SARM1 modulator, its preparation, and use

Abstract

This disclosure provides compounds of formula 1, compositions comprising the same, and methods of using the same, including the modification of SARM1 and its use in the treatment of various diseases and conditions, such as diseases and conditions caused by or associated with axonal degeneration. JPEG2026514952000328.jpg68128

Description

[Technical Field]

[0001] Related applications This application claims priority to international application PCT / CN2023 / 091176, filed on 27 April 2023, the contents of which are incorporated in their entirety by reference.

[0002] Technical field This disclosure relates to compounds that modulate SARM1, compositions comprising such compounds, methods for preparing such compounds, and methods for using such compounds to treat various diseases or conditions, such as diseases or conditions caused by or associated with axonal degeneration. [Background technology]

[0003] Axonal degeneration causes disease progression and accumulation of disability, or acute conditions such as traumatic brain injury, in many degenerative diseases of the peripheral nervous system (PNS) and central nervous system (CNS), including multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). (Hughes 2021 (R. Hughes et al., Small Molecule SARM1 Inhibitors Recapitulate the SARM1- / -Phenotype and Allow Recovery of a Metastable Pool of Axon Fated to Degenerate, Cell Rep. 2021 Jan 5;34(1):108588); Bosanac 2021 (T. Bosanac et al., Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy, Brain, Vol.144, Issue 10, 2021, pages 3226-3238)). Therefore, axonal protection is an important neuroprotective approach to the treatment of chronic and acute neurodegenerative disorders of the CNS and PNS. (Hughes 2021; Bosanac 2021).

[0004] SARM1 (Sterile Alpha and TIR Motif-containing 1) is an intrinsic member of the Myd88 family of adapter proteins and is considered a key driver of evolutionarily conserved programs of axonal degeneration downstream of chemical, inflammatory, mechanical, or metabolic injury to axons (Hughes 2021; Bosanac 2021). SARM1 is recognized as a central mediator of axonal degeneration in numerous diseases or conditions, including ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, and diabetic neuropathy, as well as chemotherapy-induced peripheral neuropathy (CIPN), which is a major cause of disease and a major cause of dose reduction and discontinuation in cancer treatment (Hughes 2021; Bosanac 2021). SARM1 is a promising target for treating neurodegeneration characterized by axonal damage in the peripheral and central nervous systems.

[0005] SARM1 contains a mitochondrial targeting sequence, an N-terminal domain with an armadillo repeat (ARM), two sterilyl α-motif (SAM) domains, and a Toll / interleukin-1 receptor (TIR) ​​domain (Gerdts 2013 (J. Gerdts et al., Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci. 2013 Aug 14;33(33):13569-80)). The TIR domain of SARM1 is NAD + It is a hydrolase (NADase), which is NAD +It converts to ADPR or cADPR and NAM (Sporny 2019 (M. Sporny et al., Structural Evidence for an Octameric Ring Arrangement of SARM1. J Mol Biol., 2019 Sep 6;431(19):3591-3605)). This NADase activity is essential for its axonal degeneration function (Bosanac 2021). SARM1 activity is also dependent on oligomerization formed via the SAM domain (Sporny 2019) and is autoinhibited by the ARM domain (Chen (2021) (C. Shen et al., Multiple domain interfaces mediate SARM1 autoinhibition. Proc Natl Acad Sci US A. 2021 Jan 26;118-4)).

[0006] Specific SARM1 inhibitors are disclosed in Bosanac 2021, Hughes 2021, Sporny 2020 (M. Sporny et al, Structural basis for SARM1 inhibition and activation under energetic stress. Elife. 2020 Nov 13;9:e62021.doi:10.7554 / eLife.62021.PMID:33185189;PMCID:PMC7688312.), International Publication No. 2018 / 057989(A1), International Publication No. 2020 / 081923(A1), International Publication No. 2021 / 142006(Al), International Publication No. 2021207302(A1), and International Publication No. 2021207308(A1). Certain dipeptidyl peptidase inhibitors (e.g., biphenyl or phenylbenzimidazole derivatives) are disclosed in U.S. Patent Application Publication 2005 / 0272765(A1). Certain benzylbenzoxazole derivatives as Met kinase inhibitors are disclosed in International Publication 2008 / 148449(A1). Certain dihydroisoquinolinone derivatives and their combinatorial library are described in International Publication 01 / 14879. Certain compositions for promoting read-through of immature stop codons and methods for using the same are described in International Publication 2017 / 049409. Certain nitrogen-containing heterocyclyl cyclic compounds having nematodic properties, their preparation and use are described in CN108276352.

[0007] This disclosure describes SARM1 inhibitors that can be used to prevent axonal degeneration in peripheral and central axonal disorders and to provide innovative disease-modifying therapies for related diseases or conditions. [Overview of the Initiative]

[0008] One aspect of this disclosure is the formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3 disclosed herein. This specification provides compounds selected from the compounds 12-4, 12-5, 12-6, 12-7, and 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts thereof, which may be used in the treatment of various diseases or conditions, such as diseases or conditions caused by or associated with axonal degeneration. For example, this specification provides the following structural formula 1: [ka] [In the formula, X1, X2, X3, X4, and X5 are each independently either C or N. Y1 is C or N, Y2 is C or N, and Y1 and Y2 are two adjacent ring atoms on ring B. Ring B is a phenyl, a 5-6 membered heteroaryl, a 3-6 membered cycloalkyl, or a 4-6 membered heterocyclyl, where the 5-6 membered heteroaryl or 4-7 membered heterocyclyl of ring B contains 1-4 heteroatoms selected from N, O, and S. Ring C is a phenyl molecule, a 3-10 membered cycloalkyl group, a 4-10 membered heterocycline, a 5-6 membered heteroaryl group, or a 9-10 membered heteroaryl group, where the 4-10 membered heterocycline, 5-6 membered heteroaryl group, or 9-10 membered heteroaryl group of ring C contains 1-3 heteroatoms selected from N, S, and O. R 1 H, halogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, -CN, -OH, -COOH, -C(=O)NH2, -OR m -S(=O) p (C1-C4 alkyl), -NR m Rn 、 -C(=O)R n 、 -C(=O)OR m 、 -C(=O)NR m R n 、 -P(=O)R m R n 、 -SF5、 A 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, A 3- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and Selected from 3- to 10-membered cycloalkyl, R 1 The C1-C8 alkyl, C1-C8 alkenyl, or 1-C8 alkynyl of is optionally substituted with 1 to 3 groups selected from halogen, -OH, -OR m 、 -CN, -NH2, -NR m R n 、 -C(=O)OCH3, -O(C1-C6 alkyl), -COOH, -C(=O)NH2, phenyl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl (optionally substituted with 1 to 3 groups selected from OH and halogen), and is optionally substituted with 1 to 3 groups selected from R 1 The 5- to 6-membered heteroaryl of is D, halogen, -OH, -CN, -COOH, -(C1-C6 alkyl)OH, -C(=O)O(C1-C6 alkyl), =O, -NH2, -C(=O)NR m R n 、 5- to 6-membered heteroaryl, -OR m 、 R m 、 C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from halogen, -C(=O)NH2, R m 、 and OR m ), and is optionally substituted with 1 to 3 groups selected from R 1 The 3- to 10-membered heterocyclyl of is D, halogen, -OH, -CN, -COOH, -(C1-C6 alkyl)OH, -C(=O)O(C1-C6 alkyl), =O, -NH2, -C(=O)NR m Rn , 5-6 member heteroaryl, -OR m , R m , C1-C6 alkyl(halogen, -C(=O)NH2, R m , and OR m (Selected from, and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are selected from, R 1 3-10 member cycloalkyl groups include D, halogen, -OH, -CN, -COOH, -(C1-C6alkyl)OH, -C(=O)O(C1-C6alkyl), =O, -NH2, and -C(=O)NR m R n , 5-6 member heteroaryl, -OR m , R m , C1-C6 alkyl(halogen, -C(=O)NH2, R m , and OR m (Selected from, and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are selected from, R m and R n For each occurrence, independently, H, C1-C6 alkyl, and -S (=O) p Selected from (C1-C4 alkyl), phenyl, 3-8 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, R m The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from D, -C(=O)NH2, -OH, -OMe, -S(=O)2CH3, and halogens. R 2 H, halogen, C1-C6 alkyl, C1-C6 alkenyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkyl)O(C1-C6 alkyl), -C(=O)NH2, -S(=O) p Selected from (C1-C4 alkyl), -CN, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-10 membered heterocyclyl (containing 1-3 heteroatoms independently selected from S, O, and N), R 2The C1-C6 alkyl or C1-C6 alkenyl is optionally substituted with 1 to 3 groups selected from halogens, CN, and -C(=O)O(C1-C6 alkyl). R 2 The 3-5 membered cycloalkyl group is optionally substituted with 1-3 groups selected from OH, CN, and halogens. R 2 The C1-C6 alkyl group of -O(C1-C6 alkyl) is optionally substituted with 1 to 3 groups selected from halogens and CN. R 2 The 3-10 member heterocyclyl is optionally substituted with 1-3 groups selected from OH, CN, and halogens, or R 1 and R 2 is combined [ka] Forming, R 3 and R 4 Each of these is independently selected from H, halogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from OH and halogen), and -O(C1-C6 alkyl), R 5 is absent, H, -CN, halogen, -C(=O)NH2, -S(=O)p(C1-C4 alkyl), -OR p Selected from phenyl, 5-6 membered heteroaryls, 4-6 membered heterocyclines, 3-8 membered cycloalkyls, and C1-C6 alkyls, R 5 The C1-C6 alkyl group is OH, -NHR p , -OR p , and are optionally substituted with 1 to 3 groups selected from -S(=O)p(C1-C4 alkyl), R 5 The 4-6 membered heterocyclyl is substituted with 1-3 groups selected from C1-C3 alkyl, CN, halogen, and =O. R 5The 3-8 member cycloalkyl group is optionally substituted with 1-3 groups selected from C1-C3 alkyl, CN, and halogens. R p R is selected from C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, and 5-6 membered heteroaryl groups. p The C1-C6 alkyl, 3-6 membered cycloalkyl, or 5-6 membered heteroaryl groups are optionally substituted with 1-3 groups selected from CN, OH, and halogens. R 6 For each occurrence, independently, D, halogen, -CN, =O, -OR s -SH, -S(C1-C4 alkyl), -S(=O) p R t -C(=O)NR t R o , -NR t R o Selected from 4-6 member heterocyclyls and C1-C6 alkyl groups, R 6 C1-C6 alkyl groups are halogens, -OR s , =O, -S(=O) p R t , -NHS(=O) p R t -S(=O)(=NH)R t , [ka] -NHS(=O) p (C1-C4 alkyl), -CN, -C(=O)NR t R o , -NR t R o , halogens, 5-6 member heteroaryls, 3-6 member cycloalkyls (halogens, OH, and R t (Optionally substituted with 1 to 3 groups selected from), as well as halogens, OH, and R t Selected from 4-10 member heterocyclines, which are optionally substituted with 1-3 groups selected from, R 6The 4- to 8-membered heterocyclyl of C1-C6 alkyl is optionally substituted with 1 to 3 groups selected from halogen, OH, C1-C3 alkyl, and =O. R s is selected from H, C1-C6 alkyl, 4- to 6-membered heterocyclyl, and 3- to 6-membered cycloalkyl. R s The C1-C6 alkyl of is optionally substituted with 1 to 3 groups selected from -OH, -OMe, and halogen. R s The 3- to 6-membered cycloalkyl of is optionally substituted with -OH or -OMe. R t And R o are each independently selected, for each occurrence, from H, C1-C6 alkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclyl, and 3- to 5-membered cycloalkyl. R t And R o The C1-C6 alkyl of is optionally substituted with 1 to 3 groups selected from D, halogen, -OH, CN, C(=O)NH2, -O(C1-C3 alkyl), and -S(=O)2CH3. R 7 is, for each occurrence, independently D, halogen, -OR a , -CN, -CONH2, -C(=O)NR b R c , NR b R c , -C(=O)OR b , =O, =S, -P(=O)2R b R c , -S(=O) p (C1-C4 alkyl), -O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl. R 7 The C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl of is halogen, -OH, CN, -S(=O) pIt is optionally substituted with 1 to 3 groups selected from (C1-C4 alkyl), -C(=O)2NH2, and 3- to 6-membered heterocyclines. R 7 The 4-6 member heterocyclyls are =O, halogen, and R b It is optionally replaced by 1 to 3 elements selected from the following: R a R is selected from H, C1-C8 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl. a The C1-C8 alkyl group consists of D, halogen, OH, CN, and -S (=O). p It is optionally substituted with 1 to 4 groups selected from (C1-C4 alkyl), -C(=O)NH2, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl. R b and R c For each occurrence, each is independently selected from H, C1-C8 alkyl, 4-6 member heterocyclyl, phenyl, 5-6 member heteroaryl, and 3-6 member cycloalkyl, R b and R c The C1-C8 alkyl groups are optionally substituted with 1-3 groups selected from D, halogen, OH, -C(=O)NH2, CN, -OCH3, and -S(=O)2CH3. m is an integer selected from 0, 1, and 2. n is an integer selected from 0, 1, 2, 3, and 4. Compounds of p, tautomers thereof, solvates or stereoisomers of said compound or tautomer, or pharmaceutically acceptable salts thereof are disclosed.

[0009] In one aspect of this disclosure, the compounds of the formulas disclosed herein are selected from compounds 1 to 468 shown in Table 1, their tautomers, solvates or stereoisomers of the compounds or their tautomers, or pharmaceutically acceptable salts thereof.

[0010] In some embodiments, this disclosure relates to formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11 The present invention provides a pharmaceutical composition comprising a compound of -5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition may comprise a compound selected from compounds 1 to 468 shown below, its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. These compositions may further comprise additional active pharmaceutical ingredients.

[0011] Another aspect of the present disclosure is a method for treating a disease or condition, to a subject in need thereof, a therapeutically effective amount of a compound of formula 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 disclosed herein (e.g., compounds 1 to 468), its tautomers, the compound The present invention provides a method comprising administering a compound or a solvate or stereoisomer of the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, the tautomer, the solvate, the stereoisomer, and the pharmaceutically acceptable salt thereof, wherein the disease or condition is a demyelinating disease such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinsonian syndrome, ischemia, stroke, herpes infection, multiple sclerosis, traumatic brain injury, sepsis, chronic diseases of PNS including hereditary neuropathy, for example, but not limited to Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (chronic The treatment is selected from peripheral neuropathy such as inflammatory demyelinating polyneuropathy (CIDP), optic neuropathy, such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or disorders, such as diabetic neuropathy, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and CIPN induced by various drugs.

[0012] Further aspects of this disclosure relate to a method for treating a disease or condition caused by or associated with axonal degeneration or nerve damage mediated by SARM1, wherein the therapeutically effective amount of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 1 The present invention provides a method comprising administering a pharmaceutical composition comprising one of the compounds 1-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (for example, compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, or any of the compound, its tautomer, its solvate, its stereoisomer, and a pharmaceutically acceptable salt.

[0013] In some embodiments, a therapeutic method involves administering to a subject in need a compound selected from the following compounds 1 to 468, its tautomers, solvates or stereoisomers of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, its tautomer, its solvate, its stereoisomer, and / or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the treatment method applies to a subject requiring it using formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, The treatment method includes administering an additional active pharmaceutical agent in the same pharmaceutical composition as, or in a separate composition from, a compound of 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof. In some embodiments, the treatment method includes administering a compound selected from compounds 1 to 468 shown below, its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, together with an additional active pharmaceutical agent in the same pharmaceutical composition as, or in a separate composition from, a compound of 1 to 468 shown below, its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof. When administered as a separate composition, the additional therapeutic agent may be administered before, simultaneously with, or after the administration of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts disclosed herein.

[0015] Furthermore, this specification provides a method for modifying, for example inhibiting, SARM1 in a target as needed, wherein the target is subjected to an effective amount of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 1 Methods are disclosed that involve contacting a compound selected from compounds 1-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (e.g., compounds 1-468), its tautomers, solvates or stereoisomers of the compound or its tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing any of the compound, its tautomer, its solvate, its stereoisomer, and any of the pharmaceutically acceptable salts. In some embodiments, a method for modulating, for example inhibiting, SARM1 in a subject as needed involves contacting the subject with an effective amount of a compound selected from the following compounds 1-468, its tautomers, solvates or stereoisomers of the compound or its tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition containing any of the compound, its tautomer, its solvate, its stereoisomer, and any of the pharmaceutically acceptable salts.

[0016] Furthermore, this specification provides a method for inhibiting or preventing axonal degeneration in a target subject, wherein the target is subjected to an effective amount of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, A method is disclosed that involves contacting a compound of 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (for example, compound 1 to 468), its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition containing any of the compound, its tautomer, its solvate, its stereoisomer, or a pharmaceutically acceptable salt. In some embodiments, a method for inhibiting or preventing SARM1-mediated axonal degeneration or nerve damage in a subject where required includes contacting the subject with a compound selected from the following compounds 1 to 468, its tautomers, solvates or stereoisomers of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any of the compound, its tautomer, its solvate, its stereoisomer, and a pharmaceutically acceptable salt. [Modes for carrying out the invention]

[0017] I. Definition The terms "a" or "an," when used herein to refer to nouns, encompass the expression "at least one" and therefore include both singular and plural units of the noun. For example, "additional medicines" means one or more additional medicines.

[0018] The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups containing 1 to 20 carbon atoms, for example, 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 carbon atoms, preferably 1 to 6, more preferably 1 to 4, and more preferably 1 to 3 carbon atoms.

[0019] The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 20 carbon atoms, for example, 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4. Examples of alkenyl groups include ethenyl or vinyl, propa-1-enyl, propa-2-enyl, 2-methylpropa-1-enyl, buta-1-enyl, buta-2-enyl, buta-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, hexa-1-enyl, hexa-2-enyl, hexa-3-enyl, hexa-4-enyl, and hexa-1,3-dienyl. Lower alkenyls contain 2 to 8 carbon atoms, preferably 2 to 6, more preferably 2 to 4.

[0020] The term "alkynyl" means at least one [ka] This refers to hydrocarbon groups selected from linear and branched hydrocarbon groups that contain a triple bond and 2 to 20 carbon atoms, for example, 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups. Lower alkynyls contain 2 to 8 carbon atoms, preferably 2 to 6, and more preferably 2 to 4.

[0021] The term "heteroalkyl" refers to alkyl groups as defined herein, in which one or more of the constituent carbon atoms are replaced by heteroatoms, such as nitrogen, oxygen, or sulfur, e.g., CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5, etc. In some embodiments, in addition to the substitution of one or more constituent carbon atoms with nitrogen, oxygen, or sulfur, the heteroalkyl groups are further optionally substituted as defined herein.

[0022] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, such as monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group may have 3 to 12, 3 to 10, 3 to 8, 3 to 6, 3 to 4, or 5 to 6 carbon atoms. Furthermore, for example, a cycloalkyl group may be a monocyclic group with 3 to 12, 3 to 8, 3 to 6, 3 to 4, or 5 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopenta-1-enyl, 1-cyclopenta-2-enyl, 1-cyclopenta-3-enyl, cyclohexyl, 1-cyclohexa-1-enyl, 1-cyclohexa-2-enyl, 1-cyclohexa-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a bicyclic ring selected from the [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 an aromatic ring like the “aromatic ring” as defined herein.

[0023] The terms “heterocyclic,” “heterocyclyl ring,” or “heterocyclyl” refer to rings selected from 3- to 12 membered rings, e.g., 3- to 6 membered, 3- to 5 membered, 4- to 5 membered, or 5- to 6 membered monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated rings, containing at least one carbon atom in addition to one, two, three, or four heteroatoms selected from oxygen, sulfur, nitrogen, and silicon. “Heterocyclyl ring” also refers to a 5- to 7 membered heterocyclyl ring containing at least one heteroatom selected from N, O, and S, condensed with a 5-, 6-, and / or 7-membered cycloalkyl ring, an aromatic carbocyl ring, or a heteroaromatic ring, provided that when the heterocyclyl ring is condensed with an aromatic carbocyl ring or a heteroaromatic ring, the bond site is on the heterocyclyl ring; and when the heterocyclyl ring is condensed with a cycloalkyl ring, the bond site may be on the cycloalkyl ring or the heterocyclyl ring.

[0024] A "heterocyclyl ring" also refers to an aliphatic spiro ring containing at least one heteroatom selected from N, O, and S, wherein the bonding site is located in the heterocyclyl ring. The ring may be saturated or may have at least one double bond (i.e., partially unsaturated). The heterocyclyl ring may be substituted with an oxo. The bonding site may be a carbon or heteroatom in the heterocyclyl ring. A heterocyclyl ring is not a heteroaryl as defined herein.

[0025] Examples of heterocyclyl rings include (numbered from the linking position assigned priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranil, 2-morpholinyl, 3-morpholinyl, oxyranil, azilidinyl, thyranil, azetidi Nyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanil, piperazinyl, homopiperazinyl, homopiperidinyl, azepanil, oxepanil, thiepanil, 1,4-oxathianil, 1,4-dioxepanil, 1,4-oxathiepanil, 1,4-oxazepanil, 1,4-dithiepani L, 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, Examples of substituted heterocyclyl rings include, but are not limited to, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabisco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocyclyl rings 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.

[0026] In this specification, the term “condensed ring” refers to a polycyclic ring system, such as a bicyclic or tricyclic ring system, in which two rings share only two common ring atoms and one bond. Examples of condensed rings include condensed bicyclic cycloalkyl rings having 7 to 12 ring atoms arranged as a bicyclic ring selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems described above; condensed bicyclic aryl rings, such as the 7 to 12-membered bicyclic aryl ring system described above; condensed tricyclic aryl rings, such as the 10 to 15-membered tricyclic aryl ring system described above; condensed bicyclic heteroaryl rings, such as the 8 to 12-membered bicyclic heteroaryl ring described above; condensed tricyclic heteroaryl rings, such as the 11 to 14-membered tricyclic heteroaryl ring described above; and the condensed bicyclic or tricyclic heterocyclyl ring described above.

[0027] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, and silicon, including all oxidation forms of nitrogen or sulfur, all basic nitrogen or quaternary forms of a heterocyclyl ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + [The R in the formula includes, for example, an optionally substituted alkyl group (as in N-substituted pyrrolidinyl).

[0028] As used herein, the term “unsaturated” means that a part of a compound has one or more unsaturated units or degrees of unsaturation. Unsaturation is a state in which not all available valence bonds in a compound are filled by substituents, and therefore the compound contains one or more double or triple bonds. Double bonds are, [ka] This can be represented as (two solid lines). [ka] The depictions (solid and dashed lines) indicate bonds that may be double or single bonds, as used herein.

[0029] As used herein, the term "alkoxy" refers to an alkyl group as defined above, wherein one carbon atom of the alkyl group is replaced by an oxygen atom, but the oxygen atom is bonded between two carbon atoms.

[0030] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodine, respectively.

[0031] As used herein, the "CN", "cyano", or "nitrile" group is defined as [ka] It refers to.

[0032] As used herein, “aromatic ring” refers to a carbocyclyl or heterocyclyl ring containing a conjugated planar ring system having a delocalized π-electron orbital composed of [4n+2]p orbital electrons where n is an integer from 0 to 6. “Non-aromatic” ring refers to a carbocyclyl or heterocyclyl ring that does not satisfy the requirements for an aromatic ring as described above, and may be fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined as follows: “Aromatic ring” refers to, [ka] It can also be depicted as a ring having a conjugated double bond, and [ka] It may also be depicted as a ring with a circle inside, as shown.

[0033] The term "aryl" as used herein refers to a group selected from monocyclic aromatic carbocyclyl rings, bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered, where at least one ring is a carbocyclyl ring and an aromatic ring, selected from monocyclic aromatic carbocyclyl rings, e.g., phenyl, e.g., naphthalene, indan, and 1,2,3,4-tetrahydroquinoline, as well as tricyclic ring systems such as 10-15 membered, tricyclic ring systems such as fluorene, where at least one ring is a carbocyclyl ring and an aromatic ring.

[0034] For example, an aryl group may be a 6-membered aromatic carbocylic ring fused to a 5-7 membered cycloalkyl ring or heterocyclyl ring, which optionally contains at least one heteroatom selected from N, O, and S, provided that when the aromatic carbocylic ring is fused to a heterocyclyl ring, the bond site is on the aromatic carbocylic ring, and when the aromatic carbocylic ring is fused to a cycloalkyl group, the bond site may be on the aromatic carbocylic ring or the cycloalkyl group. A divalent group formed from a substituted benzene derivative and having free valence on the ring atom is called a substituted phenylene group. Divalent groups derived from monovalent polycyclic hydrocarbon groups whose names end in "-yl" by removing one hydrogen atom from a carbon atom with free valence are named by adding "-idene" to the name of the corresponding monovalent group; for example, a naphthyl group with two bond sites is called naphthylidene.

[0035] The term "heteroaryl" refers to a group selected from a 5-7 membered monocyclic aromatic ring, e.g., a 5-6 membered ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; an 8-12 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 an aromatic ring, and at least one heteroatom residing in the aromatic ring; and an 11-14 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 an aromatic ring, and at least one heteroatom residing in the aromatic ring.

[0036] For example, the heteroaryl group may be a 5-7 membered heteroaromatic ring fused to a 5-7 membered cycloalkyl ring. In such a fused bicyclic heteroaryl ring system, if only one of the rings contains at least one heteroatom, the bonding site may be either a heteroaromatic ring or a cycloalkyl ring.

[0037] If the total number of S and O atoms in the heteroaryl group is greater than 1, those heteroatoms are not adjacent to each other. 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.

[0038] Examples of heteroaryl groups include (as numbered from the linking position assigned priority 1) pyridyl (2-pyridyl, 3-pyridyl, or 4-pyridyl, etc.), synnolinyl, 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, pyridadinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (1H-pyrrolo[2,3-b]pyridinyl, etc.), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b Examples include, but are not limited to, benzoxazolyl (such as benzo[d]thiazolyl-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, flazanil, benzoflazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinil, quinoxalinil, naphthilidinyl, phlopyridinil, benzothiazolyl (such as benzo[d]thiazolyl-6-yl), indazolyl (such as 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinolinil.

[0039] The term "acyl" refers to a substituent whose bond site is a carbonyl group. 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 by one or more substituents.

[0040] Some compounds exhibit different hydrogen bond sites, known as "tautomers." For example, compounds containing a carbonyl-CH2C(O)- group (keto form) can tautomerize to form a hydroxyl-CH=C(OH)- group (enol form). Both keto and enol forms are intended to be included, either individually or in mixtures, where applicable. For example, [ka] teeth, [ka] This is thought to be a tautomer form of [the plant].

[0041] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the Disclosure may contain chiral centers and therefore may exist as enantiomers. For example, if a compound has two or more chiral centers, they may further exist as diastereoisomers. Enantiomers and diastereoisomers are included in a broader class of stereoisomers. All such possible stereoisomers, such as substantially pure divided enantiomers, racemic mixtures thereof, and mixtures of diastereoisomers, are intended to be included in the Disclosure. All stereoisomers of the compounds, their tautomers, solvates, and pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomer composition is not specified, all possible isomers are included.

[0042] Diastereomer mixtures can be separated into individual diastereoisomers based on their physicochemical differences by methods known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomer mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Moscher acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers back into their corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by the use of a chiral HPLC column.

[0043] A single stereoisomer, for example, a substantially pure enantiomer, can be obtained by the separation of a racemic mixture using methods such as the formation of diastereoisomers with an optically active resolving agent. Racemic mixtures of chiral compounds of the present disclosure can be separated and isolated by any preferred method, including (1) the formation of ionic diastereomer salts by the chiral compound and separation by fractional crystallization or other methods, (2) the formation of diastereomer compounds, separation of diastereoisomers and conversion to pure stereoisomers with a chiral derivatizing reagent, and (3) the direct separation of substantially pure or concentrated stereoisomers under chiral conditions.

[0044] In this disclosure, a particular single stereoisomer, for example, a substantially pure enantiomer, is separated from each other, for example, by chiral separation. However, the absolute configuration of a particular separated single stereoisomer is not currently known. For example, the compounds of Examples 186 and 187 are synthesized and separated by chiral separation, and the compounds are shown as a "single unknown stereoisomer". As a further example, the compounds of Examples 433 and 434 are synthesized and separated by chiral separation, and the compounds are shown as a "single unknown enantiomer", with the stereocenter shown as "or 1".

[0045] In the context of stereoisomers, the term "substantially pure" means that the target stereoisomer contains any other stereoisomer in amounts of 35% by weight or less, for example, 30% by weight or less, further for example, 25% by weight or less, and even further for example, 20% by weight or less. In some embodiments, the term "substantially pure" means that the target stereoisomer contains any other stereoisomer in amounts of 10% by weight or less, for example, 5% by weight or less, and further for example, 1% by weight or less.

[0046] Unless otherwise specified, the structures shown herein include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and geometric (or conformational) isomers such as (Z) and (E) conformational isomers. Accordingly, geometric and conformational mixtures of the compounds disclosed herein are within the scope of this disclosure. Unless otherwise specified, all tautomeric forms of the compounds disclosed herein are within the scope of this disclosure.

[0047] This disclosure provides pharmaceutically acceptable salts of disclosed compounds, tautomers, solvates, and stereoisomers. Salts of compounds are 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.

[0048] As used herein, the term “pharmaceutically acceptable” means a component that, within the bounds of sound medical judgment, is suitable for use in contact with human and other mammalian tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that is commensurate with a reasonable benefit / risk ratio. “pharmaceutically acceptable salt” means any non-toxic salt that can provide the compounds of this disclosure, either directly or indirectly, at the time of administration to a recipient.

[0049] Examples of "pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids selected from hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, and nitrate, as well as salts with organic acids selected from alkanates such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and acetate, and salts with HOOC-(CH2)n-COOH selected from n in the formula from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, magnesium, aluminum, lithium, and ammonium. Preferred pharmaceutically acceptable salts are disclosed, for example, in SMBerge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1-19.

[0050] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as 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. Therefore, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, hydrochlorides, hydrobroms, hydroiodides, acetates, propions, decanoates (i.e., caprinates), caprylates, acrylates, formates, isobutyrates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-diates. Examples of salts include hexyn-1,6-diates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed using mineral acids such as hydrochloric acid and hydrobromic acid, and those formed using organic acids such as maleic acid.

[0051] Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Examples include alkyl)4 salts. This disclosure also assumes quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Preferred non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, and magnesium salts. Further non-limiting examples of pharmaceutically acceptable salts include salts of ammonium, quaternary ammonium, and amine cations formed with counterions, such as halide salts, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfons, and aryl sulfons. Other preferred non-limiting examples of pharmaceutically acceptable salts include besylates and glucosamine salts.

[0052] When a compound is obtained as an acid addition salt, the free base can be obtained by basicizing the solution of the acid addition salt. Conversely, when 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 excessive experimentation to prepare non-toxic, pharmaceutically acceptable addition salts.

[0053] The compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts of the Disclosure may also contain atomic isotopes of one or more atoms constituting such compounds in proportions different from those of nature. For example, -CD3, -CD2H, or -CDH2 may contain one or more deuterium atoms instead of hydrogen. For example, the compounds may contain radioactive isotopes, such as tritium. 3 H), Iodine-125( 125 I) or carbon-14 ( 14 It can be radioactively labeled with C). All isotopic variants of the compounds of this disclosure, whether radioactive or not, are intended to be included within the scope of this disclosure.

[0054] As used herein, “optionally substituted” is interchangeable with the phrase “substituted or unsubstituted.” Generally, the term “substituted” refers to replacing a hydrogen radical in a given structure with a radical of a particular substituent. Unless otherwise specified, an “optionally substituted” group may have substituents at each of its substituted positions, and if two or more positions in any given structure may be substituted with two or more substituents selected from a particular group, those substituents may be the same or different at all positions.

[0055] The chemical components envisioned in this disclosure, such as substituents, ring structures, linkers, and / or heteroatom combinations, form stable or chemically feasible compounds.

[0056] In some embodiments, the substituents are optionally substituted heteroatoms and optionally substituted, optionally hetero-, optionally cyclic C1-C atoms. 18 Independently selected from hydrocarbyl, and in particular, optionally substituted, optionally hetero-, optionally cyclic C1-C 18 Hydrocarbyl is optionally substituted, optionally hetero-, optionally cyclic alkyl, alkenyl or alkynyl, or optionally substituted, optionally hetero-, optionally aryl, and / or optionally substituted heteroatoms are halogens, optionally substituted hydroxyls (alkoxy, aryloxy, etc.), optionally substituted acyls (formyl, alkanoyl, carbamoyl, carboxyl, amide, etc.), optionally substituted aminos (amino, alkylamino, dialkylamino, amide, sulfamidyl, etc.), optionally substituted thiols (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyls (alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, etc.), nitro, or cyano.

[0057] In some embodiments, substituents are independently in numbers ranging from 0 to 3, including halogens, -R', -OR', =O, =NR', =N-OR', -NR'R'', -SR', -SiR'R''R''', -OC(=O)R', -C(=O)R', -CO2R', -C(=O)NR'R'', -OC(=O)NR'R'', -NR''C(=O)R', -NR'-C(=O)NR''R''', and -NR'-SO2NR''R Groups selected from ''', -NR''CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'R'', -NR''SO2R', -CN, -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, having 0, 1, or 2 substituents are particularly preferred. R', R'', and R''' each independently refer to hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl groups, C1-C8 alkyl and heteroalkyl groups substituted with 1 to 3 halogens, unsubstituted aryl groups, aryl groups substituted with 1 to 3 halogens, unsubstituted alkyl groups, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When R' and R'' are bonded to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-membered, 6-membered, 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".

[0058] In some embodiments, the substituents are selected from halogens, -R', -OR', =O, -NR'R'', -SR', -SiR'R''R''', -OC(=O)R', -C(=O)R', -CO2R', -C(=O)NR'R'', -OC(=O)NR'R'', -NR''C(=O)R', -NR''CO2R', -NR'-SO2NR''R''', -S(=O)R', -SO2R', -SO2NR'R'', -NR''SO2R', -CN, -NO2, perfluoroC1-C4 alkoxy, and perfluoroC1-C4 alkyl, where R' and R'' are as defined above.

[0059] In some embodiments, the substituents are independently a substituted or unsubstituted heteroatom, a substituted or unsubstituted C1-C6 alkyl (e.g., C1-C3 alkyl or C1-C2 alkyl) containing 0 to 3 heteroatoms, a substituted or unsubstituted C2-C6 alkenyl (e.g., C2-C4 alkenyl) containing 0 to 3 heteroatoms, a substituted or unsubstituted C2-C6 alkynyl (e.g., C2-C4 alkynyl) containing 0 to 3 heteroatoms, or a substituted or unsubstituted C5-C 14 Selected from aryl groups (e.g., C5-C6 aryl groups), each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0060] In some embodiments, the substituents are independently selected from aldehyde groups, aldimine groups, alkanoyloxy groups, alkoxy groups, alkoxycarbonyl groups, alkyloxy groups, alkyl groups, alkenyl groups, alkynyl groups, amine groups, azo groups, halogen groups, carbamoyl groups, carbonyl groups, carboxamide groups, carboxyl groups, cyanyl groups, ester groups, haloformyl groups, hydroperoxyl groups, hydroxyl groups, imine groups, isocyanide groups, isocyanate groups, N-tert-butoxycarbonyl groups, nitrate bases, nitrile groups, nitrite bases, nitro groups, nitroso groups, phosphate bases, phosphono groups, sulfide groups, sulfonyl groups, sulfo groups, sulfhydryl groups, thiol groups, thiocyanyl groups, trifluoromethyl groups, and trifluoromethyl ether groups (OCF3).

[0061] In certain embodiments, substituents are represented structurally. For example, [ka] In cases where a substituent is bonded to a ring structure without having a specific position, such as in the example above, substituent R 6 If m is a positive integer, the substituent R may be attached to any chemically feasible position on ring B, regardless of whether ring B is monocyclic or polycyclic, and 7 If n is a positive integer, it may be bonded to any chemically feasible position on the five-membered ring C.

[0062] Preferred substituents are disclosed herein and illustrated in the tables, structures, examples, and claims, and may be applied across the various compounds of this disclosure. For example, substituents of a given compound may be used in combination with other compounds.

[0063] It may be beneficial to separate reaction products from each other and / or from the starting materials. The target products of each step or series of steps are separated and / or purified (hereinafter referred to as "separation") to the desired degree of homogeneity by techniques common in the art. Typically, such separations include multi-stage extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography includes many methods and apparatus, such as reversed-phase and normal-phase, size exclusion, ion exchange, high-pressure, medium-pressure and low-pressure liquid chromatography, small-scale analysis, simulated moving bed ("SMB") and preparative thin-layer or preparative thick-layer chromatography, as well as techniques for small-scale thin-layer chromatography and flash chromatography. Those skilled in the art can apply such techniques to achieve the desired separation.

[0064] Non-limiting examples of preferred solvents that may be used in this disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (SiO), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl-tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0065] Non-limiting examples of preferred bases that may be used in this disclosure include 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N, TEA), diisopropyl ethylamine (i-Pr2EtN, DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0066] The term "subject" refers to animals, including humans.

[0067] The term "therapeutic dose" refers to the amount of compound administered that produces the desired effect (e.g., improvement of a disease or condition, such as ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN; reduction of the severity of the disease or condition; and / or reduction of the progression of the disease or condition). The disease or condition may be caused by or associated with axonal degeneration. The exact amount of the therapeutic dose will vary depending on the therapeutic purpose and can be determined by the known techniques of the art (see, for example, Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0068] As used herein, the term “treatment” and its synonyms mean delaying or halting the progression of a disease. As used herein, “treatment” and its synonyms include, but are not limited to, complete or partial remission, cure, and a reduction in the risk of a disease or condition, or its symptoms, such as ALS, Parkinson’s disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN. The disease or condition may be caused by or associated with axonal degeneration. Improvement or reduction in the severity of any of these symptoms can be evaluated according to methods and techniques known in the art.

[0069] When the terms "about" and "approximately" are used in relation to numbers such as percentages, they include a range of the specified number and a range of numbers recognized by those skilled in the art (e.g., a range of percentages, e.g., a range of ±10% for a given point value).

[0070] II. Compounds and Compositions In the first embodiment, the compound of the present disclosure has the following structural formula 1: [ka] [In the formula, X1, X2, X3, X4, and X5 are each independently C or N (for example, X1, X2, X3, X4, and X5 are all C, and X1, X2, X3, X4, and X5 are all N), one of X1, X2, X3, X4, and X5 is N, the remaining X1, X2, X3, X4, and X5 are C, two of X1, X2, X3, X4, and X5 are N, the remaining X1, X2, X3, X4, and X5 are C, and three of X1, X2, X3, X4, and X5 are N. The remaining of X1, X2, X3, X4, and X5 are C, four of X1, X2, X3, X4, and X5 are N, the remaining of X1, X2, X3, X4, and X5 are C, X1, X2, X3, and X4 are C, X5 is N, X2, X3, and X4 are C, X1 and X5 are N, X1, X3, and X4 are C, X2 and X5 are N, X1, X2, and X4 are C, X3, and X5 are N, X1, X2, and X3 are C, X4 and X5 are N, Y1 is C or N, Y2 is C or N, and Y1 and Y2 are two adjacent ring atoms on ring B. Ring B is a phenyl, a 5-6 membered heteroaryl, a 3-6 membered cycloalkyl, or a 4-6 membered heterocyclyl, where the 5-6 membered heteroaryl or 4-7 membered heterocyclyl of ring B contains 1-4 heteroatoms selected from N, O, and S. Ring C is a phenyl molecule, a 3-10 membered cycloalkyl group, a 4-10 membered heterocycline, a 5-6 membered heteroaryl group, or a 9-10 membered heteroaryl group, where the 4-10 membered heterocycline, 5-6 membered heteroaryl group, or 9-10 membered heteroaryl group of ring C contains 1-3 heteroatoms selected from N, S, and O. R 1 H, halogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, -CN, -OH, -COOH, -C(=O)NH2, -OR m -S(=O) p (C1-C4 alkyl), -NR m R n -C(=O)Rn , -C(=O)OR m -C(=O)NR m R n ,-P(=O)R m R n ,-SF5, A 5-6 member heteroaryl compound containing 1-3 heteroatoms independently selected from N, O, and S. A 3-10 membered heterocycline containing 1-2 heteroatoms independently selected from N, O, and S, and Selected from 3-10 member cycloalkyl groups, R 1 The C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl compounds are halogens, -OH, -OR m -CN, -NH2, -NR m R n , selected from -C(=O)OCH3, -O(C1-C6 alkyl), -COOH, --C(=O)NH2, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, and 3-6 membered cycloalkyl (optionally substituted with 1-3 groups selected from OH and halogens), optionally substituted with 1-3 groups, R 1 5-6 member heteroaryls include D, halogen, -OH, -CN, -COOH, -(C1-C6alkyl)OH, -C(=O)O(C1-C6alkyl), =O, -NH2, and -C(=O)NR m R n , 5-6 member heteroaryl, -OR m , R m , C1-C6 alkyl(halogen, -C(=O)NH2, R m , and OR m (Selected from, and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are selected from, R 1 The 3-10 member heterocyclyls are D, halogen, -OH, -CN, -COOH, -(C1-C6 alkyl)OH, -C(=O)O(C1-C6 alkyl), =O, -NH2, -C(=O)NR m R n, 5-6 member heteroaryl, -OR m , R m , C1-C6 alkyl(halogen, -C(=O)NH2, R m , and OR m (Selected from, and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are selected from, R 1 3-10 member cycloalkyl groups include D, halogen, -OH, -CN, -COOH, -(C1-C6alkyl)OH, -C(=O)O(C1-C6alkyl), =O, -NH2, and -C(=O)NR m R n , 5-6 member heteroaryl, -OR m , R m , C1-C6 alkyl(halogen, -C(=O)NH2, R m , and OR m (Selected from, and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are selected from, R m and R n For each occurrence, independently, H, C1-C6 alkyl, and -S (=O) p Selected from (C1-C4 alkyl), phenyl, 3-8 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, R m The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from D, -C(=O)NH2, -OH, -OMe, -S(=O)2CH3, and halogens. R 2 H, halogen, C1-C6 alkyl, C1-C6 alkenyl, -OH, -O(C1-C6 alkyl), -O(C1-C6 alkyl)O(C1-C6 alkyl), -C(=O)NH2, -S(=O) p Selected from (C1-C4 alkyl), -CN, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-10 membered heterocyclyl (containing 1-3 heteroatoms independently selected from S, O, and N), R 2The C1-C6 alkyl or C1-C6 alkenyl is optionally substituted with 1 to 3 groups selected from halogens, CN, and -C(=O)O(C1-C6 alkyl). R 2 The 3-5 membered cycloalkyl group is optionally substituted with 1-3 groups selected from OH, CN, and halogens. R 2 The C1-C6 alkyl group of -O(C1-C6 alkyl) is optionally substituted with 1 to 3 groups selected from halogens and CN. R 2 The 3-10 member heterocyclyl is optionally substituted with 1-3 groups selected from OH, CN, and halogens, or R 1 and R 2 is combined [ka] Forming, R 3 and R 4 Each of these is independently selected from H, halogen, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from OH and halogen), and -O(C1-C6 alkyl), R 5 is absent, H, -CN, halogen, -C(=O)NH2, -S(=O)p(C1-C4 alkyl), -OR p Selected from phenyl, 5-6 membered heteroaryls, 4-6 membered heterocyclines, 3-8 membered cycloalkyls, and C1-C6 alkyls, R 5 The C1-C6 alkyl group is OH, -NHR p , -OR p , and are optionally substituted with 1 to 3 groups selected from -S(=O)p(C1-C4 alkyl), R 5 The 4-6 membered heterocyclyl is substituted with 1-3 groups selected from C1-C3 alkyl, CN, halogen, and =O. R 5The 3-8 member cycloalkyl group is optionally substituted with 1-3 groups selected from C1-C3 alkyl, CN, and halogens. R p R is selected from C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, and 5-6 membered heteroaryl groups. p The C1-C6 alkyl, 3-6 membered cycloalkyl, or 5-6 membered heteroaryl groups are optionally substituted with 1-3 groups selected from CN, OH, and halogens. R 6 For each occurrence, independently, D, halogen, -CN, =O, -OR s -SH, -S(C1-C4 alkyl), -S(=O) p R t -C(=O)NR t R o , -NR t R o Selected from 4-6 member heterocyclyls and C1-C6 alkyl groups, R 6 C1-C6 alkyl groups are halogens, -OR s , =O, -S(=O) p R t , -NHS(=O) p R t -S(=O)(=NH)R t , [ka] -NHS(=O) p (C1-C4 alkyl), -CN, -C(=O)NR t R o , -NR t R o , halogens, 5-6 member heteroaryls, 3-6 member cycloalkyls (halogens, OH, and R t (Optionally substituted with 1 to 3 groups selected from), as well as halogens, OH, and R t Selected from 4-10 member heterocyclines, which are optionally substituted with 1-3 groups selected from, R 6The 4-8 membered C1-C6 alkyl heterocyclyl is optionally substituted with 1-3 groups selected from halogens, OH, C1-C3 alkyl, and =O. R s These are selected from H, C1-C6 alkyl groups, 4-6 membered heterocyclines, and 3-6 membered cycloalkyl groups. R s The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from -OH, -OMe, and halogens. R s The 3-6 member cycloalkyl group is optionally substituted with -OH or -OMe. R t and R o For each occurrence, each is independently selected from H, C1-C6 alkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and 3-5 membered cycloalkyl, R t and R o The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from D, halogen, -OH, CN, C(=O)NH2, -O(C1-C3 alkyl), and -S(=O)2CH3. R 7 For each occurrence, independently, D, halogen, -OR a -CN, -CONH2, -C(=O)NR b R c , NR b R c , -C(=O)OR b ,=O,=S,-P(=O)2R b R c -S(=O) p These include (C1-C4 alkyl), -O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl. R 7 C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl compounds are halogens, -OH, CN, -S(=O) pIt is optionally substituted with 1 to 3 groups selected from (C1-C4 alkyl), -C(=O)2NH2, and 3- to 6-membered heterocyclines. R 7 The 4-6 member heterocyclyls are =O, halogen, and R b It is optionally replaced by 1 to 3 elements selected from the following: R a R is selected from H, C1-C8 alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl. a The C1-C8 alkyl group consists of D, halogen, OH, CN, and -S (=O). p It is optionally substituted with 1 to 4 groups selected from (C1-C4 alkyl), -C(=O)NH2, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl. R b and R c For each occurrence, each is independently selected from H, C1-C8 alkyl, 4-6 member heterocyclyl, phenyl, 5-6 member heteroaryl, and 3-6 member cycloalkyl, R b and R c The C1-C8 alkyl groups are optionally substituted with 1-3 groups selected from D, halogen, OH, -C(=O)NH2, CN, -OCH3, and -S(=O)2CH3. m is an integer selected from 0, 1, and 2. n is an integer selected from 0, 1, 2, 3, and 4. [where p is an integer selected from 0, 1, and 2] A compound, its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof. Here, in each occurrence, C1-C8 alkyl can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, or C8 alkyl; C1-C6 alkyl can be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; C1-C4 alkyl can be C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl; 3-5 member means 3-membered, 4-membered, or 5-membered; 3-6 member means 3-membered, 4-membered, 5-membered, or 6-membered; 3-8 member means 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, or 8-membered; 3-1 0 members means 3, 4, 5, 6, 7, 8, 9, or 10 members; 4-6 members means 4, 5, or 6 members; 4-7 members means 4, 5, 6, or 7 members; 4-8 members means 4, 5, 6, 7, or 8 members; 5-7 members means 5, 6, or 7 members; 1-3 or 1-3 groups means 1, 2, or 3 groups; 1-3 or 1-3 heteroatoms means 1, 2, or 3 heteroatoms; 1-4 or 1-4 heteroatoms means 1, 2, 3, or 4 heteroatoms. Heteroatoms can be located at any chemically feasible position in the cyclic structure.

[0071] The combinations of chemical components (e.g., substituents, ring structures, or heteroatoms) disclosed herein result in the formation of stable or chemically feasible compounds. In abbreviations or by convention, specific hydrogen atoms bonded to specific atoms (e.g., carbon atoms C or nitrogen atoms N) are not specifically shown in the chemical structure, formula, or symbol, and the hydrogen atoms are assumed to be present to the extent that the valence of the specific atom (e.g., C or N) is satisfied.

[0072] In the second embodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers of the disclosed compounds or tautomers, or pharmaceutically acceptable salts, X1, X2, X3, and X4 are C, and all other variables not specifically defined herein are as defined in the prior embodiments.

[0073] In the third embodiment, the compound of the present disclosure has the following structural formula 2: [Chemical formula] [In the formula, Y2, Y3, and Y4 are each independently selected from N and C, at least one of Y2, Y3, and Y4 is N, and Y5 is selected from S and C], a tautomer thereof, a solvate or stereoisomer of the compound or the 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 appropriate preceding embodiments.

[0074] In the fourth embodiment, the compound of the present disclosure has the following structural formulas 3-1, 3-2, or 3-3: [Chemical formula] [In the formula, Y3, Y4, Y5, and Y6 are each independently selected from N and C, and at least one of Y3, Y4, Y5, and Y6 is N], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0075] In the fifth embodiment, the compound of the present disclosure has the following structural formula 4: [Chemical formula] [In the formula, Z1, Z2, and Z3 are each independently selected from C and N], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0076] In the 6th embodiment, the compound of the present disclosure has the following structural formula 5:

Chemical formula

[0077] In the 7th embodiment, the compound of the present disclosure has the following structural formula 6-1 or 6-2:

Chemical formula

[0078] In the 8th embodiment, the compound of the present disclosure has the following structural formula 7-1 or 7-2:

Chemical formula

[0079] In the ninth embodiment, the compounds of the present disclosure have the following structural formulas 8-1, 8-2, 8-3, 8-4, 8-5, or 8-6: [ka] [In the formula, In equations 8-2, 8-4, and 8-6, Y3, Y4, Y5, and Y6 are each independently selected from N and C, and at least one of Y3, Y4, Y5, and Y6 is N. In equations 8-1, 8-3, and 8-5, Y2, Y3, and Y4 are each independently selected from N and C, and at least one of Y2, Y3, and Y4 is N, and Y5 in equation 8-1 is selected from S and C. Z1, Z2, and Z3 are each independently selected from C and N] a compound, its tautomer, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof. All other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0080] In the tenth embodiment, the compounds of the present disclosure have the following structural formulas 9-1, 9-2, 9-3, or 9-4: [ka] [In the formula, In equations 9-2 and 9-4, Y3, Y4, Y5, and Y6 are each independently selected from N and C, and at least one of Y3, Y4, Y5, and Y6 is N. In equations 9-1 and 9-3, Y2, Y3, and Y4 are each independently selected from N and C, and at least one of Y2, Y3, and Y4 is N, and Y5 in equation 9-1 is selected from S and C. Z1 and Z2 are each independently selected from N and S, and Z3 is selected from N and C, and at least one of Z1, Z2, and Z3 is a heteroatom] a compound thereof, its tautomer, a solvate or stereoisomer of said compound or tautomer, or a pharmaceutically acceptable salt thereof, all other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0081] In the eleventh embodiment, the compounds of the present disclosure have the following structural formulas 10-1, 10-2, 10-3, 10-4, 10-5, or 10-6: [ka] [In the formula, In formulas 10-1 to 10-5, Y2, Y3, and Y4 are each independently selected from N and C, and Y5 is selected from N, S, and C, and at least one of Y2, Y3, Y4, and Y5 is a heteroatom. The compounds of formula 10-6, Y3, Y4, Y5, and Y6 are each independently selected from N and C, and at least one of Y3, Y4, Y5, and Y6 is a heteroatom, their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts thereof, all other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0082] In the twelfth embodiment, the compounds of the present disclosure have the following structural formulas 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, or 11-7: [Chemical formula] [wherein, In Formulas 11-1 to 11-5, Y2, Y3, and Y4 are each independently selected from N and C, Y5 is selected from N, S, and C, and at least one of Y2, Y3, Y4, and Y5 is a heteroatom, and Z1, Z2, and Z3 are each independently selected from N and C, In Formulas 11-6 to 11-7, Y3, Y4, Y5, and Y6 are each independently selected from N and C, and at least one of Y3, Y4, Y5, and Y6 is a heteroatom, and Z1, Z2, and Z3 are each independently selected from N and C], a tautomer thereof, a solvate or stereoisomer of the compound or the 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 appropriate preceding embodiments.

[0083] In the 13th embodiment, the compound of the present disclosure has the following Structural Formulas 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8: [Chemical formula] [wherein, In Formulas 12-1 to 12-5, Y2 and Y5 are each independently selected from N and C, Y3 and Y4 are each independently selected from N, S, and C, and at least one of Y2, Y3, Y4, and Y5 is a heteroatom, and ZI, Zz, and Z3 are each independently selected from N and C, In formulas 12-6 to 12-8, Y3, Y4, Y5, and Y6 are each independently selected from N and C, at least one of Y3, Y4, Y5, and Y6 is a heteroatom, and Z1, Z2, and Z3 are each independently selected from N and C] a compound thereof, its tautomer, a solvate or stereoisomer of said compound or tautomer, or a pharmaceutically acceptable salt thereof, all other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0084] In the fourteenth embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from, [ka] teeth, [ka] Selected from, [ka] teeth, [ka] All other variables selected from and not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0085] In the 15th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from, During the ceremony, R 8 The following are selected from H, F, Cl, Me, CHF2, CF3, CN, SO2Me, SMe, CH2CF3, and CH2SO2Me. [ka] and R 9 These are Me, CF3, CHF2, CH2CF3, acetyl-C(=O)CH3), SO2Me [ka] All other variables selected from and not specifically defined herein are as defined in any of the appropriate above embodiments.

[0086] In the sixteenth embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from, [ka] teeth, [ka] Selected from, [ka] teeth, [ka] Selected from, In the formula, T1, T2, and T3 are each independently selected from N and C, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0087] In the seventeenth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer of the present disclosure, or a pharmaceutically acceptable salt, ring A is [ka] Selected from, ring A is R 1 , R 2 , R 3 , R 4 , and R 5 All other variables, which are replaced by and not specifically defined herein, are as defined in any one of the appropriate prior embodiments.

[0088] In the eighteenth embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from, In the formula, L is -NH- or -O-, q is 1, 2, or 3, and R p The members are selected from C1-C4 alkyl groups, 3-6 membered cycloalkyl groups, and 5-7 membered heteroaryl groups, and all other variables not specifically defined herein are as defined in any of the appropriate above embodiments.

[0089] In the 19th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] [ka] [ka] [ka] [ka] [ka] All other variables selected from and not specifically defined herein are as defined in any of the appropriate above embodiments.

[0090] In the 20th embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer of the disclosed, or a pharmaceutically acceptable salt, ring B is [ka] Selected from, ring B has m R 6 All other variables that are substituted by the base and not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0091] In the 21st embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer of the disclosed, or a pharmaceutically acceptable salt, ring B is [ka] Selected from, ring B has m R 6All other variables that are substituted by the base and not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0092] In the 22nd embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] [ka] [ka] Selected from, All other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0093] In the 23rd embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer of the present disclosure, or a pharmaceutically acceptable salt, ring C is [ka] Selected from, ring C is made up of n R 7 All other variables that are substituted by the base and not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0094] In the 24th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from, in the formula, R 8 For each occurrence, independently, H, F, Cl, Me, CHF2, CF3, CN, SO2Me, SMe, CH2CF3, CH2SO2Me, [ka] Selected from, R 9 For each occurrence, independently, Me, CF3, CHF2, CH2CF3, acetyl, SO2Me, [ka] All other variables selected from and not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0095] In the 25th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, [ka] teeth, [ka] [ka] [ka] Selected from, All other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0096] In the 26th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 1are H, Me, Cl, F, Br, OMe, CF3, OCF3, CHF2, SO2Me, CN, OH, CH2OH, COOH, CONH2, [ka] Selected from, in the formula, R 10 For each occurrence, the elements are independently selected from H, Me, Cl, F, CF3, and CN, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0097] In the 27th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 1 is H, -CH3, -CF3, -CHF2, -OCF3, -C(CH3)2OH, Br, Cl, -S(=O)2CH3, -SF5, [ka] [ka] All other variables selected from and not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0098] In the 28th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 1 This is a halogen, -C(=O)R f , -OR f , -NR f R g ,-SF5, C1-C6 alkyl(F, -CN, -OR) f , phenyl, -NR f R g (and optionally substituted with 1 to 3 groups selected from 5-6 member heteroaryls), C1-C6 alkenyl(F, -CN, -OR) f, phenyl, -NR f R g (and optionally substituted with 1 to 3 groups selected from 5-6 member heteroaryls), 3-6 member cycloalkyl (D, halogen, -CN, R f , -OR f CH2OR f -C(=O)NR f R g (and optionally substituted with 1-2 groups selected from 5-6 member heteroaryls), 4-8 member heterocyclines ( Rf , -OR f (Optionally replaced by 1-2 groups selected from halogen and -CN), and 5-6 member heteroaryl ( Rf , -OR f (Optionally replaced by 1-2 elements selected from halogen and -CN) During the ceremony, R f and R g For each occurrence, each is independently selected from H, a 5-6 member heteroaryl, a 3-6 member cycloalkyl, and a C1-C3 alkyl (optionally substituted with 1-3 groups selected from D, halogen, -OH, -OCH3, -C(=O)NH2, and -CN), and all other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0099] In the 29th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 1 The elements are selected from CF3, F, Cl, C1-C3 alkyl, and C3-C5 cycloalkyl, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0100] In the 30th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 2 are H, Me, Cl, F, Br, -OMe, CF3, -CN, -CONH2, -SO2Me, -S(=O)CH3, -SCH3, [ka] All other variables selected from and -OH, which are not specifically defined herein, are as defined in any one of the appropriate prior embodiments.

[0101] In the 31st embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 2 The s(CH3), s(=O)CH3, s(SCH3), s(CN), and s(=O)2CH3 are selected from -CH3, -S(=O)CH3, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0102] In the 32nd embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 3 and R 4 Each of these is independently selected from H, Me, Cl, F, Br, and OMe, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0103] In the 33rd embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 3 and R 4 These are, independently, H, Me, Cl, F, Br, OMe, CF3, and [ka] All other variables selected from and not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0104] In the 34th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 4 The variables are selected from F and Cl, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0105] In the 35th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 5 The is selected from -CN and -CH2OH, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0106] In the 36th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 5 is absent, H, -CN, -CH2OH, [ka] All other variables selected from and not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0107] In the 37th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 5The member is selected from absent, H, CN, halogen, -S(=O)2CH3, -CH2S(=O)2CH3, 3-4 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, CH2OH, and CH2CH2OH, and all other variables not specifically defined herein are defined in any one of the appropriate prior embodiments.

[0108] In the 38th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 6 teeth, [ka] Selected from, in the formula, R t and R o Each is independently selected from H and C1-C6 alkyl, and R t and R o The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from halogens, and all other variables not specifically defined herein are as defined in any of the appropriate above embodiments.

[0109] In the 39th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 6 -CN, =O, -CH3, -CH2S(=O)2CH3, -CH2OH, -CH2CH2OH, -C(=O)NH2, -O(CH2)2OH, -OCH3, -SH, -SCH3, [ka] All other variables selected from OH, -OCH3, and =O, and not specifically defined herein, are as defined in any one of the appropriate prior embodiments.

[0110] In the 40th embodiment, in a compound of the disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 6 teeth, [ka] All other variables selected from and not specifically defined herein are as defined in any appropriate prior embodiment.

[0111] In the 41st embodiment, in a compound of the disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 6 D, halogen, -S(=O)2R h , -NR h R i -C(=O)NR h R i ,and C1-C4 alkyl (halogen, -OR) h -C(=O)NR h R i , -NR h R i -S(=O)2R h , -NHS(=O) p R h -S(=O)R h , [ka] 5-6 member heteroaryls, 3-5 member cycloalkyls (halogens and R h (Optionally replaced by 1 to 3 groups selected from), as well as halogens and R h Selected from (a 3-8 member heterocyclyl which is optionally substituted with 1-3 groups selected from), During the ceremony, R h and R iFor each occurrence, each is independently selected from H, C1-C3 alkyl (optionally substituted with 1 to 3 groups selected from halogen, -OH, -O(C1-C3 alkyl), and -S(=O)2CH3), and 3 to 5-membered cycloalkyl, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0112] In the 42nd embodiment, in a compound of the disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 7 F, Cl, Me, CHF2, CF3, CN, -SO2Me, -SMe, CH2CF3, CH2SO2Me, acetyl, [ka] n is selected from 0, 1, 2, or 3, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0113] In the 43rd embodiment, in a compound of the disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 7 The is selected from Cl, F, -CN, -S(=O)2CH3, -CH3, -OCH3, and -OH, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0114] In the 44th embodiment, in a compound of the disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 7 D, Halogen, CN, =O, =S, -OR j , -NR j R k -C(=O)NR j R k , -C(=O)OR j-S(=O)2CH3, 3-5 member cycloalkyl, 5-6 member heteroaryl, C1-C6 alkyl (optionally substituted with 1-3 groups selected from halogens, -OH, -S(=O)2CH3, and 4-6 membered heteroterocyclines), and 4-6 member heterocyclyl (=O and R) k (Optionally replaced by 1-2 elements selected from) During the ceremony, R j and R k For each occurrence, independently, is selected from H, C1-C6 alkyl (optionally substituted with 1-3 groups selected from halogen, OH, -C(=O)NH2, and -S(=O)2CH3), 4-6 member heterocyclyl, and 3-5 member cycloalkyl, and all other variables not specifically defined herein are as defined in any one of the appropriate prior embodiments.

[0115] In the 45th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 1 are CH3, CF3, OCF3, S(=O)2CH3, Br, Cl, [ka] Selected from, R 2 It is selected from H, CN, and S(=O)2CH3. R 3 , R 4 , and R 5 H is, R 6 m is selected from =O, CH3, Cl, -C(=O)NH2, -CH2CH2OH, -CH2OH, and -CH2S(=O)2CH3, and m is 0, 1, or 2. R 7 n is selected from CH3, Cl, F, CN, OCH3, and OH, and n is 0, 1, 2, or 3. All other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0116] In the 46th embodiment, in a compound of the Disclosure, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt, R 1 C1-C6 alkyl (halogen, -OH, CN, -OCH3, -NR) d R e (Optionally substituted with 1 to 3 groups selected from 5-membered heteroaryls containing 1 to 3 heteroatoms selected from phenyl, N, O, and S, and 6-membered heteroaryls containing 1 to 3 nitrogen atoms), C2-C4 alkenyls (optionally substituted with 1 to 3 groups selected from halogens, -OH, -CN, and -OCH3), -OR d , -NR d R e -S(=O) p CH3, -SF5, halogen, -C(=O)CH3, [ka] Selected from 5-membered heteroaryls containing 1-2 heteroatoms selected from N and S (optionally substituted with 1-2 groups selected from C1-C3 alkyls), and 6-membered heteroaryls containing 1-2 nitrogen atoms (optionally substituted with 1-2 groups selected from C1-C3 alkyls), R 2 R is selected from H, CN, CH3, F, and S(=O)2CH3. 3 H is R 4 It is selected from F, Cl, and H. R 5This is selected from the absence of H, F, -CN, -C(=O)NH2, 3-4 membered cycloalkyls (optionally substituted with 1-3 groups selected from CN and halogens), C1-C4 alkyls (optionally substituted with 1-3 groups selected from halogens, -S(=O)2CH3, and -OH), 5-6 membered heterocyclines, 5-membered heteroaryls containing 1-3 heteroatoms selected from -S(=O)2CH3, N, and O, and 6-membered heteroaryls containing 1-3 nitrogen atoms. R 6 Absent, D, C1-C4 alkyl(halogen, S(=O)CH3, -S(=O)2CH3, -C(=O)NHCH3, -OH, -C(=O)NH2, -NR d R e , -NR d Ure e , and are optionally replaced with 1 to 3 groups selected from -NHS(=O)2CH3, selected from =O, Cl, and C(=O)NH2, R 7 D, Halogen, CF3, -OCF3, CN, -OR d , -NR d R e , -C(=O)OH, =O, =S, -S(=O)2CH3, -C(=O)NR d R e Selected from C1-C6 (optionally substituted with 1-3 groups selected from halogens, -OH, -S(=O)2CH3, -C(=O)2NH2, and 3-6 membered heterocyclines), 5-6 membered heteroaryls, 3-5 membered cycloalkyls, and 4-6 membered heterocyclines (optionally substituted with 1-3 groups selected from =O and C1-C3 alkyls), During the ceremony, R d and R e For each occurrence, independently, the group is selected from H, C1-C4 alkyl (optionally substituted with 1-3 groups selected from D, halogen, -OH, CN, -C(=O)NH2, -S(=O)2CH3, and -OCH3), 5-6 member heteroaryl, 4-6 member heterocyclyl, and 3-5 member cycloalkyl. q is 0, 1, 2, or 3. U1 and U2 are independently selected from O and C. All other variables not specifically defined herein are as defined in any of the appropriate prior embodiments.

[0117] In certain embodiments, the compounds of the present disclosure are selected from compounds 1 to 468 shown in Table 1, their tautomers, solvates or stereoisomers of the compounds or their tautomers, or pharmaceutically acceptable salts thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25

[0118] Another aspect of this disclosure is the formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12- The present invention provides a pharmaceutical composition comprising at least one compound selected from compounds 1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, and 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier.

[0119] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0120] It is also understood that the pharmaceutical compositions of this disclosure may be used in combination therapy, i.e., the pharmaceutical compositions described herein may further contain additional active pharmaceutical ingredients, or formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4 A pharmaceutical composition comprising a compound selected from the compounds 12-5, 12-6, 12-7, and 12-8 (e.g., compounds 1 to 468), its tautomers, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, may be administered as a separate composition simultaneously with, before, or after, a composition containing additional active pharmaceutical ingredients.

[0121] In some embodiments, pharmaceutically acceptable carriers may be selected from adjuvants and vehicles. As used herein, pharmaceutically acceptable carriers can be selected from, for example, all solvents, diluents, other liquid vehicles, dispersing agents, suspension agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the desired specific dosage form. Various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation are disclosed in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JCBoylan, 1988 to 1999, Marcel Dekker, New York. For example, all use of conventional carriers is considered to be within the scope of this disclosure, except in cases where they are incompatible with the compounds of this disclosure by producing any undesirable biological effect or otherwise interacting in a harmful manner with any other component of the pharmaceutical composition.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffers (such as phosphates, 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, lanolin fat, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (carboxymethylcellulose). Examples of excipients include sodium cellulose, ethylcellulose, and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (e.g., 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, water free of pyrogens, 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, flavoring agents, fragrances, preservatives, and antioxidants.

[0122] The chemical formulas for equations 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, and 12-8 Compounds selected from the compounds (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein, can be administered orally in solid dosage forms such as capsules, tablets, lozenges, sugar-coated tablets, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersants, 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 for administering the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein, such as ointments, creams, drops, transdermal patches, or powders for topical administration; ophthalmic solutions or suspensions for intraocular administration, such as eye drops; aerosol sprays or powder compositions for inhalation or intranasal administration; or creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0123] Gelatin capsules containing the compounds disclosed herein, their tautomers, solvates or stereoisomers of the compounds or their tautomers, and / or pharmaceutically acceptable salts thereof, and powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, or stearic acid can also be used. Compressed tablets can be manufactured using similar diluents. Both tablets and capsules can be manufactured as sustained-release products, allowing for the sustained release of the pharmaceutical product over a period of time. Compressed tablets may be coated with sugar or film to mask unpleasant tastes and protect the tablets from the air, or coated with enteric coating to selectively disintegrate in the gastrointestinal tract.

[0124] The liquid dosage form for oral administration may further contain at least one agent selected from colorants and flavoring agents to enhance patient acceptability.

[0125] In general, water, suitable oils, physiological saline, aqueous solutions of dextrose (glucose), and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, may be examples of carriers suitable for parenteral solutions. A parenteral solution may comprise a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and optionally at least one buffer. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, may be examples of suitable stabilizers. Citric acid and its salts, as well as sodium EDTA, may also be used as examples of suitable stabilizers. Furthermore, the parenteral solution may further comprise at least one preservative selected from, for example, benzalkonium chloride, methylparaben, and propylparaben, and chlorobutanol.

[0126] A pharmaceutically acceptable carrier is selected from carriers that are compatible with the active ingredient of the composition (and can stabilize the active ingredient in some embodiments) and are not harmful to the target being treated. For example, solubilizers such as cyclodextrins (which can form specific and more soluble complexes with at least one of the compounds and / or at least one pharmaceutically acceptable salt disclosed herein) can be used as pharmaceutical excipients for the delivery of the active ingredient. 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.

[0127] For administration by inhalation, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can be conveniently delivered in the form of aerosol sprays from a pressurized pack or nebulizer. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can also be delivered as a formulation of powder, and the powder composition can be inhaled using a blown powder inhalation device. One exemplary delivery system for inhalation may 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 fluorocarbons and hydrocarbons, for example.

[0128] For intraocular administration, ophthalmic preparations can be formulated using a solution or suspension of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in a suitable ophthalmic vehicle, such that the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein remains in contact with the surface of the eye for a sufficient amount of time to allow the compound to penetrate the cornea or internal regions of the eye.

[0129] Useful pharmaceutical dosage forms 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.

[0130] The term "unit dosage form" refers to a physically distinct unit suitable as a single dosage form for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a desired therapeutic effect in combination with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled and pre-measured ampoules or syringes for liquid compositions, or pills, tablets, capsules, or drops for solid compositions. In such compositions, the active substance is typically present in an amount ranging from about 0.1% to about 50% by weight, preferably about 1% to about 40% by weight, with the remainder being a vehicle or carrier and various processing aids that help form 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 for continuous use, such as blister packs containing at least 6, 9, or 12 sheets of unit dosage forms.

[0131] In some embodiments, unit capsules can be prepared by filling each of a standard two-piece hard gelatin capsule with, for example, 100 milligrams of powder of one of the compounds specified herein, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

[0132] In some embodiments, a mixture of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein with a digestible oil such as soybean oil, cottonseed oil, or olive oil can be prepared and injected into gelatin by a volumetric pump to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

[0133] In some embodiments, tablets can be prepared by conventional procedures such that the 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 slow absorption.

[0134] In some embodiments, parenteral compositions suitable for administration by injection can be prepared by stirring 1.5% by weight of the compounds disclosed herein and / or at least one enantiomer, diastereoisomer, or pharmaceutically acceptable salt thereof in 10% by volume of propylene glycol. The solution is then prepared to the desired volume with sterile water for injection and sterilized.

[0135] In some embodiments, aqueous suspensions can be prepared for oral administration. For example, a 5 ml aqueous suspension can be used containing 100 ml of a finely powdered compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, 100 ml of sodium carboxymethylcellulose, 5 ml of sodium benzoate, 1.0 g of sorbitol solution (USP), and 0.025 ml of vanillin.

[0136] When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein are administered sequentially or concurrently 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 route of administration must be selected according to the compatibility of the drugs being combined. Therefore, the term co-administration is understood to include administering at least two drugs simultaneously or sequentially, or as a combination of fixed doses of at least two active ingredients.

[0137] The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts disclosed herein may be administered as a single active ingredient or in combination with at least one second active ingredient.

[0138] The compounds, tautomers, solvates, or stereoisomers described herein can be used in the forms described above, or in the form of pharmaceutically acceptable salts thereof, such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, or trifluoroacetate. If the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein contain relatively acidic functional groups, the salts can be obtained in their original form or by adding the desired base in a suitable inert solvent. Examples of pharmaceutically acceptable base-added salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts. If the compounds, tautomers, solvates, or stereoisomers described herein contain relatively basic functional groups, the salts can be obtained in their original form or by adding the desired acid in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monocarbonate, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as 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, and methanesulfonic acid. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0139] The pharmaceutically acceptable neutral forms of the salts described herein can be regenerated by contacting the salt with a base or acid and isolating the parent compound by conventional means.

[0140] This disclosure provides prodrugs. Prodrugs of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein readily undergo chemical changes under physiological conditions to provide the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the disclosure. Furthermore, prodrugs can be converted to the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the disclosure by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, prodrugs can be slowly converted to the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the disclosure. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. For example, oral administration may result in higher bioavailability than the parent drug. Prodrugs may also have improved solubility in pharmacological compositions than the parent drug. A wide variety of prodrug derivatives are known in the art, including those resulting from hydrolytic cleavage or oxidative activation of prodrugs. Examples of prodrugs, but not limited to them, include compounds of the disclosure that are administered as esters ("prodrugs") but are subsequently metabolically hydrolyzed to carboxylic acids, i.e., the active product.

[0141] Certain compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts of the Disclosure may exist in non-solvated forms as well as solvated forms, including hydrated forms. Certain compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the Disclosure may exist in multiple crystalline or amorphous forms.

[0142] Certain compounds, tautomers, solvates, or pharmaceutically acceptable salts in this disclosure have a chiral carbon atom (optical center) or a double bond, and racemates, enantiomers, diastereoisomers, geometric isomers, and individual isomers are all intended to be included within the scope of this disclosure.

[0143] III. Treatment and Method of Use This disclosure relates to the compounds described in any one of the various embodiments in Section II (Compounds and Compositions) and Table 1, for example, formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, The present invention provides a therapeutic method and use utilizing a pharmaceutical composition comprising compounds 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8, as well as compounds 1 to 468 of Table 1, their tautomers, solvates or stereoisomers of said compounds or their tautomers, or pharmaceutically acceptable salts thereof, or any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts.

[0144] One aspect of this disclosure is a method for treating a disease or condition, wherein a therapeutically effective amount of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4 disclosed herein. Compounds of 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (for example, compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts of the aforementioned, or any of the compound, its tautomer, its solvate, its stereoisomer, or its pharmaceutically acceptable salt. The present invention provides a method comprising administering a pharmaceutical composition containing the above, where the disease or condition is a demyelinating disease such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinsonian syndromes, ischemia, stroke, herpes infection, multiple sclerosis, traumatic brain injury, sepsis, chronic diseases of PNS including hereditary neuropathy such as, but not limited to, Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathy such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or metabolic disorders such as diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathy such as CIPN induced by various drugs such as, but not limited to, taxanes, vinca alkaloids and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or nerve cell injury.

[0145] In another embodiment, this specification discloses formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12- Disclosed are pharmaceutical compositions comprising compounds 5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or their tautomers, or pharmaceutically acceptable salts thereof, as described herein, or any of said compounds, said tautomers, said solvates, said stereoisomers, and said pharmaceutically acceptable salts.

[0146] In another embodiment, this specification includes formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12 Compounds of -5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, as described herein, or any of said compounds, said tautomers, said solvates, said stereoisomers, or said pharmaceutically acceptable salts. The use of a pharmaceutical composition containing the above for the manufacture of a drug for the treatment of a disease or condition is disclosed, including, but is not limited to, demyelinating diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinsonian syndromes, ischemia, stroke, herpes infections, and multiple sclerosis, chronic diseases of PNS including traumatic brain injury, sepsis, hereditary neuropathy such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathy such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or metabolic disorders such as diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathy such as CIPN induced by various drugs such as, but is not limited to, taxanes, vinca alkaloids and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or nerve cell injury.

[0147] In a further aspect of this disclosure, formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12 Compounds of -4, 12-5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts thereof, as described herein, or said compounds, said tautomers, said solvates, said stereoisomers, or pharmaceutically acceptable salts thereof, or said compounds, said tautomers, said solvates, said stereoisomers, and said pharmaceutically acceptable Pharmaceutical compositions comprising any of the salts included are intended for use in the treatment of diseases or conditions, including, but are not limited to, demyelinating diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinsonian syndromes, ischemia, stroke, herpes infections, and multiple sclerosis; chronic diseases of PNS, including traumatic brain injury, sepsis, and hereditary neuropathy, such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathy, such as glaucoma and retinal ganglion degeneration; colitis; metabolic diseases or disorders, such as diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); and peripheral neuropathy such as CIPN induced by various drugs, such as taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or nerve cell damage.

[0148] Another aspect of this disclosure is a method for inhibiting or preventing axonal degeneration, comprising, to a subject in need thereof, a therapeutically effective amount of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, The present invention provides a method comprising administering a pharmaceutical composition comprising one of the compounds 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (for example, compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, or any of the compound, its tautomer, its solvate, its stereoisomer, and a pharmaceutically acceptable salt.

[0149] In another aspect, this specification discloses formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12- The use of a pharmaceutical composition comprising any of the compounds described herein, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts thereof, including compounds 3, 12-4, 12-5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or their tautomers, or pharmaceutically acceptable salts thereof, is disclosed.

[0150] In a further aspect of this disclosure, the chemical formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 disclosed herein Pharmaceutical compositions comprising compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein, including compounds (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or their tautomers, or pharmaceutically acceptable salts thereof, are intended for use in inhibiting or preventing axonal degeneration or nerve cell damage.

[0151] Another aspect of this disclosure relates to a method for modifying, for example inhibiting, SARM1 in a subject where it is needed, by providing the subject with a therapeutically effective amount of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, The present invention provides a method comprising administering a pharmaceutical composition comprising one of the compounds 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (for example, compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or a pharmaceutically acceptable salt thereof, or any of the compound, its tautomer, its solvate, its stereoisomer, and a pharmaceutically acceptable salt.

[0152] In another embodiment, this specification discloses formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3 to modulate, for example, inhibit SARM1 in the target area where desired. The use of a pharmaceutical composition comprising any of the compounds described herein, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts thereof, including compounds 12-4, 12-5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or their tautomers, or pharmaceutically acceptable salts thereof, is disclosed.

[0153] In another aspect of this disclosure, compounds of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 disclosed herein (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or A pharmaceutical composition comprising any of the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers described herein, or pharmaceutically acceptable salts thereof, including a pharmaceutically acceptable salt thereof, is intended for use in modifying, for example inhibiting, SARM1 in a subject by contacting the subject with the compound, tautomer, solvates or stereoisomers of the compounds or tautomers, pharmaceutically acceptable salts, or the pharmaceutical composition thereof.

[0154] Formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12 Compounds of -5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any of the compound, its tautomer, its solvate, its stereoisomer, and its pharmaceutically acceptable salt, for example, for the treatment of a disease or condition, taken once a day. It may be administered once, twice, or three times a day, and the diseases or conditions include, but are not limited to, demyelinating diseases such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinsonian syndromes, ischemia, stroke, herpes infections, and multiple sclerosis, traumatic brain injury, sepsis, chronic diseases of PNS including hereditary neuropathy such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), optic neuropathy such as glaucoma and retinal ganglion degeneration, colitis, metabolic diseases or metabolic disorders such as diabetic neuropathy, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathy such as CIPN induced by various drugs such as taxanes, vinca alkaloids and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or nerve cell injury.

[0155] Compounds of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 disclosed herein (e.g., compounds 1 to 468), their tautomers, and the Pharmaceutical compositions comprising a compound or a solvate or stereoisomer of the tautomer, or a pharmaceutically acceptable salt thereof, or any of the compound, the tautomer, the solvate, the stereoisomer, and the pharmaceutically acceptable salt, can be administered in various ways, for example, orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, but in any case the most appropriate route will vary depending on the specific host and the nature and severity of the condition to which the active ingredient is administered. As used herein, the term “parenterally” includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein are provided in convenient unit-dosage forms and can be prepared by any method known in the art. Parenteral administration may be by continuous infusion over a selected time. Other dosage forms contemplated in this disclosure are described in International Publication Nos. 2013 / 075083, 2013 / 075084, 2013 / 078320, 2013 / 120104, 2014 / 124418, 2014 / 151142, and 2015 / 023915.

[0156] Generally, contact is carried out by administering to a subject an effective amount of one or more compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts disclosed herein. Generally, the administration is adjusted to achieve a therapeutic dose of about 0.1 to 50, preferably 0.5 to 10, more preferably 1 to 10 mg / kg, although the optimal dose varies for each compound and is generally determined empirically for each compound.

[0157] The dosage varies depending on factors such as the recipient's age, health condition and weight, the severity of the disease, the type and frequency of any concurrent treatments, 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 / day. For example, 10 to 500 milligrams once or multiple times a day may be effective in achieving the desired results.

[0158] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of formulas 1, 2, 3-1, 3-2, 3-3, 4, 5, 6-1, 6-2, 7-1, 7-2, 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 9-1, 9-2, 9-3, 9-4, 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 12-1, Compounds 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising any of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, are administered once, twice, or three times daily. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein are administered in the morning / daytime, with no doses given at night. A. Examples To enable a more complete understanding of the disclosures set forth herein, the following examples are disclosed herein. These examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way.

[0159] Example I. Synthesis of an exemplary compound Compounds of the present disclosure, selected from the compounds of the formulas shown herein, their tautomers, solvates or stereoisomers of said compounds or tautomers, or pharmaceutically acceptable salts thereof, can be synthesized according to standard chemical methods or as illustrated herein, including the following general synthetic procedures and specific synthetic schemes for compounds 1 to 468. Preparation of 2-(1-cyclopentylimidazole-2-yl)-5-methyl-1H-benzoimidazole (2) Method 1 [ka] Step 1. Preparation of 1-cyclopentyl-1H-imidazole-2-carbaldehyde To a stirred solution of 1H-imidazole-2-carbaldehyde (1.00 equivalent, 1000 mg, 10.4 mmol) in DMF (5 mL), dicesium carbonate (2.00 equivalent, 6782 mg, 20.8 mmol) was added. The resulting mixture was stirred for 30 minutes. Then, bromocyclopentane (1.50 equivalent, 1.7 mL, 15.6 mmol) was added dropwise, and the reaction solution was heated to 80°C and stirred for a further 3 hours. The reaction mixture was diluted with water, extracted with  (3 × 20 mL), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product, which was purified by column chromatography to obtain 1-cyclopentylimidazole-2-carbaldehyde (1700 mg, 10.4 mmol, 99.5% yield). MS(ESI)m / z165[M+H] + . Step 2: Preparation of 2-(1-cyclopentylimidazole-2-yl)-5-methyl-1H-benzoimidazole A solution of 1-cyclopentylimidazole-2-carbaldehyde (1.00 equivalent, 200 mg, 1.22 mmol) and 4-methylbenzene-1,2-diamine (67 mg, 0.552 mmol) in water (5 mL) was stirred at room temperature for 20 minutes. Then, K2CO3 (114 mg, 0.828 mmol) was added, and the mixture was stirred for a further 10 minutes. KI (23 mg, 0.138 mmol) and I2 (1.00 equivalent, 140 mg, 0.552 mmol) were added, and the mixture was heated at 90°C for 2 hours with stirring. Sodium thiosulfate solution (10 mL; 5%) was added, and the product was extracted with Â(15 mL × 3). The combined siRNA layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, which was purified by preparative HPLC to obtain the product 2-(1-cyclopentylimidazole-2-yl)-5-methyl-1H-benzimidazole (178 mg, 0.668 mmol, yield 54.9%) as a white solid. MS(ESI)m / z267[M+H] + . 1 H NMR(400MHz,DMSO)δ12.78(brs,1H),7.59(s,1H),7.48(brs,1H),7.36(brs,1H),7.18(s,1H),7 .03(d,J=8.1Hz,1H),6.14(p,J=7.4Hz,1H),2.42(s,3H),2.26-2.16(m,2H),1.92-1.65(m,6H). Examples (compounds) 3, 4, 6, 10, and 33 were synthesized using the same method as in Example 2. [Table 2] Preparation of 2-(3-cyclopentylpyridine-2-yl)-5-methyl-1H-benzo[d]imidazole (7) Method 2 [ka] Step 1.2-(3-bromopyridine-2-yl)-5-methyl-1H-benzo[d]imidazole A solution of 3-bromopyridine-2-carbaldehyde (500 mg, 2.69 mmol) and 4-methylbenzene-1,2-diamine (328 mg, 2.69 mmol) in water (10 mL) was stirred at room temperature for 20 minutes. Then, K2CO3 (556 mg, 4.03 mmol) was added, and the mixture was stirred for a further 10 minutes. KI (112 mg, 0.67 mmol) and I2 (682 mg, 2.69 mmol) were added, and the mixture was heated at 90°C with stirring for 2 hours. Sodium thiosulfate solution (10 mL) was added, and the product was extracted with RINKAN (10 mL x 3). The combined  layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. This was purified by flash chromatography (silica gel column, 10 g,  / PE, 0-100%) to obtain the product 2-(3-bromopyridine-2-yl)-5-methyl-1H-benzo[d]imidazole (260 mg, yield 33.6%) as a yellow solid. MS(ESI)m / z288[M+H] + . Step 2.2-(3-(cyclopenta-1-en-1-yl)pyridine-2-yl)-5-methyl-1H-benzo[d]imidazole To a solution of 2-(3-bromo-2-pyridyl)-5-methyl-1H-benzimidazole (250 mg, 0.868 mmol), 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (253 mg, 1.30 mmol), and Na2CO3 (184 mg, 1.74 mmol) in 1,4-dioxane (10 mL) and water (2 mL), Pd(dppf)Cl2 (63 mg, 0.0868 mmol) was added under N2 at room temperature. After the addition, the mixture was stirred at 110 °C for 12 hours. LC-MS indicated that the reaction was complete. Next, water (20 mL) was added to the reaction mixture and extracted with siRNA (20 mL x 3). The organic layers were then combined, dried (Na2SO4), and concentrated to dryness. The crude substance was purified by flash chromatography (silica gel column, 10 g, EA / PE, 0-50%) to obtain the product 2-[3-(cyclopenten-1-yl)-2-pyridyl]-5-methyl-1H-benzimidazole (100 mg, 0.36 mmol, yield 41.8%) as a yellow solid. MS(ESI)m / z276[M+H] + . Step 3.2-(3-cyclopentylpyridine-2-yl)-5-methyl-1H-benzo[d]imidazole To a solution of 2-[3-(cyclopenten-1-yl)-2-pyridyl]-5-methyl-1H-benzimidazole (100 mg, 0.363 mmol) in methanol (5 mL), PtO2 (30 mg) was added under N2 at room temperature. After the addition, the mixture was stirred at 75 °C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was then filtered and concentrated to dryness. The crude product was purified by preparative HPLC to obtain the product 2-(3-cyclopentylpyridin-2-yl)-5-methyl-1H-benzimidazole (0.98 mg, yield 1%) as a white solid. MS(ESI)m / z278[M+H] + . 1¹H NMR (400MHz, methanol-d4): δ 8.51 (s, 1H), 7.99 (d, J=8.0Hz, 1H), 7.69-7.33 (m, 3H), 7.13 (d, J=7.2Hz, 1H), 4.13-3.89 (m, 1H), 2.48 (s, 3H), 2.14-2.00 (m, 2H), 1.90-1.51 (m, 6H). Examples (compounds) 8, 9, and 25 were synthesized using the same method as in Example 7. [Table 3] Preparation of [2-(4-cyclopentyl-1,2,4-triazol-3-yl)-5-methyl-1H-indole-3-yl]methanol (11) [ka] Step 1. 4-Cyclopentyl-4H-1,2,4-Triazole To a solution of cyclopentanamine (10.0 equivalents, 6.9 mL, 70.3 mmol) in toluene (7 mL), N'-[(E)-dimethylaminomethyleneamino]-N,N-dimethyl-formamidine (1.00 equivalent, 1.00 g, 7.03 mmol) and 4-methylbenzenesulfonic acid (0.100 equivalents, 121 mg, 0.703 mmol) were added. The mixture was heated under reflux and stirred for 24 hours. The mixture was diluted with siRNA and washed with saturated NaHCO3. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (DCM / MeOH=3 / 97) to obtain 4-cyclopentyl-1,2,4-triazole (542 mg, 3.95 mmol, yield 56.2%). MS(ESI)m / z138[M+H] + . Step 2.3-Bromo-4-cyclopentyl-4H-1,2,4-triazole A solution of 4-cyclopentyl-1,2,4-triazole (1.00 equivalent, 287 mg, 2.09 mmol) in DCM (10 mL) was mixed with NBS (1.10 equivalent, 410 mg, 2.30 mmol). The mixture was stirred overnight in the dark at room temperature. The mixture was concentrated and purified by silica gel flash column chromatography (DCM / MeOH = 3 / 97) to obtain 3-bromo-4-cyclopentyl-1,2,4-triazole (188 mg, 0.870 mmol, yield 41.6%). MS(ESI)m / z216[M+H] + . Step 3.2-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole To a solution of 3-bromo-4-cyclopentyl-1,2,4-triazole (1.00 equivalent, 132 mg, 0.611 mmol) and 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.00 equivalent, 157 mg, 0.611 mmol) in water (0.6000 mL) and 1,4-dioxane (3 mL), K2CO3 (3.00 equivalent, 253 mg, 1.83 mmol) and Pd(dppf)Cl2 (0.100 equivalent, 45 mg, 0.0611 mmol) were added. The mixture was heated to 90°C and stirred overnight under N2. The mixture was diluted with  and washed with brine. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (DCM / MeOH=3 / 97) to obtain 2-(4-cyclopentyl-1,2,4-triazole-3-yl)-5-methyl-1H-indole (142 mg, 0.533 mmol, yield 87.3%). MS(ESI)m / z267[M+H] +- . Step 4.2-(4-cyclopentyl-4H-1,2,4-triazole-3-yl)-5-methyl-1H-indole-3-carbaldehyde POCl3 (3.00 equivalents, 0.040 mL, 0.428 mmol) was added to DMF (0.1100 mL) at 0°C and stirred for 2 hours. The mixture was added at 0°C to a solution of 2-(4-cyclopentyl-1,2,4-triazole-3-yl)-5-methyl-1H-indole (1.00 equivalents, 38 mg, 0.143 mmol) in DCM (0.5000 mL). The reaction product was quenched with saturated NaHCO3 and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (DCM / MeOH=3 / 97) to obtain 2-(4-cyclopentyl-1,2,4-triazole-3-yl)-5-methyl-1H-indole-3-carbaldehyde (19 mg, 0.0645 mmol, yield 45.2%). MS(ESI)m / z295[M+H] +- . Step 5. (2-(4-cyclopentyl-4H-1,2,4-triazole-3-yl)-5-methyl-1H-indole-3-yl)methanol To a solution of 2-(4-cyclopentyl-1,2,4-triazole-3-yl)-5-methyl-1H-indole-3-carbaldehyde (1.00 equivalent, 19 mg, 0.0645 mmol) in methanol (1 mL), NaBH4 (1.20 equivalent, 2.9 mg, 0.0775 mmol) was added at 0°C. The reaction mixture was stirred for 30 minutes. The reaction product was quenched with saturated NH4Cl. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain [2-(4-cyclopentyl-1,2,4-triazole-3-yl)-5-methyl-1H-indole-3-yl]methanol (4.0 mg, 0.0135 mmol, yield 20.9%) as a white solid. MS(ESI)m / z297[M+H] +- . 1H NMR(400MHz,MeOD)δ8.86(s,1H),7.62(dt,J=1.7,0.9Hz,1H),7.35(d,J=8.3Hz,1H),7.13(dd,J=8 .4,1.6Hz,1H),4.73(s,2H),4.71-4.66(m,1H),2.48(s,3H),2.24-2.12(m,2H),1.97-1.62(m,6H). Preparation of 5-cyclopentyl-4-(5-methyl-1H-benzo[d]imidazole-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-one (12) Method 3 [ka] Step 1. Ethylcyclopentanecarboimidate hydrochloride Cyclopentane carboninitrile (5.00 g, 52.6 mmol) in ethanol (40 mL) was cooled to 0°C by ice bath, and acetyl chloride (33.0 g, 420 mmol) was added dropwise over 0.5 hours. After the addition was complete, the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was concentrated under reduced pressure, the solid was polished with diethyl ether, and dried under vacuum to obtain ethylcyclopentane carboimidate hydrochloride (3 g, 16.9 mmol, yield 32%) as a white solid. MS(ESI)m / z142[M+H] + . Step 2. Ethyl 2-(cyclopentyl(ethoxy)methylene)hydrazine-1-carboxylate Ethylcyclopentanecarboimidate hydrochloride (3 g, 16.9 mmol) in anhydrous ethanol (60 mL) was cooled using an ice bath. Ethyl ethylhydrazine carboxylate (1.75 g, 16.9 mmol) was added dropwise to the mixture in anhydrous ethanol (60 mL). The reaction mixture was stirred at 0°C for 6 hours. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (silica gel column, 10 g, DCM / MeOH, 0-10%) to obtain ethyl 2-(cyclopentyl(ethoxy)methylene)hydrazine-1-carboxylate (3.3 g, 16.9 mmol, yield 85.6%) as a colorless oil. MS(ESI)m / z229[M+H] + . Step 3. 5-Cyclopentyl-4-(5-methyl-1H-benzo[d]imidazole-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-one A mixture of ethyl 2-(cyclopentyl(ethoxy)methylene)hydrazine-1-carboxylate (200 mg, 0.876 mmol) and 5-methyl-1H-benzimidazole-2-amine (129 mg, 0.876 mmol) was stirred at 165°C for 2 hours. The reaction mixture was then cooled, diluted with MeOH, and purified by preparative HPLC to obtain the product 5-cyclopentyl-4-(5-methyl-1H-benzo[d]imidazole-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-one (1.6 mg, 0.0055 mmol, yield 0.63%) as a white solid. MS(ESI)m / z284[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ7.59-7.30(m,2H),7.17(d,J=8.4Hz,1H),3.45-3.35(m,1H),2.48(s,3H),1.94-1.47(m,8H). Example (compound) 14 was synthesized using the same method as that used in Example 12. [Table 4] Preparation of (1-cyclopentyl-5-(5-methyl-1H-benzo[d]imidazole-2-yl)-1H-pyrrole-3-yl)methanol (16) Method 4 [ka] Step 1. Methyl 4-bromo-1-cyclopentyl-1H-pyrrole-2-carboxylate To a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (1.00 equivalent, 1000 mg, 4.90 mmol) in DMF (10 mL), cesium carbonate (2.00 equivalent, 3194 mg, 9.80 mmol) was added, and the mixture was stirred for 30 minutes. Then, bromocyclopentane (1.50 equivalent, 0.79 mL, 7.35 mmol) was added, and the mixture was stirred at 80°C for 24 hours. The progress of the reaction was monitored by TLC. Once complete, the mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=3:1) to obtain the product (760 mg, 57%). Step 2.4-Bromo-1-cyclopentyl-1H-pyrrole-2-carboxylic acid To a solution of methyl 4-bromo-1-cyclopentyl pyrrole-2-carboxylate (1.00 equivalent, 760 mg, 2.79 mmol) in THF (10 mL), 5 mL of 15% NaOH solution was added, and the mixture was stirred overnight at 85°C. The progress of the reaction was monitored by LC / MS. Once complete, the mixture was acidified with 4N HCl solution and extracted with siRNA. The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was used directly in the next step. MS(ESI)m / z259[M+H] + . Step 3.2-(4-bromo-1-cyclopentyl-1H-pyrrole-2-yl)-5-methyl-1H-benzo[d]imidazole To a solution of 4-methylbenzene-1,2-diamine (1.00 equivalent, 201 mg, 1.65 mmol) in toluene (5 mL), DIEA (1.90 equivalent, 0.54 mL, 3.13 mmol), HBTU (2.00 equivalent, 1249 mg, 3.29 mmol), and 4-bromo-1-cyclopentyl-pyrrole-2-carboxylic acid (1.00 equivalent, 425 mg, 1.65 mmol) were added. The mixture was then stirred at room temperature for 4 hours. The progress of the reaction was monitored by LC / MS. Once complete, the solvent was removed under reduced pressure, the crude product was dissolved in ethyl acetate, and washed with water. The organic layer was dried and concentrated. The residue was dissolved in AcOH (2 mL), and the solution was stirred at 90°C for 2 hours. The progress of the reaction was monitored by LC / MS. Once complete, the solvent was removed, and the residue was purified by column chromatography (PE / EA=1:1) to obtain the product (270 mg, 48%). MS(ESI)m / z345[M+H] + . Step 4. (1-Cyclopentyl-5-(5-methyl-1H-benzo[d]imidazole-2-yl)-1H-pyrrole-3-yl)methanol To a solution of 2-(4-bromo-1-cyclopentyl-pyrrole-2-yl)-5-methyl-1H-benzimidazole (1.00 equivalent, 65 mg, 0.189 mmol) in THF (5 mL), n-BuLi (2.00 equivalent, 24 mg, 0.378 mmol) was added dropwise at -78°C, and the mixture was stirred at the same temperature for 10 minutes. Then, DMF (5.00 equivalent, 0.073 mL, 0.944 mmol) was added, and the mixture was warmed to room temperature and stirred for a further 1 hour. Then, NaBH4 (3.00 equivalent, 21 mg, 0.562 mmol) was added to the mixture at 0°C, and the mixture was stirred at the same temperature for 2 hours. The progress of the reaction was monitored by LC / MS. After completion, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to obtain the product (3.5 mg, 6%). MS(ESI)m / z295[M+H] + . 1H NMR(400MHz,CDCl3)δ7.54(s,1H),7.43(s,1H),7.16-7.04(m,1H),6.86(s,1H),6.75 (s,1H),5.76(s,1H),4.56(s,2H),2.48(s,3H),2.29-2.12(m,2H),1.83-1.57(m,7H). Examples (compounds) 13, 17, 18, 19, 20, 24, 27, and 28 were synthesized using the same method as in Example 16. [Table 5-1] [Table 5-2] Preparation of 5-(2,3-dichlorophenyl)-1-(5-methyl-1H-benzo[d]imidazole-2-yl)-1,2-dihydro-3H-1,2,4-triazole-3-one (26) [ka] Step 1. O-methyl(2,3-dichlorobenzoyl)carbamothioate To a solution of 2,3-dichlorobenzoyl chloride (1.0 equivalent, 2000 mg, 9.55 mmol) in 30 mL of acetone, KSCN (1.0 equivalent, 928 mg, 9.55 mmol) was added. The mixture was stirred at 60°C for 3 hours until the starting materials were completely consumed. The reaction mixture was then cooled to room temperature, and MeOH (2.5 equivalents, 765 mg, 23.9 mmol) was added to the reaction mixture. After stirring at 60°C for a further 8 hours, O-methyl(2,3-dichlorobenzoyl)carbamothioate (1600 mg, 6.06 mmol, yield 63.4%) was obtained. The crude product was used directly in the next step without further purification. MS(ESI)m / z264 / 266[M+H] + . Step 2.2-[5-(2,3-dichlorophenyl)-3-methoxy-1,2,4-triazol-1-yl]-5-methyl-1H-benzimidazole A solution of 5-methyl-1H-benzimidazole-2-yl)hydrazine (1.00 equivalent, 246 mg, 1.51 mmol) and O-methyl N-(2,3-dichlorobenzoyl)carbamothioate (1.00 equivalent, 400 mg, 1.51 mmol) in methanol (6 mL) was stirred at 80°C for 48 hours. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2-[5-(2,3-dichlorophenyl)-3-methoxy-1,2,4-triazole-1-yl]-5-methyl-1H-benzimidazole (130 mg, 0.347 mmol, yield 22.9%). MS(ESI)m / z374 / 376[M+H] + . Step 3.3-(2,3-dichlorophenyl)-2-(5-methyl-1H-benzimidazole-2-yl)-1H-1,2,4-triazole-5-one 2-[5-(2,3-dichlorophenyl)-3-methoxy-1,2,4-triazole-1-yl]-5-methyl-1H-benzimidazole (1.00 equivalent, 200 mg, 0.534 mmol) was dissolved in a solution of hydrogen bromide (10.0 equivalent, 432 mg, 5.34 mmol) in acetic acid (1 mL), and the resulting solution was heated to 100°C and stirred for 6 hours. The reaction mixture was quenched with saturated NaHCO3 (aqueous solution) and then extracted with siRNA. All organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 3-(2,3-dichlorophenyl)-2-(5-methyl-1H-benzimidazole-2-yl)-1H-1,2,4-triazole-5-one (5.0 mg, 0.0139 mmol, yield 2.6%). MS(ESI)m / z360 / 362[M+H] + . 1H NMR(400MHz,DMSO)δ12.99(s,1H),12.12(s,1H),7.87-7.82(m,1H),7.65(dd,J=7.7,1.5Hz,1H),7.52(t,J= 7.9Hz,1H),7.33-7.24(m,1H),7.20(d,J=27.5Hz,1H),6.98(dd,J=31.9,8.1Hz,1H),2.36(d,J=23.6Hz,3H). Preparation of 3-(2,3-dichlorophenyl)-4-(5-methyl-1H-benzo[d]imidazole-2-yl)-1,2,4-oxadiazole-5(4H)-one (29) Method 5 [ka] Step 1. (1E)-2,3-Dichlorobenzaldehyde oxime To a solution of 2,3-dichlorobenzaldehyde (1.00 equivalent, 1000 mg, 5.71 mmol) in methanol (30 mL), hydroxylammonium chloride (1.20 equivalent, 476 mg, 6.86 mmol) was added, followed by the addition of pyridine (1.00 equivalent, 0.46 mL, 5.71 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The solvent was then removed under vacuum, and the residue was suspended in DCM (120 mL) and washed with 1 M HCl solution (3 × 30 mL), H₂O (3 × 30 mL), and brine solution. The organic layer was dried with (Na₂SO₄) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with hexane-siRNA or by recrystallization to obtain (1E)-2,3-dichlorobenzaldehyde oxime (630 mg, 3.32 mmol, yield 58.0%). MS(ESI)m / z190 / 192[M+H] + . Step 2. (1Z)-2,3-dichloro-N-hydroxy-benzimidoyl chloride To a stirred solution of (1E)-2,3-dichlorobenzaldehyde oxime (1.00 equivalent, 200 mg, 1.05 mmol) in DMF (5 mL), m-CPBA (5.00 equivalent, 703 mg, 5.26 mmol) was added and the mixture was stirred overnight at 20°C. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and Na2S2O3, and then extracted with Â. All organic layers were combined and concentrated under reduced pressure. The residue was purified to obtain (1Z)-2,3-dichloro-N-hydroxybenzimidoyl chloride (120 mg, 0.535 mmol, yield 50.79%). MS(ESI)m / z224 / 226[M+H] + . Step 3. 2,3-Dichloro-N'-hydroxy-N-(5-methyl-1H-benzimidazole-2-yl)benzamidine Triethylamine (2.00 equivalents, 108 mg, 1.07 mmol) was added to a stirred solution of (1Z)-2,3-dichloro-N-hydroxy-benzimidoyl chloride (1.00 equivalent, 120 mg, 0.535 mmol) and 5-methyl-1H-benzimidazole-2-amine (1.00 equivalent, 79 mg, 0.535 mmol) in DMF (1 mL). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2,3-dichloro-N'-hydroxy-N-(5-methyl-1H-benzimidazole-2-yl)benzamidine (155 mg, 0.462 mmol, yield 86.5%). MS(ESI)m / z335 / 337[M+H] + . Step 4.3-(2,3-dichlorophenyl)-4-(5-methyl-1H-benzimidazole-2-yl)-1,2,4-oxadiazole-5-one To a solution of 2,3-dichloro-N'-hydroxy-N-(5-methyl-1H-benzimidazole-2-yl)benzamidine (1.00 equivalent, 155 mg, 0.462 mmol) in MeCN (4 mL), CDI (1.20 equivalent, 90 mg, 0.555 mmol) was added, followed by the addition of K2CO3 (5.00 equivalent, 320 mg, 2.31 mmol). The resulting mixture was stirred at room temperature for 20 minutes. The crude mixture was concentrated under reduced pressure and then purified by short column chromatography using  in hexane to obtain the corresponding product, 3-(2,3-dichlorophenyl)-4-(5-methyl-1H-benzimidazole-2-yl)-1,2,4-oxadiazole-5-one (23 mg, 0.0637 mmol, yield 13.8%). MS(ESI)m / z361 / 363[M+H] + . 1 H NMR (400MHz, DMSO) δ13.01 (brs, 1H), 7.85-7.75 (m, 2H), 7.62-7.51 (m, 2H), 7.37-7.10 (m, 2H), 2.42 (d, J = 4.1Hz, 3H). Example (compound) 32 was synthesized using the same method as in Example 29. [Table 6] Preparation of 4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-one (36) [ka] Step 1. N-(2,3-dichlorophenyl)-2-(2-hydroxyacetyl)hydrazine-1-carboxamide To a solution of 1,2-dichloro-3-isocyanatobenzene (4 g, 21.3 mmol) in THF (100 mL), 2-hydroxyacetohydrazide (1.86 g, 20.6 mmol) was added under N2 conditions. The mixture was stirred under N2 conditions at room temperature for 2 hours. The mixture was filtered and concentrated under vacuum to obtain N-(2,3-dichlorophenyl)-2-(2-hydroxyacetyl)hydrazine-1-carboxamide (5.05 g, 86%) as a white solid. MS(ESI)m / z278[M+H] + . Step 2. 4-(2,3-dichlorophenyl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole-3-one A solution of N-(2,3-dichlorophenyl)-2-(2-hydroxyacetyl)hydrazine-1-carboxamide (50 mg, 0.18 mmol) in H2O (0.5 mL) was mixed with an aqueous NaOH solution (0.18 mL, 0.18 mmol, 1 mol / L in H2O) and stirred at 105°C for 3 hours. The mixture was concentrated. The residue was purified by reverse-phase HPLC to obtain 4-(2,3-dichlorophenyl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (41.5 mg, 11%) as a white solid. MS(ESI)m / z260[M+H] + . Step 3.4-(2,3-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carbaldehyde To a solution of 4-(2,3-dichlorophenyl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazole-3-one (100 mg, 0.39 mmol) in EA / DMSO (10 mL / 1.5 mL), IBX (540 mg, 1.93 mmol) was added. The mixture was refluxed for 1 hour. Then, water (5 mL) was added to the mixture and extracted with  (5 mL x 2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse-phase HPLC to obtain 4-(2,3-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carbaldehyde (91 mg, 92%) as a white solid. MS(ESI)m / z258[M+H]+ . Step 4. 4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-one To a solution of 4-(2,3-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carbaldehyde (91 mg, 0.35 mmol) in EtOH / H2O (20 mL / 5.3 mL), NaHSO3 (73 mg, 0.7 mmol) was added. The mixture was stirred at 0°C for 1 hour. 4-(trifluoromethyl)benzene-1,2-diamine (62 mg, 0.35 mmol) was added to the mixture. The mixture was stirred at 80°C for 16 hours. The mixture was concentrated, water (5 mL) was added, and it was extracted with RINKAN (5 mL x 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to obtain 4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-one (39.3 mg, 27%) as a white solid. MS(ESI)m / z414[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.11(s,2H),7.86(dd,J=8.0,1.2Hz,1H),7.78(s,1H),7.72-7.63(m,2H),7.58-7.51(m,2H). Preparation of 2-(3-(2,3-dichlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazole-4-yl)-5-(trifluoromethyl)-1H-indole-3-carbonitrile (41) Method 6 [ka] Step 1. 2-Iodo-N-(4-methoxybenzyl)-4-(trifluoromethyl)aniline To a solution of 2-iodo-4-(trifluoromethyl)aniline (1.00 equivalent, 1430 mg, 4.98 mmol) and 4-methoxybenzaldehyde (1.00 equivalent, 678 mg, 4.98 mmol) in toluene (15 mL), one drop of AcOH was added. The mixture was stirred at 100 °C for 16 hours. The mixture was then concentrated, and methanol (15 mL) was added to the residue. Then, NaBH4 (2.00 equivalent, 2112 mg, 9.96 mmol) was added. The mixture was stirred at room temperature for 1 hour. 20 mL of water was added to the reaction mixture, and the reaction mixture was extracted with siRNA. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was subjected to flash chromatography (20% siRNA in hexane) to obtain 2-iodo-N-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (1.20 g, 2.95 mmol, yield 59.15%) as a yellow solid. MS(ESI)m / z406.1[M+H] + . Step 2.2-Amino-1-(4-methoxybenzyl)-5-(trifluoromethyl)-1H-indole-3-carbonitrile To a solution of 2-iodo-N-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (1.00 equivalent, 700 mg, 1.72 mmol) in DMSO (50 mL), propanedinitrile (1.20 equivalent, 136 mg, 2.06 mmol), L-proline (0.200 equivalent, 40 mg, 0.344 mmol), CuI (0.100 equivalent, 33 mg, 0.172 mmol), and K2CO3 (2.00 equivalent, 475 mg, 3.44 mmol) were added. The reaction mixture was stirred under an argon atmosphere at 60°C for 16 hours. 100 mL of water was added to the reaction mixture, and the reaction mixture was extracted with RINKAN. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by elution with ethyl acetate in 0-40% hexane using an SiO2 gel column to obtain 2-amino-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-3-carbonitrile (350 mg, 0.963 mmol, yield 56.01%) as a brown oil. MS(ESI)m / z 346.1[M+H] + . Step 3.2,3-Dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-2-yl]benzamide To a stirred solution of 2-amino-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-3-carbonitride (1.00 equivalent, 350 mg, 1.01 mmol) in THF (15 mL), LiHMDS (2.00 equivalent, 2.0 mL, 2.03 mmol) in THF (1.0 M) was added dropwise at -10°C. The resulting mixture was stirred for 30 minutes. Then, 2,3-dichlorobenzoyl chloride (2.00 equivalent, 425 mg, 2.03 mmol) in THF (5 mL) was added dropwise. The resulting mixture was stirred for 1 hour. The reaction was quenched with NaHCO3 (aqueous solution). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (C18) to obtain 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-2-yl]benzamide (402 mg, 0.776 mmol, yield 76.52%) as a white solid. MS(ESI)m / z516.1[M+H] + Step 4. 2,3-Dichloro-N-[3-Cyano-1-[(4-Methoxyphenyl)methyl]-5-(Trifluoromethyl)indole-2-yl]benzenecarbothioamide To a solution of 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-2-yl]benzamide (1.00 equivalent, 150 mg, 0.289 mmol) in toluene (5 mL), Lawson's reagent (2.00 equivalent, 234 mg, 0.579 mmol) was added. The solution was then stirred at 60°C for 4 hours. After cooling to room temperature, 20 mL of water was added. The mixture was extracted with DCM (20 mL x 3), the organic layers were combined, washed with water, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (C18) to obtain 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-2-yl]benzenecarbothioamide (100 mg, 0.187 mmol, yield 64.66%) as a yellow solid. (ESI)m / z534.2[M+H] + . Step 5. N'-Amino-2,3-Dichloro-N-[3-Cyano-1-[(4-Methoxyphenyl)methyl]-5-(Trifluoromethyl)Indole-2-yl]benzamidine To a solution of TEA (2.00 equivalents, 0.052 mL, 0.374 mmol) in THF (10 mL), 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-2-yl]benzenecarbothioamide (1.00 equivalents, 100 mg, 0.187 mmol) and hydrazine hydrate (1.00 equivalents, 12 mg, 0.187 mmol) were added. The mixture was then stirred at 80°C for 1 hour. After cooling to room temperature, 20 mL of water was added. The mixture was extracted with DCM (20 mL x 3), the organic layers were combined, washed with water, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (C18) to obtain N'-amino-2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-2-yl]benzamidine (60 mg, 0.113 mmol, yield 60.23%) as a yellow solid. (ESI)m / z 532.1[M+H] + . Step 6.2-[3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazole-4-yl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-3-carbonitrile To a solution of N'-amino-2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-2-yl]benzamidine (1.00 equivalent, 20 mg, 0.0376 mmol) in MeCN (10 mL), di(imidazole-1-yl)methanone (3.00 equivalent, 18 mg, 0.113 mmol) was added. The reaction mixture was stirred at 80°C for 2 hours. After cooling to room temperature, 10 mL of water was added to the mixture. The mixture was extracted with DCM (10 mL x 3), the organic layers were combined, washed with water, dried over Na2SO4, and evaporated. The residue was purified by flash chromatography (C18) to obtain 2-[3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazole-4-yl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-3-carbonitrile (15 mg, 0.0269 mmol, yield 71.51%) as a yellow solid. (ESI)m / z 558.2[M+H] + . Step 7.2-(3-(2,3-dichlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4triazole-4-yl)-5-(trifluoromethyl)-1H-indole-3-carbonitrile To a solution of 2-[3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazole-4-yl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-3-carbonitrile (1.00 equivalent, 12 mg, 0.0215 mmol) in DCM (2 mL), TFA (1.0 mL) was added at 0°C. The solution was stirred at 0°C for 2 hours. The pH of the solution was adjusted to 9 with saturated K2CO3 (aqueous solution). The resulting solution was extracted with DCM (10 mL x 3). The organic layers were combined, washed with water (15 mL), dried, and concentrated under vacuum. The residue was purified by preparative TLC (MeOH / DCM = 1 / 10) to obtain 2-[3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazole-4-yl]-5-(trifluoromethyl)-1H-indole-3-carbonitrile (5.0 mg, 0.0114 mmol, yield 53.09%) as a white solid. (ESI)m / z438.2[M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.41(s,1H),7.79-7.73(m,2H),7.70(dd,J=8.6,1.9Hz,1H),7.58(dd,J=7.7,1.6Hz,1H),7.46(t,J=7.9Hz,1H). Examples (compounds) 30 and 31 were synthesized using the same method as in Example 41. [Table 7] Preparation of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole (49) Method 7 [ka] Step 1. Preparation of 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole A mixture of 2,3-dichloroaniline (10 g, 0.0617 mol) and (E)-N'-((E)-(dimethylamino)methylene)-N,N-dimethylformohydrazoneamide (8.77 g, 0.0617 mol) was stirred at 260°C for 20 hours. After cooling, the reaction mixture was diluted with water (60 mL) and extracted with siRNA (20 mL x 3). All organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (CH3OH / DCM = 1:10) to obtain 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole (11.5 g, yield 87.03%) as a white solid. MS(ESI)m / z 214.1[M+H] + . Step 2. Preparation of 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-carbaldehyde POCl3 (11 mL) was dissolved in DMF (32 mL), and the resulting solution was cooled to 0°C for 2 hours under an N2 atmosphere. 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole (5 g, 0.0234 mol) dissolved in DCM (42 mL) was added to the system by syringe, and the mixture was stirred at 0°C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with ELISA (20 mL x 3). All organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (EA / PE = 1:1) to obtain 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-carbaldehyde (4.5 g, yield 79.49%) as a white solid. MS(ESI) m / z 242.1[M+H] + . Step 3.5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole A mixture of 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-carbaldehyde (4.5 g, 0.0186 mol), 4-bromobenzene-1,2-diamine (3.48 mg, 0.0186 mol), and FeCl3·H2O (1.01 g, 0.0037 mol) was stirred at 85°C for 16 hours. Then, a second batch of FeCl3·H2O (1.01 g, 0.0037 mol) was added. The reaction mixture was stirred under O2 at 85°C for 2 hours. After cooling, the reaction mixture was diluted with water (60 mL) and extracted with RINKAN (20 mL x 3). All organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (EA:PE=1:3) to obtain 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole (2.5 g, yield 32.8%) as a reddish-white solid. MS(ESI)m / z410[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.79(s,1H),9.05(s,1H),7.92(dd,J=8.2,1.5Hz,1H),7.78(dd,J=8.0,1.5Hz ,1H),7.66(d,J=1.9Hz,1H),7.59(t,J=8.1Hz,1H),7.45(d,J=8.6Hz,1H),7.34(dd,J=8.7,1.9Hz,1H). Examples (compounds) 1, 5, 15, 46, 50, 72, 93, 94, 95, 96, 109, 128, and 132 were synthesized using the same method as in Example 49. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] Preparation of 2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(3-methyl-1H-pyrazole-5-yl)-1H-benzo[d]imidazole (51) Method 8 [ka] To a solution of 5-bromo-2-[4-(2,3-dichlorophenyl)-1,2,4-triazol-3-yl]-1H-benzimidazole (1.00 equivalent, 155 mg, 0.379 mmol) in 1,4-dioxane (5 mL) and water (1 mL), (3-methyl-1H-pyrazole-5-yl)boronic acid (2.00 equivalent, 95 mg, 0.758 mmol), Pd(dppf)Cl2 (0.300 equivalent, 92 mg, 0.114 mmol), and K3PO4 (3.00 equivalent, 241 mg, 1.14 mmol) were added. The mixture was stirred at 100°C for 2 hours. The mixture was diluted with  and washed with water. The organic layers were combined, dried over anhydrous sodium sulfate, and purified by preparative HPLC to obtain 2-[4-(2,3-dichlorophenyl)-1,2,4-triazol-3-yl]-5-(3-methyl-1H-pyrazole-5-yl)-1H-benzimidazole (13 mg, 0.0301 mmol, yield 7.9%). MS(ESI)m / z410 / 412[M+H] + . 1 H NMR (400MHz, DMSO) δ13.56(s,1H),12.52(s,1H),9.03(s,1H),7.95-7.75(m,3H),7.64-7.43(m,3H),6.43(s,1H),2.23(s,3H). Examples (compounds) 55, 56, 68, 73, 74, 78, 79, and 81 were synthesized using the same method as in Example 51. [Table 9-1] [Table 9-2] Preparation of 5-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole-5-yl)-3-methylisothiazole (80) Method 9 [ka] Step 1. Preparation of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole A solution of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole (1.85 g, 0.0045 mol) and NaH (60% dispersion in mineral oil, 0.22 g, 0.0055 mol) was added to THF (15 mL). The reaction mixture was stirred at 0°C for 30 minutes, and then SEM-Cl (0.76 g, 0.0046 mol) was added. The reaction mixture was stirred at 25°C for 18 hours. The reaction mixture was extracted with toluene (100 mL x 3), concentrated, and the residue was purified by silica gel chromatography (PE / EA = 5:1) to obtain 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.2 g, yield 50%) as an oily substance. MS(ESI)m / z538[M+H] + . Step 2. Preparation of 2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole A mixture of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.163 g, 0.0022 mol), B(Pin)2 (1.100 g, 0.0043 mol), Pd(dppf)Cl2 (0.158 g, 0.0002 mol), and AcOH (1.061 g, 0.0108 mol) in 1,4-dioxane (20 mL) was stirred at 90°C for 18 hours under an N2 atmosphere. After the reaction was complete, the reaction product was diluted with H2O (50 mL) and then extracted with SiO (50 mL x 3). All organic layers were combined and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EA = 5:1) to obtain 2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (0.7 g, yield 55.1%) as an oily substance. MS(ESI)m / z586.2[M+H] + . Step 3.5 Preparation of (2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)-3-methylisothiazole (3) A mixture of 2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (100 mg, 0.1702 mmol), 5-bromo-3-methylisothiazole (36.36 mg, 0.2042 mmol), Pd(dppf)Cl2 (18.68 mg, 0.0255 mmol), and K2CO3 (70.57 mg, 0.5102 mmol) in 1,4-dioxane / H2O (10 / 2 mL) was stirred at 90°C for 16 hours under an N2 atmosphere. After cooling, the reaction mixture was diluted with water (60 mL) and extracted with Âxa (20 mL x 3). All organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (EA / PE = 1:1) to obtain 5-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)-3-methylisothiazole (60 mg, yield 82.49%) as an oil. MS(ESI)m / z 557.1[M+H] + . Step 4.5 Preparation of (2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole-5-yl)-3-methylisothiazole A mixture of 5-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)-3-methylisothiazole (60 mg, 0.1074 mmol) in TFA / DCM (1 / 5 mL) was stirred at 25°C for 16 hours. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with DCM (20 mL × 3). All organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to obtain the crude product, which was purified by perp-HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-H₂O (0.1% TFA)) to obtain the desired product (12.5 mg, yield 27.28%) as a white solid. MS(ESI)m / z427.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ13.84(s,1H),9.08(s,1H),7.94(d,J=7.8Hz,1H),7.81(d,J=8.2Hz,2H),7.61(t,J=8.2Hz,4H),2.43(s,3H). Examples (compounds) 82 and 83 were synthesized using the same method as in Example 80. [Table 10] Preparation of 5-(2,3-dichlorophenyl)-4-[5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1H-pyridine-2-one (40) Method 10 [ka] Step 1.5-(2,3-dichlorophenyl)-2-methoxyisonicotinaldehyde To a solution of 5-bromo-2-methoxypyridine-4-carbaldehyde (1.00 equivalent, 400 mg, 1.85 mmol) in DMF (9 mL), (2,3-dichlorophenyl)boronic acid (1.00 equivalent, 353 mg, 1.85 mmol), Na2CO3 (3.00 equivalent, 589 mg, 5.55 mmol), and Pd(dppf)Cl2 (0.100 equivalent, 135 mg, 0.185 mmol) were added. The mixture was stirred under N2 at 110°C for 12 hours. The mixture was diluted with  and washed with brine. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / EA=20 / 1) to obtain 5-(2,3-dichlorophenyl)-2-methoxypyridine-4-carbaldehyde (351 mg, 1.24 mmol, yield 67.19%). MS(ESI)m / z282[M+H] +- . Step 2.2-(5-(2,3-dichlorophenyl)-2-methoxypyridine-4-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 5-(2,3-dichlorophenyl)-2-methoxypyridine-4-carbaldehyde (1.00 equivalent, 350 mg, 1.24 mmol) in water (12 mL) and THF (2 mL), 4-(trifluoromethyl)benzene-1,2-diamine (1.00 equivalent, 219 mg, 1.24 mmol) was added. The reaction mixture was stirred for 20 minutes, after which K2CO3 (2.00 equivalent, 343 mg, 2.48 mmol) was added. The reaction mixture was stirred for a further 10 minutes, and then the THF was evaporated. I2 (1.00 equivalent, 315 mg, 1.24 mmol) and KI (0.250 equivalent, 51 mg, 0.310 mmol) were added. The mixture was heated to 80°C and stirred for 2 hours. The reaction mixture was quenched with saturated Na2S2O3 and extracted with RINKAN. The combined organic phases were dried with Na2SO4 and concentrated to obtain the crude product, which was used in the next step without further purification. MS(ESI)m / z438[M+H] +- . Step 3.5-(2,3-dichlorophenyl)-4-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)pyridine-2(1H)-one To a solution of 2-[5-(2,3-dichlorophenyl)-2-methoxy-4-pyridyl]-5-(trifluoromethyl)-1H-benzimidazole (1.00 equivalent, 543 mg, 1.24 mmol) in DMF (3 mL), TsOH (5.00 equivalent, 1068 mg, 6.20 mmol) and LiCl (5.00 equivalent, 263 mg, 6.20 mmol) were added. The mixture was stirred at 120°C for 30 minutes. The reaction mixture was diluted with  and washed with brine. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 5-(2,3-dichlorophenyl)-4-[5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1H-pyridine-2-one (130 mg, 0.306 mmol, yield 24.7%) as a white solid. MS(ESI)m / z424[M+H] +- . 1 H NMR(400MHz,DMSO)δ13.26(s,1H),12.19(s,1H),7.75(s,1H),7.64(d,J=8.5Hz,1H),7.58( dd,J=6.9,2.6Hz,1H),7.53(s,1H),7.48(d,J=8.5Hz,1H),7.41-7.33(m,2H),6.94(s,1H). Examples (compounds) 21, 22, 23, 34, 35, 37, 38, 39, 42, 43, 44, 48, 54, 57, 60, 61, 64, 65, 75, 76, 86, 92, and 98 were synthesized using the same method as in Example 40. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5] [Table 11-6] Preparation of 6-[(1-oxo-2-isoquinolyl)methyl]-3H-1,3-benzoxazole-2-one (45) [ka] Step 1. Ethyl 1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxylate To a solution of ethyl 2-oxoacetate (0.83 mL, 4.18 mmol) in toluene (20 mL), 2,3-dichloroaniline (678 mg, 4.18 mmol) and Ti(OiPr)4 (2.5 mL, 8.37 mmol) were added. The reaction mixture was heated to 70°C and stirred for 4 hours. The resulting mixture was evaporated to remove the solvent, and the residue was then dissolved in EtOH. K2CO3 (1.73 g, 12.6 mmol) and TosMIC (980 mg, 5.02 mmol) were added to this solution. The mixture was heated to 80°C and stirred for 5 hours. The mixture was diluted with siRNA and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash column chromatography eluted with (PE / Â)(1 / 5) to obtain ethyl 1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxylate (1.1 g, yield 92.6%) as a yellow solid. MS(ESI)m / z285[M+H] + . Step 2.1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxylic acid To a solution of ethyl 1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxylate (1.1 g, 3.8 mmol) in THF / H2O (10:1, 22 mL), lithium hydroxide monohydrate (1.6 g, 38.5 mmol) was added at room temperature. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with water and the pH was adjusted to 7. The mixture was diluted with ELISA and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain 1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxylic acid (0.9 g, yield 90.4%) as a yellow solid, which was used in the next step without further purification. MS(ESI)m / z257[M+H] + . Step 3. N-(2-amino-4-(trifluoromethyl)phenyl)-1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxamide To a solution of 0.9 g (3.65 mmol) of 1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxylic acid in 20 mL of DMF, HBTU (2.8 g, 7.3 mmol), 4-(trifluoromethyl)benzene-1,2-diamine (0.78 g, 4.4 mmol), and DIEA (1.43 g, 11.1 mmol) were added. The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the mixture was diluted with ELISA and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain N-(2-amino-4-(trifluoromethyl)phenyl)-1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxamide (1.5 g) as a red oil, which was used in the next step without further purification. MS(ESI)m / z415[M+H] + . Step 4.2-(1-(2,3-dichlorophenyl)-1H-imidazole-5-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole A solution of N-(2-amino-4-(trifluoromethyl)phenyl)-1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxamide (400 mg, crude) in AcOH (20 mL) was heated to 90°C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water and the pH was adjusted to 7. The mixture was diluted with  and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 2-(1-(2,3-dichlorophenyl)-1H-imidazole-5-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (5.0 mg, yield 1%) as a yellow powder. MS(ESI)m / z397[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.27(bs,1H),7.86(dd,J=8.0Hz,J=1.2Hz1H),7.72(s,1H),7.69-7.59(m,3H),7.56(t,J=8.0Hz,1H),7.52-7.41(m,2H). Preparation of 2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole-3-carbonitrile (47) [ka] Step 1. 3-Bromo-4-(2,3-dichlorophenyl)pyridine To a solution of 3-bromo-4-iodopyridine (4 g, 14.1 mmol) in dioxane / H2O (100 mL / 20 mL), 2-(2,3-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.6 g, 16.9 mmol), Pd(PPh3)4 (1.63 g, 1.41 mmol), and Na2CO3 (2.99 g, 28.2 mmol) were added. The reaction mixture was stirred under N2 at 100°C for 16 hours. The mixture was diluted with water (50 mL) and extracted with ELISA (50 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and purified by FCC (PE / EA=5 / 1) to obtain 3-bromo-4-(2,3-dichlorophenyl)pyridine (2.1 g, 50%) as a yellow oil. MS(ESI)m / z302[M+H] + . Step 2. tert-butyl 2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate To a solution of 3-bromo-4-(2,3-dichlorophenyl)pyridine (300 mg, 1 mmol) in dioxane / H2O (15 mL / 3 mL), (1-(tert-butoxycarbonyl)-5-(trifluoromethyl)-1H-indole-2-yl)boronic acid (492 mg, 1.49 mmol), K2CO3 (412 mg, 2.99 mmol), and Pd(dppf)Cl2 (73 mg, 0.1 mmol) were added. The mixture was stirred under N2 at 90°C for 2 hours. H2O (20 mL) was added to the mixture, and the reaction mixture was then extracted with Âr (10 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by FCC (PE / EA=1 / 1) to obtain tert-butyl 2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (120 mg, 24%) as a yellow solid. MS(ESI)m / z507[M+H] + . Step 3.2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole A solution of tert-butyl 2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (450 mg, 0.89 mmol) in DCM / TFA (10 mL / 10 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated, adjusted to pH=9 with saturated NaHCO3, and then extracted with DCM (10 mL x 2). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by FCC (PE / EA=1 / 1) to obtain 2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole (250 mg, 70%) as a yellow solid. MS(ESI)m / z407[M+H] + . Step 4.2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole-3-carbonitride To a solution of 2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole (200 mg, 0.49 mmol) in DCM (15 mL), sulfur isocyanatide chloride (347 mg, 2.46 mmol) was added. The mixture was stirred at room temperature for 16 hours. Then, DMF (2 mL) was added to the mixture and stirred at room temperature for 1 hour. H2O (10 mL) was added to the reaction mixture and then extracted with DCM (10 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to obtain 2-(4-(2,3-dichlorophenyl)pyridine-3-yl)-5-(trifluoromethyl)-1H-indole-3-carbonitol (56.4 mg, 27%) as a grayish-white solid. MS(ESI)m / z432[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.93(s,1H),8.96(s,1H),8.90(d,J=5.2Hz,1H),7.90(s,1H),7.74-7.56(m,4H),7.43-7.27(m,2H). Preparation of 5-(2,3-dichlorophenyl)-4-(5-(2-hydroxypropan-2-yl)-1H-benzo[d]imidazole-2-yl)-1-methylpyridine-2(1H)-one (83) [ka] Step 1. Methyl 5-(2,3-dichlorophenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate To a solution of methyl 5-bromo-1-methyl-2-oxopyridine-4-carboxylate (1.00 equivalent, 1040 mg, 4.23 mmol) in 1,4-dioxane (30 mL), (2,3-dichlorophenyl)boronic acid (1.00 equivalent, 807 mg, 4.23 mmol), cesium carbonate (3.00 equivalent, 4131 mg, 12.7 mmol), and Pd(dppf)Cl2 (0.100 equivalent, 309 mg, 0.423 mmol) were added under Ar. The reaction mixture was then stirred at 100°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE / EA=1:1) to obtain the product (314 mg, 25%). MS(ESI)m / z312[M+H] + . Step 2.5-(2,3-dichlorophenyl)-1-methyl-2-oxopyridine-4-carboxylic acid To a solution of methyl 5-(2,3-dichlorophenyl)-1-methyl-2-oxopyridine-4-carboxylate (1.00 equivalent, 314 mg, 1.01 mmol) in THF (4 mL), 15% NaOH (2.0 mL) was added, and the mixture was stirred at 85°C for 2 hours. The progress of the reaction was monitored by LC / MS. Once complete, the mixture was diluted with water and washed with DCM. The aqueous layer was acidified to pH=2 with 4N HCl. The mixture was extracted with ELISA, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step. MS(ESI)m / z298[M+H] + . Step 3.5-(2,3-dichlorophenyl)-4-(5-isopropenyl-1H-benzimidazole-2-yl)-1-methylpyridine-2-one In a solution of 4-isopropenylbenzene-1,2-diamine (1.00 equivalent, 149 mg, 0.503 mmol) and 5-(2,3-dichlorophenyl)-1-methyl-2-oxopyridine-4-carboxylic acid (1.00 equivalent, 150 mg, 0.503 mmol) in DCM (20 mL), HOBT (1.30 equivalents, 0.653 mmol), EDCI (1.30 equivalents, 0.653 mmol), and DIPEA (10.00 equivalents, 5.03 mmol) were added. The mixture was stirred at 25°C for 2 hours. After the reaction was complete, the mixture was diluted with DCM and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to obtain an oily substance, which was used in the next step without further purification. The solution of the previously prepared crude product in AcOH (20 mL) was heated to 90°C and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water and the pH was adjusted to 7. The mixture was diluted with  and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain the product (70 mg, 34%). MS(ESI)m / z410[M+H] + . Step 4.5-(2,3-dichlorophenyl)-4-[5-(1-hydroxy-1-methyl-ethyl)-1H-benzimidazole-2-yl]-1-methylpyridine-2-one To a solution of 5-(2,3-dichlorophenyl)-4-(5-isopropenyl-1H-benzimidazole-2-yl)-1-methylpyridine-2-one (1.00 equivalent, 38 mg, 0.0926 mmol) in 2-propanol (5 mL), phenylsilane (2.00 equivalent, 0.023 mL, 0.185 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (0.100 equivalent, 5.6 mg, 0.00926 mmol) were added at 0°C under an O2 atmosphere. The reaction mixture was then stirred for 2 hours. After completion, the reaction mixture was quenched with water and extracted by DCM. The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the product (1 mg, 2.5%) as a white solid. MS(ESI)m / z428[M+H] + . 1 H NMR (400MHz, CDCl3) δ8.01(s,1H),7.54(d,J=6.4Hz,2H),7.31(m,2H),7.18(m,2H),6.99(s,1H),3.64(s,3H),1.26(s,6H). Preparation of 2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (59) Method 11 [ka] Step 1. 4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazole Chloro(trimethyl)silane (5598 mg, 51.5 mmol) was added to a solution of 2-chloro-3-fluoroaniline (0.50 g, 3.44 mmol) and N-formamideformamide (0.91 g, 10.3 mmol) in pyridine (30 mL), and the mixture was stirred at 110 °C for 12 hours. LC-MS indicated that the reaction was complete. The reaction mixture was then cooled, filtered, and concentrated to dryness. The crude product was purified by flash chromatography (silica gel column, 30 g, MeOH / Â, 0-20%) to obtain the product 4-(2-chloro-3-fluorophenyl)-1,2,4-triazole (420 mg, 2.13 mmol, yield 61.9%) as a white solid. MS(ESI)m / z198[M+H] + Step 2.4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazole-3-carbaldehyde To a solution of 4-(2-chloro-3-fluorophenyl)-1,2,4-triazole (260 mg, 1.32 mmol) in DMF (0.5 mL), POCl3 (0.61 mL, 6.58 mmol) dissolved in DMF (1.9 mL) was added dropwise under N2 at 0°C. The reaction mixture was stirred at 0°C for 1 hour. Then, the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction mixture was quenched with aqueous NaHCO3 solution (30 mL) and extracted with RINKAN (20 mL x 3). The organic layers were combined, dried, and concentrated to obtain the crude product 4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazole-3-carbaldehyde (200 mg, 0.886 mmol, yield 67.4%) as a white solid. MS(ESI)m / z226[M+H] + . Step 3.2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole A solution of 4-(2-chloro-3-fluorophenyl)-1,2,4-triazole-3-carbaldehyde (200 mg, 0.886 mmol) and 4-(trifluoromethyl)benzene-1,2-diamine (156 mg, 0.886 mmol) in water (10 mL) was stirred at room temperature for 20 minutes. K2CO3 (184 mg, 1.33 mmol) was added to this mixture and stirred for a further 10 minutes. Then KI (37 mg, 0.222 mmol) and I2 (225 mg, 0.886 mmol) were added. The mixture was then stirred at 90°C for 2 hours. The reaction mixture was quenched with sodium thiosulfate solution (10 mL; 5%). The reaction mixture was extracted with Âr (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude substance was purified by preparative HPLC to obtain 2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (1 mg, 0.0025 mmol, yield 0.6%) as a brown solid. MS(ESI)m / z382[M+H] + . 1 ¹H NMR (400MHz, methanol-d4): δ 8.88 (s, 1H), 7.84 (s, 1H), 7.69 (d, J=8.4Hz, 1H), 7.63-7.45 (m, 4H). Example (compound) 69 was synthesized using the same method as that used in Example 59. [Table 12] Preparation of 2-(4-(4,5-dichloro-1-methyl-1H-pyrazole-3-yl)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (53) Method 12 [ka] Step 1. 4,5-Dichloro-3-isothiocyanato-1-methylpyrazole To a mixture of 4,5-dichloro-1-methylpyrazole-3-amine (1.00 equivalent, 500 mg, 3.01 mmol) in DCM (5 mL) and saturated NaHCO3 (5 mL), thiocarbonyl dichloride (1.10 equivalent, 0.25 mL, 3.31 mmol) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After the reaction was complete, the reaction mixture was extracted with DCM, the organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step. Step 2. N-(4,5-dichloro-1-methyl-1H-pyrazole-3-yl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-carbonyl)hydrazine-1-carbothioamide To a solution of 4,5-dichloro-3-isothiocyanato-1-methylpyrazole (1.00 equivalent, 624 mg, 3.00 mmol) in THF (5 mL), 5-(trifluoromethyl)-1H-benzimidazole-2-carbohdrazide (1.00 equivalent, 733 mg, 3.00 mmol) was added. The reaction mixture was stirred at 70°C for 2 hours. After the reaction was complete, the organic layer was separated and concentrated. The resulting crude product was used directly in the next step. Step 3.4-(4,5-dichloro-1-methyl-1H-pyrazole-3-yl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-4H-1,2,4-triazole-3-thiol A suspension of 1-(4,5-dichloro-1-methylpyrazole-3-yl)-3-[[5-(trifluoromethyl)-1H-benzimidazole-2-carbonyl]amino]thiourea (1.00 equivalent, 146 mg, 0.323 mmol) in 1 M NaOH (1.00 equivalent, 4.0 mL, 0.323 mmol) was stirred at 80°C for 4 hours. After the reaction was complete, 3 M HCl was added to the mixture to adjust the pH to 7. The reaction mixture was extracted with ELISA. The organic layer was dried and concentrated. The resulting crude product was used directly in the next step. Step 4.2-(4-(4,5-dichloro-1-methyl-1H-pyrazole-3-yl)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 4-(4,5-dichloro-1-methylpyrazole-3-yl)-5-[5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1,2,4-triazole-3-thiol (1.00 equivalent, 30 mg, 0.0691 mmol) in DCM (10 mL), mCPBA (2.00 equivalent, 24 mg, 0.138 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solvent was removed, and the residue was purified by preparative HPLC to obtain the product (2 mg, 7%). MS(ESI)m / z402[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ14.09(bs,1H),9.14(s,1H),7.93(s,1H),7.77(d,J=8.5Hz,1H),7.58(s,1H),3.97(s,3H). Example (compound) 53 was synthesized using the same method as that used in Example 58. [Table 13] Preparation of 2-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (84) Method 13 [ka] Step 1. N-(2,3-difluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbothioamide To a solution of 2,3-difluoroaniline (70 mg, 0.541 mmol) in THF (5 mL), LiHMDS (1.20 equivalents, 0.50 mL, 0.590 mmol) was added under N2 at 0°C. The mixture was stirred at 0°C for 0.5 hours. Next, methyl 5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-carboditioate (200 mg, 0.492 mmol) was added to the mixture. The mixture was stirred at room temperature for 0.5 hours. The resulting mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. MS(ESI)m / z488[M+H] + . Step 2. N-(2,3-difluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbohydrazonamide To a solution of N-(2,3-difluorophenyl)-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-carbothioamide (239 mg, 0.490 mmol) in THF (5 mL), NH2NH2.H2O (0.12 mL, 1.96 mmol) was added at room temperature. The reaction mixture was stirred at 75 °C for 1 hour. The mixture was then concentrated directly and used in the next step without further purification. MS(ESI)m / z486[M+H] + . Step 3.2-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole A solution of N-(2,3-difluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbohydrazonamide (40 mg, 0.0824 mmol) in trimethoxymethane (3.0 mL, 27.4 mmol) was stirred at 110°C for 5 hours. The reaction mixture was then concentrated and used in the next step without further purification. MS(ESI)m / z496[M+H] + . Step 4.2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-(4-(2,3-difluorophenyl)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (42 mg, 0.0838 mmol) in DCM (1 mL), TFA (1.0 mL, 13.1 mmol) was added at room temperature. The reaction mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to obtain the product 2-[4-(2,3-difluorophenyl)-1,2,4-triazole-3-yl]-5-(trifluoromethyl)-1H-benzoimidazole (5.0 mg, 0.013 mmol, yield 15.5%) as a white solid. MS(ESI)m / z366[M+H] + . 1 ¹H NMR (400MHz, methanol-d4): δ 8.93 (s, 1H), 7.86 (s, 1H), 7.72 (d, J=8.4Hz, 1H), 7.62-7.50 (m, 2H), 7.48-7.34 (m, 2H). Examples (compounds) 52, 62, 63, 66, 67, 70, 71, 85, 91, 99, 105, 106, 114, 115, 118, 119, 120, and 123 were synthesized using the same method as in Example 84. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] Preparation of 2-(4-(2,3-dichlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (87) [ka] Step 1. N-(2-amino-4-(trifluoromethyl)phenyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide To a solution of 4-(trifluoromethyl)benzene-1,2-diamine (2.0 g, 0.01 mol) in DMF (20 mL), 5-methyl-1,3,4-oxadiazole-2-carboxylic acid (2.17 g, 0.016 mol), HATU (6.44 g, 0.016 mol), and DIEA (4.38 g, 0.033 mol) were added. The reaction mixture was stirred under N2 at 25°C for 12 hours. The reaction mixture was diluted with HCl and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / HCl = 2 / 1) to obtain N-(2-amino-4-(trifluoromethyl)phenyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (1.0 g, yield 29.20%) as a yellow solid. MS(ESI)m / z287[M+H] + . Step 2. 2-Methyl-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1,3,4-oxadiazole A solution of N-(2-amino-4-(trifluoromethyl)phenyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (1.0 g, 3.5 mmol) in AcOH (5 mL) was heated to 80°C and stirred for 2 hours. After the reaction was complete, the resulting mixture was concentrated under reduced pressure to obtain 2-methyl5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1,3,4-oxadiazole (0.8 g, yield 82.86%) as a white solid. MS(ESI)m / z269[M+H] + . Step 3.2-(4-(2,3-dichlorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-methyl-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1,3,4-oxadiazole (800 mg, 2.97 mmol) in toluene (10 mL), 2,3-dichloroaniline (722 mg, 4.45 mmol) and p-toluenesulfonic acid (767 mg, 4.45 mmol) were added. The reaction mixture was stirred under N2 at 110°C for 12 hours. The mixture was diluted with  and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 2-(4-(2,3-dichlorophenyl)-5-methyl-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (90 mg, yield 7.0%) as a white solid. MS(ESI)m / z412[M+H] +。 1 H NMR (400MHz, DMSO-d6) δ13.97(bs,1H),7.94(dd,J=8.0Hz,J=1.2Hz,1H),7.81-7.77(m,2H),7.66-7.62(m,3H),2.27(s,3H). Preparation of 2-(4-(2,3-dichlorophenyl)-5-((methylsulfonyl)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (88) Method 14 [ka] Step 1. N-(2,3-dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbothioamide A solution of 2,3-dichloroaniline (90 mg, 0.55 mmol) in THF (3 mL) in an ice bath was added dropwise to a solution of LiHMDS (1.0 M, 0.8 mL, 0.8 mmol) in THF. The mixture was stirred for 5 minutes, and a solution of methyl 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carboditioate (220 mg, 0.55 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL) and  (20 mL). The organic layer was collected, washed with brine, dried over Na2SO4, and concentrated to obtain a crude product (300 mg) as a yellow oil, which was used in the next step without further purification. MS(ESI)m / z520[M+H] + . Step 2. N-(2,3-dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbohydrazonamide To a solution of N-(2,3-dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbothioamide (300 mg) in THF (5 mL), hydrazine (80%, 500 mg, 9.88 mmol) was added. The reaction mixture was heated to 75°C and stirred for 1 hour. The resulting mixture was concentrated to obtain a crude product (300 mg) as a yellow oil, which was used directly in the next step without further purification. MS(ESI)m / z518[M+H] + . Step 3.2-(5-(chloromethyl)-4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole A solution of N-(2,3-dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-carbohydrazonamide (300 mg) in 2-chloro-1,1,1-trimethoxyethane (3 mL) was heated to 110°C and stirred for 4 hours. The resulting mixture was concentrated, and the residue was purified by preparative TLC to obtain the product (100 mg, 31.5% yield in 3 steps) as a yellow solid. MS(ESI)m / z576[M+H] + . Step 4.2-(4-(2,3-dichlorophenyl)-5-((methylthio)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole A solution of 2-(5-(chloromethyl)-4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (80 mg, 0.14 mmol) in DMF (2 mL) was mixed with an aqueous solution of sodium thiomethoxide (30%, 400 mg, 1.7 mmol). The reaction mixture was stirred for 2 hours. The resulting mixture was diluted with water and ethyl acetate. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to obtain the product (50 mg, yield 61%) as a yellow oil. MS(ESI)m / z588[M+H] + . Step 5.2-(4-(2,3-dichlorophenyl)-5-((methylsulfonyl)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole To a solution of 2-(4-(2,3-dichlorophenyl)-5-((methylthio)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (50 mg, 0.085 mmol) in DCM (3 mL), mCPBA (45 mg, 0.26 mmol) was added. The reaction mixture was stirred for 2 hours. The resulting mixture was diluted with water and ethyl acetate. The organic layer was washed with aqueous NaHCO-3 solution, dried over Na2SO4, and concentrated to obtain the product (50 mg, yield 75%) as a yellow oil. MS(ESI)m / z620[M+H] + . Step 6.2-(4-(2,3-dichlorophenyl)-5-((methylsulfonyl)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-(4-(2,3-dichlorophenyl)-5-((methylsulfonyl)methyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (50 mg, 0.08 mmol) in DCM (2 mL), TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated. The residue was purified by preparative HPLC to obtain the product (15 mg, yield 37.5%) as a white solid. MS(ESI)m / z490[M+H] + . 1 H NMR(400MHz,d6-DMSO)δ14.08(bs,1H),7.94(dd,J=8.0Hz,J=1.6Hz,1H),7.80(s,1H),7.74(dd,J=8.0Hz,J=1.6Hz,1H),7.69 (d,J=8.8Hz,1H),7.64(t,J=8.0Hz,1H),7.54(d,J=8.0Hz,1H),4.92(d,J=15.2Hz,1H),4.64(d,J=15.2Hz,1H),3.19(s,3H). Examples (compounds) 90, 124, 125, 126, and 127 were synthesized using the same method as in Example 88. [Table 15-1] [Table 15-2] Preparation of 6-[(1-oxo-2-isoquinolyl)methyl]-3H-1,3-benzoxazole-2-one (89) [ka] Step 1.2-(1-(2,3-dichlorophenyl)-1H-imidazole-5-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole To a solution of 2-(1-(2,3-dichlorophenyl)-1H-imidazole-5-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (500 mg, 1.26 mmol) in DCM (20 mL), TEA (382 mg, 3.81 mmol) and SEMCl (252 mg, 1.51 mmol) were added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with  and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography eluting at (PE / EA = 1 / 6) to obtain ethyl 1-(2,3-dichlorophenyl)-1H-imidazole-5-carboxylate (300 mg, yield 45.2%) as a yellow solid. MS(ESI)m / z527[M+H] + . Step 2. Methyl 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)-1Himidazole-2-carboxylate To a solution of 2-(1-(2,3-dichlorophenyl)-1H-imidazole-5-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (300 mg, 0.56 mmol) in THF (10 mL), LiHMDS (1.1 mL, 1.1 mmol) was added in an ice bath. The mixture was stirred for 30 minutes, and then methyl carbonochloride (80.5 mg, 0.85 mmol) was added. The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with  and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / Â=1 / 8) to obtain methyl 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)-1H-imidazole-2-carboxylate (200 mg, yield 60.0%) as a yellow solid. MS(ESI)m / z585[M+H] + . Step 3. 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)-1H-imidazole-2-carboxamide 20 mL of NH3 / MeOH solution of methyl 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)-1H-imidazole-2-carboxylate (200 mg, 0.34 mmol). The mixture was stirred for 16 hours. After the reaction was complete, the mixture was concentrated to obtain 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)-1H-imidazole-2-carboxamide (200 mg, 100% yield) as a yellow solid, which was used in the next step without further purification. MS(ESI)m / z570[M+H] + . Step 4.1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1H-imidazole-2-carboxamide To a solution of 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)-1H-imidazole-2-carboxamide (200 mg, crude) in DCM (10 mL), TFA (10 mL) was added at 0°C. The reaction mixture was stirred for 4 hours. After the reaction was complete, it was diluted with water and the pH was adjusted to 7. The resulting mixture was diluted with  and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-1H-imidazole-2-carboxamide (6.7 mg, yield 4.3%) as a yellow powder. MS(ESI)m / z440[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.34(bs,1H),8.03-7.97(m,2H),7.76(d,J=8.0Hz,J=1 .6Hz,1H),7.73-7.55(m,3H),7.53(d,J=8.0Hz,J=1.6Hz,1H),7.50-7.40(m,2H). Preparation of 2-(4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-4H-1,2,4-triazole-3-yl)ethane-1-ol (121) [ka] Step 1. Ethyl 3-(2-(((2,3-dichlorophenyl)amino)(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)methylene)hydrazineyl)-3-oxopropanoate To a solution of 3-ethoxy-3-oxopropanoic acid (1.00 equivalent, 0.17 mL, 1.46 mmol) in DMF (10 mL), DIEA (3.00 equivalent, 0.76 mL, 4.37 mmol) and T3P (1.50 equivalent, 1390 mg, 2.18 mmol) were added. The mixture was then stirred overnight at 25°C. The progress of the reaction was monitored by LC / MS. Upon completion, the mixture was diluted with DCM and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step. MS(ESI)m / z632[M+H] + . Step 2. Ethyl 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-1,2,4-triazole-3-yl]acetate To a solution of ethyl 3-(2-(((2,3-dichlorophenyl)amino)(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-2-yl)methylene)hydrazineyl)-3-oxopropanoate (1.00 equivalent, 470 mg, 0.743 mmol) in 1,4-dioxane (10 mL), Burgess's reagent (3.00 equivalent, 531 mg, 2.23 mmol) was added, and the mixture was stirred at 80°C for 1 hour. The progress of the reaction was monitored by LC / MS. After completion, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (PE / EA=1 / 1) to obtain the product (180 mg, 39%). MS(ESI)m / z614[M+H] + . Step 3.2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-1,2,4-triazole-3-yl]ethanol To a solution of ethyl 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-1,2,4-triazole-3-yl]acetate (1.00 equivalent, 107 mg, 0.174 mmol) in THF (2 mL), LiAlH4 (1.00 equivalent, 6.6 mg, 0.174 mmol) was added, and the mixture was stirred at 0°C for 1 hour. The progress of the reaction was monitored by LC / MS. Once complete, 6.6 µl of water, 6.6 µl of 15% NaOH, and 13 µl of water were added to the mixture. The reaction product was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step. MS(ESI)m / z572[M+H] + . Step 4.2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1,2,4-triazole-3-yl]ethanol To a solution of 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-1,2,4-triazole-3-yl]ethanol (1.00 equivalent, 100 mg, 0.174 mmol) in DCM (2 mL), TFA (1 mL) was added, and the mixture was stirred at 25°C for 1 hour. The progress of the reaction was monitored by LC / MS. After completion, the solvent was removed, and the residue was purified by preparative HPLC to obtain the desired product (2 mg, 3%). MS(ESI)m / z442[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ13.96(bs,1H),7.95(dd,J=8.2,1.5Hz,1H),7.80-7.74(m,2H),7.69-7. 61(m,2H),7.52(s,1H),4.82(t,J=5.6Hz,1H),3.70(tt,J=11.7,5.8Hz,2H),2.80-2.64(m,2H). Preparation of 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1,2,4-triazole-3-yl]acetamide (122) [ka] Step 1.2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-1,2,4-triazole-3-yl]acetamide To a solution of ethyl 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-1,2,4-triazole-3-yl]acetate (1.00 equivalent, 155 mg, 0.253 mmol) in ethanol (1 mL), ammonia (25%, 1 mL) was added, and the mixture was stirred at 80°C for 2 hours. The progress of the reaction was monitored by LC / MS. After completion, the solvent was removed, and the residue was used directly in the next step. MS(ESI)m / z585[M+H] + . Step 2.2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1H-benzimidazole-2-yl]-1,2,4-triazole-3-yl]acetamide To a solution of 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-yl]-1,2,4-triazole-3-yl]acetamide (1.00 equivalent, 148 mg, 0.253 mmol) in DCM (1 mL), TFA (1.0 mL) was added, and the mixture was stirred at 25°C for 2 hours. The progress of the reaction was monitored by LC / MS. After completion, the solvent was removed, and the residue was purified by preparative HPLC to obtain the product (4 mg, 3%). MS(ESI)m / z455[M+H] + . 1H NMR(400MHz,DMSO-d6)δ14.02(bs,1H),7.92(dd,J=8.1,1.6Hz,1H),7.78(s,1H),7.67(dd,J=8.0,1.6H z,1H),7.60(t,J=8.0Hz,1H),7.45(s,1H),7.04(s,1H),3.79(d,J=16.5Hz,1H),3.46(d,J=16.5Hz,1H). Preparation Method 15 for 4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-4H-1,2,4-triazole-3-thiol (108), 2-(4-(2,3-dichlorophenyl)-5-(methylthio)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (109), and 2-(4-(2,3-dichlorophenyl)-5-(oxetan-3-yloxy)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (117) [ka] Step 1. N-(2,3-dichlorophenyl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-carbonyl)hydrazine-1-carbothioamide To a solution of 5-(trifluoromethyl)-1H-benzimidazole-2-carbohydrazide (1000 mg, 4.10 mmol) in THF (5 mL), 1,2-dichloro-3-isothiocyanatobenzene (919 mg, 4.51 mmol) was added and the mixture was stirred at 80°C for 4 hours. The reaction was monitored by LC-MS. Upon completion, the organic layer was separated and concentrated to obtain the crude product N-(2,3-dichlorophenyl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-carbonyl)hydrazine-1-carbothioamide (1700 mg, 3.79 mmol, yield 92.6%) as a brown solid, which was used directly in the next step. MS(ESI)m / z448[M+H] + Step 2. 4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-yl)-4H-1,2,4-triazole-3-thiol A suspension of 1-(2,3-dichlorophenyl)-3-[[5-(trifluoromethyl)-1H-benzimidazole-2-carbonyl]amino]thiourea (3671 mg, 8.19 mmol) in 2N NaOH (100 mL) was stirred at 100°C for 1 hour. The reaction mixture was stirred at 100°C for 2 hours. 1M HCl (2 mL) was added to the reaction mixture to adjust the pH to 7. The reaction mixture was extracted with ELISA (10 mL x 3). The organic layer was dried and concentrated. The resulting crude material was used directly in the next step. MS(ESI)m / z430[M+H] + . Step 3.2-(4-(2,3-dichlorophenyl)-5-(methylthio)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of N-(2,3-dichlorophenyl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazole-2-carbonyl)hydrazine-1-carbothioamide (380 mg, 0.883 mmol) in K2CO3 (244 mg, 1.77 mmol), iodomethane (0.082 mL, 1.32 mmol) was added at room temperature and the mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and concentrated. The resulting crude product was used directly in the next step. MS(ESI)m / z444[M+H] + . Step 4.2-(4-(2,3-dichlorophenyl)-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-(4-(2,3-dichlorophenyl)-5-(methylthio)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (250 mg, 0.563 mmol) in DCM (5 mL), mCPBA (388 mg, 2.25 mmol) was added under N2 at room temperature. The reaction mixture was stirred at 25 °C for 2 hours. The reaction was quenched by adding aqueous Na2S2O3 (10 mL) and NaHCO3 (10 mL). The reaction mixture was extracted with RINKAN (20 mL x 3). Next, the organic matter was combined and dried (Na2SO4), then concentrated to dryness to obtain the product 2-(4-(2,3-dichlorophenyl)-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (150 mg, 0.32 mmol, yield 56%) as a brown solid. MS(ESI)m / z476[M+H] + . Step 5.2-(4-(2,3-dichlorophenyl)-5-(oxetane-3-yloxy)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-(4-(2,3-dichlorophenyl)-5-(methylsulfonyl)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (50 mg, 0.105 mmol) and oxetan-3-ol (19 mg, 0.262 mmol) in DMF (2 mL), NaH (10 mg, 0.262 mmol) was added under N2 at room temperature. The reaction mixture was stirred at 25 °C for 2 hours. Then, H2O (20 mL) was added to the reaction mixture and extracted with siRNA (20 mL x 3). The organic layers were combined, dried, and concentrated under vacuum in (Na2SO4). The crude product was purified by preparative HPLC to obtain the product 2-(4-(2,3-dichlorophenyl)-5-(oxetan-3-yloxy)-4H-1,2,4-triazole-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (10 mg, 0.02 mmol, yield 19.9%) as a white solid. MS(ESI)m / z470[M+H] + . 1 ¹H NMR (400MHz, methanol-d4) δ 7.98-7.86 (m,2H), 7.77-7.22 (m,2H), 7.70-7.56 (m,2H), 5.91-5.84 (m,1H), 5.14-5.06 (m,2H), 4.83-4.73 (m,2H). Example (compound) 131 was synthesized using the same method as in Example 117. [Table 16] Preparation of methyl 2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)propanoate (101) and 2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)propan-1-ol (104) Method 16 [ka] Step 1. Methyl 2-(4-aminophenyl)propanoate To a solution of methyl 2-(4-nitrophenyl)propanoate (1.00 equivalent, 5.00 g, 23.9 mmol) in ethanol (100 mL), Pd / C (0.0100 equivalent, 253 mg, 0.239 mmol) was added. The reaction mixture was then stirred overnight at room temperature under a hydrogen atmosphere (balloon). The reaction solution was filtered, and the filtrate was concentrated to obtain methyl 2-(4-aminophenyl)propanoate (3.50 g, 19.5 mmol, yield 81.71%) as a yellow oil. The crude product was used directly in the next step without further purification. MS(ESI)m / z 180.1[M+H]+. Step 2.3-(4-methoxybenzyl)-6-methylbenzo[d]oxazole-2(3H)-one A solution of methyl 2-(4-aminophenyl)propanoate (1.00 equivalent, 1.5 g, 8.37 mmol) in Ac2O (20 mL) was heated at 60°C for 1 hour. The reaction solution was poured into H2O. The crude product was extracted with SiO (20 mL x 3). The combined organic layers were washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude methyl 2-(4-acetamidophenyl)propanoate (1.80 g, 8.14 mmol, yield 97.20%) as a yellow oil. The crude substance was used directly in the next step. MS(ESI)m / z222.1[M+H]+. Step 3. Methyl 2-(4-acetamido-3-nitrophenyl)propanoate A solution of methyl 2-(4-acetamidophenyl)propanoate (1.00 equivalent, 1.80 g, 8.14 mmol) in Ac2O (15 mL) was cooled to 0°C. Concentrated HNO3 (1 mL, 14 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hours. The yellow solution was poured onto ice. The aqueous layer was extracted with DCM, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, and evaporated to obtain methyl 2-(4-acetamido-3-nitro-phenyl)propanoate (1.10 g, 4.13 mmol, yield 50.78%) as a yellow solid. (ESI)m / z 267.1[M+H]+. Step 4. Methyl 2-(4-amino-3-nitrophenyl)propanoate A solution of methyl 2-(4-acetamido-3-nitrophenyl)propanoate (1.00 equivalent, 1.10 g, 4.13 mmol) in ethanol (20 mL) was mixed with concentrated HCl (2.0 mL). The reaction solution was stirred at 90 °C for 5 hours. After the reaction mixture was cooled to room temperature, the solution was concentrated under vacuum to obtain methyl 2-(4-amino-3-nitrophenyl)propanoate (720 mg, 3.43 mmol, yield 82.91%) as a yellow solid. MS(ESI)m / z 225.2[M+H]+. Step 5. Methyl 2-(3,4-diaminophenyl)propanoate To a solution of methyl 2-(4-amino-3-nitrophenyl)propanoate (1.00 equivalent, 720 mg, 3.21 mmol) in ethanol (20 mL), 10% Pd / C (0.0500 equivalent, 170 mg, 0.161 mmol) was added. The mixture was then stirred overnight at room temperature under a hydrogen atmosphere (balloon). The reaction solution was filtered, and the filtrate was concentrated. Purification by flash (C18) yielded methyl 2-(3,4-diaminophenyl)propanoate (460 mg, 2.37 mmol, yield 73.75%) as a yellow oil. MS(ESI)m / z 195.1[M+H]+. Step 6. Methyl 2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole-5-yl)propanoate A mixture of 4-methylsulfonylbenzene-1,2-diamine (1.20 equivalents, 185 mg, 0.991 mmol) and 4-(2,3-dichlorophenyl)-1,2,4-triazole-3-carbaldehyde (1.00 equivalent, 200 mg, 0.826 mmol) in water (15 mL) was stirred at 90°C for 2 hours. After the reaction mixture cooled to room temperature, K2CO3 (3.00 equivalents, 343 mg, 2.48 mmol), KI (0.500 equivalents, 69 mg, 0.413 mmol), and I2 (2.00 equivalents, 419 mg, 1.65 mmol) were added to the mixture. The reaction mixture was then stirred at 90°C for 30 minutes. After cooling to room temperature, the mixture was extracted with DCM (20 mL x 3), the organic layers were combined, washed with water, dried over Na2SO4, and evaporated. The residue was purified by flash (C18) to obtain methyl 2-[2-[4-(2,3-dichlorophenyl)-1,2,4-triazole-3-yl]-1H-benzimidazole-5-yl]propanoate (210 mg, 0.504 mmol, yield 24.50%) as a white solid. (ESI)m / z416.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.53(s,1H),9.02(s,1H),7.91(dd,J=8.2,1.5Hz,1H),7.77(dd,J=8.0,1.5Hz,1H),7.59(t, J=8.1Hz,1H),7.43(d,J=8.4Hz,1H),7.37(s,1H),7.12(s,1H),3.92-3.85(m,1H),3.56(s,3H),1.40(d,J=7.1Hz,3H). Step 7.2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)propan-1-ol A solution of methyl 2-[2-[4-(2,3-dichlorophenyl)-1,2,4-triazole-3-yl]-1H-benzimidazole-5-yl]propanoate (1.00 equivalent, 40 mg, 0.0961 mmol) in THF (10 mL) was mixed with LiAlH4 (5.00 equivalent, mg, 0.480 mmol) in THF at -40°C. The mixture was then stirred at -40°C for 3 hours. The reaction was then quenched by adding 1 mL of NH4Cl solution and H2O (10 mL). The reaction mixture was extracted with DCM (10 mL x 3), the organic layers were combined, washed with water, dried over Na2SO4, and evaporated. The residue was purified by preparative HPLC to obtain 2-[2-[4-(2,3-dichlorophenyl)-1,2,4-triazole-3-yl]-1H-benzimidazole-5-yl]propan-1-ol (10 mg, 0.0258 mmol, yield 26.80%) as a white solid. (ESI)m / z388.2[M+H] + . 1H NMR(400MHz,DMSO-d6)δ13.32(s,1H),9.00(s,1H),7.91(d,J=8.1Hz,1H),7.76(dd,J=8.0,1.5Hz,1H),7.59(t,J=8.1Hz ,1H),7.46-7.22(m,2H),7.20-6.99(m,1H),4.79-4.47(m,1H),3.56-3.39(m,2H),3.00-2.77(m,1H),1.26-1.15(m,3H). Examples (compounds) 102, 103, 107, 110, 111, 112, 113, 129, 130, 133, 134, and 135 were synthesized using the same method as in Example 104. [Table 17-1] [Table 17-2] [Table 17-3] Preparation of 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)pyrrolidine-2-one (137) Method 17 [ka] Step 1. Preparation of 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)pyrrolidine-2-one (3) A mixed solution of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (100 mg, 0.1859 mmol), pyrrolidine-2-one (18.9 mg, 0.2230 mmol), Cs2CO3 (12.06 mg, 0.3718 mmol), Pd2(dba)3 (1.69 mg, 0.0186 mmol), X-phos (1.76 mg, 0.0372 mmol), and 1,4-Dio (10 mL) was stirred at 100°C for 16 hours under an N2 atmosphere. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted three times with EA (10 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel column chromatography (MeOH:DCM=1:10) to obtain 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)pyrrolidine-2-one (74 mg, yield 73.27%) as an oil. MS(ESI)m / z543.1[M+H] + . Step 2. Preparation of 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)pyrrolidine-2-one 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)pyrrolidine-2-one (74 mg, 0.1363 mmol) and TFA / DCM (3 / 3 mL) were stirred at 25°C for 2 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product, which was purified by perp-HPLC (column: Gemini-C18 150 × 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% TFA), 30%~50%) to obtain the desired product SIR-00015146 (1.4 mg, yield 2.49%) as a white solid. MS(ESI) m / z 413.1[M+H] + . 1 H NMR(400MHz)δ8.82(s,1H),7.78(dd,J=8.0,1.4Hz,1H),7.73(s,1H),7.59(dd,J=8.0,1.2Hz,1H),7. 51(d,J=8.2Hz,2H),7.48-7.41(m,1H),3.59-3.42(m,2H),2.58(t,J=8.0Hz,2H),2.22-2.14(m,2H). Table 18-1 Table 18-2 Table 18-3 Table 18-4 Table 18-5 Table 18-6 Table 18-7 Table 18-8 Table 18-9 Table 18-10 Table 18-11 Table 18-12 Table 18-13 Table 18-14 Table 18-15 Table 18-16 Table 18-17 Table 18-18 Table 18-19 Table 18-20 Table 18-21 Table 18-22 Table 18-23 Table 18-24 Table 18-25 Table 18-26 Table 18-27 Table 18-28 Table 18-29 Table 18-30 [Table 18-31] [Table 18-32] [Table 18-33] [Table 18-34] [Table 18-35] [Table 18-36] [Table 18-37] [Table 18-38] [Table 18-39] [Table 18-40] [Table 18-41] [Table 18-42] 2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-3-(methylsulfonyl)-5-(trifluoromethyl)-1H-indole (346) Method 18 [ka] Step 1.2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazole-3-yl]-3-iodo-5-(trifluoromethyl)-1H-indole A mixture of 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazole-3-yl]-5-(trifluoromethyl)-1H-indole (140 mg, 0.36 mmol) in DCM (5 mL) was mixed with NIS (82 mg, 0.36 mmol) in an ice bath. The reaction mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (DCM / MeOH = 20 / 1) to obtain 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazole-3-yl]-3-iodo-5-(trifluoromethyl)-1H-indole (190 mg, yield 96%) MS(ESI) m / z 507 [M+H]. + I obtained it. Step 2.2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazole-3-yl]-3-methanesulfonyl-5-(trifluoromethyl)-1H-indole To a solution of 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazole-3-yl]-3-iodo-5-(trifluoromethyl)-1H-indole (55 mg, 0.10 mmol) in NMP (4 mL), copper(I) iodide (103 mg, 0.54 mmol) and sodium methanesulfinate (55 mg, 0.54 mmol) were added at room temperature. The mixture was stirred under N2 at 105°C for 0.5 hours. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (NH4HCO3) to obtain (7.0 mg, yield 11%) as a pale yellow solid. MS(ESI)m / z459[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ: 13.38 (s, 0.5H), 9.22 (s, 1H), 8.19 (s, 1H), 7.83-7.35 (m, 5H), 3.06 (s, 3H). Preparation of 7-fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]-1H-benzimidazole (338) Method 19 [ka] Step 1. (1,3-Dioxoisoindolin-2-yl)spiro[2,2]pentan-2-carboxylate To a solution of spiro[2.2]pentane-2-carboxylic acid (100 mg, 891.85 μmol, 1 equivalent) and 2-hydroxyisoindoline-1,3-dione (160.04 mg, 981.04 μmol, 1.1 equivalents) in DCM (5 mL), DIC (123.81 mg, 981.05 μmol, 151.91 μL, 1.10 equivalents) and DMAP (10.90 mg, 89.19 μmol, 0.1 equivalents) were added. The resulting mixture was stirred under N2 protection at 20°C for 2 hours. LC-MS did not show the desired mass. TLC showed that the spiro[2.2]pentane-2-carboxylic acid (100 mg, 891.85 μmol, 1 equivalent) was completely consumed and several new spots were formed. The reaction mixture was poured into water (5 mL) and extracted with DCM (10 mL × 3). The organic layer was washed with brine (5 mL), dried over Na2SO4, and filtered. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® silica flash column, eluent with a 0-15% ethyl acetate / petroleum ether gradient, 20 mL / min). The compound (1,3-dioxoisoindorin-2-yl)spiro[2.2]pentane-2-carboxylate (160 mg, 621.98 μmol, yield 69.74%) was obtained as a white solid. 1 H NMR(400MHz,CDCl3)δ7.93-7.84(m,2H),7.84-7.74(m,2H),2.32(dd,J=4.2,7.5Hz, 1H),1.77(t,J=4.1Hz,1H),1.72-1.66(m,1H),1.18-1.07(m,2H),1.06-1.00(m,2H) Step 2.7-Fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]-1H-benzoimidazole In a solution of 2-[[5-bromo-7-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (20 mg, 35.88 μmol, 1 equivalent) in DMA (1 mL), (1,3-dioxoisoindorin-2-yl)spiro[2.2]pentan-2-carboxylate (11.0 8 mg (43.06 μmol, 1.2 equivalents), N-cyano-4-methoxypyridine-2-carboxamidine (9.48 mg, 53.82 μmol, 1.5 equivalents), NiCl2 (DME) (8.67 mg, 39.47 μmol, 1.1 equivalents), TBAI (11.93 mg, 32.29 μmol, 0.9 equivalents), and Zn (7.88 mg, 143.52 μmol, 7.81 μL, 4 equivalents) were added. The mixture was stirred at 25°C for 16 hours. LC-MS showed the desired mass. TLC showed new spots. The reaction mixture was poured into water (2 mL) and extracted with RINKAN (3 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated and purified by preparative TLC (Pe:siRNA=3:1) to obtain 2-[[7-fluoro-5-spiro[2,2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (13 mg, 12.41 μmol, yield 34.59%, purity 52%) as a colorless oil. MS(ESI)m / z545[M+H] + . Step 3.7-Fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]-1H-benzoimidazole To a solution of 2-[[7-fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (34 mg, 62.43 μmol, 1 equivalent) in DCM (1 mL), TFA (1.54 g, 13.46 mmol, 1 mL, 215.64 equivalents) was added. The mixture was stirred at 15°C for 0.5 hours. LC-MS showed that reactant 1 was completely consumed and one main peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (TFA)-ACN]; gradient: 55%-75% B over 11 minutes). Compound 7-fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]-1H-benzimidazole (3.4 mg, 7.83 μmol, yield 12.54%, purity 95.41%) was obtained as a colorless oil. MS(ESI)m / z415[M+H] + . 1 H NMR(400MHz,CDCl3)δ9.11(d,J=5.0Hz,1H),8.88(s,1H),8.45(s,1H),7.86(d,J=5.1Hz,1H),7.27-7.24(m,1H),6.69(br d,J=11.8Hz,1H),2.33(dd,J=4.5,7.8Hz,1H),1.56(dd,J=4.3,7.9Hz,1H),1.07-0.91(m,4H),0.75(br dd,J=4.6,8.8Hz,1H) [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4] Table 19-5 Table 19-6 Table 19-7 Table 19-8 Table 19-9 Table 19-10 Table 19-11 Table 19-12 Table 19-13 Table 19-14 Table 19-15 Table 19-16 Table 19-17 Table 19-18 Table 19-19 Table 19-20 Table 19-21 [Table 19-22] [Table 19-23] [Table 19-24] Preparation of 2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-ethyl-1,5-dihydro-4H-pyrrolo[3,2-c]pyridine-4-one (308) [ka] Process 1. To a solution of NaH (1.30 equivalents, 306 mg, 7.65 mmol) in THF (30 mL), methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1.00 equivalent, 1239 mg, 5.88 mmol) was added at 0°C. The mixture was stirred for 30 minutes. SEMCl (1.30 equivalents, 1.4 mL, 7.65 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The reaction product was extracted with saturated NH4Cl and EA. The organic phase was dried over anhydrous Na2SO4, concentrated, and the residue was purified by FCC to obtain methyl 4-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-2-carboxylate (1250 mg, 3.67 mmol, yield 62.34%). Process 2. Methyl 4-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-2-carboxylate (1.00 equivalent, 969 mg, 2.84 mmol) was dissolved in iodoethane (10.0 equivalent, 2.3 mL, 28.4 mmol). The mixture was heated to 80°C and stirred overnight. The mixture was concentrated under reduced pressure. The residue was used directly in the next step. Process 3. To a solution of methyl 4-chloro-5-ethyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-5-ium-2-carboxylate iodide (1.00 equivalent, 1391 mg, 2.80 mmol) in 1,4-dioxane (15 mL) and water (15 mL), NaOH (10.0 equivalent, 1120 mg, 28.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was acidified with 4N HCl and extracted with EA. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC to obtain 5-ethyl-4-oxo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-2-carboxylic acid (813 mg, 2.42 mmol, yield 86.30%). Step 4. To a solution of 5-ethyl-4-oxo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.00 equivalent, 1360 mg, 4.04 mmol) in DCM (20 mL), TFA (64.6 equivalents, 20 mL, 261 mmol) was added. The mixture was stirred at room temperature for 4 hours, then concentrated, and the residue was used directly in the next step. Process 5. To a solution of 5-ethyl-1-(hydroxymethyl)-4-oxo-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.00 equivalent, 945 mg, 4.00 mmol) in THF (20 mL), NH3 in water (10 mL) was added. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. Water was added. HCl (1N) aqueous solution was added until the pH became 1. The mixture was extracted with EA and dried over anhydrous Na2SO4. The organic phase was removed under reduced pressure. The residue was purified by FCC to obtain 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (531 mg, 2.58 mmol, yield 64.38%). Process 6. To a solution of 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.00 equivalent, 531 mg, 2.58 mmol) in THF (15 mL), N-methylmorpholine (3.00 equivalent, 0.85 mL, 7.73 mmol) was added, followed by isobutyl chloroformate (1.20 equivalent, 0.40 mL, 3.09 mmol) at 0°C. The mixture was stirred for 20 minutes, and N2H4·H2O (5.00 equivalent, 805 mg, 12.9 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 1.5 hours. The mixture was extracted with EA, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC to obtain 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridine-2-carbohydrazide (423 mg, 1.92 mmol, yield 74.59%). Step 7. To a solution of N'-(2-chloro-3-fluorophenyl)-N,N-dimethylformamidine (2.00 equivalents, 164 mg, 0.817 mmol) in MeCN (3 mL) and acetic acid (1 mL), 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridine-2-carbozide (1.00 equivalent, 90 mg, 0.409 mmol) was added. The mixture was heated to 90°C and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazole-3-yl]-5-ethyl-1H-pyrrolo[3,2-c]pyridine-4-one (2.0 mg, 0.00559 mmol, yield 1.37%) as a white solid. MS(ESI)m / z358[M+H] + . 1 H NMR(400MHz,MeOD)δ8.73(s,1H),7.69-7.62(m,2H),7.59-7.55(m,1H),7.37(d,J=7.3H z,1H),6.64(d,J=7.3Hz,1H),6.15(s,1H),4.03(q,J=7.2Hz,2H),1.29(t,J=7.1Hz,4H). Preparation of 2-(5-(2,3-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (315) [ka] Step 1. 2-Hydrazineyl-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 2-chloro-5-(trifluoromethyl)-1H-benzo[d]imidazole (1 g, 4.54 mmol) in THF (10 mL), hydrazine (80%, 2 mL) was added. The reaction mixture was heated to 80°C and stirred overnight. The resulting mixture was diluted with EA and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the crude product (1 g, 100%) as a yellow oil. MS(ESI)m / z217[M+H] + . Step 2. 2-Azide-5-(trifluoromethyl)-1H-benzo[d]imidazole A mixture of 2-hydrazineyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (300 mg, 1.39 mmol) in an HCl aqueous solution (3N, 5 mL) in an ice bath was met with dropwise addition of an aqueous NaNO2 solution (200 mg, 2.90 mmol). The reaction mixture was stirred for 2 hours. The resulting mixture was diluted with water and EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated to obtain the crude product (0.3 g, 100% yield) as a yellow oil. MS(ESI)m / z359[M+H] + . Step 3. ((2,3-dichlorophenyl)ethynyl)trimethylsilane A mixture of 1,2-dichloro-3-iodobenzene (1.0 g, 3.68 mmol), ethynyltrimethylsilane (3 mL), triethylamine (3 mL), Pd(PPh3)2Cl2 (100 mg, 0.14 mmol), and CuI (30 mg, 0.16 mmol) in DMF (5 mL) was heated to 100°C and stirred overnight under an N2 atmosphere. The resulting mixture was diluted with water and EA. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash to obtain the product (0.8 g, 90% yield) as a yellow oil. Step 4.2-(5-(2,3-dichlorophenyl)-1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole A mixture of 2-hydrazineyl-5-(trifluoromethyl)-1H-benzo[d]imidazole (300 mg, 1.24 mmol) and 2-azido-5-(trifluoromethyl)-1H-benzo[d]imidazole (280 mg, 1.23 mmol) in water (5 mL) was heated under reflux overnight. The resulting mixture was diluted with water and EA. The organic layer was concentrated, and the residue was purified by preparative HPLC to obtain the product (3 mg, yield 6.1%) as a white solid. MS(ESI)m / z398[M+H] + . 1 H NMR(400MHz,d6-DMSO)δ14.15(bs,1H),8.26(s,1H),7.85(s,1H),7.81(d,J=8.0Hz,1H),7.70(d,J=8.0Hz,1H),7.60-7.47(m,3H). Preparation of 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)ethyl)thiazole (412) Method 20 [ka] Step 1.1-(thiazole-2-yl)vinyltrifluoromethanesulfonate To a solution of 1-thiazole-2-ylethanone (1.00 equivalent, 1000 mg, 7.86 mmol) in DCM (20 mL), DIEA (3.00 equivalent, 4.1 mL, 23.6 mmol) and trifluoromethanesulfonic anhydride (2.00 equivalent, 4438 mg, 15.7 mmol) were added at -30°C. The mixture was stirred at -30°C for 1 hour under an inert atmosphere. The mixture was diluted with  and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (PE / Â=1 / 9) to obtain 1-thiazole-2-ylvinyltrifluoromethanesulfonate (1000 mg, 3.47 mmol, yield 44.15%) as a brown oil. MS(ESI)m / z260[M+H]+. Step 2. 7-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole Pd(dppf)Cl2 (0.100 equivalents, 293 mg, 0.359 mmol) and potassium acetate (3.00 equivalents, 1055 mg, 10.8 mmol) were added to a mixture of 5-bromo-7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.00 equivalent, 2000 mg, 3.59 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.00 equivalents, 1822 mg, 7.18 mmol) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 100°C for 1 hour under an inert atmosphere. The mixture was diluted with siRNA and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative HPLC (H2O:ACN = 30:70~100:0; product collected at 90% ACN) to obtain 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (2000 mg, 2.98 mmol, yield 82.99%) as a brown oil. MS(ESI)m / z605[M+H]+. Step 3.2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)vinyl)thiazole Pd2(dba)3 (0.200 equivalents, 91 mg, 0.0993 mmol) and K2CO3 (3.00 equivalents, 191 mg, 1.49 mmol) were added to a mixture of 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole (1.00 equivalent, 300 mg, 0.496 mmol) and 1-(thiazole-2-yl)vinyltrifluoromethanesulfonate (2.00 equivalents, 257 mg, 0.993 mmol). The reaction mixture was stirred at 100°C for 1 hour under an inert atmosphere. The mixture was diluted with Âi and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative HPLC (H2O:ACN = 30:70~100:0; product collected at 90% ACN) to obtain 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)vinyl)thiazole (160 mg, 0.245 mmol, yield 49.37%) as a yellow oil. MS(ESI)m / z588[M+H]+. Step 4.2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)ethyl)thiazole A mixture of 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)vinyl)thiazole (1.00 equivalent, 160 mg, 0.272 mmol) in methanol (15 mL) was mixed with Pd / C (95 mg, 10%). The mixture was stirred under an H2 atmosphere at 25°C for 1 hour. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated to obtain 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)ethyl)thiazole (100 mg) as a yellow oily substance, which was used in the next step without further purification. MS(ESI)m / z590[M+H]+. Step 5.2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)ethyl)thiazole A mixture of 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazole-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-yl)ethyl)thiazole (1.00 equivalent, 100 mg, 0.170 mmol) in DCM (10 mL) was mixed with TFA (10 mL). The mixture was stirred at 25°C for 1 hour. The mixture was diluted with ELISA and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by preparative HPLC (H2O:ACN = 30:70~100:0; product recovered with 60% ACN) to obtain 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole-5-yl)ethyl)thiazole (33 mg, 0.0682 mmol, yield 40.24%) as a white solid. MS(ESI)m / z460[M+H]+. 1 ¹H NMR (400MHz, chloroform-d) δ 12.96 (brs, 1H), 9.09 (d, J=5.2Hz, 1H), 8.86 (s, 1H), 8.45 (s, 1H), 7.83 (d, J=5.2Hz, 1H), 7.75 (d, J=3.2Hz, 1H), 7.26-7.23 (m, 2H), 6.91 (d, J=11.2Hz, 1H), 4.72-4.63 (m, 1H), 1.84 (d, J=6.8Hz, 3H). Preparation of 6-(difluoro(pyridine-4-yl)methyl)-4-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole (464) Method 21 [ka] Step 1.2-[[4-fluoro-6-[1-(4-pyridyl)vinyl]-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane 2-[[6-bromo-4-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (1.00 equivalent, 2000 mg, 3.59 mmol), XPhos (0.100 equivalent, 171 mg, 0.359 mmol), Pd(CH3CN) 2Cl2 (0.100 equivalents, 93 mg, 0.359 mmol) and t-BuOLi (3.00 equivalents, 862 mg, 10.8 mmol) were added under an N2 atmosphere to a solution of 4-methyl-N-[(E)-1-(4-pyridyl)ethylideneamino]benzenesulfonamide (2.00 equivalents, 2076 mg, 7.18 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 90°C for 3 hours, and the precipitate was removed by filtration. The filtrate was concentrated under vacuum to obtain the crude product. The crude product was purified by column chromatography using petroleum / ethyl acetate to obtain 2-[[4-fluoro-6-[1-(4-pyridyl)vinyl]-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (1780 mg, 3.06 mmol, yield 85.29%). MS(ESI)m / z582[M+H] + . Step 2. [7-Fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-5-yl]-(4-pyridyl)methanone A solution of 2-[[4-fluoro-6-[1-(4-pyridyl)vinyl]-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (1.00 equivalent, 1780 mg, 3.06 mmol) in DCM (30 mL) was prepared in a three-necked round-bottom flask equipped with a drying tube and a gas dispersion tube. The solution was cooled to -78°C. The solution was saturated with O2. An O3 / O2 (approximately 1% O3) stream was applied to the solution. After 15 minutes, the mixture turned green-blue. The ozone generator was set to 0V. The solution was purged with O2 for 15 minutes. After the departure of the starting materials (determined by TLC), the reaction mixture was returned to room temperature. Me2S (3.00 equivalent, 570 mg, 9.18 mmol) was added to the reaction mixture. The resulting orange solution was stirred overnight. The resulting orange solution was concentrated under reduced pressure. The residue was purified by chromatography using silica gel to obtain [7-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-5-yl]-(4-pyridyl)methanone (1210 mg, 2.07 mmol, yield 67.75%). MS(ESI)m / z584[M+H] + . Step 3.2-[[6-[difluoro(4-pyridyl)methyl]-4-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane A solution of [7-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]-3-(2-trimethylsilylethoxymethyl)benzimidazole-5-yl]-(4-pyridyl)methanone (1.00 equivalent, 130 mg, 0.223 mmol) was prepared in DAST (10 mL). The mixture was stirred overnight at room temperature. After the reaction was complete, the residue was dissolved in DCM (50 mL) and washed with ice-cold saturated sodium bicarbonate solution (50 mL). The aqueous phase was washed with ethyl acetate (2 × 20 mL), and the combined organic extract was dried and concentrated. Purification by preparative HPLC yielded the title compound 2-[[6-[difluoro(4-pyridyl)methyl]-4-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (100 mg, 0.165 mmol, yield 74.13%) as a grayish-white solid. MS(ESI)m / z606[M+H] + . Step 4.6-(difluoro(pyridine-4-yl)methyl)-4-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole TFA was added dropwise to a stirred solution of 2-[[6-[difluoro(4-pyridyl)methyl]-4-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazole-3-yl]benzimidazole-1-yl]methoxy]ethyl-trimethyl-silane (1.00 equivalent, 100 mg, 0.165 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred for 4 hours. The reaction was monitored by LC-MS. The resulting mixture was concentrated under vacuum. The residue was neutralized to pH 9 with K2CO3 (aqueous solution). The resulting mixture was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (MeOH / DCM = 1 / 5) to obtain 6-(difluoro(pyridine-4-yl)methyl)-4-fluoro-2-(4-(4-(trifluoromethyl)pyridine-3-yl)-4H-1,2,4-triazole-3-yl)-1H-benzo[d]imidazole (46 mg, 0.0968 mmol, yield 58.61%) as a white solid. MS(ESI)m / z476[M+H] + . 1 ¹H NMR (400MHz, methanol-d4): δ 9.06 (d, J=5.2Hz, 1H), 8.97 (d, J=4.4Hz, 2H), 8.66 (s, 2H), 7.97 (d, J=5.2Hz, 1H), 7.61-7.46 (m, 3H), 7.10 (s, 1H). [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5] [Table 20-6] [Table 20-7] [Table 20-8] [Table 20-9] [Table 20-10] [Table 20-11] [Table 20-12] [Table 20-13] [Table 20-14] [Table 20-15] [Table 20-16] [Table 20-17]

[0160] Example II. SAMR1 (50-724) Enzyme Assay The enzyme assay was performed in a 384-well plate using Dulbecco's phosphate-buffered saline (PBS) as the reaction buffer. Purified SARM1 (50-724) at a final concentration of 2 nM was pre-incubated at room temperature for 15 minutes with the test compound at the final assay concentration in 1% DMSO. 200 μM nicotinamide mononucleotide (NMN) was used as the activator and 100 μM NAD as the substrate. +The mixture was added to initiate the reaction. After incubation at room temperature for 1 hour, the reaction was stopped with 10 times the volume of 70% acetonitrile, and then the mixture was centrifuged at 3800 rpm for 10 minutes. The sample was diluted to the appropriate concentration with 10 mM ammonium acetate (pH 9.75) and then analyzed by LC-MS / MS.

[0161] Table 2 summarizes the SARM1 inhibitory activity of compounds 1-468. In Table 2, the activity is shown as follows: A=IC 50 ≤100nM; B:100nM <IC 50 ≤500nM;C:500nM <IC 50 ≤1000nM;D:IC 50 >1000nM. [Table 21-1] [Table 21-2] [Table 21-3]

[0162] All publications, including but not limited to disclosures and disclosure applications, cited herein are incorporated herein by reference as if they were fully described. In the event of any conflict or inconsistency between any particular publication cited herein and this disclosure, this disclosure shall prevail.

[0163] Those skilled in the art will readily recognize that various changes, modifications, and variations can be made within the present disclosure and claims without departing from the spirit and scope of the disclosure as defined in the following claims.

Claims

1. The following structural formula 1: 【Chemistry 1】 [In the formula, X １ , X ２ , X ３ , X ４ , and X ５ Each of them is independently either C or N, Y １ is C or N, and Y ２ is C or N, and Y １ and Y ２ are two adjacent ring atoms on ring B, Ring B is a phenyl molecule, a 5-6 membered heteroaryl molecule, a 3-6 membered cycloalkyl molecule, or a 4-6 membered heterocyclyl molecule, wherein the 5-6 membered heteroaryl molecule or the 4-7 membered heterocyclyl molecule of ring B contains 1-4 heteroatoms selected from N, O, and S. Ring C is a phenyl molecule, a 3-10 membered cycloalkyl group, a 4-10 membered heterocyclil group, a 5-6 membered heteroaryl group, or a 9-10 membered heteroaryl group, and the 4-10 membered heterocyclil, 5-6 membered heteroaryl, or 9-10 membered heteroaryl group of ring C contains 1-3 heteroatoms selected from N, S, and O. R １ H, halogen, C １ -C ８ Alkyl, C １ -C ８ Alkenil, C １ -C ８ Alkinyl, -CN, -OH, -COOH, -C(=O)NH ２ , -OR ｍ -S (=O) ｐ (C １ -C ４ Alkyl), -NR ｍ R ｎ , -C(=O)R ｎ , -C (=O) OR ｍ , -C(=O)NR ｍ R ｎ , -P(=O)R ｍ R ｎ , -SF ５ , A 5-6 member heteroaryl compound containing 1-3 heteroatoms independently selected from N, O, and S. A 3- to 10-membered heterocycline containing one or two heteroatoms independently selected from N, O, and S, and Selected from 3- to 10-membered cycloalkyl groups, R １ C １ -C ８ Alkyl, C １ -C ８ Alkenil, or C １ -C ８ Alkynnyl is a halogen, -OH, -OR ｍ -CN, -NH ２ , -NR ｍ R ｎ , -C(=O)OCH ３ , -O(C １ -C ６ Alkyl), -COOH, -C(=O)NH ２ , selected from phenyl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, and 3-6 membered cycloalkyl (optionally substituted with 1-3 groups selected from OH and halogens), optionally substituted with 1-3 groups, R １ Five- to six-membered heteroaryls include D, halogen, -OH, -CN, -COOH, -(C １ -C ６ Alkyl)OH, -C(=O)O(C １ -C ６ Alkyl), = O, -NH ２ , -C(=O)NR ｍ R ｎ , 5-6 member heteroaryl, -OR ｍ , R ｍ , C １ -C ６ Alkyl (halogen, -C(=O)NH ２ , R ｍ , and OR ｍ (Selected from, and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are selected from, R １ The 3- to 10-membered heterocyclyls are D, halogen, -OH, -CN, -COOH, -(C １ -C ６ Alkyl)OH, -C(=O)O(C １ -C ６ Alkyl), = O, -NH ２ , -C(=O)NR ｍ R ｎ , 5-6 member heteroaryl, -OR ｍ , R ｍ , C １ -C ６ Alkyl (halogen, -C(=O)NH ２ , R ｍ , and OR ｍ (Selected from, and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are arbitrarily chosen and replaced by 1 to 3 elements of which are selected from, R １ The 3- to 10-membered cycloalkyl of R is D, halogen, -OH, -CN, -COOH, -(C １ -C ６ -alkyl)OH, -C(=O)O(C １ -C ６ -alkyl), =O, -NH ２ , -C(=O)NR ｍ R ｎ , 5- to 6-membered heteroaryl, -OR ｍ , R ｍ , C １ -C ６ -alkyl (optionally substituted with 1 to 3 groups selected from halogen, -C(=O)NH ２ , R ｍ , and OR ｍ ), and is optionally substituted with 1 to 3 groups selected therefrom. R ｍ and R ｎ for each occurrence, are each independently selected from H, C １ -C ６ alkyl, -S(=O) ｐ (C １ -C ４ alkyl), phenyl, 3- to 8-membered cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, and the C ｍ of R １ -C ６ alkyl is optionally substituted with 1 to 3 groups selected from D, -C(=O)NH ２ , -OH, -OMe, -S(=O) ２ CH ３ , and halogen. R ２ H, halogen, C １ -C ６ Alkyl, C １ -C ６ Alkenyl, -OH, -O(C) １ -C ６ Alkyl), -O (C １ -C ６ Alkyl)O(C １ -C ６ Alkyl), -C(=O)NH ２ , -S (=O) ｐ (C １ -C ４ Selected from alkyl), -CN, 3-6 membered cycloalkyls, phenyl, 5-6 membered heteroaryls, and 4-10 membered heterocyclines (containing 1-3 heteroatoms independently selected from S, O, and N), R ２ C １ -C ６ Alkyl or C １ -C ６ Alkenyls are halogens, CN, and -C(=O)O(C １ -C ６ It is optionally substituted with 1 to 3 groups selected from alkyl groups. R ２ The 3- to 5-membered cycloalkyl group is optionally substituted with 1 to 3 groups selected from OH, CN, and halogens. R ２ -O(C) １ -C ６ C of alkyl １ -C ６ The alkyl group is optionally substituted with 1 to 3 groups selected from halogens and CNs. R ２ The 3- to 10-membered heterocyclyl is optionally substituted with 1 to 3 groups selected from OH, CN, and halogens, or R １ and R ２ is combined 【Chemistry 2】 Forming, R ３ and R ４ These are H, halogen, and C, respectively, independently. １ -C ６ Alkyl (optionally substituted with 1 to 3 groups selected from OH and halogens), and -O (C １ -C ６ Selected from alkyl, R ５ is absent, H, -CN, halogen, -C(=O)NH ２ , -S(=O)p(C １ -C ４ Alkyl), -OR ｐ phenyl, 5-6 member heteroaryls, 4-6 member heterocyclyls, 3-8 member cycloalkyls, and C １ -C ６ Selected from alkyl groups, R ５ C １ -C ６ Alkyl is OH, -NHR ｐ , -OR ｐ , and -S(=O)p(C １ -C ４ It is optionally substituted with 1 to 3 groups selected from alkyl groups. R ５ These 4-6 member heterocyclines are C １ -C ３ Substituted with 1 to 3 groups selected from alkyl, CN, halogen, and =O, R ５ The 3-8 member cycloalkyl group is C １ -C ３ It is optionally substituted with 1 to 3 groups selected from alkyl, CN, and halogen. R ｐ C １ -C ６ Selected from alkyl, 3-6 membered cycloalkyl, and 5-6 membered heteroaryl, R ｐ C １ -C ６ Alkyl, 3-6 membered cycloalkyl, or 5-6 membered heteroaryl groups are optionally substituted with 1-3 groups selected from CN, OH, and halogens. R ６ For each occurrence, independently, D, halogen, -CN, =O, -OR ｓ , -SH, -S(C １ -C ４ Alkyl), -S (=O) ｐ R ｔ , -C(=O)NR ｔ R ｏ , -NR ｔ R ｏ , 4-6 member heterocyclyl, and C １ -C ６ Selected from alkyl groups, R ６ C １ -C ６ Alkyl is halogen, -OR ｓ ,=O, -S(=O) ｐ R ｔ , -NHS (=O) ｐ R ｔ , -S(=O)(=NH)R ｔ , 【Transformation 3】 - NHS (= O) ｐ (C １ -C ４ Alkyl), -CN, -C(=O)NR ｔ R ｏ , -NR ｔ R ｏ , halogens, 5-6 member heteroaryls, 3-6 member cycloalkyls (halogens, OH, and R ｔ (Optionally substituted with 1 to 3 groups selected from), as well as halogens, OH, and R ｔ Selected from a 4- to 10-membered heterocycline, which is optionally substituted with 1 to 3 groups selected from, R ６ C １ -C ６ Alkyl heterocyclyls with 4 to 8 members contain halogens, OH groups, and C groups. １ -C ３ It is optionally substituted with 1 to 3 groups selected from alkyl and =O groups. R ｓ H, C １ -C ６ Selected from alkyl groups, 4-6 membered heterocyclines, and 3-6 membered cycloalkyl groups, R ｓ C １ -C ６ The alkyl group is optionally substituted with 1 to 3 groups selected from -OH, -OMe, and halogens. R ｓ The 3-6 member cycloalkyl group is optionally substituted with -OH or -OMe. R ｔ and R ｏ For each occurrence, H and C are considered independently. １ -C ６ Selected from alkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and 3-5 membered cycloalkyl, R ｔ and R ｏ C １ -C ６ Alkyls are D, halogen, -OH, CN, C(=O)NH ２ , -O(C １ -C ３ Alkyl), and -S (=O) ２ CH ３ It is arbitrarily replaced by 1 to 3 elements selected from the following: R ７ For each occurrence, independently, D, halogen, -OR ａ , -CN, -CONH ２ , -C(=O)NR ｂ R ｃ , NR ｂ R ｃ , -C (=O) OR ｂ ,=O,=S,-P(=O) ２ R ｂ R ｃ , -S (=O) ｐ (C １ -C ４ Alkyl), -O (C １ -C ６ Alkyl), C １ -C ６ Alkyl, C １ -C ６ Alkenil, C １ -C ６ These are alkynyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl. R ７ C １ -C ６ Alkyl, C １ -C ６ Alkenyl, or C １ -C ６ Alkynnyl is a halogen, -OH, CN, -S (=O) ｐ (C1-C ４ Alkyl), -C (=O) ２ NH ２ , and are optionally substituted with 1 to 3 groups selected from 3 to 6-membered heterocyclines, R ７ The 4-6 member heterocyclyls are =O, halogen, and R ｂ It is arbitrarily replaced by 1 to 3 elements selected from the following: R ａ H, C １ -C ８ Selected from alkyl, 3-6 membered cycloalkyl, 4-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, R ａ C １ -C ８ Alkyl is composed of D, halogen, OH, CN, -S (=O). ｐ (C1-C ４ Alkyl), -C(=O)NH ２ It is optionally substituted with 1 to 4 groups selected from 3-6 membered cycloalkyl groups, 4-6 membered heterocyclyl groups, and 5-6 membered heteroaryl groups. R ｂ and R ｃ For each occurrence, H and C are considered independently. １ -C ８ Selected from alkyl, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and 3-6 membered cycloalkyl, R ｂ and R ｃ C １ ~C ８ Alkyl is D, halogen, OH, -C(=O)NH ２ , CN, -OCH ３ , and -S (=O) ２ CH ３ It is arbitrarily replaced by 1 to 3 elements selected from the following: m is an integer selected from 0, 1, and 2. n is an integer selected from 0, 1, 2, 3, and 4. Compounds of the compound p selected from 0, 1, and 2, their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts thereof.

2. X １ , X ２ , X ３ , and X ４ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1, wherein C is C.

3. The aforementioned compound has the following structural formula 2: 【Chemistry 4】 [In the formula, Y ２ , Y ３ , and Y ４ Each is independently selected from N and C, and Y ２ , Y ３ , and Y ４ At least one of them is N, and Y ５ A compound according to any one of claims 1 to 2, having [selected from S and C], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound has the following structural formulas 3-1, 3-2, or 3-3: 【Transformation 5】 [In the formula, Y ３ , Y ４ , Y ５ , and Y ６ Each is independently selected from N and C, and Y ３ , Y ４ , Y ５ , and Y ６ A compound according to any one of claims 1 to 2, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, wherein at least one of the is N.

5. The aforementioned compound has the following structural formula 4: 【Transformation 6】 [In the formula, Z １ Z ２ , and Z ３ A compound according to any one of claims 1 to 2, having [each independently selected from N and C], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

6. The aforementioned compound has the following structural formula 5: 【Transformation 7】 [In the formula, Z １ Z ２ , and Z ３ A compound according to any one of claims 1 to 2, having each independently selected from N, S, and C, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

7. The aforementioned compound has the following structural formula 6-1 or 6-2: 【Transformation 8】 [In the formula, Y ３ and Y ４ and Y ５ Each is independently selected from N, S, O, and C, and Y ２ is selected from N and C, and Z in Equation 6-1 １ Z ２ , and Z ３ These are independently selected from N and C, and Z in Equation 6-2. １ Z ２ , and Z ３ A compound according to any one of claims 1 to 2, having each independently selected from N, S, and C, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

8. The aforementioned compound has the following structural formula 7-1 or 7-2: 【Chemistry 9】 [In the formula, Y ３ , Y ４ , Y ５ , and Y ６ Each is independently selected from N and C, and Y ３ , Y ４ , Y ５ , and Y ６ At least one of them is N, and Z in equation 7-1. １ Z ２ , and Z ３ These are independently selected from N and C, and Z in Equation 7-2. １ Z ２ , and Z ３ A compound according to any one of claims 1 to 2, having each independently selected from N, S, and C, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

9. The aforementioned compound has the following structural formulas 8-1, 8-2, 8-3, 8-4, 8-5, or 8-6: 【Chemistry 10】 [In the formula, Y in equations 8-2, 8-4, and 8-6 ３ , Y ４ , Y ５ , and Y ６ Each is independently selected from N and C, and Y ３ , Y ４ , Y ５ , and Y ６ At least one of them is N, Y in equations 8-1, 8-3, and 8-5 ２ , Y ３ , and Y ４ Each is independently selected from N and C, and Y ２ , Y ３ , and Y ４ At least one of them is N, and Y in equation 8-1 ５ It is selected from N, S, and C. Z １ Z ２ , and Z ３ A compound according to any one of claims 1 to 2, having [each independently selected from C and N], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

10. The aforementioned compound has the following structural formulas 9-1, 9-2, 9-3, or 9-4: 【Chemistry 11】 [In the formula, Y in Equations 9-2 and 9-4 ３ , Y ４ , Y ５ , and Y ６ Each is independently selected from N and C, and Y ３ , Y ４ , Y ５ , and Y ６ At least one of them is N, Y in Equations 9-1 and 9-3 ２ , Y ３ , and Y ４ Each is independently selected from N and C, and Y ２ , Y ３ , and Y ４ At least one of them is N, and Y in equation 9-1 ５ It is selected from S and C, Z １ and Z ２ Each is independently selected from N and S, and Z ３ is selected from N and C, Z １ Z ２ , and Z ３ A compound according to any one of claims 1 to 2, having at least one of which is a heteroatom, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

11. The aforementioned compound has the following structural formulas 10-1, 10-2, 10-3, 10-4, 10-5, or 10-6: 【Chemistry 12】 [In the formula, Y in equations 10-1 to 10-5 ２ , Y ３ , and Y ４ Each is independently selected from N and C, and Y ５ is selected from N, S, and C, and Y ２ , Y ３ , Y ４ , and Y ５ At least one of them is a heteroatom, Y in Equation 10-6 ３ , Y ４ , Y ５ , and Y ６ Each is independently selected from N and C, and Y ３ , Y ４ , Y ５ , and Y ６ A compound according to claim 1, having at least one of which is a heteroatom, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound has the following structural formulas 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, or 11-7: 【Chemistry 13】 [In the formula, In equations 11-1 to 11-5, Y ２ , Y ３ , and Y ４ Each is independently selected from N and C, and Y ５ is selected from N, S, and C, and Y ２ , Y ３ , Y ４ , and Y ５ At least one of them is a heteroatom, Z １ Z ２ , and Z ３ These are each independently selected from N and C, In equations 11-6 to 11-7, Y ３ , Y ４ , Y ５ , and Y ６ Each is independently selected from N and C, and Y ３ , Y ４ , Y ５ , and Y ６ At least one of them is a heteroatom, Z １ Z ２ , and Z ３ The compound according to claim 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof, each having independently selected from N and C.

13. The aforementioned compound has the following structural formulas 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8: 【Chemistry 14】 [In the formula, In equations 12-1 to 12-5, Y ２ and Y ５ Each is independently selected from N and C, and Y ３ and Y ４ Each is independently selected from N, S, and C, and Y ２ , Y ３ , Y ４ , and Y ５ At least one of them is a heteroatom, Z １ Z ２ , and Z ３ These are each independently selected from N and C, In equations 12-6 to 12-8, Y ３ , Y ４ , Y ５ , and Y ６ Each is independently selected from N and C, and Y ３ , Y ４ , Y ５ , and Y ６ At least one of them is a heteroatom, Z １ Z ２ , and Z ３ The compound according to claim 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof, each having independently selected from N and C. 【Request Item 14】 【Chemistry 15】 but, 【Chemistry 16】 Selected from, 【Chemistry 17】 but, [Chemistry 18] Selected from, 【Chemistry 19】 but, 【Chemistry 20】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 2. 【Request Item 15】 【Chemistry 21】 but, 【Chemistry 22】 During the ceremony, R ８ は、H、F、Cl、Me、CHF ２ 、CF ３ 、CN、SO ２ Me, Sme, CH ２ CF ３ CH ２ SO ２ Me 【Chemistry 23】 Selected from, and R ９ Me, CF ３ CHF ２ ,CH ２ CF ３ acetyl(-C(=O)CH) ３ ), SO ２ Me, 【Chemistry 24】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 14, selected from [selected from]. 【Request Item 16】 【Chemistry 25】 but, 【Chemistry 26】 Selected from, 【Chemistry 27】 but, 【Chemistry 28】 Selected from, 【Chemistry 29】 but, 【Transformation 30】 Selected from, In the ceremony, T １ , T ２ , and T ３ However, each is independently selected from N and C, and comprises the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1.

17. Ring A is 【Chemistry 31】 Selected from, in the formula, ring A is R １ , R ２ , R ３ , R ４ , and R ５ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, which is substituted with. 【Request Item 18】 【Chemistry 32】 but, 【Transformation 33】 Selected from, where L is -NH- or -O-, q is 1, 2, or 3, R ｐ However, C １ -C ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2 and 17, selected from alkyl, 3-6 membered cycloalkyl, and 5-7 membered heteroaryl. 【Request Item 19】 【Chemistry 34】 but, 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 and 17.

20. Ring B is 【Chemistry 42】 Selected from, ring B has m R ６ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2, 5-6, and 17-19, substituted with a group.

21. Ring B is 【Chemistry 43】 Selected from, ring B has m R ６ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2, 5-6, and 17-19, substituted with a group. 【Request Item 22】 【Chemistry 44】 but, 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1-2, 5-6, and 17-21.

23. Ring C is 【Chemistry 48】 Selected from, ring C has n R ７ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 4, 11, and 17 to 22, substituted with a group. 【Request Item 24】 【Chemistry 49】 but, [Transformation 50] Selected from, in the formula, R ８ However, for each occurrence, independently, H, F, Cl, Me, CHF ２ CF ３ , CN, SO ２ Me, SMe, CH ２ CF ３ ,CH ２ SO ２ Me, 【Chemistry 51】 Selected from, R ９ However, for each occurrence, Me, CF ３ CHF ２ ,CH ２ CF ３ acetyl, SO ２ Me, 【Chemistry 52】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4, 11, and 17 to 22. 【Request Item 25】 【Chemistry 53】 but, 【Chemistry 54】 【Transformation 55】 【Transformation 56】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 4, 11, and 17 to 23.

26. R １ が、H、Me、Cl、F、Br、OMe、CF ３ 、OCF ３ 、CHF ２ 、SO ２ Me、CN、OH、CH ２ OH、COOH、CONH ２ 、 【Chemistry 57】 Selected from, in the formula, R １０ However, for each occurrence, independently, H, Me, Cl, F, CF ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from CN, and any one of claims 1 to 18 and 20 to 25.

27. R １ が、H、-CH ３ 、-CF ３ 、-CHF ２ 、-OCF ３ 、-C(CH ３ ) ２ OH、Br、Cl、-S(=O) ２ CH ３ 、-SF ５ 、 【Chemistry 58】 【Chemistry 59】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 18 and 20 to 25.

28. R １ However, halogen, -C(=O)R ｆ , -OR ｆ , -NR ｆ R ｇ , -SF ５ , C １ -C ６ Alkyl (F, -CN, -OR ｆ phenyl, -NR ｆ R ｇ (and optionally substituted with 1 to 3 groups selected from 5-6 member heteroaryls), C １ -C ６ Alkenyl(F, -CN, -OR) ｆ phenyl, -NR ｆ R ｇ (and optionally substituted with 1 to 3 groups selected from 5-6 member heteroaryls), 3-6 member cycloalkyl (D, halogen, -CN, R) ｆ , -OR ｆ ,CH ２ OR ｆ , -C(=O)NR ｆ R ｇ (and optionally substituted with one or two groups selected from 5-6 member heteroaryls), 4-8 member heterocyclines ( Ｒｆ , -OR ｆ (Optionally substituted with one or two groups selected from halogens and -CN), 5-6 member heteroaryl ( Ｒｆ , -OR ｆ (Optionally substituted with one or two groups selected from halogen and -CN) During the ceremony, R ｆ and R ｇ However, for each occurrence, independently, H, a 5-6 member heteroaryl, a 3-6 member cycloalkyl, and C １ -C ３ Alkyl (D, halogen, -OH, -OCH) ３ , -C(=O)NH ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 18 and 20 to 25, selected from (and optionally substituted with one to three groups selected from -CN).

29. R １ However, CF ３ F, Cl, C １ -C ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from alkyl and C3-C5 cycloalkyl groups according to any one of claims 1 to 18 and 20 to 28.

30. R ２ が、H、Me、Cl、F、Br、-OMe、CF ３ 、-CN、-CONH ２ 、-SO ２ Me、-S(=O)CH ３ 、-SCH ３ 、 【Transformation 60】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 17 and 20 to 29, selected from and -OH.

31. R ２ However, -CH ３ , -S(=O)CH ３ , -SCH ３ -CN, and -S (=O) ２ CH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 17 and 20 to 30.

32. R ３ and R ４ However, each is independently selected from H, Me, Cl, F, Br, and OMe, and is a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 17 and 20 to 31.

33. R ３ and R ４ However, each is independent of H, Me, Cl, F, Br, OMe, CF ３ , and 【Chemistry 61】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 17 and 20 to 31.

34. R ４ However, a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 17 and 20 to 33, selected from F and Cl.

35. R ５ However, -CN and -CH ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from OH according to any one of claims 1 to 13, 17, and 20 to 34.

36. R ５ However, absent, H, -CN, -CH ２ OH, 【Transformation 62】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 17 and 20 to 34.

37. R ５ However, absent, H, CN, halogen, -S (=O) ２ CH ３ ien-CH ２ S (=O) ２ CH ３ , 3-4 membered cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, CH ２ OH and CH ２ CH ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from OH according to any one of claims 1 to 17 and 20 to 34.

38. R ６ but, 【Transformation 63】 Selected from, in the formula, R ｔ and R ｏ However, H and C are independent of each other. １ -C ６ Selected from alkyl groups, R ｔ and R ｏ C １ -C ６ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 21 and 23 to 37, wherein the alkyl group is optionally substituted with one to three groups selected from halogens.

39. R ６ が、-CN、=O、-CH ３ 、-CH ２ S (=O) ２ CH ３ 、-CH ２ OH、-H ２ CH ２ OH、-C(=O)NH ２ ,-O(CH ２ ) ２ OH、-OCH ３ ,-SH,-SCH ３ 、 【Chemistry 64】 OH, -OCH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 21 and 23 to 37, selected from , and =O.

40. R ６ but, 【Transformation 65】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from any one of claims 1 to 21 and 23 to 37.

41. R ６ However, D stands for halogen, -S (=O) ２ R ｈ , -NR ｈ R ｉ , -C(=O)NR ｈ R ｉ ,and C １ -C ４ Alkyl (halogen, -OR ｈ , -C(=O)NR ｈ R ｉ , -NR ｈ R ｉ , -S (=O) ２ R ｈ , -NHS (=O) ｐ R ｈ , -S(=O)R ｈ , 【Chemical Formula 66】 5-6 member heteroaryl, 3-5 member cycloalkyl (halogen and R ｈ (Optionally replaced by 1 to 3 groups selected from), as well as halogens and R ｈ Selected from 3-8 member heterocyclines that are optionally substituted with 1-3 groups selected from, During the ceremony, R ｈ and R ｉ However, for each occurrence, H and C are considered independently. １ -C ３ Alkyl(halogen, -OH, -O(C) １ -C ３ Alkyl), and -S (=O) ２ CH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 21 and 23 to 37, which is optionally substituted with one to three groups selected from, and selected from three to five-membered cycloalkyl groups.

42. R ７ However, F, Cl, Me, CHF ２ CF ３ , CN, -SO ２ Me, -SMe, CH ２ CF ３ ,CH ２ SO ２ Me, Acetyl, 【Transformation 67】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 14, 16 to 23, and 26 to 41, selected from, where n is 0, 1, 2, or 3.

43. R ７ However, Cl, F, -CF ３ , -OCF ３ , -CN, -S (=O) ２ CH ３ ien-CH ３ , -OCH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 14, 16 to 23, and 26 to 42, selected from , and -OH.

44. R ７ However, D, halogen, CN, =O, =S, -OR ｊ , -NR ｊ R ｋ , -C(=O)NR ｊ R ｋ , -C (=O) OR ｊ , -S (=O) ２ CH ３ , 3-5 membered cycloalkyl, 5-6 membered heteroaryl, C １ -C ６ Alkyl (halogen, -OH, -S (=O)) ２ CH ３ , and optionally substituted with 1 to 3 groups selected from 4 to 6-membered heterocyclines), 4-6 member heterocyclines (= O and R) ｋ (Optionally replaced by one or two elements selected from) During the ceremony, R ｊ and R ｋ However, for each occurrence, H and C are independent. １ -C ６ Alkyl(halogen, OH, -C(=O)NH) ２ , and -S (=O) ２ CH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 14, 16 to 23, or 26 to 41, selected from 4-6 member heterocyclyls and 3-5 member cycloalkyls, which are optionally substituted with 1 to 3 groups selected from the above.

45. R １ が、CH ３ 、CF ３ 、OCF ３ 、S(=O) ２ CH ３ 、Br、Cl、 【Transformation 68】 Selected from, R ２ However, H, CN, and S (=O) ２ CH ３ Selected from, R ３ , R ４ , and R ５ H is, R ６ However, = O, CH ３ , Cl, -C(=O)NH ２ ien-CH ２ CH ２ OH, -CH ２ OH and -CH ２ S (=O) ２ CH ３ Selected from, where m is 0, 1, or 2, R ７ However, CH ３ ,Cl,F,CN,OCH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 17, 20 to 21, and 23, selected from , and OH, wherein n is 0, 1, 2, or 3.

46. R １ However, C １ -C ６ Alkyl (halogen, -OH, CN, -OCH) ３ , -NR ｄ R ｅ (Optionally substituted with 1 to 3 groups selected from a 5-membered heteroaryl group containing 1 to 3 heteroatoms selected from phenyl, N, O, and S, and a 6-membered heteroaryl group containing 1 to 3 nitrogen atoms), C ２ -C ４ Alkenyl (halogen, -OH, -CN, and -OCH) ３ (Optionally replaced by 1 to 3 elements selected from) - OR ｄ , -NR ｄ R ｅ , -S (=O) ｐ CH ３ , -SF ５ , halogen, -C(=O)CH ３ , 【Transformation 69】 A five-membered heteroaryl (C) containing one or two heteroatoms selected from N and S. １ -C ３ (Optionally substituted with one or two groups selected from alkyl groups), and a six-membered heteroaryl (C) containing one or two nitrogen atoms. １ -C ３ Selected from (which are optionally substituted with one or two groups selected from alkyl groups), R ２ However, H, CN, CH ３ , F, and S (=O) ２ CH ３ Selected from, R ３ However, H is R ４ However, it is selected from F, Cl, and H, R ５ is absent, H, F, -CN, -C(=O)NH ２ , 3-4 membered cycloalkyl (optionally substituted with 1- or more groups selected from CN and halogens), C １ -C ４ Alkyl (halogen, -S (=O)) ２ CH ３ , and -OH, which are optionally substituted with 1 to 3 groups selected from -S (=O) , 5-6 member heterocyclyl, -S (=O) ２ CH ３ , selected from a 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O, and a 6-membered heteroaryl containing 1 to 3 nitrogen atoms, R ６ But, absent, D, C １ -C ４ Alkyl (halogen, S(=O)CH) ３ , -S (=O) ２ CH ３ , -C(=O)NHCH ３ , -OH, -C(=O)NH ２ , -NR ｄ R ｅ , -NR ｄ OR ｅ , and -NHS (=O) ２ CH ３ (Optionally substituted with 1 to 3 groups selected from) =O, Cl, and C(=O)NH ２ Selected from, R ７ However, D, halogen, CF ３ , -OCF ３ , CN, -OR ｄ , -NR ｄ R ｅ , -C(=O)OH, =O, =S, -S(=O) ２ CH ３ , -C(=O)NR ｄ R ｅ , C １ -C ６ (Halogen, -OH, -S (=O)) ２ CH ３ , -C (=O) ２ NH ２ (and optionally substituted with 1 to 3 groups selected from 3 to 6-membered heterocyclines), 5 to 6-membered heteroaryls, 3 to 5-membered cycloalkyls, and 4 to 6-membered heterocyclines (= O and C) １ -C ３ Selected from (which are optionally substituted with 1 to 3 groups selected from alkyl groups), During the ceremony, R ｄ and R ｅ However, for each occurrence, H and C are considered independently. １ -C ４ Alkyl(D, halogen, -OH, CN, -C(=O)NH) ２ , -S (=O) ２ CH ３ , and -OCH ３ (Optionally substituted with 1 to 3 groups selected from), selected from 5-6 membered heteroaryls, 4-6 membered heterocyclyls, and 3-5 membered cycloalkyls, q is 0, 1, 2, or 3, U １ and U ２ However, independently selected from O and C, a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 17, 20 to 21, and 23.

47. The compound according to claim 1, wherein the compound is selected from compounds 1 to 468, their tautomers, solvates or stereoisomers of the compound or its tautomer, or pharmaceutically acceptable salts thereof.

48. A pharmaceutical composition comprising a compound according to any one of claims 1 to 47, 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.

49. A method for treating a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 47, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48, wherein the disease or condition is selected from ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN.

50. A method for treating a disease or condition related to axonal degeneration, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 47, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

51. A method for preparing SARM1, comprising contacting a subject requiring SARM1 with a compound according to any one of claims 1 to 47, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

52. A method for inhibiting or preventing axonal degeneration, comprising contacting an object requiring such inhibition with a compound according to any one of claims 1 to 47, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 48.

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