiting glycolate oxidase (GO), comprising administering to a patient in need thereof a therapeutically effective dose of a compound selected from:

20. The method according to claim 19, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable excipient.

21. A method for inhibiting the production of glyoxylic acid and / or oxalate in a patient and / or inhibiting glycolate oxidase (GO), comprising administering to a patient in need thereof a therapeutically effective dose of a compound having the following structure: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof.

22. The method of claim 21, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising the compound of claim 21 and a pharmaceutically acceptable excipient.

23. A method for inhibiting the production of glyoxylic acid and / or oxalate in a patient and / or inhibiting glycolate oxidase (GO), comprising administering to a patient in need thereof a therapeutically effective dose of a compound having the following structure: or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analogue thereof.

24. The method of claim 23, comprising administering to a patient in need thereof a therapeutically effective dose of a pharmaceutical composition comprising the compound of claim 23 and a pharmaceutically acceptable excipient.

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