RIP1 Modulators, Their Preparation, and Uses

Abstract

The present disclosure provides compounds of formula I, compositions comprising same, and methods of using same, including use in the treatment of various diseases and conditions, including, for example, diseases and conditions mediated by receptor interacting protein 1 (RIP1) signaling. JPEG2025510009000524.jpg64128

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to International Application No. PCT / CN2021 / 078424, filed February 28, 2022, the contents of which are incorporated by reference in their entirety.

[0002] The present disclosure relates to compounds that modulate receptor-interacting protein 1 (RIP1), compositions containing the compounds, methods for preparing the compounds, and methods of using the compounds to treat various diseases or conditions, including diseases or conditions mediated by RIP1. [Background technology]

[0003] Necroptosis is a key form of programmed cell death (PCD) and is a highly regulated, caspase-independent form of cell death that plays a key role in many necrotic cell disorders, including ischemic brain injury, neurodegenerative diseases, viral infections, and peripheral autoimmune diseases (Dunai, et al., December 2011, Pathol. Oncol. Res.: POR 17(4):791-800. J. Med. Chem. 2020, 63, 4, 1490-1510. Nature Reviews Drug Discovery, 19, 553-571 (2020)). Tumor necrosis factor alpha (TNF-α)-induced NF-κB activation plays a central role in the immune system and inflammatory responses.

[0004] Receptor-interacting protein 1 (RIP1) is a multifunctional signal transduction pathway involved in mediating nuclear factor kappa B (NF-κB) activation, apoptosis, and necroptosis. The kinase activity of RIP1 plays a critical role in mediating necroptosis, a caspase-independent pathway of necrotic cell death (Holler et al. Nat Immunol 2000;1:489-495; Degterev et al. Nat Chem Biol 2008;4:313-321). RIP1 may contribute to PD-1 immunotherapy resistance (e.g., Manguso et al., 2017 Nature 547, 413-418) and may act as a checkpoint kinase governing tumor immunity (e.g., Wang et al., Cancer Cell 34, 757-774, Nov 12, 2018). RIP1 is a promising target for the treatment of a wide range of human neurodegenerative, autoimmune, and inflammatory diseases, including psoriasis, rheumatoid arthritis, and ulcerative colitis (Pharmacol. Res. Perspect. 2017, 5, e00365, PNAS May 14, 2019 116(20)9714-9722), as well as CNS conditions such as ALS and Alzheimer's disease (Nat. Rev. Neurosci. 2019, 20, 19-33).

[0005] Certain compounds for modulating necrosis or necroptosis are disclosed in U.S. Patent Nos. 9,974,762, 10,092,529, 6,756,394, 8,278,344, U.S. Patent Application Publication No. 2012 / 0122889, U.S. Patent Application Publication No. 2009 / 0099242, U.S. Patent Application Publication No. 2010 / 0317701, U.S. Patent Application Publication No. 2011 / 0144169, U.S. Patent Application Publication No. 2003 / 0083386, U.S. Patent Application Publication No. 2012 / 0122889 ... These are disclosed in Patent Application Publication No. 2012 / 00309795, WO 2009 / 023272, WO 2010 / 075290, WO 2010 / 075561, WO 2012 / 125544, WO 2020 / 103884, WO 2021 / 233397, WO 2021 / 233396, WO 2021 / 233394, WO 2020 / 103884, and WO 2020 / 103859. Summary of the Invention

[0006] One aspect of the present disclosure provides a compound selected from the formulas disclosed herein, compounds disclosed herein (e.g., Formulas I, IIa, IIb, IIc, IId, IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IVa, IVb, Va, Vb, Vc, Vd, VIa, VIb, VIc, VId, VIe, VIf, VIIa, VIIb, VIIc, VIIIa, VIIIb, VIIIc, VIIId, VIIIe, VIIIf, and compounds 1-702), a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be used in the treatment of various diseases or conditions, such as diseases or conditions caused by axonal degeneration. For example, disclosed herein is a compound selected from the formula I: [ka] or a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0007] In one aspect of the present disclosure, the compound of the formula disclosed herein is selected from compounds 1-702 shown below, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0008] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of a formula disclosed herein, a tautomer thereof, a hydrate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1-702 shown below, a tautomer thereof, a hydrate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. These compositions may further comprise an additional active pharmaceutical agent.

[0009] Another aspect of the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formulae disclosed herein, a tautomer thereof, a hydrate or stereoisomer of the compound or of the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing, wherein the disease or condition is selected from an inflammatory disease, an immune disease (e.g., an autoimmune disease), an allergic disease, a transplant rejection, a necrotic cell disease, a neurodegenerative disease, a central nervous system (CNS) disease, an eye disease, an infectious disease, and a malignancy.

[0010] A further aspect of the present disclosure provides a method of treating a disease or condition mediated by RIP1, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of a formula disclosed herein, a tautomer thereof, a hydrate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0011] In some embodiments, the method of treatment comprises administering to a subject in need thereof a compound selected from compounds 1-702 shown below, a tautomer thereof, a hydrate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0012] In some embodiments, the method of treatment comprises administering to a subject in need thereof an additional active pharmaceutical agent, either in the same pharmaceutical composition as a compound of the formulae disclosed herein, a tautomer thereof, a hydrate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or in a separate composition. In some embodiments, the method of treatment comprises administering a compound selected from compounds 1-702 shown below, a tautomer thereof, a hydrate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, together with the additional active pharmaceutical agent, either in the same pharmaceutical composition or in a separate composition. When administered as a separate dosage form, the additional therapeutic agent can be administered before, simultaneously with, or after the administration of a compound, tautomer, hydrate, stereoisomer, or pharmaceutically acceptable salt of any of the foregoing disclosed herein.

[0013] Also disclosed herein are methods of mediating, e.g., inhibiting, RIP1, comprising contacting a RIP1 protein or a fragment thereof with a compound of a formula disclosed herein, a tautomer thereof, a hydrate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In some embodiments, the method of inhibiting RIP1 comprises contacting a RIP1 protein or a fragment thereof with a compound selected from compounds 1-702 shown below, a tautomer thereof, a hydrate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the foregoing. DETAILED DESCRIPTION OF THE INVENTION

[0014] I. Definition The terms "a" or "an," when used herein to refer to a noun, encompass the expression "at least one," and thus encompass both the singular and plural units of the noun. For example, "an additional pharmaceutical agent" means one or more than one additional pharmaceutical agent.

[0015] The term "alkyl" refers to a hydrocarbon group selected from straight- and branched-chain saturated hydrocarbon groups containing 1 to 20, e.g., 1 to 18, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkyl groups include methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. Lower alkyl groups contain 1 to 8, preferably 1 to 6, more preferably 1 to 4, and more preferably 1 to 3 carbon atoms.

[0016] The term "alkenyl" refers to a hydrocarbon group selected from straight- and branched-chain hydrocarbon groups containing at least one C=C double bond and 2 to 20, e.g., 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4, carbon atoms. Examples of alkenyl groups include ethenyl or vinyl groups, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups. A lower alkenyl contains 2 to 8, preferably 2 to 6, more preferably 2 to 4 carbon atoms.

[0017] The term "alkynyl" refers to at least one

number

[0018] The term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of the member carbon atoms has been replaced with a heteroatom, e.g., nitrogen, oxygen, or sulfur, e.g., CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5. In some embodiments, in addition to the replacement of one or more member carbon atoms with nitrogen, oxygen, or sulfur, a heteroalkyl group is optionally further substituted as defined herein.

[0019] The term "ring" or "ring system" refers to monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. Rings can be carbocyclic or heterocyclic, aromatic or non-aromatic. For example, bicyclic rings can be fused, bridged, or spiro ring systems.

[0020] The term "cycloalkyl" refers to saturated and partially unsaturated cyclic hydrocarbon groups, e.g., hydrocarbon groups selected from monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group can be of 3 to 12, 3 to 10, 3 to 8, 3 to 6, 3 to 4, or 5 to 6 carbon atoms. Further for example, a cycloalkyl group can be a monocyclic group of 3 to 12, 3 to 8, 3 to 6, 3 to 4, or 5 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopent-1-enyl group, a 1-cyclopent-2-enyl group, a 1-cyclopent-3-enyl group, a cyclohexyl group, a 1-cyclohex-1-enyl group, a 1-cyclohex-2-enyl group, a 1-cyclohex-3-enyl group, a cyclohexadienyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a cycloundecyl group, and a cyclododecyl group. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The ring may be saturated and may have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not aromatic as "aromatic ring" is defined herein.

[0021] The terms "heterocyclic" or "heterocycle" or "heterocyclyl" refer to a ring selected from 3-12 membered, e.g., 3-6 membered, 3-5 membered, 4-5 membered, or 5-6 membered, monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated rings, containing at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms selected from, for example, oxygen, sulfur, nitrogen, and silicon. "Heterocycle" also refers to a 5- to 7-membered heterocycle containing at least one heteroatom selected from N, O, and S fused to a 5-, 6-, and / or 7-membered cycloalkyl ring, aromatic carbocycle, or heteroaromatic ring, with the proviso that when the heterocycle is fused to the aromatic carbocycle or heteroaromatic ring, the point of attachment is on the heterocycle, and when the heterocycle is fused to the cycloalkyl, the point of attachment can be on the cycloalkyl or heterocycle.

[0022] "Heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocycle. The ring may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle may be substituted with oxo. The point of attachment may be at a carbon or heteroatom in the heterocycle. A heterocycle is not heteroaryl as defined herein.

[0023] Examples of heterocycles include (numbered from the attachment position assigned to priority 1): 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4 Substituted heterocycles include, but are not limited to, H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0024] The term "fused ring" as used herein refers to a polycyclic ring system, e.g., a bicyclic or tricyclic ring system, in which two rings share only two common ring atoms and one bond. Examples of fused rings include fused bicyclic cycloalkyl rings, such as those having 7 to 12 ring atoms arranged as a bicyclic ring selected from the aforementioned [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems; fused bicyclic aryl rings, such as the aforementioned 7- to 12-membered bicyclic aryl ring systems; fused tricyclic aryl rings, such as the aforementioned 10- to 15-membered tricyclic aryl ring systems; fused bicyclic heteroaryl rings, such as the aforementioned 8- to 12-membered bicyclic heteroaryl rings; fused tricyclic heteroaryl rings, such as the aforementioned 11- to 14-membered tricyclic heteroaryl rings; and fused bicyclic or tricyclic heterocyclyl rings.

[0025] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, and silicon, including any oxidized form of nitrogen or sulfur; a quaternized form of any basic or substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + where R is, for example, an optionally substituted alkyl group (as in N-substituted pyrrolidinyl).

[0026] As used herein, the term "unsaturated" means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are filled by substituents, and thus the compound contains one or more double or triple bonds. A double bond can be: [ka] It can be shown as (two solid lines). [ka] As used herein, depictions (solid and dashed lines) indicate bonds that may be double or single bonds.

[0027] The term "alkoxy," as used herein, refers to an alkyl group, as defined above, wherein one carbon of the alkyl group has been replaced with an oxygen atom, provided that the oxygen atom is linked between two carbon atoms.

[0028] The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively.

[0029] As used herein, a "CN," "cyano," or "nitrile" group refers to

number

[0030] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system with delocalized π-electron orbitals composed of [4n+2]p orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring and may be either fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, further defined as follows: An "aromatic ring" refers to a carbocyclic or heterocyclic ring that is: [ka] It can also be depicted as a ring with conjugated double bonds, such as [ka] It is sometimes depicted as a ring with a circle inside, such as

[0031] The term "aryl" as used herein refers to groups selected from monocyclic aromatic carbocyclic rings, e.g., phenyl; bicyclic ring systems, such as 7-12 membered, e.g., 9-10 membered, bicyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems, such as 10-15 membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., fluorene.

[0032] For example, an aryl group can be a 6-membered aromatic carbocyclic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring, optionally containing at least one heteroatom selected from N, O, and S, provided that when the aromatic carbocyclic ring is fused to the heterocyclic ring, the point of attachment is on the aromatic carbocyclic ring, and when the aromatic carbocyclic ring is fused to the cycloalkyl group, the point of attachment can be on the aromatic carbocyclic ring or the cycloalkyl group. Divalent groups formed from substituted benzene derivatives and having free valences on ring atoms are called substituted phenylene groups. Divalent groups derived from monovalent polycyclic hydrocarbon groups ending in "-yl" by removing one hydrogen atom from the carbon atom having the free valence are named by adding "-ydene" to the name of the corresponding monovalent group; for example, a naphthyl group having two points of attachment is called naphthylidene.

[0033] The term "heteroaryl" refers to a group selected from: a 5- to 7-membered, e.g., 5- to 6-membered, monocyclic aromatic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; an 8- to 12-membered bicyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being present in the aromatic ring; and an 11- to 14-membered tricyclic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being present in the aromatic ring.

[0034] For example, a heteroaryl group can be a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkyl ring. In such fused bicyclic heteroaryl ring systems, when only one of the rings contains at least one heteroatom, the point of attachment can be at either the heteroaromatic ring or the cycloalkyl ring.

[0035] When the total number of S and O atoms in the heteroaryl group exceeds 1, then these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less.

[0036] Examples of heteroaryl groups include (numbered from the attachment position assigned priority 1) pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b 1H-indazol-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinolinyl.

[0037] The term "acyl" refers to a substituent where the point of attachment to the substituent is a carbonyl. Exemplary acyl groups include, but are not limited to, -C(=O)R', -C(=O)NR'R'', or -C(=O)OR', where R' and R'' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, any of which may be further substituted with one or more substituents.

[0038] Some compounds exist that have different points of attachment of hydrogen, called "tautomers." For example, a compound containing a carbonyl -CHC(O)- group (keto form) may tautomerize to form a hydroxyl -CH=C(OH)- group (enol form). Both the keto and enol forms, either alone or in mixtures, are intended to be included where applicable.

[0039] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the present disclosure may contain asymmetric centers and therefore exist as enantiomers. For example, when a compound has two or more asymmetric centers, it may further exist as diastereoisomers. Enantiomers and diastereoisomers are included within the broader class of stereoisomers. All such possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereoisomers, are intended to be included in the present disclosure. All stereoisomers of the compounds, their tautomers, solvates, and pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to an isomer refers to any possible isomer. Whenever the isomeric composition is not specified, all possible isomers are included.

[0040] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0041] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereoisomers with optically active resolving agents. Racemic mixtures of chiral compounds of the present disclosure can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of diastereoisomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions.

[0042] In the present disclosure, certain single stereoisomers, e.g., substantially pure enantiomers, are separated from one another, e.g., by chiral separation. However, the absolute configuration of certain separated single stereoisomers is not currently known. Such unknown chiral centers are not shown in the structural formula. * and the corresponding compound is designated as "single unknown stereoisomer." For example, compounds 3 and 4 (Examples 3 and 4) were synthesized and separated by chiral separation, and the chemical structures of compounds 3 and 4 each have an asterisk to indicate the unknown absolute configuration and are designated as "single unknown stereoisomer."

[0043] The term "substantially pure" in the context of stereoisomers means that the stereoisomer of interest contains 35% by weight or less, such as 30% by weight or less, further such as 25% by weight or less, and even further such as 20% by weight or less of any other stereoisomer. In some embodiments, the term "substantially pure" means that the stereoisomer of interest contains 10% by weight or less, such as 5% by weight or less, for example 1% by weight or less of any other stereoisomer.

[0044] Unless otherwise indicated, structures depicted herein are meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, e.g., (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds disclosed herein are within the scope of the present disclosure. Unless otherwise indicated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0045] The present disclosure provides pharmaceutically acceptable salts of the disclosed compounds, tautomers, solvates, and stereoisomers. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0046] As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure.

[0047] "Pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids selected from hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfinates, and nitrates; and salts with organic acids selected from alkanoates such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, acetate, and salts with HOOC-(CH)-COOH (wherein n is selected from 0 to 4). Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, magnesium, aluminum, lithium, and ammonium. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.

[0048] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids (e.g., hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid), and organic acids (e.g., para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid). Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (i.e., caprate), caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate, 1,4-but ... 1,6-dioic acid, hexyne-1,6-dioic acid, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0049] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Examples of suitable pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cation salts formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Suitable non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts. The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali metal and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cation salts formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

[0050] If a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0051] The compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, -CD3, -CD2H, or -CDH2 contain one or more deuterium atoms in place of hydrogen. For example, the compounds may contain radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0052] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be either the same or different at all positions.

[0053] Combinations of chemical moieties, e.g., substituents, ring structures, linkers (L), and / or heteroatoms, envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0054] In some embodiments, the substituents are optionally substituted heteroatoms and optionally substituted, optionally hetero-, optionally cyclic C-C 18 independently selected from hydrocarbyls, in particular optionally substituted, optionally hetero-, optionally cyclic C-C 18 The hydrocarbyl is an optionally substituted, optionally hetero-, optionally cyclic alkyl, alkenyl or alkynyl, or an optionally substituted, optionally hetero-, optionally aryl, and / or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (alkoxy, aryloxy, etc.), optionally substituted acyl (formyl, alkanoyl, carbamoyl, carboxyl, amido, etc.), optionally substituted amino (amino, alkylamino, dialkylamino, amido, sulfamidyl, etc.), optionally substituted thiol (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyl (alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, etc.), nitro, or cyano.

[0055] In some embodiments, the substituents are selected from the group consisting of halogen, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(═O)R′, —C(═O)R′, —COR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR′—SONR″R′″, —N Particularly preferred are groups having 0, 1 or 2 substituents independently selected from R', R'' and R''. R' and R'" each independently represent hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted with 1-3 halogens, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy, or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. Thus, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. When the aryl group is 1,2,3,4-tetrahydronaphthalenyl, it may be substituted with a substituted or unsubstituted C3-C7 spirocycloalkyl group. The C3-C7 spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl."

[0056] In some embodiments, the substituents are selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —SiR′R″R′″, —OC(═O)R′, —C(═O)R′, —COR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR″COR′, —NR′-SONR″R′″, —S(═O)R′, —SOR′, —SONR′R″, —NR″SOR, —CN, —NO, perfluoroC1-C4 alkoxy, and perfluoroC1-C4 alkyl, wherein R′ and R″ are as defined above.

[0057] In some embodiments, the substituent is a substituted or unsubstituted heteroatom, a substituted or unsubstituted 0-3 heteroatom-containing C 1- C6 alkyl (e.g., C1-C3 alkyl or C1-C2 alkyl), substituted or unsubstituted C2-C6 alkenyl containing 0-3 heteroatoms (e.g., C2-C4 alkenyl), substituted or unsubstituted C2-C6 alkynyl containing 0-3 heteroatoms (e.g., C 2- C4 alkynyl), or substituted or unsubstituted C6-C containing 0-3 heteroatoms 14 aryl (e.g., C5-C6 aryl), and each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0058] In some embodiments, the substituents are independently selected from an aldehyde group, an aldimine group, an alkanoyloxy group, an alkoxy group, an alkoxycarbonyl group, an alkyloxy group, an alkyl group, an alkenyl group, an alkynyl group, an amine group, an azo group, a halogen group, a carbamoyl group, a carbonyl group, a carboxamide group, a carboxyl group, a cyanyl group, an ester group, a haloformyl group, a hydroperoxyl group, a hydroxyl group, an imine group, an isocyanide group, an isocyanate group, an N-tert-butoxycarbonyl group, a nitrate group, a nitrite group, a nitro group, a nitroso group, a phosphate group, a phosphono group, a sulfide group, a sulfonyl group, a sulfo group, a sulfhydryl group, a thiol group, a thiocyanyl group, a trifluoromethyl group, and a trifluoromethyl ether group (OCF).

[0059] In some embodiments, the substituents are structurally depicted herein. For example, a ring substituted with R at any chemically feasible position is: [ka] where the symbol " * " indicates the point of attachment to another component of the molecule. In another example, a bicyclic group substituted with R at any chemically feasible position is [ka] where the symbol " * " indicates the point of attachment to another component of the molecule, and R may be substituted at any chemically feasible position on the 4- or 5-membered ring of the bicyclic group.

[0060] Preferred substituents are disclosed herein and are illustrated in the tables, structures, examples, and claims, and may apply across different compounds of the disclosure, e.g., substituents of a given compound may be used in combination with other compounds.

[0061] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter, "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any of a number of methods, including, for example, reverse-phase and normal-phase; size exclusion; ion exchange; high-, medium-, and low-pressure liquid chromatography methods and apparatus; small-scale analytical; simulated moving bed ("SMB") and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and flash chromatography techniques. Those skilled in the art will be able to apply such techniques to achieve the desired separation.

[0062] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0063] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropyl-ethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0064] The term "subject" refers to animals, including humans.

[0065] The term "therapeutically effective amount" refers to the amount of a compound for which it is administered that produces the desired effect (e.g., amelioration of the disease or condition, reduction in the severity of the disease or condition, and / or reduction in the progression of a disease or condition, e.g., ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN). The disease or condition may be caused by axonal degeneration. The precise amount of a therapeutically effective amount will depend on the purpose of the treatment, and may be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0066] As used herein, the term "treatment" and its synonyms refer to slowing or stopping disease progression. As used herein, "treatment" and its synonyms include, but are not limited to, the complete or partial remission, cure, or reduction in the risk of a disease or condition or a symptom thereof, such as ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN. The disease or condition may be caused by axonal degeneration. Improvement or reduction in the severity of any of these symptoms can be assessed according to methods and techniques known in the art.

[0067] The terms "about" and "approximately," when used in connection with a number, such as a percentage, include the specified number and a range of numbers recognized by one of ordinary skill in the art (e.g., a percentage range, e.g., a range of ±10% relative to a particular point value).

[0068] II. Compounds and Compositions In a first embodiment, the compounds of the present disclosure have the following structural formula I: [ka] [In the formula, X1 is C or N, X2 is C or N, X3 is C, N or absent, and X4 is C or N; Ring A is phenyl, 5- to 9-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 9-membered heterocyclyl; Ring B is phenyl, 5- to 9-membered heteroaryl, 5- to 6-membered cycloalkyl, or 4- to 8-membered heterocyclyl; Ring C is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered cycloalkyl, or 5- to 6-membered heterocyclyl; Bond a and bond b are each independently selected from a single bond and a double bond, provided that bond a and bond b are not simultaneously double bonds, and when X3 is absent, the bond between X2 and X4 is a single bond or a double bond; R a is, for each occurrence, independently selected from halogen, cyano, ═O, NO, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted acyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted 5-10 membered heteroaryl, optionally substituted nitrogen, and optionally substituted oxygen; R b is, for each occurrence, independently selected from halogen, CN, ═O, and C1-C4 alkyl optionally substituted with 1 to 3 groups of halogen; R c is, for each occurrence, independently selected from halogen, CN, C1-C6 alkyl, OR s1 , and -C(=O)OR s1 is selected from R1 is H and R2 is H, halogen, CN, OR s1 , -NR p1 R q1 , ═O, and C1-C3 alkyl optionally substituted with 1 to 3 groups selected from halogen; or R1 and R2 together form a 5-6 membered carbocyclic or heterocyclic ring optionally substituted with 1 to 3 groups selected from halogen, and C1-C3 alkyl optionally substituted with 1 to 3 groups selected from halogen; R3 is selected from H and =O, provided that when R3 is =O, X2 is C; R4 is selected from H and C1-C3 alkyl; L is -NR x -, -(CH2) u O(CH2) u -, -(CH2) u S(=O) w -(CH2) u -, -S(=O) w (=NR x )-, -NR x S(=O) w -, -S(=O) w (NR x )-, -C(=O)-, and C1-C3 alkylene, and the C1-C3 alkylene of L is selected from OH, C1-C3 alkyl, and ═CHR x wherein the C1-C3 alkyl of the C1-C3 alkylene of L are optionally joined together to form a C3-C4 cycloalkyl; R p1 and R q1 are, for each occurrence, independently selected from hydrogen and C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen, CN, and OH; R s1is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl optionally substituted with 1 to 3 groups selected from halogen, CN, and OH; R x is selected from H and C1-C4 alkyl; m and p are each an integer independently selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, and 2; w, for each occurrence, is an integer independently selected from 0, 1, and 2; u is an integer independently selected from 0, 1, and 2 for each occurrence; however, [ka] [ka] wherein P1, P2, and P3, for each occurrence, are each independently selected from C and N, and P6 is independently selected from S and O, a compound, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0069] Combinations of substituents or other variables (e.g., the optional presence of heteroatoms in rings) disclosed herein are those that result in the formation of stable or chemically feasible compounds. In the case of abbreviations or by convention, a particular hydrogen atom bonded to a particular atom (e.g., a carbon atom C or a nitrogen atom N) is not specifically shown in a chemical structure, formula, or symbol; the hydrogen atom is considered to be present to the extent that the valence of the particular atom (e.g., C or N) is satisfied.

[0070] In a second embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, Ring A is a phenyl, pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridazinyl, piperazinyl, oxazolyl, isoxazolyl, triazolyl, cyclopentyl, cyclohexanyl, tetrahydro-furanyl, or tetrahydro-pyranyl group, and all other variables not specifically defined herein are defined in the preceding embodiment.

[0071] In a third embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, Ring B is a phenyl, pyridinyl, thiazolyl, cyclopentenyl, cyclobutanyl, cyclohexanyl, piperidyl, or pyrrolidinyl group, or a 5- to 8-membered bicyclic group optionally containing 1 or 2 N atoms, and all other variables not specifically defined herein are defined as in any one of the preceding embodiments.

[0072] In a fourth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, Ring C is a phenyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, cyclopentyl, cyclopentenyl, cyclohexanyl, cyclohexenyl, isoxazolyl, tetrahydropyranyl, or dihydropyranyl group, and all other variables not specifically defined herein are defined as in any one of the preceding embodiments.

[0073] In a fifth embodiment, the compound of the present disclosure has the following structural formula IIa: [ka] [In the formula, R 1 and R 2do not together form a 5- to 6-membered carbocyclic or heterocyclic ring, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments.

[0074] In a sixth embodiment, the compound of the present disclosure has the following structural formula IIb: [ka] wherein V1, V2, and V3 are each independently selected from C, O, and N; f is, for each occurrence, independently selected from C1-C3 alkyl and halogen; and q is selected from 0, 1, and 2; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0075] In a seventh embodiment, the compound of the present disclosure has the following structural formula IIc: [ka] wherein V1 and V2 are each independently selected from C, O, and N; f is, for each occurrence, independently selected from C1-C3 alkyl and halogen; and q is selected from 0, 1, and 2; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0076] In an eighth embodiment, the compound of the present disclosure has the following structural formula IId: [ka] [In the formula, R 1 and R 2 do not together form a 5- to 6-membered carbocyclic or heterocyclic ring, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0077] In a ninth embodiment, the compound of the present disclosure has the following structural formula IIIa: [ka] wherein Y and Y are each independently selected from C and N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0078] In a tenth embodiment, the compound of the present disclosure has the following structural formula IIIb: [ka] wherein Y is selected from S, C, O, and N; and Y and Y are each independently selected from S, C, O, and N; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0079] As disclosed herein, combinations of heteroatoms are those that result in the formation of stable or chemically feasible compounds. For example, with respect to Formula IIIb, the phrase "Y2 and Y3 are each independently selected from S, C, O, and N" refers to combinations of heteroatoms that result in the formation of stable or chemically feasible compounds. For example, if Y2 and Y3 in Formula IIIb are both O, such combinations of Y2 and Y3 result in unstable or chemically infeasible compounds. Such unstable or chemically infeasible compounds are not intended to be encompassed by the compounds of the present disclosure.

[0080] In an eleventh embodiment, the compound of the present disclosure has the following structural formula IIIc: [ka] wherein Y is selected from C and N, and Y and Y are each independently C or absent, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0081] In a twelfth embodiment, the compound of the present disclosure has the following structural formula IIId: [ka] wherein Y is selected from C and N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0082] In a thirteenth embodiment, the compound of the present disclosure has the following structural formula IIIe: [ka] or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0083] In a fourteenth embodiment, the compound of the present disclosure has the following structural formula IIIf: [ka] wherein Y is selected from C and N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0084] In a fifteenth embodiment, the compound of the present disclosure has the following structural formula IVa: [ka] wherein Z1, Z2, Z3, and Z4 are each independently selected from C and N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0085] In a sixteenth embodiment, the compound of the present disclosure has the following structural formula IVb: [ka] wherein Z1, Z2, and Z3 are each independently selected from S, O, C, and N, and Z4 is selected from C and N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0086] In a seventeenth embodiment, the compound of the present disclosure has the following structural formula Va: [ka] wherein Q1, Q2, and Q3 are each independently selected from C and N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0087] In an eighteenth embodiment, the compound of the present disclosure has the following structural formula Vb: [ka] wherein Q1, Q2, Q3, and Q4 are each independently selected from C, N, S, and O, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0088] In a nineteenth embodiment, the compound of the present disclosure has the following structural formula Vc: [ka] wherein Q1 is C, O, or absent, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0089] In a twentieth embodiment, the compound of the present disclosure has the following structural formula Vd: [ka] wherein Q1 is C or absent, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0090] In a twenty-first embodiment, the compound of the present disclosure has the following structural formula VIa: [ka] wherein Q1, Q2, and Q3 are each independently selected from C and N; Y1 and Y2 are each independently selected from C and N; Z1, Z2, and Z3 are each independently selected from S, O, C, and N; and Z4 is selected from C and N; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0091] In a twenty-second embodiment, the compound of the present disclosure has the following structural formula VIb: [ka] [In the formula, R ais, for each occurrence, independently selected from absent, halogen, CN, NO, NH, —NH(C-C alkyl), —OH, —O(C-C alkyl), —C(═O)H, —C(═O)O(C-C alkyl), —C(═O)NH, and C-C alkyl optionally substituted with 1 to 3 groups selected from halogen, OH, CN, and NH; m′ is 0, 1, and 2; R a1 is an optionally substituted C1-C3 alkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered heterocyclyl, -NC(=O)R p2 , and -NR p2 R q2 Selected from R p2 and R q2 are, for each occurrence, independently selected from hydrogen and optionally substituted C-C alkyl, or R p2 and R q2 taken together to form an optionally substituted 3- to 10-membered heterocyclyl, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0092] In a twenty-third embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R a is, for each occurrence, independently selected from absent, CH, CF, F, Cl, CN, NH, NHCH, OH, —CHOH, —COOMe, —COOEt, —CONH, —C(═O)H, —CHCN, —CHNH, CF, and NO; R a1 COOMe, COOEt, [ka] and NR p2 R q2 Selected from R p2 and Rq2 are taken together to form a 3- to 10-membered heterocyclyl optionally substituted with 1 or 2 groups selected from halogen, OH, CN, —O(C-C alkyl), NH, NHBoc, NH(C-C alkyl), and C-C alkyl optionally substituted with 1-3 groups selected from halogen, CN, NH, NHBoc, and OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0093] In a twenty-fourth embodiment, the compound of the present disclosure has the following structural formula VIc: [ka] [In the formula, R a is, for each occurrence, independently selected from absent, halogen, CN, NO, NH, —NH(C-C alkyl), OH, —O(C-C alkyl), —C(═O)H, —C(═O)O(C-C alkyl), —C(═O)NH, and C-C alkyl optionally substituted with 1 to 3 groups selected from halogen, OH, CN, and NH; m′ is 0, 1, and 2; R p2 and R q2 are independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 3-10 membered heteroaryl, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0094] In a twenty-fifth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R ais, for each occurrence, independently selected from absent, CH, CF, F, Cl, CN, NH, NHCH, and OH, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0095] In a twenty-sixth embodiment, the compound of the present disclosure has the following structural formula VId: [ka] [Wherein, L is —O—, —N(R x L is selected from C1-C3 alkylene optionally substituted with 1 or 2 groups selected from -, -CH2-, -S-, -S(=O)-, -S(=O)2-, and C1-C2 alkyl, wherein the C1-C2 alkyl of the C1-C3 alkylene of L optionally joins together to form a C3-C4 cycloalkyl; R a is, for each occurrence, independently selected from H and C-C alkyl (e.g., C alkyl, C alkyl, preferably methyl); R b is, for each occurrence, independently selected from absent, F, Cl, Br, CH, and CN; R c is selected from F, Cl, Br, CH3, -OCH3, and CN, and p is 0, 1, or 2, provided that L is -O- or -N(R x )-, Z4 is C; and when L is -CH2-, -S-, -S(=O)-, -S(=O)2-, or C1-C3 alkylene, Z4 is C or N; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0096] In a twenty-seventh embodiment, the compound of the present disclosure has the following structural formula VIe: [ka] wherein V1 and V2 are each independently selected from C, N, and O; and L is -O-, -N(R x L is selected from C1-C3 alkylene optionally substituted with 1 or 2 groups selected from -, -CH2-, -S-, -S(=O)-, -S(=O)2-, and C1-C2 alkyl, wherein the C1-C2 alkyl of the C1-C3 alkylene of L optionally joins together to form a C3-C4 cycloalkyl; R a is, for each occurrence, independently selected from H and C-C alkyl (e.g., C alkyl, C alkyl, preferably methyl); R b is, for each occurrence, independently selected from absent, F, Cl, Br, CH, and CN; R c is selected from F, Cl, Br, —OCH3, CH3, and CN; R f is, for each occurrence, independently selected from C-C alkyl and halogen; p is 0, 1, or 2; and q is 0, 1, or 2; provided that L is -O- or -N(R x )-, Z4 is C; and when L is -CH2-, -S-, -S(=O)-, -S(=O)2-, or C1-C3 alkylene, Z4 is C or N; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0097] In a twenty-eighth embodiment, the compound of the present disclosure has the following structural formula VIf: [ka] wherein V1, V2, and V3 are each independently selected from C, N, and O; and L is -O-, -N(R xL is selected from C1-C3 alkylene optionally substituted with 1 or 2 groups selected from -, -CH2-, -S-, -S(=O)-, -S(=O)2-, and C1-C2 alkyl, wherein the C1-C2 alkyl of the C1-C3 alkylene of L optionally joins together to form a C3-C4 cycloalkyl; R a is, for each occurrence, independently selected from H and C-C alkyl (e.g., C alkyl, C alkyl, preferably methyl); R b is, for each occurrence, independently selected from absent, F, Cl, Br, CH, and CN; R c is selected from F, Cl, Br, CH, —OCH, and CN; R f is, for each occurrence, independently selected from C-C alkyl and halogen; p is 0, 1, or 2; and q is 0, 1, or 2; provided that L is -O- or -N(R x )-, Z4 is C; and when L is -CH2-, -S(=O)-, -S(=O)2-, or C1-C3 alkylene optionally substituted with C3-C4 cycloalkyl, Z4 is C or N; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0098] In a twenty-ninth embodiment, the compound of the present disclosure has the following structural formula VIIa: [ka] wherein Q1, Q2, and Q3 are each independently selected from C and N, and Y1 and Y2 are each independently selected from C and N, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0099] In a thirtieth embodiment, the compound of the present disclosure has the following structural formula VIIb: [ka] wherein Q1, Q2, and Q3 are each independently selected from C and N; Y1 and Y2 are each independently selected from C and N; Z1 is selected from C and N; and R a is, for each occurrence, independently selected from absent, halogen, CN, NO, NH, —NH(C-C alkyl), —OH, —O(C-C alkyl), —C(═O)H, —C(═O)O(C-C alkyl), —C(═O)NH, and C-C alkyl optionally substituted with 1 to 3 groups selected from halogen, OH, CN, and NH; m′ is 0, 1, and 2; R a1 is an optionally substituted C1-C3 alkyl, an optionally substituted 3- to 6-membered cycloalkyl, an optionally substituted 3- to 6-membered heterocyclyl, -NC(=O)R p2 , and -NR p2 R q2 Selected from R p2 and R q2 are, for each occurrence, independently selected from hydrogen and optionally substituted C-C alkyl, or R p2 and R q2 taken together to form an optionally substituted 3- to 10-membered heterocyclyl, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0100] In a thirty-first embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R ais, for each occurrence, independently selected from absent, CH, CF, F, Cl, CN, NH, NHCH, OH, —CHOH, —COOMe, —COOEt, —CONH, —C(═O)H, —CHCN, —CHNH, CF, and NO; R a1 COOMe, COOEt, [ka] and NR p2 R q2 Selected from R p2 and R q2 are taken together to form a 3- to 10-membered heterocyclyl optionally substituted with 1 or 2 groups selected from halogen, OH, CN, —O(C-C alkyl), NH, NHBoc, NH(C-C alkyl), and C-C alkyl optionally substituted with 1-3 groups selected from halogen, CN, NH, NHBoc, and OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0101] In a thirty-second embodiment, the compound of the present disclosure has the following structural formula VIIc: [ka] wherein Q1, Q2, and Q3 are each independently selected from C and N; Y1 and Y2 are each independently selected from C and N; Z1 is selected from C and N; and R a is, for each occurrence, independently selected from absent, halogen, CN, NO, NH, —NH(C-C alkyl), OH, —O(C-C alkyl), —C(═O)H, —C(═O)O(C-C alkyl), —C(═O)NH, and C-C alkyl optionally substituted with 1 to 3 groups selected from halogen, OH, CN, and NH; m′ is 0, 1, and 2; R p2 and R q2are independently selected from H, optionally substituted C1-C6 alkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 3-10 membered heteroaryl, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0102] In a thirty-third embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R a is, for each occurrence, independently selected from absent, CH, CF, F, Cl, CN, NH, NHCH, OH, —CHOH, —COOMe, —COOEt, —CONH, —C(═O)H, —CHCN, —CHNH, CF, and NO; R p2 and R q2 wherein the 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl are optionally substituted with one or two groups selected from halogen, OH, CN, —O(C-C alkyl), NH, NHBoc, NH(C-C alkyl), and C-C alkyl optionally substituted with halogen, CN, NH, NHBoc, and OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0103] In a thirty-fourth embodiment, the compound of the present disclosure has the following structural formula VIIIa, VIIIb, or VIIIc: [ka] wherein Q1, Q2, and Q3 are each independently selected from C and N; Y1 and Y2 are each independently selected from C and N; Z' is selected from C and N; Z1, Z2, and Z3 are each independently selected from S, O, C, and N; Z4 is selected from C and N; and R a is, for each occurrence, independently selected from absent, halogen, CN, NO, NH, —NH(C-C alkyl), —OH, —O(C-C alkyl), —C(═O)H, —C(═O)O(C-C alkyl), —C(═O)NH, and C-C alkyl optionally substituted with 1-3 groups selected from halogen, OH, CN, and NH; ring D is a 3- to 10-membered heterocyclyl; and R g is, for each occurrence, independently selected from halogen, OH, CN, —O(C-C alkyl), NH, NHBoc, NH(C-C alkyl), and C-C alkyl optionally substituted with 1 to 3 groups selected from halogen, CN, NH, NHBoc, and OH, and s is an integer selected from 0, 1, and 2; a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0104] In a thirty-fifth embodiment, the compound of the present disclosure has the following structural formula VIIId, VIIIe, or VIIIf: [ka] wherein Q1, Q2, and Q3 are each independently selected from C and N; Y1 and Y2 are each independently selected from C and N; Z' is selected from C and N; Z1, Z2, and Z3 are each independently selected from S, O, C, and N; Z4 is selected from C and N; and R ais, for each occurrence, independently selected from absent, halogen, CN, NO, NH, NH(C-C alkyl), OH, —O(C-C alkyl), —C(═O)H, —C(═O)O(C-C alkyl), —C(═O)NH, and C-C alkyl optionally substituted with 1 to 3 groups selected from halogen, OH, CN, and NH; R h is, for each occurrence, independently selected from H, C1-C3 alkyl optionally substituted with 1-3 groups selected from halogen and 3-4 membered cycloalkyl, 3-6 membered cycloalkyl optionally substituted with 1-3 groups selected from halogen and C1-C3 alkyl, and 3-6 membered heterocyclyl optionally substituted with 1-3 groups selected from halogen and C1-C3 alkyl, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0105] In a thirty-sixth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, a compound of formula I [ka] is selected from R b Ring B substituted with n groups is [ka] is selected from R c Ring C substituted with p groups is [ka] is selected from L is [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0106] In a thirty-seventh embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R a Ring A substituted with m groups of the formula: [ka] Selected from R a’ is, for each occurrence, independently selected from F, Cl, —OCH 3 , CH 3 , NH 2 , and CN; L is -0—; and * The position indicated by is connected to L and is on the right side of the structure above. * The position indicated by R a All other variables linked to and not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0107] In a thirty-eighth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R a Ring A substituted with m groups of the formula: [ka] wherein L is -SO2-, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0108] In a thirty-ninth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, a compound of formula I [ka] Selected from R 2 is selected from H, halogen, CN, —NH, OH, OCH, ═O, and C-C alkyl optionally substituted with 1-3 groups selected from halogen, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0109] In a fortieth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, a compound of formula I [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0110] In a forty-first embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the present disclosure, a compound of formula I [ka] wherein R f is, for each occurrence, independently selected from C-C alkyl and halogen; q is selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0111] In a forty-second embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, a compound of formula I [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0112] In a forty-third embodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the present disclosure, ring A is [ka] wherein ring A is selected from R a and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0113] In a forty-fourth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R a Ring A substituted with m groups of the formula: [ka] wherein R k is selected from -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, wherein R j is, for each occurrence, independently selected from F, Cl, CH, and CN, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0114] In a forty-fifth embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, ring B is [ka] wherein ring B is selected from R b and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0115] In a forty-sixth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R b Ring B substituted with n groups is [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0116] In a forty-seventh embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, Ring C is [ka] wherein ring C is selected from R c and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0117] In a forty-eighth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R c Ring C substituted with p groups is [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0118] In a forty-ninth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R ais, for each occurrence, independently, absent, halogen, cyano, =O, NO2, Halogen, CN, -OR s , -C(=O)NR p R q , -C(=O)OR s , -N3, =NRp, =NOR s , -NR p R q , 3-10-membered cycloalkyl, and 3-10-membered heterocyclyl, wherein the 3-10-membered cycloalkyl and 3-10-membered heterocyclyl are each selected from C1-C6 alkyl, halogen, and OR s C1-C6 alkyl optionally substituted with 1 to 4 groups selected from Halogen, CN, -OR s , -C(=O)NR p R q , -C(=O)OR s , -N3, =NRp, =NOR s , -NR p R q C2-C6 alkenyl optionally substituted with 1 to 4 groups selected from , 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclyl, wherein the 3- to 10-membered cycloalkyl and 3- to 10-membered heterocyclyl are each selected from C1-C6 alkyl, halogen, and OR s C2-C6 alkenyl optionally substituted with 1 to 4 groups selected from Halogen, CN, -OR s , -C(=O)NR p R q , -C(=O)OR s , -N3, =NRp, =NOR s , -NR p R q C2-C6 alkynyl optionally substituted with 1 to 4 groups selected from , 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclyl, wherein the 3- to 10-membered cycloalkyl and 3- to 10-membered heterocyclyl are each selected from C1-C6 alkyl, halogen, and OR s C2-C6 alkynyl optionally substituted with 1 to 4 groups selected from Halogen, CN, OR s , -C(=O)NR p R q , -C(=O)OR s , and -NR p R q 3 to 10-membered cycloalkyl optionally substituted with 1 to 4 groups selected from Halogen, CN, OR s , -C(=O)NR p R q , -C(=O)OR s , and -NR p R q 3- to 10-membered heterocyclyl optionally substituted by 1 to 4 groups selected from -C(=O)R s , -C(=O)OR s , -C(=O)(C=O)OR s , -C(=O)NR p R q NR p R q , -C(=O)NR p R q OR s , -C(=O)NR p R q , -NR p R q , -NR p C(=O)R s [In the formula, R p and R s is defined below in the claims, or NR p C(=O)R s R p and R s together form a 5- to 10-membered heterocyclyl], -NR p2 C(=O)OR s2 [In the formula, R p2 and R s2 is defined below in the claims, or -NR p2C(=O)OR s2 R p2 and R s2 together form a 5- to 10-membered heterocyclyl], -OR s [In the formula, R p and R q is, for each occurrence, independently selected from hydrogen and C1-C6 alkyl, or R p and R q taken together to form a 3- to 10-membered heterocyclyl, R p and R q Any one of C1-C4 alkyl is halogen, -NR p1 C(=O)OR s1 , cyano, -OH, -OR s1 , -O(C1-C3 alkyl)OR s1 , 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, and phenyl, wherein R p and R q any one of 3- to 10-membered heterocyclyl and R p and R q The 3-10 membered cycloalkyl and 3-10 membered heterocyclyl of any one of C1-C4 alkyl and C1-C4 alkyl are each optionally selected from halogen, CN, =O, NR p1 R q1 , OR s1 , -NR p1 C(=O)R s1 , -NR p1 C(=O)OR s1 , 3- to 10-membered cycloalkyl, and C1-C3 alkyl optionally substituted with C3-C4 cycloalkyl; R s is, for each occurrence, independently selected from hydrogen, C-C alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocyclyl; R s C1-C6 alkyl, phenyl, 5- to 6-membered heteroaryl, The 3- to 10-membered cycloalkyl and the 3- to 10-membered heterocyclyl are each optionally selected from halogen, NR p1 R q1 , -NR p1 C(=O)OR s1 , cyano, -OH, -O(C1-C3 alkyl), -O(C1-C3 alkyl)OH, -O(C1-C3 alkyl)O(C1-C3 alkyl), 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, and phenyl; R p1 and R q1 are, for each occurrence, independently selected from hydrogen and C1-C4 alkyl optionally substituted with 1 to 3 groups of halogen, CN, and OH; R s1 is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl optionally substituted with 1 to 3 groups of halogen, CN, and OH; R p2 is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl optionally substituted with 1 to 3 groups of halogen, CN, and OH; R s2 is, for each occurrence, independently selected from hydrogen and C1-C4 alkyl optionally substituted with 1 to 3 groups of halogen, CN, and OH; All other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0119] In a 50th embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R ais absent, NH2, NO2, =O, cyano, I, F, Cl, Br, -CH3, -CH(CH3)2, -CH2CN, -CF3, -CH2OH, -CH2CH2OH, -C(CH3)2OH, -CH2C(CH3)2OH, -CHF2, -CHCH3OH, -CH2CONH2, -CH2COOH, -CHCH3NH2, -CH2OH, -CH2CH2OH, -CH2N3, -CH2NH2, -CH2OCH3, [ka] [ka] [ka] [ka] [ka] [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0120] In a fifty-first embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R a is, for each occurrence, independently: absent, CH3, CF2, F, Cl, CN, NH2, NHCH3, OH, -CH2OH, -COOMe, -COOEt, -CONH2, -C(=O)H, -CH2CN, -CH2NH2, CF3, NO2, [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0121] In a fifty-second embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R b is, for each occurrence, independently selected from absent, halogen, ═O, and C-C alkyl, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0122] In a fifty-third embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R b is, for each occurrence, independently selected from absent, —CH, ═O, F, and Cl, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0123] In a fifty-fourth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R c is, for each occurrence, independently, absent, C1-C3 alkyl, CN, halogen, -OR s1 , and -C(=O)OR s1 Selected from R s1 is H or C1-C4 alkyl, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0124] In a fifty-fifth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the present disclosure, R cis, for each occurrence, independently selected from absent, CH, CN, F, Cl, —OCH, and —C(═O)OC(CH), and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0125] In a fifty-sixth embodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the present disclosure, R2 is H, halogen, CN, OR s1 , -NR p1 R q1 , ═O, and halogen; R s1 , R p1 , and R q1 is independently selected from H and CH, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0126] In a fifty-seventh embodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the present disclosure, R2 is selected from H, CH3, CF3, CN, F, Cl, Br, OH, OCH3, NH2, and =O, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0127] In a fifty-eighth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R1 and R2 together form a 5-6 membered ring optionally substituted with one or two groups selected from halogen and C1-C2 alkyl optionally substituted with one or two groups selected from halogen, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0128] In a fifty-ninth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R1 and R2 together form a 5- to 6-membered ring optionally substituted with one or two groups selected from F and CH3, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0129] In a sixtieth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, L is -N(R x )-, -(CH2) u O(CH2) u -, -(CH2) u S(=O) w -(CH2) u -, -S(=O)(=NR x )-, -(NR x )S(=O) w -, -S(=O) w (NR x )-, -C(=O)-, and C1-C3 alkylene, and the C1-C3 alkylene of L is selected from OH, C1-C3 alkyl, and ═CHR x wherein the C1-C3 alkyl of the C1-C3 alkylene of L optionally joins together to form a C3-C4 cycloalkyl; x is selected from H and C1-C2 alkyl; u for each occurrence is independently 0 or 1; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0130] In a sixty-first embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, L is [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0131] In a sixty-second embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, L is [ka] and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0132] In certain embodiments, at least one compound of the present disclosure is selected from compounds 1-702, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0133] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound selected from a compound of the formulae disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and at least one pharmaceutically acceptable carrier.

[0134] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant, hi some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0135] It will also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy: i.e., the pharmaceutical compositions described herein can further comprise an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from a compound of the formulas disclosed herein (e.g., Compounds 1-702), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, can be administered as a separate composition simultaneously with, before, or after a composition comprising the additional active pharmaceutical agent.

[0136] In some embodiments, the pharmaceutically acceptable carrier may be selected from adjuvants and vehicles. The pharmaceutically acceptable carrier used herein may be selected from, for example, any solvent, diluent, other liquid vehicle, dispersant, suspending agent, surfactant, isotonicity agent, thickener, emulsifier, preservative, solid binder, and lubricant suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 to 1999, Marcel Dekker, New York, disclose various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, for example, by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphate, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethylcellulose), and the like. Examples of suitable carriers include: sodium sucrose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavors, fragrances, preservatives, and antioxidants.

[0137] A compound selected from the compounds of the formulae disclosed herein (Compounds 1-702), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition disclosed herein, can be administered orally in solid dosage forms such as capsules, tablets, lozenges, dragees, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions, or solutions. Other dosage forms may also be used to administer the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein; as ointments, creams, drops, transdermal patches, or powders for topical administration; as ophthalmic solution or suspension formulations, e.g., eye drops, for ophthalmic administration; as aerosol sprays or powder compositions for inhalation or intranasal administration; or as creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0138] Gelatin capsules containing a compound disclosed herein, its tautomer, a solvate or stereoisomer of the compound or tautomer, and / or a pharmaceutically acceptable salt thereof and a powdered carrier such as lactose, starch, a cellulose derivative, magnesium stearate, or stearic acid can also be used. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be manufactured as sustained-release products, releasing the medication over a sustained period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated to selectively disintegrate in the gastrointestinal tract.

[0139] Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring and flavoring agents to enhance patient acceptance.

[0140] In general, water, a suitable oil, saline, aqueous dextrose (glucose) solution, and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, are examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may contain a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer substance. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are examples of suitable stabilizers. Citric acid and its salts and sodium EDTA are also examples of suitable stabilizers. Furthermore, parenteral solutions may further contain at least one preservative selected from, for example, benzalkonium chloride, methylparaben and propylparaben, and chlorobutanol.

[0141] Pharmaceutically acceptable carriers are selected from carriers that are compatible with the active ingredients of the composition (and in some embodiments, can stabilize the active ingredients) and are not harmful to the subject being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with at least one compound and / or at least one pharmaceutically acceptable salt disclosed herein) can be used as pharmaceutical excipients for delivering the active ingredients. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol.

[0142] For administration by inhalation, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can also be delivered as powders that can be formulated, and the powder compositions can be inhaled using an insufflation powder inhaler. One exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol, which can be formulated as a suspension or solution of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons.

[0143] For ocular administration, ophthalmic preparations can be formulated using a solution or suspension of an appropriate weight percentage of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in a suitable ophthalmic vehicle so that the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein is maintained in contact with the ocular surface for a period of time sufficient to allow the compound to penetrate the corneal and internal regions of the eye.

[0144] Pharmaceutical dosage forms useful for administering the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions. In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of controlled-release or sustained-release compositions known in the art.

[0145] The term "unit dosage form" refers to physically discrete units suitable as unitary dosage forms for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce a desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, or drops for solid compositions. In such compositions, the active agent typically comprises from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight, with the remainder being various vehicles or carriers and processing aids useful for forming the desired dosage form. Unit-dose formulations are preferably about 5, 10, 25, 50, 100, 250, 500, or 1,000 mg per unit. In certain embodiments, unit dosage forms are packaged in multipacks adapted for sequential use, such as blister packs containing at least 6, 9, or 12 sheets of unit dosage forms.

[0146] In some embodiments, unit capsules can be prepared by filling each standard two-piece hard gelatin capsule with, for example, 100 milligrams of powder of a compound described herein, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

[0147] In some embodiments, a mixture of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein and a digestible oil such as soybean oil, cottonseed oil, or olive oil can be prepared and injected into gelatin via a positive displacement pump to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

[0148] In some embodiments, tablets can be prepared by conventional procedures so that a dosage unit contains, for example, 100 milligrams of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.8 milligrams of lactose. Appropriate coatings can be applied to enhance palatability or delay absorption.

[0149] In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of a compound disclosed herein and / or at least one enantiomer, diastereoisomer, or pharmaceutically acceptable salt thereof in 10% by volume of propylene glycol. The solution is made up to volume with water for injection and sterilized.

[0150] In some embodiments, an aqueous suspension can be prepared for oral administration. For example, 5 milliliters of an aqueous suspension containing 100 milligrams of micronized compound, its stereoisomer, or its pharmaceutically acceptable salt, 100 milligrams of sodium carboxymethylcellulose, 5 milligrams of sodium benzoate, 1.0 gram of sorbitol solution (USP), and 0.025 milliliters of vanillin can be used.

[0151] When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein are administered stepwise or in combination with at least one other therapeutic agent, the same dosage form can generally be used.When drugs are administered in physical combination, the dosage form and administration route should be selected according to the compatibility of the combined drugs.Therefore, the term co-administration is understood to include the simultaneous or sequential administration of at least two drugs, or the administration of at least two active ingredients as a fixed-dose combination.

[0152] The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts disclosed herein can be administered as the sole active ingredient or in combination with at least one second active ingredient.

[0153] The compounds, tautomers, solvates, or stereoisomers described herein can be used in the form described above or in the form of their pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein contain a relatively acidic functional group, the salts can be obtained by adding a desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts. When the compounds, tautomers, solvates, or stereoisomers described herein contain a relatively basic functional group, the salts can be obtained by adding a desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid), and salts derived from relatively non-toxic organic acids (e.g., acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc.). Also included are salts of amino acids such as arginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0154] The neutral forms of the pharmaceutically acceptable salts described herein can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0155] The present disclosure provides prodrugs. Prodrugs of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein undergo readily chemical changes under physiological conditions to provide the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure. Furthermore, prodrugs can be converted to the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. For example, they may be more bioavailable than the parent drug upon oral administration. Prodrugs may also have improved solubility in pharmacological compositions compared to the parent drug. A wide variety of prodrug derivatives are known in the art, including those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example of a prodrug, without limitation, is a compound of the present disclosure that is administered as an ester (the "prodrug") but then metabolically hydrolyzed to the carboxylic acid, ie, the active form.

[0156] Certain compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure can exist in multiple crystalline or amorphous forms.

[0157] Certain compounds, tautomers, solvates, or pharmaceutically acceptable salts in this disclosure possess asymmetric carbon atoms (optical centers) or double bonds. The racemates, enantiomers, diastereoisomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of this disclosure.

[0158] III. Treatment Methods and Uses The compounds, tautomers, hydrates, stereoisomers, or pharmaceutically acceptable salts described herein, including compounds of the formulae disclosed herein, Compounds 1-702, tautomers thereof, hydrates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in treating a disease or condition selected from inflammatory diseases, immune diseases (e.g., autoimmune diseases), allergic diseases, transplant rejection, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ischemic brain injury, eye diseases, infectious diseases, and malignancies. In some embodiments, the disease or condition is mediated by receptor-interacting protein 1 (RIP1) signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infections.

[0159] In another aspect, disclosed herein are compounds, tautomers, hydrates, stereoisomers, or pharmaceutically acceptable salts described herein, including compounds of the formulas disclosed herein, compounds 1-702, tautomers thereof, hydrates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, for use as a pharmaceutical.

[0160] In another aspect, disclosed herein is the use of a compound, tautomer, hydrate, stereoisomer, or pharmaceutically acceptable salt described herein, including a compound of the formulas disclosed herein, compounds 1-702, a tautomer, a hydrate, or stereoisomer thereof, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease or condition selected from inflammatory diseases, immune diseases (e.g., autoimmune diseases), allergic diseases, transplant rejection, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ischemic brain injury, eye diseases, infectious diseases, and malignancies. In some embodiments, the disease or condition is mediated by RIP1 signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infections. In yet another aspect, disclosed herein is a method of treating a disease or condition selected from inflammatory diseases, immune diseases (e.g., autoimmune diseases), allergic diseases, transplant rejection, necrotic cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ischemic brain injury, eye diseases, infectious diseases, and malignancies in a subject, comprising administering a therapeutically effective amount of a compound described herein, a tautomer, a hydrate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, including a compound of the formulas disclosed herein, compounds 1-702, a tautomer, a hydrate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof. In some embodiments, the disease or condition is mediated by RIP1 signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and a viral infection.

[0161] In a further aspect of the present disclosure, the compounds, tautomers, hydrates, stereoisomers, or pharmaceutically acceptable salts described herein, including compounds of the formulae disclosed herein, compounds 1-702, tautomers thereof, hydrates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in treating a disease or condition mediated by RIP1 signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infections. In another aspect, disclosed herein is the use of a compound described herein, a tautomer, a hydrate or stereoisomer of the compound or of the tautomer, or a pharmaceutically acceptable salt thereof, including a compound of the formulas disclosed herein, compounds 1-702, a tautomer thereof, a hydrate or stereoisomer of the compound or of the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a disease or condition mediated by RIP1 signaling. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and a viral infection. In yet another aspect, disclosed herein are methods of treating a disease or condition mediated by RIP1 signaling in a subject, comprising administering a therapeutically effective amount of a compound, tautomer, hydrate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt thereof, as described herein, including compounds of the formulae disclosed herein, compounds 1-702, tautomers thereof, hydrates or stereoisomers of the compound or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof. In some embodiments, the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and viral infections.

[0162] In another aspect of the disclosure, the compounds, tautomers, hydrates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof described herein, including compounds of the formulae disclosed herein, compounds 1-702, tautomers thereof, hydrates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, are for use in mediating RIP1, e.g., inhibiting RIP1 by contacting a RIP1 protein or fragment thereof (e.g., the kinase domain, intermediate domain, and / or death domain) with the compound, tautomer, hydrate or stereoisomer of the compound or tautomer, pharmaceutically acceptable salt, or pharmaceutical composition. In yet another aspect, disclosed herein is a method of inhibiting RIP1, comprising contacting a RIP1 protein or a fragment thereof (e.g., the kinase domain, the intermediate domain, and / or the death domain) in a subject with a compound, tautomer, hydrate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt described herein, including a compound of the formula disclosed herein, compounds 1-702, a tautomer thereof, a hydrate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition thereof.

[0163] A compound of the formulae disclosed herein, Compounds 1-702, tautomers thereof, hydrates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition thereof, can be administered once daily, twice daily, or three times daily, for example, for the treatment of the diseases or conditions described above, e.g., a disease or condition selected from inflammatory diseases, immune diseases (e.g., autoimmune diseases), allergic diseases, transplant rejection, necrotic cell diseases, neurodegenerative diseases, CNS diseases, ischemic brain injury, eye diseases, infectious diseases, and malignancies (including those mediated by RIP1 signaling), a disease or condition selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, ALS, Alzheimer's disease, and viral infections (including those mediated by RIP1 signaling), a disease or condition mediated by RIP1 signaling.

[0164] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of a formula disclosed herein, Compounds 1-702, a tautomer thereof, a hydrate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition thereof, is administered once daily, twice daily, or three times daily.

[0165] Compounds of the formulae disclosed herein, Compounds 1-702, their tautomers, hydrates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions thereof, can be administered in a variety of ways, for example, orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir; the most suitable route in any given case will vary depending on the particular host and the nature and severity of the condition for which the active ingredient is being administered. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein are conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art. Parenteral administration can be by continuous infusion over a selected period of time. Other dosage forms contemplated in the present disclosure are as described in WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142, and WO 2015 / 023915.

[0166] Contacting is generally achieved by administering to the subject an effective amount of one or more compounds, tautomers, hydrates, stereoisomers, and pharmaceutically acceptable salts disclosed herein. Generally, administration is adjusted to achieve a therapeutic dose of about 0.1-50, preferably 0.5-10, and more preferably 1-10 mg / kg, although optimal doses vary from compound to compound and are generally determined empirically for each compound.

[0167] The dosage will vary depending on factors such as the recipient's age, health and weight, the extent of the disease, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect. Generally, the daily dose of the active ingredient can vary, for example, from 0.1 to 2000 milligrams per day. For example, 10 to 500 milligrams, one or more times a day, can be effective to obtain the desired results.

[0168] The subject compositions may also be co-formulated and / or co-administered with different compounds to treat applicable indications or to treat programmed cell death, which in some embodiments include brain injury, neurodegenerative diseases, viral infections, immune tolerance, and cancer to promote tumor immunity, for example, in pancreatic cancer and melanoma. [Example]

[0169] In order that the disclosure set forth herein may be more fully understood, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any way.

[0170] Example 1. Synthesis of exemplary compounds Compounds of the present disclosure selected from compounds of the formulae set forth herein, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, can be made according to standard chemical methods or as illustrated herein, including the following synthetic schemes for compounds 1-702 as representative of Formula I.

[0171] The intermediates 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one, methyl 5-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxylate, and 2-(3-fluoro-4-hydroxyphenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one were purified by chiral HPLC to give two stereoisomers. These were used as starting materials to synthesize the corresponding target compounds.

[0172] Example 1: Method 1 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 2,4-Dihydro-3H-1,2,4-triazol-3-one (41.06 g, 0.483 mol) was dissolved in 300 mL of DMF. K2CO3 (138 g, 1 mol) was added. 2-(Bromomethyl)-1,3-difluorobenzene (100 g, 0.483 mol) in 200 mL of DMF was added dropwise to the solution at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated to dryness to give a residue. Water was added to the residue and extracted with EA (2 L × 3). The organic layers were combined and evaporated to dryness to give the crude product. It was triturated with tert-butyl methyl ether to give 59 g of a white solid. Yield: 57.9%. LC-MS (m / z): 212.2 [M+H] + .

[0173] Step 2: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 4-(2,6-Difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20 g, 0.094 mol) and 4-bromo-2-fluorophenol (17.8 g, 0.094 mol) were mixed in 400 mL of 1,4-dioxane. K2Co3 (39.0 g, 0.28 mol), CuI (2.66 g, 0.014 mol), and DMDACH ((1S,2S)-N 1 ,N 2To the reaction mixture was added 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10 g, yield: 33.1%) as a beige solid. LC-MS (m / z): 322.3 [M+H] + .

[0174] Step 3: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 5-bromo-4-methylthiazole (4.96 g, 0.0279 mol) in NMP (50 mL) was added 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (6.87 g, 0.0214 mol) and potassium carbonate (5.92 g, 0.0429 mol) under Ar. The reaction mixture was stirred at 150 °C for 2 h. Water was added, and the reaction solution was extracted with EtOAc (300 mL × 3). The organic phases were combined and washed with water (150 mL) and brine. The organic layer was dried over MgSO, filtered, and evaporated to dryness to give a residue. The residue was purified by column chromatography (PE / EA = 9 / 1 to 4 / 1) to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5.9 g, yield: 66.0%) as a pale yellow solid. LC-MS (m / z): 419.1 [M+H] + .

[0175] Step 4: 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2 g, 4.78 mmol) in MeCN (50 mL) was added 1-bromopyrrolidine-2,5-dione (1.70 g, 9.56 mmol). The reaction was stirred at 90° C. for 2 hours. The progress of the reaction was monitored by LCMS. Once the starting material was consumed, the reaction solution was concentrated to dryness and the residue was extracted with EtOAc (100 mL×3). The organic layers were combined and washed with water (50 mL) and brine. The organic layer was dried over MgSO4, filtered, and evaporated to dryness to give a residue. The residue was purified by column chromatography (PE / EA = 9 / 1 to 1 / 1) to give 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.82 g, yield: 76.56%) as a pale yellow solid. LC-MS (m / z): 497.1, 499.1. [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.35(s,1H),7.88(dd,J=12.4,2.4Hz,1H),7.71-7.64(m,1H),7.48(tt,J=8.4, 6.8Hz, 1H), 7.33 (t, J=9.2Hz, 1H), 7.21-7.10 (m, 2H), 4.98 (s, 2H), 2.21 (s, 3H).

[0176] Using the same method as that used in Example 1, Examples (compounds) 2 to 9 were synthesized. [Table 1-1] [Table 1-2] [Table 1-3]

[0177] Example 10: Method 2 Methyl 5-(4-(4-((4-chloropyridin-2-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazole-2-carboxylate [ka] Step 1: 4-(4-Methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 2,4-dihydro-3H-1,2,4-triazol-3-one (85 g, 1 mol, 1.0 equiv.) and KCO (207 g, 1.5 mol, 1.5 equiv.) in DMF (800 mL) was slowly added dropwise a solution of PMBCl (172 g, 1.1 mol, 1.1 equiv.) in DMF (200 mL) at 0 °C. The resulting solution was stirred at 28 °C overnight. It was filtered, and the filtrate was concentrated in vacuo, diluted with EA (500 mL), washed with brine (50 mL × 2), dried over NaSO, concentrated to 200 mL, added with PE (400 mL), and filtered to obtain a solid. 4-(4-Methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (90 g, yield: 90%) was obtained as a white solid. LC-MS(m / z):206.1[M+H] + .

[0178] Step 2: 5-(4-bromo-2-fluorophenoxy)-4-methylthiazole A solution of 4-bromo-2-fluorophenol (54 g, 281 mmol), 5-bromo-4-methyl-1,3-thiazole (50 g, 281 mmol), and K2CO3 (78 g, 562 mmol) in DMF (800 mL) was stirred at 150 °C for 2 h. The resulting solution was filtered, and the filtrate was diluted with EA (1.5 L), washed with water (500 mL × 2) and brine (1 L), dried over Na2SO4, concentrated, and purified by silica gel column (EA:PE = 0:1 to 1:1) to give 5-(4-bromo-2-fluorophenoxy)-4-methylthiazole (77 g, yield: 85%) as an off-white solid. LC-MS (m / z): 287.9 ​​[M+H] + .

[0179] Step 3: 2-(3-fluoro-4-((4-methylthiazol-5-yl)oxy)phenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A solution of 4-(2-methoxy-5-methylphenyl)-2H-1,2,4-triazol-3-one (55 g, 267 mmol), 5-(4-bromo-2-fluorophenoxy)-4-methyl-1,3-thiazole (77 g, 267 mmol), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (11.4 g, 80 mmol), CuI (15 g, 80 mmol), and CsCO (174 g, 534 mmol) in DMF (1 L) was stirred at 100 °C for 16 h. The resulting solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (EA:PE = 0:1 to 2:1) to give 2-(3-fluoro-4-((4-methylthiazol-5-yl)oxy)phenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (65 g, yield: 78%) as a colorless oil. LC-MS (m / z): 413.1 [M+H] + .

[0180] Step 4: 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 2-{3-fluoro-4-[(4-methyl-1,3-thiazol-5-yl)oxy]phenyl}-4-(2-methoxy-5-methylphenyl)-1,2,4-triazol-3-one (60 g, 146 mmol) in ACN (200 mL) was slowly added a solution of NBS (31 g, 175 mmol) in ACN (800 mL) at 0 °C, and the reaction was stirred at room temperature for 10 min. The resulting solution was filtered, and the filtrate was concentrated and purified by silica gel column (EA:PE = 0:1 to 2:1) to give 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 g, yield: 75%) as a yellow solid. LC-MS(m / z):491.0[M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.92(dd,J=12.2,2.5Hz,1H),7.79-7.72(m,1H),7.41(s,1H),7.29(d,J=2.9Hz,1H),7.27 (s,1H),7.04(t,J=8.9Hz,1H),6.94-6.89(m,2H),4.79(s,2H),3.81(s,3H),2.30(s,3H).

[0181] Step 5: Methyl 5-(2-fluoro-4-(4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxylate A solution of 2-{4-[(2-bromo-4-methyl-1,3-thiazol-5-yl)oxy]-3-fluorophenyl}-4-(2-methoxy-5-methylphenyl)-1,2,4-triazol-3-one (1.2 g, 2.4 mmol), Pd(OAc) (110 mg, 0.4 mmol), Xant-Phos (280 mg, 0.4 mmol), and TEA (1.2 g, 12 mmol) in MeOH (30 mL) was stirred at 75 °C under a CO atmosphere for 16 h. The resulting solution was concentrated and purified by Combi-Flash® (EA:PE=0:1 to 2:1) to give methyl 5-(2-fluoro-4-(4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxylate (600 mg, yield: 48%) as an off-white solid. LC-MS (m / z) 471.0 [M+H] + .

[0182] Step 6: Methyl 5-(2-fluoro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxylate A solution of methyl 5-{2-fluoro-4-[4-(2-methoxy-5-methylphenyl)-5-oxo-1,2,4-triazol-1-yl]phenoxy}-4-methyl-1,3-thiazole-2-carboxylate (600 mg, 1.3 mmol) and TfOH (574 mg, 3.8 mmol) in TFA (3 mL) was stirred for 16 hours at 80 ° C. The resulting solution was diluted with EA (30 mL), washed with water (30 mL), brine (30 mL), dried over Na SO , concentrated, and purified by Combi-Flash (EA:PE = 0:1 to 2:1) to give methyl 5-(2-fluoro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxylate (350 mg, yield: 70%) as a green solid. LC-MS(m / z):413.0[M+H] + .

[0183] Step 7: Methyl 5-(4-(4-((4-chloropyridin-2-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazole-2-carboxylate: To a solution of 4-chloro-2-(chloromethyl)pyridine (30 mg, 0.185 mmol) in DMF (5 mL) was added methyl 5-[2-fluoro-4-(5-oxo-4H-1,2,4-triazol-1-yl)phenoxy]-4-methyl-thiazole-2-carboxylate (32 mg, 0.0926 mmol) and potassium carbonate (38 mg, 0.278 mmol). The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was dissolved in EtOAc (100 mL) and the organic layers were combined and washed with water (2 x 50 mL) followed by brine (50 mL). The reaction mixture was dried over MgSO and evaporated to dryness. The crude product was then purified by preparative TLC (PE:EA=2:3) to give methyl 5-[4-[4-[(4-chloro-2-pyridyl)methyl]-5-oxo-1,2,4-triazol-1-yl]-2-fluoro-phenoxy]-4-methyl-thiazole-2-carboxylate (25 mg, yield: 28.4%) as a white solid. MS (m / z): 476.1 [M+H] + . 1 H NMR(400MHz,DMSO)δ 8.51(d,J=5.4Hz,1H),8.40(s,1H),7.96(dd,J=12.5,2.5Hz,1H),7.78(ddd,J=9.1,2.5,1. 4Hz, 1H), 7.64 (d, J=2.0Hz, 1H), 7.54-7.42 (m, 2H), 5.05 (s, 2H), 3.87 (s, 3H), 2.35 (s, 3H).

[0184] Using the same method as that used in Example 10, Examples (compounds) 11 and 12 were synthesized. [Table 2]

[0185] Example 13: Method 3 [ka] Step 1: 5-(4-bromo-2-fluoro-phenoxy)-4-methyl-thiazole To a solution of 4-bromo-2-fluorophenol (1.00 equiv., 20.0 g, 105 mmol) in NMP (200 mL) was added 5-bromo-4-methylthiazole (1.10 equiv., 20.5 g, 115 mmol) and CsF (3.00 equiv., 49.9 g, 314 mmol), and the mixture was stirred at 150 °C under a nitrogen atmosphere for 3 h. The reaction was diluted with EtOAc (1000 mL), and the organics were washed with water (500 mL × 2) followed by saturated brine (500 mL). The organics were then separated, dried (MgSO), and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 50% EtOAc in petroleum ether to give 5-(4-bromo-2-fluoro-phenoxy)-4-methyl-thiazole (18 g, 56.2 mmol, 53.7% yield) as a yellow oil. MS (m / z): 288.2, 290.2 [M + H] + .

[0186] Step 2: 5-(4-Bromo-2-fluoro-phenoxy)-2-iodo-4-methyl-thiazole To a solution of 5-(4-bromo-2-fluoro-phenoxy)-4-methyl-thiazole (1.00 equiv., 14 g, 48.6 mmol) in MeCN (300 mL) was added NIS (2.20 equiv., 18.6 g, 106.8 mmol), AcOH (30.0 mL), and the mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The reaction was quenched with a saturated solution of NaSO. The mixture was diluted with EtOAc (500 mL), and the organics were washed with water (200 mL × 2) followed by saturated brine (200 mL). The organics were then separated, dried (MgSO), and concentrated to dryness. The residue was purified by silica gel chromatography eluting with 30% EtOAc in petroleum ether to give 5-(4-bromo-2-fluoro-phenoxy)-2-iodo-4-methyl-thiazole (12 g, 29.0 mmol, 59.6% yield) as a yellow solid. MS (m / z): 414.2, 416.2 [M+H] + .

[0187] Step 3: Methyl 5-(4-bromo-2-fluoro-phenoxy)-4-methyl-thiazole-2-carboxylate. To a solution of 5-(4-bromo-2-fluoro-phenoxy)-2-iodo-4-methyl-thiazole (1.00 equiv., 10 g, 24.2 mmol) in methanol (300 mL) was added Pd(OAc) (0.30 equiv., 1.62 g, 7.24 mmol), Xantphos (0.60 equiv., 8.42 g, 14.50 mmol), and TEA (5.0 mL), and the mixture was stirred at 50 °C under a CO balloon for 16 h. The reaction was dissolved in EtOAc (500 mL), and the organics were washed with water (300 mL × 2) and saturated brine (200 mL). The organics were then separated, dried (MgSO), and concentrated to dryness. The crude material was then purified by flash column chromatography eluting with 30% EtOAc in petroleum ether. The desired fractions were concentrated to dryness in vacuo to give methyl 5-(4-bromo-2-fluoro-phenoxy)-4-methyl-thiazole-2-carboxylate (5.8 g, 15.1 mmol, 62.43% yield) as a brown oil. MS (m / z): 346.2, 348.2 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ 7.38(ddd,J=10.0,2.4,0.8Hz,1H),7.27-7.23(m,1H),6.94(t,J=8.4Hz,1H),3.98(d,J=0.8Hz,3H),2.41(d,J=0.8Hz,3H).

[0188] Step 4: 5-phenylpyrrolidin-2-one A solution of benzene (242 g, 3.10 mol, 2.0 equiv) in Eaton's reagent (500 mL) was added to a suspension of (S)-5-oxopyrrolidine-2-carboxylic acid (200 g, 1.55 mol, 1.0 equiv) in Eaton's reagent (1500 mL). The reaction was heated to 60° C. under a nitrogen atmosphere for 72 hours. The reaction mixture was poured into ice water and adjusted to pH >7 with aqueous NaOH. The aqueous layer was extracted with EtOAc, washed with water and brine, dried over NaSO, filtered, and concentrated to give 5-phenylpyrrolidin-2-one (130 g, 52% yield) as a white solid. MS (m / z): 162.2 [M+H] + .

[0189] Step 5: 5-phenylpyrrolidine-2-thione To a solution of 5-phenylpyrrolidin-2-one (130 g, 0.80 mol, 1.0 equiv.) in toluene (1200 mL) was added Lawession's reagent (640.3 g, 1.59 mol, 2.0 equiv.). The mixture was stirred at 80 °C under a nitrogen atmosphere for 4 h. It was then cooled to 20 °C, concentrated, and purified by chromatography (EtOAc / petroleum ether = 1 / 6 to 1:1) to give 5-phenylpyrrolidine-2-thione (128 g, 91% yield) as a white solid. MS (m / z): 178.0 [M+H] + .

[0190] Step 6: 5-(methylthio)-2-phenyl-3,4-dihydro-2H-pyrrole To a solution of 5-phenylpyrrolidine-2-thione (128 g, 0.72 mol, 1.0 equiv.) in MeCO (1750 mL) was added MeI (122.5 g, 0.86 mol, 1.2 equiv.) and KCO (249.7 g, 1.80 mol, 2.5 equiv.). The reaction mixture was stirred under a nitrogen atmosphere at 25 °C for 16 h. The mixture was extracted with EtOAc, and the organic layer was washed with water and brine, then dried over NaSO, filtered, and concentrated. The residue was purified by chromatography (EtOAc / petroleum ether = 2 / 1) to give 5-(methylthio)-2-phenyl-3,4-dihydro-2H-pyrrole (77 g, 55.7% yield) as a white oil. MS (m / z): 192.1 [M+H] + .

[0191] Step 7: Ethyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 5-(methylthio)-2-phenyl-3,4-dihydro-2H-pyrrole (77 g, 0.40 mol, 1.0 equiv.) in EtOH (500 mL) was added ethyl hydrazine carboxylate (41.9 g, 0.40 mol, 1.0 equiv.), and the reaction mixture was heated to 90° C. under a nitrogen atmosphere for 48 hours. The reaction mixture was concentrated, and the residue was washed with EtOAc / petroleum ether (5 / 1). The solid was collected to give ethyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (80 g, 80.0% yield) as a white solid. MS (m / z): 248.2 [M+H] + .

[0192] Step 8: 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Ethyl 2-(2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (40 g, 0.16 mol) in DMF (200 mL) was stirred at 130 °C for 16 hours. The DMF was evaporated in vacuo. The residue was purified by chromatography (MeOH / DCM = 2% to 10%) to give 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (16 g, 49.0% yield) as a white solid. MS (m / z): 202.1 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 9.35 (brs, 1H), 7.41-7.29 (m, 3H), 7.20 (d, J = 7.2 Hz, 2H), 5.22 (dd, J = 8.0, 4.0 Hz, 1H), 3.08-2.98 (m, 1H), 2.97-2.86 (m, 1H), 2.86-2.75 (m, 1H), 2.51-2.39 (m, 1H).

[0193] Step 9: Methyl 5-[2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy]-4-methyl-thiazole-2-carboxylate To a solution of 5-phenyl-2,5,6,7-tetrahydropyrrolo[2,1-c][1,2,4]triazol-3-one (1.00 equiv., 2906 mg, 14.4 mmol) in DMF (250 mL) was added CuI (0.50 equiv., 1379 mg, 7.22 mmol), KCO (2.00 equiv., 3986 mg, 28.9 mmol), methyl 5-(4-bromo-2-fluorophenoxy)-4-methyl-thiazole-2-carboxylate (1.00 equiv., 5000 mg, 14.4 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.00 equiv., 2051 mg, 14.4 mmol). The reaction mixture was stirred under nitrogen at 100 °C for 1 h. The reaction was concentrated to dryness, and the residue was dissolved in EtOAc (1000 mL). The organics were washed with water (300 mL x 2) and saturated brine (300 mL). The organics were then separated, dried (MgSO4), and concentrated to dryness. The crude was then purified by flash column chromatography eluting with 50% EtOAc in petroleum ether. The desired fractions were concentrated to dryness in vacuo to give methyl 5-[2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy]-4-methyl-thiazole-2-carboxylate (5 g, 10.2 mmol, 70.5% yield) as a yellow oil. MS (m / z): 467.2 [M+H] + .

[0194] Methyl 5-[2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy]-4-methyl-thiazole-2-carboxylate (10.0 g) was purified by chiral separation by SFC under the following conditions: (Column: Lux Cellulose-4, Column size: 5 cm × 25 cm, 5 μm, Mobile phase A: CO2 / Mobile phase B: MeOH:CAN, Wavelength: UV 220 nm, 25 °C).

[0195] Methyl (R)-5-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxylate 4.545 g of white solid, first peak (Peak-1: ee% = 99.86%, chemical purity = 96.97%, retention time: 1.356 min), MS (m / z): 467.2 [M+H] + H NMR (400 MHz, chloroform-d) 1 H NMR (400 MHz, chloroform-d) δ 7.93 (dd, J = 12.4, 2.4 Hz, 1H), 7.76 (dt, J = 9.2, 2.0 Hz, 1H), 7.44-7.32 (m, 3H), 7.27-7.23 (m, 2H), 7.11 (t, J = 8.8 Hz, 1H), 5.32-5.25 (m, 1H), 3.96 (s, 3H), 3.13-2.99 (m, 2H), 2.99-2.87 (m, 1H), 2.59-2.45 (m, 1H), 2.43 (s, 3H).

[0196] Methyl (S)-5-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxylate 4.575 g of white solid, second peak (Peak-2: ee% = 99.92%, chemical purity = 99.50%, retention time: 1.766 min), MS (m / z): 467.2 [M+H] + . δ7.93(dd,J=12.4,2.4 Hz,1H),7.76(dt,J=9.2,2.0 Hz,1H),7.44-7.32(m,3H),7.26-7.22(m,2H),7.11(t,J=8.8 Hz,1H),5.28(dd,J=7.6,4.0 Hz, 1H), 3.96 (s, 3H), 3.18-2.99 (m, 2H), 2.97-2.91 (m, 1H), 2.59-2.47 (m, 1H), 2.43 (s, 3H).

[0197] Step 10: 5-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxamide To a solution of methyl 5-[2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy]-4-methyl-thiazole-2-carboxylate (1.00 equiv., 5 g, 10.7 mmol) in methanol (5 mL) was added NH (7 M in MeOH) (30 mL). The reaction mixture was stirred under nitrogen at 100° C. for 1 hour. The reaction mixture was concentrated to dryness and then triturated with MeOH to give 5-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxamide (4 g, 8.8 mmol, 68.2% yield) as an off-white solid. MS(m / z):452.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.09(brs,1H),7.88(dd,J=12.8,2.4Hz,1H),7.79(brs,1H),7.70(dt,J=9.2,2.0Hz,1H),7.42-7.37(m,3H),7.36 -7.30(m,3H),5.32(dd,J=8.0,4.8Hz,1H),3.07-2.97(m,2H),2.97-2.85(m,1H),2.38-2.32(m,1H),2.31(s,3H).

[0198] Step 11: 5-(2-Fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxamide (1.0 g) was separated by chiral separation by SFC under basic conditions [Column: Lux Cellulose-4, Column size: 5 cm × 25 cm, 5 μm; Mobile phase A: CO / Mobile phase B: MeOH:CAN (0.5% 2 mM NH-MeOH), Wavelength: UV 220 nm, 25 °C] to give two compounds.

[0199] (R)-5-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxamide 0.403 g of white solid, yield: 40.3%, first peak (Peak-1: ee% = 97.50%, chemical purity = 99.41%, retention time: 1.940 min), MS (m / z): 452.2 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ 7.92(dd,J=12.4,2.4Hz,1H),7.74(dt,J=9.2,2.0 Hz,1H),7.43-7.37(m,2H),7.36-7.31(m,1H),7.27-7.23(m,1H),7.15-7.04(m,2H),5.50(brs,1H),5.28(dd,J=7.6,4.0 Hz, 1H), 3.13-2.98 (m, 2H), 2.98-2.86 (m, 1H), 2.61-2.46 (m, 1H), 2.37 (s, 3H).

[0200] (S)-5-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)phenoxy)-4-methylthiazole-2-carboxamide 0.374 g of white solid, yield: 37.4%, second peak (Peak-2: ee% = 98.50%, chemical purity = 98.91%, retention time: 2.198 min), MS (m / z): 452.2 [M+H] +. 1 H NMR(400MHz,DMSO-d6)δ 8.09(brs,1H),7.88(dd,J=12.8,2.4Hz,1H),7.79(brs,1H),7.73-7.66(m,1H),7.43-7.37(m,3H),7.36-7.30(m,3H),5.32(dd,J=8.0,4.8 Hz, 1H), 3.09-2.96 (m, 2H), 2.96-2.87 (m, 1H), 2.39-2.28 (m, 4H).

[0201] Using the same method as that used in Example 13, Examples (compounds) 14 to 36 and 685 to 702 were synthesized. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12]

[0202] Example 37: Method 4 [ka] Step 1: 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A solution of methyl 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(4-methoxybenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3.192 g, 6.5 mmol), TfOH (2.87 g, 19.0 mmol) in TFA (15 mL) was stirred at 80° C. for 16 h. The resulting solution was diluted with EA (150 mL), washed with water (150 mL) and brine (1000 mL), dried over Na2SO4, concentrated, and purified by Combi-Flash® with EA:PE = 0:1 to 2:1 to give methyl 5-(2-fluoro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxylate (1.445 g, yield: 60%) as a green solid. LCMS: (m / z) 371.3 [M+H] + .

[0203] Step 2: 5-(2-fluoro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carbonitrile 2-(4-((2-Bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (800 mg, 2.155 mmol) and CuCN (231.6 mg, 2.586 mmol) were dissolved in 6 mL of NMP. The reaction mixture was stirred at 150° C. for 2 hours. Water was added to the solution, and it was extracted with ethyl acetate (30 mL×3). The organic layers were combined and evaporated to dryness. 18Column purification gave 5-(2-fluoro-4-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carbonitrile (400 mg, yield: 58.5%) as an off-white solid. LCMS: (m / z) 318.3 [M+H] + .

[0204] Step 3: 5-(4-(4-((3-chloropyridin-2-yl)methyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazole-2-carbonitrile To a solution of 2-(bromomethyl)-3-chloro-pyridine (1.00 equiv., 200 mg, 0.969 mmol) in DMF (5 mL) was added KCO (3.00 equiv., 401 mg, 2.91 mmol), 5-[2-fluoro-4-(5-oxo-4H-1,2,4-triazol-1-yl)phenoxy]-4-methyl-thiazole-2-carbonitrile (1.00 equiv., 307 mg, 0.969 mmol), and the mixture was stirred under nitrogen at 25 °C for 30 min. The reaction mixture was concentrated to dryness, the residue was dissolved in EA (50 mL), and the organics were washed with 2 × 20 mL of water, followed by 1 × 20 mL of saturated brine solution. The organics were then separated, dried (MgSO), and concentrated to dryness. The crude material was then purified by flash column chromatography eluting with 50% ACN in HO. The desired fractions were concentrated to dryness in vacuo to give 5-[4-[4-[(3-chloro-2-pyridyl)methyl]-5-oxo-1,2,4-triazol-1-yl]-2-fluoro-phenoxy]-4-methyl-thiazole-2-carbonitrile (80 mg, 0.168 mmol, 17.34% yield) as a white solid. MS (m / z): 443.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 8.49-8.43 (m, 1H), 8.02 (dd, J = 12.4, 2.4 Hz, 1H), 7.92-7.84 (m, 1H), 7.80-7.71 (m, 2H), 7.29-7.24 (m, 1H), 7.17 (t, J = 8.8 Hz, 1H), 5.17 (s, 2H), 2.44 (s, 3H).

[0205] Example 38 was synthesized using a method similar to that used in Example 37. [Table 4]

[0206] Example 39: Method 5 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carbonitrile [ka] To an 8 mL vial equipped with a stir bar was added Ir[dF(CF)ppy](dtbbpy)PF (1.51 mg, 10.4 μmol, 0.05 equiv.), 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazole-3 (100 mg, 0.21 mmol), 3-iodocyclobutane-1-carbonitrile (41.63 mg, 0.2 mmol), and tris(trimethylsilyl)silane (103.47 mg, 0.42 mmol). The vial was sealed and placed under nitrogen, and then DME (4 mL) was added. To a separate vial, NiCl(dtbbpy) (4.15 mg, 10.4 μmol) and 2,6-lutidine (44.6 mg, 0.41 mmol) were added. The catalyst vial was sealed and purged with nitrogen, and then DME (2 mL) was added to it. The pre-catalyst solution was sonicated or stirred for 5 minutes, after which 1 mL (0.5 mol% catalyst, 2.5 μmol, 0.005 equiv.) was injected into the reaction vessel. The solution was degassed by sparging with nitrogen while stirring for 10 minutes and then sealed with parafilm. The reaction was stirred and irradiated with a 34 W blue LED lamp (7 cm away) equipped with a cooling fan to maintain the reaction temperature at 25 °C for 12 hours. The resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using the following conditions: Column: Gemini 5u C18 150 x 21.2 mm, Mobile phase B: ACN, Flow rate: 20 mL / min, Gradient: 40% B to 60% B in 20 min, Detector: 214 nm. Concentration under reduced pressure gave the title compound (1.6 mg, 1.6% yield) as a white solid. LC-MS (m / z) 480.1 [M+H] +. 1H NMR(400MHz,CDCl3)δ ppm7.97(d,J=8.4Hz,2H),7.57(s,1H),7.32-7.40(m,1H),7.04-7.06(m,2H),6.95-6.99(m,2H),4. 97(s,2H),4.08-4.06(m,1H),3.12-3.18(m,1H),2.91-2.98(m,2H),2.71-2.64(m,2H),2.35(s,3H).

[0207] Using the same method as that used in Example 39, Examples (compounds) 40 to 42 were synthesized. [Table 5]

[0208] Example 43: Method 6 [ka] Step 1: (2S,3S)-1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate To a stirred solution of (2S,3S)-1-benzhydryl-2-methylazetidin-3-ol (1 g, 3.95 mmol), MsCl (533.52 mg, 4.68 mmol), and TEA (472.68 mg, 4.68 mmol) in DCM (50 mL) was added. The resulting mixture was stirred for an additional 1 h at 25 °C. The resulting mixture was diluted with 1 N HCl (10 mL). The organics were diluted with NaHCO3 solvent. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. No further purification was performed. (2S,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (800 mg, yield: 61.5%) was obtained as an oil. LC-MS (m / z): 332.1 [M+H] + .

[0209] Step 2: (2S,3R)-1-benzhydryl-2-methylazetidine-3-carbonitrile To a stirred solution of (2S,3S)-1-benzhydryl-2-methylazetidin-3-yl methanesulfonate (800 mg, 2.4 mmol), KCN (234 mg, 3.6 mmol), and TEA (363.6 mg, 3.6 mmol) in DMSO (50 mL) was added. The resulting mixture was stirred at 25 °C for another 2 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE: EtOAc = 1:1) to give (2S,3R)-1-benzhydryl-2-methylazetidine-3-carbonitrile (410 mg, yield: 65.2%) as a yellow solid. LC-MS (m / z): 263.3 [M+H] + .

[0210] Step 3: (2S,3R)-2-Methylazetidine-3-carbonitrile To a stirred solution of (2S,3R)-1-benzhydryl-2-methylazetidine-3-carbonitrile (200 mg, 0.76 mmol) and 1-chloroethyl carbonochloridate (163.0 mg, 1.14 mmol) in DCE (20 mL) was added the resulting mixture. The resulting mixture was stirred at 70 °C for an additional 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. MeOH (20 mL) was added to the mixture. The resulting mixture was stirred at 70 °C for an additional 1 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE:EtOAc = 1:1) to give (2S,3R)-2-methylazetidine-3-carbonitrile (60 mg, yield: 82.3%) as a white solid. LC-MS(m / z):97.07[M+H] + .

[0211] Step 4: (2S,3R)-1-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazol-2-yl)-2-methylazetidine-3-carbonitrile To a stirred solution of (2S,3R)-2-methylazetidine-3-carbonitrile (60 mg, 0.62 mmol), 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (297.0 mg, 0.62 mmol), BINAP (38.5 mg, 0.06 mmol), Pd(dba) (35.6 mg, 0.062 mmol), and CsCO (606.4 mg, 1.86 mmol) in toluene (20 mL). The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using the following conditions: Column: Gemini 5u C 18 150 x 21.2 mm, Mobile phase B: ACN, Flow rate: 20 mL / min, Gradient: 40% B to 60% B in 20 min, Detector: 214 nm. The desired fractions were concentrated under reduced pressure to give the title compound (28.8 mg, Yield: 9.4%) as a white solid. LC-MS (m / z): 495.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.91(d,J=8.1Hz,2H),7.58(s,1H),7.39-7.35(m,1H),7.02-6.98(m,4H),4.98(s,2H) ,4.70(s,1H),4.38(d,J=30.9Hz,2H),3.78(d,J=19.8Hz,1H),2.16(s,3H),1.70(s,3H)

[0212] Using a method similar to that used in Example 43, Examples 44 to 58 were synthesized. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4]

[0213] Example 59: Method 7 4-(2,6-Difluorobenzyl)-2-(3-fluoro-4-((4-methylthiazol-5-yl)methyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: Methyl 4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzoate A mixture of 4-[(2,6-difluorophenyl)methyl]-2H-1,2,4-triazol-3-one (4 g, 0.0189 mol), methyl 4-bromo-2-fluorobenzoate (5.6 g, 0.0227 mmol), cuprous iodide (3.6 g, 0.0189 mmol), DMDACH (8.07 g, 0.0567 mol), and KCO (5.21 g, 0.0378 mol) in dioxane (50 mL) was stirred at 110 °C for 1 h. After cooling, the reaction mixture was diluted with water (40 mL) and extracted three times with ethyl acetate (40 mL). The organic layers were combined, the solvent was removed under vacuum, and the crude was purified by silica gel chromatography (PE / EA=1:1) to give methyl 4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzoate (5 g, 66.67% yield) as a white solid. MS (m / z): 378.0 [M+H] + .

[0214] Step 2: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-(hydroxymethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A solution of methyl 4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzoate (11 g, 0.0303 mol) and LiAlH (1.39 g, 0.03672 mol) in THF (20 mL) was stirred at 25 °C under 1 atm N atmosphere for 1 h. After filtration of the reaction mixture, the filtrate was concentrated, and the residue was purified by silica gel chromatography (DCM / CH OH = 10:1) to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-(hydroxymethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.5 g, 100% yield) as an orange solid. MS (m / z): 336.1 [M+H] + .

[0215] Step 3: 2-(4-(bromomethyl)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A mixture of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-(hydroxymethyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10.5 g, 0.0313 mol) and pBR3 (9.3 g, 0.0344 mol) in DCM (20 mL) was stirred at 25 °C for 2 h. The reaction mixture was diluted with water (40 mL) and extracted three times with ethyl acetate (40 mL). The organic layers were combined, the solvent was removed in vacuo, and the crude product was purified by silica gel chromatography (DCM / CHOH = 10:1) to give 2-(4-(bromomethyl)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (9.0 g, 72.3% yield) as a white solid. MS (m / z): 398.0 [M+H] + .

[0216] Step 4: 2-(4-(bromomethyl)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 2-[4-(bromomethyl)-3-fluorophenyl]-4-[(2,6-difluorophenyl)methyl]-1,2,4-triazol-3-one (500 mg, 1.26 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (637 mg, 2.51 mmol), potassium acetate (370 mg, 3.77 mmol), (acetyloxy)palladium acetate in dioxane (40 mL). A solution of methylpropanol (56 mg, 0.25 mmol) and dppf (278 mg, 0.50 mmol) was heated at 110 °C under nitrogen for 1 h, then cooled to room temperature. The solvent was removed in vacuo, and the crude material was purified by silica gel chromatography (DCM / MeOH = 10:1) to give 2-(4-(bromomethyl)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.2 g, 34.0% yield) as a white solid. MS (m / z): 446.1 [M+H] + .

[0217] Step 5: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-methylthiazol-5-yl)methyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.00 equiv., 100 mg, 0.225 mmol), 5-bromo-4-methylthiazole (2.00 equiv., 80 mg, 0.449 mmol), and CsCO (2.00 equiv., 146 mg, 0.449 mmol) in 1,4-dioxane (6 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.300 equiv., 35 mg, 0.0674 mmol) at room temperature under N. After the addition, the mixture was stirred at 85 °C for 5 h. LCMS of the reaction mixture showed 30% product conversion. The reaction mixture was then cooled, water (10 mL) was added, and extracted with EtOAc (20 mL x 3). The organic layers were then combined, dried (Na2SO4), and concentrated to dryness. The crude was purified by preparative TLC (PE / EtOAc = 1 / 1) to give the product (20 mg, 18.60% yield) as a yellow solid. MS (m / z): 417.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.81(s,1H),8.33(s,1H),7.71-7.65(m,2H),7.50-7.45(m,1H),7.37(t,J =8.4Hz,1H),7.15(t,J=8.1Hz,2H),4.97(s,2H),4.13(s,2H),2.37(s,3H).

[0218] Example 60: Method 7 2-(4-((2-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)-4-methylthiazol-5-yl)methyl)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 1-(5-bromo-4-methylthiazol-2-yl)-3-(trifluoromethyl)pyrrolidin-3-amine tert-Butyl (3-(trifluoromethyl)-112-pyrrolidin-3-yl)carbamate (500 mg, 1.97 mmol), 2,5-dibromo-4-methylthiazole (558 mg, 2.17 mmol), and Cs2CO3 (1.284 g, 3.94 mmol) were mixed in 10 mL of NMP. It was stirred at 140 °C for 16 h. Water was added to the reaction mixture, which was then extracted with EtOAc (30 mL × 3). The organic layers were combined and evaporated to dryness. 18 Purification by column chromatography gave 1-(5-bromo-4-methylthiazol-2-yl)-3-(trifluoromethyl)pyrrolidin-3-amine (364 mg, yield: 56%) as a brown oil. MS (m / z): 331.2 [M+H] + .

[0219] Step 2: 2-(4-((2-(3-amino-3-(trifluoromethyl)pyrrolidin-1-yl)-4-methylthiazol-5-yl)methyl)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 4-[(2,6-difluorophenyl)methyl]-2-[3-fluoro-4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl]phenyl]-1,2,4-triazol-3-one (1.20 equiv., 125 mg, 0.280 mmol), CsCO (2.00 equiv., 152 mg, 0.466 mmol), 1-(5-bromo-4-methyl-thiazol-2-yl)-3-(trifluoromethyl)pyrrolidin-3-amine (1.00 equiv., 77 mg, 0.233 mmol) in 1,4-dioxane (6 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.300 equiv., 36 mg, 0.0700 mmol) at room temperature under N. After the addition, the mixture was stirred at 110° C. for 5 hours. LCMS of the reaction mixture showed 20% product conversion. Then, it was cooled, water (20 mL) was added, and extracted with EtOAc (20 mL×3). The organic layers were then combined, dried (Na2SO4), and concentrated to dryness. The crude product was purified by preparative HPLC (0.1% TFA as an additive) to give the product (6.0 mg, 3.77% yield) as a yellow solid.

[0220] MS(m / z):569.2[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.32(d,J=2.9Hz,1H),7.72-7.61(m,2H),7.57-7.41(m,2H),7.33(t,J=8.4Hz,1H),7.19-7.12(m,2 H),4.97(s,2H),3.93(s,2H),3.52-3.43(m,2H),3.28-3.23(m,2H),2.14(s,3H),2.03-1.96(m,2H).

[0221] Using the same method as that used in Example 59, Examples (compounds) 61 to 67 were synthesized. [Table 7-1] [Table 7-2] [Table 7-3]

[0222] Example 68: Method 8 2-(4-((2-(3-(2-aminopropan-2-yl)azetidin-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: tert-butyl (2-(1-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazol-2-yl)azetidin-3-yl)propan-2-yl)carbamate To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.1 mmol) and tert-butyl (2-(azetidin-3-yl)propan-2-yl)carbamate (38 mg, 0.15 mmol) in toluene (1 mL) was added BINAP (12 mg, 0.02 mmol), Pd(dba) (9 mg, 0.01 mmol), and CsCO (100 mg, 0.3 mmol). The resulting mixture was stirred at 100 °C under N for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:1) to give tert-butyl (2-(1-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazol-2-yl)azetidin-3-yl)propan-2-yl)carbamate (20 mg, 36% yield) as a white solid. MS (m / z): 613.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ 7.88(s,1H),7.77-7.66(m,2H),7.40-7.29(m,1H),7.00-6.90(m,4H),4.93(s,2H), 3.94-3.75(m,4H),2.15-2.02(m,1H),1.93(s,3H),1.31(s,9H),1.26-1.20(m,6H).

[0223] Step 2: 2-(4-((2-(3-(2-aminopropan-2-yl)azetidin-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of tert-butyl (2-(1-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazol-2-yl)azetidin-3-yl)propan-2-yl)carbamate (20 mg, 0.03 mmol) in DCM (5 mL) was added 4N HCl in dioxane or TFA (0.5 mL) at room temperature. The resulting mixture was stirred at 25° C. for an additional 2 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: spherical C 18 40-60 μm, 40 g, Mobile phase B: ACN, Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were concentrated under reduced pressure to give the title compound 2-(4-((2-(3-(2-aminopropan-2-yl)azetidin-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (3.4 mg, 21% yield) as an off-white solid. LC-MS (m / z): 513.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ 7.91(s,1H),7.83(d,J=5.2Hz,2H),7.42-7.28(m,1H),7.20-6.90(m,4H),4.94(s ,2H),4.43-4.19(m,2H),3.69-3.45(m,2H),2.25-1.90(m,4H),1.57-1.25(m,6H).

[0224] Using the same method as used in Example 68, Examples (compounds) 69 to 73 were synthesized. [Table 8-1] [Table 8-2]

[0225] Example 74: Method 9 4-(2,6-Difluorobenzyl)-2-(4-((2-(3-ethoxyazetidin-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.21 mmol) was added a solution of 73-ethoxyazetidine (32 mg, 0.32 mmol) and CsCO (102 mg, 0.32 mmol) in MeCN (5 mL). The reaction mixture was stirred at 100 °C for 2 h. The resulting mixture was diluted with EtOAc (10 mL), and the solution was washed successively with water (2 × 5 mL) and brine (5 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by TLC overlaid with (DCM:MeOH) (50:1) to give the title compound (32 mg, 30.5% yield) as a white solid. MS(m / z):500.2[M+H] + .

[0226] 1 H NMR(400MHz,CDCl3)δ 7.92-7.83(m,2H),7.55(s,1H),7.42-7.29(m,1H), 7.07-6.94(m,4H),4.97(s,2H),4.54-4.40(m,1H),4.3-4.21(m,2H),4.04-3.93(s,2H),3.48(q,J=7.2 Hz,2H),2.11(s,3H),1.23(t,J=6.8 Hz,3H).

[0227] Example (compound) 75 was synthesized using a method similar to that used in Example 74. [Table 9]

[0228] Example 76: Method 10 (S)-4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(4-hydroxy-2-oxopyrrolidin-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.10 mmol) and (S)-4-hydroxypyrrolidin-2-one (10 mg, 0.10 mmol) in dioxane (10 mL) was added CuI (10 mg, 0.05 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (7 mg, 0.05 mmol) and KCO (42 mg, 0.03 mmol) at room temperature. The resulting mixture was stirred at 110 °C under Ar for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:1) to give the title compound (30 mg, yield 57.7%) as an off-white solid. LC-MS (m / z): 518.0 [M+H] + . 1 H NMR(400MHz,DMSO)δ 8.33(s,1H),7.86(dd,J=12.6,2.4Hz,1H),7.65(d,J=9.2Hz,1H),7.51-7.43(m,1H),7.21-7.08(m,3H),5.45(d,J=3.8Hz,1H),4.97(s,2H) ),4.53-4.41(m,1H),4.07(dd,J=11.4,4.9Hz,1H),3.91-3.83(m,1H),2.95(dd,J=17.4,5.9Hz,1H),2.38(d,J=17.5Hz,1H),2.15(s,3H). [Table 10]

[0229] Example 77: Method 11 2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)thiazole-5-carbonitrile [ka] A solution of 4-[(2,6-difluorophenyl)methyl]-2-(4-hydroxyphenyl)-1,2,4-triazol-3-one (50 mg, 0.16 mmol), 2-bromo-1,3-thiazole-5-carbonitrile (47 mg, 0.24 mmol), and K2CO3 (46 mg, 0.33 mmol) in DMSO (2 mL) was stirred at 50 °C for 16 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE=1:1) to give 2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)thiazole-5-carbonitrile (21.1 mg, 28.8% yield) as a white solid. LC-MS (m / z): 412.0 [M+H] + . 1 H NMR (400MHz, CDCl3) δ 8.15-8.08(m,1H),7.76(s,1H),7.61(s,1H),7.42-7.31(m,2H),7.03-6.94(m,4H),4.99(s,2H).

[0230] Using the same method as that used in Example 77, Examples (compounds) 78 to 79 were synthesized. [Table 11]

[0231] Example 80: Method 12 5-(2-fluoro-4-(7-fluoro-3-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy)-4-methylthiazole-2-carboxamide [ka] Step 1: Methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate To a stirred solution of benzaldehyde oxime (120 g, 0.99 mol) in 1,4-dioxane (1200 mL), methyl prop-2-enoate (94 g, 1.09 mol), NaI (164 g, 1.09 mmol), 2,6-lutidine (117 g, 1.09 mol), and tert-butyl hypochlorite (118 g, 1.09 mmol) were added batchwise at 25 °C. The resulting mixture was stirred at 25 °C for an additional 18 h. The resulting mixture was quenched with water (1000 mL). The resulting mixture was extracted with EtOAc (3 × 800 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel eluting with (PE: EtOAc) (10:1) to give crude methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (140 g, 65.4% yield) as a yellow solid. MS (m / z): 206.0 [M+H] + .

[0232] Step 2: Ethyl 5-bromo-4-methylisoxazole-3-carboxylate To a solution of methyl 3-phenyl-4,5-dihydroisoxazole-5-carboxylate (46 g, 224 mmol) in EtOH (1000 mL) was added Pd / C (23 g) at 25° C. The mixture was stirred at 25° C. under 250 psi H for 5 h. The reaction solution was filtered, and the filtrate was concentrated in vacuo to give crude 3-hydroxy-5-phenylpyrrolidin-2-one (48 g crude) as a yellow oil with 74% purity by LCMS. LC-MS (m / z) 178.0 [M+H] + .

[0233] Step 3: 3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one To a mixture of 3-hydroxy-5-phenylpyrrolidin-2-one (75 g, 423.2 mmol) in DCM (750 mL) was added imidazole (57.5 g, 0.85 mol) and TBSCl (95.5 g, 0.64 mmol) batchwise at room temperature, and the reaction mixture was stirred at 30 °C for 18 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with DCM (3 × 500 mL). The combined organic layers were washed with brine (800 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel eluting with (PE:EtOAc) (10:1) to give 3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (86 g, 69.9% yield) as a yellow solid. LC-MS(m / z)292.1[M+H] + .

[0234] Step 4: 4-((tert-butyldimethylsilyl)oxy)-5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole To a stirred solution of 3-((tert-butyldimethylsilyl)oxy)-5-phenylpyrrolidin-2-one (86 g, 291 mmol) in DCM (800 mL) was added trimethyloxonium tetrafluoroborate (47.5 g, 320 mmol). The reaction mixture was stirred at 25° C. for 18 hours. The reaction solution was used directly in the next step.

[0235] Step 5: Methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate To a solution of 4-((tert-butyldimethylsilyl)oxy)-5-methoxy-2-phenyl-3,4-dihydro-2H-pyrrole in DCM (750 mL) was added a solution of methoxycarbohydrazide (29.5 g, 320 mmol) in DCM (200 mL) dropwise at 25 °C under N2, and the mixture was stirred at 25 °C for 6 h. The mixture was quenched with ice-water. The mixture was extracted with DCM (100 mL × 3). The combined organic layers were washed with water (500 mL × 2), brine (500 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel eluting with (DCM:MeOH) (30:1) to give methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (67 g, 62.6% yield over two steps) as a yellow solid. LC-MS (m / z): 364.2 [M+H] + .

[0236] Step 6: Methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate Methyl 2-(4-((tert-butyldimethylsilyl)oxy)-2-phenyl-3,4-dihydro-2H-pyrrol-5-yl)hydrazine-1-carboxylate (30 g, 82.5 mmol) in a vial was heated at 170° C. under N2 without solvent for 4 h. The mixture was cooled to room temperature to give crude 7-((tert-butyldimethylsilyl)oxy)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (27 g crude) as a yellow solid with 88% purity by LCMS. LC-MS (m / z): 332.1 [M+H] + .

[0237] Step 7: 7-Hydroxy-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a stirred solution of 7-((tert-butyldimethylsilyl)oxy)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (27 g, 81.5 mmol) in MeOH (270 mL) was added 4 M HCl in dioxane (30 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 3 h. The mixture was treated with saturated Na2CO3 solution to adjust the pH to 9 and concentrated. The residue was purified by silica gel eluting with (DCM:MeOH) (20:1) to give 7-hydroxy-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (4 g, 21.8% yield) as a yellow solid. LC-MS (m / z): 218.1 [M+H] + . 1 H NMR(400MHz,DMSO_d6)δ 11.47(d,J=11.6Hz,1H),7.38-7.22(m,5H),5.95-5.99(m,1H),5.28-4.89(m,2H),3.26-3.19(m,0.5H),2.74-2.68(m,0.5 H),2.58-2.53(m,0.5 H),2.13-2.08(m,0.5 H).

[0238] Step 8: 5-(2-fluoro-4-(7-hydroxy-3-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy)-4-methylthiazole-2-carboxamide To a solution of 7-hydroxy-5-phenyl-6,7-dihydro-2H-pyrrolo[2,1-c][1,2,4]triazol-3(5H)-one (1.00 equiv., 200 mg, 0.92 mmol) in DMF (4 mL) was added CuI (0.500 equiv., 88 mg, 0.46 mmol), KCO (2.00 equiv., 254 mg, 1.84 mmol), 5-(4-bromo-2-fluorophenoxy)-4-methylthiazole-2-carboxamide (1.00 equiv., 302 mg, 0.92 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (1.00 equiv., 132 mg, 0.92 mmol). The reaction mixture was stirred at 110 °C under nitrogen for 1 h. The reaction was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (4 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:2) to give 5-(2-fluoro-4-(7-hydroxy-3-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy)-4-methylthiazole-2-carboxamide (300 mg, 70% yield) as a tan oil. LC-MS (m / z) 468.1 [M+H] + .

[0239] Step 9: 5-(2-fluoro-4-(7-fluoro-3-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy)-4-methylthiazole-2-carboxamide To a solution of 5-(2-fluoro-4-(7-hydroxy-3-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy)-4-methylthiazole-2-carboxamide (1.00 equiv., 77 mg, 0.16 mmol) in DCM (1 mL) was added DAST (1.5 equiv., 17 μL 0.24 mmol) in DCM (0.6 mL) dropwise and stirred at 0° C. under nitrogen for 1 h. The reaction was quenched with saturated NaHCO (2 mL) and extracted with DCM (10 mL × 3). The combined organic layers were dried over anhydrous NaSO and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give 5-(2-fluoro-4-(7-fluoro-3-oxo-5-phenyl-3,5,6,7-tetrahydro-2H-pyrrolo[2,1-c][1,2,4]triazol-2-yl)phenoxy)-4-methylthiazole-2-carboxamide: a polar spot (35 mg, 45% yield) and a less polar spot (28.7 mg, 37% yield) as a tan oil. LC-MS (m / z) 470.1 [M+H] + . [Table 12]

[0240] Example 82: Method 13 [ka] 2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)thiazole-5-carboxamide A solution of 4-[(2,6-difluorophenyl)methyl]-2-(4-hydroxyphenyl)-1,2,4-triazol-3-one (80 mg, 0.26 mmol), 2-bromo-1,3-thiazole-5-carbonitrile (75 mg, 0.4 mmol), and K2CO3 (73 mg, 0.5 mmol) in DMF (2 mL) was stirred at 100 °C for 16 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE = 1:1) to give the product (25.1 mg, 20.8% yield) as a white solid. LC-MS (m / z): 430.0 [M+H] + . 1 H NMR(400MHz, CDCl3)δ 8.08(d,J=9.1Hz,2H),7.61(d,J=15.1Hz,2H),7.42-7.31(m,3H),7.04-6.94(m,2H),5.61(s,2H),4.99(s,2H). [Table 13]

[0241] Example 83: Method 14 4-(2,6-Difluorobenzyl)-2-(4-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] A solution of 4-[(2,6-difluorophenyl)methyl]-2-(4-hydroxyphenyl)-1,2,4-triazol-3-one (50 mg, 0.16 mmol), 2-bromo-4,5,6,7-tetrahydro-1,3-benzothiazole (72 mg, 0.3 mmol), and NaH (8 mg, 0.2 mmol) in DMF (3 mL) was stirred at 80° C. for 16 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-(2,6-difluorobenzyl)-2-(4-((4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.1 mg, 1.5% yield) as a white solid. 1 H NMR(400MHz,CDCl3)δ 8.00(d,J=9.1Hz,2H),7.58(s,1H),7.37(s,1H),7.29(d,J=9.1Hz,2H),7 .02-6.95(m,2H),4.98(s,2H),2.62(d,J=5.6Hz,4H),1.85-1.81(m,4H). [Table 14]

[0242] Example 84: Method 15 4-(2,6-Difluorobenzyl)-2-(4-((2-(3-ethoxyazetidin-1-yl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 5-(4-bromophenoxy)thiazol-2-amine To a stirred solution of 5-bromothiazol-2-amine (5 g, 27.9 mmol) in acetone (100 mL) was added 4-bromophenol (4.8 g, 27.9 mmol) and CsCO (18.2 g, 56 mmol). The resulting mixture was stirred at 60 °C under N for an additional 6 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 2:1) to give 5-(4-bromophenoxy)thiazol-2-amine (460 mg, 6% yield) as a white solid. MS (m / z): 270.9 [M+H] + .

[0243] Step 2: 2-Bromo-5-(4-bromophenoxy)thiazole To a stirred solution of 5-(4-bromophenoxy)-1,3-thiazol-2-amine (460 mg, 1.7 mmol) in MeCN (10 mL) was added CuBr (758 mg, 3.4 mmol), and the reaction mixture was cooled to 0 °C. Then, isoamyl nitrite (400 mg, 3.4 mmol) was added dropwise. The resulting mixture was stirred at 25 °C for an additional 1 h. The reaction mixture was quenched with NH Cl (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na SO , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 5:1) to give 2-bromo-5-(4-bromophenoxy) thiazole (280 mg, 27% yield) as a white solid. MS (m / z): 335.8 [M+H] + .

[0244] Step 3: 5-(4-bromophenoxy)-2-(3-ethoxyazetidin-1-yl)thiazole To a stirred solution of 2-bromo-5-(4-bromophenoxy)thiazole (280 mg, 0.83 mmol) and 3-ethoxyazetidine (115 mg, 0.83 mmol) in DMSO (5 mL) was added K2CO3 (345 mg, 2.5 mmol). The resulting mixture was stirred under N2 at 150 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE:EtOAc = 1:1) to afford 5-(4-bromophenoxy)-2-(3-ethoxyazetidin-1-yl)thiazole (140 mg, 47% yield) as a white solid. MS(m / z):354.9[M+H] + .

[0245] Step 4: 4-(2,6-difluorobenzyl)-2-(4-((2-(3-ethoxyazetidin-1-yl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 5-(4-bromophenoxy)-2-(3-ethoxyazetidin-1-yl)thiazole (130 mg, 0.366 mmol) and 4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (78 mg, 0.366 mmol) in DMF (5 mL) was added (1S,2S)-N 1 ,N 2To the mixture was added 25 mg (0.18 mmol), CuI (34 mg, 0.18 mmol), and K2Co3 (138 mg, 1 mmol). The resulting mixture was stirred at 105 °C under N2 for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: C18 spherical 40-60 μm, 40 g; Mobile phase B: ACN; Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. The fractions containing the desired product were concentrated under reduced pressure to give 4-(2,6-difluorobenzyl)-2-(4-((2-(3-ethoxyazetidin-1-yl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (24 mg, 13% yield) as an off-white solid. LC-MS (m / z): 486.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.94-7.84(m,2H),7.56(s,1H),7.35(td,J=8.4,4.2Hz,1H),7.14-7.05(m,2H),6.98(p,J=3.5Hz,2H),6.85(s,1H),4.97 (s,2H),4.52-4.39(m,1H),4.30-4.16(m,2H),3.96(dd,J=8.8,4.4Hz,2H),3.48(q,J=7.0Hz,2H),1.24(t,J=7.0Hz,3H).

[0246] Example (compound) 85 was synthesized using a method similar to that used in Example 84. [Table 15]

[0247] Example 86: Method 16 5-(2-chloro-4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carbonitrile [ka] Step 1: 2-(3-chloro-4-((4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(3-chloro-4-hydroxyphenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2 g, 5.92 mmol) and 5-bromo-4-methylthiazole (1.27 g, 7.11 mmol) in NMP (100 mL) was added K2CO3 (2.46 g, 17.77 mmol) at room temperature. The resulting mixture was stirred at 150 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:0 to 1:1) to give 2-(3-chloro-4-((4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.6 g, quantitative yield) as a tan solid. MS (m / z): 436.2 [M+H] + .

[0248] Step 2: 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-chlorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(3-chloro-4-((4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.6 g, 5.98 mmol) in MeCN (100 mL) was added NBS (2.13 g, 11.96 mmol) at room temperature. The resulting mixture was stirred at 90° C. for an additional 10 minutes. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:0 to 1:1) to give 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-chlorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.68 g, 54.7% yield) as a brown solid. MS (m / z): 513.1 [M+H] + .

[0249] Step 3: 5-(2-chloro-4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carbonitrile To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-chlorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, 0.58 mmol) in NMP (15 mL) was added CuCN (131 mg, 1.46 mmol) at room temperature. The resulting mixture was stirred at 150° C. for an additional 4 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:0 to 1:1) to give 5-(2-chloro-4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carbonitrile (1.2 mg, 0.45% yield) as a white solid. LC-MS (m / z) 461.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.22(d,J=2.5Hz,1H),7.98-7.93(m,1H),7.61(s,1H),7.37(td,J=8.3,4.1Hz ,1H),7.11(d,J=9.0Hz,1H),6.99(t,J=7.9Hz,2H),4.98(s,2H),2.43(s,3H).

[0250] Using the same method as that used in Example 86, Examples (compounds) 87 to 88 were synthesized. [Table 16]

[0251] Example 89: Method 17 N-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)acetamide [ka] Step 1: 2-(4-((2-amino-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (400 mg, 1.25 mmol) and 5-bromo-4-methylthiazol-2-amine (264 mg, 1.37 mmol) in DMF (20 mL) was added CsCO (1.22 g, 3.74 mmol) at room temperature. The resulting mixture was stirred at 60 °C for an additional 3 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:0 to 1:1) to give 2-(4-((2-amino-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (140 mg, 25.94% yield) as a tan solid. MS (m / z): 434.3 [M+H] + .

[0252] Step 2: N-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)acetamide To a stirred solution of 2-(4-((2-amino-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (140 mg, 0.32 mmol) and TEA (98 mg, 0.97 mmol) in DCM (15 mL) was added acetyl chloride (28 mg, 0.36 mmol) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC to give N-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)acetamide (10.4 mg, 6.77% yield) as a white solid. MS(m / z):476.1[M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.88(dd,J=12.3,2.2Hz,1H),7.70(d,J=9.1Hz,1H),7.57(s,1H),7.42-7.31(m,1H),7.03-6.94(m,3H),4.97(s,2H),2.23(s,3H),2.19(s,3H).

[0253] Using the same method as that used in Example 89, Examples (compounds) 90 to 91 were synthesized. [Table 17]

[0254] Example 92: Method 18 Methyl 2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-5-methylthiazole-4-carboxylate [ka] A solution of 4-[(2,6-difluorophenyl)methyl]-2-(4-hydroxyphenyl)-1,2,4-triazol-3-one (80 mg, 0.26 mmol), methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate (93 mg, 0.4 mmol), and K2CO3 (73 mg, 0.52 mmol) in DMF (2 mL) was stirred at 100 °C for 16 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc:PE = 1:1) to give the product (20.1 mg, 15.8% yield) as a white solid. MS (m / z): 459.0 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.09-7.98(m,2H),7.59(s,1H),7.40-7.28(m,3H),7.04-6.94(m,2H),4.98(s,2H),3.88(s,3H),2.67(s,3H).

[0255] Using a method similar to that used in Example 92, Examples (compounds) 93 to 96 were synthesized. [Table 18]

[0256] Example 97: Method 19 4-(2,6-Difluorobenzyl)-2-(4-((2,4-dimethylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] To a stirred solution of 4-[(2,6-difluorophenyl)methyl]-2-(4-hydroxyphenyl)-1,2,4-triazol-3-one (200 mg, 0.6595 mmol), 5-bromo-2,4-dimethyl-1,3-thiazole (152.01 mg, 0.7914 mmol), and 1-N,2-N-dimethylcyclohexane-1,2-diamine (18.76 mg, 0.1319 mmol) in DMF, CuI (25.12 mg, 0.1319 mmol) and CsCO (537.2 mg, 1.6487 mmol) were added. The resulting mixture was stirred at 110 °C for an additional 16 h. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash (PE:EA=1:2) to give the title compound (65 mg, 24.48% yield) as a white solid. LC-MS (m / z): 415.4 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 8.03-7.84(m,2H),7.56(s,1H),7.42-7.31(m,1H),7.05-6.94(m,4H),4.97(s,2H),2.63(s,3H),2.22(s,3H).

[0257] Using a method similar to that used in Example 97, Examples (compounds) 98 to 99 were synthesized. [Table 19]

[0258] Example 100: Method 20 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxamide [ka] A solution of methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxylate (332 mg, 0.697 mmol) in NH in MeOH (20 mL) was stirred at 90 °C in a sealed tube for 16 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: spherical C 18 40-60 μm, 40 g, Mobile phase B: ACN, Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were collected at 51% B and concentrated under reduced pressure to give the title compound 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxamide (139 mg, 41% yield) as a white solid. LC-MS (m / z): 462.1 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 8.02(s,1H),7.91(dd,J=12.3,2.4Hz,1H),7.78(d,J=8.9Hz,1H),7.50-7.41( m,1H),7.35(t,J=8.9Hz,1H),7.06(t,J=8.1Hz,2H),5.04(s,2H),2.58(s,3H).

[0259] Using the same method as that used in Example 100, Examples (compounds) 101 to 104 were synthesized. [Table 20]

[0260] Example 105: Method 21 Methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-2-carboxylate [ka] Step 1: 2-(4-((2-aminothiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5.0 g, 15.56 mmol) and 5-bromothiazol-2-amine (3.1 g, 17.31 mmol) in 1,4-dioxane (50 mL) was added CsCO (12.7 g, 38.98 mmol) at room temperature. The resulting mixture was stirred at 70 °C for an additional 1 h. The mixture was allowed to cool to room temperature and concentrated under pressure at 50 °C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (CHCl / MeOH) (1:1) to give 2-(4-((2-aminothiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.2 g, 33.48% yield) as a yellow solid. MS (m / z): 419.9 [M+H] + .

[0261] Step 2: 2-(4-((2-bromothiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(4-((2-aminothiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (450 mg, 1.07 mmol) and isoamyl nitrite (151 mg, 1.29 mmol) in ACN (5 mL) was added CuBr (287 mg, 1.29 mmol) at −10° C. The resulting mixture was stirred at −10° C. for an additional 1 h. The mixture was allowed to warm to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous NaSO, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH) (20:1) to give 2-(4-((2-bromothiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (70 mg, 12.15% yield) as a yellow oil. MS (m / z): 482.7 [M+H] + .

[0262] Step 3: Methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-2-carboxylate To a stirred solution of 2-(4-((2-bromothiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.12 mmol), Pd(OAc) (6 mg, 0.02 mmol), and Xantphos (22 mg, 0.04 mmol) in MeOH (3 mL) was added TEA (126 mg, 0.12 mmol) at room temperature. The resulting mixture was stirred at 70 °C for an additional 16 h. The solution was filtered, and the filtrate was collected. The reaction mixture was concentrated under reduced pressure at 40 °C. The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-2-carboxylate (19 mg, 33.06% yield) as a white solid. LC-MS (m / z) 462.9 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.98(dd,J=12.0,2.5Hz,1H),7.85(ddd,J=9.0,2.5,1.6Hz,1H),7.61(s,1H),7.45(s,1H) ),7.42-7.34(m,1H),7.28(m,J=8.8Hz,1H),7.03-6.95(m,2H),4.98(s,2H),3.97(s,3H).

[0263] Using the same method as that used in Example 105, Examples (compounds) 106 to 108 were synthesized. [Table 21]

[0264] Example 109: Method 22 2-(4-((2-(3-amino-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 2-(4-((2-(3-(benzyloxy)-1-hydroxycyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5 g, 10.1 mmol) in THF (100 mL) at −78° C. under a N atmosphere, n-BuLi in THF solution (4.1 mL, 2.5 M, 10.1 mmol) was added. The mixture was then stirred at −78° C. for 20 minutes. 3-(benzyloxy)cyclobutan-1-one (2.7 g, 15.2 mmol) was added to the reaction mixture, and the resulting mixture was stirred at −78° C. for 100 minutes. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc (100 mL). The resulting solution was then washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (2:1) to give 2-(4-((2-(3-(benzyloxy)-1-hydroxycyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.4 g, 40.0% yield) as a yellow solid. MS (m / z): 595.1 [M+H] + . 1H NMR(400MHz,CDCl3)δ 7.90(dd,J=12.0,2.4Hz,1H),7.72(d,J=8.8Hz,1H),7.57(s,1H),7.44-7.27(m,6H),7.09-6.92(m,3H ),4.97(s,2H),4.48(s,2H),4.13(p,J=6.4Hz,1H),3.06-2.96(m,2H),2.53-2.43(m,2H),2.29(s,3H).

[0265] Step 2: 2-(4-((2-(3-(benzyloxy)-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(4-((2-(3-(benzyloxy)-1-hydroxycyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2.4 g, 4.04 mmol) in DCM (30 mL) was added diethylaminosulfur trifluoride (0.78 g, 4.85 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (2:1) to give 2-(4-((2-(3-(benzyloxy)-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.5 g, 61.9% yield) as a white solid. MS (m / z): 597.2 [M+H] + .

[0266] 1H NMR(400MHz,CDCl3)δ 7.90(dd,J=12.0,2.4Hz,1H),7.71(d,J=8.8Hz,1H),7.58(s,1H),7.44-7.28(m,6H),7.06- 6.94(m,3H),4.97(s,2H),4.49(s,2H),4.47-4.41(m,1H),2.94-2.66(m,4H),2.31(s,3H).

[0267] Step 3: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(1-fluoro-3-hydroxycyclobutyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(4-((2-(3-(benzyloxy)-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.5 g, 2.5 mmol) in DCM (20 mL) at −78° C. under a N atmosphere was added BBr3 (3.0 mL, 1 M, 2.0 mmol) in DCM solution. The mixture was then stirred at −78° C. for 1 h. The reaction was quenched with saturated NaHCO3 solution and diluted with DCM (20 mL). The resulting solution was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(1-fluoro-3-hydroxycyclobutyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (600 mg, 47.4% yield) as a white solid. MS (m / z): 507.2 [M+H] + .

[0268] 1H NMR(400MHz,CDCl3)δ 7.98-7.87(m,1H),7.73(t,J=10.8Hz,1H),7.58(d,J=2.8Hz,1H),7.44-7.32(m,1H),7.12-6.95(m, 3H),4.97(s,2H),4.60-4.29(m,1H),3.25-2.95(m,2H),2.88-2.57(m,2H),2.32(d,J=26.8Hz,3H).

[0269] Step 4: 2-(4-((2-(3-azido-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(1-fluoro-3-hydroxycyclobutyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (200 mg, 0.40 mmol) in THF (10 mL) under a N atmosphere at 0 °C, PPh (157 mg, 0.60 mmol) and DIAD (121 mg, 0.60 mmol) were added sequentially. The mixture was then stirred at 0 °C for 15 min. Diphenylphosphoryl azide (165 mg, 0.60 mmol) was then added to the reaction mixture, which was then stirred at room temperature for 16 h. The reaction was quenched with saturated NaHCO3 solution and diluted with EtOAc (10 mL). The resulting solution was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (2:1) to give 2-(4-((2-(3-azido-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (130 mg, 61.2% yield) as a white solid. MS (m / z): 531.2 [M+H] + .

[0270] Step 5: 2-(4-((2-(3-amino-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(4-((2-(3-azido-1-fluorocyclobutyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (110 mg, 0.22 mmol) in a THF / HO mixed solvent (10 / 1, 10 mL) under a N atmosphere, PPh (86 mg, 0.33 mmol) was added. The mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with EtOAc (10 mL), and the resulting solution was washed with water (10 mL) and brine (10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH) (15:1) to give the title compound (60 mg, 54.1% yield) as a white solid. MS(m / z):506.2[M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.90(d,J=12.4Hz,1H),7.71(d,J=8.8Hz,1H),7.57(s,1H),7.44-7.30(m,1H),7.06-6.92( m,3H),4.97(s,2H),3.51-3,38(m,1H),3.18-2.81(m,2H),2.65-2.32(m,2H),2.29(s,3H).

[0271] Using the same method as that used in Example 109, Examples (compounds) 110 to 112 were synthesized. [Table 22]

[0272] Example 113: Method 23 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carboxamide [ka] Step 1: Methyl 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-3-hydroxycyclobutane-1-carboxylate To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (800 mg, 1.61 mmol) in THF (10 mL) at −78° C. under a N atmosphere, n-BuLi in THF solution (0.64 mL, 2.5 M, 1.61 mmol) was added. The mixture was then stirred at −78° C. for 20 minutes. Methyl 3-oxocyclobutane-1-carboxylate (309 mg, 2.42 mmol) was added to the reaction mixture, which was then stirred at −78° C. for 100 minutes. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc (20 mL). The resulting solution was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (2:1) to give methyl 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-3-hydroxycyclobutane-1-carboxylate (350 mg, 39.8% yield) as a yellow solid. MS (m / z): 547.1 [M+H] + .

[0273] Step 2: 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carboxylic acid A solution of methyl 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-3-hydroxycyclobutane-1-carboxylate (150 mg, 0.27 mmol) in TFA / TES (3 / 1, 5 mL) was stirred O / N (overnight) at 80° C. The resulting mixture was diluted with saturated NaHCO solution (10 mL). The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH) (15:1) to give 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carboxylic acid (80 mg, 57.4% yield) as a white solid. MS (m / z): 517.2 [M+H] + .

[0274] Step 3: 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carboxamide A solution of 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carboxylic acid (80 mg, 0.16 mmol), ammonium chloride (13 mg, 0.24 mmol), HATU (93 mg, 0.16 mmol), and DIEA (31 mg, 0.24 mmol) in DMF (5 mL) was stirred at room temperature under a N atmosphere for 1 h. The resulting mixture was diluted with EtOAc (10 mL), and the solution was washed with water (3 × 5 mL) and brine (5 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH=10:1) to give the title compound (25.5 mg, 30.9% yield) as a white solid. MS (m / z): 516.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.97(t,J=13.2Hz,1H),7.87-7.76(m,1H),7.60(d,J=4.4Hz,1H),7.46-7.28(m,1H),7.19-6.93 (m,3H),4.98(s,2H),4.03(s,1H),3.38-3.09(m,1H),2.98-2.72(m,4H),2.50(d,J=14.0Hz,3H).

[0275] Using the same method as used in Example 113, Examples (compounds) 114 to 115 were synthesized. [Table 23]

[0276] Example 116: Method 24 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetamide [ka] Step 1: Ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2-oxoacetate To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (500 mg, 1.01 mmol) in THF (10 mL) at −78° C. under a N atmosphere was added n-BuLi in THF solution (0.41 mL, 2.5 M, 1.01 mmol). The mixture was then stirred at −78° C. for 20 minutes. Diethyl oxalate (221 mg, 1.52 mmol) was added to the reaction mixture and stirred at −78° C. for 100 minutes. The reaction was quenched with saturated NH4Cl solution, diluted with EtOAc (10 mL), and the resulting solution was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (2:1) to give ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2-oxoacetate (200 mg, 38.2% yield) as a white solid. MS (m / z): 519.1 [M+H] + .

[0277] Step 2: Ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetate To a stirred solution of ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2-oxoacetate (150 mg, 0.29 mmol) in DCM (10 mL) was added diethylaminosulfur trifluoride (140 mg, 0.87 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (2:1) to give ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetate (100 mg, 63.9% yield) as a white solid. MS (m / z): 541.2 [M+H] + .

[0278] Step 3: 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetamide A solution of ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetate (50 mg, 0.09 mmol) in NH in MeOH solution was stirred at 50° C. for 16 hours. The resulting solution was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH=20 / 1) to give the title compound (25 mg, 54.4% yield) as a white solid. MS (m / z): 512.2 [M+H] + . 1H NMR(400MHz,CDCl3)δ 7.95(dd,J=12.0,2.4Hz,1H),7.77(d,J=9.2Hz,1H),7.59(s,1H),7.45-7.29(m,1H),7.15-6.91(m,3H),4.97(s,2H),2.36(s,3H).

[0279] Using the same method as that used in Example 116, Examples (compounds) 117 to 118 were synthesized. [Table 24]

[0280] Example 119: Method 25 4-(2,6-Difluorobenzyl)-2-(3-fluoro-4-((2-(3-hydroxy-3-methylcyclobutyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-methyl-2-(3-oxocyclobut-1-en-1-yl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(1-fluoro-3-hydroxycyclobutyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, 0.59 mmol) in DCM (10 mL) was added pyridinium chlorochromate (153 mg, 0.71 mmol), and the mixture was stirred at room temperature for 2 h. The reaction was quenched with saturated NH4Cl solution and diluted with DCM (20 mL). The resulting solution was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc=2:1) ​​to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-methyl-2-(3-oxocyclobut-1-en-1-yl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (160 mg, 56.0% yield) as a white solid. MS(m / z): 485.1 [M+H] + .

[0281] Step 2: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(3-hydroxy-3-methylcyclobut-1-en-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2-oxoacetate (160 mg, 0.33 mmol) in THF (10 mL) at 0 °C under a N atmosphere was added MeMgCl (0.2 mL, 3 M, 0.66 mmol) in THF solution. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc (20 mL), and the resulting solution was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(3-hydroxy-3-methylcyclobut-1-en-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 60.6% yield) as a white solid. MS (m / z): 501.2 [M+H] + .

[0282] Step 3: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(3-hydroxy-3-methylcyclobutyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(3-hydroxy-3-methylcyclobut-1-en-1-yl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.20 mmol) in MeOH (10 mL) was added Pd / C (10%, 20 mg) under H atmosphere, and the reaction solution was stirred at room temperature for 4 hours. The resulting solution was filtered and concentrated under reduced pressure. The residue was purified by TLC. (DCM / MeOH) (30 / 1) to give the title compound product 1 (50 mg, 49.8% yield) as a white solid. MS (m / z): 503.2 [M+H] + .1 H NMR(400MHz,CDCl3)δ 7.92(d,J=12.0Hz,1H),7.76(d,J=8.4Hz,1H),7.58(s,1H),7.43-7.32(m,1H),7.09-6.96(m,3H),4 .97(s,2H),4.06-3.92(m,1H),2.62(t,J=9.2Hz,2H),2.53-2.45(m,2H),2.39(s,3H),1.44(s,3H). [Table 25]

[0283] Example 120: Method 26 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carbonitrile [ka] To a stirred solution of 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxamide (139 mg, 0.301 mmol) and TEA (91 mg, 0.904 mmol) in DCM (10 mL) was added TFAA (127 mg, 0.602 mmol). The resulting mixture was stirred at 0 °C for an additional 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: spherical C 18 40-60 μm, 40 g, Mobile phase B: ACN, Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were collected at 51% B and concentrated under reduced pressure to give the title product (9.1 mg, 6% yield) as a white solid. LC-MS (m / z): 444.0 [M+H] + .1 H NMR(400MHz,DMSO)δ 8.39(s,1H),7.96(dd,J=12.5,2.4Hz,1H),7.80(d,J=9.1Hz,1H),7.70(t,J=8 .9Hz,1H),7.55-7.43(m,1H),7.16(t,J=8.1Hz,2H),4.99(s,2H),2.58(s,3H).

[0284] Using the same method as that used in Example 120, Examples (compounds) 121 to 125 were synthesized. [Table 26-1] [Table 26-2]

[0285] Example 126: Method 27 4-(2,6-Difluorobenzyl)-2-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)-2-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: Methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxylate To a stirred solution of 2,4-dichloro-5-fluoropyrimidine (300 mg, 0.934 mmol) and methyl 5-bromo-2-methylthiazole-4-carboxylate (220 mg, 0.934 mmol) in DMF (15 mL) was added K2CO3 (194 mg, 1.40 mmol). The resulting mixture was stirred at 110 °C for an additional 16 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxylate (210 mg, 42.5% yield) as a yellow solid. MS (m / z): 477.0 [M+H] + .

[0286] Step 2: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)-2-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxylate (60 mg, 0.126 mmol) in THF (10 mL) was added CHMgBr (1.26 mL, 1.26 mmol). The resulting mixture was stirred at 60° C. for an additional 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: spherical C18 40-60 μm, 40 g; Mobile phase B: ACN; Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were collected at 51% B and concentrated under reduced pressure to give the title compound 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(2-hydroxypropan-2-yl)-2-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (9.3 mg, 15% yield) as a white solid. LC-MS (m / z): 477.0 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 8.00(s,1H),7.84(dd,J=12.4,2.4Hz,1H),7.70(dd,J=9.1,1.6Hz,1H),7.51-7.39(m,1 H),7.19(t,J=9.0Hz,1H),7.06(t,J=8.1Hz,2H),5.03(s,2H),2.57(s,3H),1.57(s,6H).

[0287] Using the same method as that used in Example 126, Examples (compounds) 127 to 137 were synthesized. [Table 27-1] [Table 27-2] [Table 27-3]

[0288] Example 138: Method 28 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazol-4-yl)acetamide [ka] Step 1: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(hydroxymethyl)-2-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazole-4-carboxylate (323 mg, 0.678 mmol) in THF (10 mL) was added LiAlH (51.5 mg, 1.36 mmol). The resulting mixture was stirred at 25 °C for an additional 2 h. The resulting mixture was quenched with water (0.5 mL), 10% NaOH solution (1.5 mL), and water (0.5 mL). The resulting mixture was filtered through Celite and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(hydroxymethyl)-2-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (167 mg, 49.4% yield) as a yellow solid. MS (m / z): 449.1 [M+H] + .

[0289] Step 2: 2-(4-((4-(chloromethyl)-2-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(hydroxymethyl)-2-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (167 mg, 0.372 mmol) in DCM (10 mL) was added SOCl (133 mg, 1.12 mmol). The resulting mixture was stirred at 25 °C for an additional 1 h. The resulting mixture was adjusted to pH 8 with NaHCO and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (10:1) to give 2-(4-((4-(chloromethyl)-2-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (132 g, 68% yield) as a yellow oil. MS (m / z): 467.0 [M+H] + .

[0290] Step 3: 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazol-4-yl)acetonitrile To a stirred solution of 2-(4-((4-(chloromethyl)-2-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (132 mg, 0.283 mmol) was added TMSCN (42 mg, 0.424 mmol) and CsCO (184 mg, 0.565 mmol) in MeCN (10 mL). The resulting mixture was stirred at 65 °C for an additional 2 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (2:1) to give 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazol-4-yl)acetonitrile (89 mg, 62% yield) as a yellow solid. LC-MS (m / z) 458.1 [M+H] + .

[0291] Step 4: 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazol-4-yl)acetamide To a stirred solution of 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazol-4-yl)acetonitrile (89 mg, 0.195 mmol) was added CuO (30.7 mg, 0.389 mmol) and acetaldoxime (34.4 mg, 0.584 mmol) in MeOH (5 mL) and HO (5 mL). The resulting mixture was stirred at 95 °C for an additional 16 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: spherical C 18 40-60 μm, 40 g, Mobile phase B: ACN, Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were collected at 51% B and concentrated under reduced pressure to give the title compound 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-2-methylthiazol-4-yl)acetamide (24.8 mg, 25% yield) as a white solid. LC-MS (m / z): 476.0 [M+H] + . 1 H NMR(400MHz,DMSO)δ 8.34(s,1H),7.85(dd,J=12.6,2.4Hz,1H),7.64(d,J=9.2Hz,1H),7.53-7.44(m,1H),7.35(dd, J=17.8,8.7Hz,2H),7.16(t,J=8.1Hz,2H),6.94(s,1H),4.97(s,2H),3.40(s,2H),2.55(s,3H).

[0292] Using the same method as used in Example 138, Examples (compounds) 139 to 143 were synthesized. [Table 28-1] [Table 28-2]

[0293] Example 144: Method 29 4-(2,6-Difluorobenzyl)-2-(4-((4-(difluoromethyl)-2-(3-hydroxy-3-methylazetidin-1-yl)thiazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(hydroxymethyl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-4-carboxylate (4.13 g, 8.93 mmol) in THF (50 mL) was added Dibal-H (1.91 g, 13.4 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(hydroxymethyl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.12 g, 26% yield) as a yellow solid. MS (m / z): 435.0 [M+H] + .

[0294] Step 2: 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-4-carbaldehyde To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((4-(hydroxymethyl)thiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.12 g, 2.59 mmol) in DCM (20 mL) was added Dess-Martin (1.43 g, 3.36 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 3:1) to give 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-4-carbaldehyde (915 mg, 74% yield) as a yellow solid. MS (m / z): 433.0 [M+H] + .

[0295] Step 3: 4-(2,6-difluorobenzyl)-2-(4-((4-(difluoromethyl)thiazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-4-carbaldehyde (915 mg, 2.12 mmol) in DCM (10 mL) was added DAST (3.41 g, 21.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The mixture was acidified to pH 8-9 with 1 N NaHCO3. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 5: 1) to give 4-(2,6-difluorobenzyl)-2-(4-((4-(difluoromethyl) thiazol-5-yl) oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (695 mg, 65% yield) as a yellow solid. LC-MS (m / z): 455.0 [M+H] + .

[0296] Step 4: 2-(4-((2-bromo-4-(difluoromethyl)thiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(4-((4-(difluoromethyl)thiazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (695 mg, 1.53 mmol) and t-BuONa (441 mg, 4.59 mmol) in DMF (10 mL) was added CBr (507 mg, 1.53 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over anhydrous NaSO, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 10: 1) to give 2-(4-((2-bromo-4-(difluoromethyl) thiazol-5-yl) oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (137 mg, 15% yield) as a yellow solid. LC-MS (m / z): 532.9, 534.9 [M+H] + .

[0297] Step 5: 4-(2,6-difluorobenzyl)-2-(4-((4-(difluoromethyl)-2-(3-hydroxy-3-methylazetidin-1-yl)thiazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A mixture of 2-(4-((2-bromo-4-(difluoromethyl)thiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (70 mg, 0.131 mmol), 3-methylazetidin-3-ol hydrochloride (24 mg, 0.197 mmol), Pd(dba) (12 mg, 0.013 mmol), BINAP (16 mg, 0.026 mmol), and CsCO (64 mg, 0.197 mmol) in dioxane (10 mL) was stirred at 110 °C for 16 h. After cooling to room temperature, 30 mL of water was added. The resulting mixture was extracted with EtOAc (3 × 20 mL). The organic phases were combined, dried over NaSO, filtered, and concentrated. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: spherical C18 40-60 μm, 40 g; Mobile phase B: ACN; Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were collected at 51% B and concentrated under reduced pressure to give the title compound (40 mg, 39.6% yield) as an off-white solid. LC-MS (m / z): 540.0 [M+H] + . 1 H NMR(400MHz,CD3OD_SPE)δ 8.01(s,1H),7.87(dd,J=12.4,2.1Hz,1H),7.74(d,J=9.1Hz,1H),7.50-7.40(m,1H),7.25(t,J=9.0Hz ,1H),7.06(t,J=8.0Hz,2H),6.69(t,J=53.5Hz,1H),5.03(s,2H),3.93(d,J=3.7Hz,4H),1.52(s,3H).

[0298] Using the same method as used in Example 144, Examples (compounds) 145 to 147 were synthesized. [Table 29]

[0299] Example 148: Method 30 N-(2-aminoethyl)-5-(2-fluoro-4-(4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxamide [ka] Step 1: tert-butyl (2-(5-(2-fluoro-4-(4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxamido)ethyl)carbamate A solution of methyl 5-(2-fluoro-4-(4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxylate (50 mg, 0.1 mmol) in tert-butyl (2-aminoethyl)carbamate (500 mg, 3.1 mmol) was stirred at 80° C. for 1 hour. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC eluting with (EtOAc:PE=1:1) to give the product (45 mg, 68.7% yield) as a white solid. MS (m / z) 531.1 [M-55] + . 1 H NMR(400MHz,DMSO-d6)δ 8.71(t,J=5.8Hz,1H),8.37(s,1H),7.93(dd,J=12.5,2.4Hz,1H),7.74(d,J=9.2Hz,1H),7.38(dd,J=11.2,7.1Hz,3H ),7.29-7.18(m,2H),6.88(s,1H),4.96(s,2H),3.27(d,J=6.5Hz,2H),3.13-3.03(m,2H),2.31(s,3H),1.37(s,9H).

[0300] Step 2: N-(2-aminoethyl)-5-(2-fluoro-4-(4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxamide A solution of tert-butyl (2-(5-(2-fluoro-4-(4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenoxy)-4-methylthiazole-2-carboxamido)ethyl)carbamate (35 mg, 0.06 mmol) in HCl (3 mL, 4 M in dioxane) was stirred at 25° C. for 1 h. The mixture was concentrated and purified by preparative HPLC to give the product (18 mg, 57% yield) as a white solid. MS (m / z): 487.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.88(t,J=5.8Hz,1H),8.38(s,1H),7.94(dd,J=12.6,2.3Hz,1H),7.75(d,J=9.1Hz,1H),7.57(s,2H),7.39(d d,J=11.9,6.2Hz,3H),7.29-7.20(m,2H),4.96(s,2H),3.54-3.45(m,2H),2.95(t,J=6.0Hz,2H),2.33(s,3H). [Table 30]

[0301] Example 149: Method 31 (5S)-2-(3-fluoro-4-((2-(1-hydroxyethyl)-4-methylthiazol-5-yl)oxy)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one [ka] Step 1: 1-(5-(4-bromo-2-fluorophenoxy)-4-methylthiazol-2-yl)ethan-1-one To a stirred solution of 5-(4-bromo-2-fluorophenoxy)-2-iodo-4-methylthiazole (500 mg, 1.207 mol) in THF (70 mL) was added n-BuLi dropwise at −78° C. The resulting mixture was stirred for an additional 20 minutes at −78° C. Then, N-methoxy-N-methylacetamide (311.29 mg, 3.019 mol) was added to the resulting mixture at −78° C. The resulting mixture was stirred for an additional 2 hours at −78° C. The reaction was then quenched by the addition of 300 mL of NH4Cl. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash (PE / EA=1:1) to give 1-(5-(4-bromo-2-fluorophenoxy)-4-methylthiazol-2-yl)ethan-1-one (232 mg, 57.5% yield) as a yellow oil. MS (m / z): 330.2 [M+H] + .

[0302] Step 2: (S)-2-(4-((2-acetyl-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a stirred solution of 1-(5-(4-bromo-2-fluorophenoxy)-4-methylthiazol-2-yl)ethan-1-one (60 mg, 0.1817 mol) and (S)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (100 mg, 0.497 mmol) and DCHDMA (11.33 mg, 0.099 mmol) in DMF (5 mL) was added CuI (18.9 mg, 0.0994 mmol) and K2Co3 (171.72 mg, 1.2425 mmol) at room temperature. The resulting mixture was stirred at 110 °C under N2 for an additional 1 h. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (1×400 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash (PE / EA = 1:1) to give the desired product (50 mg, 54.65% yield) as a yellow oil. MS (m / z): 451.1 [M+H] + .

[0303] Step 3: (5S)-2-(3-fluoro-4-((2-(1-hydroxyethyl)-4-methylthiazol-5-yl)oxy)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a stirred solution of (S)-2-(4-((2-acetyl-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (50 mg, 0.111 mol) in THF (2 mL) was added NaBH (8.39 mg, 0.2217 mol) at 0 °C. The resulting mixture was stirred under nitrogen at 0 °C for an additional 10 minutes. To the mixture was added CuBr (4.05 g, 0.0181 mol) at 0 °C. The resulting mixture was stirred under nitrogen at room temperature for an additional 34 hours. The reaction was then quenched by the addition of 10 mL of NH Cl. The resulting mixture was extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (90 mL), dried over anhydrous Na SO , filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (3:1) to give the title compound (20 mg, 27.6% yield) as a white solid. LC-MS (m / z) 453.1 [M+H] + . 1 H NMR (400 MHz, CDCl) δ 7.87 (d, J = 12.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.41-7.32 (m, 3H), 7.24 (s, 2H), 7.00 (t, J = 8.4 Hz, 1H), 5.31-5.24 (m, 1H), 5.01 (d, J = 5.6 Hz, 1H), 3.11-2.86 (m, 4H), 2.30 (s, 3H), 1.60 (d, J = 4.8 Hz, 3H). The racemate was purified by chiral separation to give two compounds: Peak 1: (S)-2-(3-fluoro-4-((2-((R)-1-hydroxyethyl)-4-methylthiazol-5-yl)oxy)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (single unknown stereoisomer) 1H NMR(400MHz,CDCl3)δ 7.87(dd,J=12.4,2.0Hz,1H),7.68(d,J=9.2Hz,1H),7.46-7.26(m,5H),6.99(t,J=9.2Hz,1H),5.36-5.23 (m,1H),4.99(q,J=6.4Hz,1H),3.16-2.83(m,3H),2.68-2.45(m,1H),2.29(s,3H),1.59(d,J=6.8Hz,3H).

[0304] Peak 2: (S)-2-(3-fluoro-4-((2-((S)-1-hydroxyethyl)-4-methylthiazol-5-yl)oxy)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (single unknown stereoisomer) 1 H NMR(400MHz,CDCl3)δ 7.87(dd,J=12.4,2.0Hz,1H),7.68(d,J=9.2Hz,1H),7.46-7.26(m,5H),6.99(t,J=9.2Hz,1H),5.36-5.23 (m,1H),4.99(q,J=6.4Hz,1H),3.16-2.83(m,3H),2.68-2.45(m,1H),2.29(s,3H),1.59(d,J=6.8Hz,3H).

[0305] Using the same method as used in Example 149, Examples (compounds) 150 to 151 were synthesized. [Table 31]

[0306] Example 152: Method 32 4-(2,6-Difluorobenzyl)-2-(4-((5-(difluoromethyl)thiazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1. 4-(2,6-Difluorobenzyl)-2-(3-fluoro-4-((5-(hydroxymethyl)thiazol-4-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one Diisobutylaluminum hydride in hexane (1 M, 0.76 mL) was added to a solution of ethyl 4-(4-{4-[(2,6-difluorophenyl)methyl]-5-oxo-1,2,4-triazol-1-yl}-2-fluorophenoxy)-1,3-thiazole-5-carboxylate (180 mg, 0.38 mmol) in THF (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, and water (1 mL) was added. The resulting reaction mixture was filtered, the solvent was removed in vacuo, and the crude was purified by silica gel chromatography (PE:EA=3:1) to give the desired product (130 mg, 79% yield) as a yellow solid. LCMS (m / z): 435.0 [M+H] + .

[0307] Step 2. 4-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)thiazole-5-carbaldehyde Dess-Martin reagent (176 mg, 0.41 mmol) was added to a solution of 4-[(2,6-difluorophenyl)methyl]-2-(3-fluoro-4-{[5-(hydroxymethyl)-1,3-thiazol-4-yl]oxy}phenyl)-1,2,4-triazol-3-one (120 mg, 0.28 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 h, then filtered and the solvent removed in vacuo to give the desired product (120 mg, 100%) as a yellow solid. LCMS (m / z): 433.0 [M+H] + , Room temperature: 1.305 minutes.

[0308] Step 3. 4-(2,6-Difluorobenzyl)-2-(4-((5-(difluoromethyl)thiazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 4-(4-{4-[(2,6-difluorophenyl)methyl]-5-oxo-1,2,4-triazol-1-yl}-2-fluorophenoxy)-1,3-thiazole-5-carbaldehyde (30 mg, 0.069 mmol) in DCM (5 mL) was added DAST (224 mg, 1.39 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water (30 mL), and extracted three times with ethyl acetate (20 mL). The organic layers were combined, the solvent removed under vacuum, and the crude material was purified by preparative HPLC (column—Gemini-C18 150 × 21.2 mm, 5 μm, mobile phase: ACN-HO (0.1% FA), 5%–20%) to give the desired product (4.7 mg, 14.9%) as a white solid. LCMS (m / z): 455.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.60(s,1H),7.93(dd,J=12.1,2.3Hz,1H),7.82(d,J=9.0Hz,1H),7.58(s,1H),7.37(t,J=7.5Hz,2H),7.10-6.95(m,3H),4.97(s,2H). [Table 32]

[0309] Example 153: Method 33 2-(4-((2-(3-amino-3-methylazetidin-1-yl)-4-(difluoromethyl)thiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: tert-butyl (1-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-(difluoromethyl)thiazol-2-yl)-3-methylazetidin-3-yl)carbamate A mixture of 2-(4-((2-bromo-4-(difluoromethyl)thiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.11 mmol), tert-butyl (3-methylazetidin-3-yl)carbamate (37 mg, 0.17 mmol), CsCO (110 mg, 0.34 mmol), BINAP (14 mg, 0.022 mmol), Pd(dba) (21 mg, 0.022 mmol), and dioxane (10 mL) was stirred at 110 °C for 3 h. The reaction mixture was then cooled to room temperature, diluted with water (30 mL), and extracted three times with ethyl acetate (20 mL). The organic layers were combined, the solvent was removed in vacuo, and the crude was purified by silica gel chromatography (PE:EA=7:1) to give the desired product (30 mg, 41.9% yield) as a yellow solid. LCMS (m / z): 639.1 [M+H] + , Room temperature: 1.428 min.

[0310] Step 2: 2-(4-((2-(3-amino-3-methylazetidin-1-yl)-4-(difluoromethyl)thiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of tert-butyl {1-[4-(difluoromethyl)-5-(4-{4-[(2,6-difluorophenyl)methyl]-5-oxo-1,2,4-triazol-1-yl}-2-fluorophenoxy)-1,3-thiazol-2-yl]-3-methylazetidin-3-yl}aminoformate (4) (30 mg, 0.047 mmol) in DCM (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 2 h, the solvent was removed in vacuo, and the crude was purified by preparative HPLC (column - Gemini-C18 150 × 21.2 mm, 5 μm, mobile phase: ACN-HO (0.1% FA), 5%-20%) to give the desired product (4.1 mg, 16.2% yield) as a white solid. LCMS (m / z): 539.1 [M+H] + , Room temperature: 1.098 min. 1H NMR(400MHz,DMSO-d6)δ 8.36(s,1H),8.30(s,2H),7.88(dd,J=12.6,2.3Hz,1H),7.72(d,J=9.3Hz,1H),7.48(t,J=7.6Hz,1H),7.33(t,J=9 .1Hz,1H),7.16(t,J=8.0Hz,2H),6.97(t,J=53.0Hz,1H),4.98(s,2H),4.02(dd,J=33.8,8.9Hz,4H),1.56(s,3H). [Table 33]

[0311] Example 154: Method 34 4-(2,6-Difluorobenzyl)-2-(3-fluoro-4-((2-(2-hydroxy-2-methylpropyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.20 mmol) in THF (5 mL) at −78 °C under a N atmosphere, n-BuLi in THF solution (0.08 mL, 2.5 M, 0.20 mmol) was added. The mixture was then stirred at −78 °C for 20 min, followed by the sequential addition of 2,2-dimethyloxirane (23 mg, 0.30 mmol) and BF EtO (43 mg, 0.30 mmol). The resulting mixture was stirred at −78 °C for 100 min. The reaction was quenched with saturated NH4Cl solution and diluted with EtOAc (10 mL). The solution was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by TLC (PE / EtOAc) (1:1) to give the title compound (14 mg, 14.3% yield) as a white solid. MS (m / z): 491.2 [M+H] + .1 H NMR(400MHz,CDCl3)δ 7.94-7.86(m,1H),7.79-7.69(m,1H),7.59-7.49(m,1H),7.44-7.32(m,2H ),7.13-6.78(m,3H),4.97(s,2H),2.78(s,2H),2.06(s,3H),1.26(s,6H). [Table 34]

[0312] Example 155: Method 35 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)acetonitrile [ka] Step 1: Methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazole-2-carboxylate To a stirred solution of 2-(4-((2-bromo-4-methylthiazol-5-yl)oxy)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.2 g, 2.5 mmol), Pd(OAc)2 (56 mg, 0.25 mmol), DPPF (138.5 mg, 0.25 mmol), TEA (757.5 mg, 7.5 mmol) in MeOH (50 mL) was added under CO. The resulting mixture was stirred at 70° C. for an additional 12 h. The resulting mixture was filtered and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazole-2-carboxylate (960 mg, 40.0% yield) as a white solid. LC-MS (m / z) 477.1 [M+H]+ .

[0313] Step 2: Methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazole-2-carboxylate To a stirred solution of methyl 5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazole-2-carboxylate (340 mg, 0.71 mmol) in MeOH (20 mL) was added NaBH4 (269.8 mg, 7.1 mmol). The resulting mixture was stirred at 25 °C for an additional 1 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous NaSO and filtered, and the filtrate was concentrated under reduced pressure to give 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(hydroxymethyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (210 mg, 66.0% yield) as a white solid. LC-MS (m / z) 449.1 [M+H] + .

[0314] Step 3: 2-(4-((2-(chloromethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(hydroxymethyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.22 mmol) in DCM was added SOCl (20 mL) at room temperature. The resulting mixture was stirred at 70 °C for an additional 1 h. The filtrate was concentrated under reduced pressure to give 2-(4-((2-(chloromethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 58.8% yield) as a white solid. LC-MS (m / z): 467.1 [M+H] + .

[0315] Step 4: 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)acetonitrile To a stirred solution of 2-(4-((2-(chloromethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.13 mmol) in DMSO (20 mL) was added KCN (25.3 mg, 0.39 mmol). The resulting mixture was stirred at 25° C. for an additional 2 h. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were dried over anhydrous NaSO and filtered, and the filtrate was concentrated under reduced pressure to give 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)acetonitrile (4.7 mg, 7.9% yield) as a white solid. LC-MS (m / z) 458.1 [M+H] + .

[0316] 1H NMR NMR(400MHz,CDCl3)δ 7.91(dd,J=12.2,2.4Hz,1H),7.73(m,1H),7.58(s,1H),7.36(ddd,J=14.9,8.3, 6.7Hz, 1H), 6.99 (dd, J=17.6, 8.7Hz, 3H), 4.96 (s, 2H), 3.98 (s, 2H), 2.29 (s, 3H).

[0317] Using the same method as used in Example 155, Examples (compounds) 156 to 158 were synthesized. [Table 35]

[0318] Example 159: Method 36 2-(4-((2-(aminomethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 2-(4-((2-(azidomethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(hydroxymethyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.22 mmol) in DMA (10 mL) was added NaN (42.9 mg, 0.66 mmol). The resulting mixture was stirred at 25 °C for an additional 2 h. The filtrate was concentrated under reduced pressure to give 2-(4-((2-(azidomethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 57.6% yield) as a white solid. LC-MS (m / z) 474.1 [M+H]+ .

[0319] Step 2: 2-(4-((2-(aminomethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(4-((2-(azidomethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.12 mmol) in MeOH (10 mL) was added Pd / C (60 mg). The resulting mixture was stirred at 25° C. under 1-2 atmospheres of nitrogen pressure for an additional 2 h. The resulting mixture was filtered and extracted with EtOAc (3×30 mL). The combined organic layers were concentrated under reduced pressure and purified by preparative HPLC to give 2-(4-((2-(aminomethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (30 mg, 55.9% yield) as a white solid. LC-MS (m / z) 448.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.82(d,J=11.3Hz,1H),7.65(d,J=8.3Hz,1H),7.59(s,1H),7.35(t,J=7.5H z,1H),6.97(dd,J=14.5,6.5Hz,3H),4.96(s,2H),4.36(s,2H),2.20(s,3H).

[0320] Example 160 was synthesized using a method similar to that used in Example 159. [Table 36]

[0321] Example 161: Method 37 4-(2,6-Difluorobenzyl)-2-(3-phenoxycyclopentyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 3-phenoxycyclopentan-1-ol To a stirred solution of cyclopentane-1,3-diol (498 mg, 4.88 mmol), phenol (303 mg, 3.22 mmol), and PPh3 (1279 mg) in THF (15 mL) at 0 °C under nitrogen, a solution of DEAD (849 mg, 4.88 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under pressure at 45 °C. The residue was purified by silica gel column chromatography eluting with (DCM:MeOH = 20:1) to give 3-phenoxycyclopentan-1-ol (468 mg, 53.9% yield) as a tan oil. MS (m / z): 179.0 [M+H] + .

[0322] Step 2: 3-phenoxycyclopentyl methanesulfonate To a stirred solution of 3-phenoxycyclopentan-1-ol (450 mg, 2.52 mmol) and TEA (511 mg, 5.05 mmol) in DCM (10 mL) under nitrogen was added MsCl (434 mg, 3.79 mmol). The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under pressure at 45° C. to give 3-phenoxycyclopentyl methanesulfonate (400 mg, 61.2%) as a yellow solid. MS (m / z): 279.1 [M+Na] + .

[0323] Step 3: 4-(2,6-difluorobenzyl)-2-(3-phenoxycyclopentyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-[(2,6-difluorophenyl)methyl]-2H-1,2,4-triazol-3-one (365 mg, 1.73 mmol) and 3-phenoxycyclopentyl methanesulfonate (443 mg, 1.73 mmol) in DMF (8 mL) was added CsO (1408 mg, 4.32 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was concentrated under pressure at 50 °C. The residue was extracted with EA (2 × 50 mL). The residue was purified by silica gel column chromatography eluting with (PE:EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(3-phenoxycyclopentyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (170 mg, 26.5% yield) as a white solid. LC-MS(m / z) 372.1 [M+H] + . 1 NMR(400MHz,CDCl3)δ 7.37(s,1H),7.32(ddd,J=13.0,7.4,4.2Hz,1H),7.28-7.21(m,2H),6.99-6.88(m,3H),6.87-6.8 2(m,2H),4.93(ddd,J=13.3,7.7,5.1Hz,2H),4.88(s,2H),2.38-2.14(m,4H),1.98-1.86(m,2H). [Table 37]

[0324] Example 162: Method 38 4-(2,6-Difluorobenzyl)-2-(4-((4-methylthiazol-5-yl)oxy)cyclohexyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 4-((4-methylthiazol-5-yl)oxy)cyclohexan-1-ol To a stirred solution of cyclohexane-1,4-diol (1 g, 8.6 mmol) and 5-bromo-4-methylthiazole (1.5 g, 8.6 mmol) in DMF was added K2CO3 (3.5 g, 25.8 mmol). The resulting mixture was stirred at 100 °C for an additional 12 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE: EtOAc = 1:1) to give 4-((4-methylthiazol-5-yl)oxy)cyclohexan-1-ol (70 mg, 3.8% yield) as a yellow solid. LC-MS (m / z): 214.08 [M+H] + .

[0325] Step 2: Methane 4-((4-methylthiazol-5-yl)oxy)cyclohexyl methanesulfonate To a stirred solution of 4-((4-methylthiazol-5-yl)oxy)cyclohexyl-1-ol (45 mg, 0.21 mmol) and TEA (31.3 mg, 0.31 mmol) in DCM (5 mL) was added MsCl (23.9 mg, 0.31 mmol). The resulting mixture was stirred at 25 °C for an additional 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE: EtOAc = 1:1) to give 4-((4-methylthiazol-5-yl)oxy)cyclohexyl methanesulfonate (60 mg, 98.3% yield) as an oil. LC-MS (m / z) 292.06 [M+H] + .

[0326] Step 3: 4-(2,6-difluorobenzyl)-2-(4-((4-methylthiazol-5-yl)oxy)cyclohexyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-((4-methylthiazol-5-yl)oxy)cyclohexyl methanesulfonate (60 mg, 0.20 mmol) and 4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (42.2 mg, 0.20 mmol) in DMF (10 mL) was added CsCO (195.6 mg, 0.60 mmol). The resulting mixture was stirred at 90 °C for an additional 3 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using the following conditions: Column: Gemini 5u C 18 150 × 21.2 mm, Mobile phase B: ACN, Flow rate: 20 mL / min, Gradient: 40% B to 60% B in 20 min, Detector: 214 nm. The desired fractions were concentrated under reduced pressure to give 4-(2,6-difluorobenzyl)-2-(4-((4-methylthiazol-5-yl)oxy)cyclohexyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (12 mg, 14.7% yield) as a white solid. LC-MS (m / z): 407.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.68(s,1H),7.40(s,1H),7.35(td,J=8.4,4.2Hz,1H),6.97(dd,J=13.4,5.8Hz,2H),4.92(s,2H),4.17(m,1H),3. 97(m,1H),2.35(s,3H)2.28(d,J=11.1Hz,2H),2.01(d,J=10.6Hz,2H),1.86(td,J=13.3,3.1Hz,2H),1.69(m,2H). [Table 38]

[0327] Example 163: Method 39 2-(4-((2-(1-aminoethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((2-(1-(hydroxyimino)ethyl)-4-methylthiazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A solution of 2-(4-((2-acetyl-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.1 mmol), NHOH.HCl (15 mg, 0.2 mmol), and TEA (33 mg, 0.3 mmol) in DMF (2 mL) was stirred at 120° C. for 2 h. The resulting solution was diluted with EtOAc (20 mL), washed with brine (20 mL), dried over NaSO, and concentrated to give a white solid, which was used in the next step without further purification. MS (m / z): 476.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.79(s,1H),8.34(s,1H),7.88(dd,J=12.7,2.4Hz,1H),7.68(d,J=9.1Hz,1H),7.47(d,J=8. 2Hz,1H), 7.30(t,J=9.1Hz,1H),7.16(t,J=8.1Hz,2H),4.98(s,2H),2.24(s,3H),2.16(s,3H).

[0328] Step 2: 2-(4-((2-(1-aminoethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one The above white solid was diluted with MeOH (5 mL), and Zn (14 mg, 0.2 mmol) and NH4Cl (12 mg, 0.2 mmol) were added and stirred at room temperature for 16 h. LCMS showed 60% product conversion, with 40% SM (starting material) remaining. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 2-(4-((2-(1-aminoethyl)-4-methylthiazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (13.2 mg, 26.4% yield) as a white solid.

[0329] MS(m / z):462.0[M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.88(d,J=12.0Hz,1H),7.70(d,J=8.9Hz,1H),7.57(s,1H),7.43-7.31(m,1H),6.99(q,J =8.1Hz,3H),4.97(s,2H),4.35(s,1H),3.73(s,2H),2.26(s,3H),1.58(t,J=11.0Hz,3H).

[0330] Example (compound) 164 was synthesized using a method similar to that used in Example 163. [Table 39]

[0331] Example 165: Method 40 4-(2,6-Difluorobenzyl)-2-(2-phenoxythiazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 5-Bromo-2-phenoxythiazole To a stirred solution of 2,5-dibromothiazole (500 mg, 2.06 mmol) and phenol (194 mg, 2.06 mmol) in ACN (8 mL) was added CsCO (2012 mg, 6.17 mmol) at room temperature. The resulting mixture was stirred at 70 °C for an additional 5 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:1) to give 5-bromo-2-phenoxythiazole (350 mg, 66.4% yield) as a white solid. MS (m / z): 255.9, 257.9 [M+H] + .

[0332] Step 2: 4-(2,6-difluorobenzyl)-2-(2-phenoxythiazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 5-bromo-2-phenoxythiazole (150 mg, 0.59 mmol) and 4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (124 mg, 0.59 mmol) in DMF (5 mL) was added CuI (56 mg, 0.29 mmol), DMG (30 mg, 0.29 mmol), and K2CO3 (243 mg, 1.76 mmol) at room temperature. The resulting mixture was stirred at 110 °C under Ar for an additional 5 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: Column: spherical C 1840-60 μm, 40 g, Mobile phase B: ACN, Flow rate: 40 mL / min; Gradient: 35% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were collected at 51% B and concentrated under reduced pressure to give the title compound (20 mg, 8.84% yield) as an off-white solid. LC-MS (m / z): 387.0 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ 8.37 (s, 1H), 7.52-7.42 (m, 3H), 7.41-7.24 (m, 4H), 7.15 (t, J = 8.1Hz, 2H), 4.96 (s, 2H).

[0333] Example (compound) 166 was synthesized using a method similar to that used in Example 165. [Table 40]

[0334] Example 167: Method 41 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carboxamide [ka] To a stirred solution of 3-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)cyclobutane-1-carbonitrile (2.4 mg, 4.8 mmol) and (E)-acetaldehyde oxime (0.28 mg, 4.8 mmol) in MeOH:HO (2 mL) was added CuO (0.75 mg, 9.6 mmol). The resulting mixture was stirred at 65 °C for an additional 2 h. The resulting mixture was diluted with water (2 mL). The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous NaSO, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using the following conditions: Column: Gemini 5u C 18 150 x 21.2 mm, Mobile phase B: ACN, Flow rate: 20 mL / min, Gradient: 40% B to 60% B in 20 min, Detector: 214 nm. The desired fractions were concentrated under reduced pressure to give the title compound (1.02 mg, 41.1% yield) as an off-white solid. LC-MS (m / z): 516.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.90-7.92(d,J=10.6Hz,1H),7.73(d,J=7.3Hz,1H),7.58(s,1H),7.32-7.38(m,1H),6.96-7.04(m,3H),6. 12(br,1H),5.59(br,1H),4.96(s,2H),3.92(s,1H),3.22(s,1H),2.78(br,2H),2.68(br,2H),2.34(s,3H).

[0335] Example (compound) 168 was synthesized using a method similar to that used in Example 167. [Table 41]

[0336] Example 169: Method 42 4-(2,6-Difluorobenzyl)-2-(2-((2-methoxypyridin-4-yl)oxy)-4-methylthiazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] A solution of 2-(2-bromo-4-methylthiazol-5-yl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (500 mg, 1.3 mmol), 2-methoxypyridin-4-ol (162 mg, 1.3 mmol), and CsF (392 mg, 2.6 mmol) in DMF (10 mL) was stirred at 100° C. for 16 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Combi-Flash® (PE: EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(2-((2-methoxypyridin-4-yl)oxy)-4-methylthiazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (270 mg, 43.5% yield) as a brown solid. MS (m / z): 432.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.21(s,1H),7.57(s,1H),7.44-7.34(m,1H),6.99(dd,J=13.6,5.7Hz,2H), 6.87(d,J=4.8Hz,1H),6.73(s,1H),4.97(s,2H),3.97(s,3H),2.29(s,3H). [Table 42]

[0337] Example 170: Method 43 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetic acid [ka] To a stirred solution of ethyl 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetate (30 mg, 0.06 mmol) in a THF / HO mixed solvent (3 / 1, 4 mL), LiOH was added. The reaction solution was stirred at room temperature for 5 hours. The resulting solution was adjusted to pH 6 and concentrated under reduced pressure. The residue was purified by TLC (DCM / MeOH) (10 / 1) to give 2-(5-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-4-methylthiazol-2-yl)-2,2-difluoroacetic acid (13 mg, 42.3% yield) as a white solid. MS (m / z): 513.2 [M+H] + . 1 H NMR(400MHz,MeOD)δ 7.90(s,1H),7.80(dd,J=12.4,2.4Hz,1H),7.64(d,J=9.2Hz,1H),7.41-7.29 (m,1H),7.12(t,J=9.2Hz,1H),6.99-6.92(m,2H),4.93(s,2H),2.20(s,3H). [Table 43]

[0338] Example 171: Method 44 Methyl 5-((4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl)amino)thiazole-4-carboxylate [ka] Step 1: Preparation of 4-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.5 g, 2.37 mmol) and 1-fluoro-4-nitrobenzene (334 mg, 2.37 mmol) in DMF (20 mL) was added K2CO3 (654 mg, 4.74 mmol) at room temperature. The resulting mixture was stirred at 90 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (530 mg, 67.4% yield) as a tan solid. LCMS (m / z): 333.0 [M+H] + , Room temperature: 1.303 min.

[0339] Step 2: Preparation of 2-(4-aminophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one Pd / C (250 mg) was added to a solution of 4-[(2,6-difluorophenyl)methyl]-2-(4-nitrophenyl)-1,2,4-triazol-3-one (510 mg, 1.53 mmol) in MeOH (10 mL), and the resulting mixture was stirred under H at room temperature for 2 h, then filtered to give the desired product (450 mg, 97% yield) as a yellow solid. LCMS (m / z): 303.1 [M+H] + , Room temperature: 1.015 minutes.

[0340] Step 3: Preparation of methyl 5-((4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)phenyl)amino)thiazole-4-carboxylate A mixture of 2-(4-aminophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (170 mg, 0.56 mmol), methyl 5-bromothiazole-4-carboxylate (150 mg, 0.67 mmol), CsCO (366 mg, 1.12 mmol), Xantphos (65 mg, 0.11 mmol), Pd(dba) (103 mg, 0.11 mmol), and dioxane (10 mL) was stirred at 110 °C for 1 h. The mixture was then cooled to room temperature, diluted with water (30 mL), and extracted three times with ethyl acetate (20 mL). The organic layers were combined, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC (Gemini-C column). 18 Purification using a 150×21.2 mm column, 5 μm column, mobile phase: ACN-HO (0.1% FA), 5%-20% yield gave the desired product (20 mg, 8.0% yield) as a white solid. LCMS (m / z): 444.0 [M+H] + , Room temperature: 1.246 minutes. 1 H NMR(400MHz, CDCl3)δ 9.71(s,1H),8.01-7.98(m,3H),7.58(s,1H),7.37(s,1H),7.30(d,J=8.9Hz,1H),6.99(m,2H),4.98(s,2H),3.98(s,3H). [Table 44]

[0341] Example 172: Method 45 4-(2,6-Difluorobenzyl)-2-(4-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 5-(2-fluoro-4-nitrophenoxy)-1,3-dimethyl-1H-pyrazole To a stirred solution of 1,2-difluoro-4-nitrobenzene (6.4 g, 0.04 mol) and 2,5-dimethylpyrazol-3-ol (4.51 g, 0.04 mol) in DMF (35 mL) was added K2CO3 (16.8 g, 0.08 mol) at room temperature. The resulting mixture was stirred at 70 °C under N2 for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with EA / PE = 1-15% to give 5-(2-fluoro-4-nitrophenoxy)-1,3-dimethyl-1H-pyrazole (8.4 g, 89% yield) as a yellow solid. MS(m / z):252.0[M+H] + .

[0342] Step 2: 4-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluoroaniline To a stirred solution of 5-(2-fluoro-4-nitrophenoxy)-1,3-dimethylpyrazole (2.5 g, 0.01 mol) and Fe (5.5 g, 0.1 mol) in EtOH / HO (80 mL) was added NH4Cl (5.3 g, 0.1 mol) at room temperature. The resulting mixture was stirred at 80 °C for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1-20%) to give 4-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluoroaniline (1.2 g, 68.1% yield) as a yellow solid. MS(m / z): 222.2 [M + H] + .

[0343] Step 3: 5-(4-bromo-2-fluorophenoxy)-1,3-dimethyl-1H-pyrazole To a stirred solution of 4-[(2,5-dimethylpyrazol-3-yl)oxy]-3-fluoroaniline (1.9 g, 8.6 mmol) in MeCN (20 mL) was added dropwise isopentyl nitrite (1.2 g, 9.46 mmol) under N at 0 °C. The resulting mixture was stirred at 0 °C for 10 minutes. CuBr (1.97 g, 9.46 mmol) was then added to the above reaction mixture and stirred at room temperature for 48 hours. The resulting reaction mixture was filtered, and the residue was extracted with EtOAc (3 × 45 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE:EtOAc) (1:2) to afford 5-(4-bromo-2-fluorophenoxy)-1,3-dimethyl-1H-pyrazole (254 mg, 18% yield) as a tan solid. LC-MS(m / z):284.9[M+H] + .

[0344] Step 4: 4-(2,6-difluorobenzyl)-2-(4-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 5-(4-bromo-2-fluorophenoxy)-1,3-dimethylpyrazole, 4-[(2,6-difluorophenyl)methyl]-2H-1,2,4-triazol-3-one (506.3 mg, 0.77 mmol) and 4-[(2,6-difluorophenyl)methyl]-2H-1,2,4-triazol-3-one (250 mg, 1.18 mmol) in dioxane (20 mL), copper(I) iodide (60.3 mg, 0.59 mmol), potassium carbonate (262.9 mg, 3.55 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (50.2 mg, 0.59 mmol) were added at room temperature. The resulting mixture was stirred at 100 °C for an additional 4 hours. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1-20%) to give 4-(2,6-difluorobenzyl)-2-(4-((1,3-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (80 mg, 21.9% yield) as a white solid. LC-MS (m / z): 416.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.92(dd,J=12.0,2.5Hz,1H),7.79-7.74(m,1H),7.59(s,1H),7.37(m,J=8.4Hz,1H),7.19(t,J=8.8Hz,1H),6.98(dd,J=8.3,7.5Hz,2 H),5.32(s,1H),4.97(s,2H),3.75(s,3H),2.19(s,3H). [Table 45]

[0345] Example 173: Method 46 Methyl 2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylate [ka] Step 1: Methyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate To a stirred solution of methyl 1-methyl-1H-imidazole-4-carboxylate (1.4 g, 10 mmol) in THF (20 mL) was added NBS (2.67 g, 15 mmol) at room temperature. The resulting mixture was stirred at 25 °C for an additional 19 hours. The mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:1) to give methyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (1.4 g, 64.0% yield) as a yellow solid. MS (m / z): 218.9, 220.9 [M+H] + .

[0346] Step 2: 2-(4-bromo-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylic acid To a solution of methyl 2-bromo-1-methyl-1H-imidazole-4-carboxylate (600 mg, 2.74 mmol), 4-bromo-2-fluorophenol (523 mg, 2.74 mmol) in DMF (10 mL) was added NaH (131 mg, 3.29 mmol) at room temperature. The resulting mixture was stirred at 200 °C under microwave conditions for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The aqueous solution was acidified to pH 3-4 with 1 N HCl. The resulting mixture was extracted with EtOAc (3 × 45 mL). The combined organic layers were washed with brine (80 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give crude 2-(4-bromo-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylic acid (5 g, 97.0% yield) as a brown oil. MS (m / z): 314.9, 317.0 [M + H] + This was used in the next reaction.

[0347] Step 3: Methyl 2-(4-bromo-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylate To a stirred solution of 2-(4-bromo-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylic acid (1.9 g, 0.006 mol) in DMF (20 mL) was added KCO (2.49 g, 0.018 mol) and MeI (1.02 g, 0.007 mol) at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE:EtOAc = 1:1) to afford methyl 2-(4-bromo-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylate (0.4 g, 20.0% yield) as a yellow solid. MS (m / z): 329.0, 330.9 [M + H] + .

[0348] Step 4: Methyl 2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylate To a stirred solution of methyl 2-(4-bromo-2-fluorophenoxy)-1-methyl-1H-imidazole-4-carboxylate (370 mg, 1.12 mmol), 4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (475 mg, 2.25 mmol), N,N-dimethylglycine (116 mg, 1.12 mmol), and CuI (214 mg, 1.12 mmol) in DMF (10 mL) was added CsCO (1099 mg, 3.37 mmol) at room temperature. The resulting mixture was stirred at 90 °C under Ar for an additional 38 h. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc = 1:1) to give the title compound (150 mg, yield: 29.0%) as a white solid. LC-MS (m / z): 460.0 [M+H] + . 1 H NMR(400MHz,DMSO)δ 8.37(s,1H),7.89(dd,J=12.3,2.4Hz,1H),7.78-7.72(m,2H),7.58(t,J=8.9Hz,1H ),7.53-7.44(m,1H),7.16(t,J=8.1Hz,2H),4.99(s,2H),3.67(s,3H),3.62(s,3H). [Table 46]

[0349] Example 174: Method 47 2-(4-((2-acetyl-1,4-dimethyl-1H-imidazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 2-(4-((2-acetyl-4-bromo-1-methyl-1H-imidazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1 g, 3.1 mmol), 1-(4,5-dibromo-1-methyl-1H-imidazol-2-yl)ethan-1-one (0.874 g, 3.1 mmol) in DMA (50 mL) was added K2CO3 (1.28 g, 9.3 mmol). The resulting mixture was stirred at 100 °C for an additional 12 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (PE: EtOAc = 1: 1) to give 2-(4-((2-acetyl-4-bromo-1-methyl-1H-imidazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (220 mg, 13.5% yield) as a yellow solid. LC-MS (m / z) 522.01 [M+H] + .

[0350] Step 2: 2-(4-((2-acetyl-1,4-dimethyl-1H-imidazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 2-(4-((2-acetyl-4-bromo-1-methyl-1H-imidazol-5-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (20 mg, 0.038 mmol), trimethylboroxine (7.1 mg, 0.057 mmol), and NaHCO (9.57 mg, 0.11 mmol) in dioxane (2 mL) was added Pd(AmPhos)Cl (2.7 mg, 0.0038 mmol) under an argon atmosphere. The resulting mixture was stirred at 100 °C for an additional 16 h. The resulting mixture was diluted with water (2 mL). The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous NaSO, and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography using the following conditions: Column: Gemini 5u C18 150 x 21.2 mm, Mobile phase B: ACN, Flow rate: 20 mL / min, Gradient: 40% B to 60% B in 20 min, Detector: 214 nm. The desired fractions were concentrated under reduced pressure to give the title compound (1.2 mg, 6.9% yield) as a white solid. LC-MS (m / z) 458.1 [M+H] + . [Table 47]

[0351] Example 175: Method 48 2-(4-((1,4-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one [ka] Step 1: 5-(4-bromo-2-fluorophenoxy)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid To a stirred solution of ethyl 5-(4-bromo-2-fluorophenoxy)-1,4-dimethylpyrazole-3-carboxylate (350 mg, 0.98 mmol) in HO (1 mL) was added 12 N HCl (10 mL). The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was concentrated under pressure at 50 °C. The residue was purified by flash chromatography eluting with CHCl / MeOH (20:1) to give 5-(4-bromo-2-fluorophenoxy)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid (280 mg, 86.82% yield) as a yellow solid. MS (m / z): 328.9 [M+H] + .

[0352] Step 2: 5-(4-bromo-2-fluorophenoxy)-1,4-dimethyl-1H-pyrazole A solution of 5-(4-bromo-2-fluorophenoxy)-1,4-dimethylpyrazole-3-carboxylic acid (270 mg, 0.82 mmol) in tetramethylene sulfone (10 mL) was stirred at 280° C. for 1 h. The residue was extracted with EA (50 mL). The residue was purified by flash chromatography eluting with PE / EtOAc (3:1) to give 5-(4-bromo-2-fluorophenoxy)-1,4-dimethyl-1H-pyrazole (170 mg, 64.13% yield) as a yellow oil. MS (m / z): 284.9 [M+H] + .

[0353] Step 3: 2-(4-((1,4-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a stirred solution of 5-phenyl-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (90 mg, 0.45 mmol), 5-(4-bromo-2-fluorophenoxy)-1,4-dimethylpyrazole (127 mg, 0.45 mmol), cuprous iodide (17 mg, 0.09 mmol), and K2Co3 (154 mg, 1.12 mmol) in DMF (5 mL) was added dropwise a solution of DMDACH (25 mg, 0.18 mmol) in DMF (1 mL) at 25 °C under nitrogen gas. The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was concentrated under pressure at 50 °C. The residue was extracted with EA (2 × 30 mL). The residue was purified by flash chromatography, eluting with PE / EtOAc (6:1) to give 2-(4-((1,4-dimethyl-1H-pyrazol-5-yl)oxy)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (5.0 mg, 2.75% yield) as a white solid. LC-MS (m / z) 406.0 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.89(dd,J=12.5,2.5Hz,1H),7.66(dd,J=6.5,4.8Hz,1H),7.43-7.32(m,4H),7.25(d,J=6.9Hz,2H),6.83(t, J=8.9Hz,1H),5.30-5.26(m,1H),3.73(s,3H),3.08-2.90(m,3H),2.53(dd,J=10.0,5.6Hz,1H),1.79(s,3H). [Table 48]

[0354] Example 176: Method 49 4-(2,6-Difluorobenzyl)-2-(4-((1,4-dimethyl-1H-pyrazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 5-chloro-1-methyl-1H-pyrazole-4-carbaldehyde DMF (2.98 g, 40.8 mmol) was added to 2-methylpyrazol-3-ol (1 g, 10.2 mmol). Phosphoryl trichloride (12.51 g, 81.6 mmol) was then added dropwise over 10 minutes. The reaction mixture was stirred at 80 °C for 6 hours, then cooled to room temperature, diluted with NaHCO solution, and extracted three times with ethyl acetate (20 mL). The organic layers were combined, the solvent removed in vacuo, and the crude material was purified by silica gel chromatography (PE:EA = 4:1) to give the desired product (1.03 g, 63% yield) as a yellow solid.

[0355] Step 2: 5-(4-bromophenoxy)-1-methyl-1H-pyrazole-4-carbaldehyde To a stirred solution of 5-chloro-1-methylpyrazole-4-carbaldehyde (1.03 g, 7.1 mmol), 4-bromophenol (1.60 g, 9.23 mmol) in DMSO (20 mL) was added NaOH (0.37 g, 9.23 mmol). The reaction mixture was stirred at 110 °C for 16 h, then cooled to room temperature, diluted with water, and extracted three times with ethyl acetate (50 mL). The organic layers were combined, the solvent removed in vacuo, and the crude material was purified by silica gel chromatography (PE:EA = 5:1) to give the desired product (1.39 g, 66% yield) as a yellow solid. LCMS (m / z): 280.1, 282.0 [M+H] + , Room temperature: 1.288 min.

[0356] Step 3: (5-(4-bromophenoxy)-1-methyl-1H-pyrazol-4-yl)methanol To a solution of 5-(4-bromophenoxy)-1-methylpyrazole-4-carbaldehyde (1.39 g, 4.9 mmol) in THF (10 mL) and MeOH (10 mL) was added NaBH (0.2 g, 5.3 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with HO (30 mL) and extracted with EA (3 × 30 mL). The organic layers were combined, the solvent was removed in vacuo, and the crude was purified by silica gel chromatography (PE:EA = 2:1) to give the desired product (1.16 g, yield: 80%) as a yellow oil. LCMS (m / z): 283.0, 285.0 [M+H] + , Step 4: 5-(4-bromophenoxy)-1,4-dimethyl-1H-pyrazole To a solution of (5-(4-bromophenoxy)-1-methyl-1H-pyrazol-4-yl)methanol (1.16 g, 4.1 mmol) in CF3COOH (20 mL) was added Et3SiH (0.95 g, 8.2 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction was then diluted with NaHCO3 solution and extracted three times with ethyl acetate (30 mL). The organic layers were combined, the solvent removed in vacuo, and the crude material was purified by silica gel chromatography (PE:EA=15:1) to give the desired product (0.93 g, 80% yield) as a yellow oil. LCMS (m / z): 267.0, 269.0 [M+H] + .

[0357] Step 5: 4-(2,6-difluorobenzyl)-2-(4-((1,4-dimethyl-1H-pyrazol-5-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 5-(4-bromophenoxy)-1,4-dimethyl-1H-pyrazole (50 mg, 0.19 mmol), 4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (39.53 mg, 0.19 mmol), (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (5.33 mg, 0.037 mmol), and copper(I) iodide (3.57 mg, 0.019 mmol) in DMF (10 mL) was added KCO (52 mg, 0.37 mmol). The reaction mixture was stirred at 120 °C under a N atmosphere for 16 h. After cooling to room temperature, 30 mL of water was added to the reaction mixture. The mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated. The crude product was purified by preparative TLC (PE:EA=2:1) ​​to give the desired product (12.2 mg, 16% yield) as a yellow solid. LCMS (m / z): 398.1 [M+H] + . 1 H NMR(400MHz,MeOH-d4)δ 7.99(s,1H),7.85(d,J=9.2Hz,2H),7.41-7.49(m,1H),7.33(s,1H),7.0 6(t,2H),6.99(d,J=9.1Hz,2H),5.03(s,2H),3.62(s,3H),1.80(s,3H). [Table 49]

[0358] Example 177: Method 50 4-(2,6-Difluorobenzyl)-2-(4-((3,5-dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 3-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)pentane-2,4-dione To a stirred solution of 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (2 g, 6.22 mmol) and 3-chloropentane-2,4-dione (1.1 g, 2.37 mmol) in acetone (50 mL) was added CsCO (3042 mg, 9.33 mmol) at room temperature. The resulting mixture was stirred at 60 °C for an additional 5 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1300 mg, 49.8% yield) as a tan oil. LCMS (m / z): 420.1 [M+H] + .

[0359] Step 2: 4-(2,6-difluorobenzyl)-2-(4-((3,5-dimethyl-1H-pyrazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one NH2NH 2.HO (235 mg, 4.65 mmol) was added to a solution of 3-(4-{4-[(2,6-difluorophenyl)methyl]-5-oxo-1,2,4-triazol-1-yl}-2-fluorophenoxy)pentane-2,4-dione (1300 mg, 3.1 mmol) in CHCOOH (30 mL), and the mixture was stirred at room temperature for 2 h. The solvent was then removed under vacuum. The residue was purified by silica gel column chromatography eluting with (PE:EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(4-((3,5-dimethyl-1H-pyrazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1000 mg, 77.7%) as a white solid. LCMS (m / z): 416.1 [M+H] + . 1 H NMR(400MHz, CDCl3)δ 7.83(m,1H),7.62-7.56(m,2H),7.36(m,1H),6.98(m,2H),6.75(m,1H),4.97(s,2H),2.14(s,6H).

[0360] Step 3: 4-(2,6-difluorobenzyl)-2-(4-((3,5-dimethyl-1-(oxetan-3-yl)-1H-pyrazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-[(2,6-difluorophenyl)methyl]-2-{4-[(3,5-dimethyl-1H-pyrazol-4-yl)oxy]-3-fluorophenyl}-1,2,4-triazol-3-one (100 mg, 0.24 mmol) and 3-iodooxetane (133 mg, 0.72 mmol) in DMF (5 mL) was added CsCO (314 mg, 0.96 mmol) at room temperature. The resulting mixture was stirred at 100 °C for an additional 16 h. The mixture was allowed to cool to room temperature, diluted with water (30 mL), and extracted three times with ethyl acetate (20 mL). The organic layers were combined, the solvent was removed under vacuum, and the crude product was purified by preparative HPLC (column - Gemini-C 18Purification using a 150x21.2mm column, 5µm column, mobile phase: ACN-HO (0.1% FA), 5%-20%, gave the desired product (10.8mg, 9.5%) as a white solid. LCMS (m / z): 472.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.83(m,1H),7.62-7.58(m,1H),7.56(s,1H),7.41-7.32(m,1H),6.99(m,2H),6.72( m,1H),5.36(d,J=6.8Hz,1H),5.21(m,2H),5.00-4.96(m,4H),2.12(d,J=9.2Hz,6H).

[0361] The synthetic procedures for Examples (compounds) 178 to 179 were similar to that for Example (compound) 177. [Table 50]

[0362] Example 180: Method 51 4-(2,6-Difluorobenzyl)-2-(3-fluoro-4-((1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 4-(2,6-difluorobenzyl)-2-(4-((3,5-dimethyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a stirred solution of 4-(2,6-difluorobenzyl)-2-(4-((3,5-dimethyl-1H-pyrazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.1 g, 0.24 mmol) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (55 mg, 0.26 mmol) in DMF (10 mL) was added K2CO3 (72 mg, 0.52 mmol) at room temperature. The resulting mixture was stirred at 25 °C for an additional 2 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(4-((3,5-dimethyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy) ethyl)-1H-pyrazol-4-yl)oxy)-3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (120 mg, 91.7% yield) as a white solid. LCMS (m / z): 544.2 [M+H] + Step 2: 4-(2,6-difluorobenzyl)-2-(3-fluoro-4-((1-(2-hydroxyethyl)-3,5-dimethyl-1H-pyrazol-4-yl)oxy)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one p-Toluenesulfonic acid (57 mg, 0.33 mmol) was added to a solution of 4-[(2,6-difluorophenyl)methyl]-2-[4-({3,5-dimethyl-1-[2-(oxan-2-yloxy)ethyl]pyrazol-4-yl}oxy)-3-fluorophenyl]-1,2,4-triazol-3-one (120 mg, 0.22 mmol) in MeOH (10 mL). The mixture was stirred at room temperature for 2 hours, then diluted with water (30 mL) and extracted three times with ethyl acetate (20 mL). The organic layers were combined, the solvent removed under vacuum, and the crude material was purified by preparative HPLC (column—Gemini-C18 150 × 21.2 mm, 5 μm, mobile phase: ACN-HO (0.1% FA), 5%–20%) to give the desired product (8.7 mg, 27.99% yield) as a white solid. LCMS(m / z):460.1[M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.86(m,1H),7.64(m,1H),7.56(s,1H),7.40-7.33(m,1H),6.98(m,2H),6.78 (m,1H),4.97(s,2H),4.27(s,2H),4.08-4.03(m,2H),2.18(d,J=6.3Hz,6H). [Table 51]

[0363] Example 181: Method 52 Ethyl-2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-1,5-dimethyl-1H-imidazole-4-carboxylate [ka] Step 1: Ethyl-1,5-dimethyl-1H-imidazole-4-carboxylate A solution of ethyl-5-methyl-1H-imidazole-4-carboxylate (5 g, 32.4 mmol), CHI (5.52 g, 38.9 mmol), and KCO (5.37 g, 38.9 mmol) in DMF (60 mL) under a N atmosphere was stirred at 50 °C overnight. The mixture was allowed to cool to room temperature and diluted with EtOAc (200 mL). The resulting solution was washed with water (3 × 50 mL) and brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (3:1) to give ethyl-1,5-dimethyl-1H-imidazole-4-carboxylate (2 g, 36.7% yield) as a white solid. MS (m / z): 169.2 [M+H] + .

[0364] Step 2: Ethyl-2-bromo-1,5-dimethyl-1H-imidazole-4-carboxylate To a stirred solution of ethyl-1,5-dimethyl-1H-imidazole-4-carboxylate (2 g, 11.9 mmol) in MeCN (20 mL) was added NBS (2.12 g, 1.39 mmol) at 0 °C under a N atmosphere. The mixture was then stirred at room temperature for 3 h. The reaction was quenched with saturated NaHCO solution and diluted with EtOAc (50 mL). The resulting solution was washed with water (20 mL) and brine (20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (3:1) to give ethyl-2-bromo-1,5-dimethyl-1H-imidazole-4-carboxylate (1.8 g, 61.5% yield) as a white solid. MS (m / z): 247.2, 249.2 [M+H] + .

[0365] Step 3: Ethyl-2-(4-bromo-2-fluorophenoxy)-1,5-dimethyl-1H-imidazole-4-carboxylate To a stirred solution of ethyl 2-bromo-1,5-dimethyl-1H-imidazole-4-carboxylate (1.8 g, 7.32 mmol) and 4-bromo-2-fluorophenol (1.39 g, 7.32 mmol) in DMF (30 mL) was added t-BuONa (1.05 g, 10.9 mmol). The mixture was then stirred at 170 °C for 5 h. The mixture was allowed to cool to room temperature and diluted with EtOAc (60 mL). The resulting solution was washed with water (3 × 30 mL) and brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE / EtOAc) (2:1) to afford ethyl 2-(4-bromo-2-fluorophenoxy)-1,5-dimethyl-1H-imidazole-4-carboxylate (900 mg, 34.5% yield) as a yellow solid. MS(m / z):357.2[M+H] + .

[0366] Step 4: Ethyl-2-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-1,5-dimethyl-1H-imidazole-4-carboxylate A solution of ethyl 2-(4-bromo-2-fluorophenoxy)-1,5-dimethyl-1H-imidazole-4-carboxylate (800 mg, 2.25 mmol), CuI (86 mg, 0.45 mmol), N,N-dimethylglycine (46 mg, 0.45 mmol), and KCO (466 mg, 3.38 mmol) in DMF (20 mL) was stirred at 110 °C under a N atmosphere for 5 h. The resulting mixture was filtered through diatomaceous earth, and after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (DCM / MeOH) (30:1) to afford the title compound (350 mg, 32% yield) as a white solid. MS (m / z): 488.2 [M+H] + . 1H NMR(400MHz,CDCl3)δ 7.92(dd,J=12.4,2.4Hz,1H),7.78(d,J=9.2Hz,1H),7.63-7.55(m,1H),7.43-7.32(m,2H),7.02- 6.95(m,2H),4.97(s,2H),4.31(q,J=7.2Hz,2H),3.52(s,3H),2.53(s,3H),1.34(t,J=7.2Hz,3H).

[0367] The synthetic procedures for Examples (compounds) 182 to 183 were similar to those for Example 181. [Table 52]

[0368] Example 184: Method 53 2-(4-((4-bromo-3-methyl-1H-pyrazol-1-yl)methyl)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] A solution of 2-[4-(bromomethyl)phenyl]-4-[(2,6-difluorophenyl)methyl]-1,2,4-triazol-3-one (50 mg, 0.13 mmol), 4-bromo-3-methyl-1H-pyrazole (25 mg, 0.15 mmol), and K2CO3 (36 mg, 0.26 mmol) in DMF (4 mL) was stirred at 70 °C for 16 h. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by chiral preparative HPLC to give the title product (8.1 mg, 18.4% yield) as a white solid. MS (m / z): 460.0 [M+H] + . 1H NMR(400MHz,CDCl3)δ 7.99-7.93(m,2H),7.58(s,1H),7.35(d,J=8.4Hz,1H),7.29-7.26(m,3H),7.02-6.94(m,2H),5.19(s,2H),4.97(s,2H),2.24(s,3H).

[0369] The synthetic procedures for Examples (compounds) 185 to 211 were similar to those for Example 184. [Table 53-1] [Table 53-2] [Table 53-3] [Table 53-4] [Table 53-5] [Table 53-6] [Table 53-7]

[0370] Example 212: Method 54 4-[(2,6-difluorophenyl)methyl]-2-(3-fluoro-4-{[4-methyl-2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-5-yl]oxy}phenyl)-1,2,4-triazol-3-one [ka] A mixture of 2-(4-{[2-(chloromethyl)-4-methyl-1,3-thiazol-5-yl]oxy}-3-fluorophenyl)-4-[(2,6-difluorophenyl)methyl]-1,2,4-triazol-3-one (100 mg, 0.2142 mmol), pyrrolidine (15.23 mg, 0.2142 mmol), and DIEA (55.37 mg, 0.4284 mmol) in CHCN (10 mL) was stirred at 55° C. for 12 hours. The reaction mixture was stirred at 110° C. for 2 hours. Water (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (30 mL×3). The residue was purified by flash chromatography under the following conditions (PE: EtOAc = 1:1) to give 4-[(2,6-difluorophenyl)methyl]-2-(3-fluoro-4-{[4-methyl-2-(pyrrolidin-1-ylmethyl)-1,3-thiazol-5-yl]oxy}phenyl)-1,2,4-triazol-3-one (54 mg, 49.8% yield) as an off-white solid. MS (m / z): 502.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.93-7.84(m,1H),7.74-7.67(m,1H),7.57(s,1H),7.41-7.31(m,1H),6.97(dd,J=8.4,7.5 Hz,3H),4.96(s,2H),4.21-3.67(m,2H),2.27(s,3H),1.96-1.78(m,3H),1.63-1.48(m,5H). [Table 54]

[0371] Example 213: Method 55 2-(4-((2,4-dimethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one [ka] Step 1: 1-(4-bromo-2-fluorobenzyl)-2,4-dimethyl-1H-imidazole To a stirred solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (200 mg, 0.7522 mmol) and 2,4-dimethyl-1H-imidazole (72.22 mg, 0.7522 mmol) in DMF (4 mL) was added KCO (311.4 mg, 2.257 mmol) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The organic layers were combined, the solvent was removed in vacuo, and the crude product was purified by silica gel chromatography (PE:EA = 1:1) to give 1-(4-bromo-2-fluorobenzyl)-2,4-dimethyl-1H-imidazole. MS (m / z): 283.02 [M+H] + .

[0372] Step 2: 2-(4-((2,4-dimethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one To a stirred solution of 1-(4-bromo-2-fluorobenzyl)-2,4-dimethyl-1H-imidazole (100 mg, 0.3545 mmol) and 5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (71.30 mg, 0.3545 mmol) in dioxane (4 mL) was added copper(I) iodide (67.36 mg, 0.3545 mmol) and 1,2-diaminocyclohexane (50.39 mg, 0.3545 mmol) at room temperature. The resulting mixture was stirred at 110° C. under a nitrogen atmosphere for an additional 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (20 mL). The residue was purified by reverse-phase flash chromatography under the following conditions: Column: spherical C18 40-60 μm, 40 g; Mobile phase B: ACN; Flow rate: 40 mL / min; Gradient: 30% B to 60% B in 20 min; Detector: 254 nm. Fractions containing the desired product were collected at 55% B and concentrated under reduced pressure to give the title compound 2-(4-((2,4-dimethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (10 mg, 6.99%) yield as an off-white solid. LC-MS (m / z): 404.2 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.85(d,J=12.0Hz,1H),7.79(d,J=8.3Hz,1H),7.38(d,J=7.0Hz,2H),7.34(d,J=6.7Hz,1H),7.28-7.23(m,2H),7.09(t,J=7.9Hz,1 H),6.58(s,1H),5.27(s,1H),5.01(s,2H),3.13-2.99(m,2H),2.93(m,J=19.2,11.8Hz,1H),2.54(s,3H),2.48(s,1H),2.23(s,3H). [Table 55]

[0373] Example 214: Method 56 N-(3,5-difluorobenzyl)-1-(4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-5-fluoropyrimidin-2-yl)-N-hydroxypiperidine-4-carboxamide [ka] 4-(2,6-Difluorobenzyl)-2-(4-((3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one A stirred solution of 1,4-dimethyl-1,3-dihydro-2H-imidazol-2-one (106 mg, 0.95 mmol) and NaH (47 mg, 1.18 mmol) in DMF (15 mL) was stirred at 50° C. for 1 h. Then, 2-(4-(bromomethyl)phenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (300 mg, 0.79 mmol) was added to the mixture at 50° C. The resulting mixture was stirred at 80° C. for an additional 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was quenched with water (1 mL). The resulting mixture was filtered. The filtrate was diluted with EA (100 mL), washed with water (150 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-(2,6-difluorobenzyl)-2-(4-((3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)methyl)phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (5 mg, 1.54% yield) as a white solid. MS (m / z): 412.2 [M+H] + . 1H NMR(400MHz,CD3OD)δ 7.97(s,1H),7.84(d,J=8.7Hz,2H),7.43(m,1H),7.25(d,J=8.8Hz,2H),7.05(t,J=8.1Hz, 2H),6.20(d,J=1.3Hz,1H),5.02(s,2H),4.87(s,2H),3.24(s,3H),1.94(d,J=1.3Hz,3H). [Table 56]

[0374] Example 215: Method 57 Ethyl 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-2,5-dimethyl-1H-imidazole-4-carboxylate [ka] Step 1: Ethyl 2,5-dimethyl-1H-imidazole-4-carboxylate TEA (3.89 g, 0.0385 mol) was added to a solution of ethyl 2-amino-3-oxobutanoate hydrochloride (2.0 g, 0.011 mol) and ethyl ethanecarboxyimidate hydrochloride (3.4 g, 0.0275 mol) in EtOH (50 mL). The mixture was stirred at room temperature for 16 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The organic layers were combined, the solvent was removed under vacuum, and the crude product was purified by silica gel chromatography (PE / EA = 1:1) to give 1-(4-bromo-2-fluorobenzyl)-2,4-dimethyl-1H-imidazole (900 mg, 49.1% yield) as a yellow solid. LCMS (m / z): 169.1 [M+H] + , Room temperature: 0.415 minutes.

[0375] Step 2: Ethyl 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-2,5-dimethyl-1H-imidazole-4-carboxylate To a stirred solution of ethyl 2,5-dimethyl-1H-imidazole-4-carboxylate (0.84 g, 5.02 mmol) and 2-[4-(bromomethyl)-3-fluorophenyl]-4-[(2,6-difluorophenyl)methyl]-1,2,4-triazol-3-one (2000 mg, 5.02 mmol) in DMF (40 mL) was added K2CO3 (2082 mg, 15.07 mmol) at room temperature. The resulting mixture was stirred at 25 °C for an additional 16 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (PE: EtOAc) (1:1) to give 4-(2,6-difluorobenzyl)-2-(4-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1200 mg, 49.2% yield) as a white solid. LCMS (m / z): 486.1 [M+H] + , Room temperature: 1.091 min. 1 H NMR(400MHz,CDCl3)δ 7.86(d,J=12.0Hz,1H),7.76(d,J=7.8Hz,1H),7.58(s,1H),7.39-7.35(m,1H),6.99(d,J=7.8Hz,2H ),6.88(s,1H),5.60(s,2H),4.96(s,2H),4.31(d,J=7.1Hz,2H),2.62(s,6H),1.33(t,J=7.1Hz,3H). [Table 57]

[0376] Example 216: Method 58 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid [ka] A solution of 2-(4-(bromomethyl)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.13 mmol) and NaH (8 mg, 0.19 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. Then, ethyl 5-methyl-1H-pyrazole-3-carboxylate (23 mg, 0.15 mmol) was added to the mixture at room temperature. The resulting mixture was stirred at room temperature for another 2 hours. The reaction was quenched with water (10 mL). The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid (1 mg, 1.80% yield) as a white solid. MS (m / z): 444.4 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.86(dd,J=11.8,2.0Hz,1H),7.74(d,J=8.3Hz,1H),7.57(s,1H),7.41-7.30(m,1H),7.04 (t,J=8.4Hz,1H),7.00-6.95(m,2H),6.64(s,1H),5.36(s,2H),4.96(s,2H),2.26(s,3H). [Table 58]

[0377] Example 217: Method 59 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-2,5-dimethyl-1H-imidazole-4-carboxamide [ka] Step 1: 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-2,5-dimethyl-1H-imidazole-4-carboxylic acid LiOH·HO (0.34 g, 8.24 mmol) was added to a solution of ethyl 1-[(4-{4-[(2,6-difluorophenyl)methyl]-5-oxo-1,2,4-triazol-1-yl}-2-fluorophenyl)methyl]-2,5-dimethylimidazole-4-carboxylate (0.4 g, 0.82 mmol) in THF / water (1:1, 40 mL). The mixture was heated to 70 °C for 48 h and then cooled to room temperature. The solvent was removed in vacuo. The resulting mixture was diluted with water (20 mL) and adjusted to pH = 3 with 1 N HCl. The resulting mixture was extracted with EtOAc (3 × 20 mL). The organic layers were combined and the solvent removed in vacuo to give 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-2,5-dimethyl-1H-imidazole-4-carboxylic acid (360 mg, 95.5% yield). LCMS (m / z): 458.1 [M+H] + .

[0378] Step 2: 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-2,5-dimethyl-1H-imidazole-4-carboxamide HATU (50 mg, 0.13 mmol) and triethylamine (27 mg, 0.087 mmol) were added to a solution of 1-[(4-{4-[(2,6-difluorophenyl)methyl]-5-oxo-1,2,4-triazol-1-yl}-2-fluorophenyl)methyl]-2,5-dimethylimidazole-4-carboxylic acid (40 mg, 0.087 mmol) in DMF (10 mL). The mixture was stirred at room temperature for 30 minutes, and then NH4Cl (19 mg, 0.35 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column - Gemini-C 18 Purification using a 150 x 21.2 mm column, 5 μm column, mobile phase: ACN-HO (0.1% FA), 5%-20% yield gave 1-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorobenzyl)-2,5-dimethyl-1H-imidazole-4-carboxamide (4.7 mg, 11.8% yield). LCMS (m / z): 457.1 [M+H] + . 1 H NMR (400MHz, CDCl3)δ 7.86-7.76(m,2H),7.58(s,1H),7.36(m,1H),7.18(s,1H),6.99(m,2H),5.56(s,2H),4.96(s,2H),2.64(s,6H).

[0379] The synthetic procedures for Examples (compounds) 218 ​​to 219 were similar to those for Example 217. [Table 59]

[0380] Example 220: Method 60 2-(3-fluoro-4-((4-(hydroxymethyl)-2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one [ka] Step 1: Methyl 1-(4-bromo-2-fluorobenzyl)-2-methyl-1H-imidazole-4-carboxylate To a stirred solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (100 mg, 0.37 mmol) and methyl 2-methyl-1H-imidazole-4-carboxylate (52.3 mg, 0.37 mmol) in DMF (5 mL) was added K2CO3 (154.7 mg, 1.12 mmol) at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined, the solvent was removed in vacuo, and the crude product was purified by silica gel chromatography (PE / EA = 1:1) to give 1-(4-bromo-2-fluorobenzyl)-2,4-dimethyl-1H-imidazole (100 mg, 81.9% yield) as a yellow solid. LCMS (m / z): 327.3 [M+H] + Step 2: Methyl 1-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)benzyl)-2-methyl-1H-imidazole-4-carboxylate To a stirred solution of 5-phenyl-2H,5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-3-one (93 mg, 0.46 mmol) and methyl 1-[(4-bromo-2-fluorophenyl)methyl]-2-methylimidazole-4-carboxylate (100 mg, 0.31 mmol) in dioxane (5 mL), copper(I) iodide (58 mg, 0.31 mmol) and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (85 mg, 0.61 mmol)K2CO3 (154.7 mg, 1.12 mmol) were added at room temperature. The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for an additional 8 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layer was washed with brine (20 mL) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EA=1:1) to give methyl 1-(2-fluoro-4-(3-oxo-5-phenyl-6,7-dihydro-3H-pyrrolo[2,1-c][1,2,4]triazol-2(5H)-yl)benzyl)-2-methyl-1H-imidazole-4-carboxylate (110 mg, 80% yield) as a yellow solid. LCMS (m / z): 448.2 [M+H] + Step 3: 2-(3-fluoro-4-((4-(hydroxymethyl)-2-methyl-1H-imidazol-1-yl)methyl)phenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one Diisobutylaluminum hydride in hexane (1 M, 0.45 mL) was added to a solution of methyl 1-[(2-fluoro-4-{3-oxo-5-phenyl-5H,6H,7H-pyrrolo[2,1-c][1,2,4]triazol-2-yl}phenyl)methyl]-2-methylimidazole-4-carboxylate (100 mg, 0.22 mmol) in THF at 0 °C. The mixture was stirred at 0 °C for 2 h. The resulting mixture was quenched with water (2 mL), filtered, and the solvent was removed under vacuum. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: spherical C 1840-60 μm, 40 g, Mobile phase B: ACN, Flow rate: 40 mL / min; Gradient: 30% B to 60% B in 20 min, Detector: 254 nm. Fractions containing the desired product were collected at 55% B and concentrated under reduced pressure to give the title compound 2-(4-((2,4-dimethyl-1H-imidazol-1-yl)methyl)-3-fluorophenyl)-5-phenyl-2,5,6,7-tetrahydro-3H-pyrrolo[2,1-c][1,2,4]triazol-3-one (8 mg, 8.55% yield) as a white solid. LCMS (m / z): 420.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.85(m,2H),7.42-7.34(m,3H),7.24(m,2H),7.13(m,1H),6.82(m,1H), 5.30-5.26(m,1H),5.07(s,2H),4.60(s,2H),3.01(m,4H),2.58(s,3H).

[0381] The synthetic procedures for Examples (compounds) 221 to 222 were similar to those for Example 220. [Table 60]

[0382] Example 223: Method 61 2-(4-((2-amino-5-fluoropyridin-4-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one [ka] Step 1: 2-(4-((2-chloro-5-fluoropyridin-4-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 4-(2,6-Difluorobenzyl)-2-(3-fluoro-4-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1 g, 3.115 mmol), 2,4-dichloro-5-fluoropyridine (568 mg, 3.427 mmol), and K2CO3 (860 mg, 6.23 mmol) were dissolved in 10 mL of DMF. The resulting mixture was stirred at 130 °C for 3 hours. Water was added to the solution, and the reaction mixture was extracted with EtOAc (50 mL × 3). The combined organic layer was washed with water. It was evaporated to dryness and purified by column chromatography (PE / EA=3 / 1) to give 2-(4-((2-chloro-5-fluoropyridin-4-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (702 mg, yield: 50%) as a white solid. MS (m / z): 451.3 [M+H] + .

[0383] Step 2: tert-butyl (4-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-5-fluoropyridin-2-yl)carbamate To a solution of tris(dibenzylideneacetonyl)bis-palladium (0.150 equiv., 152 mg, 0.166 mmol), tert-butyl carbamate (1.50 equiv., 195 mg, 1.66 mmol), CsCO (2.00 equiv., 723 mg, 2.22 mmol), and BINAP (0.300 equiv., 207 mg, 0.333 mmol) in toluene (5 mL), 2-[4-[(2-chloro-5-fluoro-4-pyridyl)oxy]-3-fluoro-phenyl]-4-[(2,6-difluorophenyl)methyl]-1,2,4-triazol-3-one (1.00 equiv., 500 mg, 1.11 mmol) was added at room temperature under N. The mixture was heated to 110 °C and stirred for 4 h. The reaction mixture was then added with water (20 mL) and extracted with EtOAc (20 mL × 3). The organic layers were then combined, dried (NaSO), and concentrated to dryness. The crude material was purified by flash chromatography (silica gel column, 30 g, EtOAc / PE, 0–50%) to give the product tert-butyl N-[4-[4-[4-[(2,6-difluorophenyl)methyl]-5-oxo-1,2,4-triazol-1-yl]-2-fluoro-phenoxy]-5-fluoro-2-pyridyl]carbamate (300 mg, 0.452 mmol, 40.71% yield) as a yellow gum. MS (m / z): 532.2 [M+H] + .

[0384] Step 3: 2-(4-((2-amino-5-fluoropyridin-4-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 2-(4-((2-amino-5-fluoropyridin-4-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (33 mg, 0.062 mmol) was dissolved in 2 mL of DCM. 1 mL of DCM / TFA (v / v=1 / 1) was added to the solution at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to dryness and purified by preparative HPLC to give 2-(4-((2-amino-5-fluoropyridin-4-yl)oxy)-3-fluorophenyl)-4-(2,6-difluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (21.4 mg, yield: 79.13%) as a yellow solid. MS (m / z): 432.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.40(s,1H),7.98-7.88(m,2H),7.81-7.78(m,1H),7.55-5.45(m,2H),7.17(t,J=8.1Hz,2H),5.86(s,2H),5.82-5.77(m,1H),5.00(s,2H).

[0385] The synthetic procedures for Examples (compounds) 224 to 401 were similar to those for Example 223. [Table 61-1] [Table 61-2] [Table 61-3] [Table 61-4] [Table 61-5] [Table 61-6] [Table 61-7]

Table 61-8

Table 61-9

Table 61-10

Table 61-11

Table 61-12

Table 61-13

Table 61-14

Table 61-15

Table 61-16

Table 61-17

Table 61-18

Table 61-19

Table 61-20

Table 61-21

Table 61-22

Table 61-23

Table 61-24

Table 61-25

Table 61-26

Table 61-27

Table 61-28

Table 61-29

Table 61-30

Table 61-31

Table 61-32

Table 61-33

Table 61-34

Table 61-35

Table 61-36

Table 61-37

Table 61-38

Table 61-39

Table 61-40

[0386] Example 402: Method 62 4-(4-(4-(2,6-difluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-fluorophenoxy)-5-fluoropicolinonitrile [ka] A mixture of 2-{4-[(2-chloro-5-fluoropyridin-4-yl)oxy]-3-fluorophenyl}-4-[(2,6-difluorophenyl)methyl]-1,2,4-triazol-3-one (100 mg, 0.22 mmol), ZnCN (52.09 mg, 0.44 mmol), Zn (14.51 mg, 0.22 mmol), DPPF (61.48 mg, 0.11 mmol), and Pd(dba) (101.55 mg, 0.11 mmol) in DMA (10 mL). The reaction mixture was stirred at 110 °C for 6 h. Water (20 mL) was added to the mixture, and the mixture was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (4 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography under the following conditions (PE: EtOAc = 1:1) to give the title compound (8.3 mg, 8.39% yield) as an off-white solid. MS (m / z): 441.9 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.53(d,J=2.5Hz,1H),8.04(dd,J=12.0,2.5Hz,1H),7.94(ddd,J=9.0,2.5,1.5Hz,1H),7.63(s,1H),7.37( tt,J=8.4,6.5Hz,1H),7.27(d,J=8.7Hz,1H),7.05(dd,J=6.3,1.3Hz,1H),7.02-6.96(m,2H),4.99(s,2H).

[0387] The synthetic procedures for Examples (compounds) 403 to 406 were similar to those for Example 402. [Table 62]

[0388] Example 407: Method 63...

Claims

1. The following structural formula I: 【Chemistry 1】 [In the formula, X １ is C or N, and X ２ is C or N, and X ３ is C, N, or non-existent, X ４ is C or N, Ring A is phenyl, a 5-9 member heteroaryl, a 5-6 member cycloalkyl, or a 5-9 member heterocyclyl. Ring B is a phenyl, a 4-9 membered heteroaryl, a 5-6 membered cycloalkyl, or a 4-8 membered heterocyclyl. Ring C is phenyl, a 5-6 member heteroaryl, a 5-6 member cycloalkyl, or a 5-6 member heterocyclyl. Bonds a and b are independently selected from single and double bonds, provided that bond a and bond b are not both double bonds at the same time. ３ If X does not exist, ２ and X ４ The bond between and is a single bond or a double bond. R ａ For each occurrence, independently, halogen, cyano, =O, NO ２ , optionally substituted C １ ~C ６ alkyl, optionally substituted C ２ ~C ６ alkenyl, optionally substituted C ２ ~C ６ alkynyl, optionally substituted acyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted phenyl, optionally substituted 5- to 10-membered heteroaryl, optionally substituted nitrogen, and optionally substituted oxygen, and is selected from R ｂ For each occurrence, independently, C is substituted with halogen, CN, =O, and one to three halogen groups, which are arbitrarily substituted. １ -C ４ Selected from alkyl groups, R ｃ For each occurrence, independently, halogen, CN, and C are identified. １ -C ６ Alkyl, OR ｓ１ , and -C(=O)OR ｓ１ Selected from, R １ H is R ２ H, halogen, CN, OR ｓ１ , -NR ｐ１ R ｑ１ C is optionally substituted with 1 to 3 groups selected from ,=O and halogens. １ ~C ３ Selected from alkyl groups, or R １ and R ２ Together, they form a 5-6 membered heterocycle optionally substituted with 1-3 groups selected from halogens, and a C12 ring optionally substituted with 1-3 groups selected from halogens. １ ~C ３ Forming alkyl groups, R ３ is selected from non-existence, H, and =O, where R ３ If = O, then X ２ C is, R ４ H and C １ ~C ３ Selected from alkyl groups, L is -NR ｘ -, - (CH ２ ) ｕ O(CH ２ ) ｕ -, - (CH ２ ) ｕ S (=O) ｗ - (CH ２ ) ｕ -, -S (=O) ｗ (=NR ｘ ) -, -NR ｘ S (=O) ｗ -, -S (=O) ｗ (NR ｘ )-, -C(=O)-, and C １ -C ３ Selected from alkylenes, L of C １ -C ３ Alkylenes are OH, C １ -C ３ Alkyl, and =CHR ｘ It is optionally substituted with one or two groups selected from the C of L. １ -C ３ Alkylene C １ -C ３ Alkyl groups optionally combine with C ３ -C ４ It forms a cycloalkyl group, in the formula, R ｐ１ and R ｑ１ For each occurrence, the carbon is independently substituted with hydrogen and one to three groups selected from halogens, CN, and OH. １ -C ４ Selected from alkyl groups, R ｓ１ For each occurrence, independently, hydrogen and C are optionally substituted with 1 to 3 groups selected from halogens, CN, and OH. １ -C ４ Selected from alkyl groups, R ｘ H and C １ -C ４ Selected from alkyl groups, m and p are integers independently selected from 0, 1, 2, 3, and 4, respectively. n is an integer selected from 0, 1, and 2. w is an integer that is independently selected from 0, 1, and 2 for each occurrence. [For each occurrence, u is an integer independently selected from 0, 1, and 2] however, 【Chemistry 2】 【Transformation 3】 [P １ , P ２ , and P ３ For each occurrence, C and N are independently selected, and P ６ Compounds, tautomers thereof, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts thereof, which are independently selected from S and O.

2. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein ring A is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyridadinyl, piperazinyl, oxazolyl, isoxazolyl, triazolyl, cyclopentyl, cyclohexanyl, tetrahydro-furanyl, or tetrahydro-pyranyl group.

3. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein ring B is a phenyl, pyridinyl, thiazolyl, cyclopentenyl, cyclobutanyl, cyclohexanyl, piperidyl, or pyrrolidinyl group, or a 5-8 membered bicyclic group optionally containing one or two N atoms.

4. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein the ring C is a phenyl, pyridinyl, thiazolyl, isothiazolyl, oxazolyl, cyclopentyl, cyclopentenyl, cyclohexanyl, cyclohexenyl, isoxazolyl, tetrahydropyranyl, or dihydropyranyl group.

5. The following structural formula IIa: 【Chemistry 4】 [In the formula, R １ and R ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [these compounds not together form a 5-6 membered heterocycle].

6. The following structural formula IIb: 【Transformation 5】 [Wherein, V １ , V ２ , and V ３ are each independently selected from C, O, and N, and R ｆ is, for each occurrence, independently selected from C １ -C ３ alkyl and halogen, and q is selected from 0, 1, and 2], a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4.

7. The following structural formula IIc: 【Transformation 6】 [In the formula, V １ and V ２ Each is independently selected from C, O, and N, and R ｆ For each occurrence, independently, C １ -C ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [a selected element from alkyl and halogen, where q is selected from 0, 1, and 2].

8. The following structural formula IId: 【Transformation 7】 [wherein, R １ and R ２ do not together form a 5- or 6-membered heterocyclic ring], a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4.

9. The following structural formula IIIa: 【Transformation 8】 [In the formula, Y １ and Y ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, each having independently selected from C and N.

10. The following structural formula IIIb: 【Chemistry 9】 [In the formula, Y １ is selected from S, C, O, and N, and Y １ and Y ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, each having independently selected from C and N.

11. The following structural formula IIIc: 【Chemistry 10】 [In the formula, Y １ is selected from C and N, and Y ２ and Y ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, each independently having [C or not present].

12. The following structural formula IIId: 【Chemistry 11】 [In the formula, Y １ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [selected from C and N].

13. The following structural formula IIIe: 【Chemistry 12】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having the above.

14. The following structural formula IIIf: 【Chemistry 13】 [In the formula, Y １ is selected from C and N, and Y ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [C or not present].

15. The following structural formula IVa: 【Chemistry 14】 [In the formula, Z １ Z ２ Z ３ and Z ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, each having independently selected from C and N.

16. The following structural formula IVb: 【Chemistry 15】 [In the formula, Z １ Z ２ , and Z ３ Each is independently selected from S, O, C, and N, and Z ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [selected from C and N].

17. The following structural formula Va: 【Chemistry 16】 [In the formula, Q １ Q ２ , and Q ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, each having independently selected from C and N.

18. The following structural formula Vb: 【Chemistry 17】 [In the formula, Q １ Q ２ Q ３ , and Q ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, each having independently selected from C, N, S, and O.

19. The following structural formula Vc: [Chemistry 18] [In the formula, Q １ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [C, O, or absent].

20. The following structural formula Vd: 【Chemistry 19】 [In the formula, Q １ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [C or not present].

21. The following structural formula VIa: 【Chemistry 20】 [In the formula, Q １ Q ２ and Q ３ Each is independently selected from C and N, and Y １ and Y ２ Each is independently selected from C and N, and Z １ Z ２ , and Z ３ Each is independently selected from S, O, C, and N, and Z ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [selected from C and N].

22. The following structural formula VIB: 【Chemistry 21】 [In the formula, R ａ For each occurrence, independently, halogen, CN, NO ２ NH ２ ,-NH(C １ -C ３ Alkyl), -OH, -O (C １ -C ３ Alkyl), -C(=O)H, -C(=O)O(C １ -C ３ Alkyl), -C(=O)NH ２ , as well as halogens, OH, CN, and NH ２ C is optionally substituted with 1 to 3 groups selected from the above. １ -C ３ Selected from alkyl, m' is 0, 1, and 2, R ａ１ This is C, which is optionally substituted. １ -C ３ Alkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, -NHC(=O)R ｐ２ , and -NR ｐ２ R ｑ２ Selected from, R ｐ２ and R ｑ２ For each occurrence, independently, hydrogen and optionally substituted C are considered. １ -C ６ Selected from alkyl groups, or R ｐ２ and R ｑ２ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 21, having [together to form an optionally substituted 3- to 10-membered heterocycline].

23. R ａ However, for each occurrence, independently, CH ３ CHF ２ , F, Cl, CN, NH ２ , NHCH ３ ,OH,-CH ２ OH, -COOMe, -COOEt, -CONH ２ , -C(=O)H, -CH ２ CN, -CH ２ NH ２ CF ３ , and NO ２ Selected from, R ａ１ COOMe, COOEt, 【Chemistry 22】 and NR ｐ２ R ｑ２ Selected from, R ｐ２ and R ｑ２ However, together they form halogen, OH, CN, -O(C) １ -C ３ Alkyl), NH ２ ,NHBoc,NH(C １ -C ３ Alkyl, as well as halogens, CN, NH ２ C is optionally substituted with 1 to 3 groups selected from NHBoc and OH. １ -C ３ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 22, which forms a 3- to 10-membered heterocycline optionally substituted with one or two groups selected from alkyl groups.

24. The following structural formula VIC: 【Chemistry 23】 [In the formula, R ａ For each occurrence, independently, non-existence, halogen, CN, NO ２ NH ２ ,-NH(C １ -C ３ Alkyl), OH, -O (C １ -C ３ Alkyl), -C(=O)H, -C(=O)O(C １ -C ３ Alkyl), -C(=O)NH ２ , as well as halogens, OH, CN, and NH ２ C is optionally substituted with 1 to 3 groups selected from the above. １ -C ３ Selected from alkyl, m' is 0, 1, and 2, R ｐ２ and R ｑ２ These are H and C, which are substituted independently and optionally. １ ~C ６ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 21, having [selected from alkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 3-10 membered heteroaryl].

25. R ａ However, for each occurrence, independently, CH ３ CHF ２ , F, Cl, CN, NH ２ , NHCH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 24, selected from , and OH.

26. The following structural formula VID: 【Chemistry 24】 [In the formula, L is -O-, -N(R ｘ ) -, -CH ２ -, -S-, -S(=O)-, -S(=O) ２ -, and C １ -C ２ C is optionally substituted with one or two groups selected from alkyl groups. １ -C ３ Selected from alkylenes, L of C １ -C ３ Alkylene C １ -C ２ Alkyl groups can optionally combine with C ３ -C ４ Forms a cycloalkyl group, R ａ For each occurrence, H and C are considered independently. １ -C ３ Selected from alkyl groups, R ｂ For each occurrence, independently, F, Cl, Br, CH ３ Selected from , and CN, R ｃ F, Cl, Br, CH ３ , -OCH ３ Selected from , and CN, where p is 0, 1, or 2, where L is -O- or -N(R ｘ ) - If Z ４ C is C, and L is -CH ２ -, -S-, -S(=O)-, -S(=O) ２ -, or C １ -C ３ If it is alkylene, Z ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 21, wherein [ is C or N].

27. The following structural formula VIe: 【Chemistry 25】 [In the formula, V １ and V ２ Each is independently selected from C, N, and O, and L is -O-, -N(R ｘ ) -, -CH ２ -, -S-, -S(=O)-, -S(=O) ２ -, and C １ -C ２ C is optionally substituted with one or two groups selected from alkyl groups. １ -C ３ Selected from alkylenes, L of C １ -C ３ Alkylene C １ -C ２ Alkyl groups can optionally combine with C ３ -C ４ Forms a cycloalkyl group, R ａ For each occurrence, H and C are considered independently. １ -C ３ Selected from alkyl groups, R ｂ For each occurrence, independently, H, F, Cl, Br, CH ３ Selected from , and CN, R ｃ F, Cl, Br, -OCH ３ ,CH ３ Selected from , and CN, R ｆ For each occurrence, independently, C １ -C ３ Selected from alkyl and halogen, where p is 0, 1, or 2, and q is 0, 1, or 2, where L is -O- or -N(R ｘ ) - If Z ４ C is C, and L is -CH ２ -, -S-, -S(=O)-, -S(=O) ２ -, or C １ -C ３ If it is alkylene, Z ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 21, wherein [ is C or N].

28. The following structural formula VIF: 【Chemistry 26】 [In the formula, V １ , V ２ , and V ３ Each is independently selected from C, N, and O, and L is -O-, -N(Rx)-, -CH ２ -, -S-, -S(=O)-, -S(=O) ２ -, and C １ -C ２ C is optionally substituted with one or two groups selected from alkyl groups. １ -C ３ Selected from alkylenes, L of C １ -C ３ Alkylene C １ -C ２ Alkyl groups can optionally combine with C ３ -C ４ Forms a cycloalkyl group, R ａ For each occurrence, H and C are considered independently. １ -C ３ Selected from alkyl groups, R ｂ For each occurrence, independently, H, F, Cl, Br, CH ３ Selected from , and CN, R ｃ F, Cl, Br, CH ３ , -OCH ３ Selected from , and CN, R ｆ For each occurrence, independently, C １ -C ３ Selected from alkyl and halogen, where p is 0, 1, or 2, and q is 0, 1, or 2, where L is -O- or -N(R ｘ ) - If Z ４ C is C, and L is -CH ２ -, -S(=O)-, -S(=O) ２ -, or C ３ -C ４ C is optionally substituted with a cycloalkyl group. １ -C ３ If it is alkylene, Z ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 21, wherein [ is C or N].

29. The following structural formula VIIa: 【Chemistry 27】 [In the formula, Q １ Q ２ and Q ３ Each is independently selected from C and N, and Y １ and Y ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, each having independently selected from C and N.

30. The following structural formula VIIb: 【Chemistry 28】 [In the formula, Q １ Q ２ , and Q ３ Each is independently selected from C and N, and Y １ and Y ２ Each is independently selected from C and N, and Z １ is selected from C and N, R ａ For each occurrence, independently, halogen, CN, NO ２ NH ２ ,-NH(C １ -C ３ Alkyl), OH, -O (C １ -C ３ Alkyl), -C(=O)H, -C(=O)O(C １ -C ３ Alkyl), -C(=O)NH ２ , as well as halogens, OH, CN, and NH ２ C is optionally substituted with 1 to 3 groups selected from the above. １ -C ３ Selected from alkyl, m' is 0, 1, and 2, R ａ１ This is C, which is optionally substituted. １ -C ３ Alkyl, optionally substituted 3- to 6-membered cycloalkyl, optionally substituted 3- to 6-membered heterocyclyl, -NC(=O)R ｐ２ , and -NR ｐ２ R ｑ２ Selected from, R ｐ２ and R ｑ２ For each occurrence, independently, hydrogen and optionally substituted C are considered. １ -C ６ Selected from alkyl groups, or R ｐ２ and R ｑ２ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 29, having [together form an optionally substituted 3- to 10-membered heterocycline].

31. R ａ However, for each occurrence, independently, CH ３ CHF ２ , F, Cl, CN, NH ２ , NHCH ３ ,OH,-CH ２ OH, -COOMe, -COOEt, -CONH ２ , -C(=O)H, -CH ２ CN, -CH ２ NH ２ CF ３ , and NO ２ Selected from, R ａ１ COOMe, COOEt, 【Chemistry 29】 and NR ｐ２ R ｑ２ Selected from, R ｐ２ and R ｑ２ However, together they form halogen, OH, CN, -O(C) １ -C ３ Alkyl), NH ２ ,NHBoc,NH(C １ -C ３ Alkyl, as well as halogens, CN, NH ２ C is optionally substituted with 1 to 3 groups selected from NHBoc and OH. １ -C ３ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 29, which forms a 3- to 10-membered heterocycline optionally substituted with one or two groups selected from alkyl groups.

32. The following structural formula VIIc: 【Transformation 30】 [In the formula, Q １ Q ２ , and Q ３ Each is independently selected from C and N, and Y １ and Y ２ Each is independently selected from C and N, and Z １ is selected from C and N, R ａ For each occurrence, independently, halogen, CN, NO ２ NH ２ ,-NH(C １ -C ３ Alkyl), OH, -O (C １ -C ３ Alkyl), -C(=O)H, -C(=O)O(C １ -C ３ Alkyl), -C(=O)NH ２ , as well as halogens, OH, CN, and NH ２ C is optionally substituted with 1 to 3 groups selected from the above. １ -C ３ Selected from alkyl, m' is 0, 1, and 2, R ｐ２ and R ｑ２ These are H and C, which are substituted independently and optionally. １ ~C ６ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 29, having [selected from alkyl, optionally substituted 3-10 membered cycloalkyl, optionally substituted 3-10 membered heterocyclyl, and optionally substituted 3-10 membered heteroaryl].

33. R ａ However, for each occurrence, independently, CH ３ CHF ２ , F, Cl, CN, NH ２ , NHCH ３ ,OH,-CH ２ OH, -COOMe, -COOEt, -CONH ２ , -C(=O)H, -CH ２ CN, -CH ２ NH ２ CF ３ , and NO ２ Selected from, R ｐ２ and R ｑ２ The aforementioned 3-10 member cycloalkyl, 3-10 member heterocyclyl, and 3-10 member heteroaryl are halogens, OH, CN, -O(C １ -C ３ Alkyl), NH ２ ,NHBoc,NH(C １ -C ３ Alkyl, as well as halogens, CN, NH ２ C, optionally substituted with NHBoc and OH １ -C ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 32, optionally substituted with one or two groups selected from alkyl groups.

34. The following structural formulas VIIIa, VIIIb, or VIIIc: 【Chemistry 31】 [In the formula, Q １ Q ２ , and Q ３ Each is independently selected from C and N, and Y １ and Y ２ Each is independently selected from C and N, and Z' is selected from C and N, Z １ Z ２ , and Z ３ Each is independently selected from S, O, C, and N, and Z ４ is selected from C and N, R ａ For each occurrence, independently, H, halogen, CN, NO ２ NH ２ ,-NH(C １ -C ３ Alkyl), -OH, -O (C １ -C ３ Alkyl), -C(=O)H, -C(=O)O(C １ -C ３ Alkyl), -C(=O)NH ２ , as well as halogens, OH, CN, and NH ２ C is optionally substituted with 1 to 3 groups selected from the above. １ -C ３ Selected from alkyl groups, ring D is a 3- to 10-membered heterocycline, and R ｇ For each occurrence, independently, halogen, OH, CN, -O(C) １ -C ３ Alkyl), NH ２ ,NHBoc,NH(C １ -C ３ Alkyl, as well as halogens, CN, NH ２ C is optionally substituted with 1 to 3 groups selected from NHBoc and OH. １ -C ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [selected from alkyl, where s is an integer selected from 0, 1, and 2].

35. The following structural formulas VIIId, VIIIe, or VIIIf: 【Chemistry 32】 [In the formula, Q １ Q ２ , and Q ３ Each is independently selected from C and N, and Y １ and Y ２ Each is independently selected from C and N, and Z' is selected from C and N, Z １ Z ２ , and Z ３ Each is independently selected from S, O, C, and N, and Z ４ is selected from C and N, R ａ For each occurrence, independently, H, halogen, CN, NO ２ NH ２ NH(C １ -C ３ Alkyl), OH, -O (C １ -C ３ Alkyl), -C(=O)H, -C(=O)O(C １ -C ３ Alkyl), -C(=O)NH ２ , as well as halogens, OH, CN, and NH ２ C is optionally substituted with 1 to 3 groups selected from the above. １ -C ３ Selected from alkyl groups, R ｈ For each occurrence, C is independently and optionally substituted with 1 to 3 groups selected from H, halogens, and 3-4 membered cycloalkyl groups. １ -C ３ Alkyl, halogen and C １ -C ３ 3-6 membered cycloalkyls optionally substituted with 1-3 groups selected from alkyl groups, as well as halogens and C １ -C ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, having [selected from a 3-6 membered heterocyclyl optionally substituted with 1-3 groups selected from alkyl groups].

36. Equation I 【Transformation 33】 Selected from, R ｂ A ring B substituted with n groups of the following: 【Transformation 34】 Selected from, R ｃ A ring C substituted with p groups of the following: 【Chemistry 35】 Selected from, L, 【Transformation 36】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

37. R ａ A ring A substituted with m groups of the following: 【Chemistry 37】 Selected from, R ａ’ However, for each occurrence, independently, F, Cl, -OCH ３ ,CH ３ NH ２ , and selected independently from CN, where L is -O-, and the left side of the above structure ＊ The position indicated by is connected to L, and is on the right side of the structure shown above. ＊ The position indicated by R ａ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, linked to the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4.

38. R ａ A ring A substituted with m groups of the following: 【Transformation 38】 Selected from, L is -SO ２ - A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4.

39. Equation I 【Chemistry 39】 Selected from, R ２ However, H, halogen, CN, -NH ２ OH, OCH ３ C is optionally substituted with 1 to 3 groups selected from ,=O and halogens. １ ~C ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 1 to 4.

40. Equation I 【Chemistry 40】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

41. Equation I 【Chemistry 41】 Selected from, R ｆ However, for each occurrence, independently, C １ -C ２ Selected from alkyl and halogen, q is selected from 0, 1, and 2, and R is halogen and C １ -C ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 1 to 4.

42. Equation I 【Chemistry 42】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

43. Ring A is 【Chemistry 43】 Selected from, ring A is R ａ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, which is substituted with m groups.

44. R ａ A ring A substituted with m groups of the following: 【Chemistry 44】 Selected from, R ｋ is -C(=O)NH ２ , -C(=O)NHCH ３ , -C(=O)N(CH ３ ) ２ Selected from, R ｊ However, for each occurrence, independently, F, Cl, CH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from CN, and CN, according to any one of claims 1 to 4.

45. Ring B is 【Chemistry 45】 Selected from, ring B is R ｂ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, which is substituted with n groups of the compound.

46. R ｂ A ring B substituted with n groups of the following: 【Chemistry 46】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

47. Ring C is 【Chemistry 47】 Selected from, Ring C is R ｃ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, which is substituted with p groups.

48. R ｃ A ring C substituted with p groups of the following: 【Chemistry 48】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

49. R ａ However, for each occurrence, independently, halogen, cyano, =O, NO ２ , Halogen, CN, -OR ｓ , -C(=O)NR ｐ R ｑ , -C (=O) OR ｓ , -N3, =NRp, =NOR ｓ , -NR ｐ R ｑ C, optionally substituted with 1 to 4 groups selected from 3-10 membered cycloalkyl and 3-10 membered heterocyclyl groups. １ ~C ６ Alkyl, wherein the 3-10 member cycloalkyl and the 3-10 member heterocyclyl are each C １ ~C ６ C is optionally substituted with 1 to 4 groups selected from alkyl, halogen, and ORs. １ ~C ６ Alkyl, Halogen, CN, -OR ｓ , -C(=O)NR ｐ R ｑ , -C (=O) OR ｓ , -N3, =NRp, =NOR ｓ , -NR ｐ R ｑ A C2-C6 alkenyl optionally substituted with 1-4 groups selected from 3-10 membered cycloalkyls and 3-10 membered heterocyclines, wherein the 3-10 membered cycloalkyl and the 3-10 membered heterocycline are each C １ ~C ６ Alkyl, halogen, and OR ｓ C2-C6 alkenyls, which are optionally substituted with 1 to 4 groups selected from the following: Halogen, CN, -OR ｓ , -C(=O)NR ｐ R ｑ , -C (=O) OR ｓ , -N3, =NRp, =NOR ｓ , -NR ｐ R ｑ C, optionally substituted with 1 to 4 groups selected from 3-10 membered cycloalkyl and 3-10 membered heterocyclyl groups. ２ ~C ６ Alkinyl, wherein the 3-10 member cycloalkyl and the 3-10 member heterocyclil are each C １ ~C ６ Alkyl, halogen, and OR ｓ C is optionally substituted with 1 to 4 groups selected from the above. ２ ~C ６ Alkinil, Halogen, CN, OR ｓ , -C(=O)NR ｐ R ｑ , -C (=O) OR ｓ , and -NR ｐ R ｑ 3-10 membered cycloalkyl groups optionally substituted with 1-4 groups selected from the following, Halogen, CN, OR ｓ , -C(=O)NR ｐ R ｑ , -C (=O) OR ｓ , and -NR ｐ R ｑ A 3-10 member heterocycline, optionally substituted with 1-4 groups selected from the following: -C(=O)R ｓ 、 -C(=O)OR ｓ 、 -C(=O)(C=O)OR ｓ 、 -C(=O)NR ｐ NR ｐ R ｑ 、 -C(=O)NR ｐ OR ｓ 、 -C(=O)NR ｐ R ｑ 、 -NR ｐ R ｑ 、 -NR ｐ C(=O)R ｓ [In the formula, R ｐ and R ｓ This is defined below in the claims, or NR ｐ C(=O)R ｓ of the aforementioned R ｐ and R ｓ [They combine to form a 5-10 member heterocycline] -NR ｐ２ C (=O) OR ｓ２ [In the formula, R ｐ２ and R ｓ２ This is defined in the claims below, or -NR ｐ２ C (=O) OR ｓ２ of the aforementioned R ｐ２ and R ｓ２ [They combine to form a 5-10 member heterocycline] -OR ｓ [In the formula, R ｐ and R ｑ For each occurrence, independently, hydrogen and C １ -C ６ Selected from alkyl groups, or R ｐ and R ｑ They combine to form 3-10 member heterocyclines. R ｐ and R ｑ any one of the above C １ -C6 alkyl is halogen, -NR ｐ１ C (=O) OR ｓ１ cyano, -OH, -OR ｓ１ , -O(C １ ~C ３ Alkyl) OR ｓ１ , optionally substituted with 1 to 3 groups selected from 3-10 membered cycloalkyl groups, 3-10 membered heterocyclil groups, and phenyl groups, R ｐ and R ｑ Any one of the 3- to 10-membered heterocyclyl and R ｐ and R ｑ any one of the above C １ -C ４ The 3-10 membered cycloalkyl and 3-10 membered heterocyclyl alkyls can each be optionally represented by halogen, CN, =O, or NR. ｐ１ R ｑ１ , OR ｓ１ , -NR ｐ１ C(=O)R ｓ１ , -NR ｐ１ C (=O) OR ｓ１ , 3-10 membered cycloalkyl, and C ３ -C ４ C is optionally substituted with a cycloalkyl group. １ ~C ３ It is substituted with 1 to 3 groups selected from alkyl groups. R ｓ For each occurrence, independently, hydrogen and C １ -C ６ Selected from alkyl, phenyl, 5-6 member heteroaryl, 3-10 member cycloalkyl, and 3-10 member heterocyclyl, R ｓ C １ -C ６ Alkyl, phenyl, 5-6 member heteroaryl, 3-10 membered cycloalkyls and 3-10 membered heterocyclines are each optionally selected from halogens and NRs. ｐ１ R ｑ１ , -NR ｐ１ C (=O) OR ｓ１ cyano, -OH, -O(C) １ ~C ３ Alkyl), -O (C １ ~C ３ Alkyl)OH, -O(C １ ~C ３ Alkyl)O(C １ ~C ３ Substituted with 1 to 3 groups selected from alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, and phenyl, R ｐ１ and R ｑ１ For each occurrence, independently, hydrogen and C are optionally substituted with one to three groups of halogen, CN, and OH. １ -C ４ Selected from alkyl groups, R ｓ１ For each occurrence, independently, hydrogen and C are optionally substituted with one to three groups of halogen, CN, and OH. １ -C ４ Selected from alkyl groups, R ｐ２ For each occurrence, independently, hydrogen and C are optionally substituted with one to three groups of halogen, CN, and OH. １ -C ４ Selected from alkyl groups, R ｓ２ For each occurrence, independently, hydrogen and C are optionally substituted with one to three groups of halogen, CN, and OH. １ -C ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, selected from alkyl groups.

50. R ａ が、NH ２ 、NO ２ 、=O、シアノ、I、F、Cl、Br、-CH ３ 、-CH(CH ３ ) ２ 、-CH ２ CN、-CF ３ 、-CH ２ OH、-CH ２ CH ２ OH、-C(CH ３ ) ２ OH、-CH ２ C(CH ３ ) ２ OH、-CHF ２ 、-CHCH ３ OH、-CH ２ CONH ２ 、-CH ２ COOH、-CHCH ３ NH ２ 、-CH ２ OH、-CH ２ CH ２ OH、-CH ２ N ３ 、-CH ２ NH ２ 、-CH ２ OCH ３ 、 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

51. R ａ However, for each occurrence, independently, CH ３ , CHF ２ , F, Cl, CN, NH ２ , NHCH ３ , OH, -COOMe, -COOEt, -CONH ２ , -C(=O)H, CF ３ NO ２ , 【Transformation 55】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

52. R ｂ However, for each occurrence, independently, halogen, =O, and C １ -C ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from alkyl groups according to any one of claims 1 to 4.

53. R ｂ However, for each occurrence, independently, -CH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, selected from ,=O, F, and Cl.

54. R ｃ However, for each occurrence, independently, C １ -C ３ Alkyl, CN, halogen, -OR ｓ１ , and -C(=O)OR ｓ１ Selected from, R ｓ１ However, H or C １ -C ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, which is alkyl.

55. R ｃ However, for each occurrence, independently, CH ３ ,CN,F,Cl,-OCH ３ , and -C(=O)OC(CH ３ ) ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

56. R ２ However, H, halogen, CN, OR ｓ１ , -NR ｐ１ R ｑ１ C is optionally substituted with 1 to 3 groups selected from ,=O and halogens. １ ~C ２ Selected from alkyl groups, R ｓ１ , R ｐ１ , and R ｑ１ However, independently, H and CH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4.

57. R ２ However, H, CH ３ CF ３ , CN, F, Cl, Br, OH, OCH ３ NH ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, selected from , and =O.

58. R １ and R ２ However, together, C is optionally substituted with halogens and one or two groups selected from halogens. １ ~C ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, forming a 5- to 6-membered ring optionally substituted with one or two groups selected from alkyl groups.

59. R １ and R ２ However, together, F and CH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, forming a 5-6 membered ring optionally substituted with one or two groups selected from the above.

60. L is -N(R ｘ )-,-(CH ２ ) ｕ O(CH ２ ) ｕ -, - (CH ２ ) ｕ S (=O) ｗ - (CH ２ ) ｕ -, -S(=O)(=NR ｘ )-,-(NR ｘ )S (=O) ｗ -, -S (=O) ｗ (NR ｘ )-, -C(=O)-, and C １ -C ３ Selected from alkylenes, L of C １ -C ３ Alkylenes are OH, C １ -C ３ Alkyl, and =CHR ｘ It is optionally substituted with one or two groups selected from the C of L. １ -C ３ Alkylene C １ -C ３ Alkyl groups, optionally, come together as C ３ -C ４ Forms a cycloalkyl group, R ｘ However, H and C １ -C ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, selected from alkyl groups, wherein u is independently 0 or 1 for each occurrence.

61. L, 【Transformation 56】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 60, selected from the above.

62. L, 【Chemistry 57】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 61, selected from the above.

63. The following structural formula VIe: 【Chemistry 58】 [In the formula, Q １ Q ２ , and Q ３ Each is independently selected from C and N. Y1 and Y2 are each independently selected from C and N. Z １ Z ２ , and Z ３ Each is independently selected from S, C, and N. Z4 is selected from C and N, V1 and V2 are each independently selected from C and N. L is selected from C1-C3 alkylenes optionally substituted with one or two groups selected from -O-, -N(Rx)-, -CH2-, -S-, -S(=O)-, -S(=O)2-, and C1-C2 alkyl groups. For each occurrence, Ra is independently selected from non-existence, H, and C1-C3 alkyl. R b is independently selected for each occurrence from H, F, Cl, Br, CH3, and CN. Rc is selected from F, Cl, Br, -OCH3, CH3, and CN. For each occurrence, R f is independently selected from C1-C3 alkyl and halogen. R p2 and R q2 are, independently, hydrogen, or optionally substituted C. １ -C ６ Selected from alkyls, optionally substituted 3-10 membered cycloalkyls, optionally substituted 3-10 membered heterocyclines containing 1-3 heteroatoms selected from N, O, and S, and optionally substituted 3-10 membered heteroaryls containing 1-3 heteroatoms selected from N, O, and S, p is 0, 1, or 2. q is 0, 1, or 2. However, if L is -O- or -N(Rx)-, Z4 is C, and if L is -CH2-, -S-, -S(=O)-, -S(=O)2-, or C1-C3 alkylene, Z4 is C or N. Compounds having, tautomers thereof, stereoisomers or tautomers thereof, or pharmaceutically acceptable salts thereof.

64. Z1 is S, Z2 is C, Z 3 is N, Z 4 is C, V1 and V2 are each independently selected from C and N. L is selected from -O-, -CH2-, -S(=O)-, and -S(=O)2-. When Ra is linked to Z2, it is selected from H and C1-C3 alkyl, and when Ra is linked to Z1, it is absent. R b is independently selected for each occurrence from H, F, Cl, Br, CH3, and CN. Rc is selected from F, Cl, Br, -OCH3, CH3, and CN. For each occurrence, R f is independently selected from C1-C3 alkyl and halogen. R p2 and R q2 are, independently, hydrogen and C １ -C ６ Selected from alkyl groups, p is 0 or 1, q is either 0 or 1. The compound according to claim 59, its tautomer, the stereoisomer of the compound or its tautomer, or pharmaceutically acceptable salts thereof.

65. The following structure 【Chemistry 59-1】 【Chemistry 59-2】 【Chemistry 59-3】 【Chemistry 59-4】 【Chemistry 59-5】 【Chemistry 59-6】 【Chemistry 59-7】 【Chemistry 59-8】 【Chemistry 59-9】 【Chemistry 59-10】 【Chemistry 59-11】 【Chemistry 59-12】 【Chemistry 59-13】 【Chemistry 59-14】 【Chemistry 59-15】 【Chemistry 59-16】 【Chemistry 59-17】 【Chemistry 59-18】 【Chemistry 59-19】 【Chemistry 59-20】 【Chemistry 59-21】 【Chemistry 59-22】 【Chemistry 59-23】 Compounds selected from, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts thereof.

66. The compound has the following structure 【Transformation 60】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, selected from the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts thereof described in claim 55.

67. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and 63 to 66, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

68. A pharmaceutical composition for use in the treatment of a disease or condition, comprising a compound, tautomer, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition, comprising a compound, tautomer, solvate or stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 4 and 63 to 66, a tautomer thereof, a solvate or stereoisomer, or pharmaceutically acceptable salt thereof, as described in any one of claims 1 to 4 and 63 to 66, and at least one pharmaceutically acceptable carrier, wherein the disease or condition is selected from inflammatory diseases, immune diseases, allergic diseases, graft rejection, necrotizing cell diseases, neurodegenerative diseases, central nervous system (CNS) diseases, ischemic brain injury, eye diseases, infectious diseases, and malignant tumors.

69. The compound, tautomer, solvate, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition according to claim 68, wherein the disease or condition is mediated by receptor interacting protein 1 (RIP1) signaling.

70. A pharmaceutical composition for treating a disease or condition mediated by receptor interacting protein 1 (RIP1) signaling, comprising: a compound according to any one of claims 1 to 4 and 63 to 66; a tautomer thereof; a solvate or stereoisomer of the compound or the tautomer thereof; or a pharmaceutically acceptable salt thereof; or a compound according to any one of claims 1 to 4 and 63 to 66; a tautomer thereof; a solvate or stereoisomer of the compound or the tautomer thereof; or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.

71. The compound, tautomer, solvate, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition according to claim 70, wherein the disease or condition is selected from ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and viral infection.

72. A method for inhibiting receptor interacting protein 1 (RIP1), comprising contacting RIP1 or a fragment thereof with a pharmaceutical composition comprising: a compound according to any one of claims 1 to 4 and 63 to 66, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof; or a compound according to any one of claims 1 to 4 and 63 to 66, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof; and at least one pharmaceutically acceptable carrier.

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