Heterocyclic carboxylates as glycolate oxidase inhibitors

Abstract

The present disclosure generally relates to modulators of human glycolate oxidase and methods of using and making the same.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] Pursuant to 35 U.S.C. §119(e), this application claims the benefit of U.S. Provisional Application Nos. 62 / 929,476, filed on November 1, 2019, and 63 / 093,094, filed on October 16, 2020, each of which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present disclosure relates to compounds, compositions and methods for treating primary hyperoxaluria type 1 and recurrent kidney stone formers. The present disclosure relates to novel substituted heterocyclic carboxylate compounds and methods for preparing the same, as well as their use as therapeutic or preventive agents. In particular, the present disclosure provides novel inhibitors of human glycolate oxidase, pharmaceutical compositions containing such compounds, and methods for using these compounds to treat primary hyperoxaluria type 1 and recurrent kidney stone formers. Background Art

[0004] 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 glycolate oxidase, those patients will show a significant increase in glyoxylate and oxalate production and calcium oxalate stone deposition. Medical procedures to remove kidney stones exist and are effective. However, after these procedures, the recurrence rate of kidney stones can be high (e.g., over 50%). Therefore, drugs that inhibit glycolate oxidase activity are needed to treat PH1 patients and reduce the recurrence rate of kidney stones in kidney stone formers. Summary of the invention

[0005] The present disclosure relates to novel substituted heterocyclic carboxylate compounds that inhibit the activity of human glycolate oxidase, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and the use of such compounds in treating primary hyperoxaluria type 1. The compounds disclosed herein can be used to treat recurrent kidney stone formers.

[0006] In one aspect, a compound having the structure of Formula I is provided:

[0007]

[0008] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein A, R 1 and R 2 As described herein.

[0009] 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 formulae 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 analog thereof.

[0010] Some embodiments provide methods of using (or administering) a compound of Formula I, or a compound of other formulae described throughout, in the treatment of a disease or condition in a mammal, particularly a human, that is treatable by a human glycolate oxidase inhibitor.

[0011] Some embodiments provide methods of using (or administering) the compounds described herein in the treatment of a disease or condition in a mammal, particularly a human, that is treatable by an inhibitor of human glycolate oxidase. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 Shown are 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).

[0013] Figure 2 Shown are the plasma concentration-time curves of Example 68 following 30-minute intravenous infusion at 1.0 mg / kg and oral dose at 5.0 mg / kg in SD rats (mean ± SD, n = 3).

[0014] Figure 3 The plasma concentration-time curves of Example 168 and Example 175 in SD rats are shown.

[0015] Figure 4 The plasma concentration-time profiles of Example 168 and Example 175 in male beagle dogs are shown. DETAILED DESCRIPTION

[0016] Definition and general parameters

[0017] The following description sets forth exemplary methods, parameters, etc. However, it should be appreciated that such description is not intended to limit the scope of the present disclosure, but is provided as a description of exemplary embodiments.

[0018] As used in this specification, the following words, phrases and symbols generally have the meanings set forth below, unless otherwise indicated in the context in which they are used.

[0019] 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. The dash at the front or end of a chemical group is for convenience; chemical groups may be depicted with one or more dashes or without dashes without losing their usual 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.

[0020] The prefix "C u-v " means that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms.

[0021] The modifier "about" used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error associated with measurement of the particular quantity). In addition, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0022] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 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 1-4 Alkyl). 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 particular number of carbon atoms is named by chemical name or identified by molecular formula, all positional isomers having that number of carbon atoms may be included; 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).

[0023] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C 2120 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., C2-4 Examples of the alkenyl group include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0024] "Alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), alkyl of 2-8 carbon atoms (i.e. C 2-8 Alkynyl), alkyl with 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl) or alkyl of 2 to 4 carbon atoms (i.e. C 2-4 The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0025] "Alkoxy" refers to an "alkyl-O-" group. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[0026] "Haloalkoxy" refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen element.

[0027] "Alkylthio" refers to an "alkyl-S-" group.

[0028] "Acyl" refers to a -C(O)R group, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0029] "Amido" refers to a "C-amido" group (referring to the group -C(O)NR y R z ) and "N-amido" groups (referring to the group -NR y C(O)R z ), where R y and R z independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may be optionally substituted.

[0030] "Amino" refers to the group -NR y R z , wherein Ry and Rz are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl or heteroaryl; each of which may be optionally substituted.

[0031] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, an aryl group has 6-20 ring carbon atoms (i.e., C 6-20 aryl), 6-12 carbon ring atoms (i.e., C 6-12 aryl) or 6-10 carbon ring atoms (i.e., C 6-10 The term "aryl" refers to a group consisting of a phenyl group, a naphthyl group, a fluorenyl group, and an anthracenyl group. However, an aryl group does not in any way include or overlap with a heteroaryl group as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is a heteroaryl group. If one or more aryl groups are fused to a heterocyclyl group, the resulting ring system is a heterocyclyl group.

[0032] "Carbamoyl" refers to an "O-carbamoyl" group (referring to -OC(O)NR y R z group) and an "N-carbamoyl" group (referring to an -NR y C(O)OR z A group), wherein Ry and Rz are independently selected from hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may be optionally substituted.

[0033] "Carboxyl ester" refers to -OC(O)R and -C(O)OR, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0034] "Cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings, including fused systems, bridged ring systems, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). Cycloalkyl groups as used herein have 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 The cycloalkyl group may be a cycloalkyl group having 3 to 8 ring carbon atoms (i.e., a C3-8 cycloalkyl group) or 3 to 6 ring carbon atoms (i.e., a C3-6 cycloalkyl group). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] "Imino" refers to a -C(NR)R group, wherein each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0036] "Halogen" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted with more than one halogen, the residue can be referred to by using a prefix corresponding to the number of halogen moieties connected. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two ("two") or three ("three") halogen groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0037] "Heteroalkyl" refers to 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 an unbranched or branched saturated chain with carbon and heteroatoms. For example, 1, 2 or 3 carbon atoms can 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., wherein R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl or heterocyclic radical, each of which can be optionally substituted. The example of heteroalkyl includes-OCH3,-CH2OCH3,-SCH3,-CH2SCH3,-NRCH3, and-CH2NRCH3, wherein R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which can be optionally 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.

[0038] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple condensed rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group 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 carbon ring atoms (i.e., C 3-8and 1-5 heteroatoms, 1-4 heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxane, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxin, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanone The fused heteroaryl rings may be attached via any of the rings of the fused system. Any aromatic ring having single or multiple fused rings containing at least one heteroatom is considered a heteroaryl group, regardless of how it is attached to the rest of the molecule (ie, through any of the fused rings). Heteroaryl groups are not exclusive of or overlapping with aryl groups as defined above.

[0039] "Heterocyclic radical" refers to a saturated or unsaturated cycloalkyl group with one or more ring heteroatoms, which are independently selected from nitrogen, oxygen and sulfur. The term "heterocyclic radical" includes heterocyclic alkenyl (i.e., heterocyclic radicals with at least one double bond), bridged heterocyclic radicals, fused heterocyclic radicals and spiro heterocyclic radicals. Heterocyclic radicals can be monocyclic or polycyclic, wherein polycyclics can be fused rings, bridged rings or spirocyclic rings. Any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclic radical, regardless of how it is connected (i.e., it can be combined by carbon atoms or heteroatoms). In addition, the term heterocyclic radical is intended to include any non-aromatic ring containing at least one heteroatom, which ring can be fused with an aromatic ring or a heteroaryl ring, regardless of how it is connected to the rest of the molecule. As used herein, a heterocyclic radical has 2-20 ring carbon atoms (i.e., C 2-20 Heterocyclic group), 2-12 ring carbon atoms (i.e. C 2-12 Heterocyclic group), 2-10 ring carbon atoms (i.e. C 2-10 Heterocyclic group), 2-8 ring carbon atoms (i.e. C 2-8Heterocyclic group), 3-12 ring carbon atoms (i.e. C 3-12 Heterocyclic group), 3-8 ring carbon atoms (i.e. C 3-8 heterocyclic group) or 3-6 ring carbon atoms (i.e. C 3-6 Heterocyclic radical);Having 1-5 ring heteroatoms, 1-4 ring heteroatoms, 1-3 ring heteroatoms, 1-2 ring heteroatoms or 1 ring heteroatom, the ring heteroatoms are independently selected from nitrogen, sulfur or oxygen, and optional one or more oxo groups. Examples of heterocyclic radicals include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. As used herein, the term "bridged heterocyclic radical" refers to a four-membered to ten-membered ring portion connected at two non-adjacent atoms of a heterocyclic radical, wherein one or more (e.g., 1 or 2) four-membered to ten-membered ring portions have at least one heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. As used herein, bridged heterocyclic radicals include bicyclic and tricyclic systems. Also used in this article, the term "spiro heterocyclic radical" refers to a ring system in which a three-membered to ten-membered heterocyclic radical has one or more additional rings, wherein the one or more additional rings are three-membered to ten-membered cycloalkyl or three-membered to ten-membered heterocyclic radicals, wherein the single atom of one or more additional rings is also the atom of a three-membered to ten-membered heterocyclic radical. The example of a spiro heterocyclic radical ring includes a bicyclic and tricyclic ring system, such as 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.4] octanyl and 6-oxa-1-azaspiro [3.3] heptyl. The example of a fused heterocyclic radical ring includes but is not limited to 1,2,3,4-tetrahydroisoquinolyl, 4,5,6,7-tetrahydrothieno [2,3-c] pyridinyl, indolinyl and isoindolinyl (e.g. 2-methylisoquinoline-1 (2H)-one), wherein the heterocyclic radical can be connected by any ring of the fused system.

[0040] "Oxo" refers to a (=O) or (O) group.

[0041] "Sulfonyl" refers to a -S(O)2R group, where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0042] "Alkylsulfonyl" refers to a -S(O)2R radical where R is alkyl.

[0043] "Alkylsulfinyl" refers to a -S(O)R group where R is alkyl.

[0044] "Thiol" refers to a -SR group where R is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl.

[0045] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" groups or "alkylenyl" groups, "arylene" groups or "arylenyl" groups, respectively. In addition, unless otherwise expressly stated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last-mentioned group contains the atom through which the moiety is attached to the rest of the molecule.

[0046] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that 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.

[0047] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, compounds containing amides can exist in equilibrium with imidic acid tautomers. No matter which tautomer is shown, and no matter how the equilibrium properties between the tautomers are, those of ordinary skill in the art understand that these compounds contain amide tautomers and imidic acid tautomers. Therefore, compounds containing amides are understood to include their imidic acid tautomers. Equally, compounds containing imidic acid should be understood to include their amide tautomers.

[0048] Any formula or structure given herein is also intended to represent unlabeled forms of the compound as well as isotopically labeled forms. An isotopically labeled compound has a structure depicted by a formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds 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, for example, compounds into which a radioactive isotope such as 3 H. 13 C and 14Such isotopically labeled compounds are useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiotherapy of patients.

[0049] The present disclosure also includes "deuterated analogs" of compounds of Formula I, wherein 1 to n hydrogens attached to a carbon atom are replaced by deuterium, wherein n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and, therefore, 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, for example, by using starting materials in which one or more hydrogens are replaced by deuterium.

[0050] Deuterium-labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes (such as deuterium) may provide certain therapeutic advantages that result from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements and / or improvements in therapeutic index. 18 F-labeled compounds can be used for PET or SPECT studies. Isotope-labeled compounds and prodrugs thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the schemes or examples and preparations described below, by replacing non-isotope-labeled reagents with readily available isotope-labeled reagents. It should be understood that deuterium is considered as a substituent in the compounds of Formula I herein.

[0051] The concentration of such heavier isotopes, particularly deuterium, can be defined by an 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. Therefore, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium.

[0052] In many cases, the compounds of the present disclosure form acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0053] 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.

[0054] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of a given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by alkalizing the acid salt solution. On the contrary, if the product is a free base, the addition salt (particularly a pharmaceutically acceptable addition salt) can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to the conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts are derived from inorganic acids, and the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts are derived from organic acids including 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. Likewise, 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, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (i.e., NH2(substituted alkyl)), di(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl)amines (i.e., N(substituted alkyl)3), alkenylamines (i.e., NH2(alkenyl)), dienylamines (i.e., HN(alkenyl)2), tris(substituted alkyl)amines (i.e., N(substituted alkyl)3), Alkenylamine (i.e., N(alkenyl)3), substituted alkenylamine (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amine (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl)amine (i.e., N(substituted alkenyl)3), mono-, di-, or tri-cycloalkylamine (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di-, or tri-aromaticamine (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, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0055] The term "replacement" refers to any one or more hydrogen atoms on a specified atom or group being 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, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halogen, haloalkyl, haloalkoxy, assorted alkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The polymer or similar indefinite structure obtained by defining the substituent with unlimited additional other substituents (for example, substituted aryl with substituted alkyl, itself substituted by substituted aryl, further substituted assorted alkyl, etc.) is not intended to be included in the present application. Unless otherwise indicated, the maximum number of continuous substitutions in the compounds described herein is three. For example, the continuous substitution of substituted aryl with other two substituted aryl is limited to ((substituted aryl) substituted aryl). Similarly, the above definition is not intended to include unallowed substitution patterns (e.g., methyl substituted by 5 fluorine or heteroaryl with two adjacent oxygen ring atoms). Such unallowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" can describe other chemical groups defined herein. Unless otherwise specified, when a group is described as optionally substituted, any substituent of the group itself is unsubstituted. For example, in some embodiments, the term "substituted alkyl" refers to an alkyl with one or more substituents, which include hydroxyl, halogen, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl. In other embodiments, one or more substituents may be further substituted by halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0056] In certain embodiments, as used herein, the phrase "one or more" refers to one to five. In certain embodiments, as used herein, the phrase "one or more" refers to one to three.

[0057] As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated. Supplementary active ingredients may also be incorporated into the composition.

[0058] A "solvate" is formed by the interaction of a solvent and a compound. Also provided are solvates of the salts of the compounds described herein. Also provided are hydrates of the compounds described herein.

[0059] Compound

[0060] Provided herein are compounds useful as glycolate oxidase inhibitors. In certain embodiments, provided herein are compounds of formula I:

[0061]

[0062] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0063] A is N or CH;

[0064] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0065] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0066] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0067] Each R 4 are independently halogen, hydroxyl, -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 Replace; if there is only one R 4 is a heterocyclic group;

[0068] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0069] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0070] R 7 and R 8 are 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, they form a heterocyclic group;

[0071] Each R a are 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;

[0072] Each R b are independently hydrogen or C 1-4 alkyl.

[0073] In some embodiments, when A is N, at least one of the following is true:

[0074] 1) R 1 Optionally 1-3 R 3 Substituted fused tricyclic ring;

[0075] 2) R 1 is an optionally substituted fused bicyclic ring, which is replaced by at least one R 3 Replacement, R 3 Selected from cyano, -C≡CC 1-9 Alkyl, - with 1-3 R 6 Substituted C 1-9 Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OC 1-4 alkyl, -O-phenyl, -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which may be optionally substituted by 1 to 3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0076] 3) R 1 is a substituted monocyclic ring, which is substituted by at least one R selected from the following 3 replace:

[0077] i) Cyano, -C≡CC 1-9 Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 , -C≡C-aryl, -C≡C-heteroaryl or -C≡C-heterocyclyl, each of which may be optionally substituted by 1 to 3 R 6 replace;

[0078] ii) monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclic group, each of which is further substituted by 1 to 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0079] iii) optionally substituted fused aryl, optionally substituted fused heteroaryl or optionally substituted fused heterocyclyl, each of which is further optionally substituted by 1-3 R 6 replace; or

[0080] iv) Formula-L 1 -L 2 A substituent, wherein L 1 is aryl, heteroaryl or heterocyclic, each of which is optionally substituted by 1-3 R 6 Replace; and L 2 is phenyl, heterocyclic or heteroaryl, each of which is optionally substituted by 1 to 3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution; or

[0081] 4) R 2 -(CH2CH2O) 1-9 CH2CH2OCH3, 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 Substituted heteroaryl; and

[0082] In some embodiments, when A is CH, R 1 is not a 10-membered heteroaryl substituted by methoxy or methyl; or R 1 is not C6 aryl optionally substituted by 1-3 substituents independently selected from cyano, halogen, C 1-4 Alkyl, -OR 7 , C 1-4 Halogenated alkyl and NR 7 R 8 , where R 7 and R 8 are independently hydrogen or C 1-4 Alkyl; or R 1 Not unsubstituted C10 Aryl; or R 1 It is not an unsubstituted heterocyclic group.

[0083] In one aspect, a compound having the structure of Formula I is provided:

[0084]

[0085] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0086] A is N or CH;

[0087] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0088] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 alkyl, or optionally 1-3 R 5 substituted heteroaryl;

[0089] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently a bond or -C≡C-;

[0090] Each R 4 are independently halogen, hydroxyl, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or a monocyclic heterocyclic group; each of which is optionally substituted by 1-3 R 5 Replace; if there is only one R 4 is a heterocyclic group;

[0091] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0092] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0093] R 7 and R 8 are 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 they form a heterocyclic group.

[0094] In certain embodiments, when R 1 When it is phenyl, R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 to 3 R 6 replace.

[0095] In certain embodiments, when R 1 When it is a heteroaryl group, R 2 Not unsubstituted C 1-6 alkyl.

[0096] In certain embodiments,

[0097] A is N or CH;

[0098] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0099] R 2Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 alkyl, or optionally 1-3 R 5 substituted heteroaryl;

[0100] Each R 3 are independently halogen, -LC 1-9 Alkyl, -C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 , -OR 7 , -L-5-6 membered heteroaryl or -L-5-6 membered heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently a bond or -C≡C-;

[0101] Each R 4 are independently halogen, hydroxyl, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or a monocyclic heterocyclic group; each of which is optionally substituted by 1-3 R 5 Replace; if there is only one R 4 is a heterocyclic group;

[0102] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0103] Each R 6 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 haloalkyl; and

[0104] R 7 and R 8 are independently hydrogen or C 1-4 Alkyl, or R 7 and R 8 Together with the nitrogen atom to which they are attached they form -(CH2)2-O-(CH2)2-.

[0105] Also provided are compounds of formula IIa:

[0106]

[0107] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0108] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0109] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 alkyl, or optionally 1-3 R 5 substituted heteroaryl;

[0110] Each R 3 are 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 heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently a bond or -C≡C-;

[0111] Each R 4 are independently halogen, hydroxyl, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or a monocyclic heterocyclic group; each of which is optionally substituted by 1-3 R 5 Replace; if there is only one R 4 is a heterocyclic group;

[0112] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0113] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0114] R 7 and R 8 are 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 they form a heterocyclic group.

[0115] In certain embodiments, compounds of Formula IIa are provided:

[0116]

[0117] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0118] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0119] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0120] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0121] Each R 4 are independently halogen, hydroxyl, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2, -OC(O)Ra, -OC(O)ORa, -OP(O)(ORb)2 or a monocyclic heterocyclic group; each of which is optionally substituted by 1-3 R 5 Replace; if there is only one R 4 is a heterocyclic group;

[0122] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0123] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0124] R 7 and R 8 are independently hydrogen, C 1-4 Alkyl or phenyl, pyridyl, or R7 and R 8 Together with the nitrogen atom to which they are attached, they form a heterocyclic group;

[0125] Each Ra is independently optionally substituted with -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or -OP(O)(ORb)2 substituted C 1-6 alkyl;

[0126] Each Rb is independently hydrogen or C 1-4 alkyl.

[0127] In some embodiments, for compounds of Formula IIa, at least one of the following is true:

[0128] 1) R 1 Optionally 1-3 R 3 Substituted fused tricyclic ring;

[0129] 2) R 1 is an optionally substituted fused bicyclic ring, which is replaced by at least one R 3 Replacement, R 3 Selected from cyano, -C≡CC 1-9 Alkyl, - with 1-3 R 6 Substituted C 1-9 Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OC 1-4 alkyl, -O-phenyl, -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which may be optionally substituted by 1 to 3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0130] 3) R 1 is a substituted monocyclic ring, which is substituted by at least one R selected from the following 3 replace:

[0131] i) Cyano, -C≡CC 1-9 Alkyl, -C≡CC 1-4 Haloalkyl, -C≡C-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 , -C≡C-aryl, -C≡C-heteroaryl or -C≡C-heterocyclyl, each of which may be optionally substituted by 1 to 3 R 6 replace;

[0132] ii) monocyclic aryl, monocyclic heteroaryl or monocyclic heterocyclic group, each of which is further substituted by 1 to 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0133] iii) optionally substituted fused aryl, optionally substituted fused heteroaryl or optionally substituted fused heterocyclyl, each of which is further optionally substituted by 1-3 R 6 replace; or

[0134] iv) Formula-L 1 -L 2 A substituent, wherein L 1 is aryl, heteroaryl or heterocyclic, each of which is optionally substituted by 1-3 R 6 Replace; and L 2 is phenyl, heterocyclyl or heteroaryl, each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution; or

[0135] 4) R 2 -(CH2CH2O) 1-9 CH2CH2OCH3, 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 Substituted heteroaryl.

[0136] Also provided are compounds of formula IIb:

[0137]

[0138] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0139] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0140] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0141] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0142] Each R 4 are independently halogen, hydroxyl, -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 Replace; if there is only one R 4 is a heterocyclic group;

[0143] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0144] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0145] R 7 and R 8 are 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, they form a heterocyclic group;

[0146] Each R a are independently optionally substituted with -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or -OP(O)(ORb)2 substituted C 1-6 alkyl;

[0147] Each R b are independently hydrogen or C 1-4 alkyl.

[0148] In some embodiments, for the compound of Formula IIb, R 1 is not a 10-membered heteroaryl substituted by methoxy or methyl; or R 1 is not C6 aryl optionally substituted by 1-3 substituents independently selected from cyano, halogen, C 1-4 Alkyl, -OR 7 , C 1-4 Halogenated alkyl and NR 7 R 8 , where R 7 and R 8 are independently hydrogen or C1-4 Alkyl; or R 1 Not unsubstituted C 10 Aryl; or R 1 It is not an unsubstituted heterocyclic group.

[0149] In certain embodiments, A is N. In certain embodiments, A is CH.

[0150] In certain embodiments, R 1 Optionally 1-3 R 3 Substituted aryl.

[0151] In certain embodiments, R 1 Optionally 1-3 R 3 Substituted heteroaryl.

[0152] In certain embodiments, R 1 Optionally 1-3 R 3 Substituted heterocyclic group.

[0153] In certain embodiments, R 1 Optionally 1-3 R 3 Substituted cycloalkyl.

[0154] In certain embodiments, R 1 for Each n is independently 1, 2 or 3, and Y is CR 8 R 9 , C(O), O or NR 10 ; R 8 and R 9 are independently hydrogen, halogen or C 1-4 alkyl; and R 10 is hydrogen or C 1-4 alkyl.

[0155] In certain embodiments, L is a bond (ie, absent). In certain embodiments, L is -C≡C-.

[0156] In certain embodiments, R 8 and R 9 In certain embodiments, R 8 and R 9 Each is fluorine.

[0157] In certain embodiments, R 8 and R 9 Each is hydrogen.

[0158] In certain embodiments, R 2 For hydrogen.

[0159] In certain embodiments, R 3 For halogen, C 1-9 Alkyl, C 1-4 Haloalkyl or -OR 7 .

[0160] In certain embodiments, at least one R 3 For halogen, C 1-9 Alkyl or -OR 7 In certain embodiments, R 3 For halogen, C 1-9 Alkyl or -OR 7 .

[0161] In certain embodiments, at least one R 3 is fluorine, chlorine, bromine, methyl, tert-butyl, methoxy or phenoxy. 3 is fluorine, chlorine, bromine, methyl, tert-butyl, methoxy or phenoxy.

[0162] In certain embodiments, R 3 Optionally 1-3 R 6 Substituted aryl.

[0163] In certain embodiments, R 3 for

[0164] In certain embodiments, at least one R 3 is an aryl group substituted by a phenyl group, a heterocyclyl group or a heteroaryl group. 3 It is an aryl group substituted by a phenyl group, a heterocyclic group or a heteroaryl group.

[0165] In certain embodiments, at least one R 3 for

[0166]

[0167] In certain embodiments, R 3 for

[0168]

[0169] In certain embodiments, at least one R 3 is an aryl group substituted by a heteroaryl group, the heteroaryl group being C 1-4 Alkyl, -C(O)OH or C 1-4 In certain embodiments, R 3 is an aryl group substituted by a heteroaryl group, the heteroaryl group being C 1-4Alkyl, -C(O)OH or C 1-4 Haloalkyl substitution.

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

[0171] In certain embodiments, R 3 for

[0172] In certain embodiments, at least one R 3 Optionally 1-3 R 6 In certain embodiments, R 3 Optionally 1-3 R 6 Substituted heterocyclic group.

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

[0174] In certain embodiments, at least one R 3 Optionally 1-3 R 6 In certain embodiments, R 3 Optionally 1-3 R 6 Substituted heteroaryl.

[0175] In certain embodiments, at least one R 3 for In certain embodiments, R 3 for

[0176] In certain embodiments, R 2 is hydrogen, optionally substituted by 1-3 R 4 Substituted C 1-6 Alkyl or cycloalkyl; each R 4 independently -OC(O)R a 、-OC(O)OR a 、-OP(O)(OR b )2 or a monocyclic heterocyclic group; provided that there is only one R 4 is a heterocyclic group; each R a are independently optionally substituted with -NH2 or -OP(O)(OR b )2 substituted C1-6 alkyl; and R b For hydrogen.

[0177] In certain embodiments, provided herein are compounds of formula III:

[0178]

[0179] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein:

[0180] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0181] Each R 3 are independently aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1-3 R 6 replace;

[0182] Each R 4 are independently halogen, hydroxyl, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6 Alkyl)2, -OC(O)R a 、-OC(O)ORa、-OP(O)(OR b )2 or a monocyclic heterocyclic group; each of which is optionally substituted by 1-3 R 5 Replace; if there is only one R 4 is a heterocyclic group;

[0183] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0184] Each R 6 are 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 、-OR7 , C 1-4 Alkyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl, -OC 1-4 haloalkyl, phenyl, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0185] R 7 and R 8 are 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, they form a heterocyclic group;

[0186] Each R a are independently optionally substituted with -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or -OP(O)(ORb)2 substituted C 1-6 alkyl; and

[0187] Each R b are independently hydrogen or C 1-4 alkyl.

[0188] In certain embodiments, provided herein are compounds of formula IV:

[0189]

[0190] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein:

[0191] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0192] Each R 4 are independently halogen, hydroxyl, -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 R5 Replace; if there is only one R 4 is a heterocyclic group;

[0193] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0194] Each R a are 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; and

[0195] Each R b are independently hydrogen or C 1-4 alkyl.

[0196] In certain embodiments, R 2 is hydrogen, optionally substituted by 1-3 R 4 Substituted C 1-6 In certain embodiments, R 2 is hydrogen or optionally 1-3 R 4 Substituted C 1-6 In certain embodiments, R 2 is hydrogen or optionally 1 R 4 Substituted C 1-6 In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 Optionally 1-3 R 4 Substituted C 1-6 In certain embodiments, R 2 C 1-6 In certain embodiments, R 2 C 1-4 alkyl.

[0197] In certain embodiments, R 2 is hydrogen, optionally substituted by 1-3 R 4 Substituted C 1-6 Alkyl or cycloalkyl; each R 4 Independently for -OC 1-6 Alkyl, -OC(O)R a 、-OC(O)OR a ,-OP(O)(OR b )2 or a monocyclic heterocyclic group; each Ra are independently optionally substituted with -NH2 or -OP(O)(OR b )2 substituted C 1-6 alkyl; and R b For hydrogen.

[0198] In certain embodiments, each R 4 Independently for -OC 1-6 Alkyl, -OC(O)R a 、-OC(O)OR a ,-OP(O)(OR b )2 or a monocyclic heterocyclic group; wherein each R a are independently optionally substituted with -NH2 or -OP(O)(OR b )2 substituted C 1-6 Alkyl, and R b For hydrogen.

[0199] In certain embodiments, each R 4 independently -OC(O)R a 、-OC(O)OR a ,-OP(O)(OR b )2 or a monocyclic heterocyclic group; wherein each R a are independently optionally substituted with -NH2 or -OP(O)(OR b )2 substituted C 1-6 Alkyl, and R b For hydrogen.

[0200] In certain embodiments, a compound selected from Table 1 or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is provided. In certain embodiments, the compound is selected from the compounds of Table 1:

[0201] Table 1

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212] In certain embodiments, provided are compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof. In certain embodiments, the compound is selected from:

[0213]

[0214] In certain embodiments, provided are compounds described herein or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, or deuterated analogs thereof. In certain embodiments, the compound is selected from:

[0215]

[0216]

[0217] Where R 2 As defined herein.

[0218] In certain embodiments, R 2 Optionally 1-3 R 4 Substituted C 1-6 In certain embodiments, R 2 C 1-6 In certain embodiments, R 2 It is ethyl.

[0219] In certain embodiments, the compound is selected from:

[0220]

[0221] Typically, the specific compounds exemplified herein are named using ChemBioDraw Ultra. However, it will be appreciated 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 symbols generally recognized in the chemical arts, including, for example, Chemical Abstracts Service (CAS) and International Union of Pure and Applied Chemistry (IUPAC). Other compounds or groups may be named using common names, systematic names, or non-systematic names.

[0222] In certain embodiments, there is provided an optical isomer, racemate or other mixture of a compound described herein or a pharmaceutically acceptable salt thereof or mixture. 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, for example, conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, such as using a chiral high pressure liquid chromatography (HPLC) column.

[0223] Compositions provided herein containing compounds described herein or pharmaceutically acceptable salts, isomers or mixtures thereof may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein, as if each and all isomeric forms were specifically and individually listed.

[0224] In certain embodiments, chelates, non-covalent complexes, and mixtures thereof of the compounds described herein, or pharmaceutically acceptable salts, tautomers, stereoisomers, mixtures of stereoisomers, prodrugs, or deuterated analogs thereof, are also provided. A "chelate" is formed by the coordination of a compound 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 bonds, and electrostatic interactions (also known as ionic bonds).

[0225] In certain embodiments, prodrugs of the compounds described herein are provided. "Prodrug" refers to any compound that, when administered to a biological system, produces a drug or active ingredient due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and / or a metabolic chemical reaction. Thus, a prodrug is a covalently modified analog or latent form of a therapeutically active compound. Non-limiting examples of prodrugs include ester moieties, quaternary ammonium moieties, diol moieties, and the like.

[0226] In certain embodiments, there is provided a compound of Formula I or Formula IIa, wherein R 1 for

[0227]

[0228]

[0229] Each R 12 are independently hydrogen, C 1-9 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-15Cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted by 1-4 Z 1b group substitution; and

[0230] Each Z 1b are independently oxo, thio, 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, -O(C 1-9 Alkyl), -O(C 2-6 -O(C 2-6 Alkynyl), -O(C 3-15 Cycloalkyl), -O(C 1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C 1-9 Alkyl), -NH(C 2-6 -NH(C 2-6 Alkynyl), -NH(C 3-15 Cycloalkyl), -NH(C 1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1-9 Alkyl)2, -N(C 3-15 Cycloalkyl)2, -N(C 2-6 Alkenyl)2, -N(C 2-6 Alkynyl)2, -N(C 3-15 Cycloalkyl)2, -N(C 1-8 haloalkyl)2, -N(aryl)2, -N(heteroaryl)2, -N(heterocyclyl)2, -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 Alkyl)(C 2-6 alkenyl), -N(C 1-9 Alkyl)(C 2-6 Alkynyl), -N(C 1-9 Alkyl)(C 3-15 Cycloalkyl), -N(C 1-9 Alkyl)(C 1-8 Haloalkyl), -N(C 1-9 alkyl)(aryl), -N(C 1-9 alkyl)(heteroaryl), -N(C 1-9 alkyl)(heterocyclic), -C(O)(C 1-9 alkyl), -C(O)(C 2-6alkenyl), -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)(heterocyclyl), -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(heterocyclyl), -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(heterocyclyl), -C(O)N(C 1-9 Alkyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(C 2-6 Alkenyl)2, -C(O)N(C 2-6 Alkynyl)2, -C(O)N(C 3-15 Cycloalkyl)2, -C(O)N(C 1-8 haloalkyl)2, -C(O)N(aryl)2, -C(O)N(heteroaryl)2, -C(O)N(heterocyclyl)2, -NHC(O)(C 1-9 Alkyl), -NHC(O)(C 2-6 -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)(heterocyclyl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 2-6 alkenyl), -NHC(O)O(C 2-6 Alkynyl), -NHC(O)O(C 3-15 Cycloalkyl), -NHC(O)O(C 1-8haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C 1-9 alkyl), -NHC(O)NH(C 2-6 alkenyl), -NHC(O)NH(C 2-6 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(heterocyclyl), -SH, -S(C 1-9 Alkyl), -S(C 2-6 -S(C 2-6 Alkynyl), -S(C 3-15 Cycloalkyl), -S(C 1-8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C 1-9 Alkyl), -N(C 1-9 Alkyl)(S(O)(C 1-9 alkyl), -S(O)N(C 1-9 Alkyl)2, -S(O)(C 1-9 alkyl), -S(O)(NH)(C 1-9 Alkyl), -S(O)(C 2-6 -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)(heterocyclyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 2-6 -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(heterocyclyl), -S(O)2NH(C 1-9 alkyl) or -S(O)2N(C 1-9 Alkyl)2;

[0231] wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group is optionally substituted by 1-4 of the following groups: halogen, C 1-9 Alkyl, C 1-8 Haloalkyl, -OH, -NH2, -NH(C 1-9Alkyl), -NH(C 3-15 Cycloalkyl), -NH(C 1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C 1-9 Alkyl)2, -N(C 3-15 Cycloalkyl)2, -NHC(O)(C 3-15 Cycloalkyl), -NHC(O)(C 1-8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C 1-9 alkyl), -NHC(O)O(C 2-6 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(heterocyclyl), -NHC(O)NH(C 1-9 alkyl), -S(O)(NH)(C 1-9 Alkyl), -S(O)2(C 1-9 Alkyl), -S(O)2(C 3-15 Cycloalkyl), -S(O)2(C 1-8 haloalkyl), -S(O)2(aryl), -S(O)2(heteroaryl), -S(O)2(heterocyclyl), -S(O)2NH(C 1-9 alkyl), -S(O)2N(C 1-9 Alkyl)2, -O(C 3-15 Cycloalkyl), -O(C 1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), or O(C 1-9 alkyl).

[0232] In certain embodiments, a compound of Formula I or any subformula provided herein is provided, wherein R 2 for

[0233]

[0234] Such substituents also include all individual stereoisomers and mixtures thereof, including but not limited to chirality at the phosphorus atom, such as in the exemplary moieties shown above.

[0235] Also provided herein are the in vivo metabolic products of the compounds described herein. These products may result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compounds, primarily due to enzymatic processes.

[0236] Therapeutic uses of compounds

[0237] "Treatment" or "treating" is a method of obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the extent of the disease or condition); b) slowing or preventing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis); and / or c) relieving the disease, i.e., causing regression of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another drug, delaying the progression of the disease, improving the quality of life, and / or prolonging survival).

[0238] "Prevention" or "preventing" refers to any treatment of a disease or condition so that clinical symptoms of the disease or condition do not develop. In some embodiments, the compound can be administered to a subject (including a human) who is at risk for the disease or condition or has a family history of the disease or condition. Type 1 primary hyperoxaluria 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.

[0239] "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.

[0240] The term "therapeutically effective amount" or "effective amount" of a compound described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, refers to an amount sufficient to effect treatment to provide a therapeutic benefit (e.g., improvement of symptoms or slowing of disease progression) when administered to a subject. For example, a therapeutically effective amount can be an amount sufficient to alleviate the symptoms of a disease or condition responsive to inhibition of glycolate oxidase activity. The therapeutically effective amount can vary depending on the subject, the disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the mode of administration, which can be readily determined by one skilled in the art.

[0241] The term "inhibit" means a decrease in the baseline activity of a biological activity or process. "Inhibiting the activity of glycolate oxidase" or variants thereof means that the activity of glycolate oxidase is reduced as a direct or indirect response to the presence of a compound of the present application relative to the activity of glycolate oxidase in the absence of a compound of the present application. "Inhibiting glycolate oxidase" means that the activity of glycolate oxidase is reduced as a direct or indirect response to the presence of a compound described herein relative to the activity of glycolate oxidase in the absence of a compound described herein. In some embodiments, the inhibition of glycolate oxidase activity can be compared in the same subject or in other subjects who have not received treatment prior to treatment.

[0242] The methods described herein can be applied to cell populations in vivo or in vitro. "In vivo" means in a living body, such as in an animal or human body. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside the living body. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. These samples can be obtained by methods known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. 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 best regimen and / or dosage for administering glycolate oxidase inhibitors for a given indication, cell type, individual, and other parameters. The information collected from this use can be used for experimental purposes or clinically for formulating in vivo treatment regimens. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below 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 known to those skilled in the art.

[0243] Compounds disclosed herein can be used to treat, prevent, diagnose or monitor diseases or conditions mediated by glycolate oxidase. Non-limiting examples of diseases or conditions mediated by glycolate oxidase include, but are not limited to, nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, type 1 hyperoxaluria, hyperoxaluria, glycolic aciduria, end-stage renal disease (ESRD), renal failure, renal transplant failure and type II diabetes.

[0244] In certain embodiments, the compounds disclosed herein can be used to treat, prevent, diagnose or monitor diseases or conditions mediated by oxalate or calcium oxalate or glycolate oxidase. In certain embodiments, the disease or condition is nephrolithiasis (kidney stones), nephrocalcinosis, bladder stones, type 1 hyperoxaluria, hyperoxaluria, glycolic aciduria, end-stage renal disease (ESRD), renal failure, renal transplant failure and type II diabetes.

[0245] In further embodiments, methods of alleviating symptoms of a disease or disorder mediated by glycolate oxidase are provided. In some embodiments, the method comprises 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 improve (i.e., reduce the severity of) the symptoms.

[0246] In further embodiments, methods of alleviating symptoms of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase are provided. In some embodiments, the method comprises identifying a mammal having symptoms of a disease or disorder mediated by oxalate or calcium oxalate or glycolate oxidase, and providing the mammal with a compound as described herein in an amount effective to improve (i.e., reduce the severity of) the symptoms.

[0247] In some embodiments, the disease or condition mediated by glycolate oxidase is kidney stone formation. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is kidney stone formation. In specific embodiments, kidney stone formation is recurrent. In specific embodiments, kidney stone formation is associated with type 1 primary hyperoxaluria.

[0248] In some embodiments, the disease or condition mediated by glycolate oxidase is renal failure, including failure of a single kidney and failure of both kidneys. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is renal failure. In some embodiments, renal failure is failure of a single kidney or both kidneys.

[0249] In some embodiments, the disease or condition prevented is renal transplant failure.

[0250] In some embodiments, the disease or condition 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 condition mediated by oxalate or calcium oxalate or glycolate oxidase is diabetes. In some embodiments, diabetes is type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glucose or impaired glucose tolerance. Type 1 diabetes is also called insulin-dependent diabetes (IDDM). Type 2 diabetes is also called non-insulin-dependent diabetes (NIDDM).

[0251] In some embodiments, the disease or condition mediated by glycolate oxidase is bladder stone formation. In some embodiments, the disease or condition mediated by oxalate or calcium oxalate or glycolate oxidase is bladder stone formation.

[0252] Criteria that can be used to assess disease activity in subjects with type 1 primary hyperoxaluria can be found in Brooks et al. (2016) Am. J. Nephrol. 43, 4: 293-303. Oxalate and calcium levels can be monitored in urine.

[0253] The currently disclosed treatment methods can also be applied to any time point in the disease process. In certain embodiments, the method is applied to a subject suffering from type 1 primary hyperoxaluria in the remission period (i.e., inactive disease, after kidney transplantation). In such embodiments, the method of the present invention provides benefits by extending the remission period (e.g., extending the inactive disease period) or by preventing, reducing or delaying the onset of active disease. An example is the increase in the interval between kidney stone events. In other embodiments, the method can be applied to a subject suffering from type 1 primary hyperoxaluria in the active disease period. This method provides benefits by shortening the duration of the active disease period, alleviating or improving one or more symptoms of type 1 primary hyperoxaluria, or treating type 1 primary hyperoxaluria. This improvement can be the size, quantity or frequency of reducing kidney stones.

[0254] Measures used to determine treatment efficacy for type 1 primary hyperoxaluria in clinical practice have been described and include, for example: symptom control; calcium oxalate concentrations in body fluids; renal function measures; and improved quality of life.

[0255] In certain embodiments, provided herein is a method of treating primary hyperoxaluria type 1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutical composition described herein, or a compound of formula I:

[0256]

[0257] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0258] A is N or CH;

[0259] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0260] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0261] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0262] Each R 4 are independently halogen, hydroxyl, -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 Replace; if there is only one R 4 is a heterocyclic group;

[0263] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0264] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0265] R 7 and R 8 are 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, they form a heterocyclic group;

[0266] Each R a are 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; and

[0267] Each R b are independently hydrogen or C 1-4 alkyl.

[0268] In certain embodiments, when R 1 When it is phenyl, R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 to 3 R 6 Replace; and when R 1 When it is a heteroaryl group, R 2 Not unsubstituted C 1-6 alkyl.

[0269] In certain embodiments, provided herein is a method of treating a recurrent kidney stone former, 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:

[0270]

[0271] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0272] A is N or CH;

[0273] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0274] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0275] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0276] Each R 4 are independently halogen, hydroxyl, -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 R5 Replace; if there is only one R 4 is a heterocyclic group;

[0277] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0278] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0279] R 7 and R 8 are 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, they form a heterocyclic group;

[0280] Each R a are 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; and

[0281] Each R b are independently hydrogen or C 1-4 alkyl.

[0282] In certain embodiments, when R 1 When it is phenyl, R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 to 3 R 6 Replace; and when R 1When it is a heteroaryl group, R 2 Not unsubstituted C 1-6 alkyl.

[0283] In certain embodiments, provided herein are methods of inhibiting the production of glyoxylate and / or oxalate 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:

[0284]

[0285] or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers or deuterated analog thereof, wherein

[0286] A is N or CH;

[0287] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0288] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0289] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0290] Each R 4 are independently halogen, hydroxyl, -OC 1-6 Alkyl, -NH2, -NHC 1-6 Alkyl, -N(C 1-6Alkyl)2, -OC(O)R a 、-OC(O)OR a 、-OP(O)(OR b )2 or a monocyclic heterocyclic group; each of which is optionally substituted by 1-3 R 5 Replace; if there is only one R 4 is a heterocyclic group;

[0291] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0292] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0293] R 7 and R 8 are 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, they form a heterocyclic group;

[0294] Each R a are independently optionally substituted with -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or -OP(O)(ORb)2 substituted C 1-6 alkyl; and

[0295] Each R b are independently hydrogen or C 1-4 alkyl.

[0296] In some embodiments, when R1 When it is phenyl, R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 to 3 R 6 Replace; and when R 1 When it is a heteroaryl group, R 2 Not unsubstituted C 1-6 alkyl.

[0297] In certain embodiments, the use of the compounds described herein or pharmaceutical compositions described herein is to control or inhibit the development of recurrent kidney stone formers in a patient in need thereof.

[0298] In certain embodiments, the use of a compound of Formula I or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, or deuterated analog thereof is to control or inhibit the production of recurrent kidney stone formers in a patient in need thereof, wherein the compound of Formula I:

[0299]

[0300] A is N or CH;

[0301] R 1 is alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by 1 to 3 R 3 replace;

[0302] R 2 Hydrogen, -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl or optionally 1-3 R 5 substituted heteroaryl;

[0303] Each R 3 are independently cyano, halogen, -LC 1-9 Alkyl, -LC 1-4 Halogenated alkyl, -L-OC 1-4 Haloalkyl, -NR 7 R 8 、-C(O)NR 7 R 8 、-S(O)2NR 7 R 8 、-NR 7 C(O)R 8 、-OR 7 , -L-aryl, -L-heteroaryl or -L-heterocyclyl, each of which is optionally substituted by 1-3 R 6 substituted, and each L is independently -C≡C- or L is absent;

[0304] Each R 4 are independently halogen, hydroxyl, -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 Replace; if there is only one R 4 is a heterocyclic group;

[0305] Each R 5 are independently cyano, halogen, C 1-4 Alkyl, hydroxyl, -OC 1-4 Alkyl, C 1-4 Haloalkyl or -OC 1-4 Haloalkyl;

[0306] Each R 6 are 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, heterocyclyl or heteroaryl; each of which is optionally substituted by 1-3 C 1-4 Alkyl, -C(O)OH or C 1-4 haloalkyl substitution;

[0307] R 7 and R 8 are 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, they form a heterocyclic group;

[0308] Each R a are independently optionally substituted with -NH2, -NHC 1-6 Alkyl, -N(C 1-6 alkyl)2 or -OP(O)(ORb)2 substituted C 1-6 alkyl; and

[0309] Each R b are independently hydrogen or C 1-4 alkyl;

[0310] When R 1 When it is phenyl, R 3 is aryl or heteroaryl, each of which is optionally substituted by 1 to 3 R 6 Replace; and when R 1 When it is a heteroaryl group, R 2 Not unsubstituted C 1-6 alkyl.

[0311] Combination therapy

[0312] In one embodiment, the compounds disclosed herein can be used in combination with one or more additional therapeutic agents or interventions being used and / or developed for the treatment of type 1 primary hyperoxaluria. Examples of such therapeutic agents are calcium oxalate crystallization inhibitors, oxalate degrading enzyme inhibitors, siRNA, oxazyme, and lumasiran. Examples of such therapeutic interventions are high fluid intake, dialysis, and renal transplantation.

[0313] In some embodiments, the compounds disclosed herein can be used in combination with SGLT2 inhibitors. Non-limiting examples of SGLT2 inhibitors include dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, ipragliflozin, empagliflozin and potassium citrate.

[0314] In certain embodiments, the method described herein also includes the use of another therapeutic agent. In certain embodiments, the purposes of the combination with another therapeutic agent as described herein are provided. In certain embodiments, another therapeutic agent is a calcium oxalate crystal inhibitor, an oxalate degrading enzyme inhibitor, siRNA, oxazyme, lumasiran, nedosiran, oxabate or reloxaliase. In certain embodiments, another therapeutic agent is an SGLT2 inhibitor. In certain embodiments, the SGL2 inhibitor is dapagliflozin, ertugliflozin, luseogliflozin, canagliflozin, tofogliflozin, ipragliflozin, ipragliflozin, empagliflozin or potassium citrate.

[0315] Reagent test kit

[0316] Also provided herein are kits comprising a compound of Formula I (or any other formula described herein) or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof, and suitable packaging. In one embodiment, the kit further comprises instructions for use. In one aspect, the kit comprises a compound of Formula I (or any other formula described herein) or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof, and labels and / or instructions for using the compound to treat indications described herein (including diseases or conditions).

[0317] Also provided herein are articles of manufacture comprising a compound described herein or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof in a suitable container. The container may be a vial, a jar, an ampoule, a prefilled syringe and an intravenous bag.

[0318] Pharmaceutical compositions and modes of administration

[0319] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Therefore, pharmaceutical compositions are also provided herein, containing one or more compounds described herein or their pharmaceutically acceptable salts, tautomers, prodrugs or deuterated analogs and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers and adjuvants. These compositions are prepared in a manner known in the pharmaceutical field. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (GS Banker & C. T. Rhodes, Eds.).

[0320] The pharmaceutical composition can be administered in a single dose or multiple doses. The pharmaceutical composition can be administered by various methods, including, for example, rectal, oral, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition can be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical or as an inhalant.

[0321] One mode of administration is parenteral administration, such as by injection. Forms into which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oil suspensions or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, glucose or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0322] Oral administration can be another route of administration of the compounds described herein. Administration can be by, for example, capsules or enteric coated tablets. When preparing a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof, the active ingredient is typically diluted with an excipient and / or encapsulated in a carrier that can be in the form of a capsule, sachet, paper or other container. When an excipient is used as a diluent, it can be in the form of a solid, semisolid or liquid material, as a vehicle, carrier or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), ointments, for example containing up to 10 wt % of active compounds, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0323] Some examples of suitable excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulation may additionally include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0324] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, tautomer, prodrug or deuterated analog thereof can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents No. 3,845,770; No. 4,326,525; No. 4,902,514; and No. 5,616,345. Another formulation for the methods disclosed herein employs a transdermal delivery device ("patch"). Such a transdermal patch can be used to provide a continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches for delivering medicaments are well known in the art. Such a patch can be configured for continuous, pulsatile or on-demand delivery of medicaments.

[0325] To prepare solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug or deuterated analog thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient may be evenly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms, such as tablets, pills and capsules.

[0326] The tablet or pill of compound described herein can be coated or otherwise compounded to provide a dosage form with the advantage of prolonged action, or to protect it from the influence of gastric acid conditions. For example, tablet or pill can include inner dosage component and outer dosage component, the latter is the encapsulated form on the former. These two components can be separated by an enteric layer, which is used to resist the disintegration in the stomach and allows the inner component to enter the duodenum intact or delay release. Various materials can be used for this enteric layer or coating, and this material includes a mixture of multiple polymeric acids and polymeric acids and this material (such as shellac, cetyl alcohol and cellulose acetate).

[0327] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the composition is administered by oral or nasal respiratory route to obtain local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be atomized by the use of an inert gas. The atomized solution may be inhaled directly from the atomizing device, or the atomizing device may be connected to a mask tent or an intermittent positive pressure breathing machine. The solution, suspension or powder composition may be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0328] dose

[0329] 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, administration time, route of administration and excretion rate, drug combination and the severity of the specific disease of the subject undergoing treatment. For example, the dosage can be expressed as milligrams (mg / kg) of the compound described herein per kilogram of subject body weight. The dosage may be suitable between about 0.1 to 150 mg / kg. In some embodiments, it may be suitable between about 0.1 to 100 mg / kg. In other embodiments, the dosage between 0.5 to 60 mg / kg may be suitable. When adjusting the dosage between individuals with very different sizes, such as when using drugs in children and adults, or when converting the effective dose of a non-human subject (e.g., dog) to a dosage suitable for a human subject, it is particularly useful to normalize according to the subject's body weight.

[0330] The daily dose may also be described as a unit dose or the total amount of the compound described herein administered per day. The daily dose of the compound of Formula I may 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.

[0331] When administered orally, the total daily dosage for a human subject can be between 1 mg-1,000 mg, about 1,000-2,000 mg / day, about 10-500 mg / day, about 50-300 mg / day, about 75-200 mg / day, or about 100-150 mg / day.

[0332] The compound of the present application or its composition can be applied once, twice, three times or four times a day using any suitable method described above. In addition, the application or treatment of the compound can last for several days; for example, for a treatment cycle, the treatment will usually last for at least 7 days, 14 days or 28 days. Treatment cycles are well known in cancer chemotherapy, and treatment cycles are often alternating with rest periods of about 1 to 28 days, usually about 7 days or about 14 days between cycles. In other embodiments, treatment cycles can also be continuous.

[0333] In a specific embodiment, the method comprises administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein, and increasing the dose in increments until a clinical therapeutic effect is achieved. The dose may be increased in increments of about 5, 10, 25, 50, or 100 mg. The dose may be increased daily, every other day, twice a week, or once a week.

[0334] Synthesis of compounds of formula I

[0335] Compounds can be prepared using methods disclosed herein and conventional modifications thereof, which will be apparent from the disclosure herein and methods known in the art. In addition to the teachings herein, conventional and known synthetic methods can be used. The synthesis of representative compounds described herein can be completed as described in the following examples. If available, reagents can be purchased from, for example, Sigma Aldrich or other chemical suppliers.

[0336] General Synthesis

[0337] Typical embodiments of the compounds described herein can be synthesized using the following general reaction schemes. Based on the description herein, it is apparent that the general scheme can be changed by replacing the starting material with other materials having similar structures to obtain corresponding different products. The following description of the synthesis provides many examples of how the starting materials are changed to provide corresponding products. In view of the desired product of the defined substituents, the necessary starting materials can usually be determined by inspection. The starting materials are usually obtained from commercial sources or synthesized using disclosed methods. For the compounds of the embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identification of each substituent. In view of the examples herein, the identification of the final product is usually displayed by a simple inspection method to identify the necessary starting materials. In general, the compounds described herein are usually stable and separable at room temperature and pressure.

[0338] Synthesis reaction parameters

[0339] Compounds disclosed herein 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 may also be used unless otherwise indicated. Optimum reaction conditions may vary with the specific reactants or solvents used, but these conditions may be determined by conventional optimization procedures by those skilled in the art.

[0340] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undesirable reactions. 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 TW Greene and GM Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York and the references cited therein.

[0341] The starting material for the following reaction is generally a known compound, or can be prepared by known methods or its obvious modification. 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 the method described in the standard reference or its obvious modification, such as Fieser and Fieser's "Organic Synthesis Reagents", Volumes 1-15 (John Wiley and Sons, 1991), Rodd's "Carbon Compound Chemistry", Volumes 1-5 and Supplement (Elsevier Science Press, 1989), "Organic Reactions" Volumes 1-40 (John Wiley and Sons, 1991), "March's Advanced Organic Chemistry" (John Wiley and Sons, Fifth Edition, 2001), and Larock's "Comprehensive Organic Transformations" (VCH Publishing Company, 1989).

[0342] The term "solvent" generally refers to a solvent that is inert under the reaction conditions described therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane), ether, methanol, etc.). Unless otherwise specified, the solvent is an inert organic solvent, and the reaction can be carried out under an inert gas, preferably argon or nitrogen.

[0343] The term "qs" refers to the addition of an amount sufficient to achieve a stated function, eg, to bring a solution to a desired volume (ie, 100%).

[0344] In scheme 1, A, R 1 , R 2 , R 3 and R 6As defined herein, each X is independently a halogen (eg, chlorine, bromine, or iodine), and each R 50 are independently alkyl or two R 50 Together they form a ring (eg, 4,4,5,5-tetramethyl-1,3,2-dioxaborolane), and PG is a protecting group bonded to the heteroatom.

[0345] Solution 1

[0346]

[0347] In Scheme 1, the compound of Formula I is prepared by coupling a suitably protected compound 100′ with a corresponding boronic acid or ester 200 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.), followed by deprotection. As shown in Scheme 1, compound 300 used to prepare the compound of Formula I is also prepared by coupling a suitably protected compound 400 with a corresponding halogenated compound 500 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.). Compound 400 is prepared by coupling a suitably protected compound 100′ with a corresponding boronic acid or ester 600 in the presence of a catalyst (e.g., palladium, nickel, copper, etc.). The various compounds of Formulae 100′, 200, 500, and 600 used in the methods provided herein can be purchased from commercial sources or synthesized by known methods.

[0348] In some embodiments, wherein R 2 Compound 300, which is hydrogen, can be esterified by standard coupling conditions to form compound 300, wherein R 2 As defined herein (e.g. -(CH2CH2O) 1-9 CH2CH2OCH3, optionally with 1-3 R 4 Substituted C 1-6 Alkyl, cycloalkyl, or optionally 1-3 R 5 substituted heteroaryl).

[0349] Examples

[0350] The following examples are included to illustrate specific embodiments of the present disclosure. It will be appreciated by those skilled in the art that the techniques disclosed in the following examples represent techniques that work well in the practice of the present disclosure and therefore can be considered to constitute specific modes of its practice. However, based on the present disclosure, it will be appreciated by those skilled in the art that many changes may be made to the disclosed specific embodiments without departing from the spirit and scope of the present invention and still obtaining the same or similar results.

[0351] Synthesis of intermediates 3, 4 and 6 (and their methyl esters 3', 4' and 6')

[0352]

[0353] Step 1

[0354] To a mixture of sodium azide (150.0 g, 2.25 mol) and tetrabutylammonium hydrogen sulfate (41.9 g, 123 mmol) in water (2.3 L) was slowly added a solution of trifluoromethanesulfonic anhydride (375 mL, 2.25 mol) in hexane (900 mL) at 0°C. After stirring the resulting mixture at 0°C for 1 hour, 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 ethyl acetate in petroleum ether (1:6) to give impure ethyl 2-cyano-2-diazoacetate, 2 (111 g, 99%).

[0355] Step 2

[0356] To a solution of ethyl 2-cyano-2-diazoacetate, 2 (111 g, 795 mmol) in dioxane (7 L) was bubbled hydrogen bromide gas at 0° C. for 3 hours. 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 in the next step without further purification.

[0357] Step 3

[0358] To a solution of crude 4-bromo-1H-1,2,3-triazole-5-carboxylic acid ethyl ester, 3 (50 g, 227 mmol) in DMF (500 mL) was added sodium hydride (60%, 10.1 g, 275 mmol) at 0°C and stirred for 30 minutes under N2, then 2-(trimethylsilyl)ethoxymethyl chloride (40.5 g, 238 mmol) was added at 0°C. After stirring at 0°C for 1 hour, the reaction mixture was quenched with 5% aqueous lithium chloride solution and the product was extracted with ethyl acetate. The organic fraction was dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes (2:5) to give an isomeric mixture 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 value: 372.04, measured value: 372.15.

[0359] In a similar manner to the above method, a mixture of isomers of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester (4') was prepared from commercially available 4-bromo-1H-1,2,3-triazole-5-carboxylic acid methyl ester (3') as an oil: ES / MS m / z: C 10 H 19 BrN3NaO3Si(M+Na) calculated value: 337.27, found value: 336.53.

[0360] Step 4

[0361] To a mixture of isomers of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester (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 2.0 M aqueous 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. for 4 hours under N2 atmosphere. After the reaction mixture was cooled to room temperature and diluted with water, the product was extracted with ethyl acetate (3×1 L). The organic fraction was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate in petroleum ether (1:30) to give an isomeric 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, 25.5 g, 43%) as an oil: ES / MS m / z: C 23 H 36 BN3NaO5Si(M+Na) calculated value: 496.44, found value: 496.45.

[0362] Synthesis of intermediate 8

[0363]

[0364] Step 1

[0365] To 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 a solution of 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 NaCO aqueous solution (106 mL, 215.9 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.2 g, 7.1 mmol). The reaction mixture was stirred at 70° C. under N atmosphere overnight. 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 fraction was washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with ethyl acetate in petroleum ether (1:30) to give an isomeric mixture of 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-carboxylic acid ethyl ester (8, 11.5 g, 29%) as an oil: ES / MS m / z: C 29 H 41 BN3O5Si(M+H) calculated value: 550.29, found value: 550.45.

[0366] Synthesis of intermediate 10

[0367]

[0368] Step 1

[0369] To 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 a solution of 1,4-dioxane (3 mL) with 1,4-dibromobenzene (9,178 mg, 0.76 mmol) was added tetrakis(triphenylphosphine)palladium(0) (87 mg, 0.076 mmol) and 2.0 M aqueous Na2CO3 (1.13 mL). After purging the mixture with argon for 10 minutes, the reaction mixture was stirred at 110°C for 40 minutes. After the reaction mixture was cooled to room temperature, it was diluted with saturated NaHCO3, and 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 1%-100% ethyl acetate in hexanes 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.

[0370] Synthesis of Intermediates 11 and 12

[0371]

[0372] Step 1

[0373] In a manner similar to the method for the isomeric mixture of ethyl 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (3), using p-methoxybenzyl chloride instead of 2-(trimethylsilyl)ethoxymethyl chloride, an isomeric mixture of ethyl 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylate (11, 27 g, 49%) was prepared as an oil, but the reaction was carried out at room temperature for 8 hours: ES / MS m / z: C 13 H 14 Calculated for BrN3NaO3 (M+H): 362.01, found: 362.05.

[0374] Step 2

[0375] In a manner similar to the method for the isomeric mixture of 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-carboxylic acid ethyl ester (6), a mixture of isomers of 2-(4-methoxybenzyl)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester (12) was prepared as an oil.

[0376] Synthesis of intermediate 13

[0377]

[0378] Step 1

[0379] In a manner similar to the method for the isomeric mixture of 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-carboxylic acid ethyl ester (8), a mixture of isomers of 2-(4-methoxybenzyl)-5-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester (13, 10.5 g, 26%) was prepared as an oil: ES / MS m / z: C 31 H 35 BN3O5 (M+H) calculated value: 540.27, found value: 540.55.

[0380] Synthesis of intermediates 15 and 16

[0381]

[0382] Step 1

[0383] In a manner similar to the method for preparing Intermediate 4, 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylic acid methyl ester (15, 5.1 g, 59%) was prepared as an oil from 4-bromo-1H-pyrazole-5-carboxylic acid methyl ester (14, 5.0 g, 24.5 mmol): 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.

[0384] Step 2

[0385] Methyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (16, 5.83 g, 38%) was prepared as an oil in a manner similar to the method for preparing 6 using potassium carbonate instead of sodium carbonate, except that the reaction was carried out at 110° C. overnight: 1 H NMR (400MHz, chloroform-d) δ7.82 (d, J=8.4Hz, 2H), 7.60 (s, 1H), 7.40 (d, J=8.4Hz, 2H), 5.85 (s, 2 H), 3.77 (s, 3H), 3.60 (t, J=7.2Hz, 2H), 1.32 (s, 12H), 0.89 (t, J=7.2Hz, 2H), 0.04 (s, 9H). ES / MS m / z:C 23 H 36 Calculated for BN2O5Si (M+H): 459.25, molecular weight not detected.

[0386] Synthesis of intermediate 18

[0387]

[0388] Ethyl 3-bromo-1H-pyrazole-4-carboxylate (18, 511 mg, 96%) was prepared from ethyl 3-bromo-1H-pyrazole-4-carboxylate (17, 335 mg, 1.53 mmol) in a similar manner to the preparation of intermediate 15 as an oil as a mixture of two regioisomers: ES / MS m / z: C 12 H 22 BrN2O3Si(M+H) calculated: 349.06, found: 348.46.

[0389] Synthesis of intermediate 20

[0390]

[0391] 4-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-5-carboxylic acid methyl ester (20, 690 mg, 77%) was prepared from 4-bromo-1H-imidazole-5-carboxylic acid methyl ester (19, 335 mg, 1.53 mmol) as an oil as a mixture of two regioisomers: ES / MS m / z: C 12 H22 BrN2O3Si(M+H) calculated: 335.04, found: 334.86.

[0392] Representative procedure of Suzuki reaction

[0393]

[0394] In a 5 mL microwave vial, a mixture of isomers of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester (4′, 46 mg, 0.14 mmol), 4,4,5,5-tetramethyl-2-(o-tolyl)-1,3,2-dioxaborolane (17, 20 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol), 2N potassium carbonate (0.14 mL) and dioxane (2 mL) were added. After purging with argon for 5 minutes, the resulting mixture was stirred at 110° C. for 1 hour. After cooling, the reaction mixture was diluted with saturated NaHCO3, and the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with ethyl acetate in hexanes to give 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) calculated value: 348.17, found value: 347.58.

[0395] Representative procedure for SEM deprotection by HCI

[0396]

[0397] 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 hours 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(MH) calculated value: 216.08, found value: 216.15

[0398] Representative procedure for SEM deprotection by TBAF

[0399]

[0400] 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 equiv) 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 extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography eluting with ethyl acetate in hexanes 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) calculated value: 443.49, found value: 443.16.

[0401] Representative procedure for PMB deprotection by TFA

[0402]

[0403] Ethyl 1-(4-methoxybenzyl)-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 TFA and the mixture was heated to 40° C. for 80 minutes. After cooling, the reaction mixture was concentrated and diluted with saturated NaHCO 3 , then the product was extracted with ethyl acetate, dried (MgSO 4 ), concentrated, and purified by silica gel column chromatography eluting with ethyl acetate in hexanes and 10% methanol in ethyl acetate to give 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 value: 392.45, found value: 392.16.

[0404] Representative Procedure for Ester Hydrolysis

[0405]

[0406] To a solution of crude 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylic acid methyl ester (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 the reaction mixture was cooled and neutralized with 1N HCl, the solid was filtered, and the solid was purified by HPLC and freeze-dried to give 4-(o-tolyl)-1H-1,2,3-triazole-5-carboxylic acid (24): ES / MS m / z: ES / MS m / z: C 10 H8N3O2(MH) calculated value: 202.08, found value: 201.97.

[0407] Representative Procedure for SEM Protection of Heterocyclic NH

[0408]

[0409] A solution of 5-bromo-1H-1,2,3-triazole (25,996.3 mg, 6.733 mmol) in DMF (20 mL) was stirred in an ice bath, and a 60% sodium hydride solution in mineral oil (410 mg, 10.25 mmol) was added portionwise. After 30 minutes, (2-(chloromethoxy)ethyl)trimethylsilane (1.25 mL, 7.063 mmol) was added to the reaction mixture, and the resulting mixture was stirred in an ice bath for 1 hour and then at room temperature overnight. After 19 h, the reaction mixture was diluted with saturated NH4Cl solution (~100 mL) and ethyl acetate (~100 mL) and the two layers were separated. The aqueous fraction was extracted with ethyl acetate (x1) and the organic fractions were washed with water (~150 mL x1), combined, dried (MgSO4), and concentrated. The residual oil was purified by silica gel column chromatography eluting with 0%-30% ethyl acetate in hexanes 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 Calculated for BrN2O3Si (M+H): 335.04, molecular weight not detected.

[0410] Representative Procedure for the Preparation of Boronic Esters from Aryl Bromides

[0411]

[0412] 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)ferrocenepalladium(II) chloride dichloromethane (116 mg, 0.14 mmol) and potassium acetate (384 mg, 3.92 mmol) in 1,4-dioxane (6 mL) in a 20 mL μW vial was purged with Ar gas for 15 minutes, and 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 0%-40% ethyl acetate in hexane 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).

[0413] In a manner similar to the representative procedures of the Suzuki reaction, SEM or PMB deprotection and ester hydrolysis described above, the following compounds were prepared using the previously mentioned bromide intermediates 4 (or 4'), 10 or 15 with commercially available boronate esters, or using the previously mentioned boronate ester intermediates 6 (or 6'), 8, 12, 13 and 16 with commercially available bromides:

[0414] Example 1: 4-(4′-chloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid ethyl ester

[0415]

[0416] 1 H NMR (400MHz, chloroform-d) δ7.95 (dd, J=8.3, 6.7Hz, 2H), 7.65 (dd, J=8.2, 5.5Hz, 2H), 7.60-7.49 (m, 2H ), 7.43 (dd, J=8.5, 1.9Hz, 2H), 5.90 (s, 1H), 4.45 (qd, J=7.2, 4.8Hz, 2H), 1.41 (t, J=7.1Hz, 3H). ES / MS m / z:C 17 H 13ClN3O2(MH) calculated: 326.08, found: 326.31.

[0417] Example 2: Ethyl 4-(4′-carbamoyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylate

[0418]

[0419] 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: C18H17N4O3 (M+H) calculated value: 337.13, found value: 337.03.

[0420] Example 3: 4-(o-Tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0421]

[0422] 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 N3O2 (M+H) calculated value: 204.08, found value: 347.58.

[0423] Example 4: 4-(m-Tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0424]

[0425] 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 N3O2 (M+H) calculated: 204.20, found: 203.92.

[0426] Example 5: 4-(p-Tolyl)-1H-1,2,3-triazole-5-carboxylic acid

[0427]

[0428] 1 H 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) calculated: 204.20, found: 203.92.

[0429] Example 6: 4-(3-ethylphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0430]

[0431] 1 H 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) calculated value: 218.09, found value: 217.97

[0432] Example 7: 4-(2-Fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0433]

[0434] 1 H NMR (400 MHz, methanol-d4): δ 7.61-7.45 (m, 2H), 7.32-7.17 (m, 2H). ES / MS m / z: calculated for C9H7FN3O2 (M+H): 208.04, found: 207.94.

[0435] Example 8: 4-(3-Fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0436]

[0437] 1 H 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) calculated value: 208.04, found value: 207.91.

[0438] Example 9: 4-(4-Chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0439]

[0440] 1 H NMR (400 MHz, methanol-d4): δ 7.89-7.81 (m, 2H), 7.51-7.42 (m, 2H). ES / MS m / z: calculated for C9H7ClN3O2 (M+H): 224.01, found: 223.94.

[0441] Example 10: 4-(3-methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0442]

[0443] 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(MH) calculated value: 218.20, found value: 217.98.

[0444] Example 11: 4-(4-Methoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0445]

[0446] 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 value: 220.06, found value: 219.93.

[0447] Example 12: 4-(2,4′-dichloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0448]

[0449] 1H NMR (400 MHz, methanol-d4) δ 8.34 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.78 (dt, J = 7.8, 1.4 Hz, 1H), 7.64 (t, J = 7.9 Hz, 1H). ES / MS m / z: C 10 Calculated for H7N4O2 (M+H): 215.05, found: 214.96.

[0450] Example 13: 4-(3-(Trifluoromethyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0451]

[0452] 1 H NMR (400MHz, methanol-d4) δ 8.24 (t, J=1.7Hz, 1H), 8.15 (d, J=7.9Hz, 1H), 7.74 (d, J=7.8Hz, 1H), 7.66 (t, J=7.8Hz, 1H). ES / MS m / z:C 10 H7F3N3O2 (M+H) calculated value: 258.07, found value: 257.97

[0453] Example 14: 4-(3-tert-Butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0454]

[0455] 1 H 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 N3O2 (M+H) calculated value: 246.12, found value: 246.04.

[0456] Example 15: 4-(4-(tert-butyl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0457]

[0458] 1 H 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 N3O2 (M+H) calculated value: 246.12, found value: 246.01.

[0459] Example 16: 4-(3-(Trifluoromethoxy)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0460]

[0461] 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 H7FN3O3 (M+H) calculated: 274.04, found: 273.95.

[0462] Example 17: 5-(3-Chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid

[0463]

[0464] 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 H9ClFN3O2 (MH) calculated value: 254.63, found value: 254.04.

[0465] Example 18: 4-(3-Chloro-4-fluorophenyl)-1H-pyrazole-3-carboxylic acid

[0466]

[0467] 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 for H7ClFN2O2 (M+H): 241.01, found: 240.88.

[0468] Example 19: 4-(3,4-dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0469]

[0470] 1 H NMR (400 MHz, methanol-d4) δ 8.13 (d, J = 2.1 Hz, 1H), 7.85 (dd, J = 8.4, 2.1 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H). ES / MS m / z: C9H6Cl2N3O2 (M+H) calculated value: 257.98, found value: 257.95.

[0471] Example 20: 4-(3,5-dichlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0472]

[0473] 1 H NMR (400 MHz, methanol-d4) δ 7.95 (s, 2H), 7.52 (s, 1H). ES / MS m / z: C9H6Cl2N3O2 (M+H) calculated value: 257.98, found value: 257.92.

[0474] Example 21: 4-(3,5-Dichlorophenyl)-1H-pyrazole-3-carboxylic acid

[0475]

[0476] 1 H NMR (400MHz, DMSO-d6): δ 8.00 (s, 1H), 7.68 (s, 2H), 7.58-7.44 (m, 1H). ES / MS m / z:C 10 Calculated for H5Cl2N2O2 (MH): 254.98, found: 255.02.

[0477] Example 22: 4-(3-Chloro-2-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0478]

[0479] 1 H NMR (400 MHz, methanol-d4) δ 7.59 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H), 7.50 (ddd, J = 7.9, 6.3, 1.7 Hz, 1H), 7.27 (td, J = 7.9, 1.2 Hz, 1H). ES / MS m / z: C9H6ClFN3O2 (M+H) calculated value: 242.01, found value: 241.94.

[0480] Example 23: 5-(4-Bromo-3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0481]

[0482] 1 H NMR (400 MHz, methanol-d4): δ 8.04 (s, 1H), 7.70-7.65 (m, 2H). ES / MS m / z: calculated for C9H4BrClN3O2 (MH): 299.93, found: 300.02.

[0483] Example 24: 4-(3,5-Dichloro-4-fluorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0484]

[0485] 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.

[0486] Example 25: 4-(3-Phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0487]

[0488] 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 value: 282.08, found value: 282.01.

[0489] Example 26: 4-(4-Phenoxyphenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0490]

[0491] 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 N3O3 (M+H) calculated value: 282.08, found value: 281.98.

[0492] Example 27: 4-([1,1′-biphenyl]-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0493]

[0494] 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 N3O2 (M+H) calculated value: 266.09, found value: 266.01.

[0495] Example 28: 4-([1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0496]

[0497] 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 N3O2 (M+H) calculated value: 266.09, found value: 265.96.

[0498] Example 29: 4-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0499]

[0500] 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 H6CF2N3O4 (M+H) calculated value: 270.02, found value: 269.97.

[0501] Example 30: 4-(Benzo[d][1,3]dioxol-5-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0502]

[0503] 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(MH) calculated value: 232.04, found value: 232.00.

[0504] Example 31: 4-(4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)phenyl)-1H-1,2,3-triazole-5-yl

[0505] carboxylic acid

[0506]

[0507] 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(MH) Calculated value = 344.06; Found 344.04

[0508] Example 32: 4-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0509]

[0510] 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.

[0511] Example 33: 4-(Naphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0512]

[0513] 1 H 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.

[0514] Example 34: 4-(Pyridin-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0515]

[0516] 1 H NMR (400 MHz, methanol-d4) δ 9.61-9.53 (m, 1H), 9.24 (dt, J = 8.2, 1.7 Hz, 1H), 8.89 (dt, J = 5.7, 1.2 Hz, 1H), 8.18 (ddd, J = 8.2, 5.8, 0.8 Hz, 1H). ES / MS m / z: C8H7N4O2 (M+H) calculated value: 191.05, found value: 191.01

[0517] Example 35: 4-(Pyridin-3-yl)-1H-pyrazole-3-carboxylic acid

[0518]

[0519] 1 H 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 (MH): 190.05, found: 190.02.

[0520] Example 36: 4-(Quinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0521]

[0522] 1H NMR (400MHz, DMSO-d6) δ 9.05-8.98 (m, 1H), 8.62-8.52 (m, 1H), 8.11 (d, J = 11.3Hz, 1H), 7.69-7.48 (m, 4H). ES / MS m / z:C 12 Calculated for H9N4O2 (M+H): 241.06, found: 241.07.

[0523] Example 37: 4-(Isoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0524]

[0525] 1 H NMR (400MHz, methanol-d4) δ 9.80 (s, 1H), 9.11 (s, 1H), 8.74 (d, J = 9.3Hz, 1H), 8.60 (d, J = 6.6Hz, 1H), 8.47 (d, J = 6.6Hz, 1H), 8.36 (d, J = 8.8Hz, 1H). ES / MS m / z:C 12 Calculated for H8N4O2 (M+H): 241.06, found: 241.05.

[0526] Example 38: 4-(6-phenylnaphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0527]

[0528] 1 H 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 N3O2 (M+H) calcd. 316.10, found 316.00.

[0529] Example 39: 4-(3-Chloroisoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0530]

[0531] 1H NMR (400 MHz, methanol-d4) δ 9.17 (s, 1H), 8.70 (s, 1H), 8.29 (dd, J = 8.6, 1.7 Hz, 1H), 8.12-7.86 (m, 2H). ES / MS m / z: C 12 Calculated for H8ClN4O2 (M+H) = 275.03; found 275.05.

[0532] Example 40: 4-(3-methoxyisoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0533]

[0534] 1 H NMR (400MHz, methanol-d4) δ9.06 (d, J=0.9Hz, 1H), 8.40-8.35 (m, 1H), 8.12 (dd, J=8.7, 1.9Hz, 1H), 7.94 (d, J=8.8Hz, 1H), 7.19 (s, 1H), 4.04 (s, 3H).

[0535] Example 41: 4-(3-phenylisoquinolin-7-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0536]

[0537] 1 H 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 Calculated for N4O2 (M+H) = 317.10; found 317.09.

[0538] Example 42: 4-(4-(Naphthalen-1-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0539]

[0540] 1 H 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 value = 316.11; found value 316.03.

[0541] Example 43: 4-(4-(Pyridin-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0542]

[0543] 1 H NMR (400MHz, DMSO-d6) δ8.69 (dt, J=4.7, 1.5Hz, 1H), 8.19 (d, J=12.8Hz, 2H), 8 .03 (d, J=8.0Hz, 1H), 7.90 (td, J=7.7, 1.9Hz, 3H), 7.38 (dd, J=7.6, 4.9Hz, 1H). ES / MSm / z:C 14 H 11 N4O2 (M+H) calculated value: 267.08, found value: 267.10.

[0544] Example 44: 4-(4-(Pyridin-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0545]

[0546] 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 N4O2 (M+H) calculated value: 267.09, found value: 267.04.

[0547] Example 45: 4-(4-(Naphthalen-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0548]

[0549] 1 H NMR (400MHz, DMSO-d6) δ 8.31 (s, 1H), 8.09-7.99 (m, 2H), 7.93 (tt, J=8.6, 4.4Hz, 6H), 7.54 (tt, J=6.9, 5.4Hz, 2H). ES / MSm / z:C 19 H 12 N3O2(MH) calculated value: 314.10, found value: 314.14.

[0550] Example 46: 4-(4-(6-chloronaphthalen-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0551]

[0552] 1 H NMR (400MHz, DMSO-d6) δ 8.31 (s, 1H), 8.07-7.91 (m, 6H), 7.89 (s, 2H), 7.51 (dd, J=8.7, 2.2Hz, 1H). ES / MS m / z:C 19 H 13 Calculated for ClN3O2 (M+H): 350.06, found: 350.00.

[0553] Example 47: 4-(4-(Isoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0554]

[0555] 1 H NMR (400MHz, methanol-d4) δ9.51 (s, 1H), 8.59 (d, J = 6.0Hz, 1H), 8.48 (d, J = 2.1Hz, 1H), 8.36 (d, J=8.5Hz, 1H), 8.21 (d, J=8.7Hz, 1H), 8.08 (s, 1H), 8.02 (s, 4H). ES / MS m / z:C 14 H 11 N4O2 (M+H) calculated value: 267.09, found value: 267.04.

[0556] Example 48: 4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0557]

[0558] 1 H NMR (400MHz, DMSO-d6) δ 8.36 (s, 1H), 8.00 (s, 1H), 7.85 (t, J = 15.5Hz, 4H), 7.70 (s, 2H), 3.88 (s, 3H). ES / MS m / z:C 17 H 14 N5O2 (M+H) calculated value: 320.11, found value: 320.14.

[0559] Example 49: 4-(4′-chloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0560]

[0561] 1 H 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.

[0562] Example 50: 4-(3′-chloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0563]

[0564] 1 H 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.

[0565] Example 51: 4-(4′-bromo-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0566]

[0567] 1 H NMR (400MHz, DMSO-d6) δ7.88 (s, 2H), 7.77 (d, J = 7.9Hz, 2H), 7.72-7.60 (m, 4H). ES / MS m / z:C 15 H 11 BrN3O2 (M+H) calculated: 344.00, found: 344.06.

[0568] Example 52: 4-(2,4′-dichloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0569]

[0570] 1 H NMR (400MHz, DMSO-d6) δ7.92 (t, J=1.9Hz, 2H), 7.84-7.69 (m, 3H), 7.58 (dt, J=7.9, 1.4Hz, 1H), 7.44 (t, J=7.9Hz, 2H). ES / MS m / z:C 15 H 11 BrN3O2 (M+H) calculated: 344.00, found: 343.95.

[0571] Example 53: 4-(4′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0572]

[0573] 1 H 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.

[0574] Example 54: 4-(4′-(tert-butyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0575]

[0576] 1 H 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 value: 322.15, found value: 322.06.

[0577] Example 55: 4-(4′-(trifluoromethoxy)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0578]

[0579] 1H NMR (400 MHz, methanol-d4) δ 7.95 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.41-7.34 (m, 2H). ES / MS m / z: C 16 H 11 F3N3O3 (M+H) calculated value: 350.08, found value: 350.00.

[0580] Example 56: 4-(4′-methoxy-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0581]

[0582] 1 H 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) calculated: 296.10, found: 296.03.

[0583] Example 57: 4-(4′-Fluoro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0584]

[0585] 1 H 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) calculated value = 284.08; found value 284.31.

[0586] Example 58: 4-(3′,4′-dichloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0587]

[0588] 1H NMR (400 MHz, methanol-d4) δ 7.96 (d, J = 7.9 Hz, 2H), 7.87 (d, J = 1.7 Hz, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.68-7.58 (m, 2H). ES / MS m / z: C 15 H 10 Calculated for Cl2N3O2 (M+H): 334.02, found: 334.08.

[0589] Example 59: 4-(4′-cyano-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0590]

[0591] 1 H 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 H9N4O2(MH) calculated value = 289.07, found value: 289.01.

[0592] Example 60: 4-(4′-chloro-3′-fluoro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0593]

[0594] 1 H 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 H8ClFN3O2 (MH) calculated value: 316.04, found value: 316.09.

[0595] Example 61: 4-(3′-chloro-4′-fluoro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0596]

[0597] 1H NMR (400 MHz, methanol-d4) δ 7.95 (d, J = 8.3 Hz, 2H), 7.81 (dd, J = 7.0, 2.3 Hz, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.65 (ddd, J = 8.6, 4.5, 2.3 Hz, 1H), 7.34 (t, J = 8.9 Hz, 1H). ES / MS m / z: C 15 H 10 Calculated for ClFN3O2 (M+H): 318.04, found: 317.97.

[0598] Example 62: 4-(3′-phenoxy-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0599]

[0600] 1 H NMR (400MHz, methanol-d4) δ7.91 (d, J=7.9Hz, 2H), 7.68 (d, J=8.2Hz, 2H), 7.49-7.42 (m, 2H), 7.41-7.3 1 (m, 2H), 7.29 (dt, J=2.4, 1.0Hz, 1H), 7.17-7.08 (m, 1H), 7.06-7.00 (m, 2H), 7.00-6.95 (m, 1H). ES / MS m / z:C 21 H 16 N3O3 (M+H) calculated value: 358.11, found value: 358.01.

[0601] Example 63: 4-(4′-phenoxy-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0602]

[0603] 1 H 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 value: 358.11, found value: 357.98.

[0604] Example 64: 4-(4′-(pyridin-2-yloxy)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0605]

[0606] 1 H NMR (400MHz, methanol-d4) δ8.16 (ddd, J=5.0, 2.0, 0.9Hz, 1H), 7.93 (ddd, J=7.8Hz, 2H), 7.84 (ddd, J=8.3, 7.2, 2.0Hz , 1H), 7.77-7.68 (m, 4H), 7.27-7.19 (m, 2H), 7.14 (ddd, J=7.2, 5.0, 1.0Hz, 1H), 6.99 (dt, J=8.3, 0.9Hz, 1H). ES / MS m / z:C 20 H 15 N4O3 (M+H) calculated value: 359.11, found value: 359.14.

[0607] Example 65: 4-(4′-acetyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0608]

[0609] 1 H 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 N3O3 (M+H) calculated value = 308.10; found value 308.00.

[0610] Example 66: 4-(3′-Carbamoyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0611]

[0612] 1 H NMR (400MHz, methanol-d4) δ 8.21 (t, J=1.9Hz, 1H), 8.01-7.93 (m, 2H), 7.89 (dd, J=7.8, 1.9Hz, 2H), 7.83-7.74 (m, 2H), 7.58 (t, J=7.8Hz, 1H). ES / MS m / z:C 16 H 13 N4O3 (M+H) calculated value: 309.09, found value: 309.09.

[0613] Example 67: 4-(3′-(Methylcarbamoyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0614]

[0615] 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 N4O3 (M+H) calculated value: 323.11, found value: 323.12.

[0616] Example 68: 4-(4′-Carbamoyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0617]

[0618] 1 H NMR (400 MHz, methanol-d4): δ 7.98 (d, 4H), 7.77 (d, 4H). ES / MS m / z: C 16 H 13 N4O3 (M+H) calculated value: 309.09, found value: 309.05.

[0619] Example 69: 4-(4′-(Methylcarbamoyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0620]

[0621] 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 N4O3 (M+H) calculated value: 323.11, found value: 323.16.

[0622] Example 70: 4-(4′-(dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0623]

[0624] 1 H 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 N4O3 (M+H) calculated value: 337.35, found value: 338.06.

[0625] Example 71: 4-(4′-Carbamoyl-3′-chloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0626]

[0627] 1 H 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 ClN4O3 (M+H) calculated: 343.05, found: 343.13.

[0628] Example 72: 4-(3′-sulfamoyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0629]

[0630] 1 H NMR (400MHz, methanol-d4) δ 8.22 (t, J=1.8Hz, 1H), 7.99 (d, J=8.0Hz, 2H), 7.91 (dtt, J=8.5, 3.6, 1.8Hz, 2H), 7.84-7.73 (m, 2H), 7.65 (t, J=7.9Hz, 1H). ES / MS m / z:C 15 H 13 N4O4S(MH) calculated value: 345.06, found value: 345.03.

[0631] Example 73: 4-(3′-(N,N-dimethylsulfamoyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0632]

[0633] 1 H 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 N4O4S (M+H) calculated value: 373.09, found value: 373.11.

[0634] Example 74: 4-(3′-(piperidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0635]

[0636] 1 H NMR (400MHz, DMSO-d6) δ8.09 (d, J=6.6Hz, 1H), 7.96 (s, 2H), 7.93-7.79 (m, 3H), 7.77 (d , J=6.6Hz, 2H), 2.95 (t, J=5.5Hz, 4H), 1.56 (dt, J=10.7, 5.9Hz, 4H), 1.42-1.30 (m, 2H). ES / MS m / z:C 20 H 21 N4O4S (M+H) calculated: 413.13, found: 413.17.

[0637] Example 75: 4-(3′-(Morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0638]

[0639] 1 H NMR (400MHz, 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 N4O5S (M+H) calculated: 415.10, found: 415.11.

[0640] Example 76: 4-(4′-chloro-3′-sulfamoyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0641]

[0642] 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.

[0643] Example 77: 4-(4′-sulfamoyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0644]

[0645] 1 H 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(MH) calculated value: 343.06, found value: 342.31.

[0646] Example 78: 4-(4′-(N,N-dimethylsulfamoyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0647]

[0648] 1 H 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 value: 373.09, found value: 373.06.

[0649] Example 79: 4-(4′-(piperidin-1-ylsulfonyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0650]

[0651] 1H NMR (400MHz, DMSO-d6) δ8.01 (d, J=8.2Hz, 2H), 7.97-7.85 (m, 4H), 7.82 (d, J=8. 3Hz, 2H), 2.94 (t, J=5.5Hz, 4H), 1.56 (p, J=6.2, 5.4Hz, 4H), 1.45-1.32 (m, 2H). ES / MSm / z:C 20 H 21 N4O4S (M+H) calcd. 413.13, found 413.10.

[0652] Example 80: 4-(4′-(Morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0653]

[0654] 1 H NMR (400MHz, 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 N4O5S (M+H) calculated: 415.11, found: 415.07.

[0655] Example 81: 4-(3′-Acetylamino-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0656]

[0657] 1 H 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 N4O3 (M+H) calculated value: 323.11, found value: 323.13.

[0658] Example 82: 4-(4′-Acetylamino-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0659]

[0660] 1H NMR (400MHz, DMSO-d6) δ 10.03 (s, 1H), 7.85 (s, 2H), 7.73 (d, J = 8.1Hz, 2H), 7.68 (s, 4H), 2.05 (s, 3H). ES / MS m / z:C 17 H 15 N4O3 (M+H) calculated value: 323.11, found value: 323.12.

[0661] Example 83: 4-(4′-(2-oxopyrrolidin-1-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0662]

[0663] 1 H NMR (400MHz, DMSO-d6) δ7.76 (m, 8H), 3.87 (t, J=7.0Hz, 2H), 2.52 (d, J=8.0Hz, 2H), 2.07 (p, J=7.6Hz, 2H). ES / MS m / z:C 19 H 17 N4O3 (M+H) calculated value: 349.12, found value: 349.13.

[0664] Example 84: 4-(2,4′-dichloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0665]

[0666] 1 H NMR (400MHz, methanol-d4) δ7.88 (d, J=8.0Hz, 2H), 7.69 (d, J=8.1Hz, 2H), 7.61 (d, J=8.7Hz, 2H), 7.06 (d, J=8.8Hz, 2H), 3.93-3.81 (m, 4H), 3.23-3.16 (m, 4H). ES / MS m / z:C 19 H 19 N4O2 (M+H) calculated value: 351.14, found value: 350.01.

[0667] Example 85: 4-(4′-chloro-2′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0668]

[0669] 1H NMR (400 MHz, methanol-d4) δ 7.94-7.87 (m, 2H), 7.44-7.37 (m, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.29-7.18 (m, 2H), 2.27 (s, 3H). ES / MS m / z: C 16 H 13 N3O2 (M+H) calculated value = 314.07; found value 314.01.

[0670] Example 86: 4-(9H-Fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0671]

[0672] 1 H 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) calculated value: 278.09, found value: 278.02.

[0673] Example 87: 4-(Dibenzo[b,d]furan-3-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0674]

[0675] 1 H NMR (400MHz, methanol-d4) δ8.16 (dd, J=1.3, 0.6Hz, 1H), 8.14-8.04 (m, 2H), 7.87 (d, J=8.0Hz, 1H), 7. 61 (dt, J=8.3, 0.9Hz, 1H), 7.52 (ddd, J=8.4, 7.3, 1.3Hz, 1H), 7.39 (ddd, J=7.7, 7.2, 1.0Hz, 1H). ES / MS m / z:C 15 H 10 N3O3 (M+H) calculated: 280.06, found: 280.00.

[0676] Example 88: 4-(9H-Carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0677]

[0678] 1H NMR (400 MHz, acetonitrile-d3) δ 6.77 (dd, J = 18.7, 8.0 Hz, 2H), 6.64 (s, 1H), 6.23 (s, 1H), 6.12 (d, J = 8.1 Hz, 1H), 6.05 (t, J = 7.6 Hz, 1H), 5.83 (t, J = 7.4 Hz, 1H). ES / MS m / z: C 15 H 11 N4O2 (M+H) calculated value = 279.09; found value 279.01.

[0679] Example 89: 4-(9-Oxo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0680]

[0681] 1 H 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) calculated value: 292.06, found value: 292.08.

[0682] Example 90: 4-(9,9-Dimethyl-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0683]

[0684] 1 H 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) calculated value = 306.12; found value 306.06.

[0685] Example 91: 4-(4′-chloro-3′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0686]

[0687] 1H NMR (400MHz, DMSO-d6) δ7.12 (d, J=7.9Hz, 2H), 6.91 (d, J=8.2Hz, 2H), 6.81 (d, J=2.3Hz, 1H), 6.72-6.52 (m, 3H), 1.64 (s, 3H). ES / MS m / z:C 16 H 11 ClN3O2(MH) calculated: 312.06, found: 312.08.

[0688] Example 92: 4-(4′-Carbamoyl-3′-methyl-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0689]

[0690] 1 H 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 value: 323.11, found value: 323.10.

[0691] Example 93: 4-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0692]

[0693] 1 H NMR (400MHz, methanol-d4) δ 8.01 (t, J=7.3Hz, 2H), 7.79 (d, J=8.0Hz, 3H), 7.74-7.63 (m, 2H), 3.55 (t, J=6.7Hz, 2H), 3.08 (t, J=6.6Hz, 2H). ES / MS m / z:C 18 H 15 N4O3 (M+H) calculated value: 335.11, found value: 335.16.

[0694] Example 94: 4-(4-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-pyrazole-5-carboxylic acid

[0695]

[0696] 1H NMR (400MHz, DMSO-d6) δ7.89 (d, J=8.1Hz, 2H), 7.77-7.56 (m, 5H), 3.40 (dt, J=7.2, 3.6Hz, 2H), 2.97 (t, J=6.6Hz, 2H). ES / MS m / z:C 19 H 16 N3O3 (M+H) calculated value: 334.11, found value: 334.13.

[0697] Example 95: 4-(4-(3-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0698]

[0699] 1 H NMR (400MHz, methanol-d4) δ8.01 (d, J=8.1Hz, 1H), 7.99-7.93 (m, 2H), 7.82-7.75 (m, 2H), 7.69 (dd, J=8.1, 1.8Hz, 1H), 7.62 (d, J=1.7H z, 1H), 3.84 (dqd, J=12.9, 6.5, 4.6Hz, 1H), 3.11 (dd, J=15.8, 4.5Hz, 1H), 2.84 (dd, J=15.7, 10.1Hz, 1H), 1.33 (d, J=6.5Hz, 3H). ES / MS m / z:C 19 H 17 N4O3 (M+H) calculated value: 349.13, found value: 349.10.

[0700] Example 96: 4-(4-(2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0701]

[0702] 1 H NMR (400MHz, DMSO-d6) δ13.14 (s, 1H), 7.96 (d, J=8.1Hz, 1H), 7.85 (m, 4H), 7.72 (dd, J=8 .2, 1.8Hz, 1H), 7.69 (s, 2H), 3.59 (t, J=6.6Hz, 2H), 3.07 (t, J=6.6Hz, 2H), 3.05 (s, 3H). ES / MS m / z:C 19 H 17 N4O3 (M+H) calculated value: 349.13, found value: 349.09.

[0703] Example 97: 4-(4-(1-oxoisoindolin-5-yl)phenyl)-1H-1,214,3-triazole-5-carboxylic acid

[0704]

[0705] 1 H NMR (400 MHz, methanol-d4): δ 8.00 (m, 3H), 7.94-7.77 (m, 4H), 4.55 (s, 2H). ES / MS m / z: C 17 H 13 N4O3 (M+H) calculated value: 321.09, found value: 321.07.

[0706] Example 98: 4-(4-(3,3-dimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,214,3-triazole-5-carboxylic acid

[0707]

[0708] 1 H NMR (400 MHz, methanol-d4) δ 7.98 (d, J = 8.0 Hz, 2H), 7.90-7.76 (m, 5H), 1.60 (s, 6H). ES / MS m / z: C 19 H 18 N4O3 (M+H) calculated value = 349.13; found value 349.13.

[0709] Example 99: 4-([1,1′:3′,1″-terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0710]

[0711] 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 N3O2 (M+H) calculated: 342.12, found: 342.01.

[0712] Example 100: 4-([1,1′:4′,1″-terphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0713]

[0714] 1 H NMR (400MHz, DMSO-d6) δ7.97-7.63 (m, 10H), 7.48 (t, J=7.6Hz, 2H), 7.46-7.25 (m, 2H). ES / MS m / z:C 21 H 14 N3O2(MH) calculated value: 340.12, found value: 339.95.

[0715] Example 101: 4-(4′-(pyridin-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0716]

[0717] 1 H NMR (400MHz, methanol-d4) δ 8.83 (d, J=5.3Hz, 1H), 8.62 (s, 2H), 8.41 (d, J=9.3Hz, 1H), 8.17-7.93 (m, 6H), 7.87 (d, J=9.7Hz, 2H). ES / MS m / z:C 20 H 15 N4O2 (M+H) calculated value: 343.11, found value: 343.15.

[0718] Example 102: 4-(4′-(pyridin-3-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0719]

[0720] 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 value: 343.12, found value: 343.13.

[0721] Example 103: 4-(4′-(pyridin-4-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0722]

[0723] 1 H NMR (400MHz, methanol-d4) δ8.79 (d, J=6.1Hz, 2H), 8.30-8.23 (m, 2H), 8.07 (d, J=8. 2Hz, 2H), 8.02 (d, J=8.0Hz, 2H), 7.97 (d, J=8.3Hz, 2H), 7.86 (d, J=8.3Hz, 2H). ES / MSm / z:C 20 H 15 N4O2 (M+H) calculated value: 343.12, found value: 343.13.

[0724] Example 104: 4-(4′-(pyrimidin-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0725]

[0726] 1 H NMR (400MHz, methanol-d4) δ 8.87 (d, J=4.8Hz, 2H), 8.52 (d, J=8.5Hz, 2H), 7.98 (s, 2H), 7.85 (dd, J=8.2, 6.4Hz, 4H), 7.37 (t, J=4.9Hz, 1H). ES / MS m / z:C 19 H 14 Calculated for N5O2 (M+H) = 344.11; found 344.03.

[0727] Example 105: 4-(4′-(1-methyl-1H-1,2,3-triazol-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 8.33 (s, 1H), 7.95 (dd, J = 14.0, 8.3 Hz, 4H), 7.79 (d, J = 8.2 Hz, 4H), 4.18 (s, 3H). ES / MS m / z: C 18 H 15 Calculated for N6O2 (M+H) = 347.13; found 347.14.

[0730] Example 106: 4-(4′-(1-methyl-1H-1,2,4-triazol-3-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0731]

[0732] 1 H NMR (400MHz, DMSO-d6) δ 8.53 (s, 1H), 8.14-8.04 (m, 2H), 7.84 (d, J = 8.7Hz, 6H), 3.93 (s, 3H). ES / MS m / z:C 18 H 15 N6O2 (M+H) calculated value: 347.12, found value: 347.10.

[0733] Example 107: 4-(4′-(1-methyl-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0734]

[0735] 1 H NMR (400MHz, DMSO-d6) δ7.96-7.87 (m, 4H), 7.83 (d, J=8.0Hz, 2H), 7.78 (d, J=8.3Hz, 2H), 7.76 (d, J=2.2Hz, 1H), 6.76 (d, J=2.3Hz, 1H), 3.91 (s, 3H). ES / MS m / z:C 19 H 16 N5O2 (M+H) calculated value: 346.13, found value: 346.15.

[0736] Example 108: 4-(4′-(thiazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0737]

[0738] 1 H NMR (400MHz, methanol-d4) δ 8.07 (d, J=8.4Hz, 2H), 7.97 (d, J=7.7Hz, 2H), 7.89 (d, J=3.3Hz, 1H), 7.83 (t, J=8.7Hz, 4H), 7.63 (d, J=3.3Hz, 1H). ES / MS m / z:C 18 H 13 N4O2S (M+H) calculated value: 349.07, found value: 349.03.

[0739] Example 109: 4-(4′-(5-methylthiazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0740]

[0741] 1 H NMR (400MHz, DMSO-d6): δ8.03-7.74 (m, 8H), 7.62 (s, 1H), 2.50 (s, 3H). ES / MS m / z:C 19 H 15 N4O2S (M+H) calculated value: 362.08, found value: 362.11.

[0742] Example 110: 4-(4′-(5-(Trifluoromethyl)thiazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0743]

[0744] 1 H NMR (400MHz, DMSO-d6) δ 8.58 (s, 1H), 8.15 (d, J=8.0Hz, 2H), 7.97 (d, J=8.0Hz, 2H), 7.94-7.85 (m, 4H). ES / MS m / z:C 19 H 12 F3N4O2S (M+H) calculated: 417.06, found: 417.00.

[0745] Example 111: 4-(4′-(5-methyl-1,3,4-thiadiazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0746]

[0747] 1 H NMR (400MHz, DMSO-d6) δ 8.03 (d, J=6.5Hz, 1H), 8.00 (d, J=16.3Hz, 2H), 7.96-7.89 (m, 3H), 7.85 (d, J=8.3Hz, 2H), 2.78 (s, 3H). ES / MS m / z:C 18 H 12 N5O2S(MH) calculated value: 362.07, found value: 362.03.

[0748] Example 112: 4-(4′-(Oxazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0749]

[0750] 1 H NMR (400MHz, methanol-d4) δ8.13 (s, 1H), δ8.09-7.91 (m, 4H), δ7.91-7.77 (m, 3H), δ7.39-7.28 (s, 2H). ES / MS m / z:C 18 H 13 N4O3 (M+H) calculated value = 333.10; found value 333.00.

[0751] Example 113: 4-(4′-(Isoxazolyl-3-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0752]

[0753] 1 H NMR (400MHz, DMSO-d6) δ9.02 (d, J = 1.7Hz, 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 value = 333.10; found value 333.05.

[0754] Example 114: 4-(4′-(4-methylthiazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0755]

[0756] 1 H NMR (400MHz, DMSO-d6) δ 8.03 (d, J=8.4Hz, 2H), 7.95 (d, J=8.0Hz, 2H), 7.87 (t, J=7.9Hz, 4H), 7.36 (d, J=1.2Hz, 1H), 3.33 (s, 3H). ES / MS m / z:C 19 H 15 N4O2S (M+H) calculated value: 363.09, found value: 363.08.

[0757] Example 115: 4-(4′-(2-methyl-2H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0758]

[0759] 1 H NMR (400MHz, DMSO-d6) δ 8.30 (s, 1H), 7.95 (t, J = 7.0Hz, 4H), 7.90-7.80 (m, 4H), 4.22 (s, 3H). ES / MS m / z:C 18 H 15 N6O2 (M+H) calculated value: 347.13, found value: 347.02.

[0760] Example 116: 4-(4′-(thiazol-5-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0761]

[0762] 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.39 (s, 1H), 7.81 (q, J = 8.4Hz, 8H). ES / MSm / z:C 18 H 13 N4O2S (M+H) calculated value: 349.07, found value: 348.96.

[0763] Example 117: 4-(4′-(1,5-dimethyl-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0764]

[0765] 1 H NMR (400MHz, DMSO-d6) δ7.92 (d, J=8.1Hz, 2H), 7.88-7.79 (m, 4H), 7.76 (d, J=8.2Hz, 2H), 6.54 (s, 1H), 3.78 (s, 3H), 2.30 (s, 3H). ES / MSm / z:C 20 H 18 N5O2 (M+H) calculated value: 360.15, found value: 360.16.

[0766] Example 118: 4-(4′-(1,5-dimethyl-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0767]

[0768] 1H NMR (400MHz, 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 N6O2 (M+H) calculated value: 361.14, found value: 361.13.

[0769] Example 119: 4-(4′-(1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0770]

[0771] 1 H 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 N5O2 (M+H) = 332.11; found 332.14.

[0772] Example 120: 4-(4′-(1H-1,2,3-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0773]

[0774] 1 H 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) calculated value = 333.11; found value 333.11.

[0775] Example 121: 4-(4′-(5-methyl-1H-1,2,3-triazol-1-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0776]

[0777] 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) calculated value: 347.13, found value: 347.09.

[0778] Example 122: 4-(4′-(Benzo[d]thiazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0779]

[0780] 1 H NMR (400MHz, DMSO-d6) δ8.20 (d, J=8.2Hz, 2H), 8.16 (d, J=8.0Hz, 1H), 8.08 (d, J=8.1Hz, 1H) , 7.96 (d, J=8.2Hz, 5H), 7.88 (d, J=8.3Hz, 2H), 7.55 (t, J=7.6Hz, 1H), 7.47 (t, J=7.6Hz, 1H). ES / MS m / z:C 22 H 15 N4O2S (M+H) calculated: 399.09, found: 399.08.

[0781] Example 123: 4,4′-([1,1′-biphenyl]-4,4′-diyl)bis(1H-1,2,3-triazole-5-carboxylic acid)

[0782]

[0783] 4,4′-([1,1′-biphenyl]-4,4′-diyl)bis(1H-1,2,3-triazole-5-carboxylic acid) was prepared from 5-bromo-2-(4-methoxybenzyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester (11) and 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-carboxylic acid ethyl ester (13) in a manner similar to the general procedure of the Suzuki reaction, followed by PMB deprotection and ester hydrolysis: 1 H NMR (400MHz, DMSO-d6) δ 7.95 (s, 4H), 7.86 (d, J=8.1Hz, 4H). ES / MS m / z:C 18 H13 N6O4 (M+H) calculated value: 377.10, found value: 377.03.

[0784] Example 181: 4-(4′-(5,6-Dihydro-4H-cyclopenta[d]thiazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0785]

[0786] 1 H NMR (400MHz, DMSO-d6) δ7.99 (d, J = 8.1Hz, 2H), 7.86 (m, 6H), 3.17 (s, 2H), 2.96 (s, 2H), 2.89-2.78 (m, 2H). ES / MS m / z:C 21 H 17 N4O2S (M+H) calcd. 389.11, found 389.11.

[0787] The following compounds were prepared in a manner similar to the representative procedures for Suzuki reaction and SEM or PMB deprotection described above, followed by ester hydrolysis with commercially available heterocyclic bromides after SEM protection of the heterocyclic NH using the previously mentioned boronate intermediates 6 or 8:

[0788] Example 124: 4-(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0789]

[0790] 1 H NMR (400MHz, DMSO-d6) δ 8.11 (s, 2H), 7.79 (d, J = 14.4Hz, 4H), 7.72 (s, 4H). ES / MS m / z:C 18 H 14 N5O2 (M+H) calculated value: 332.11, found value: 332.07.

[0791] Example 125: 4-(4′-(1H-pyrazol-5-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0792]

[0793] 1H NMR (400MHz, DMSO-d6) δ7.99-7.86 (m, 4H), 7.88-7.74 (m, 4H), 7.72 (d, J=2.2Hz, 1H), 6.76 (t, J=2.3Hz, 1H). ES / MS m / z:C 18 H 14 N5O2 (M+H) calculated: 332.11, found: 332.11.

[0794] Example 126: 4-(4-(1H-Benzo[d]imidazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0795]

[0796] 1 H 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) calculated value: 306.09, found value: 306.14.

[0797] Example 127: 4-(4′-(1H-1,2,3-triazol-5-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0798]

[0799] 1 H 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.

[0800] Example 128: 4-(4′-(1H-imidazol-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0801]

[0802] 1 H NMR (400 MHz, methanol-d4) δ 7.29-7.05 (m, 4H), 6.95-6.62 (m, 6H). ES / MS m / z: C18 H 14 Calculated for N5O2 (M+H) = 332.11; found 332.12.

[0803] Example 129: 4-(4′-(1H-imidazol-4-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0804]

[0805] 1 H 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 Calculated for N5O2 (M+H) = 332.11; found 332.12.

[0806] Example 130: 4-(4′-(4-methyl-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0807]

[0808] 1 H NMR (400MHz, DMSO-d6) δ 12.98 (s, 2H), 7.82 (d, J = 8.1Hz, 4H), 7.75 (d, J = 8.1Hz, 2H), 7.51 (s, 1H), 2.23 (d, J = 0.7Hz, 3H). ES / MS m / z:C 19 H 16 Calculated for N5O2 (M+H) = 346.13; found 346.18.

[0809] The following compounds were prepared in a representative procedure similar to the Suzuki reaction and SEM deprotection by HCl, followed by ester hydrolysis with commercially available bromides using the previously mentioned bromide intermediates 4 or 10 after conversion to the pinacol boronate ester:

[0810] Example 131: 4-(4′-(5-methyl-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0811]

[0812] 1H NMR (400MHz, D2O+NaHCO3) δ7.5-8.0 (m, 8H), 2.48 (s, 3H). ES / MS m / z:C 18 H 15 N6O2 (M+H) calculated value: 347.13, found value: 347.12.

[0813] Example 132: 4-(6-Chloronaphthalen-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0814]

[0815] 1 H 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 for H9ClN3O2 (M+H): 274.04, found: 273.96.

[0816] Example 133: 4-(Phenanthrene-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0817]

[0818] 1 H NMR (400MHz, 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 12 N3O2 (M+H) calculated value = 290.09; found value 290.03.

[0819] Example 134: 4-(7-Amino-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0820]

[0821] 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 N4O2 (M+H) calculated: 293.10, found: 293.05.

[0822] Example 135: 5-(3-Chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid

[0823]

[0824] Step 1

[0825] 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) followed by SEM-Cl (0.233 mL, 1.31 mmol) at 0°C. 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 ethyl acetate in hexanes to give 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 Si (M+H) calcd. 349.05, found 348.93.

[0826] Step 2, Step 3, and Step 4

[0827] 4-(3-Chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid was prepared in a similar manner to the general procedure of the Suzuki reaction using (3-chloro-4-fluorophenyl)boronic acid, followed by SEM deprotection and ester hydrolysis by HCl: 1 H 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 Calculated for H9ClFN2O2 (M+H): 255.03, found: 254.94.

[0828] Example 136: 4-(3-Chloro-4-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0829] Step 1

[0830] 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) under N2 conditions and cooled in a water bath. After 90 minutes, the reaction mixture was cooled in an ice bath and then quenched with 2M HCl. The mixture was then extracted with ethyl acetate and the organic extracts were dried (MgSO4) and concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography eluting with 0%-40% ethyl acetate in hexane to give methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropanoate (2.97 g, 44%). LC / MS m / z: C 10 H9ClFO3 (M+H) calculated value: 231.02, found value: 231.0.

[0831] Step 2 A mixture of methyl 3-(3-chloro-4-fluorophenyl)-3-oxopropanoate (537 mg, 2.33 mmol), p-methoxybenzyl azide (400 mg, 2.45 mmol) and potassium carbonate (1.36 g, 9.80 mmol) in dimethyl sulfoxide (5 mL) was vigorously stirred overnight at 80° C. The reaction mixture was then cooled and diluted with water, and the resulting solid was isolated by filtration and then further purified by silica gel column chromatography, eluting with 0%-50% ethyl acetate in hexanes 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 Calculated for ClFN3O3 (M+H): 376.09, found 376.1.

[0832] Step 3 and Step 4

[0833] To a 1:1 THF / methanol (2 mL) solution of 5-(3-chloro-4-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid methyl ester (75 mg, 0.20 mmol) was added 1M LiOH (1.0 mL, 1.0 mmol) at room temperature. After stirring for 1 hour, the reaction mixture was acidified with 2N 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 hours. After the reaction mixture was concentrated 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: 1HNMR (400 MHz, DMSO-d6) δ 13.33 (br s, 1H), 8.07 (br s, 1H), 7.84 (br s, 1H), 7.54 (br t, J=8.0 Hz, 1H). ES / MS m / z: C9H6ClFN3O2 (M+H) calculated: 242.01, found 242.0.

[0834] Example 137: 4-phenyl-1H-1,2,3-triazole-5-carboxylic acid

[0835]

[0836] 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 HNMR (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: C9H8N3O2 (M+H) calculated value: 190.06, found value 190.0.

[0837] Example 138: 4-(3-Chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0838]

[0839] In a manner similar to the procedure in Example 136, 4-(3-chlorophenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 3-chloroacetophenone: 1 H 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: calculated for C9H7ClN3O2 (M+H): 224.02, found 224.0.

[0840] Example 139: 4-(Pyridin-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0841]

[0842] Step 1

[0843] In a 5 mL microwave vial, an isomeric mixture of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester (192 mg, 0.55 mmol), 2-(tributylstannyl)pyridine (222 mg, 0.193 mL, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.055 mmol) and toluene (2 mL) were added. 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 extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with ethyl acetate in hexanes 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) calcd: 349.16, found: 349.05.

[0844] Step 2 and Step 3

[0845] 4-(Pyridin-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection by HCl followed by ester hydrolysis: 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 5.2 Hz, 1H), 8.41 (d, J = 8.0 Hz, 1H), 8.25 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 7.4, 5.4 Hz, 1H). ES / MS m / z: C8H7N4O2 (M+H) calculated value: 191.05, found value: 190.99.

[0846] Example 140: 4-(Pyridin-2-yl)-1H-pyrazole-5-carboxylic acid

[0847]

[0848] In a manner similar to the procedure of Example 141, 4-(pyridin-2-yl)-1H-pyrazole-5-carboxylic acid was prepared from 4-(tributylstannyl)pyridine: 1H NMR (400 MHz, methanol-d4) δ 8.85-8.78 (m, 1H), 8.70 (s, 1H), 8.54 (td, J = 8.0, 1.6 Hz, 1H), 8.43 (dt, J = 8.4, 1.0 Hz, 1H), 7.89 (ddd, J = 7.3, 5.9, 1.2 Hz, 1H). ES / MS m / z: C9H8N3O2 (M+H) calculated value: 190.05, found value: 190.00.

[0849] Example 141: 4-(Thiazol-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0850]

[0851] 4-(Thiazol-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from 4-(tributylstannyl)thiazole in a manner similar to Example 141: 1 H NMR (400 MHz, DMSO-d6): δ 9.32 (s, 1H), 8.65 (s, 1H), 3.15 (s, 1H). ES / MS m / z: C6H3N4O2S (MH) calculated value: 191.05, found value: 194.95.

[0852] Example 142 and Example 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

[0853]

[0854] Step 1

[0855] In a manner similar to the general procedure of the Suzuki reaction, 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:

[0856] Step 2 and Step 3

[0857] 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 similar manner to the general procedure of SEM deprotection by HCl followed by ester hydrolysis. Both compounds were isolated by precipitation followed by preparative HPLC purification:

[0858] Example 142: 4-(3′-(Dimethylcarbamoyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0859]

[0860] 1 H 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) calculated value: 310.07, found value: 310.05.

[0861] Example 143: 4-(3′-carboxy-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0862]

[0863] 1 H NMR (400MHz, methanol-d4) δ7.96 (d, J=8.4Hz, 2H), 7.86-7.72 (m, 4H), 7.57 (td, J=7.7, 0.6Hz, 1H), 7.44 (dt, J=7.6, 1.3Hz, 1H), 3.14 (s, 3H), 3.06 (s, 3H). ES / MS m / z:C 18 H 17 N4O3 (M+H) calculated value: 337.12, found value: 337.17.

[0864] Example 144: 4-(4-(1H-indazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0865]

[0866] Step 1

[0867] To a solution of 5-bromo-1H-indazole (100 mg, 0.49 mmol) in dichloromethane (2.0 mL) was added p-toluenesulfonic acid (9.0 mg, 0.049 mmol) and 3,4-dihydropyran (0.089 mL, 0.97 mmol). After the mixture was heated to 35 ° C overnight, the reaction mixture was diluted with a saturated NaHCO3 aqueous solution, and then the product was extracted with ethyl acetate (x2). The combined organic layer was washed with water (x1), dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography, eluted with a hexane solution of ethyl acetate to obtain 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole: 1 H NMR (400MHz, acetonitrile-d3) δ8.03-7.93 (m, 2H), 7.62 (dt, J=8.9, 0.8Hz, 1H), 7.52 (dd, J=8.9, 1.9Hz, 1H), 5.77 (dd, J=9.8, 2.6Hz, 1H), 4.89 (t, J=3.8Hz, 0H), 4.01-3.9 1 (m, 1H), 3.86-3.72 (m, 1H), 3.48 (dd, J=11.0, 6.0Hz, 0H), 2.47 (dddd, J=13.7, 12.2, 9.7, 4.0Hz, 1H), 2.17-1.97 (m, 2H), 1.87-1.60 (m, 3H), 1.64-1.48 (m, 1H). ES / MS m / z:C 12 H 14 BrN2O (M+H) calculated = 281.03; found 280.75.

[0868] Step 2, Step 3, and Step 4

[0869] 4-(4-(1H-indazol-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from intermediate 6 and 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole in a manner similar to the general procedure of the Suzuki reaction with PMB and THP deprotection by TFA followed by ester hydrolysis: 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 Calculated for ClN3O2 (M+H): 300.05, found: 300.00.

[0870] Example 145: 4-(4-(1H-indazol-6-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0871]

[0872] 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 Calculated for N5O2 (M+H) = 306.10; found 306.15.

[0873] Example 146: 4-(4′-chloro-3′-(morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0874]

[0875] Step 1

[0876] At 0 ℃, morpholine (220mg, 3mmol) was added to a solution of 5-bromo-2-chlorobenzenesulfonyl chloride (366mg, 10mmol) in THF (3mL). After 10 minutes, the reaction mixture was diluted with ethyl acetate and washed with 1N HCl (x2), water (x1) and saturated NaHCO (x1). The resulting organic fraction was dried (MgSO ) and concentrated. The residue was purified by silica gel column chromatography, eluted with a hexane solution of 0%-100% ethyl acetate to obtain 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).

[0877] Step 2, Step 3, and Step 4

[0878] 4-(4′-Chloro-3′-(morpholinosulfonyl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using intermediate 6 and 4-((5-bromo-2-chlorophenyl)sulfonyl)morpholine in a manner similar to the general procedure for the Suzuki reaction, with PMB deprotection followed by ester hydrolysis: 1H NMR (400MHz, methanol-d4) δ8.30 (d, J=2.3Hz, 1H), 8.07-7.91 (m, 3H), 7.76 (dd, J=16.0, 8.2Hz, 3H), 3.75-3.65 (m, 4H), 3.29 (m, 4H): ES / MS m / z: C 19 H 18 ClN4O5S (M+H) calcd. 449.06, found 449.16.

[0879] Example 147: 4-(3-Bromophenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0880]

[0881] Step 1

[0882] In a similar manner to the general procedure of the Suzuki reaction, an isomeric mixture of methyl 5-(3-aminophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared using intermediate 4′ and (3-aminophenyl)boronic acid: ES / MS m / z: C 16 H 25 N4O3Si(M+H) calculated value: 347.17, found value: 348.96.

[0883] Step 2:

[0884] To a solution of methyl 4-(3-aminophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,3-triazole-5-carboxylate (102 mg, 0.29 mmol) in 3 mL of acetonitrile at 0° C. was added tert-butyl nitrite (0.042 mL, 0.35 mmol)) and copper(II) bromide (78 mg, 0.35 mmol). After 30 minutes, the reaction mixture was diluted with saturated NaHCO3 and the product was extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography eluting with ethyl acetate in hexanes to give a mixture of isomers of methyl 5-(3-bromophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 H 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).

[0885] Step 3 and Step 4

[0886] 5-(4-Bromophenyl)-1H-1,2,3-triazole-4-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection with HCl followed by ester hydrolysis: 1 H 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: calculated for C9H7BrN3O2 (M+H): 267.96, found: 267.90.

[0887] Example 148: 4-(2-Chloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0888]

[0889] Step 1 and Step 2

[0890] In a manner similar to Example 149, Step 1 and Step 2, 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was used to prepare an isomeric mixture of 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester: ES / MS m / z: C 16 H 22 BrClN3O3Si(M+H) calcd: 446.03, found: 445.69.

[0891] Step 3, Step 4, and Step 5

[0892] 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, SEM deprotection with HCl, and ester hydrolysis: 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 Calculated for ClN3O2 (M+H): 300.05, found: 300.00.

[0893] Example 149: 4-(2,4′-dichloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0894]

[0895] 4-(2,4′-Dichloro-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from an isomeric mixture of 5-(4-bromo-3-chlorophenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid methyl ester and 4-chlorophenylboronic acid in a manner similar to the general procedure of the Suzuki reaction followed by the general method of SEM deprotection and ester hydrolysis with HCl: 1 H 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 Calculated for Cl2N3O2 (M+H): 334.01, found: 333.97.

[0896] Example 150: 4-(3-Chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid

[0897]

[0898] To a solution of 5-(3-chloro-4-fluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid (10 mg, 0.038 mmol) in 0.5 mL DMF was added NaH (60% oil suspension, 6 mg) at 0°C. After 10 minutes at 0°C, iodomethane (7 μL, 0.11 mmol) was added and the resulting mixture was stirred at 0°C for 10 minutes. After quenching the reaction by adding methanol, the product was purified by HPLC to give 5-(3-chloro-4-fluorophenyl)-1-methyl-1H-1,2,3-triazole-4-carboxylic acid: 1 H NMR (400 MHz, chloroform-d) δ 7.99 (dd, J = 7.1, 2.2 Hz, 1H), 7.82 (ddd, J = 8.6, 4.6, 2.2 Hz, 1H), 7.20 (t, J = 8.7 Hz, 1H), 4.31 (s, 3H). ES / MS m / z: C 10 H6ClFN3O2(MH) calculated value: 254.01, found value: 253.96.

[0899] Example 151: 4-(4′-(1-methyl-1H-1,2,3-triazol-5-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0900]

[0901] Step 1

[0902] To a solution of 4-(4-bromophenyl)-1H-1,2,3-triazole (242 mg, 1.05 mmol) in 2 mL DMF at 0°C was added a 60% NaH suspension in oil (48 mg, 1.2 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 hexanes 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.

[0903] Step 2, Step 3, and Step 4

[0904] 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 similar to the general procedure of the Suzuki reaction followed by SEM deprotection and ester hydrolysis with HCl: 1 H NMR (400MHz, DMSO-d6) δ 8.27 (s, 1H), 8.09 (s, 2H), 7.97-7.88 (m, 2H), 7.81 (dt, J = 13.6, 5.3Hz, 4H), 4.20 (s, 3H). ES / MS m / z:C 18 H 15 N6O2 (M+H) calculated value: 347.12, found value: 347.04.

[0905] Example 152: 4-(4-(2,3,3-trimethyl-1-oxoisoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0906]

[0907] Step 1

[0908] To a solution of 5-bromo-3,3-dimethylisoindolin-1-one (205 mg, 0.85 mmol) in N,N-dimethylformamide (2 mL) at 0°C was added 60% sodium hydride 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 x 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-100% EA in hexane to give 5-bromo-2,3,3-trimethylisoindolin-1-one: ES / MS m / z: C 11 H 13 BrNO (M+H) calcd. 254.02, found 254.12.

[0909] Step 2, Step 3, and Step 4

[0910] 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 similar to the general procedure of the Suzuki reaction, with PMB deprotection followed by ester hydrolysis: 1 H NMR (400MHz, DMSO-d6) δ8.10 (d, J=1.5Hz, 1H), 8.00 (s, 2H), 7.89 (dd, J=7.7, 5.6Hz , 2H), 7.83 (dd, J=7.9, 1.6Hz, 1H), 7.73 (d, J=7.9Hz, 1H), 2.95 (s, 3H), 1.50 (s, 6H). ES / MS m / z:C 20 H 19 N4O3 (M+H) calculated value: 363.15, found value: 363.12.

[0911] Example 153: 4-(4-(3,3-dimethyl-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0912]

[0913] In a manner similar 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 (400MHz, DMSO-d6) δ 8.11 (d, J=19.7Hz, 3H), 8.00-7.83 (m, 3H), 7.79 (d, J=7.9Hz, 1H), 4.34 (q, J=9.6Hz, 2H), 1.58 (s, 6H). ES / MS m / z:C 21 H 18 F3N4O3 (M+H) calculated: 431.13, found: 431.15.

[0914] Example 154: 4-(9-Methyl-9H-carbazol-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0915]

[0916] Step 1

[0917] Ethyl 5-(9H-carbazol-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate 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.

[0918] Step 2

[0919] 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 stirred for 30 minutes before adding MeI (0.009 mL; 0.13 mmol). The solution was stirred at room temperature overnight. Once complete, the mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH4Cl (1 mL). After extraction of the aqueous fraction with ethyl acetate (2x10 mL), the organic fractions were combined and washed with 5% LiCl (3x5 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 ethyl acetate in hexanes 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) calculated value = 451.22, found value 450.90.

[0920] Step 3

[0921] 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 from 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(MH) calculated value = 291.09, found value 291.11.

[0922] Example 155: 4-(4-(6-(1H-1,2,3-triazol-4-yl)pyridazin-3-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0923]

[0924] Step 1

[0925] In a manner similar to the procedure for the preparation of 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.

[0926] Step 2, Step 3, and Step 4

[0927] 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 of 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 Calculated for N8O2 (M+H): 335.10, found: 335.11.

[0928] Example 156: 4-(4-(5-(1H-1,2,3-triazol-4-yl)pyrazin-2-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0929]

[0930] 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) calcd. 335.10, found 335.10.

[0931] Example 157: 4-(3′-methyl-4′-(1H-1,2,3-triazol-5-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0932]

[0933] Step 1

[0934] In a similar manner to the procedure for the preparation of Intermediate 10, a mixture of isomers of ethyl 5-(4-(6-bromopyridazin-3-yl)phenyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from Intermediate 6 and 1-bromo-4-iodo-2-methylbenzene: ES / MS m / z: C 24 H 31 BrN3O3Si(M+H) calculated: 516.11, found: 516.02.

[0935] Step 2, Step 3, and Step 4

[0936] 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 of 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) calculated: 347.12, found: 347.15.

[0937] Example 158: 4-(4′-chloro-2-cyano-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0938]

[0939] Step 1

[0940] 5-Bromo-2-iodobenzonitrile (1000 mg, 3.25 mmol), (4-chlorophenyl)boronic acid (559 mg, 3.57 mmol), triphenylphosphine (26 mg, 0.097 mmol), palladium acetate (36 mg, 0.162 mmol), potassium phosphate (1347 mg, 9.74 mmol), toluene (4 mL) and water (2 mL) were combined in a flask and purged with Ar for 5 minutes. The reaction 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 diatomaceous earth / celite, and then concentrated to dryness under reduced pressure. The crude reaction mixture was purified by flash chromatography (0% to 100% ethyl acetate / hexane) to give 4-bromo-4′-chloro-[1,1′-biphenyl]-2-carbonitrile: 1 H 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).

[0941] Step 2

[0942] 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 the preparation of boronate esters.

[0943] Step 3, Step 4, and Step 5

[0944] 4-(4′-Chloro-2-cyano-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from compound 4 and 4′-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile in a manner similar to the general procedure of the Suzuki reaction, followed by SEM deprotection by TBAF and ester hydrolysis: 1 H 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 Calculated for ClN4O2 (M+H) = 325.05; found 325.03.

[0945] Example 159: 4-(4′-(1H-imidazol-1-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0946]

[0947] Step 1

[0948] Tri(benzylideneacetone)dipalladium (20 mg; 0.0039 mmol), 2-di-tert-butylphosphine-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (8 mg; 0.016 mmol) and tripotassium phosphate (83 mg, 0.39 mmol) were added to the reaction vessel and the headspace was purged with nitrogen for 10 minutes. Separately, imidazole (16 mg; 0.23 mmol) and ethyl 5-(4′-bromo-[1,1′-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate (98 mg; 0.2 mmol) were dissolved in 5:1 (v / v) toluene-dioxane (3.0 mL) and purged with nitrogen for 10 minutes. The imidazole solution was added to the reaction vessel and the reaction was heated to 110°C until the reaction was complete. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NH4Cl (3×5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL) and the combined organic fractions were washed with water (2×5 mL). Finally, the organic fractions were dried (Na2SO4), concentrated to dryness, and then purified by silica gel column chromatography, eluting with ethyl acetate in hexanes to give 5-(4′-(1H-imidazole-1-yl)-[1,1′-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester: ES / MS m / z: C 26 H 32 N5O35i (M+H) calculated value = 490.23; found value: 430.39.

[0949] Step 2 and Step 3

[0950] 4-(4'-(1H-imidazol-1-yl)-[1,1'-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure for SEM deprotection from TBAF followed by ester hydrolysis: 1 H NMR (400 MHz, methanol-d4) δ 9.48 (s, 3H), 8.145 (t, 1H) 8.00 (dd, J = 12.2, 8.5 Hz, 3H), 7.83 (dd, J = 8.4, 6.2 Hz, 4H). ES / MS m / z: C 18 H 14 Calculated for N5O2 (M+H) = 332.11; found 332.14.

[0951] Example 160: 4-((4-Chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid

[0952]

[0953] Step 1

[0954] A mixture of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester (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 to 60°C overnight. More copper(I) iodide and dichlorobis(triphenylphosphine)palladium(II) were added as needed to increase conversion to the desired product. Once judged sufficient for completion by LC / MS, the reaction was diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was washed with saturated NH4Cl (2x9 mL) and NaHCO3 (aq.). The aqueous layer was extracted with ethyl acetate (1 x 10 mL). The combined organics were washed with water (1 x 10 mL), dried (Na2SO4), concentrated, and then purified by silica gel column chromatography, eluting with 0%-100% ethyl acetate in hexanes to give ethyl 5-((4-chlorophenyl)ethynyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate: 1 H 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 H 25 Calculated value for ClN3O3Si (M+H) = 406.14; found 406.86.

[0955] Step 2 and Step 3

[0956] 4-((4-Chlorophenyl)ethynyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared using the general procedure of SEM deprotection with TBAF followed by ester hydrolysis: 1H NMR (400 MHz, methanol-d4) δ 7.57 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H). ES / MS m / z: C 11 Calculated for H7ClN3O2 (M+H) = 248.02; found: 247.96.

[0957] Example 161: 4-(1-(Oxetane-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0958]

[0959] Step 1

[0960] In a microwave reaction vial, an isomeric mixture of 5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylic acid ethyl ester (4,285 mg, 0.814 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (277 mg, 0.89 mmol), tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.081 mmol), 2N potassium carbonate (1022 mL, 2 mmol) and 1,4-dioxane (4 mL) were added. 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 extracted with ethyl acetate, dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluting with ethyl acetate in hexanes 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 H 36 Calculated value for N4O5Si (M+H): 453.25, found: 452.68.

[0961] Step 2

[0962] A solution of 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) in 4N HCl in 1,4-dioxane (2 mL) was stirred at room temperature overnight. After the reaction mixture was concentrated, the residue was purified by silica gel column chromatography eluting with methanol in ethyl acetate 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 N4O2 (M+H) calculated value: 223.11, found value: 223.01.

[0963] Step 3

[0964] A solution of 4-(1,2,3,6-tetrahydropyridin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (22 mg, 0.01 mmol) and 10% palladium on carbon (20 mg) in ethanol (1 mL) was stirred for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by preparative HPLC to give 4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid ethyl ester: ES / MS m / z: C 10 H 17 N4O2 (M+H) calculated value: 225.13, found value: 225.17.

[0965] Step 4

[0966] To a THF (1 mL) suspension of 4-(piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid ethyl ester (22 mg, 0.01 mmol) and 3-oxetanones (35 mg, 0.05 mmol), sodium triacetoxyborohydride (104 mg, 0.05 mmol) was added, and then acetic acid was added dropwise. The reaction mixture was stirred at room temperature overnight. After the reaction mixture was concentrated, the residue was purified by preparative HPLC to give 4-(1-(oxetanes-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid ethyl ester: ES / MS m / z: C 13 H 21 N4O3 (M+H) calculated value: 281.15, found value: 281.18.

[0967] Step 5:

[0968] 4-(1-(Oxetane-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from ethyl 4-(1-(oxetane-3-yl)piperidin-4-yl)-1H-1,2,3-triazole-5-carboxylate in a manner similar to the general procedure for ester hydrolysis: 1 H NMR (400MHz, methanol-d4): δ4.89 (m, 4H), 4.17-4.01 (m, 1H), 3.80 (m, 1H), 3.72-3.42 (m, 3H), 3.26-3.05 (m, 1H), 2.37-2.02 (m, 4H). ES / MS m / z:C 11 H 17 N4O3 (M+H) calculated value: 253.12, found value: 253.13.

[0969] Example 162: 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0970]

[0971] Step 1

[0972] In a similar manner to the general procedure of the Suzuki reaction, 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: ES / MS m / z: C 29 H 35 N4O5 (M+H) calculated: 519.26, found: 518.98 and 518.96.

[0973] Step 2

[0974] 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 4N HCl in 1,4-dioxane (3 mL) and the resulting mixture was stirred at room temperature for 15 minutes. After the solution was completely concentrated, acetic anhydride (0.05 mL, 0.53 mmol) was added to the residue and pyridine (0.05 mL, 0.62 mmol) in dichloromethane (3 mL) at 0°C. After 30 minutes at 0°C and 30 minutes at room temperature, the reaction mixture was diluted with ethyl acetate (~25 mL) and washed with saturated aqueous ammonium chloride solution (x1), saturated aqueous sodium bicarbonate solution (x1) and brine (x1). After the aqueous fraction was extracted with ethyl acetate (~20 mL x 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography, eluting with 50%-100% ethyl acetate in hexane and then eluting with 0%-20% methanol in ethyl acetate to give an isomeric mixture 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 N4O4 (M+H) calculated: 461.22, found: 460.94 and 461.17.

[0975] Step 3 and Step 4

[0976] In a manner similar to the general procedure for PMB deprotection followed by ester hydrolysis, 4-(4-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared: 1 H NMR (400MHz, methanol-d4) δ7.82 (d, J=8.2Hz, 2H), 7.54 (d, J=8.1Hz, 2H), 6.24 (s, 1H), 4.23 (dq, J=5.8, 2.6Hz, 2H), 3.81 (t, J= 5.8Hz, 0.83H), 3.76 (t, J=5.7Hz, 1.17H), 2.66 (d, J=6.6Hz, 1.17H), 2.59 (s, 0.83H), 2.18 (s, 1.755H), 2.15 (s, 1.245H). ES / MS m / z:C 16 H 17 N4O3 (M+H) calculated: 313.13, found: 313.10.

[0977] Example 163: 4-(4-(1-acetylpiperidin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid

[0978] Step 1

[0979] 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 hydroxide on carbon (6.6 mg) and ethanol (4 mL) were added, and the resulting mixture was stirred at room temperature for 3.5 hours under an atmosphere of H2. The reaction mixture was diluted with methanol and dichloromethane before filtering through a pad of celite. After the celite pad was washed with ethanol, the filtrate was completely concentrated 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) calcd. 463.23, found: 463.04 and 463.06.

[0980] Step 2 and Step 3

[0981] In a manner similar to the general procedure for PMB deprotection followed by ester hydrolysis, 4-(4-(1-acetylpiperidin-4-yl)phenyl)-1H-1,2,3-triazole-5-carboxylic acid was prepared: 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 value: 315.15, found value: 315.14.

[0982] Example 164: 4-(4′-(Pyrazin-2-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0983]

[0984] Step 1

[0985] 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 separation of the two layers, the aqueous fraction was extracted with dichloromethane (2×10 ml) and the combined organic fractions were dried (Na2SO4), concentrated, and purified by silica gel column chromatography eluting with 0%-100% ethyl acetate in hexanes to give 2-(4-bromophenyl)pyrazine: 1 H NMR (400 MHz, chloroform-d) δ 9.01 (d, J = 1.5 Hz, 1H), 8.63 (dd, J = 2.5, 1.5 Hz, 1H), 8.53 (d, J = 2.5 Hz, 1H), 7.94-7.86 (m, 2H), 7.69-7.61 (m, 2H). ES / MS m / z C 10 H8BrN2 (M+H) calcd. = 234.99; found 235.05.

[0986] Step 2, Step 3, and Step 4

[0987] 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 intermediate 6 using the representative procedure of the Suzuki reaction, SEM deprotection with HCl, and ester hydrolysis. 1 HNMR (400MHz, DMSO-d6) δ13.21 (s, 1H), 9.32 (d, J=1.6Hz, 1H), 8.73 (dd, J=2.5, 1.5Hz, 1H), 8.62 (d, J=2.5Hz, 1H), 8.30-8.23 (m, 2H), 7.96-7.86 (m, 6H). ES / MS m / z:C 19 H 14 Calculated for N5O2 (M+H) = 344.11; found 344.04.

[0988] Example 165: 4-(4′-(1H-1,2,4-triazol-5-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0989]

[0990] Step 1

[0991] In a similar manner to the general procedure of the Suzuki reaction, a mixture of isomers of ethyl 5-(4′-carbamoyl-[1,1′-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared from 4-bromobenzamide and intermediate 6: ES / MS m / z: C 24 H 30 Calculated value for N4O4Si (M+H) = 467.2; found 467.16.

[0992] Step 2

[0993] 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 reagent; 62 μL; 0.30 mmol). The mixture was then heated to 60° C. until the starting material was consumed and (E)-ethyl 5-(4′-(((dimethylamino)methylene)carbamoyl)-[1,1′-biphenyl]-4-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate appeared. The material from this reaction was used directly in step 3: ES / MS m / z: C 27 H 35 Calculated value for N5O4Si (M+H) = 522.25; found 522.11.

[0994] Step 3

[0995] To the reaction mixture from step 2 was added hydrazine (39 μL; 1 mmol) and acetic acid (109 μL; 2.0 mmol) and heated to 60°C. Once complete by LC / MS, the reaction mixture was diluted with ethyl acetate (10 mL) and washed with saturated NaHCO3 (2×5 mL). After extraction of the aqueous fraction with ethyl acetate (2×10 mL), the organic fractions were combined, washed with 1N HCl (5 mL) and water (5 mL), dried (Na2SO4), and concentrated to dryness. The crude product, ethyl 5-(4′-(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=7.1Hz, 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), 1.25Hz (t, J=7.1Hz, 4H), 0.95 (dt, J=15.9, 8.3Hz, 1H). ES / MS m / z:C 25 H 30 N6O3Si (M+H) calculated value = 491.21; found value 491.25.

[0996] Steps 4 and 5

[0997] 4-(4′-(1H-1,2,4-triazol-5-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a manner similar to the general procedure of SEM deprotection with HCl followed by ester hydrolysis: 1 H NMR (400MHz, 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 value 333.10; found value 333.11.

[0998] Example 166: 4-(7-Bromo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[0999]

[1000] Step 1

[1001] 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 boronate esters from aromatic bromides using bis(pinacolato)diboron (27):

[1002] Step 2

[1003] In a similar manner to the general procedure of the Suzuki reaction, 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: ES / MS m / z: C 24 H 31 N4O3Si(M+H) calculated: 451.22, found: 451.33.

[1004] Step 3

[1005] 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) at 0°C was added tert-butyl nitrite (0.32 mL, 2.69 mmol) and cupric bromide (595 mg, 2.66 mmol). 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 0%-100% ethyl acetate in hexanes 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 deamination byproducts. The mixture was used in the next reaction without further purification.

[1006] Steps 4 and 5

[1007] 4-(7-Bromo-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared in a similar manner to the general procedure of SEM deprotection with HCl, and ester hydrolysis: 1H NMR (400 MHz, methanol-d4) δ 8.03 (s, 1H), 7.94-7.82 (m, 2H), 7.81-7.71 (m, 2H), 7.54 (dd, J = 8.1, 1.8 Hz, 1H), 3.98 (s, 2H). ES / MS m / z: C 16 H 11 BrClN3O2 (M+H) calculated: 355.92, found: 356.00.

[1008] Example 167: 4-(7-Chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1009]

[1010] 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 Example 168, Step 3, using copper(II) chloride instead of copper(II) bromide, followed by the general procedure of SEM deprotection and ester hydrolysis by HCl: 1 H 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.

[1011] Example 168: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1012]

[1013] Step 1

[1014] Ethyl 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate was prepared in a manner similar to the representative procedure for the synthesis of boronates from aromatic bromides using bis(pinacolato)diboron (27).

[1015] Step 2, Step 3, and Step 4

[1016] 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared from ethyl 5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole-4-carboxylate and boronate ester 28 in a manner similar to the general procedure of the Suzuki reaction followed by SEM deprotection by HCl and 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 18 H 13 N6O2 (M+H) calculated value: 345.10, found value: 345.11.

[1017] Example 169: 4-(9,9-difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1018]

[1019] Step 1

[1020] 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 boronate 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.

[1021] Step 2

[1022] 4-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole was prepared from 4-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole in a manner similar to the representative procedure for the synthesis of boronate esters from aromatic bromides using bis(pinacolato)diboron (27): ES / MS m / z: C 27 H 35 BF2N3O3Si (M+H) calculated value: 526.25, found value: 525.96.

[1023] Step 5, Step 6, and Step 7

[1024] 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 using intermediate 4 and 4-(9,9-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-fluoren-2-yl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole, followed by SEM deprotection by HCl and ester hydrolysis: 1 H 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) calculated value: 381.09, found value: 381.06.

[1025] Example 170: 4-(9,9-Difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-pyrazole-5-carboxylic acid

[1026]

[1027] 4-(9,9-difluoro-7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-pyrazole-5-carboxylic acid was prepared from 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, followed by SEM deprotection by HCl and ester hydrolysis:1 H NMR (400MHz, methanol-d4) δ8.27 (s, 1H), 8.11 (d, J=1.7Hz, 1H), 8.03 (dd, J=7.9, 1.5Hz , 1H), 7.89 (s, 1H), 7.88-7.84 (m, 1H), 7.79 (d, J=7.9Hz, 1H), 7.77-7.70 (m, 2H). ES / MS m / z:C 19 H 12 Calculated for F2N5O2 (M+H): 380.10, found: 380.11.

[1028] Example 171: 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

[1029]

[1030] Step 1

[1031] 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)ferrocenepalladium(II) chloride 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 completely concentrated, the residue was dissolved in ethyl acetate (~300 mL) and washed with water (~250 mL×2). After the aqueous fraction was extracted 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 0%-20% ethyl acetate in hexanes to give 2,2'-(9,9-difluoro-9H-fluorene-2,7-diyl)bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolane): 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.08 (dt, J=2.0, 0.9 Hz, 2H), 7.95-7.89 (m, 2H), 7.60 (dd, J=7.5, 0.9 Hz, 2H), 1.36 (s, 24H), massless.

[1032] Step 2

[1033] In a similar manner to the general procedure of the Suzuki reaction, a mixture of isomers 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-dioxaborolan): ES / MS m / z: C 30 H 39 BF2N3O5Si (M+H) calculated: 598.27, found: 597.81 and 597.67.

[1034] Step 3, Step 4, and Step 5

[1035] 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 using 4-bromo-1,5-dimethyl-1H-1,2,3-triazole and an isomeric mixture of 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-carboxylic acid ethyl ester in a manner similar to the general procedure of the Suzuki reaction followed by SEM deprotection by HCl and ester hydrolysis: 1 H 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) calculated: 409.12, found: 409.14.

[1036] Example 172: 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

[1037]

[1038] 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 using 4-bromo-2-methyl-2H-1,2,3-triazole and an isomeric mixture of 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-carboxylic acid ethyl ester in a manner similar to the general procedure of the Suzuki reaction followed by SEM deprotection by HCl and ester hydrolysis: 1 H 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.

[1039] Example 173: 4-(6-Chloro-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid

[1040]

[1041] Step 1

[1042] A solution of trifluoroacetic acid (35 mL) and dimethylacetamide (1.75 mL) of a mixture of 1-bromo-4-iodobenzene (1.00 g, 3.5 mmol), 4-chlorobenzonitrile (973 mg, 7.1 mmol), bis(acetonitrile)palladium(II) chloride (92 mg, 0.35 mmol) and silver(I) oxide (901 mg, 3.9 mmol) 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 pad of celite, and the filtrate was concentrated. The residue was dissolved in dichloromethane and aqueous HCl solution, the insoluble matter was filtered out through a pad of celite again, and the two layers of filtrate were separated. The organic fraction was dried (MgSO4), concentrated, and purified by silica gel column chromatography eluting with 0% to 100% ethyl acetate in hexanes to provide 2-bromo-6-chloro-9H-fluoren-9-one.

[1043] Step 2

[1044] At -78 ° C, 1M lithium triethylborohydride (0.34 mL) was added to a solution of 2-bromo-6-chloro-9H-fluorene-9-one (33 mg, 0.11 mmol) in tetrahydrofuran (1 mL). After 25 minutes, the reaction mixture was quenched with saturated NH4Cl aqueous solution. After the product was extracted with ethyl acetate (x4), the organic extracts were combined, washed with brine (x1), dried (MgSO4), and concentrated to give crude 2-bromo-6-chloro-9H-fluorene-9-ol for the next step.

[1045] Step 3

[1046] Triethylsilane (0.3 mL) and trifluoroacetic acid (0.3 mL) were added to the crude 2-bromo-6-chloro-9H-fluorene-9-ol, and the resulting mixture was stirred at room temperature for 1.7 hours. After concentration, the residue was purified by silica gel column chromatography, eluting with 0%-100% ethyl acetate in hexane to give 2-bromo-6-chloro-9H-fluorene.

[1047] Step 4

[1048] The dioxane (1.5mL) solution of the mixture of 2-bromo-6-chloro-9H-fluorene (27mg, 0.095mmol), bis(pinacol)diboron (29mg, 0.11mmol), [1,1′-(bisdiphenylphosphino)ferrocene]dichloropalladium (II) (7.8mg, 9.5μmol) and potassium acetate (28mg, 0.29mmol) is placed in a microwave reaction bottle and purged with argon. The obtained mixture is stirred at 95°C for 2.25 hours and cooled, the mixture is diluted with water, and the product is extracted with ethyl acetate (x4). The combined organic extract is dried (MgSO4), and concentrated, purified by silica gel column chromatography, eluted with a hexane solution of 0%-100% ethyl acetate, to obtain 2-(6-chloro-9H-fluorene-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

[1049] Step 5, Step 6, and Step 7

[1050] 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 of 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 by HCl and ester hydrolysis: 1H NMR (400 MHz, methanol-d4) δ 8.05 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.92-7.84 (m, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.33 (dd, J = 8.0, 2.0 Hz, 1H), 3.98 (s, 2H). ES / MS m / z: C 16 H 11 Calculated for ClN3O2 (M+H): 312.05, found: 311.96.

[1051] Example 174: 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

[1052]

[1053] Step 1

[1054] A mixture of 4-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-1,2,3-triazole (28, 403 mg, 1.45 mmol), 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (5, 1.93 g, 5.84 mmol) and tetrakis(triphenylphosphine)palladium(0) (168 mg, 0.15 mmol) in a 20 mL microwave reaction vial was purged with Ar for 10 minutes and then stirred in a bath at 110° C. for 1.25 hours. The reaction mixture was dissolved in ethyl acetate (~100 mL) and washed with ~50% saturated NaHCO (x1) and water (x1). After extraction of the aqueous fraction with ethyl acetate (~50 mL x 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography, eluting with 0%-100% ethyl acetate in hexane. The partially purified product was further purified by silica gel column chromatography, eluting with 0%-20% ethyl acetate in hexane 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) calculated value: 402.24, found value: 401.96.

[1055] Step 2

[1056] A DMF (20 mL) 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) was stirred in a bath at 85°C for 18 hours. After the reaction mixture was cooled and diluted with water (100 mL), the product was extracted with ethyl acetate (100 mL x 4). After the extract was washed with water (100 mL x 1), the combined extracts were dried (Na2SO4) and concentrated.

[1057] The residue was treated with concentrated hydrochloric acid (25 mL) and the mixture was refluxed for 36 hours. The resulting mixture was cooled in a refrigerator, the insoluble matter was filtered and washed with water. The solid was dissolved in ethyl acetate (~100 mL), dried (MgSO4), and concentrated to give crude 3-(5-bromo-2-iodophenyl)pentanedioic acid: ES / MS m / z: C 11 H 11 Calculated for BriO4 (M+H): 412.89, found: 412.58.

[1058] Step 3

[1059] The mixture of the above crude 3-(5-bromo-2-iodophenyl) pentanedioic acid in acetic anhydride (~10mL) was refluxed in a 155°C bath for 3 hours. After concentrating the resulting solution, the remaining slurry was co-evaporated with toluene (x2) and dried in vacuo. The residue was dissolved in THF (50mL) and stirred at room temperature, and 28% NH3 aqueous solution (0.65mL each time) was added three times approximately every 15 minutes. The resulting mixture was stirred at room temperature for 7 hours. The resulting suspension was completely concentrated, co-evaporated with toluene (x2), and dried. The residue was refluxed with acetic anhydride (15mL) in a 155°C bath for 4 hours 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 obtain 4-(5-bromo-2-iodophenyl) piperidine-2,6-dione: 1 H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.55 (d, J=2.4Hz, 1H), 7.25 (dd, J= 8.4, 2.4Hz, 1H), 3.52 (tt, J=12.0, 4.1Hz, 1H), 2.90-2.78 (m, 2H), 2.63 (dd, J=16.7, 4.1Hz, 2H).

[1060] Step 4

[1061] A solution of 4-(5-bromo-2-iodophenyl)piperidine-2,6-dione (1.60 g, 4.06 mmol) in THF (5 mL) was stirred at 0°C while a solution of 1.0 M borane tetrahydrofuran complex in THF (10.2 mL) was added dropwise. After the resulting mixture was refluxed for 20 hours, c.HCl (16 mL) was added to the mixture and the resulting solution was refluxed in a 105°C bath for 4.5 hours. The solution was stirred in an ice bath while NaOH (solid) was added to neutralize the mixture. The alkaline solution obtained was diluted with NaHCO3 and the product was extracted with ethyl acetate (~60 mL×2). The extracts were washed with brine (x1), combined, dried (Na2SO4), and concentrated to give 4-(5-bromo-2-iodophenyl)piperidine as an oil.

[1062] At 0 ℃, while adding Boc2O (1078mg, 4.939mmol) and triethylamine (0.8mL, 5.740mmol), stir the methanol solution (~25mL) of crude 4-(5-bromo-2-iodophenyl) piperidine. After 2 hours at 0 ℃ and overnight at room temperature. The reaction mixture is concentrated, and the residue is dissolved in ethyl acetate, then washed with water (x2). The obtained organic fraction is dried (MgSO4), concentrated, and purified by silica gel column chromatography, eluted with a hexane solution of 0%-10% EA, to obtain tert-butyl 4-(5-bromo-2-iodophenyl) piperidine-1-carboxylate: 1 H NMR (400MHz, chloroform-d) δ7.68 (d, J=8.4Hz, 1H), 7.27 (d, J=2.4Hz, 1H), 7.05 (dd, J=8.4, 2.4Hz, 1H), 4.27 (s, 2H), 2.9 4-2.85 (tt, J=3.4, 12.9Hz, 1H), 2.82 (s, 2H), 1.84 (d, J=12.9Hz, 2H), 1.51 (dd, J=3.8, 12.9Hz, 2H), 1.48 (s, 9H).

[1063] Step 5

[1064] 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 a 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 0%-50% ethyl acetate in hexanes 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) calculated: 635.20, found: 635.14.

[1065] Step 6

[1066] 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)ferrocenepalladium(II) chloride dichloromethane (116 mg, 0.03 mmol) and potassium acetate (102 mg, 1.04 mmol) in 1,4-dioxane (3 mL) in a microwave reaction vial was purged with Ar gas for 15 minutes and then the mixture was heated at 120° C. for 1.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography eluting with 0%-35% ethyl acetate in hexane 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) calculated value: 683.38, found value: 683.35.

[1067] Step 7, Step 8, and Step 9

[1068] 4-(2-(Piperidin-4-yl)-4′-(1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-4-yl)-1H-1,2,3-triazole-5-carboxylic acid was prepared 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 of the Suzuki reaction, followed by SEM deprotection with HCl and ester hydrolysis; 1 H NMR (400MHz, methanol-d4) δ8.23 (s, 1H), 7.99 (d, J=1.8Hz, 1H), 7.98-7.91 (m, 2H), 7.78 (dd, J=8.0, 1.7Hz, 1H), 7.49-7.41 (m, 2H), 7.36 ( d, J=7.9Hz, 1H), 3.41 (dd, J=12.8, 3.2Hz, 2H), 3.21-3.03 (m, 1H), 2.93 (ddd, J=16.6, 8.6, 5.2Hz, 2H), 2.03 (tt, J=8.6, 3.4Hz, 4H). ES / MS m / z:C 22 H 22 N7O2 (M+H) calculated: 416.18, found: 416.14.

[1069] Example 175: Ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate

[1070]

[1071] Step 1, Step 2, Step 3, and Step 4

[1072] Ethyl 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylate was prepared in a manner similar to the methods described herein using intermediate 11 and 2,7-dibromo-9H-fluorene followed by a similar general procedure for PMB deprotection: 1H NMR (400MHz, DMSO-d6) δ8.39 (s, 1H), 8.14 (s, 1H), 8.07-8.02 (m, 3H), 7.95 (d, J=8 .0Hz, 1H), 7.82 (m, 1H), 4.32 (q, J=7.0Hz, 2H), 4.08 (s, 2H), 1.28 (t, J=7.0Hz, 3H). ES / MS m / z:C 20 H 17 N6O2 (M+H) calculated value: 373.14, found value: 373.30.

[1073] Example 176: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2-morpholinoethyl ester

[1074]

[1075] Step 1

[1076] 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) was added lithium hydroxide monohydrate (3.7 g, 88.18 mmol) at room temperature under argon. The reaction mixture was heated to 60° C. and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure to give a crude product, which was diluted with water, acidified with 1N HCl solution, and stirred for 10 minutes. 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 N6O4 (M+H) calculated value: 585.23, found value: 585.41.

[1077] Step 2

[1078] 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) was added potassium carbonate (1.41 g, 10.3 mmol) followed by 4-(2-chloroethyl)morpholine (1.53 g, 10.3 mmol) at room temperature under argon. The mixture was heated to 50° C. and stirred for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with 80%-100% ethyl acetate in petroleum ether 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-morpholinoethyl ester: ES / MS m / z: C 40 H 40 N7O5 (M+H) calculated value: 683.31, found value: 698.52.

[1079] Step 3

[1080] A mixture of 2-(4-methoxybenzyl)-5-(7-(2-(4-methoxybenzyl)-2H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-2H-1,2,3-triazole-4-carboxylic acid 2-morpholinoethyl ester (3.0 g, 4.3 mmol) in TFA (30 mL) was heated at 80° C. for 16 hours. 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 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2-morpholinoethyl ester: 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.14 (s, 1H), 8.05 (t, J=8.4Hz, 2H), 8.00 (s, 1H), 7.95 (d, J=8.4Hz, 1H), 7.81 (d , J=8.4Hz, 1H), 4.38 (t, J=5.6Hz, 2H), 4.08 (s, 2H), 3.49 (t, J=4.6Hz, 4H), 2.61 (t, J=5.6Hz, 2H), 2.49-2.33 (m, 4H). ES / MS m / z:C 24 H 24N7O3 (M+H) calculated value: 458.19, found value: 458.32.

[1081] Example 177: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 3-morpholinopropyl ester

[1082]

[1083] Step 1 and Step 2

[1084] In a manner analogous to the procedures of Example 175, Steps 2 and 3, using 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, followed by a method analogous to the general procedure for PMB deprotection, 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 3-morpholinopropyl ester was prepared: 1 H NMR (400MHz, DMSO-d6) δ15.18 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H), 8.04 (m, 2H), 7.98 (s, 1H), 7.95 (d, J=8.0Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 4.27 (t, J=6.2Hz, 2H), 4.08 (s, 2H), 3.42 (t, J=4.4Hz, 4H), 2.22-2.18 (m, 6H), 1.77 (qn, J=6.7Hz, 2H). ES / MS m / z:C 25 H 26 N7O3 (M+H) calculated value: 472.21, found value: 472.50.

[1085] Example 178: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2-((L-valyl)oxy)ethyl ester

[1086]

[1087] Step 1

[1088] 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) was added lithium hydroxide monohydrate (1.85 g, 44.24 mmol) at room temperature under argon. After the reaction mixture was stirred at room temperature for 5 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water and acidified with 1N HCl solution, and then stirred for 10 minutes. 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) calculated: 333.98, found: 334.10.

[1089] Step 2

[1090] 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) was added 4-dimethylaminopyridine (0.33 g, 2.76 mmol) at 0°C under argon, followed by a solution of dicyclohexylcarbodiimide (3.69 g, 17.96 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue was purified by silica gel column chromatography, eluting with 0%-30% ethyl acetate in petroleum ether to give (tert-butoxycarbonyl)-L-valine 2-hydroxyethyl ester (178-b): 1 H NMR (400MHz, DMSO-d6) δ7.11 (d, 2ZH), 4.77 (t, J=5.4Hz, 1H), 4.06 (m, 2H), 3.87 (dd, J=7.8 and 6.0Hz, 1H), 3.56 (appt q, J=5.2Hz, 2H), 2.50 (m, 1H), 2.01 (m, 1H), 1.39 (s, 9H), 0.87 (d, J=6.6Hz, 6H).

[1091] Step 3

[1092] 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) was added 4-dimethylaminopyridine (0.2 g, 1.63 mmol) at 0° C. under argon, followed by a solution of dicyclohexylcarbodiimide (2.18 g, 10.62 mmol) in dichloromethane (12.5 mL). The mixture was stirred at room temperature for 16 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluting with 0%-60% ethyl acetate in petroleum ether 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 BrN4O7 (M+H) calculated: 555.15, found: 555.34.

[1093] Step 4

[1094] 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 value for N7NaO8 (M+Na): 850.35, found value: 850.86.

[1095] Step 5

[1096] 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-(((tert-butoxycarbonyl)-L-valyl)oxy)ethyl (4.5 g, 5.44 mmol) in trifluoroacetic acid (45 mL) was stirred at 70° C. for 48 hours. 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 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2-((L-valyl)oxy)ethyl ester: 1 H NMR (400MHz, DMSO-d6) δ8.42 (s, 1H), 8.28 (s, 3H), 8.14 (s, 1H), 8.07-8.03 (m, 3H), 7.96 (d, J = 8.0Hz, 1H), 7.83 (d, J = 6.0Hz, 1H), 4. 56 (m, 1H), 4.55 (m, 2H), 4.43 (m, 1H), 4.08 (s, 2H), 3.92 (m, 1H), 2.05 (h, J=6.8Hz, 1H), 0.86 (d, J=6.8Hz, 3H), 0.83 (d, J=6.8Hz, 3H). ES / MS m / z:C 25 H 26 N7O4 (M+H) calculated value: 488.20, found value: 488.39.

[1097] Example 179: 2-(Phosphonooxy)ethyl 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] To a stirred solution of dibenzyl hydrogen phosphate (117, 20 g, 71.94 mmol), 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (15.22 g, 86.33 mmol) in THF (200 mL) at 0°C under argon was added triphenylphosphine (28.27 g, 107.91 mmol) followed by diethyl azadicarboxylate (18.83 g, 107.91 mmol). The resulting mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography eluting with 0%-10% ethyl acetate in petroleum ether to give dibenzyl (2-((tert-butyldimethylsilyl)oxy)ethyl) phosphate: ES / MS m / z: C 22H 34 O5PSi (M+H) calculated: 437.19, found: 437.34.

[1101] Step 2

[1102] To a stirred solution of (2-((tert-butyldimethylsilyl)oxy)ethyl)dibenzyl phosphate (23 g, 52.75 mmol) in MeOH (230 mL) was added Dowex-50W at room temperature under argon. The mixture was stirred for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude compound. The crude compound was purified by silica gel column chromatography eluting with 0%-2% MeOH in dichloromethane to give (2-hydroxyethyl)dibenzyl phosphate: ES / MS m / z: C 16 H 20 O5P (M+H) calcd. 323.10, found 323.24.

[1103] Step 3

[1104] To a stirred solution of dibenzyl (2-hydroxyethyl) phosphate (5 g, 15.52 mmol) in dichloromethane (50 mL) at 0°C under argon was added NEt3 (3.23 mL, 23.28 mmol) followed by MsCl (2.13 g, 18.63 mmol). After the mixture was stirred at room temperature for 5 hours, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to 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 O7PS (M+H) calculated value: 401.08, found value: 401.27.

[1105] Step 4

[1106] 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) at 0° C. under argon was added 2-((bis(benzyloxy)phosphoryl)oxy)ethyl methanesulfonate (3.28 g, 8.21 mmol). After the mixture was stirred at 50° C. for 14 hours, the reaction mixture was diluted with ice water and the product was extracted with ethyl acetate. The organic extract was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluting with 0%-60% ethyl acetate in petroleum ether 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) calculated value: 889.31, found value: 889.77.

[1107] Step 5

[1108] 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)ethyl ester (11.5 g, 12.94 mmol) in trifluoroacetic acid (45 mL) was stirred at 70° C. for 20 hours. After the reaction mixture was concentrated under reduced pressure, the crude residue was purified by preparative HPLC to obtain 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid 2-(phosphonyloxy)ethyl ester: 1 H NMR (400MHz, 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 = 7.3Hz, 1H), 4.36 (m, 2H), 4.06 (s, 2H), 4.03 (m, 2H). ES / MS m / z:C 20 H 18 N6O6P (M+H) calculated value: 469.10, found value: 469.16.

[1109] Example 180: 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (((2-(phosphonooxy)ethoxy)carbonyl)oxy)methyl ester

[1110]

[1111] Step 1

[1112] To a stirred solution of dibenzyl (2-hydroxyethyl) phosphate (5 g, 15.52 mmol) and pyridine (2.5 mL, 31.04 mmol) in dichloromethane (100 mL) at 0°C under argon was added chloromethyl chloroformate (2.97 g, 23.29 mmol). After the mixture was stirred 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 value: 415.07, found value: 415.31.

[1113] Step 2

[1114] 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) at 0° C. under argon 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 0%-1% MeOH in dichloromethane 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) calcd: 963.31, found: 963.39.

[1115] Step 3

[1116] 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 hours. After the reaction mixture was concentrated under reduced pressure, the crude residue was purified by preparative HPLC to give 4-(7-(1H-1,2,3-triazol-4-yl)-9H-fluoren-2-yl)-1H-1,2,3-triazole-5-carboxylic acid (((2-(phosphonyloxy)ethoxy)carbonyl)oxy)methyl ester: 1 H NMR (400MHz, methanol-d4) δ8.42 (s, 1H), 8.15 (s, 1H), 8.06 (t, J=8.0Hz, 2H), 8.00 (s, 1H), 7.95 (d , J=8.0Hz, 1H), 7.80 (d, J=8.0Hz, 1H), 5.94 (s, 2H), 4.32 (m, 2H), 4.08 (s, 2H), 4.01 (m, 2H). ES / MS m / z:C 22 H 20 N6O9P (M+H) calculated value: 543.10, found value: 543.40.

[1117] In a manner similar to the Suzuki representative procedure, the following compounds were prepared using the aforementioned bromide intermediates 18 or 20 with commercially available boronate esters, followed by SEM or PMB deprotection as described above, and ester hydrolysis:

[1118] Example 182: 3-(3-Chloro-4-fluorophenyl)-1H-pyrazole-4-carboxylic acid

[1119]

[1120] 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.

[1121] Example 183: 3-(3,5-Dichlorophenyl)-1H-pyrazole-4-carboxylic acid

[1122]

[1123] 1 H NMR (400 MHz, methanol-d4) δ 8.21 (s, 1H), 7.77 (d, J = 2.0 Hz, 2H), 7.47 (t, J = 2.0 Hz, 1H). ES / MS m / z: C 10 Calculated for H7Cl2N2O2 (M+H): 256.99, found: 257.03.

[1124] Example 184: 4-(3-Chloro-4-fluorophenyl)-1H-imidazole-5-carboxylic acid

[1125]

[1126] 1 H 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 Calculated for H7ClFN2O2 (M+H): 241.02, found: 240.94.

[1127] Example 185: 4-(3,5-Dichlorophenyl)-1H-imidazole-5-carboxylic acid

[1128]

[1129] 1 H NMR (400 MHz, methanol-d4) δ 8.03 (s, 2H), 7.67 (s, 1H), 7.31 (s, 1H). ES / MS m / z: C 10 Calculated for H7Cl2N2O2 (M+H): 256.99, found: 257.03.

[1130] Biological detection

[1131] Biological test 1: biochemical cell test

[1132] Material

[1133] Glycolate oxidase (GO) was generated at Gilead according to Jones et al., 2000 (J. Biol. Chem. 275: 12590-12597) using the HAO1 sequence. Red Hydrogen Peroxide / Peroxidase Detection Kit (Cat. No. A22188) was purchased from Thermo Fisher (Waltham, MA). Glycolic acid (Cat. No. 124737) and Tris 1M, pH 7.8 (Cat. No. T2569-1L) were from Sigma (St. Louis, MO), 10% Tween-20 (Cat. No. 51-12-02) was from SeraCare (Milford, MA), 2% BSA (Cat. No. BSA-1000) was from Rockland Immunochemicals (Pottstown, PA), and black 384-well low binding plates (Cat. No. 3860) were from Coming (Sunnyvale, CA).

[1134] method

[1135] 1. GO biochemical detection

[1136] GO bioenzymatic reactions were performed in black 384-well low-binding plates in 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 in a buffer containing 50 mM Tris pH 7.8, 0.0025% Tween-20, and 0.02% BSA. o 555 liquid handler (Labcyte, San Jose, CA) pre-spotted 25nL of 1000X test compound on 384-well low binding plates, starting at a concentration of 10μM, followed by the addition of 5μL / well of 25nM GO (5X5nM final concentration) and incubation for 15 minutes. 10μL of 2.5X0.1U / mL final concentration of HRP was added to each well, followed by 10μL of 2.5X 100μM final concentration of glycolate substrate and 2.5X 50μM final concentration of Amplex Red. The reaction mixture was incubated at room temperature for 20 minutes, and then the plate was read at 570nm excitation and 585nm emission using an EnVision plate reader (Perkin Elmer, San Jose, CA). Wells containing DMSO were used as negative controls (as 0% inhibition), and wells without GO enzyme were used as positive controls (as 100% inhibition). The % inhibition was calculated as: 100% x (well - negative) / (positive - negative).

[1137] 2. HRP counter screen test

[1138] The HRP rescreening assay was performed in parallel with the GO biochemical assay to exclude compounds that may directly inhibit HRP but have no effect on inhibiting GO. 25 nL of the same set of 1000X test compounds were pre-spotted onto a 384-well low binding plate as described in the GO biochemical assay above, followed by the addition of 10 μL of 2.5X 0.1U / mL final concentration of HRP in a buffer containing 50 mM Tris pH 7.8, 0.0025% Tween, 0.02% BSA, and incubated for 15 minutes. Then 15 μL of 1.67X 50μM final concentration of Amplex Red and 1.67X 10μM final concentration of H2O2 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 by an Envision plate reader with 570nm excitation and 585nm emission. Wells containing DMSO served as negative controls (as 0% inhibition), while wells without HR enzyme served as positive controls (as 100% inhibition). % inhibition was calculated as described above.

[1139] GO cell-based detection

[1140] 1. Detection based on GO transiently transfected cells

[1141] Material

[1142] HAO1 plasmid DNA was produced by cloning HAO1 cDNA (Jones et al., 2000) into pcDNA3.1 (+)-neomycin vector by PCR by Lake Pharma (Belmont, California). FuGENE 6 transfection reagent (Catalog No. E2692) was purchased from Promega (Madison, Wisconsin). CHO-K1 cell line (Catalog No. ATCC CCL-61) and F-12K culture medium (Catalog No. 30-2004) were purchased from ATCC (Manassas, Virginia). OptiMEM I serum-reduced culture medium (Catalog No. 31985-070) was purchased from Gibco / Life Technologies (Grand Island, New York). Fetal bovine serum (FBS) (Catalog No. SH30071.03) was purchased from HyClone (Logan, Utah), and 100X penicillin / streptomycin / L-glutamine (Catalog No. 30-009-C1) was purchased from Corbing (Fremont, California). 384-well black tissue culture plates (Catalog No. 781086) were purchased from Greiner Bio-one (Monroe, NC).

[1143] method

[1144] 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 at room temperature for 15 minutes. The mixture was mixed with CHO-K1 cells and dispensed at 45 μL / well, containing 0.025 μg HAO1 plasmid DNA, 0.075 μL FuGENE6 and 4000 cells, placed in F-12K medium and supplemented with 10% FBS. The cells were cultured in a 37°C incubator for 48 hours to allow GO expression. The cell culture medium was then removed and replaced with 25 μL of a 1:3 serial dilution of the test compound (starting at 1 μM) and incubated at room temperature for 1 hour. 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 glycolic acid and 50 μM Amplex Red were added to each well. The reaction mixture was mixed and incubated at room temperature for 20 minutes and then read using the EnVision plate reader as described above. Wells containing DMSO were used as negative controls (0% inhibition), while wells containing vector control DNA transfections were used as positive controls (100% inhibition). The inhibition rate was calculated as described above.

[1145] 2. Detection of stable cloned cells based on GO

[1146] Material

[1147] The reagents and tissue culture medium used for transient transfection are described in the transient transfection assay section. Rabbit anti-HAO1 antibody (Catalog No. ab93137) was purchased from Abcam (Cambridge, MA), and anti-rabbit IgG (H+L), F(ab′)2 fragment, Alexa Fluor 555 conjugate (Catalog #4413) was purchased from Cell Signaling Technology (Danvers, MA).

[1148] method

[1149] 1) Generation of stable clones of CHO-K1-HAO1

[1150] Stable clones of GO were generated in-house by transiently transfecting GO plasmid DNA in batches into CHO-K1 cells and culturing for 48 hours as described above. The cells were then trypsinized and 2000 cells / 200 μl were added to well A1, followed by a 1:2 serial dilution to well A2 and all the way 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 for two weeks in F-12K medium containing 10% FBS supplemented with 500 μg / mL G418. Colony formation on each plate was monitored under a microscope. Twenty-eight single colonies were picked and expanded to test GO expression.

[1151] Immunocytochemistry for intracellular GO staining

[1152] Intracellular GO staining was performed by first fixing the cells with 50 μL / well of 4% formaldehyde in PBS for 30 minutes at room temperature in a 384-well plate, and then washing 3 times with 80 μL / well of washing buffer (PBS with 0.05% Tween-20). Then, the cells were permeabilized with 50 μL / well of 0.1% Triton in PBS for 30 minutes, washed 3 times, and blocked with 50 μL / well of 3% BSA in PBS containing 0.05% Tween-20 for 1 hour. The cells were washed again 3 times, and 50 μL of anti-human GO diluted 1:100 in PBS containing 1% BSA and 0.05% Tween-20 was added to each well and incubated overnight at 4°C. The cells were washed 4 times with 15 minutes of incubation between each wash, followed by the addition of 40 μL of Alexa Fluor 555-conjugated anti-rabbit IgG (H+L) F(ab')2 fragments diluted 1:250 and Hoechst diluted 1:500 (in 1% BSA and 0.05% Tween-20) to each well. The plates were incubated at room temperature for 160 minutes and washed four times at the end of the incubation period. Sixty microliters of PBS were added to each well and the cell images were examined by an Arrayscan XTI HCS reader from Thermo Fisher Scientific (Waltham, Massachusetts).

[1153] 2) Detection of enzyme activity cells based on stable clone 2D2 GO

[1154] 384-well tissue culture plates were pre-spotted with 25 nL of test compound per well, and then 5000 cells / well / 25 μL of clone 2D2 in reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) were distributed to all wells except column 22, where 5000 cells / well / 25 μL of clone 1A1 vector control was added. Test compound and cells were incubated at room temperature for 1 hour, followed by the addition of 25 μL of reaction buffer (50 mM Tris pH 7.8, 0.0025% Tween, and 0.02% BSA) containing HRP (final concentration of 0.1 U / mL), 160 μM glycolic acid, and 50 μM Amplex Red. The reaction was mixed and incubated at room temperature for 20 minutes, and the fluorescence of the product resorufin was measured as described above. Wells with 2D2 and DMSO served as negative controls (0% inhibition), while wells with 1A1 vector control clones served as positive controls (100% inhibition). Percent inhibition was calculated as described above (Table 2).

[1155] Table 2

[1156]

[1157]

[1158]

[1159]

[1160] Biological testing 2: oral bioavailability and PK studies

[1161] The oral dose of Example 2 was formulated at 1.0 mg / mL in a sterile solution of 50% water, 37.5% PEG 300, and 12.5% ​​DMSO. The dosing group consisted of three fasted male Sprague Dawley rats. At the time of dosing, the weight of the animals was between 0.26 and 0.27 kg. For the oral dosing group, the formulated dose was administered by oral gavage at 5.0 mL / kg at a dose of 5.0 mg / kg. Non-compartmental pharmacokinetic analysis was performed on the plasma concentration-time data.

[1162] Table 3

[1163]

[1164] Table 3 shows the mean plasma pharmacokinetic parameters (mean ± SD, n = 3) of Example 2 after oral (PO) dose of 5 mg / kg of Example 2 to SD rats. Table 4 shows the mean plasma pharmacokinetic parameters (mean ± SD, n = 3) of Example 68 after oral dose of 5 mg / kg of Example 2 to SD rats. As shown in Tables 4 and 5, the AUC of Example 2 inf 1600±280nM·h, C max The AUC of Example 68 was 2390±246 nM. inf 3250±242nM·h, C max The bioavailability of Example 68 was estimated to be 19.0% ± 1.4%

[1165] Table 4

[1166]

[1167] Table 5

[1168]

[1169]

[1170] *From Table 7 below, based on the intravenous (IV) exposure (AUC inf =3420nM·hr).

[1171] Relative to rat liver blood flow (CL = 4.0 L / hr / kg), the apparent systemic clearance of Example 68 (CL = 0.95 ± 0.09 L / hr / kg) was low. Volume of distribution (V ss =0.44±0.06L / kg) is less than the volume of total body water (0.7L / kg). 1 / 2 The mean residence time (MRT) was 1.02 ± 0.06 hours and 0.47 ± 0.02 hours. The estimated oral bioavailability (%F) was 2.3% ± 0.3%. See Tables 7, 8 and Figure 2 .

[1172] Table 7. Mean plasma pharmacokinetic parameters of Example 68 after 30 minutes intravenous infusion at 1 mg / kg in SD rats (mean ± SD, n = 3)

[1173]

[1174] Table 8. Mean plasma pharmacokinetic parameters of Example 68 after an oral dose of 5 mg / kg in SD rats (mean ± SD, n = 3)

[1175]

[1176]

[1177] Example 168 or Example 175 is 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 weight of the rats was between 0.2 and 0.3 kg, and the body weight of the dogs was between 10.72 and 10.82 kg. For the oral dosing group, the formulated dose was administered by oral gavage at 5.0 mL / kg, with 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 middle.

Claims

1. A compound selected from: or a pharmaceutically acceptable salt thereof.

2. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

3. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

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