SARM1 modulators, preparation and use thereof

Abstract

The present disclosure provides compounds of Formula 1, compositions comprising the compounds, and methods of use thereof, including use in modulating SARM1 and treating various diseases and conditions (e.g., those caused by or associated with axial degeneration).

Description

[0001] Related applications This application claims priority to International Application No. PCT / CN2023 / 091176, filed on April 27, 2023, the contents of which are incorporated herein by reference in their entirety.

[0002] The scope of this disclosure This disclosure relates to compounds that regulate SARM1, compositions comprising said compounds, methods for preparing said compounds, and methods for using said compounds to treat various diseases or conditions (e.g., those caused by or related to axonal degeneration).

[0003] Background of this public disclosure Axonal degeneration contributes to the progression of disease and the accumulation of disability in many degenerative diseases of the peripheral nervous system (PNS) and central nervous system (CNS), such as multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis (ALS) or acute conditions such as traumatic brain injury. (Hughes 2021 (R. Hughes et al., Small Molecule SARM1 Inhibitors Recapitulate the SARM1- / - Phenotype and AllowRecovery of a Metastable Pool of Axons Fated to Degenerate, Cell Rep. Jan 5, 2021; 34(1):108588.); Bosanac 2021 (T. Bosanac et al., Pharmacological SARM1inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy, Brain, Vol. 144, No. 10, 2021, pp. 3226-3238)). Therefore, axonal protection is an important neuroprotective approach for treating chronic and acute CNS and PNS neurodegenerative disorders. (Hughes 2021; Bosanac 2021).

[0004] SARM1 (Sterile Alpha and TIR Motif-containing 1) is a unique member of the Myd88 family of adaptor proteins and is considered the primary driver of axonal degeneration following chemical, inflammatory, mechanical, or metabolic injury to axons. (Hughes 2021; Bosanac 2021). SARM1 has been recognized as a central mediator of axonal degeneration in a variety of 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 morbidity and a major cause of dose reduction and discontinuation in cancer treatment. (Hughes 2021; Bosanac 2021). SARM1 is an attractive target for the treatment of neurodegeneration characterized by axonopathies of the peripheral and central nervous system.

[0005] SARM1 contains a mitochondrial targeting sequence, an N-terminal domain with armadillo repeats (ARM), two sterile alpha-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 SARM1 TIR domain is an NAD + hydrolytic enzyme (nicotinamide adenine dinucleotide nucleosidase, NADase) that cleaves NAD +into 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 nicotinamide adenine dinucleotide nucleosidase activity is critical for its axon degeneration function. (Bosanac 2021). The activity of SARM1 also depends on oligomerization by the SAM domain (Sporny 2019) and is auto-inhibited by the ARM domain (Chen (2021) (C. Shen, et al., Multiple domain interfaces mediate SARM1 autoinhibition. Proc Natl Acad Sci U S A. 2021 Jan 26;118(4).)).

[0006] 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.), WO 2018 / 057989 Al, WO 2020 / 081923 Al, WO 2021 / 142006 Al, WO 2021207302 Al, and WO 2021207308 Al disclose certain SARM1 inhibitors. Certain dipeptidyl peptidase inhibitors (e.g., biphenyl or phenylbenzimidazole derivatives) are disclosed in US 2005 / 0272765 Al. Certain benzylbenzoxazole derivatives are disclosed in WO 2008 / 148449 Al as Met-kinase inhibitors. Certain dihydroisoquinolinone derivatives and combinatorial libraries thereof are described in WO 01 / 14879. Certain compositions for facilitating premature stop codon readthrough and methods of using the same are described in WO 2017 / 049409. Certain nitrogen-containing heterocyclic compounds with nematicidal properties, preparation and use thereof are described in CN 108276352.

[0007] The present disclosure describes SARM1 inhibitors that can be used to prevent axonal degeneration in peripheral and central axonopathies and provide transformational disease-modifying treatment for associated diseases or conditions.

[0008] Brief Description of the Disclosure One aspect of the present disclosure provides a compound selected from the compounds of Formulae 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 (e.g., Compounds 1 to 468) disclosed herein, a tautomer of the compound, a solvate or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be used to treat various diseases or conditions, such as diseases or conditions caused by or associated with axonal degeneration. For example, disclosed herein are compounds of the following structural Formula 1: a tautomer of the compound, a solvate or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: X1, X2, X3, X4, and X5 are each independently C or N; Y1is C or N, Y2is C or N, and Y1and Y2are two adjacent ring atoms on ring B; ring B is phenyl, 5- to 6-membered heteroaryl, 3-6-membered cycloalkyl, or 4- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or 4- to 7-membered heterocyclyl of ring B contains 1 to 4 heteroatoms selected from N, O, and S; ring C is phenyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl of ring C contains 1 to 3 heteroatoms selected from N, S, and O; R 1 is selected from H, halogen, C1-C8alkyl, C1-C8alkenyl, C1-C8alkynyl, -CN, -OH, -COOH, -C(=O)NH2, -OR m , -S(=O) p (C1-C4alkyl), -NRm R n -C(=O)R n -C(=O)OR m -C(=O)NR m R n -P(=O)R m R n -SF5 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O, and S. 3- to 10-membered heterocyclic groups containing one or two heteroatoms independently selected from N, O, and S and 3- to 10-membered cycloalkyl, wherein: R 1 The C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl groups are optionally substituted with 1-3 groups selected from halogens, -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 heterocyclic and 3- to 6-membered cycloalkyl (optionally substituted with 1-3 groups selected from OH and halogens), R 1 The 5- to 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) m and OR m ), R 1 The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) mand OR m ), and R 1 3- to 10-membered cycloalkyl of R m R n 5- to 6-membered heteroaryl, -OR m R m C1-C6 alkyl (optionally substituted with 1-3 groups selected from halo, -C(=0)NH2, R m and OR m ), and wherein R m and R n are each independently at each occurrence selected from H, C1-C6 alkyl, -S(=0) p (C1-C4 alkyl), phenyl, 3- to 8-membered cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein the C1-C6 alkyl of R m is optionally substituted with 1-3 groups selected from D, -C(=0)NH2, -OH, -OMe, -S(=0)2CH3, and halo; R 2 is selected from H, halo, C1-C6 alkyl, C1-C6 alkenyl, -OH, -0(C1-C6 alkyl), -0(C1-C6 alkyl)0(C1-C6 alkyl), -C(=0)NH2, -S(=0) p (C1-C4 alkyl), -CN, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 10-membered heterocyclyl (containing 1 to 3 heteroatoms independently selected from S, O, and N), wherein: R 2 C1-C6 alkyl or C1-C6 alkenyl of R R 2 3- to 5-membered cycloalkyl of R R 2 C1-C6 alkyl of -0(C1-C6 alkyl) of R R 2 3- to 10-membered heterocyclyl of R R 1 and R2 Connect to form ; R 3 and R 4 Each is independently selected from H, halogen, C1-C6 alkyl (optionally substituted by 1-3 groups selected from OH and halogen) and -O (C1-C6 alkyl); R 5 Selected from non-existent, H, -CN, halogen, -C(=O)NH2, -S(=O)p (C1-C4 alkyl), -OR p , phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic, 3- to 8-membered cycloalkyl and C1-C6 alkyl, wherein: R 5 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from OH, -NHR, etc. p -OR p and -S(=O)p(C1-C4 alkyl), R 5 The 4- to 6-membered heterocyclic group is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl, CN, halogen, and =O. R 5 The 3- to 8-membered cycloalkyl group is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl, CN, and halogens, wherein: R p Selected from C1-C6 alkyl, 3- to 6-membered cycloalkyl and 5- to 6-membered heteroaryl, wherein R p The C1-C6 alkyl, 3- to 6-membered cycloalkyl or 5- to 6-membered heteroaryl groups are optionally substituted by 1 to 3 groups selected from CN, OH and halogens; R 6 Each occurrence is independently selected from 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 , 4- to 6-membered heterocyclic groups and C1-C6 alkyl groups, wherein: R 6 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from halogens, -OR s =O, -S (=O) p R t -NHS(=O) p R t-S(=O)(=NH)R t , -NHS(=O) p (C1-C4 alkyl), -CN, -C(=O)NR t R o -NR t R o Halogen, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl (optionally substituted with 1 to 3 groups selected from halogen, OH and R) t ) and 4- to 10-membered heterocyclic groups (optionally substituted with 1 to 3 groups selected from halogens, OH and R) t ),in: R 6 The 4- to 8-membered heterocyclic groups of the C1-C6 alkyl group are optionally substituted with 1 to 3 groups selected from halogens, OH, C1-C3 alkyl groups and =O; R s Selected from H, C1-C6 alkyl, 4- to 6-membered heterocyclic and 3- to 6-membered cycloalkyl, wherein: R s The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from -OH, -OMe, and halogens, and R s The 3- to 6-membered cycloalkyl group is optionally replaced by -OH or -OMe; R t and R o Each of the following groups, when appearing independently, is selected from H, C1-C6 alkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic, and 3- to 5-membered cycloalkyl, wherein R t and R o The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from D, halogen, -OH, CN, C(=O)NH2, -O (C1-C3 alkyl) and -S(=O)2CH3; R 7 Each time it appears, it is independently selected from 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) pC1-C6alkyl, C1-C6alkenyl, C1-C6alkynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein: R 7 C1-C6alkyl, C1-C6alkenyl, or C1-C6alkynyl of R p (C1-C4alkyl), -C(=O)2NH2, and 3- to 6-membered heterocyclyl, R 7 4- to 6-membered heterocyclyl of R b , R a is selected from H, C1-C8alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl, wherein R a C1-C8alkyl of R p (C1-C4alkyl), -C(=O)NH2, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, R b and R c are each independently at each occurrence selected from H, C1-C8alkyl, 4- to 6-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, and 3- to 6-membered cycloalkyl, wherein R b and R c C1-C8alkyl of R m is an integer selected from 0, 1, and 2; n is an integer selected from 0, 1, 2, 3, and 4; and p is an integer selected from 0, 1, and 2.

[0009] In one aspect of the disclosure, the compound of the formula disclosed herein is selected from compounds 1 to 468 shown in Table 1, a tautomer thereof, a solvate or a stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0010] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising 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 (e.g., Compounds 1 to 468) disclosed herein, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition can comprise a compound selected from Compounds 1 to 468 shown below, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier. These compositions can further comprise an additional active pharmaceutical agent.

[0011] Another aspect of the present disclosure provides a method of treating a disease or disorder, comprising administering 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 (e.g., Compounds 1 to 468) disclosed herein, a tautomer of said compound, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of said compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt, wherein the disease or disorder is selected from amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Parkinsonism, ischemia, stroke, a herpes infection, a demyelinating disease such as multiple sclerosis, traumatic brain injury, sepsis, a PNS chronic disease including a hereditary neuropathy such as, but not limited to, Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), an optic nerve disorder such as glaucoma and retinal ganglion degeneration, colitis, a metabolic disease or disorder such as diabetic neuropathy, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), and peripheral neuropathy caused by various drugs such as CIPN.

[0012] Another aspect of the present disclosure provides a method of treating a disease or disorder caused by or associated with axonal degeneration or neuronal injury mediated by SARM1, comprising administering 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 (e.g., Compounds 1 to 468) disclosed herein, a tautomer of said compound, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of said compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0013] In certain embodiments, the treatment method comprises administering to a subject in need thereof a compound selected from Compounds 1 to 468 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0014] In certain embodiments, the treatment method comprises administering to a subject in need thereof an additional active pharmaceutical agent in the same pharmaceutical composition or in separate compositions as or with a compound selected from Compounds 1 to 468 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing. In certain embodiments, the treatment method comprises administering to a subject in need thereof an additional active pharmaceutical agent in the same pharmaceutical composition or in separate compositions as or with a compound selected from Compounds 1 to 468 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing. When administered as separate compositions, the additional therapeutic agent can be administered prior to, simultaneously with, or following administration of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt disclosed herein.

[0015] Also disclosed herein are methods of modulating (e.g., inhibiting) SARM1 in a subject in need thereof, comprising contacting the subject with an 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 (e.g., Compounds 1 to 468) thereof, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of said compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt. In certain embodiments, the methods of modulating (e.g., inhibiting) SARM1 in a subject in need thereof comprise contacting the subject with an effective amount of a compound selected from Compounds 1 to 468 shown below, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of said compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0016] Also disclosed herein are methods of inhibiting or preventing axonal degeneration in a subject in need thereof, comprising contacting the subject with an 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 (e.g., compounds 1 to 468) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing. In certain embodiments, the methods of inhibiting or preventing axonal degeneration or neuronal damage mediated by SARM1 in a subject in need thereof comprise contacting the subject with an effective amount of a compound selected from compounds 1 to 468 shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the foregoing.

[0017] Detailed description of the disclosure I. Definitions The terms “a” or “an” as used herein when referring to a noun means “at least one” and thus includes the plural as well as the singular unit. For example, “additional pharmaceutical agents” means a single or two or more additional pharmaceutical agents.

[0018] The term "alkyl" denotes a hydrocarbyl group selected from straight chain and branched chain saturated hydrocarbyl groups containing 1 to 20 (e.g., 1 to 18, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3) carbon atoms. Examples of alkyl groups include methyl, ethyl, 1 -propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1 -butyl or n-butyl ("n-Bu"), 2-methyl-1 -propyl or isobutyl ("i-Bu"), 1 -methylpropyl or sec-butyl ("s-Bu"), and 1,1 -dimethylethyl or tert-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 groups. Lower alkyl groups contain 1 to 8, preferably 1 to 6, more preferably 1 to 4, and more preferably 1 to 3 carbon atoms.

[0019] The term "alkenyl" denotes a hydrocarbyl group selected from straight chain and branched chain hydrocarbyl groups containing at least one C=C double bond and 2 to 20 (e.g., 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4) carbon atoms. Examples of alkenyl groups include ethenyl or vinyl, prop-1 -enyl, prop-2-enyl, 2-methylprop-1 -enyl, but-1 -enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, hex-1 -enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hex-1,3-dienyl groups. Lower alkenyl groups contain 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms.

[0020] The term "alkynyl" denotes a hydrocarbyl group selected from straight chain and branched chain hydrocarbyl groups containing at least one C≡C triple bond and 2 to 20 (e.g., 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4) carbon atoms. Examples of alkynyl groups include ethynyl, 1 -propynyl, 2-propynyl (propargyl), 1 -butynyl, 2-butynyl, and 3-butynyl groups. Lower alkynyl groups contain 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms.

[0021] The term "heteroalkyl" denotes an alkyl group as defined herein in which one or more of the constituting carbon atoms have been replaced by a heteroatom (e.g., nitrogen, oxygen, or sulfur), for example, CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5, and the like. In certain embodiments, in addition to the replacement of one or more of the constituting carbon atoms by a nitrogen, oxygen, or sulfur, the heteroalkyl group is further optionally substituted as defined herein.

[0022] The term "cycloalkyl" denotes a hydrocarbyl group selected from saturated and partially unsaturated cyclic hydrocarbyl groups (e.g., monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups). For example, cycloalkyl groups can have 3-12, 3-10, 3-8, 3-6, 3-4, or 5-6 carbon atoms. Even further, for example, cycloalkyl groups can be monocyclic groups of 3-12, 3-8, 3-6, 3-4, or 5-6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. Examples of bicyclic cycloalkyl groups include those having 7-12 ring atoms arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The rings can be saturated or have at least one double bond (i.e., partially unsaturated), but not fully conjugated, and not aromatic rings, which are defined herein.

[0023] The term "heterocyclic" or "heterocycle" or "heterocyclyl" denotes a ring selected from 3- to 12-membered (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, which contain at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms selected from, for example, oxygen, sulfur, nitrogen, and silicon. "Heterocycle" also denotes a 5- to 7-membered heterocycle containing at least one heteroatom selected from N, O, and S fused to a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, provided that when the heterocycle is fused to a carbocyclic aromatic or heteroaromatic ring, the point of attachment is at the heterocycle, and when the heterocycle is fused to a cycloalkyl, the point of attachment can be at either the cycloalkyl or the heterocycle.

[0024] "Heterocycle" also denotes aliphatic spirocycles containing at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocycle. The ring can be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle can be substituted with oxo. The point of attachment can be a carbon or a heteroatom in the heterocycle. Heterocycle is not heteroaryl as defined herein.

[0025] Examples of heterocycles include, but are not limited to (numbering from the indicated point of attachment of priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepinyl, oxepinyl, thiepinyl, 1,4-oxathianyl, 1,4-dioxepinyl, 1,4-oxothiepinyl, 1,4-oxaazepinyl, 1,4-dithiepinyl, 1,4-thioazepinyl, 1,4-diazepinyl, 1,4-dithianyl, 1,4-azathiepinyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1, 1-dioxo-1-thiomorpholinyl.

[0026] The term "fused ring" denotes herein a polycyclic ring system, e.g., a bicyclic or tricyclic ring system, in which two rings share only two ring atoms and one bond in common. Examples of fused rings can include: fused bicyclic cycloalkyl rings such as those having 7-12 ring atoms as described above arranged as a bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems; fused bicyclic aryl rings such as 7- to 12-membered bicyclic aryl ring systems as described above; fused tricyclic aryl rings such as 10- to 15-membered tricyclic aryl ring systems as described above; fused bicyclic heteroaryl rings such as 8- to 12-membered bicyclic heteroaryl rings as described above; fused tricyclic heteroaryl rings such as 11- to 14-membered tricyclic heteroaryl rings as described above; and fused bicyclic or tricyclic heterocyclyl rings as described above.

[0027] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, and silicon, including any oxidized form of nitrogen or sulfur; any quaternized form of any basic nitrogen; or any salt thereof, and further including any substitutable nitrogen or sulfur of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (wherein R is, for example, an optionally substituted alkyl group) (as in N-substituted pyrrolidinyl).

[0028] The term "unsaturated" as used herein means that a moiety has one or more units or degrees of unsaturation. Unsaturated is a state in which not all available valences in a compound are saturated by substituents, and thus the compound contains one or more double or triple bonds. A double bond can be depicted as (two solid lines). The depiction of a (solid and dashed lines) indicates a bond that can be either a double or single bond.

[0029] The term "alkoxy" as used herein denotes an alkyl group as defined above wherein one carbon of the alkyl group is replaced by an oxygen atom, provided that the oxygen atom is attached between two carbon atoms.

[0030] The term "halogen" includes F, CI, Br, and I, i.e., fluorine, chlorine, bromine, and iodine, respectively.

[0031] The "CN", "cyano", or "nitrile" group as used herein denotes -CºN.

[0032] As used herein, "aromatic ring" means a carbocyclic or heterocyclic ring containing a conjugated planar ring system having a delocalized pi electron orbitals composed of [4n+2] pi orbitals electrons, where n is an integer from 0 to 6. A "non-aromatic" ring means a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for aromatic rings, and can be fully or partially saturated. Non-limiting examples of aromatic rings include aryl rings and heteroaryl rings, which are further defined below. An "aromatic ring" can be depicted as a ring having conjugated double bonds, such as , or a ring having internal rings, such as .

[0033] The term "aryl" denotes herein a group selected from monocyclic carbocyclic aromatic rings, e.g., phenyl; bicyclic ring systems such as 7- to 12-membered (e.g., 9- to 10-membered) bicyclic ring systems in which at least one ring is carbocyclic and aromatic, selected from, e.g., naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10- to 15-membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic, e.g., fluorene.

[0034] For example, an aryl group can be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring (optionally containing at least one heteroatom selected from N, O, and S), provided that when the carbocyclic aromatic ring is fused to a heterocyclic ring, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to a cycloalkyl group, the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group. A divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene group. A divalent group derived from a monovalent polycyclic hydrocarbon group (the name of which ends in "-yl") by removal of one hydrogen atom from a carbon atom having a free valence is named by adding "-idene" to the name of the corresponding monovalent group, e.g., a naphthyl group having two points of attachment is named naphthylidene.

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

[0036] For example, a heteroaryl group can be a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For such fused bicyclic heteroaryl ring systems in which only one ring contains at least one heteroatom, the point of attachment can be at the heteroaromatic ring or at the cycloalkyl ring.

[0037] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In certain embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In certain embodiments, the total number of S and O atoms in an aromatic heterocyclic ring does not exceed 1.

[0038] Examples of heteroaryl groups include, but are not limited to, (numbering from the indicated position of attachment with priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thiophenyl, triazinyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (such as 1H-pyrazolo[3,4-b]pyridin-5-yl), benzoxazolyl (such as benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinolinyl.

[0039] The term “acyl” denotes a substituent in which the point of attachment is a carbonyl group. Exemplary acyl groups include, but are not limited to, -C(=O)R’, -C(=O)NR’R”, or -C(=O)OR’, wherein R’ and R” are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, any of which can be further substituted with one or more substituents.

[0040] Some compounds can exist at different hydrogen bonding sites, a phenomenon known as tautomerism. For example, a compound containing a carbonyl group (CH₂C(O)-) (ketone form) can undergo tautomerism to form a hydroxyl group (CH=C(OH)-) (enol form). Where applicable, it is also intended to include individual ketone and enol forms, as well as mixtures thereof. For example, regarded as The tautomer form.

[0041] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of this disclosure may contain asymmetric centers and therefore may exist as enantiomers. For example, in the case where the compound has two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers fall into the broader category of stereoisomers. All such possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers, are intended to be included in this disclosure. It is intended to include all stereoisomers of the compound, their tautomers, solvates, and pharmaceutically acceptable salts. Unless otherwise specifically mentioned, reference to one isomer applies to any possible isomer. Whenever an isomer composition is not specified, all possible isomers are included.

[0042] Based on their physicochemical differences, diastereomer mixtures can be separated into their individual diastereomers using methods well-known to those skilled in the art, such as chromatography and / or stepwise crystallization. Enantiomers can be separated as follows: by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acyl chloride), converting the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) each diastereomer into its corresponding pure enantiomer. Enantiomers can also be separated using a chiral HPLC column.

[0043] Methods such as using optically active resolving agents to form diastereomers to resolve racemic mixtures can yield a single stereoisomer, such as a substantially pure enantiomer. Racemic mixtures of chiral compounds of this disclosure can be separated and isolated by any suitable method, including: (1) forming ionic diastereomer salts with chiral compounds and separating them by stepwise crystallization or other methods; (2) forming diastereomer compounds with chiral derivatizing agents, separating the diastereomers and converting them to pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions.

[0044] In the present disclosure, certain single stereoisomers (e.g., substantially pure enantiomers) are separated from each other, for example, by chiral separation. However, the absolute configuration of certain separated single stereoisomers is presently unknown. For example, the compounds in Examples 186 and 187 were synthesized and separated by chiral separation, and the compounds are labeled as “single unknown stereoisomer.” As another example, the compounds in Examples 433 and 434 were synthesized and separated by chiral separation, and the compounds are labeled as “single unknown enantiomer,” and the stereocenter is labeled as “or 1.”

[0045] The term “substantially pure” in the context of stereoisomers means that the target stereoisomer contains no more than 35% by weight, such as no more than 30%, further such as no more than 25%, even further such as no more than 20% of any other stereoisomer. In certain embodiments, the term “substantially pure” means that the target stereoisomer contains no more than 10% by weight, for example, no more than 5%, such as no more than 1% of any other stereoisomer.

[0046] Unless otherwise indicated, structures depicted herein are also meant to include all isomeric forms of the structure, for example, racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as ( Z ) and ( E ) double-bond isomers, and ( Z ) and ( E ) conformational isomers. Thus, geometric and conformational mixtures of the compounds disclosed herein are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0047] The present disclosure provides pharmaceutically acceptable salts of the disclosed compounds, tautomers, solvates, and stereoisomers. Salts of the 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] The term “pharmaceutically acceptable” as used herein refers to components that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and other mammals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. “Pharmaceutically acceptable salts” means any non-toxic salt or salt of an ester that, upon

[0049] "Pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as p-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, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. Such pharmaceutically acceptable salts thus include: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (i.e., caprate), caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, and others. In certain embodiments, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, as well as those formed with organic acids such as maleic acid. J . Pharmaceutical Sciences , 1977, 66 , pp. 1-19.

[0050] Acids commonly employed to form pharmaceutically acceptable salts from basic compounds include inorganic acids such as dihydrogen sulfate, hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, and phosphoric acid, as well as organic acids such as p-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, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. Such pharmaceutically acceptable salts thus include: sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (i.e., caprate), caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, and others. In certain embodiments, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, as well as those formed with organic acids such as maleic acid.

[0051] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4alkyl)4 salts. The present disclosure also contemplates quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable, non-limiting examples of alkali and alkaline earth salts include sodium, lithium, potassium, calcium, and magnesium salts. Other, non-limiting examples of pharmaceutically acceptable salts include salts of ammonia, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0052] If the compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is the 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, in accordance with conventional procedures for making acid addition salts from base compounds. Those of skill in this art will recognize a wide variety of synthetic methodologies that can be used to prepare nontoxic, pharmaceutically acceptable addition salts without undue experimentation.

[0053] The compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, -CD3, -CD2H, or -CDH2 contain one or more deuterium in place of hydrogen. For example, the compounds can be radiolabeled with a radioisotope such as, for example, tritium 3 H), iodine-125 125 I), or carbon-14 14 C). All isotopic variations of the compounds of the present disclosure, whether or not radioactive, are intended to be encompassed within the scope of the present disclosure.

[0054] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" means that a hydrogen radical in a given structure is replaced with a radical of a particular substituent. Unless otherwise indicated, an "optionally substituted" group can have a substituent at each substitutable position of the group, and when more than one position can be substituted with more than one substituent selected from a specified group, the substituents can be the same or different at each position.

[0055] The combinations of chemical components (e.g., substituents, ring structures, linkers, and / or heteroatoms) contemplated by the present disclosure are those that result in the formation of stable or chemically feasible compounds.

[0056] In certain embodiments, substituents are independently selected from the group consisting of optionally substituted heteroatoms and optionally substituted, optionally hetero, optionally cyclic C1-C 18hydrocarbyl, in particular wherein the optionally substituted, optionally hetero, optionally cyclic C1-C 18 hydrocarbyl is an optionally substituted, optionally hetero, optionally cyclic alkyl, alkenyl or alkynyl group, or an optionally substituted, optionally hetero aryl group; and / or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (such as alkoxy, aryloxy), optionally substituted acyl (such as formyl, alkanoyl, carbamoyl, carboxyl, amido), optionally substituted amino (such as amino, alkylamino, dialkylamino, amido, sulfamidyl), optionally substituted thiol (such as mercapto, alkylthiol, arylthiol), optionally substituted sulfinyl or sulfonyl (such as alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl), nitro or cyano.

[0057] In certain embodiments, the substituents are independently selected from the group consisting of: halogen, -R', -OR', =0, =NR', =N-OR', -NR'R", -SR', -SiR'R"R"', -OC(=0)R', -C(=0)R', -C02R', -C(=0)NR'R", -OC(=0)NR'R", -NR"C(=0)R', -NR'-C(=0)NR"R", -NR'-S02NR"R", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R', -CN, -N02, -N3, -CH(Ph)2, perfluoro(Ci-C4)alkoxy, and perfluoro(Ci-C4)alkyl, in a number ranging from zero to three, with those groups having zero, one, or two substituents being particularly preferred. R', R", and R'" each independently represent hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted with one to three halogens, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy, or thioalkoxy groups, or aryl-(Ci-C4)alkyl groups. When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-, 6-, or 7-membered ring. Thus, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. When the aryl group is 1,2,3,4-tetrahydronaphthyl, it can be substituted with a substituted or unsubstituted C3-C7spirocycloalkyl group. The C3-C7spirocycloalkyl group can be substituted in the same manner as defined herein for "cycloalkyl."

[0058] In certain embodiments, the substituents are selected from the group consisting of: halogen, -R', -OR', =0, -NR'R", -SR', -SiR'R"R"', -OC(=0)R', -C(=0)R', -C02R', -C(=0)NR'R", -OC(=0)NR'R", -NR"C(=0)R', -NR"CO2R', -NR'-SO2NR"R", -S(=0)R', -SO2R', -SO2NR'R", -NR"SO2R', -CN, -N02, perfluoroC1-C4alkoxy, and perfluoroC1-C4alkyl, wherein R' and R" are as defined above.

[0059] In certain embodiments, the substituents are independently selected from the group consisting of a substituted or unsubstituted heteroatom; a substituted or unsubstituted, 0-3 heteroatom-containing C1-C6alkyl (e.g., C1-C3alkyl or C1-C2alkyl); a substituted or unsubstituted, 0-3 heteroatom-containing C2-C6alkenyl (e.g., C2-C4alkenyl); a substituted or unsubstituted, 0-3 heteroatom-containing C2-C6alkynyl (e.g., C2-C4alkynyl); or a substituted or unsubstituted, 0-3 heteroatom-containing C6-C 14 aryl (e.g., C5-C6aryl), wherein each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0060] In certain embodiments, the substituents are independently selected from the group consisting of an aldehyde, aldimine, alkylcarbonyloxy, alkoxyl, alkoxycarbonyl, alkoxyl, alkyl, alkenyl, alkynyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamido, carboxyl, cyanyl, ester, halogenated formyl, hydroperoxyl, hydroxyl, imine, isocyanide, isocyanate, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl, and trifluoromethylether (OCF3) groups.

[0061] In certain embodiments, certain substituents are structurally depicted. For example, when a substituent is attached to a ring structure without specifying a position, such as in In certain embodiments, the substituents are independently selected from the group consisting of a substituted or unsubstituted heteroatom; a substituted or unsubstituted, 0-3 heteroatom-containing C1-C6alkyl (e.g., C1-C3alkyl or C1-C2alkyl); a substituted or unsubstituted, 0-3 heteroatom-containing C2-C6alkenyl (e.g., C2-C4alkenyl); a substituted or unsubstituted, 0-3 heteroatom-containing C2-C6alkynyl (e.g., C2-C4alkynyl); or a substituted or unsubstituted, 0-3 heteroatom-containing C6-C 6 may be attached to any chemically feasible position of ring B, whether ring B is a monocyclic or polycyclic structure; and when n is a positive integer, substituent R 7 may be attached to any chemically feasible position of 5-membered ring C.

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

[0063] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter referred to as separation) to a desired degree of homogeneity using techniques commonly used in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example: reversed-phase and normal-phase; size exclusion; ion exchange; high, medium, and low-pressure liquid chromatography methods and apparatus; small-scale analytical; simulated moving bed (“SMB”) and preparative thin-layer or thick-layer chromatography, as well as techniques for small-scale thin-layer and rapid chromatography. Those skilled in the art can apply such techniques to achieve the desired separation.

[0064] Non-limiting examples of suitable solvents that can be used in this disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or dichloromethane (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IPAc), tert-butyl acetate (... t -BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), 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 suitable bases that can be used in this disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), and 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 "object" refers to animals, including humans.

[0067] The term "therapeutically effective amount" means an amount of a compound that produces effects that are the result of the administration of it (e.g., improvement of a disease or condition, reduction in severity of a disease or condition, and / or reduction in the progression of a disease or condition, such as ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN). The disease or condition can be caused by or associated with axonal degeneration. The exact amount of a therapeutically effective amount will depend on the purpose of the treatment, and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0068] The term "treat" and its cognates, as used herein, means to slow down or stop the progression of a disease. "Treat" and its cognates, as used herein, include, but are not limited to, the following: completely or partially alleviating, curing, or healing a disease or condition or symptoms thereof, reducing the risk of a disease or condition, such as ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN. The disease or condition can be caused by or associated with axonal degeneration. Improvement of any of these symptoms or reduction in the severity thereof can be assessed according to methods and techniques known in the art.

[0069] The terms "about" and "approximately," when used in connection with a number, such as a percentage, include the specified number and a range of numbers known to one of ordinary skill in the art (e.g., a range of percentages, such as a range of ±10% from a particular point value).

[0070] II. Compounds and Compositions In a first embodiment, the compound of the present disclosure is a compound of the following structural Formula 1 : a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: X1, X2, X3, X4and X5are each independently C or N (e.g., X1, X2, X3, X4and X5are all C, X1, X2, X3, X4and X5are all N; one of X1, X2, X3, X4and X5is N and the rest of X1, X2, X3, X4and X5are C; two of X1, X2, X3, X4and X5are N and the rest of X1, X2, X3, X4and X5are C; three of X1, X2, X3, X4and X5are N and the rest of X1, X2, X3, X4and X5are C; four of X1, X2, X3, X4and X5are N and the rest of X1, X2, X3, X4and X5are C; X1, X2, X3and X4are C and X5is N; X2, X3and X4are C and X1and X5are N; X1, X3and X4are C and X2and X5are N; X1, X2and X4are C and X3and X5are N; X1, X2and X3are C and X4and X5are N); Y1is C or N, Y2is C or N, and Y1and Y2are two adjacent ring atoms on ring B; Ring B is phenyl, 5- to 6-membered heteroaryl, 3-6-membered cycloalkyl, or 4- to 6-membered heterocyclyl, wherein the 5- to 6-membered heteroaryl or 4- to 7-membered heterocyclyl of ring B contains 1 to 4 heteroatoms selected from N, O, and S; Ring C is phenyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclyl, 5- to 6-membered heteroaryl, or 9- to 10-membered heteroaryl of ring C contains 1 to 3 heteroatoms selected from N, S, and O; R 1 is selected from the group consisting of H, halogen, C1-C8alkyl, C1-C8alkenyl, C1-C8alkynyl, -CN, -OH, -COOH, -C(=O)NH2, -OR m , -S(=O) p (C1-C4alkyl), -NR m R n , -C(=O)R n , -C(=O)OR m , -C(=O)NR m R n , -P(=O)R m R n , -SF5, 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms independently selected from N, O, and S, 3- to 10-membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O, and S, and 3- to 10-membered cycloalkyl, wherein: R1 The C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl groups are optionally substituted with 1-3 groups selected from halogens, -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 heterocyclic and 3- to 6-membered cycloalkyl (optionally substituted with 1-3 groups selected from OH and halogens), R 1 The 5- to 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) m and OR m ), R 1 The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) m and OR m ),and R 1 The 3- to 10-membered cycloalkyl group is optionally substituted with 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) m and ORm ),and Where R m and R n Each occurrence is independently selected from H, C1-C6 alkyl groups, and -S (=O). p (C1-C4 alkyl), phenyl, 3- to 8-membered cycloalkyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl, wherein R m The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from D, -C(=O)NH2, -OH, -OMe, -S(=O)2CH3 and halogens; R 2 Selected from H, halogens, 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 (C1-C4 alkyl), -CN, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 10-membered heterocyclic (containing 1 to 3 heteroatoms independently selected from S, O, and N), wherein: R 2 The C1-C6 alkyl or C1-C6 alkenyl group is optionally substituted with 1-3 groups selected from halogens, CN, and -C(=O)O (C1-C6 alkyl). R 2 The 3- to 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 the -O (C1-C6 alkyl) is optionally substituted with 1-3 groups selected from halogens and CN, and R 2 The 3- to 10-membered heterocyclic group is optionally substituted with 1-3 groups selected from OH, CN, and halogens; or R 1 and R 2 Connect to form ; R 3 and R 4 Each is independently selected from H, halogen, C1-C6 alkyl (optionally substituted by 1-3 groups selected from OH and halogen) and -O (C1-C6 alkyl); R 5 Selected from non-existent, H, -CN, halogen, -C(=O)NH2, -S(=O)p (C1-C4 alkyl), -OR p , phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic, 3- to 8-membered cycloalkyl and C1-C6 alkyl, wherein: R 5 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from OH, -NHR, etc. p -OR p and -S(=O)p(C1-C4 alkyl), R 5 The 4- to 6-membered heterocyclic group is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl, CN, halogen, and =O. R 5 The 3- to 8-membered cycloalkyl group is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl, CN, and halogens, wherein: R p Selected from C1-C6 alkyl, 3- to 6-membered cycloalkyl and 5- to 6-membered heteroaryl, wherein R p The C1-C6 alkyl, 3- to 6-membered cycloalkyl or 5- to 6-membered heteroaryl groups are optionally substituted by 1 to 3 groups selected from CN, OH and halogens; R 6 Each occurrence is independently selected from 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 , 4- to 6-membered heterocyclic groups and C1-C6 alkyl groups, wherein: R 6 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from halogens, -OR s =O, -S (=O) p R t -NHS(=O) p R t -S(=O)(=NH)R t , -NHS(=O) p (C1-C4 alkyl), -CN, -C(=O)NR t R o -NR t R o Halogen, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl (optionally substituted with 1 to 3 groups selected from halogen, OH and R) t ) and 4- to 10-membered heterocyclic groups (optionally substituted with 1 to 3 groups selected from halogens, OH and R) t ),in: R 6 The 4- to 8-membered heterocyclic groups of the C1-C6 alkyl group are optionally substituted with 1 to 3 groups selected from halogens, OH, C1-C3 alkyl groups and =O; R s Selected from H, C1-C6 alkyl, 4- to 6-membered heterocyclic and 3- to 6-membered cycloalkyl, wherein: R s The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from -OH, -OMe, and halogens, and R s The 3- to 6-membered cycloalkyl group is optionally replaced by -OH or -OMe; R t and R o Each of the following groups is independently selected from H, C1-C6 alkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic, and 3- to 5-membered cycloalkyl, wherein R t and R o The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from D, halogen, -OH, CN, C(=O)NH2, -O (C1-C3 alkyl) and -S(=O)2CH3; R 7 Each time it appears, it is independently selected from 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 ynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl, wherein: R 7 The C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl groups are optionally substituted with one to three groups selected from halogens, -OH, CN, and -S (=O). p (C1-C4 alkyl), -C(=O)2NH2 and 3- to 6-membered heterocyclic groups, R 7 The 4- to 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from O, halogens, and R. b , R aSelected from H, C1-C8 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein R a The C1-C8 alkyl group is optionally substituted with 1 to 4 groups selected from D, halogens, OH, CN, -S (=O). p (C1-C4 alkyl), -C(=O)NH2, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl R b and R c Each of the following groups, when appearing independently, is selected from H, C1-C8 alkyl, 4- to 6-membered heterocyclic, phenyl, 5- to 6-membered heteroaryl, and 3- to 6-membered cycloalkyl, wherein R b and R c The C1-C8 alkyl group is optionally substituted with 1 to 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; and p is an integer selected from 0, 1, and 2.

[0071] In each occurrence, C1 to C8 alkyl can independently be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, or C8 alkyl; C1 to C6 alkyl can be C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, or C6 alkyl; C1 to C4 alkyl can be C1 alkyl, C2 alkyl, C3 alkyl, or C4 alkyl; 3- to 5-member refers to 3-, 4-, or 5-member; 3- to 6-member refers to 3-, 4-, 5-, or 6-member; 3- to 8-member refers to 3-, 4-, 5-, 6-, 7-, or 8-member; 3- to 10-member... - Yuan refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-yuan; 4- to 6-yuan refers to 4-, 5-, or 6-yuan; 4- to 7-yuan refers to 4-, 5-, 6-, or 7-yuan; 4- to 8-yuan refers to 4-, 5-, 6-, 7-, or 8-yuan; 5- to 7-yuan refers to 5-, 6-, or 7-yuan; 1-3 or 1-3 groups refers to 1 group, 2 groups, or 3 groups; 1-3 or 1-3 heteroatoms refers to 1 heteroatom, 2 heteroatoms, or 3 heteroatoms; and 1-4 or 1-4 heteroatoms refers to 1 heteroatom, 2 heteroatoms, 3 heteroatoms, or 4 heteroatoms. The heteroatoms can be located at any chemically feasible position in the cyclic structure.

[0072] Combinations of chemical moieties (such as substituents, ring structures, or heteroatoms) disclosed herein are those resulting in the formation of stable or chemically feasible compounds. With respect to abbreviations or according to convention, specific hydrogen atoms attached to a particular atom (e.g., carbon atom C or nitrogen atom N) are not specified in chemical structures, formulas, or symbols; hydrogen atoms are considered to be present to the extent necessary to complete the valency of the particular atom (e.g., C or N).

[0073] In a 2ndembodiment, in the compounds of the disclosure, tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, X1, X2, X3, and X4are C; and all other variables not specifically defined herein are as defined in the preceding embodiments.

[0074] In a 3rdembodiment, the compounds of the disclosure are compounds of the following Structural Formula 2: tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, wherein Y2, Y3, and Y4are each independently selected from N and C, at least one of Y2, Y3, and Y4is N, and Y5is selected from S and C; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0075] In a 4thembodiment, the compounds of the disclosure are compounds of the following Structural Formula 3-1, 3-2, or 3-3: tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, wherein Y3, Y4, Y5, and Y6are each independently selected from N and C and at least one of Y3, Y4, Y5, and Y6is N; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0076] In a 5thembodiment, the compounds of the disclosure are compounds of the following Structural Formula 4: tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, wherein Z1, Z2, and Z3are each independently selected from N and C; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0077] In a 6thembodiment, the compounds of the disclosure are compounds of the following Structural Formula 5: a tautomer of the compound, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Z1, Z2, and Z3 are each independently selected from N, S, and C; and all other variables not specifically defined herein are as defined in any of the suitable preceding embodiments.

[0078] In a seventh embodiment, the compound of the disclosure is a compound of the following structural Formula 6-1 or 6-2: a tautomer of the compound, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Y3, Y4, and Y5 are each independently selected from N, S, O, and C, Y2 is selected from N and C, Z1, Z2, and Z3 of Formula 6-1 are each independently selected from N and C, and Z1, Z2, and Z3 of Formula 6-2 are each independently selected from N, S, and C; and all other variables not specifically defined herein are as defined in any of the suitable preceding embodiments.

[0079] In an eighth embodiment, the compound of the disclosure is a compound of the following structural Formula 7-1 or 7-2: a tautomer of the compound, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein 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, Z1, Z2, and Z3 of Formula 7-1 are each independently selected from N and C, and Z1, Z2, and Z3 of Formula 7-2 are each independently selected from N, S, and C; and all other variables not specifically defined herein are as defined in any of the suitable preceding embodiments.

[0080] In a ninth embodiment, the compound of the disclosure is a compound of the following structural Formula 8-1, 8-2, 8-3, 8-4, 8-5, or 8-6: a tautomer of the compound, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: Y3, Y4, Y5, and Y6 of Formula 8-2, Formula 8-4, and Formula 8-6 are each independently selected from N and C and at least one of Y3, Y4, Y5, and Y6 is N, Y2, Y3, and Y4of Formula 8-1, Formula 8-3, and Formula 8-5 are each independently selected from N and C, at least one of Y2, Y3, and Y4is N, Y5of Formula 8-1 is selected from S and C; Z1, Z2, and Z3are each independently selected from N and C; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0081] In a tenth embodiment, the compounds of the present disclosure are compounds of the following structural Formula 9-1, 9-2, 9-3, or 9-4: a tautomer thereof, solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: Y3, Y4, Y5, and Y6of Formula 9-2 and Formula 9-4 are each independently selected from N and C and at least one of Y3, Y4, Y5, and Y6is N, Y2, Y3, and Y4of Formula 9-1 and Formula 9-3 are each independently selected from N and C and at least one of Y2, Y3, and Y4is N, Y5of Formula 9-1 is selected from S and C; Z1and Z2are each independently selected from N and S, Z3is selected from N and C, and at least one of Z1, Z2, and Z3is a heteroatom; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0082] In an eleventh embodiment, the compounds of the present disclosure are compounds of the following structural Formula 10-1, 10-2, 10-3, 10-4, 10-5, or 10-6: a tautomer thereof, solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: Y2, Y3, and Y4of Formula 10-1 to 10-5 are each independently selected from N and C, Y5is selected from N, S, and C, and at least one of Y2, Y3, Y4, and Y5is a heteroatom; Y3, Y4, Y5, and Y6of Formula 10-6 are each independently selected from N and C, and at least one of Y3, Y4, Y5, and Y6is a heteroatom; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0083] In a 12th embodiment, the compound of the disclosure is a compound of structural formula 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, or 11-7: a tautomer thereof, solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: In formulae 11-1 to 11-5, Y2, Y3, and Y4are each independently selected from N and C, Y5is selected from N, S, and C, at least one of Y2, Y3, Y4, and Y5is a heteroatom, Z1, Z2, and Z3are each independently selected from N and C; In formulae 11-6 to 11-7, Y3, Y4, Y5, and Y6are each independently selected from N and C, at least one of Y3, Y4, Y5, and Y6is a heteroatom, Z1, Z2, and Z3are each independently selected from N and C; and all other variables not specifically defined herein are as defined in any of the suitable preceding embodiments.

[0084] In a 13th embodiment, the compound of the disclosure is a compound of structural formula 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, or 12-8: a tautomer thereof, solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: In formulae 12-1 to 12-5, Y2and Y5are each independently selected from N and C, Y3and Y4are each independently selected from N, S, and C, at least one of Y2, Y3, Y4, and Y5is a heteroatom, and Z1, Z2, and Z3are each independently selected from N and C; In formulae 12-6 to 12-8, Y3, Y4, Y5, and Y6are each independently selected from N and C, at least one of Y3, Y4, Y5, and Y6is a heteroatom, and Z1, Z2, and Z3are each independently selected from N and C; and all other variables not specifically defined herein are as defined in any of the suitable preceding embodiments.

[0085] In a 14th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of the disclosure, is selected from: selected from the group consisting of: selected from the group consisting of: and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0086] In a 15th embodiment, in the compounds of the disclosure, tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, selected from the group consisting of: wherein: R 8 selected from the group consisting of: H, F, Cl, Me, CHF2, CF3, CN, SO2Me, SMe, CH2CF3, CH2SO2Me, and R 9 selected from the group consisting of: Me, CF3, CHF2, CH2CF3, acetyl (-C(=0)CH3), SO2Me, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0087] In a 16th embodiment, in the compounds of the disclosure, tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, selected from the group consisting of: selected from the group consisting of: and selected from the group consisting of: wherein T1, T2and T3are each independently selected from N and C; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0088] In a 17th embodiment, in the compounds of the disclosure, tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, wherein ring A is substituted with R 1 , R 2 , R 3 , R 4 , and R 5 ; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0089] In an 18thembodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, is selected from: wherein L is -NH- or -O-, q is 1, 2, or 3, and R p is selected from C1-C4alkyl, 3- to 6-membered cycloalkyl, and 5- to 7-membered heteroaryl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0090] In a 19thembodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, is selected from: and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0091] In a 20thembodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, wherein ring B is substituted with m groups of R 6 ; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0092] In a 21stembodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, ring B is selected from: wherein ring B is substituted with m groups of R 6 and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0093] In a 22ndembodiment, in the compounds, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the present disclosure, selected from: and and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0094] In a 23rdembodiment, in the compounds, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the present disclosure, ring C is selected from: wherein ring C is substituted with n groups of R 7 and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0095] In a 24thembodiment, in the compounds, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the present disclosure, selected from: wherein: R 8 is, at each occurrence, independently selected from H, F, Cl, Me, CHF2, CF3, CN, SO2Me, SMe, CH2CF3, CH2SO2Me, and R 9 is, at each occurrence, independently selected from Me, CF3, CHF2, CH2CF3, acetyl, SO2Me, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0096] In a 25th embodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, selected from: and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0097] In a 26th embodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, R 1 selected from: H, Me, Cl, F, Br, OMe, CF3, OCF3, CHF2, SO2Me, CN, OH, CH2OH, COOH, CONH2, wherein R 10 is independently selected at each occurrence from H, Me, Cl, F, CF3, and CN; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0098] In a 27th embodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, R 1 selected from: H, -CH3, -CF3, -CHF2, -OCF3, -C(CH3)2OH, Br, Cl, -S(=O)2CH3, -SF5, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0099] In a 28th embodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, R 1 selected from: halogen, -C(=O)R f , -OR f, -NR f R g , -SF5, C1-C6alkyl (optionally substituted with 1 to 3 groups selected from F, -CN, -OR f , phenyl, -NR f R g , and 5- to 6-membered heteroaryl), C1-C6alkenyl (optionally substituted with 1 to 3 groups selected from F, -CN, -OR f , phenyl, -NR f R g , and 5- to 6-membered heteroaryl), 3- to 6-membered cycloalkyl (optionally substituted with 1-2 groups selected from D, halogen, -CN, R f , -OR f , CH2OR f , -C(=O)NR f R g , and 5- to 6-membered heteroaryl), 4- to 8-membered heterocyclyl (optionally substituted with 1-2 groups selected from R f , -OR f , halogen, and -CN), and 5- to 6-membered heteroaryl (optionally substituted with 1-2 groups selected from R f , -OR f , halogen, and -CN), wherein: R f and R g are each independently at each occurrence selected from H, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl, and C1-C3alkyl (optionally substituted with 1 to 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 preceding embodiments as appropriate.

[0100] In a 29th embodiment, in the compounds, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, of the disclosure, R 1 is selected from: CF3, F, Cl, C1-C3alkyl, and C3-C5cycloalkyl; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0101] In a 30thembodiment, in a compound of the disclosure, tautomer, solvate, or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 2 is selected from: H, Me, Cl, F, Br, -OMe, CF3, -CN, -CONH2, -SO2Me, -S(=O)CH3, -SCH3, and -OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0102] In a 31stembodiment, in a compound of the disclosure, tautomer, solvate, or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 2 is selected from: -CH3, -S(=O)CH3, -SCH3, -CN, and S(=O)2CH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0103] In a 32ndembodiment, in a compound of the disclosure, tautomer, solvate, or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 3 and R 4 are each independently selected from H, Me, Cl, F, Br, and OMe; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0104] In a 33rdembodiment, in a compound of the disclosure, tautomer, solvate, or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 3 and R 4 are each independently selected from H, Me, Cl, F, Br, OMe, CF3, and ; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0105] In a 34thembodiment, in a compound of the disclosure, tautomer, solvate, or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 4 is selected from F and Cl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0106] In a 35thembodiment, in a compound of the disclosure, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 5 is selected from -CN and -CH2OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0107] In a 36thembodiment, in a compound of the disclosure, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, wherein R 5 is selected from: absent, H, -CN, -CH2OH, and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0108] In a 37thembodiment, in a compound of the disclosure, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 5 is selected from: absent, H, CN, halogen, -S(=0)2CH3, -CH2S(=0)2CH3, 3- to 4- membered cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, CH2OH, and CH2CH2OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0109] In a 38thembodiment, in a compound of the disclosure, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 6 is selected from: wherein R t and R o are each independently selected from H and C1-C6alkyl, wherein R t and R o C1-C6alkyl of R

[0110] In a 39thembodiment, in a compound of the disclosure, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt, R 6 is selected from: and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0111] In a 40th embodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, R 6 is selected from: and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0112] In a 41st embodiment, in the compounds of the disclosure, tautomers, solvates, or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts, R 6 is selected from D, halogen, -S(=0)2R h , -NR h R i , -C(=0)NR h R i and C1-C4 alkyl (optionally substituted with 1 to 3 groups selected from halogen, -OR h , -C(=0)NR h R i , -NR h R i , -S(=0)2R h , -NHS(=0) p R h , -S(=0)R h , , , 5- to 6-membered heteroaryl, 3- to 5-membered cycloalkyl (optionally substituted with 1 to 3 groups selected from halogen and R h ) and 3- to 8-membered heterocyclyl (optionally substituted with 1 to 3 groups selected from halogen and R h ), wherein: R h and R ieach occurrence 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(=0)2CH3), and 3- to 5-membered cycloalkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0113] In a 42ndembodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the disclosure, R 7 is selected from F, Cl, Me, CHF2, CF3, CN, -SO2Me, -SMe, CH2CF3, CH2SO2Me, acetyl, and n is 0, 1, 2, or 3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0114] In a 43rdembodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the disclosure, R 7 is selected from: Cl, F, -CN, -S(=0)2CH3, -CH3, -OCH3, and -OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0115] In a 44thembodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the disclosure, R 7 is selected from: D, halogen, CN, =0, =S, -OR j , -NR j R k , -C(=0)NR j R k , -C(=0)OR j , -S(=0)2CH3, 3- to 5-membered cycloalkyl, 5- to 6-membered heteroaryl, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from halogen, -OH, -S(=0)2CH3, and 4- to 6-membered heterocyclyl), and 4- to 6-membered heterocyclyl (optionally substituted with 1 to 2 groups selected from =0 and R k ), wherein: R j and Rk Each time it appears, it is independently selected from H, C1-C6 alkyl (optionally substituted with 1 to 3 groups selected from halogens, OH, -C(=O)NH2 and -S(=O)2CH3), 4- to 6-membered heterocyclic groups and 3- to 5-membered cycloalkyl groups; and all other variables not specifically defined herein are as defined in any of the suitable foregoing embodiments.

[0116] In the 45th embodiment, the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure are included. R 1 Selected from R 2 Selected from H, CN and S(=O)2CH3, R 3 R 4 and R 5 It's H. R 6 Selected from =O, CH3, Cl, -C(=O)NH2, -CH2CH2OH, -CH2OH and -CH2S(=O)2CH3, where m is 0, 1 or 2. R 7 The components are selected from CH3, Cl, F, CN, OCH3, and OH, and n is 0, 1, 2, or 3; Furthermore, all other variables not specifically defined herein are defined in any of the appropriate foregoing implementation schemes.

[0117] In the 46th embodiment, the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure are included. R 1 Selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens, -OH, CN, -OCH3, -NR) d R e phenyl, 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S and 6-membered heteroaryl containing 1 to 3 nitrogen atoms, C2-C4 alkenyl (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 5-membered heteroaryl containing 1 to 2 heteroatoms selected from N and S (optionally substituted with 1 to 2 groups selected from C1-C3alkyl) and 6-membered heteroaryl containing 1 to 2 nitrogen atoms (optionally substituted with 1 to 2 groups selected from C1-C3alkyl); R 2 selected from H, CN, CH3, F and S(=0)2CH3; R 3 is H; R 4 selected from F, Cl and H; R 5 selected from absent, H, F, -CN, -C(=0)NH2, 3- to 4-membered cycloalkyl (optionally substituted with 1 to 2 groups selected from CN and halogen), C1-C4alkyl (optionally substituted with 1 to 3 groups selected from halogen, -S(=0)2CH3and -OH), 5- to 6-membered heterocyclyl, -S(=0)2CH3, 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O and 6-membered heteroaryl containing 1 to 3 nitrogen atoms; R 6 selected from absent, D, C1-C4alkyl (optionally substituted with 1-3 groups selected from halogen, -S(=0)CH3, -S(=0)2CH3, -C(=0)NHCH3, -OH, -C(=0)NH2, -NR d R e , -NR d OR e and -NHS(=0)2CH3), =0, Cl and -C(=0)NH2; R 7 selected from D, halogen, CF3, -OCF3, CN, -OR d , -NR d R e , -C(=0)OH, =0, =S, -S(=0)2CH3, -C(=0)NR d R e , C1-C6 (optionally substituted with 1-3 groups selected from halogen, -OH, -S(=0)2CH3, -C(=0)2NH2and 3- to 6-membered heterocyclyl), 5- to 6-membered heteroaryl, 3- to 5-membered cycloalkyl and 4- to 6-membered heterocyclyl (optionally substituted with 1 to 3 groups selected from =0 and C1-C3alkyl); wherein: R d and R eEach of the groups is independently selected from H, C1-C4 alkyl (optionally substituted by 1 to 3 groups selected from D, halogen, -OH, CN, -C(=O)NH2, -S(=O)2CH3 and -OCH3), 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic and 3- to 5-membered cycloalkyl; q is 0, 1, 2, or 3; U1 and U2 are independently selected from O and C; Furthermore, all other variables not specifically defined herein are defined in any of the appropriate foregoing implementation schemes.

[0118] In some embodiments, the compounds of this 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 of the foregoing substances.

[0119] Table 1. Compounds 1 to 468

[0120] Another aspect of this disclosure provides a pharmaceutical composition comprising at least one of the formulas disclosed herein: 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. Compounds of 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 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, and at least one pharmaceutically acceptable carrier.

[0121] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable mediators and pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0122] It should also be understood that the pharmaceutical compositions of this disclosure can be used in combination therapies; that is, the pharmaceutical compositions described herein may further include additional active pharmaceutical agents. Alternatively, they may comprise ingredients selected from 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, 1 Pharmaceutical compositions comprising compounds of 2-1, 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 compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing substances may be administered as separate compositions in parallel with, before or after compositions containing additional active pharmaceutical agents.

[0123] In some embodiments, the pharmaceutically acceptable carrier may be selected from excipients and mediators. Pharmaceutically acceptable carriers as used herein may be selected from, for example, any and all solvents, diluents, other liquid mediators, dispersants, suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants, suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology J. Swarbrick and JC Boylan, eds., 1988–1999, Marcel Dekker, New York, disclose various carriers for formulating pharmaceutical compositions and known techniques for their preparation. The use of any conventional carrier is considered within the scope of this disclosure unless it is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effects 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), mixtures of metaglycerides 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, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as carboxymethyl methacrylate). Sodium cellulose, ethyl cellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solutions, non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavoring agents, flavoring agents, preservatives, and antioxidants.

[0124] 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. Compounds of 12-5, 12-6, 12-7, and 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions disclosed herein may be administered orally in solid dosage forms, such as capsules, tablets, lozenges, sugar-coated pills, granules, and powders, or orally in liquid dosage forms, such as elixirs, syrups, emulsions, dispersants, and suspensions. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein may also be administered parenterally in sterile liquid dosage forms (such as dispersions, suspensions, or solutions). Other dosage forms that can be used to administer the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein include ointments, creams, drops, transdermal patches, or powders for topical application, ophthalmic solutions or suspensions for ocular application, such as eye drops, aerosol sprays or powder compositions for inhalation or intranasal application, or creams, ointments, sprays, or suppositories for rectal or vaginal application.

[0125] Gelatin capsules may also be used, containing the compounds disclosed herein, their tautomers, solvates or stereoisomers of said compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, as well as powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be formulated as sustained-release products to provide continuous release of the drug over a period of time. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant tastes and protect the tablets from atmospheric effects, or they may be enteric-coated for selective disintegration in the gastrointestinal tract.

[0126] Liquid dosage forms for oral administration may further include at least one agent selected from colorants and flavoring agents to increase patient acceptability.

[0127] Generally, water, suitable oils, saline solutions, aqueous solutions of dextrose (glucose) and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, can be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may contain a water-soluble salt of at least one of the compounds described herein, at least one suitable stabilizer, and, if necessary, at least one buffering substance. Antioxidants, alone or in combination, such as sodium bisulfite, sodium sulfite, or ascorbic acid, can be examples of suitable stabilizers. Citric acid and its salts, and sodium EDTA can also be examples of suitable stabilizers. Furthermore, parenteral solutions may further contain at least one preservative selected from, for example, benzalkonium chloride, methylparaben, propylparaben, and chlorobutanol.

[0128] Pharmaceutically acceptable carriers are selected from those that are compatible with (and in some embodiments, capable of stabilizing) the active ingredient of the composition and are harmless to the subject of treatment. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with at least one compound disclosed herein and / or at least one pharmaceutically acceptable salt) can be used as pharmaceutical excipients for delivering the active ingredient. Examples of other carriers include colloidal silica, 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.

[0129] For inhalation administration, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can be conveniently delivered in aerosol spray form from a pressurized pack or nebulizer. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can also be delivered as powders, which can be formulated and inhaled using a blow-through powder inhaler device. An 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, for example, from fluorocarbons and hydrocarbons.

[0130] For ocular application, an ophthalmic preparation may be formulated in a solution or suspension of an appropriate weight percentage of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in a suitable ophthalmic medium, such that the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein remains in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the cornea and internal regions of the eye.

[0131] 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.

[0132] The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance, calculated to produce the desired therapeutic effect, when mixed with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, lozenges, etc. In such compositions, the active substance is typically a component ranging from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight, with the balance being various media or carriers and processing aids that contribute to the formation of the desired form of administration. Unit dosage formulations are preferably about 5, 10, 25, 50, 100, 250, 500, or 1,000 mg per unit. In one particular embodiment, the unit dosage form is packaged in multiple packages suitable for sequential use, such as blister packs of sheets containing at least 6, 9, or 12 unit dosage forms.

[0133] In some embodiments, unit capsules may be prepared as follows: each of a standard two-piece hard gelatin capsule is filled, for example, in powder form, with 100 mg of the compound described herein, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

[0134] In some embodiments, a mixture of the compounds described herein, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts, and digestible oils such as soybean oil, cottonseed oil, or olive oil can be prepared and injected into gelatin using a volumetric pump to form a soft gelatin capsule containing 100 mg of the active ingredient. The capsules are then washed and dried.

[0135] In some embodiments, tablets can be prepared using conventional procedures such that a dosage unit contains, for example, 100 mg of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coating may be applied to increase palatability or delay absorption.

[0136] In some embodiments, a parenteral composition suitable for injection can be prepared as follows: 1.5% by weight of the compound disclosed herein and / or at least its enantiomers, diastereomers, or pharmaceutically acceptable salts are stirred in 10% by volume of propylene glycol. The solution is then brought to the desired volume with water for injection and sterilized.

[0137] In some embodiments, an aqueous suspension can be prepared for oral administration. For example, an aqueous suspension containing 100 mg of finely pulverized compound, its stereoisomer or a pharmaceutically acceptable salt thereof, 100 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (United States Pharmacopeia), and 0.025 mL of vanillin per 5 mL can be used.

[0138] When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein are administered stepwise or in combination with at least one other therapeutic agent, the same dosage form can generally be used. When drugs are administered in a physical combination manner, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. Therefore, the term co-administration should be understood to include the simultaneous or sequential administration of at least two agents, or alternatively, the administration of a fixed-dose combination of at least two active components.

[0139] The compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts disclosed herein may be administered as the sole active ingredient or in combination with at least one second active ingredient.

[0140] The compounds, tautomers, solvates, or stereoisomers described herein may be used in the foregoing form, or in the form of their pharmaceutically acceptable salts such as hydrochlorides, hydrobromicates, acetates, sulfates, citrates, carbonates, trifluoroacetates, etc. When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein contain relatively acidic functional groups, the salts can be obtained by adding a pure base or a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts. When the compounds, tautomers, solvates, or stereoisomers described herein contain relatively basic functional groups, the salts can be obtained by adding a pure acid or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrocarbonic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrosulfuric 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, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginine, 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).

[0141] The neutral form of the pharmaceutically acceptable salt described herein can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner.

[0142] This disclosure provides prodrugs. Prodrugs, including 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 this disclosure. Additionally, prodrugs can be converted into the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of this disclosure by chemical or biochemical methods in an in vitro environment. For example, prodrugs can be slowly converted into the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of this disclosure when placed in a transdermal patch reservoir with suitable enzymes or chemical reagents. Prodrugs are often useful because, in certain situations, they may be easier to administer than the parent drug. For example, their bioavailability by oral administration may be higher than that of the parent drug. Prodrugs may also have increased solubility in pharmacological compositions compared to the parent drug. A variety of prodrug derivatives are known in the art, such as those dependent on the hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug is a compound of this disclosure that is administered as an ester (“prodrug”) but subsequently metabolized and hydrolyzed into a carboxylic acid (i.e., the active entity).

[0143] Certain compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts of this disclosure may exist in unsolvated and solvated forms (including hydrates). Certain compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of this disclosure may exist in various crystalline or amorphous forms.

[0144] Certain compounds, tautomers, solvates, or pharmaceutically acceptable salts described in this disclosure have asymmetric carbon atoms (optical centers) or double bonds; racemates, enantiomers, diastereomers, geometric isomers, and various isomers are all intended to be included within the scope of this disclosure.

[0145] III. Treatment methods and uses This disclosure provides treatment methods and uses that utilize any of the various embodiments of Part II (compounds and compositions) and the compounds described in Table 1, such as 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 Compounds of -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, and compounds 1 to 468 in Table 1, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.

[0146] One aspect of this disclosure provides a method for treating a disease or ailment, comprising administering to a subject in need a therapeutically effective amount of the formulas disclosed herein: 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 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, or packages thereof. A pharmaceutical composition comprising any one of the said compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt, wherein said disease or condition includes, but is not limited to, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinson's syndrome, ischemia, stroke, herpes infection, demyelinating diseases (such as multiple sclerosis), traumatic brain injury, sepsis, chronic PNS diseases including hereditary neuropathy (such as, but not limited to, peroneal muscular dystrophy and chronic inflammatory demyelinating polyneuropathy (CIDP)), optic nerve disorders (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 caused by various drugs (such as, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors). In some embodiments, said disease or condition is caused by or related to axonal degeneration or neuronal cell damage.

[0147] In another aspect, compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts as described herein are disclosed, including those 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, 1 A compound of 1-4, 11-5, 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 tautomers, solvates or stereoisomers of the compound or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for use as a medicine.

[0148] In another aspect, this document discloses compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts as described herein (including those 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. A compound of 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 (e.g., compounds 1 to 468), its tautomers, solvates or stereoisomers of the compound or its tautomers, or pharmaceutically acceptable salts of the foregoing substances, or a compound comprising the aforementioned compounds. The use of a pharmaceutical composition comprising any one of tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts for the preparation of a medicament for the treatment of a disease or condition, including but not limited to amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinson's syndrome, ischemia, stroke, herpes infection, demyelinating diseases (such as multiple sclerosis), traumatic brain injury, sepsis, chronic PNS diseases including hereditary neuropathy (such as, but not limited to, peroneal muscular dystrophy and chronic inflammatory demyelinating polyneuropathy (CIDP)), optic nerve disorders (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 caused 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 or related to axonal degeneration or neuronal cell damage.

[0149] In another aspect of this disclosure, compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts as described herein (including those 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, etc.) disclosed herein may be used. Compounds of 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 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, or Pharmaceutical compositions comprising any one of the said compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt are intended for the treatment of diseases or conditions, including but not limited to amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinsonian syndrome, ischemia, stroke, herpes infection, demyelinating diseases (such as multiple sclerosis), traumatic brain injury, sepsis, chronic PNS diseases including hereditary neuropathy (such as, but not limited to, peroneal muscular dystrophy and chronic inflammatory demyelinating polyneuropathy (CIDP)), optic nerve disorders (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 caused 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 or related to axonal degeneration or neuronal cell damage.

[0150] Another aspect of this disclosure provides methods for inhibiting or preventing axonal degeneration, including administering a therapeutically effective amount of 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 disclosed herein. Compounds of 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 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.

[0151] In another respect, compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts as described herein (including those 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) disclosed herein are also disclosed. The use of a compound of 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 tautomers, solvates or stereoisomers of the compound or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for the preparation of a medicament for the inhibition or prevention of axonal degeneration or neuronal cell damage.

[0152] In another aspect of this disclosure, compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts as described herein (including those 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...) 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 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for the purpose of inhibiting or preventing axonal degeneration or neuronal cell damage.

[0153] Another aspect of this disclosure provides a method for modulating (e.g., inhibiting) SARM1 in a subject in which this is desired, the method comprising administering to the subject a therapeutically effective amount of 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, 12-4, 12-5, 12-6, 12-7 or 12-8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.

[0154] In another respect, this document discloses compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts as described herein (including those 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... The use of compounds of 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 to 468), their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for the purpose of modulating (e.g., inhibiting) SARM1 in a subject in which this is desired.

[0155] In another aspect of this disclosure, compounds, tautomers, solvates or stereoisomers of said compounds or tautomers, or pharmaceutically acceptable salts (including those 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. A compound of 12-4, 12-5, 12-6, 12-7 or 12-8 (e.g., compounds 1 to 468), its tautomers, solvates or stereoisomers of the compound or the tautomers, or pharmaceutically acceptable salts of the foregoing substances, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for regulating (e.g., inhibiting) SARM1 in a subject in which such regulation is desired, wherein the subject is contacted with the compound, the tautomer, the solvate or stereoisomer of the compound or the tautomers, a pharmaceutically acceptable salt or a pharmaceutical composition.

[0156] 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 disclosed herein may be applied once, twice, or three times daily. Compounds of 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 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, or substances comprising said compounds, tautomers, solvates, or other compounds. Pharmaceutical compositions comprising any of stereoisomers and pharmaceutically acceptable salts, for example, for treating diseases or conditions including, but not limited to, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Parkinsonian syndrome, ischemia, stroke, herpes infection, demyelinating diseases (such as multiple sclerosis), traumatic brain injury, sepsis, chronic PNS diseases including hereditary neuropathy (such as, but not limited to, peroneal muscular dystrophy and chronic inflammatory demyelinating polyneuropathy (CIDP)), optic nerve disorders (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 caused 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 or related to axonal degeneration or neuronal cell damage.

[0157] 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 disclosed herein can be applied in various ways. Compounds of type -8 (e.g., compounds 1 to 468), their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of said compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, although the most appropriate route in any given case will depend on the particular host and the nature and severity of the condition to which the active ingredient is administered. The term “parentereal” as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein can be readily available in unit dosage forms and prepared by any method well known in the art. Parentereal administration can be performed by continuous infusion over a selected time period. Other applications considered in this disclosure are described in international patent applications WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142 and WO 2015 / 023915.

[0158] Contact is typically achieved by administering to the subject an effective amount of one or more compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts disclosed herein. Typically, the administration is adjusted to achieve a therapeutic dose of about 0.1 to 50 mg / kg, preferably 0.5 to 10 mg / kg, more preferably 1 to 10 mg / kg, although the optimal dose is compound-specific and is generally determined empirically for each compound.

[0159] The dosage administered will depend on factors such as the recipient's age, health and weight, the severity of the disease, the type of concurrent treatment (if any), the frequency of treatment, and the nature of the desired effect. Generally, the daily dose of the active ingredient can vary, for example, from 0.1 to 2000 mg daily. For example, 10–500 mg once or more daily may be effective in achieving the desired results.

[0160] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of the formulas disclosed herein are administered once, twice, or three times daily. Compounds of 2-1, 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 said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances, or pharmaceutical compositions comprising any one of said compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts. Administration of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein is for morning / daytime administration, with a withdrawal period at night.

[0161] A. Example To provide a more complete understanding of the disclosure described herein, the following embodiments are disclosed. It should be understood that these embodiments are for illustrative purposes only and should not be construed as limiting the scope of this disclosure in any way.

[0162] Example I. Synthesis of an Exemplary Compound The compounds of this disclosure may be prepared according to standard chemical practice or, as shown herein, the following general synthetic procedures and specific synthetic schemes including compounds 1 to 468, which are selected from compounds of the formulas described herein, their tautomers, solvates or stereoisomers of said compounds or said tautomers, or pharmaceutically acceptable salts of the foregoing substances.

[0163] Preparation method of cyclopentylimidazol-2-yl)-5-methyl-1H-benzimidazole (2) 1 Step 1.1 Preparation of cyclopentyl-1H-imidazol-2-carboxaldehyde Cesium dicarbonate (2.00 equivalents, 6782 mg, 20.8 mmol) was added to a stirred solution of 1H-imidazolium-2-carboxaldehyde (1.00 equivalent, 1000 mg, 10.4 mmol) in DMF (5 mL). The resulting mixture was stirred for 30 min. Subsequently, 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 another 3 h. The reaction mixture was diluted with water and extracted with EtOAc extract (3 × 20 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography to provide 1-cyclopentylimidazolium-2-carboxaldehyde (1700 mg, 10.4 mmol, 99.5% yield). MS (ESI) m / z 165 [M+H] + .

[0164] Step 2: Preparation of 2-(1-cyclopentylimidazol-2-yl)-5-methyl-1H-benzimidazole A solution of 1-cyclopentylimidazol-2-carboxaldehyde (1.00 equivalent, 200 mg, 1.22 mmol) and 4-methylphenyl-1,2-diamine (67 mg, 0.552 mmol) in water (5 mL) was stirred at room temperature for 20 min, then K₂CO₃ (114 mg, 0.828 mmol) was added and the mixture was stirred for another 10 min. 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 h with stirring. Sodium thiosulfate solution (10 mL; 5%) was added, and the product was extracted with EtOAc (15 mL x 3). The combined EtOAc layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce a crude product, which was then purified by preparative HPLC to produce 2-(1-cyclopentylimidazol-2-yl)-5-methyl-1H-benzimidazole as a white solid (178 mg, 0.668 mmol, 54.9% yield).

[0165] MS (ESI) m / z 267 [M+H] + .

[0166] 1 H NMR (400 MHz, DMSO) δ 12.78 (br s, 1H), 7.59 (s, 1H), 7.48 (br s,1H), 7.36 (br s, 1H), 7.18 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.14 (p, J =7.4 Hz, 1H), 2.42 (s, 3H), 2.26 - 2.16 (m, 2H), 1.92 - 1.65 (m, 6H).

[0167] Compounds 3, 4, 6, 10, and 33 were synthesized using a method similar to that used in Example 2.

[0168] Preparation method of cyclopentylpyridin-2-yl)-5-methyl-1H-benzo[d]imidazolium (7) 2 Step 1. 2-(3-bromopyridin-2-yl)-5-methyl-1H-benzo[d]imidazole A solution of 3-bromopyridine-2-carboxaldehyde (500 mg, 2.69 mmol) and 4-methylphenyl-1,2-diamine (328 mg, 2.69 mmol) in water (10 mL) was stirred at room temperature for 20 min, then K₂CO₃ (556 mg, 4.03 mmol) was added and the mixture was stirred for another 10 min. KI (112 mg, 0.67 mmol) and I₂ (682 mg, 2.69 mmol) were added and the mixture was heated at 90 °C for 2 h with stirring. Sodium thiosulfate solution (10 mL) was added and the product was extracted with EtOAc (10 mL x 3). The combined EtOAc layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce a crude product, which was purified by rapid chromatography (silica gel column, 10 g, EtOAc / PE, 0 to 100%) to yield 2-(3-bromopyridin-2-yl)-5-methyl-1H-benzis[d]imidazole (260 mg, 33.6% yield) as a yellow solid. MS (ESI) m / z 288 [M+H] + .

[0169] Step 2.2-(3-(cyclopent-1-en-1-yl)pyridin-2-yl)-5-methyl-1H-benzi[d]imidazole Pd(dppf)Cl2 (63 mg, 0.0868 mmol) was added 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-dioxaborhexane (253 mg, 1.30 mmol), and Na2CO3 (184 mg, 1.74 mmol) in 1,4-dioxane (10 mL) and water (2 mL) at room temperature under N2. After addition, the mixture was stirred at 110 °C for 12 h. The reaction was indicated to be complete by LCMS. The reaction mixture was then added to water (20 mL) and extracted with EtOAc (20 mL x 3). The organics were then combined and dried (Na2SO4), and then concentrated to dryness. The crude product was purified by rapid chromatography (silica gel column, 10 g, EA / PE, 0 to 50%) to yield 2-[3-(cyclopenten-1-yl)-2-pyridyl]-5-methyl-1H-benzimidazole as a yellow solid (100 mg, 0.36 mmol, 41.8% yield). MS (ESI) m / z 276 [M+H] + .

[0170] Step 3.2-(3-Cyclopentypyridin-2-yl)-5-methyl-1H-benzo[d]imidazolium PtO2 (30 mg) was added to a solution of 2-[3-(cyclopenten-1-yl)-2-pyridyl]-5-methyl-1H-benzimidazole (100 mg, 0.363 mmol) in methanol (5 mL) at room temperature under N2. After addition, the mixture was stirred at 75 °C for 12 h. The reaction was indicated by LCMS to be complete. The reaction mixture was then filtered and concentrated to dryness. The crude product was purified by preparative HPLC to give 2-(3-cyclopentylpyridin-2-yl)-5-methyl-1H-benzimidazole (0.98 mg, 1% yield) as a white solid.

[0171] MS (ESI) m / z 278 [M+H] + .

[0172] 1 H NMR (400 MHz, methanol-) d 4) δ 8.51 (s, 1H), 7.99 (d, J =8.0 Hz, 1H), 7.69 -7.33 (m, 3H), 7.13 (d, J=7.2 Hz, 1H), 4.13 - 3.89 (m, 1H), 2.48 (s, 3H), 2.14-2.00 (m, 2H), 1.90 - 1.51 (m, 6H).

[0173] Compounds 8, 9, and 25 were synthesized using a method similar to that used in Example 7.

[0174] Preparation of cyclopentyl-1,2,4-triazol-3-yl)-5-methyl-1H-indol-3-yl]methanol (11) Step 1.4-Cyclopentyl-4H-1,2,4-triazole To a solution of cyclopentylamine (10.0 equivalent, 6.9 mL, 70.3 mmol) in toluene (7 mL), N'-[(E)-dimethylaminomethyleneamino]-N,N-dimethylformamidinium (1.00 equivalent, 1.00 g, 7.03 mmol) and 4-methylbenzenesulfonic acid (0.100 equivalent, 121 mg, 0.703 mmol) were added. The mixture was heated to reflux and stirred for 24 h. The mixture was diluted with EtOAc 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 rapid column chromatography (DCM / MeOH=3 / 97) to provide 4-cyclopentyl-1,2,4-triazole (542 mg, 3.95 mmol, 56.2% yield). MS (ESI) m / z 138 [M+H] + .

[0175] Step 2.3-Bromo-4-cyclopentyl-4H-1,2,4-triazole NBS (1.10 equivalent, 410 mg, 2.30 mmol) was added to a solution of 4-cyclopentyl-1,2,4-triazole (1.00 equivalent, 287 mg, 2.09 mmol) in DCM (10 mL). The mixture was stirred overnight at room temperature in the dark. The mixture was concentrated and purified by silica gel rapid column chromatography (DCM / MeOH=3 / 97) to provide 3-bromo-4-cyclopentyl-1,2,4-triazole (188 mg, 0.870 mmol, 41.6% yield). MS (ESI) m / z 216 [M+H] + .

[0176] 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 equivalence, 132 mg, 0.611 mmol) and 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-1H-indole (1.00 equivalence, 157 mg, 0.611 mmol) in water (0.6000 mL) and 1,4-dioxane (3 mL), K₂CO₃ (3.00 equivalence, 253 mg, 1.83 mmol) and Pd(dppf)Cl₂ (0.100 equivalence, 45 mg, 0.0611 mmol) were added. The mixture was heated to 90 °C and stirred overnight under N₂. The mixture was diluted with EtOAc 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 rapid column chromatography (DCM / MeOH=3 / 97) to provide 2-(4-cyclopentyl-1,2,4-triazol-3-yl)-5-methyl-1H-indole (142 mg, 0.533 mmol, 87.3% yield). MS (ESI) m / z 267 [M+H] + .

[0177] Step 4.2 - (4-cyclopentyl-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indole-3-carboxaldehyde POCl3 (3.00 equivalents, 0.040 mL, 0.428 mmol) was added to DMF (0.1100 mL) at 0 °C and stirred for 2 h. The mixture was then added to a solution of 2-(4-cyclopentyl-1,2,4-triazol-3-yl)-5-methyl-1H-indole (1.00 equivalents, 38 mg, 0.143 mmol) in DCM (0.5000 mL) at 0 °C. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic phase was separated, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (DCM / MeOH=3 / 97) to provide 2-(4-cyclopentyl-1,2,4-triazol-3-yl)-5-methyl-1H-indole-3-carboxaldehyde (19 mg, 0.0645 mmol, 45.2% yield). MS (ESI) m / z 295 [M+H] + .

[0178] Step 5. (2-(4-cyclopentyl-4H-1,2,4-triazol-3-yl)-5-methyl-1H-indol-3-yl)methanol NaBH4 (1.20 equivalent, 2.9 mg, 0.0775 mmol) was added to a solution of 2-(4-cyclopentyl-1,2,4-triazol-3-yl)-5-methyl-1H-indole-3-yl carboxaldehyde (1.00 equivalent, 19 mg, 0.0645 mmol) in methanol (1 mL) at 0 °C. The reaction mixture was stirred for 30 min. The reaction 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 yield [2-(4-cyclopentyl-1,2,4-triazol-3-yl)-5-methyl-1H-indole-3-yl]methanol (4.0 mg, 0.0135 mmol, 20.9% yield) as a white solid.

[0179] MS (ESI) m / z 297 [M+H] + .

[0180] 1 H NMR (400 MHz, MeOD) δ 8.86 (s, 1H), 7.62 (dt, J =1.7, 0.9 Hz, 1H), 7.35 (d, J =8.3 Hz, 1H), 7.13 (dd, J =8.4, 1.6 Hz, 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).

[0181] Preparation method of cyclopentyl-4-(5-methyl-1H-benzo[d]imidazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (12) 3 Step 1. Cyclopentane-methylimino ethyl ester hydrochloride Cyclopentaneformonitrile (5.00 g, 52.6 mmol) in ethanol (40 mL) was cooled to 0 °C in an ice bath and treated dropwise with acetyl chloride (33.0 g, 420 mmol) over 0.5 h. After complete addition, the reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated under reduced pressure, and the solid was ground together with diethyl ether and dried under vacuum to yield cyclopentanemethyliminolate ethyl ester hydrochloride as a white solid (3 g, 16.9 mmol, 32% yield). MS (ESI) m / z 142 [M+H] + .

[0182] Step 2.2-(cyclopentyl(ethoxy)methylene)hydrazine-1-carboxylic acid ethyl ester The cyclopentanemethyliminocyanide hydrochloride (3 g, 16.9 mmol) in absolute ethanol (60 mL) was cooled in an ice bath. Ethyl hydrazidecarboxylate (1.75 g, 16.9 mmol) in absolute ethanol (60 mL) was added dropwise to the mixture. The reaction mixture was stirred at 0 °C for 6 hours. The solvent was evaporated under reduced pressure. The residue was purified by rapid chromatography (silica gel column, 10 g, DCM / MeOH, 0 to 10%) to yield ethyl 2-(cyclopentyl(ethoxy)methylene)hydrazide-1-carboxylate (3.3 g, 16.9 mmol, 85.6% yield) as a colorless oil. MS (ESI) m / z 229 [M+H] + .

[0183] Step 3.5-Cyclopentyl-4-(5-methyl-1H-benzo[d]imidazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-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 h. The reaction mixture was then cooled and diluted with MeOH and purified by preparative HPLC to yield the product 5-cyclopentyl-4-(5-methyl-1H-benzimidazole-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (1.6 mg, 0.0055 mmol, 0.63% yield) as a white solid.

[0184] MS (ESI) m / z 284 [M+H] + .

[0185] 1 H NMR (400 MHz, DMSO- d 6) δ 7.59 - 7.30 (m, 2H), 7.17 (d, J =8.4 Hz,1H), 3.45 - 3.35 (m, 1H), 2.48 (s, 3H), 1.94 - 1.47 (m, 8H).

[0186] Compound 14 of Example 14 was synthesized using a method similar to that used in Example 12.

[0187] Preparation method of cyclopentyl-5-(5-methyl-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo-3-yl)methanol (16) 4 Step 1. Methyl 4-bromo-1-cyclopentyl-1H-pyrrole-2-carboxylate Cesium carbonate (2.00 equivalents, 3194 mg, 9.80 mmol) was added to a solution of methyl 4-bromo-1H-pyrrole-2-carboxylate (1.00 equivalents, 1000 mg, 4.90 mmol) in DMF (10 mL), and the mixture was stirred for 30 min. Then, bromocyclopentane (1.50 equivalents, 0.79 mL, 7.35 mmol) was added, and the mixture was stirred at 80 °C for 24 h. The reaction progress 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 yield the product (760 mg, 57%).

[0188] Step 2. 4-Bromo-1-cyclopentyl-1H-pyrrole-2-carboxylic acid To a solution of methyl 4-bromo-1-cyclopentylpyrrole-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 reaction progress was monitored by LC / MS. Once complete, the mixture was acidified with 4 N HCl solution and extracted with EtOAc. 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 / z 259 [M+H] + .

[0189] Step 3. 2-(4-bromo-1-cyclopentyl-1H-pyrrole-2-yl)-5-methyl-1H-benzo[d]imidazole To a solution of 4-methylphenyl-1,2-diamine (1.00 equivalence, 201 mg, 1.65 mmol) in toluene (5 mL), DIEA (1.90 equivalence, 0.54 mL, 3.13 mmol), HBTU (2.00 equivalence, 1249 mg, 3.29 mmol), and 4-bromo-1-cyclopentylpyrrole-2-carboxylic acid (1.00 equivalence, 425 mg, 1.65 mmol) were added. The mixture was then stirred at room temperature for 4 h. The reaction progress was monitored by LC / MS. Once complete, the solvent was removed under reduced pressure, and the crude product was dissolved in EtOAc 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 h. The reaction progress was monitored by LC / MS. Once finished, the solvent was removed and the residue was purified by column chromatography (PE / EA = 1:1) to yield the product (270 mg, 48%). MS (ESI) m / z 345 [M+H] + .

[0190] Step 4. (1-Cyclopentyl-5-(5-methyl-1H-benzo[d]imidazol-2-yl)-1H-pyrrolo-3-yl)methanol n-BuLi (2.00 equivalence, 24 mg, 0.378 mmol) was added dropwise to a solution of 2-(4-bromo-1-cyclopentyl-pyrrolo-2-yl)-5-methyl-1H-benzimidazole (1.00 equivalence, 65 mg, 0.189 mmol) in THF (5 mL) at -78 °C, and the mixture was stirred at the same temperature for 10 min. DMF (5.00 equivalence, 0.073 mL, 0.944 mmol) was then added, and the mixture was warmed to room temperature and stirred for another 1 h. NaBH4 (3.00 equivalence, 21 mg, 0.562 mmol) was then added to the mixture at 0 °C, and the mixture was stirred at the same temperature for 2 h. The reaction progress was monitored by LC / MS. Once complete, the solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to yield the product (3.5 mg, 6%).

[0191] MS (ESI) m / z 295 [M+H] + .

[0192] 1H NMR (400 MHz, CDCl3) δ 7.54 (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).

[0193] Compounds 13, 17, 18, 19, 20, 24, 27, and 28 were synthesized using a method similar to that used in Example 16.

[0194] (dichlorophenyl)-1-(5-methyl-1H-benzo[ d Preparation of imidazol-2-yl)-1,2-dihydro-3H-1,2,4-triazol-3-one (26) Step 1. O Methyl 2,3-dichlorobenzoyl)thiocarbamate KSCN (1.0 equivalent, 928 mg, 9.55 mmol) was added to a solution of 2,3-dichlorobenzoyl chloride (1.0 equivalent, 2000 mg, 9.55 mmol) in 30 mL of acetone. The mixture was stirred at 60 °C for 3 h until the starting material was completely exhausted. The reaction mixture was then cooled to room temperature and MeOH (2.5 equivalent, 765 mg, 23.9 mmol) was added to the reaction mixture. After stirring at 60 °C for another 8 h, the mixture was provided with... O Methyl 2-(2,3-dichlorobenzoyl)thiocarbamate (1600 mg, 6.06 mmol, 63.4% yield). The crude product was used directly in the next step without further purification. MS (ESI) m / z 264 / 266 [M+H] + .

[0195] Step 2.2-[5-(2,3-dichlorophenyl)-3-methoxy-1,2,4-triazol-1-yl]-5-methyl-1H-benzimidazole (5-methyl-1H-benzimidazol-2-yl)hydrazine (1.00 equivalent, 246 mg, 1.51 mmol) and OA solution of methyl N-(2,3-dichlorobenzoyl)thiocarbamate (1.00 equivalent, 400 mg, 1.51 mmol) in methanol (6 mL) was stirred at 80 °C for 48 h. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to provide 2-[5-(2,3-dichlorophenyl)-3-methoxy-1,2,4-triazol-1-yl]-5-methyl-1H-benzimidazole (130 mg, 0.347 mmol, 22.9% yield).

[0196] MS (ESI) m / z 374 / 376 [M+H] + .

[0197] Step 3.3-(2,3-dichlorophenyl)-2-(5-methyl-1H-benzimidazol-2-yl)-1H-1,2,4-triazol-5-one 2-[5-(2,3-dichlorophenyl)-3-methoxy-1,2,4-triazol-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). The resulting solution was heated to 100 °C and stirred for 6 h. The reaction mixture was quenched with saturated NaHCO3 (aqueous solution) and then extracted with EtOAc. All organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC to provide 3-(2,3-dichlorophenyl)-2-(5-methyl-1H-benzimidazole-2-yl)-1H-1,2,4-triazol-5-one (5.0 mg, 0.0139 mmol, 2.6% yield).

[0198] MS (ESI) m / z 360 / 362 [M+H] + .

[0199] 1 H NMR (400 MHz, DMSO) δ 12.99 (s, 1H), 12.12 (s, 1H), 7.87 - 7.82(m, 1H), 7.65 (dd, J =7.7, 1.5 Hz, 1H), 7.52 (t, J =7.9 Hz, 1H), 7.33 - 7.24 (m,1H), 7.20 (d, J =27.5 Hz, 1H), 6.98 (dd, J =31.9, 8.1 Hz, 1H), 2.36 (d,J =23.6 Hz, 3H).

[0200] Preparation method of dichlorophenyl)-4-(5-methyl-1H-benzo[d]imidazol-2-yl)-1,2,4-oxadiazol-5(4H)-one (29) 5 Step 1. (1E)-2,3-Dichlorobenzaldehyde oxime Hydroxylamine hydrochloride (1.20 equivalence, 476 mg, 6.86 mmol) was added to a solution of 2,3-dichlorobenzaldehyde (1.00 equivalence, 1000 mg, 5.71 mmol) in methanol (30 mL), followed by the addition of pyridine (1.00 equivalence, 0.46 mL, 5.71 mmol). The reaction mixture was stirred at room temperature for 2.5 h. 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 a brine solution. The organic layer was dried (Na2SO4) and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with hexane-EtOAc, or recrystallized to provide (1E)-2,3-dichlorobenzaldehyde oxime (630 mg, 3.32 mmol, 58.0% yield). MS (ESI) m / z 190 / 192[M+H] + .

[0201] Step 2. (1Z)-2,3-dichloro-N-hydroxy-iminobenzoyl chloride Add 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 equivalents, 703 mg, 5.26 mmol) was added and stirred overnight at 20 °C. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and Na2S2O3, followed by extraction with EtOAc. All organic layers were combined and concentrated under reduced pressure. The residue was purified to provide (1Z)-2,3-dichloro-N-hydroxy-iminobenzoyl chloride (120 mg, 0.535 mmol, 50.79% yield). MS (ESI) m / z 224 / 226 [M+H] + .

[0202] Step 3.2,3-Dichloro-N'-hydroxy-N-(5-methyl-1H-benzimidazol-2-yl)benzamidin Triethylamine (2.00 equivalent, 108 mg, 1.07 mmol) was added to a stirred solution of (1Z)-2,3-dichloro-N-hydroxy-iminobenzoyl chloride (1.00 equivalent, 120 mg, 0.535 mmol) and 5-methyl-1H-benzimidazol-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 provide 2,3-dichloro-N'-hydroxy-N-(5-methyl-1H-benzimidazol-2-yl)benzamidinium (155 mg, 0.462 mmol, 86.5% yield). MS (ESI) m / z 335 / 337 [M+H] + .

[0203] Step 4.3-(2,3-dichlorophenyl)-4-(5-methyl-1H-benzimidazol-2-yl)-1,2,4-oxadiazol-5-one CDI (1.20 equivalent, 90 mg, 0.555 mmol) was added to a solution of 2,3-dichloro-N'-hydroxy-N-(5-methyl-1H-benzimidazol-2-yl)benzamidin (1.00 equivalent, 155 mg, 0.462 mmol) in MeCN (4 mL), followed by K₂CO₃ (5.00 equivalent, 320 mg, 2.31 mmol). The resulting mixture was stirred at room temperature for 20 min. The crude mixture was concentrated under reduced pressure and then purified by short-column chromatography using EtOAc in hexane to yield the corresponding product 3-(2,3-dichlorophenyl)-4-(5-methyl-1H-benzimidazol-2-yl)-1,2,4-oxadiazol-5-one (23 mg, 0.0637 mmol, 13.8% yield). MS (ESI) m / z 361 / 363 [M+H] + .

[0204] 1 H NMR (400 MHz, DMSO) δ 13.01 (br s, 1H), 7.85 - 7.75 (m, 2H), 7.62- 7.51 (m, 2H), 7.37 - 7.10 (m, 2H), 2.42 (d, J =4.1 Hz, 3H).

[0205] Compound 32 was synthesized using a method similar to that used in Example 29.

[0206] Preparation of dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (36) Step 1. N-(2,3-dichlorophenyl)-2-(2-hydroxyacetyl)hydrazine-1-carboxamide 2-hydroxyacetylhydrazine (1.86 g, 20.6 mmol) was added to a solution of 1,2-dichloro-3-phenyl isocyanate (4 g, 21.3 mmol) in THF (100 mL) under N2. The mixture was stirred at room temperature under N2 for 2 hours. The mixture was filtered and concentrated under vacuum to yield N-(2,3-dichlorophenyl)-2-(2-hydroxyacetyl)hydrazine-1-carboxamide (5.05 g, 86%) as a white solid. MS (ESI) m / z 278 [M+H] + .

[0207] Step 2.4-(2,3-dichlorophenyl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of N-(2,3-dichlorophenyl)-2-(2-hydroxyacetyl)hydrazine-1-carboxamide (50 mg, 0.18 mmol) in H₂O (0.5 mL), an aqueous solution of NaOH (0.18 mL, 0.18 mmol, 1 mol / L in H₂O) was added and the mixture was stirred at 105 °C for 3 hours. The mixture was concentrated. The residue was purified by reversed-phase HPLC to yield 4-(2,3-dichlorophenyl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (41.5 mg, 11%) as a white solid. MS (ESI) m / z 260 [M+H] + .

[0208] Step 3.4-(2,3-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxaldehyde Add IBX (540 mg, 1.93 mmol) to a solution of 4-(2,3-dichlorophenyl)-5-(hydroxymethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (100 mg, 0.39 mmol) in EA / DMSO (10 mL / 1.5 mL). Reflux the mixture for 1 hour. Add water (5 mL) to the mixture and extract with EtOAc (5 mL x 2). Dry the combined organic layers over anhydrous Na₂SO₄ and concentrate. Purify the residue by reversed-phase HPLC to yield 4-(2,3-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-carboxaldehyde (91 mg, 92%) as a white solid. MS (ESI) m / z 258 [M+H] + .

[0209] Step 4.4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one To a solution of 4-(2,3-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-carboxaldehyde (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)phenyl-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 the mixture was extracted with EtOAc (5 mL x 2). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by preparative HPLC to yield 4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one (39.3 mg, 27%) as a white solid. MS (ESI) m / z 414 [M+H] + .

[0210] 1 H NMR (400 MHz, DMSO- d 6) δ 13.11 (s, 2H), 7.86 (dd, J =8.0, 1.2 Hz,1H), 7.78 (s, 1H), 7.72 - 7.63 (m, 2H), 7.58 - 7.51 (m, 2H).

[0211] Preparation method of (41)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-5-(trifluoromethyl)-1H-indole-3-carboxynitrile (41) 6 Step 1. 2-Iodo-N-(4-methoxybenzyl)-4-(trifluoromethyl)aniline One drop of AcOH was added 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). The mixture was stirred at 100 °C for 16 h. The mixture was then concentrated, and the residue was added to methanol (15 mL). NaBH4 (2.00 equivalent, 2112 mg, 9.96 mmol) was then added. The mixture was stirred at room temperature for 1 h. 20 mL of water was added to the reaction mixture, and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was subjected to rapid chromatography (20% EtOAc in hexane) to produce 2-iodo-N-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline as a yellow solid (1.20 g, 2.95 mmol, 59.15% yield). MS (ESI) m / z 406.1 [M+H] + .

[0212] Step 2.2-Amino-1-(4-methoxybenzyl)-5-(trifluoromethyl)-1H-indole-3-carboxynitrile To a solution of 2-iodo-N-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)aniline (1.00 equivalence, 700 mg, 1.72 mmol) in DMSO (50 mL), malononitrile (1.20 equivalence, 136 mg, 2.06 mmol), L-proline (0.200 equivalence, 40 mg, 0.344 mmol), CuI (0.100 equivalence, 33 mg, 0.172 mmol), and K₂CO₃ (2.00 equivalence, 475 mg, 3.44 mmol) were added. The reaction mixture was stirred at 60 °C for 16 h under an argon atmosphere. 100 mL of water was added to the reaction mixture, and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, and concentrated under vacuum. The residue was purified by SiO2 gel column chromatography, eluting with 0–40% EtOAc in hexane to provide 2-amino-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-3-carboxynitrile (350 mg, 0.963 mmol, 56.01% yield) as a brown oil. MS (ESI) m / z 346.1 [M+H] + .

[0213] Step 3.2, 3-Dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]benzamide LiHMDS (1.0 M) in THF (2.00 equivalent, 350 mg, 1.01 mmol) was added dropwise to a stirred solution of 2-amino-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-3-carboxynitrile (1.00 equivalent, 350 mg, 1.01 mmol) in THF (15 mL) at -10 °C. The resulting mixture was stirred for 30 min. Then, 2,3-dichlorobenzoyl chloride (2.00 equivalent, 425 mg, 2.03 mmol) was added dropwise to THF (5 mL). The resulting mixture was stirred for 1 h. 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 rapid chromatography (C18) to provide 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]benzamide as a white solid (402 mg, 0.776 mmol, 76.52% yield). MS (ESI) m / z 516.1 [M+H] + Step 4.2,3-Dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]thiobenzamide Lawson's reagent (2.00 equivalent, 234 mg, 0.579 mmol) was added to a solution of 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]benzamide (1.00 equivalent, 150 mg, 0.289 mmol) in toluene (5 mL). The solution was then stirred at 60 °C for 4 h. 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 rapid chromatography (C18) to provide 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]thiobenzamide as a yellow solid (100 mg, 0.187 mmol, 64.66% yield). (ESI) m / z 534.2 [M+H] + .

[0214] Step 5. N'-Amino-2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]benzamidin To a solution of TEA (2.00 equivalence, 0.052 mL, 0.374 mmol) in THF (10 mL), 2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]thiobenzamide (1.00 equivalence, 100 mg, 0.187 mmol) and hydrazine hydrate (1.00 equivalence, 12 mg, 0.187 mmol) were added. The mixture was then stirred at 80 °C for 1 h. 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 rapid chromatography (C18) to provide N'-amino-2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]benzamide as a yellow solid (60 mg, 0.113 mmol, 60.23% yield). (ESI) m / z 532.1 [M+H] + .

[0215] Step 6.2 - [3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazol-4-yl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indole-3-carboxynitrile Di(imidazol-1-yl) ketone (3.00 equivalents, 18 mg, 0.113 mmol) was added to a solution of N'-amino-2,3-dichloro-N-[3-cyano-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-2-yl]benzamidinium (1.00 equivalent, 20 mg, 0.0376 mmol) in MeCN (10 mL). The reaction mixture was stirred at 80 °C for 2 h. 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 rapid chromatography (C18) to provide 2-[3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazol-4-yl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-3-carboxynitrile (15 mg, 0.0269 mmol, 71.51% yield) as a yellow solid. (ESI) m / z 558.2 [M+H] + .

[0216] Step 7. 2-(3-(2,3-dichlorophenyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)-5-(trifluoromethyl)-1H-indole-3-carboxynitrile TFA (1.0 mL) was added to a solution of 2-[3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazol-4-yl]-1-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)indol-3-carboxynitrile (1.00 equivalent, 12 mg, 0.0215 mmol) in DCM (2 mL) at 0 °C. The solution was stirred at 0 °C for 2 h. 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 provide 2-[3-(2,3-dichlorophenyl)-5-oxo-1H-1,2,4-triazol-4-yl]-5-(trifluoromethyl)-1H-indol-3-carboxynitrile (5.0 mg, 0.0114 mmol, 53.09% yield) as a white solid.

[0217] (ESI) m / z 438.2 [M+H] + .

[0218] 1 H NMR (400 MHz, methanol-) d 4) δ 8.41 (s, 1H), 7.79 - 7.73 (m, 2H), 7.70(dd, J =8.6, 1.9 Hz, 1H), 7.58 (dd, J =7.7, 1.6 Hz, 1H), 7.46 (t, J =7.9 Hz, 1H).

[0219] Compounds 30 and 31 were synthesized using a method similar to that used in Example 41.

[0220] Preparation method of bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazolium (49) 7 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-dimethylformamide (8.77 g, 0.0617 mol) was stirred at 260 °C for 20 h. After cooling, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (20 mL x 3). All organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to produce a crude product, which was purified by column chromatography on silica gel (CH₃OH / DCM = 1:10) to produce 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole (11.5 g, 87.03% yield) as a white solid. MS (ESI) m / z 214.1 [M+H] + .

[0221] Step 2. Preparation of 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-carboxaldehyde POCl3 (11 mL) was dissolved in DMF (32 mL), and the resulting solution was cooled to 0 °C under a N2 atmosphere and maintained for 2 h. 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole (5 g, 0.0234 mol) dissolved in DCM (42 mL) was added to the above system via syringe, and the mixture was stirred at 0 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (20 mL x 3). All organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to produce a crude product, which was purified by column chromatography on silica gel (EA / PE = 1:1) to produce 4-(2,3-dichlorophenyl)-4H-1,2,4-triazole-3-carboxaldehyde (4.5 g, 79.49% yield) as a white solid. MS (ESI) m / z 242.1 [M+H] + .

[0222] Step 3. Preparation of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzimidazole A mixture of 4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-carboxaldehyde (4.5 g, 0.0186 mol), 4-bromophenyl-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 h. A second batch of FeCl3·H2O (1.01 g, 0.0037 mol) was then added. The reaction mixture was stirred at 85 °C for 2 h under O2. After cooling, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (20 mL x 3). All organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce a crude product, which was purified by column chromatography on silica gel (EA:PE=1:3) to produce 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazole (2.5 g, 32.8% yield) as a reddish-white solid.

[0223] MS (ESI) m / z 410 [M+H] + .

[0224] 1H NMR (400 MHz, DMSO-d6) δ 13.79 (s, 1H), 9.05 (s, 1H), 7.92 (dd, J=8.2, 1.5 Hz, 1H), 7.78 (dd, J=8.0, 1.5 Hz, 1H), 7.66 (d, J=1.9 Hz, 1H), 7.59(t, J=8.1 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 7.34 (dd, J=8.7, 1.9 Hz, 1H).

[0225] Compounds 1, 5, 15, 46, 50, 72, 93, 94, 95, 96, 109, 128, and 132 were synthesized using a method similar to that used in Example 49.

[0226] Preparation method of dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(3-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazolium (51) 8 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-pyrazol-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 h. The mixture was diluted with EtOAc and washed with water. The organic layers were combined, dried over anhydrous sodium sulfate, and purified by preparative HPLC to produce 2-[4-(2,3-dichlorophenyl)-1,2,4-triazol-3-yl]-5-(3-methyl-1H-pyrazol-5-yl)-1H-benzimidazole (13 mg, 0.0301 mmol, 7.9% yield).

[0227] MS (ESI) m / z 410 / 412 [M+H] + .

[0228] 1 H NMR (400 MHz, DMSO) δ 13.56 (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).

[0229] Compounds 55, 56, 68, 73, 74, 78, 79, and 81 were synthesized using a method similar to that used in Example 51.

[0230] Preparation method of dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)-3-methylisothiazol (80) 9 Step 1. Preparation of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole Add 1.85 g (0.0045 mol) of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzi[d]imidazole and 0.22 g (0.0055 mol) of NaH (60% dispersion in mineral oil, 0.0055 mol) to a solution of THF (15 mL). Stir the reaction mixture at 0 °C for 30 min, then add SEM-Cl (0.76 g, 0.0046 mol). Stir the reaction mixture at 25 °C for 18 h. The reaction mixture was extracted with EtOAc (100 mL x 3), concentrated, and the residue was purified by silica gel chromatography (PE / EA = 5:1) to produce 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzimidazole (1.2 g, 50% yield) as an oil.

[0231] MS (ESI) m / z 538 [M+H] + .

[0232] Step 2.2 Preparation of 4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole A solution of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[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 h under a nitrogen atmosphere. Once the reaction was complete, the reactants were diluted with H2O (50 mL) and then extracted with EtOAc (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 produce 2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole (0.7 g, 55.1% yield) as an oil.

[0233] MS (ESI) m / z 586.2 [M+H] + .

[0234] 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]imidazol-5-yl)-3-methylisothiazol (3) A mixture of 2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole (100 mg, 0.1702 mmol), 5-bromo-3-methylisothiazol (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-dioxacyclohexane / H2O (10 / 2 mL) was stirred at 90 °C for 16 h under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (20 mL x 3). All organic layers were combined, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure to produce a crude product, which was purified by column chromatography on silica gel (EA / PE = 1:1) to yield 5-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-3-methylisothiazolazole as an oil (60 mg, 82.49% yield). MS (ESI) m / z 557.1 [M+H] + .

[0235] Step 4.5 Preparation of 2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzi[d]imidazol-5-yl)-3-methylisothiazolium A mixture of 5-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)-3-methylisothiazolium (60 mg, 0.1074 mmol) in TFA / DCM (1 / 5 mL) was stirred at 25 °C for 16 h. After the reaction was complete, the reaction mixture was diluted with water (60 mL) and extracted with DCM (20 mL x 3). All organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC (column - Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% TFA)) to provide the desired product as a white solid (12.5 mg, 27.28% yield).

[0236] MS (ESI) m / z 427.2 [M+H] + .

[0237] 1 H NMR (400 MHz, DMSO- d 6) δ 13.84 (s, 1H), 9.08 (s, 1H), 7.94 (d, J =7.8Hz, 1H), 7.81 (d, J =8.2 Hz, 2H), 7.61 (t, J =8.2 Hz, 4H), 2.43 (s, 3H).

[0238] Compounds 82 and 83 were synthesized using a method similar to that used in Example 80.

[0239] Preparation method of dichlorophenyl)-4-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1H-pyridin-2-one (40) 10 Step 1. 5-(2,3-Dichlorophenyl)-2-methoxyisoniazol To a solution of 5-bromo-2-methoxy-pyridine-4-carboxaldehyde (1.00 equivalence, 400 mg, 1.85 mmol) in DMF (9 mL), (2,3-dichlorophenyl)boronic acid (1.00 equivalence, 353 mg, 1.85 mmol), Na₂CO₃ (3.00 equivalence, 589 mg, 5.55 mmol), and Pd(dppf)Cl₂ (0.100 equivalence, 135 mg, 0.185 mmol) were added. The mixture was stirred at 110 °C for 12 h under N₂. The mixture was diluted with EtOAc and washed with brine. The organic phase was separated, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EA=20 / 1) to provide 5-(2,3-dichlorophenyl)-2-methoxy-pyridine-4-carboxaldehyde (351 mg, 1.24 mmol, 67.19% yield). MS (ESI) m / z 282 [M+H] + .

[0240] Step 2.2-(5-(2,3-dichlorophenyl)-2-methoxypyridin-4-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole To a solution of 5-(2,3-dichlorophenyl)-2-methoxypyridine-4-carboxaldehyde (1.00 equivalence, 350 mg, 1.24 mmol) in water (12 mL) and THF (2 mL), 4-(trifluoromethyl)phenyl-1,2-diamine (1.00 equivalence, 219 mg, 1.24 mmol) was added. The reaction mixture was stirred for 20 min, and then K₂CO₃ (2.00 equivalence, 343 mg, 2.48 mmol) was added. The reaction mixture was stirred for another 10 min, and then the THF was evaporated. I₂ (1.00 equivalence, 315 mg, 1.24 mmol) and KI (0.250 equivalence, 51 mg, 0.310 mmol) were added. The mixture was heated to 80 °C and stirred for 2 h. The reaction mixture was quenched with saturated Na₂S₂O₃ and extracted with EtOAc. The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated to produce a crude product, which was used in the next step without further purification. MS (ESI) m / z 438 [M+H] + .

[0241] Step 3.5-(2,3-dichlorophenyl)-4-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)pyridin-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 min. The reaction mixture was diluted with EtOAc 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 produce 5-(2,3-dichlorophenyl)-4-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1H-pyridin-2-one as a white solid (130 mg, 0.306 mmol, 24.7% yield).

[0242] MS (ESI) m / z 424 [M+H] + .

[0243] 1 H NMR (400 MHz, DMSO) δ 13.26 (s, 1H), 12.19 (s, 1H), 7.75 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.58 (dd, J =6.9, 2.6 Hz, 1H), 7.53 (s, 1H), 7.48 (d, J =8.5 Hz, 1H), 7.41 - 7.33 (m, 2H), 6.94 (s, 1H).

[0244] 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 a method similar to that used in Example 40.

[0245] [Oxo-2-isoquinolinyl)methyl]-3 H Preparation of 1,3-benzoxazol-2-one (45) Step 1.1-(2,3-dichlorophenyl)-1H-imidazolium-5-carboxylic acid ethyl ester 2,3-Dichloroaniline (678 mg, 4.18 mmol) and Ti(OiPr)4 (2.5 mL, 8.37 mmol) were added to a solution of ethyl 2-oxoacetate (0.83 mL, 4.18 mmol) in toluene (20 mL). The reaction mixture was heated to 70 °C and stirred for 4 h. 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 the solution. The mixture was heated to 80 °C and stirred for 5 h. The mixture was diluted with EtOAc and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid column chromatography (PE / EtOAc = 1 / 5) to provide ethyl 1-(2,3-dichlorophenyl)-1H-imidazolium-5-carboxylate (1.1 g, 92.6% yield) as a yellow solid. MS (ESI) m / z 285 [M+H]+ .

[0246] Step 2.1-(2,3-dichlorophenyl)-1 H -Imidazol-5-carboxylic acid Lithium hydroxide monohydrate (1.6 g, 38.5 mmol) was added to a solution of ethyl 1-(2,3-dichlorophenyl)-1H-imidazolium-5-carboxylate (1.1 g, 3.8 mmol) in THF / H₂O (10:1, 22 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the reaction mixture was diluted with water and the pH was adjusted to 7. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to produce 1-(2,3-dichlorophenyl)-1H-imidazolium-5-carboxylate as a yellow solid. H Imidazol-5-carboxylic acid (0.9 g, 90.4% yield) was used in the next step without further purification. MS (ESI) m / z 257 [M+H] + .

[0247] Step 3. N -(2-amino-4-(trifluoromethyl)phenyl)-1-(2,3-dichlorophenyl)-1 H -Imidazole-5-formamide To 1-(2,3-dichlorophenyl)-1 H HBTU (2.8 g, 7.3 mmol), 4-(trifluoromethyl)phenyl-1,2-diamine (0.78 g, 4.4 mmol), and DIEA (1.43 g, 11.1 mmol) were added to a solution of 5-imidazolium-5-carboxylic acid (0.9 g, 3.65 mmol) in DMF (20 mL). The mixture was stirred at 25 °C for 2 h. After the reaction was complete, the mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under vacuum to provide a red oil. N -(2-amino-4-(trifluoromethyl)phenyl)-1-(2,3-dichlorophenyl)-1 H 1.5 g of imidazole-5-carboxamide was used in the next step without further purification. MS (ESI) m / z 415 [M+H] + .

[0248] Step 4.2-(1-(2,3-dichlorophenyl)-1 H -imidazol-5-yl)-5-(trifluoromethyl)-1 H -benzo[ d Imidazole Will N-(2-amino-4-(trifluoromethyl)phenyl)-1-(2,3-dichlorophenyl)-1 H A solution of 400 mg crude imidazole-5-carboxamide in AcOH (20 mL) was heated to 90 °C and stirred for 16 h. After the reaction was complete, the mixture was diluted with water and the pH was adjusted to 7. The mixture was diluted with EtOAc 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 produce 2-(1-(2,3-dichlorophenyl)-1-carboxamide as a yellow powder. H -imidazol-5-yl)-5-(trifluoromethyl)-1 H -benzo[ d Imidazole (5.0 mg, 1% yield).

[0249] MS (ESI) m / z 397 [M+H] + .

[0250] 1 H NMR (400 MHz, DMSO- d 6) δ 13.27 (bs, 1H), 7.86 (dd, J =8.0 Hz, J =1.2Hz1H), 7.72 (s, 1H), 7.69 - 7.59 (m, 3H), 7.56 (t, J =8.0 Hz, 1H), 7.52 - 7.41(m, 2H).

[0251] Preparation of dichlorophenylpyridin-3-yl)-5-(trifluoromethyl)-1H-indole-3-carboxynitrile (47) 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-dioxaborhexacyclopentane (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 at 100 °C for 16 h under N₂. The mixture was diluted with water (50 mL) and extracted with EtOAc (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 yield 3-bromo-4-(2,3-dichlorophenyl)pyridine (2.1 g, 50%) as a yellow oil. MS (ESI) m / z 302 [M+H] + .

[0252] Step 2. 2-(4-(2,3-dichlorophenyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylic acid tert-butyl ester 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-indol-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 at 90 °C for 2 h under N₂. H₂O (20 mL) was added to the mixture, and the reaction mixture was then extracted with EtOAc (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 yield tert-butyl 2-(4-(2,3-dichlorophenyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-indole-1-carboxylate (120 mg, 24%) as a yellow solid. MS (ESI) m / z 507 [M+H] + .

[0253] Step 3. 2-(4-(2,3-dichlorophenyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-indole A solution of tert-butyl 2-(4-(2,3-dichlorophenyl)pyridin-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 h. The reaction mixture was concentrated and the pH was adjusted to 9 with saturated NaHCO3, followed by extraction with DCM (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 yield 2-(4-(2,3-dichlorophenyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-indole (250 mg, 70%) as a yellow solid. MS (ESI) m / z 407 [M+H] + .

[0254] Step 4. 2-(4-(2,3-dichlorophenyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-indole-3-carboxynitrile Chlorosulfonyl isocyanate (347 mg, 2.46 mmol) was added to a solution of 2-(4-(2,3-dichlorophenyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-indole (200 mg, 0.49 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 16 h. Then DMF (2 mL) was added to the mixture and stirred at room temperature for 1 h. H2O (10 mL) was added to the reaction mixture, followed by extraction with DCM (10 mL x 2). The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by preparative HPLC to yield 2-(4-(2,3-dichlorophenyl)pyridin-3-yl)-5-(trifluoromethyl)-1H-indole-3-carboxynitrile (56.4 mg, 27%) as a grayish-white solid.

[0255] MS (ESI) m / z 432 [M+H] + .

[0256] 1 H NMR (400 MHz, DMSO- d 6) δ 12.93 (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).

[0257] Preparation of dichlorophenyl)-4-(5-(2-hydroxypropane-2-yl)-1H-benzo[d]imidazol-2-yl)-1-methylpyridin-2(1H)-one (83) Step 1. Methyl 5-(2,3-dichlorophenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate Under Ar conditions, methyl 5-bromo-1-methyl-2-oxo-pyridine-4-carboxylate (1.00 equivalent, 1040 mg, 4.23 mmol) in 1,4-dioxane (30 mL) was reacted with (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). The reaction mixture was then stirred at 100 °C for 2 h. Once 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 yield the product (314 mg, 25%). MS (ESI) m / z 312 [M+H] + .

[0258] Step 2.5-(2,3-dichlorophenyl)-1-methyl-2-oxo-pyridine-4-carboxylic acid To a solution of methyl 5-(2,3-dichlorophenyl)-1-methyl-2-oxo-pyridine-4-carboxylate (1.00 equivalent, 314 mg, 1.01 mmol) in THF (4 mL), 2.0 mL of 15% NaOH was added, and the mixture was stirred at 85 °C for 2 h. The reaction progress 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 using 4 N HCl. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step. MS (ESI) m / z 298 [M+H] + .

[0259] Step 3.5-(2,3-dichlorophenyl)-4-(5-isopropenyl-1H-benzimidazol-2-yl)-1-methyl-pyridin-2-one To a solution of 4-isopropenylphenyl-1,2-diamine (1.00 equivalence, 149 mg, 0.503 mmol) and 5-(2,3-dichlorophenyl)-1-methyl-2-oxo-pyridine-4-carboxylic acid (1.00 equivalence, 150 mg, 0.503 mmol) in DCM (20 mL), HOBT (1.30 equivalence, 0.653 mmol), EDCI (1.30 equivalence, 0.653 mmol), and DIPEA (10.00 equivalence, 5.03 mmol) were added. The mixture was stirred at 25 °C for 2 h. 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 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 h. After the reaction was complete, the mixture was diluted with water and the pH was adjusted to 7. The mixture was diluted with EtOAc 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 yield the product (70 mg, 34%). MS (ESI) m / z 410 [M+H] + .

[0260] Step 4.5-(2,3-dichlorophenyl)-4-[5-(1-hydroxy-1-methyl-ethyl)-1H-benzimidazol-2-yl]-1-methyl-pyridin-2-one Phenylsilane (2.00 equivalents, 0.023 mL, 0.185 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptadecyl)manganese(III) (0.100 equivalents, 5.6 mg, 0.00926 mmol) were added to a solution of 5-(2,3-dichlorophenyl)-4-(5-isopropenyl-1H-benzimidazol-2-yl)-1-methyl-pyridin-2-one (1.00 equivalent, 38 mg, 0.0926 mmol) in 2-propanol (5 mL) at 0 °C under an O2 atmosphere. The reaction mixture was then stirred for 2 h. Once finished, the reaction mixture was quenched with water and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to yield the product (1 mg, 2.5%) as a white solid.

[0261] MS (ESI) m / z 428 [M+H] + .

[0262] 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.54 (d, J=6.4 Hz, 2H), 7.31 (m, 2H), 7.18 (m, 2H), 6.99 (s, 1H), 3.64 (s, 3H), 1.26 (s, 6H).

[0263] Preparation method of chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazolium (59) 11 Step 1. 4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazole To 2-chloro-3-fluoroaniline (0.50 g, 3.44 mmol) and N 1,2,4-Formamide (0.91 g, 10.3 mmol) was added to a solution of pyridine (30 mL) with chloro(trimethyl)silane (5598 mg, 51.5 mmol) and stirred at 110 °C for 12 h. LC-MS indicated the end of the reaction. The reaction mixture was then cooled, filtered, and concentrated to dryness. The crude product was purified by rapid chromatography (silica gel column, 30 g, MeOH / EtOAc, 0 to 20%) to yield 4-(2-chloro-3-fluoro-phenyl)-1,2,4-triazole (420 mg, 2.13 mmol, 61.9% yield) as a white solid. MS (ESI) m / z 198 [M+H] + Step 2. 4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-carboxaldehyde To a solution of 260 mg (1.32 mmol) of 4-(2-chloro-3-fluorophenyl)-1,2,4-triazole in DMF (0.5 mL), POCl3 (0.61 mL, 6.58 mmol) dissolved in DMF (1.9 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 1 h. The mixture was then stirred at room temperature for 12 h. Once the reaction was complete, the reaction mixture was quenched with an aqueous solution of NaHCO3 (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried (Na2SO4), and concentrated to yield the crude product 4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazole-3-carboxaldehyde (200 mg, 0.886 mmol, 67.4% yield) as a white solid. MS (ESI) m / z 226 [M+H] + .

[0264] 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-fluoro-phenyl)-1,2,4-triazol-3-carboxaldehyde (200 mg, 0.886 mmol) and 4-(trifluoromethyl)phenyl-1,2-diamine (156 mg, 0.886 mmol) in water (10 mL) was stirred at room temperature for 20 min. K₂CO₃ (184 mg, 1.33 mmol) was added to the mixture and stirring was continued for another 10 min. 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 h. The reaction mixture was quenched with sodium thiosulfate solution (10 mL; 5%). The reaction mixture was extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to produce the crude product. The crude product was purified by preparative HPLC to produce 2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzis[d]imidazole as a brown solid (1 mg, 0.0025 mmol, 0.6% yield).

[0265] MS (ESI) m / z 382 [M+H] + .

[0266] 1 H NMR (400 MHz, methanol-) d 4) δ 8.88 (s, 1H), 7.84 (s, 1H), 7.69 (d, J =8.4Hz, 1H), 7.63 - 7.45 (m, 4H).

[0267] Compound 69 of Example 69 was synthesized using a method similar to that used in Example 59.

[0268] Preparation method of dichloro-1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazolium (53) 12 Step 1. 4,5-Dichloro-3-isothiocyano-1-methyl-pyrazole Thiocarbonyl chloride (1.10 equivalent, 0.25 mL, 3.31 mmol) was slowly added to a mixture of 4,5-dichloro-1-methylpyrazol-3-amine (1.00 equivalent, 500 mg, 3.01 mmol) in DCM (5 mL) and saturated NaHCO3 (5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Once 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.

[0269] Step 2. N-(4,5-dichloro-1-methyl-1H-pyrazol-3-yl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-carbonyl)hydrazine-1-thiocarboxamide To a solution of 4,5-dichloro-3-isothiocyano-1-methylpyrazole (1.00 equivalent, 624 mg, 3.00 mmol) in THF (5 mL), 5-(trifluoromethyl)-1H-benzimidazole-2-carbazide (1.00 equivalent, 733 mg, 3.00 mmol) was added. The reaction mixture was stirred at 70 °C for 2 h. Once the reaction was complete, the organic layer was separated and concentrated. The resulting crude product was used directly in the next step.

[0270] Step 3.4-(4,5-dichloro-1-methyl-1H-pyrazol-3-yl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-4H-1,2,4-triazol-3-thiol A suspension of 1-(4,5-dichloro-1-methylpyrazol-3-yl)-3-[[5-(trifluoromethyl)-1H-benzimidazole-2-carbonyl]amino]thiourea (1.00 equivalent, 146 mg, 0.323 mmol) in 1M NaOH (1.00 equivalent, 4.0 mL, 0.323 mmol) was stirred at 80 °C for 4 h. Once the reaction was complete, 3 M HCl was added to the mixture and the pH was adjusted to 7. The reaction mixture was extracted with EtOAc. The organic layer was dried and concentrated. The resulting crude product was used directly in the next step.

[0271] Step 4. 2-(4-(4,5-dichloro-1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazolium mCPBA (2.00 equivalent, 24 mg, 0.138 mmol) was added to a solution of 4-(4,5-dichloro-1-methyl-pyrazol-3-yl)-5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1,2,4-triazol-3-thiol (1.00 equivalent, 30 mg, 0.0691 mmol) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Once the reaction was complete, the solvent was removed and the residue was purified by preparative HPLC to yield the product (2 mg, 7%).

[0272] MS (ESI) m / z 402 [M+H] + .

[0273] 1 H NMR (400 MHz, DMSO- d 6) δ 14.09 (bs, 1H), 9.14 (s, 1H), 7.93 (s,1H), 7.77 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 3.97 (s, 3H).

[0274] Compound 58 was synthesized using a method similar to that used in Example 53.

[0275] Preparation method of difluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazolium (84) 13 Step 1. N -(2,3-Difluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-thiocarboxamide LiHMDS (1.20 equivalents, 0.50 mL, 0.590 mmol) was added to a solution of 2,3-difluoroaniline (70 mg, 0.541 mmol) in THF (5 mL) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then, methyl 5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-dithiocarbamate (200 mg, 0.492 mmol) was added to the mixture. The mixture was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to produce a crude product, which was used directly in the next step without further purification. MS (ESI) m / z 488 [M+H] + .

[0276] Step 2. N -(2,3-Difluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-aminocarbohydrazonamide At room temperature N 2,3-Difluorophenyl)-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-thiocarboxamide (239 mg, 0.490 mmol) was added to a solution of 2,3-(2,3-difluorophenyl)-5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazole-2-thiocarboxamide in THF (5 mL) and the reaction mixture was stirred at 75 °C for 1 h. The mixture was then directly concentrated without further purification for the next step. MS (ESI) m / z 486 [M+H] + .

[0277] Step 3.2-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazolium Will N A solution of 2,3-difluorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-aminomethylhydrazone (40 mg, 0.0824 mmol) in trimethoxymethane (3.0 mL, 27.4 mmol) was stirred at 110 °C for 5 h. The reaction mixture was then concentrated without further purification for the next step. MS (ESI) m / z 496 [M+H] + .

[0278] Step 4. 2-(4-(2-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole TFA (1.0 mL, 13.1 mmol) was added to a solution of 2-(4-(2,3-difluorophenyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzimidazole (42 mg, 0.0838 mmol) in DCM (1 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated to dryness. The crude product was purified by preparative HPLC to give the product 2-[4-(2,3-difluorophenyl)-1,2,4-triazol-3-yl]-5-(trifluoromethyl)-1H-benzimidazole (5.0 mg, 0.013 mmol, 15.5% yield) as a white solid.

[0279] MS (ESI) m / z 366 [M+H] + .

[0280] 1 H NMR (400 MHz, methanol-) d 4) 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).

[0281] Compounds 52, 62, 63, 66, 67, 70, 71, 85, 91, 99, 105, 106, 114, 115, 118, 119, 120, and 123 were synthesized using a method similar to that used in Example 84.

[0282] (dichlorophenyl)-5-methyl-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1 H -benzo[ d Preparation of imidazole (87) Step 1. N -(2-amino-4-(trifluoromethyl)phenyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide To a solution of 4-(trifluoromethyl)phenyl-1,2-diamine (2.0 g, 0.01 mol) in DMF (20 mL), 5-methyl-1,3,4-oxadiazol-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 at 25 °C for 12 h under N2. The reaction mixture was diluted with EtOAc 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 rapid column chromatography (PE / EtOAc = 2 / 1) to provide a yellow solid. N 1-(2-amino-4-(trifluoromethyl)phenyl)-5-methyl-1,3,4-oxadiazole-2-carboxamide (1.0 g, 29.20% yield). MS (ESI) m / z 287 [M+H] + .

[0283] Step 2. 2-Methyl-5-(5-(trifluoromethyl)-1 H -benzo[ d Imidazol-2-yl)-1,3,4-oxadiazole Will N A solution of 1,000-(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 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure to provide 2-methyl-5-(5-(trifluoromethyl)-1-oxadiazole-2-carboxamide as a white solid. H -benzo[ d Imidazol-2-yl)-1,3,4-oxadiazole (0.8 g, 82.86% yield). MS (ESI) m / z 269 [M+H] + .

[0284] Step 3. 2-(4-(2,3-dichlorophenyl)-5-methyl-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1 H -benzo[ d Imidazole To 2-methyl-5-(5-(trifluoromethyl)-1 H -benzo[ dImidazol-2-yl)-1,3,4-oxadiazole (800 mg, 2.97 mmol) was added to a solution of toluene (10 mL) with 2,3-dichloroaniline (722 mg, 4.45 mmol) and p-toluenesulfonic acid (767 mg, 4.45 mmol). The reaction mixture was stirred at 110 °C for 12 h under N2. The mixture was diluted with EtOAc 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 provide 2,3-(2,3-dichlorophenyl)-5-methyl-4-oxadiazole as a white solid. H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1 H -benzo[ d Imidazole (90 mg, 7.0% yield).

[0285] MS (ESI) m / z 412 [M+H] +。

[0286] 1 H NMR (400 MHz, DMSO- d 6) δ 13.97 (bs, 1H), 7.94 (dd, J =8.0 Hz, J =1.2Hz, 1H), 7.81 - 7.77 (m, 2H), 7.66 - 7.62 (m, 3H), 2.27 (s, 3H).

[0287] (dichlorophenyl)-5-((methylsulfonyl)methyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1 H -benzo[ d Preparation method of imidazole (88) 14 Step 1. N -(2,3-Dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole-2-thiocarboxamide A solution of LiHMDS in THF (1.0 M, 0.8 mL, 0.8 mmol) was added dropwise to a solution of 2,3-dichloroaniline (90 mg, 0.55 mmol) in THF (3 mL) in an ice bath. The mixture was stirred for 5 minutes and a solution of 5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazolium-2-dithiocarbamate (220 mg, 0.55 mmol) in THF (1 mL) was added dropwise. The reaction mixture was stirred for 1 hour. The resulting mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was collected, washed with brine, dried over Na2SO4, and concentrated to produce a crude product (300 mg) as a yellow oil, which was used in the next step without further purification. MS (ESI) m / z 520 [M+H] + .

[0288] Step 2. N -(2,3-Dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -Benzo[d]imidazole-2-aminomethylhydrazone Towards N -(2,3-Dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole-2-thiocarboxamide (300 mg) was dissolved in THF (5 mL) and 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 produce a crude product (300 mg) as a yellow oil, which was used directly in the following steps without further purification. MS (ESI) m / z 518 [M+H] + .

[0289] Step 3. 2-(5-(chloromethyl)-4-(2,3-dichlorophenyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole Will N -(2,3-Dichlorophenyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ dA solution of imidazole-2-aminomethylhydrazone (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 yield a product as a yellow solid (100 mg, 31.5% yield in three steps). MS (ESI) m / z 576 [M+H] + .

[0290] Step 4. 2-(4-(2,3-dichlorophenyl)-5-((methylthio)methyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole To 2-(5-(chloromethyl)-4-(2,3-dichlorophenyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole (80 mg, 0.14 mmol) was added to a solution of sodium methanethiol (30%, 400 mg, 1.7 mmol) in DMF (2 mL). The reaction mixture was stirred for 2 hours. The resulting mixture was diluted with water and EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to produce the product as a yellow oil (50 mg, 61% yield). MS (ESI) m / z 588 [M+H] + .

[0291] Step 5.2-(4-(2,3-dichlorophenyl)-5-((methylsulfonyl)methyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole To 2-(4-(2,3-dichlorophenyl)-5-((methylthio)methyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ dImidazole (50 mg, 0.085 mmol) was added to a solution of mCPBA (45 mg, 0.26 mmol) in DCM (3 mL). The reaction mixture was stirred for 2 hours. The resulting mixture was diluted with water and EtOAc. The organic layer was washed with an aqueous solution of NaHCO3, dried over Na2SO4, and concentrated to produce the product as a yellow oil (50 mg, 75% yield). MS (ESI) m / z 620 [M+H] + .

[0292] Step 6.2-(4-(2,3-dichlorophenyl)-5-((methylsulfonyl)methyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1 H -benzo[ d Imidazole To 2-(4-(2,3-dichlorophenyl)-5-((methylsulfonyl)methyl)-4 H -1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole (50 mg, 0.08 mmol) was added to a solution of TFA (2 mL) in DCM (2 mL). The reaction mixture was stirred for 1 hour. The resulting mixture was concentrated. The residue was purified by preparative HPLC to yield the product as a white solid (15 mg, 37.5% yield).

[0293] MS (ESI) m / z 490 [M+H] + .

[0294] 1 H NMR (400 MHz, d 6-DMSO) δ 14.08 (bs, 1H), 7.94 (dd, J =8.0 Hz, J =1.6Hz, 1H), 7.80 (s, 1H), 7.74 (dd, J =8.0 Hz, J =1.6 Hz, 1H), 7.69 (d, J =8.8 Hz, 1H), 7.64 (t, J =8.0 Hz, 1H), 7.54 (d, J =8.0 Hz, 1H), 4.92 (d, J =15.2 Hz, 1H), 4.64 (d,J =15.2 Hz, 1H), 3.19 (s, 3H).

[0295] Compounds 90, 124, 125, 126, and 127 were synthesized using a method similar to that used in Example 88.

[0296] [Oxo-2-isoquinolinyl)methyl]-3 H Preparation of 1,3-benzoxazol-2-one (89) Step 1. 2-(1-(2,3-dichlorophenyl)-1 H -imidazol-5-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d Imidazole To 2-(1-(2,3-dichlorophenyl)-1 H -imidazol-5-yl)-5-(trifluoromethyl)-1 H -benzo[ d Imidazole (500 mg, 1.26 mmol) was added to a solution in DCM (20 mL) with TEA (382 mg, 3.81 mmol) and SEMCl (252 mg, 1.51 mmol). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was diluted with EtOAc 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 rapid column chromatography (PE / EA = 1 / 6) to provide ethyl 1-(2,3-dichlorophenyl)-1H-imidazolium-5-carboxylate (300 mg, 45.2% yield) as a yellow solid. MS (ESI) m / z 527 [M+H] + .

[0297] Step 2. Methyl 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1H-imidazol-2-carboxylate In an ice bath, 2-(1-(2,3-dichlorophenyl)-1 H -imidazol-5-yl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ dImidazole (300 mg, 0.56 mmol) was added to a solution of LiHMDS (1.1 mL, 1.1 mmol) in THF (10 mL). The mixture was stirred for 30 minutes, and then methyl chloroformate (80.5 mg, 0.85 mmol) was added. The reaction mixture was stirred for 1 hour. The reaction mixture was diluted with EtOAc 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 rapid column chromatography (PE / EtOAc = 1 / 8) to provide methyl 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1H-imidazol-2-carboxylate (200 mg, 60.0% yield) as a yellow solid. MS (ESI) m / z 585 [M+H] + .

[0298] Step 3.1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d [Imidazol-2-yl)-1 H -Imidazole-2-formamide To 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d [Imidazol-2-yl)-1 H 1-Imidazole-2-carboxylate (200 mg, 0.34 mmol) was added to a solution of NH3 / MeOH (20 mL). The mixture was stirred for 16 hours. After the reaction was complete, the mixture was concentrated to provide 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1-carboxylate as a yellow solid. H -benzo[ d [Imidazol-2-yl)-1 H Imidazol-2-carboxamide (200 mg, 100% yield) was used in the next step without further purification. MS (ESI) m / z 570 [M+H] + .

[0299] Step 4. 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1 H -benzo[ d [Imidazol-2-yl)-1 H -Imidazole-2-formamide At 0°C, 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H -benzo[ d [Imidazol-2-yl)-1 H 1-Imidazole-2-carboxamide (200 mg, crude) was added to a solution of TFA (10 mL) in DCM (10 mL). The reaction mixture was stirred for 4 hours. After the reaction was complete, the mixture was diluted with water and the pH was adjusted to 7. The resulting mixture was diluted with EtOAc 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 provide 1-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1-carboxamide as a yellow powder. H -benzo[ d [Imidazol-2-yl)-1 H -Imidazole-2-carboxamide (6.7 mg, 4.3% yield).

[0300] MS (ESI) m / z 440 [M+H] + .

[0301] 1 H NMR (400 MHz, DMSO- d 6) δ 13.34 (bs, 1H), 8.03 - 7.97 (m, 2H), 7.76(d, J =8.0 Hz, J =1.6 Hz, 1H), 7.73 - 7.55 (m, 3H), 7.53 (d, J =8.0 Hz, J =1.6 Hz,1H), 7.50 - 7.40 (m, 2H).

[0302] Preparation of dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-4H-1,2,4-triazol-3-yl)ethane-1-ol (121) Step 1. Ethyl 3-(2-(((2,3-dichlorophenyl)amino)(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methylene)hydrazyl)-3-oxopropionic acid To a solution of 3-ethoxy-3-oxo-propionic acid (1.00 equivalence, 0.17 mL, 1.46 mmol) in DMF (10 mL), DIEA (3.00 equivalence, 0.76 mL, 4.37 mmol) and T3P (1.50 equivalence, 1390 mg, 2.18 mmol) was added. The mixture was then stirred overnight at 25 °C. The reaction progress was monitored by LC / MS. 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 used directly in the next step. MS (ESI) m / z 632 [M+H] + .

[0303] Step 2.2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,2,4-triazol-3-yl]ethyl acetate Ethyl 3-(2-(((2,3-dichlorophenyl)amino)(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methylene)hydrazino)-3-oxopropionate (1.00 equivalent, 470 mg, 0.743 mmol) in 1,4-dioxane (10 mL) was mixed with Burgess reagent (3.00 equivalent, 531 mg, 2.23 mmol) and the mixture was stirred at 80 °C for 1 h. The reaction progress was monitored by LC / MS. Once complete, the solvent was removed under reduced pressure and the residue was purified by column chromatography (PE / EA=1 / 1) to yield the product (180 mg, 39%). MS (ESI) m / z 614 [M+H] + .

[0304] Step 3. 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,2,4-triazol-3-yl]ethanol LiAlH4 (1.00 equivalent, 6.6 mg, 0.174 mmol) was added to a solution of ethyl 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,2,4-triazol-3-yl]ethyl acetate (1.00 equivalent, 107 mg, 0.174 mmol) in THF (2 mL), and the mixture was stirred at 0 °C for 1 h. The reaction progress 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 reactants were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step. MS (ESI) m / z 572 [M+H] + .

[0305] Step 4. 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1,2,4-triazol-3-yl]ethanol TFA (1 mL) was added to a solution of 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,2,4-triazol-3-yl]ethanol (1.00 equivalent, 100 mg, 0.174 mmol) in DCM (2 mL), and the mixture was stirred at 25 °C for 1 h. The reaction progress was monitored by LC / MS. Once complete, the solvent was removed, and the residue was purified by preparative HPLC to yield the desired product (2 mg, 3%).

[0306] MS (ESI) m / z 442 [M+H] + .

[0307] 1 H NMR (400 MHz, DMSO- d 6) δ 13.96 (bs, 1H), 7.95 (dd, J=8.2, 1.5 Hz,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, 5.8 Hz, 2H), 2.80 - 2.64 (m, 2H).

[0308] Preparation of dichlorophenyl)-5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1,2,4-triazol-3-yl]acetamide (122) Step 1. 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,2,4-triazol-3-yl]acetamide Ammonia (25%, 1 mL) was added to a solution of ethyl 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,2,4-triazol-3-yl]ethyl acetate (1.00 equivalent, 155 mg, 0.253 mmol) in ethanol (1 mL), and the mixture was stirred at 80 °C for 2 h. The reaction progress was monitored by LC / MS. Once complete, the solvent was removed, and the residue was used directly in the next step. MS (ESI) m / z 585 [M+H] + .

[0309] Step 2. 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-1,2,4-triazol-3-yl]acetamide TFA (1.0 mL) was added to a solution of 2-[4-(2,3-dichlorophenyl)-5-[5-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-yl]-1,2,4-triazol-3-yl]acetamide (1.00 equivalent, 148 mg, 0.253 mmol) in DCM (1 mL), and the mixture was stirred at 25 °C for 2 h. The reaction progress was monitored by LC / MS. Once complete, the solvent was removed, and the residue was purified by preparative HPLC to yield the product (4 mg, 3%). MS (ESI) m / z 455 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ 14.02 (bs, 1H), 7.92 (dd, J=8.1,1.6 Hz, 1H), 7.78 (s, 1H), 7.67 (dd, J=8.0, 1.6 Hz, 1H), 7.60 (t, J=8.0 Hz,1H), 7.45 (s, 1H), 7.04 (s, 1H), 3.79 (d, J=16.5 Hz, 1H), 3.46 (d, J=16.5 Hz, 1H).

[0310] Preparation methods of dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-4H-1,2,4-triazol-3-thiol (108), 2-(4-(2,3-dichlorophenyl)-5-(methylthio)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazol (109) and 2-(4-(2,3-dichlorophenyl)-5-(oxetane-3-yloxy)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazol (117) 15 Step 1. N -(2,3-Dichlorophenyl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-carbonyl)hydrazine-1-thiocarboxamide 1,2-Dichloro-3-isothiocyano-benzene (919 mg, 4.51 mmol) was added to a solution of 5-(trifluoromethyl)-1H-benzimidazole-2-carbazide (1000 mg, 4.10 mmol) in THF (5 mL) and stirred at 80 °C for 4 h. The reaction progress was monitored by LCMS. Once complete, the organic layer was separated and concentrated to yield the crude product as a brown solid. N -(2,3-Dichlorophenyl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-carbonyl)hydrazine-1-thiocarboxamide (1700 mg, 3.79 mmol, 92.6% yield) was used directly in the next step. MS (ESI) m / z 448 [M+H] + Step 2. 4-(2,3-dichlorophenyl)-5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-4H-1,2,4-triazol-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 h. The reaction mixture was stirred at 100 °C for 2 h. 1 M HCl (2 mL) was added to the reaction mixture and the pH was adjusted to 7. The reaction mixture was extracted with EtOAc (10 mL x 3). The organic layer was dried and concentrated. The crude product was used directly in the next step. MS (ESI) m / z 430 [M+H] + .

[0311] Step 3. 2-(4-(2,3-dichlorophenyl)-5-(methylthio)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole At room temperature N -(2,3-dichlorophenyl)-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-carbonyl)hydrazine-1-thiocarboxamide (380 mg, 0.883 mmol) was added to a solution of iodomethane (0.082 mL, 1.32 mmol) in K₂CO₃ (244 mg, 1.77 mmol) and stirred at 25 °C for 1 h. The reaction mixture was filtered and concentrated. The crude product was used directly in the next step. MS (ESI) m / z 444 [M+H] + .

[0312] Step 4. 2-(4-(2,3-dichlorophenyl)-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole mCPBA (388 mg, 2.25 mmol) was added to a solution of 2-(4-(2,3-dichlorophenyl)-5-(methylthio)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzi[d]imidazole (250 mg, 0.563 mmol) in DCM (5 mL) at room temperature under N2. The reaction mixture was stirred at 25 °C for 2 h. The reaction was quenched by adding 10 mL of aqueous Na2S2O3 solution and 10 mL of NaHCO3. The reaction mixture was extracted with EtOAc (20 mL x 3). The organic compounds were then combined and dried (Na₂SO₄), and then concentrated to dryness to yield the product 2-(4-(2,3-dichlorophenyl)-5-(methanesulfonyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole as a brown solid (150 mg, 0.32 mmol, 56% yield). MS (ESI) m / z 476 [M+H] + .

[0313] Step 5. 2-(4-(2,3-dichlorophenyl)-5-(oxetane-3-yloxy)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazolium NaH (10 mg, 0.262 mmol) was added to a solution of 2-(4-(2,3-dichlorophenyl)-5-(methanesulfonyl)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzi[d]imidazole (50 mg, 0.105 mmol) and oxetane-3-ol (19 mg, 0.262 mmol) in DMF (2 mL) at room temperature under N2. The reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was then added to H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried (Na2SO4), and concentrated under vacuum. The crude product was purified by preparative HPLC to produce 2-(4-(2,3-dichlorophenyl)-5-(oxetane-3-yloxy)-4H-1,2,4-triazol-3-yl)-5-(trifluoromethyl)-1H-benzis[d]imidazole as a white solid (10 mg, 0.02 mmol, 19.9% ​​yield).

[0314] MS (ESI) m / z 470 [M+H] + .

[0315] 1 H NMR (400 MHz, methanol-) d 4) 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).

[0316] Compound 131 was synthesized using a method similar to that used in Example 117.

[0317] Methods for preparing methyl 2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)propane-1-ol (101) and 2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)propane-1-ol (104) 16 Step 1. Methyl 2-(4-aminophenyl)propionate Pd / C (0.0100 equivalent, 253 mg, 0.239 mmol) was added to a solution of methyl 2-(4-nitrophenyl)propionate (1.00 equivalent, 5.00 g, 23.9 mmol) in ethanol (100 mL). The reaction mixture was then stirred overnight at room temperature under a hydrogen (balloon) atmosphere. The reaction solution was filtered and the filtrate was concentrated to provide methyl 2-(4-aminophenyl)propionate as a yellow oil (3.50 g, 19.5 mmol, 81.71% yield). The crude product was used directly for the next step without further purification. MS (ESI) m / z 180.1 [M+H]+.

[0318] Step 2.3-(4-methoxybenzyl)-6-methylbenzo[d]oxazol-2(3H)-one A solution of methyl 2-(4-aminophenyl)propionate (1.00 equivalent, 1.5 g, 8.37 mmol) in Ac₂O (20 mL) was heated at 60 °C for 1 h. The reaction solution was poured into H₂O. The crude product was extracted with EtOAc (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 provide crude methyl 2-(4-acetaminophenyl)propionate (1.80 g, 8.14 mmol, 97.20% yield) as a yellow oil. The crude product was used directly in the next step. MS (ESI) m / z 222.1 [M+H]+.

[0319] Step 3.2-(4-acetamido-3-nitrophenyl)propionate methyl ester A solution of methyl 2-(4-acetamidophenyl)propionate (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 h. The yellow solution was poured onto ice. The aqueous layer was extracted with DCM, washed with a saturated aqueous solution of NaHCO₃, dried over Na₂SO₄, and evaporated to provide methyl 2-(4-acetamido-3-nitro-phenyl)propionate (1.10 g, 4.13 mmol, 50.78% yield) as a yellow solid. (ESI) m / z 267.1 [M+H]⁺.

[0320] Step 4.2-(4-amino-3-nitrophenyl)propionate methyl ester Concentrated HCl (2.0 mL) was added to a solution of methyl 2-(4-acetamido-3-nitro-phenyl)propionate (1.00 equivalent, 1.10 g, 4.13 mmol) in ethanol (20 mL). The reaction solution was stirred at 90 °C for 5 h. After cooling the reaction mixture to room temperature, the solution was concentrated under vacuum to provide methyl 2-(4-amino-3-nitrophenyl)propionate as a yellow solid (720 mg, 3.43 mmol, 82.91% yield). MS (ESI) m / z 225.2 [M+H]+.

[0321] Step 5. Methyl 2-(3,4-diaminophenyl)propionate To a solution of methyl 2-(4-amino-3-nitro-phenyl)propionate (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 (balloon) atmosphere. The reaction solution was filtered and the filtrate was concentrated. Purification by rapid chromatography (C18) was performed to provide methyl 2-(3,4-diaminophenyl)propionate as a yellow oil (460 mg, 2.37 mmol, 73.75% yield). MS (ESI) m / z 195.1 [M+H]+.

[0322] Step 6. Methyl 2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)propionate A mixture of 4-methylsulfonylbenzene-1,2-diamine (1.20 equivalence, 185 mg, 0.991 mmol) and 4-(2,3-dichlorophenyl)-1,2,4-triazol-3-carboxaldehyde (1.00 equivalence, 200 mg, 0.826 mmol) in water (15 mL) was stirred at 90 °C for 2 h. After cooling the reaction mixture to room temperature, K₂CO₃ (3.00 equivalence, 343 mg, 2.48 mmol), KI (0.500 equivalence, 69 mg, 0.413 mmol), and I₂ (2.00 equivalence, 419 mg, 1.65 mmol) were added to the mixture. The reaction mixture was then stirred at 90 °C for 30 min. 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 rapid chromatography (C18) to provide methyl 2-[2-[4-(2,3-dichlorophenyl)-1,2,4-triazol-3-yl]-1H-benzimidazol-5-yl]propionate as a white solid (210 mg, 0.504 mmol, 24.50% yield).

[0323] (ESI) m / z 416.2 [M+H] + .

[0324] 1 H NMR (400 MHz, DMSO- d 6) δ 13.53 (s, 1H), 9.02 (s, 1H), 7.91 (dd, J =8.2, 1.5 Hz, 1H), 7.77 (dd, J =8.0, 1.5 Hz, 1H), 7.59 (t, J =8.1 Hz, 1H), 7.43(d, J =8.4 Hz, 1H), 7.37 (s, 1H), 7.12 (s, 1H), 3.92 - 3.85 (m, 1H), 3.56 (s,3H), 1.40 (d, J =7.1 Hz, 3H).

[0325] Step 7. 2-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)propane-1-ol Methyl 2-[2-[4-(2,3-dichlorophenyl)-1,2,4-triazol-3-yl]-1H-benzimidazol-5-yl]propionate (1.00 equivalent, 40 mg, 0.0961 mmol) in THF (10 mL) was added to a solution of THF. The mixture was then stirred at -40 °C for 3 h. The reaction mixture was then quenched by adding 1 mL of NH4Cl solution and 10 mL of H2O. 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 provide 2-[2-[4-(2,3-dichlorophenyl)-1,2,4-triazol-3-yl]-1H-benzimidazol-5-yl]propane-1-ol as a white solid (10 mg, 0.0258 mmol, 26.80% yield).

[0326] (ESI) m / z 388.2 [M+H] + .

[0327] 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 9.00 (s, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.76 (dd, J=8.0, 1.5 Hz, 1H), 7.59 (t, J=8.1 Hz, 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).

[0328] Compounds 102, 103, 107, 110, 111, 112, 113, 129, 130, 133, 134, and 135 were synthesized using a method similar to that used in Example 104.

[0329] Preparation method of dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)pyrrolidine-2-one (137) 17 Step 1. Preparation of 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)pyrrolidine-2-one (3) A mixture of 5-bromo-2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole (100 mg, 0.1859 mmol), pyrrolidone-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 a nitrogen 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 produce a crude product. This crude product was purified by column chromatography on silica gel (MeOH:DCM = 1:10) to yield 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)pyrrolidone-2-one as an oil (74 mg, 73.27% yield). MS (ESI) m / z 543.1 [M+H] + .

[0330] Step 2. Preparation of 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)pyrrolidone-2-one 1-(2-(4-(2,3-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)pyrrolidone-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 a crude product, which was purified by preparative HPLC (column-Gemini-C18 150 x 21.2 mm, 5 μm; mobile phase: ACN-H2O (0.1% TFA), 30%–50%) to provide the desired product SIR-00015146 (1.4 mg, 2.49% yield) as a white solid. MS (ESI) m / z 413.1 [M+H] + .

[0331] 1 H NMR (400 MHz) δ 8.82 (s, 1H), 7.78 (dd, J =8.0, 1.4 Hz, 1H), 7.73(s, 1H), 7.59 (dd, J =8.0, 1.2 Hz, 1H), 7.51 (d, J =8.2 Hz, 2H), 7.48 - 7.41 (m,1H), 3.59 - 3.42 (m, 2H), 2.58 (t, J =8.0 Hz, 2H), 2.22 - 2.14 (m, 2H).

[0332] (3-chloro-3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-3-(methylsulfonyl)-5-(trifluoromethyl)-1H-indole (346) Method 18 Step 1. 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazol-3-yl]-3-iodo-5-(trifluoromethyl)-1H-indole NIS (82 mg, 0.36 mmol) was added to a mixture of 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazol-3-yl]-5-(trifluoromethyl)-1H-indole (140 mg, 0.36 mmol) in DCM (5 mL) in an ice bath. The reaction mixture was stirred at 25 °C for 1 h. The mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by FCC (DCM / MeOH = 20 / 1) to produce 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazol-3-yl]-3-iodo-5-(trifluoromethyl)-1H-indole (190 mg, 96% yield). MS (ESI) m / z 507 [M+H] + .

[0333] Step 2.2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazol-3-yl]-3-methanesulfonyl-5-(trifluoromethyl)-1H-indole Cuprous iodide (I) (103 mg, 0.54 mmol) and sodium methanesulfinate (55 mg, 0.54 mmol) were added to a solution of 2-[4-(2-chloro-3-fluorophenyl)-1,2,4-triazol-3-yl]-3-iodo-5-(trifluoromethyl)-1H-indole (55 mg, 0.10 mmol) in NMP (4 mL) at room temperature. The mixture was stirred at 105 °C for 0.5 h under N2. The mixture was diluted with water (10 mL) and extracted with EA (10 mL x 2). The combined organic phases were 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 produce a pale yellow solid (7.0 mg, 11% yield). MS (ESI) m / z 459 [M+H] + .

[0334] 1 H NMR (400 MHz, DMSO- d 6) δ: 13.38 (s, 0.5H), 9.22 (s, 1H), 8.19 (s,1H), 7.83-7.35 (m, 5H), 3.06 (s, 3H).

[0335] Preparation method of fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]-1H-benzimidazole (338) 19 Step 1. Spiro[2.2]pentane-2-carboxylic acid (1,3-dioxoisoindoline-2-yl) ester 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 equivalent) in DCM (5 mL), DIC (123.81 mg, 981.05 μmol, 151.91 μL, 1.10 equivalent) and DMAP (10.90 mg, 89.19 μmol, 0.1 equivalent) were added. The resulting mixture was stirred at 20 °C for 2 h under N2 protection. LCMS showed no expected mass. TLC indicated that spiro[2,2]pentane-2-carboxylic acid (100 mg, 891.85 μmol, 1 equivalent) was completely depleted and some new spots 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 rapid silica gel chromatography (ISCO®; 4 g SepaFlash® silica gel column, 0–15% ethyl acetate / petroleum ether gradient eluent, @20 mL / min). The compound spiro[2.2]pentane-2-carboxylic acid (1,3-dioxoisoindoline-2-yl) ester was given as a white solid (160 mg, 621.98 μmol, 69.74% yield). 1 H NMR (400 MHz, CDCl3) δ 7.93 - 7.84 (m, 2H), 7.84 - 7.74 (m, 2H), 2.32 (dd, J =4.2, 7.5 Hz, 1H), 1.77 (t, J=4.1 Hz, 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-triazol-3-yl]-1H-benzimidazole To a solution of 2-[[5-bromo-7-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridinyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (20 mg, 35.88 μmol, 1 equivalent) in DMA (1 mL), spiro[2,2]pentane-2-carboxylic acid (1,3-dioxoisoindoline-2-yl) ester (11.08 mg, 43.06 μmol, 1.2 equivalent), N-cyano-4-methoxy-pyridin-2-formamidin (9.48 mg, 53.82 μmol, 1.5 equivalent), NiCl2 (DME) (8.67 mg, 39.47 μmol, 1.1 equivalent) and TBAI (11.93 mg, 32.29 μmol, 1.2 equivalent) were added. 0.9 equivalents) and Zn (7.88 mg, 143.52 μmol, 7.81 μL, 4 equivalents). The mixture was stirred at 25 °C for 16 hours. LCMS showed the desired mass. TLC showed new spots. The reaction mixture was poured into water (2 mL) and extracted with EtOAc (3 mL × 3). The organic layer was washed with brine (10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and purified by preparative TLC (Pe: EtOAc = 3:1) to produce 2-[[7-fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane as a colorless oil (13 mg, 12.41 μmol, 34.59% yield, 52% purity). MS (ESI) m / z 545 [M+H] + .

[0336] Step 3.7 - Fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]-1H-benzimidazole TFA (1.54 g, 13.46 mmol, 1 mL, 215.64 equivalents) was added to a solution of 2-[[7-fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (34 mg, 62.43 μmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 15 °C for 0.5 h. LC-MS showed complete exhaustion of reactant 1 and a major peak with the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by preparative HPLC (column: Boston Green ODS150 × 30 mm × 5 μm; mobile phase: [water (TFA)-ACN]; gradient: 55%–75% B for 11 min). The compound 7-fluoro-5-spiro[2.2]pentan-2-yl-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]-1H-benzimidazole was obtained as a colorless oil (3.4 mg, 7.83 μmol, 12.54% yield, 95.41% purity). MS (ESI) m / z 415 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 9.11 (d, J =5.0 Hz, 1H), 8.88 (s, 1H), 8.45(s, 1H), 7.86 (d, J =5.1 Hz, 1H), 7.27 - 7.24 (m, 1H), 6.69 (br d, J =11.8 Hz, 1H), 2.33 (dd, J =4.5, 7.8 Hz, 1H), 1.56 (dd, J =4.3, 7.9 Hz, 1H), 1.07 - 0.91(m, 4H), 0.75 (br dd, J =4.6, 8.8 Hz, 1H) 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]pyridin-4-one (308) Step 1. 4-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1.00 equivalent, 1239 mg, 5.88 mmol) was added to a solution of NaH (1.30 equivalent, 306 mg, 7.65 mmol) in THF (30 mL) at 0 °C. The mixture was stirred for 30 min. SEMCl (1.30 equivalent, 1.4 mL, 7.65 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with EA. The organic phase was dried over anhydrous Na2SO4 and concentrated, and the residue was purified by FCC to produce 4-chloro-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-2-carboxylate (1250 mg, 3.67 mmol, 62.34% yield).

[0337] Step 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 for the next step.

[0338] Step 3. To a solution of methyl 4-chloro-5-ethyl-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-5-onthium-2-carboxylic acid 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 h. 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 yield 5-ethyl-4-oxo-1-(2-trimethylsilylethoxymethyl)pyrrolo[3,2-c]pyridine-2-carboxylic acid (813 mg, 2.42 mmol, 86.30% yield).

[0339] Step 4. TFA (64.6 equivalents, 20 mL, 261 mmol) was added 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). The mixture was stirred at room temperature for 4 h, then concentrated, and the residue was used directly in the next step.

[0340] Step 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 (10 mL) in water was added. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. Water was added. An aqueous solution of HCl (1 N) was added until pH = 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 yield 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (531 mg, 2.58 mmol, 64.38% yield).

[0341] Step 6. N-methylmorpholine (3.00 equivalence, 0.85 mL, 7.73 mmol) was added to a solution of 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (1.00 equivalence, 531 mg, 2.58 mmol) in THF (15 mL) at 0 °C, followed by isobutyl chloroformate (1.20 equivalence, 0.40 mL, 3.09 mmol). The mixture was stirred for 20 min and N₂H₄∙H₂O (5.00 equivalence, 805 mg, 12.9 mmol) was added dropwise. The mixture was warmed to room temperature and stirred for 1.5 h. The mixture was extracted with EA, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by FCC to produce 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridine-2-carbonylhydrazine (423 mg, 1.92 mmol, 74.59% yield).

[0342] Step 7. To a solution of N'-(2-chloro-3-fluoro-phenyl)-N,N-dimethylformamidinium (2.00 equivalent, 164 mg, 0.817 mmol) in MeCN (3 mL) and acetic acid (1 mL), 5-ethyl-4-oxo-1H-pyrrolo[3,2-c]pyridin-2-carbonylhydrazine (1.00 equivalent, 90 mg, 0.409 mmol) was added. The mixture was heated to 90 °C and stirred for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to yield 2-[4-(2-chloro-3-fluoro-phenyl)-1,2,4-triazol-3-yl]-5-ethyl-1H-pyrrolo[3,2-c]pyridin-4-one (2.0 mg, 0.00559 mmol, 1.37% yield) as a white solid. MS (ESI) m / z 358 [M+H] + . 1 H NMR (400 MHz, MeOD) δ 8.73 (s, 1H), 7.69 - 7.62 (m,2H), 7.59 - 7.55 (m, 1H), 7.37 (d, J =7.3 Hz, 1H), 6.64 (d, J =7.3 Hz, 1H), 6.15(s, 1H), 4.03 (q, J =7.2 Hz, 2H), 1.29 (t, J =7.1 Hz, 4H).

[0343] (dichlorophenyl)-1 H -1,2,3-triazol-1-yl)-5-(trifluoromethyl)-1 H -benzo[ d Preparation of imidazole (315) Step 1. 2-Hydroxy-5-(trifluoromethyl)-1 H -benzo[ d Imidazole To 2-chloro-5-(trifluoromethyl)-1 H -benzo[ d Imidazole (1 g, 4.54 mmol) was added to a solution of hydrazine (80%, 2 mL) in THF (10 mL). 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 produce a crude product (1 g, 100% yield) as a yellow oil. MS (ESI) m / z 217 [M+H] + .

[0344] Step 2. 2-Azide-5-(trifluoromethyl)-1 H -benzo[ d Imidazole 2-hydrazino-5-(trifluoromethyl)-1-hydrazyl ... H -benzo[ d Imidazole (300 mg, 1.39 mmol) was added dropwise to a mixture of HCl aqueous solution (3 N, 5 mL) and NaNO2 aqueous 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 produce a crude product as a yellow oil (0.3 g, 100% yield). MS (ESI) m / z 359 [M+H] + .

[0345] 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 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 chromatography to yield the product as a yellow oil (0.8 g, 90% yield).

[0346] Step 4. 2-(5-(2,3-dichlorophenyl)-1 H -1,2,3-triazol-1-yl)-5-(trifluoromethyl)-1 H -benzo[ d Imidazole 2-hydrazino-5-(trifluoromethyl)-1 H -benzo[ d Imidazole (300 mg, 1.24 mmol) and 2-azido-5-(trifluoromethyl)-1 H -benzo[ d A mixture of imidazole (280 mg, 1.23 mmol) in water (5 mL) was heated to 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 yield the product as a white solid (3 mg, 6.1% yield). MS (ESI) m / z 398 [M+H] +. 1 H NMR (400 MHz, d 6-DMSO) δ 14.15 (bs, 1H), 8.26 (s, 1H), 7.85 (s, 1H), 7.81 (d, J =8.0 Hz, 1H), 7.70 (d, J =8.0 Hz, 1H), 7.60 - 7.47 (m, 3H).

[0347] Preparation method of fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)ethyl)thiazole (412) 20 Step 1. 1-(thiazol-2-yl)ethylene trifluoromethanesulfonate To a solution of 1-thiazolyl-2-ylethyl ketone (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 under an inert atmosphere for 1 hour. The mixture was diluted with EtOAc 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 rapid column chromatography (PE / EtOAc = 1 / 9) to yield 1-thiazolyl-2-ylethylene trifluoromethanesulfonate as a brown oil (1000 mg, 3.47 mmol, 44.15% yield). MS (ESI) m / z 260 [M+H]+.

[0348] Step 2. 7-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazolium Add Pd(dppf)Cl2 (0.100 equivalent, 293 mg, 0.359 mmol) and potassium acetate (3.00 equivalent, 1055 mg, 10.8 mmol) to a mixture of 5-bromo-7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole (1.00 equivalent, 2000 mg, 3.59 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (2.00 equivalent, 1822 mg, 7.18 mmol) in 1,4-dioxacyclohexane (20 mL). The reaction mixture was stirred at 100 °C under an inert atmosphere for 1 hour. The mixture was diluted with EtOAc 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 yield 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole (2000 mg, 2.98 mmol, 82.99% yield). MS (ESI) m / z 605 [M+H]+.

[0349] Step 3.2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)vinyl)thiazole Pd2(dba)3 (0.200 equivalent, 91 mg, 0.0993 mmol) and K2CO3 (3.00 equivalent, 191 mg, 0.0993 mmol) were added to a mixture of 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzi[d]imidazole (1.00 equivalent, 300 mg, 0.496 mmol) and 1-(thiazolyl-2-yl)vinyl trifluoromethanesulfonate (2.00 equivalent, 257 mg, 0.993 mmol) in 1,4-dioxane (15 mL) and water (1 mL). 1.49 mmol). The reaction mixture was stirred at 100 °C under an inert atmosphere for 1 hour. The mixture was diluted with EtOAc 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 yield 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)vinyl)thiazole as a yellow oil (160 mg, 0.245 mmol, 49.37% yield). MS (ESI) m / z 588 [M+H]+.

[0350] Step 4.2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)thiazole Pd / C (95 mg, 10%) was added to a mixture of 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)vinyl)thiazole (1.00 equivalent, 160 mg, 0.272 mmol) in methanol (15 mL). The mixture was stirred at 25 °C under a H2 atmosphere for 1 hour. The reactants were filtered through a diatomaceous earth mat, and the filtrate was concentrated to produce 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)thiazole (100 mg) as a yellow oil, which was used in the next step without further purification. MS (ESI) m / z 590 [M+H]+.

[0351] Step 5. 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)ethyl)thiazole TFA (10 mL) was added to a mixture of 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-5-yl)ethyl)thiazole (1.00 equivalent, 100 mg, 0.170 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was diluted with EtOAc 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 60% ACN) to yield 2-(1-(7-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazol-5-yl)ethyl)thiazole (33 mg, 0.0682 mmol, 40.24% yield) as a white solid. MS (ESI) m / z 460 [M+H]+.

[0352] 1 H NMR (400 MHz, chloroform-) d ) δ 12.96 (brs, 1H), 9.09 (d, J=5.2 Hz, 1H),8.86 (s, 1H), 8.45 (s, 1H), 7.83 (d, J =5.2 Hz, 1H), 7.75 (d, J =3.2 Hz, 1H),7.26 - 7.23 (m, 2H), 6.91 (d, J =11.2 Hz, 1H), 4.72 - 4.63 (m, 1H), 1.84 (d, J =6.8 Hz, 3H).

[0353] Preparation method of difluoro(pyridin-4-yl)methyl)-4-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1H-benzi[d]imidazolium (464) 21 Step 1.2-[[4-fluoro-6-[1-(4-pyridyl)vinyl]-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane Under a nitrogen atmosphere, 2-[[6-bromo-4-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridinyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (1.00 equivalent, 2000 mg, 3.59 mmol), XPhos (0.100 equivalent, 171 mg, 0.359 mmol), Pd(CH3CN)2Cl2 (0.100 equivalent, 93 mg, 0.359 mmol), and t-BuOLi (3.00 equivalent, 862 mg, 10.8 mmol) were added to 4-methyl-N-[(E)-1-(4-pyridinyl)ethyleneamino]benzenesulfonamide (2.00 equivalent, 2076 mg, 7.18 mmol). The solution was prepared in 1,4-dioxane (2 mL) at 1 mmol. The mixture was stirred at 90 °C for 3 h and the precipitate was removed by filtration. The filtrate was concentrated under vacuum to give the crude product. The crude product was purified by column chromatography with petroleum / ethyl acetate to produce 2-[[4-fluoro-6-[1-(4-pyridyl)vinyl]-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (1780 mg, 3.06 mmol, 85.29% yield). MS (ESI) m / z 582 [M+H] + .

[0354] Step 2. [7-Fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]-(4-pyridyl)methyl ketone A solution of 2-[[4-fluoro-6-[1-(4-pyridyl)vinyl]-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (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 stream (approximately 1% O3) was applied to the solution. After 15 minutes, the mixture turned green-blue. The ozone generator was set to 0 V. The solution was purged with O2 for 15 minutes. After the starting material disappeared (as determined by TLC), the reaction mixture was brought 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 on silica gel to yield [7-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]-(4-pyridyl)methyl ketone (1210 mg, 2.07 mmol, 67.75% yield). MS (ESI) m / z 584 [M+H] + .

[0355] Step 3.2 - [[6-[difluoro(4-pyridyl)methyl]-4-fluoro-2-[4-[4-[4-(trifluoromethyl)-3-pyridyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane A solution of [7-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridinyl]-1,2,4-triazol-3-yl]-3-(2-trimethylsilylethoxymethyl)benzimidazol-5-yl]-(4-pyridinyl)methyl ketone (1.00 equivalent, 130 mg, 0.223 mmol) in DAST (10 mL) was prepared. 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 extracts were dried and concentrated. The title compound, 2-[[6-[difluoro(4-pyridinyl)methyl]-4-fluoro-2-[4-[4-[4-(trifluoromethyl)-3-pyridinyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethylsilane (100 mg, 0.165 mmol, 74.13% yield), was provided as a grayish-white solid by preparative HPLC purification. MS (ESI) m / z 606 [M+H] + .

[0356] Step 4.6-(difluoro(pyridin-4-yl)methyl)-4-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1H-benzo[d]imidazolium TFA was added dropwise to a stirred solution of 2-[[6-[difluoro(4-pyridinyl)methyl]-4-fluoro-2-[4-[4-(trifluoromethyl)-3-pyridinyl]-1,2,4-triazol-3-yl]benzimidazol-1-yl]methoxy]ethyl-trimethyl-silane (1.00 equivalent, 100 mg, 0.165 mmol) in DCM (5 mL). The resulting mixture was stirred for 4 h. The reaction was monitored by LCMS. 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 provide 6-(difluoro(pyridin-4-yl)methyl)-4-fluoro-2-(4-(4-(trifluoromethyl)pyridin-3-yl)-4H-1,2,4-triazol-3-yl)-1H-benzis[d]imidazole as a white solid (46 mg, 0.0968 mmol, 58.61% yield). MS (ESI) m / z 476 [M+H] + . 1 ¹H NMR (400 MHz, methanol-d⁴) δ 9.06 (d, J=5.2 Hz, 1H), 8.97 (d, J =4.4 Hz, 2H), 8.66 (s, 2H), 7.97 (d, J =5.2 Hz, 1H), 7.61 - 7.46 (m, 3H), 7.10 (s, 1H).

[0357] Example II. SARM1 (50-724) enzyme assay Enzyme assays were performed in 384-well plates using Dulbecco's phosphate-buffered saline (PBS) as the reaction buffer. Purified SARM1 (50-724) at a final concentration of 2 nM was incubated with the test compound at the final assay concentration in 1% DMSO at room temperature for 15 min. The assay was performed by adding 200 μM nicotinamide mononucleotide (NMN) as an activator and 100 μM MNAD. +The reaction was initiated using a mixture of substrates. After incubation at room temperature for 1 h, the reaction was terminated with 10 volumes of 70% acetonitrile and then centrifuged at 3800 rpm for 10 min. The samples were diluted to appropriate concentrations with 10 mM ammonium acetate (pH 9.75) and analyzed by LC-MS / MS.

[0358] The SARM1 inhibitory activity of compounds 1-468 is summarized in Table 2. In Table 2, the activities are provided as follows: A: IC50 50 ≤100 nM; B: 100 nM <IC 50 ≤500 nM; C: 500 nM <IC 50 ≤1000 nM; D: IC 50 >1000 nM.

[0359] Table 2

[0360] All publications (including but not limited to public disclosures and applications) cited in this specification are incorporated herein by reference as if fully described herein. If any content of a publication cited herein contradicts or is inconsistent with this disclosure, this disclosure shall prevail.

[0361] Those skilled in the art will readily recognize from this disclosure and the claims that various changes, modifications and variations may be made therein without departing from the spirit and scope of this disclosure as defined in the following claims.

Claims

1. The following compounds with structural formula 1: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein: X1, X2, X3, X4, and X5 are each independently 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 phenyl, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclic, wherein the 5- to 6-membered heteroaryl or 4- to 7-membered heterocyclic group of ring B contains 1 to 4 heteroatoms selected from N, O and S; The ring C is phenyl, 3- to 10-membered cycloalkyl, 4- to 10-membered heterocyclic, 5- to 6-membered heteroaryl or 9- to 10-membered heteroaryl, wherein the 4- to 10-membered heterocyclic, 5- to 6-membered heteroaryl or 9- to 10-membered heteroaryl of the ring C contains 1 to 3 heteroatoms selected from N, S and O; R 1 Selected from 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)R n -C(=O)OR m -C(=O)NR m R n -P(=O)R m R n -SF5 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms independently selected from N, O, and S. 3- to 10-membered heterocyclic groups containing one or two heteroatoms independently selected from N, O, and S, and 3- to 10-membered cycloalkyl, wherein: R 1 The C1-C8 alkyl, C1-C8 alkenyl, or C1-C8 alkynyl groups are optionally substituted by 1-3 groups selected from halogens, -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 heterocyclic and 3- to 6-membered cycloalkyl (optionally substituted with 1-3 groups selected from OH and halogens), R 1 The 5- to 6-membered heteroaryl group is optionally substituted by 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) m and OR m ), R 1 The 3- to 10-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) m and OR m ),and R 1 The 3- to 10-membered cycloalkyl group is optionally substituted with 1 to 3 groups selected from 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 groups (optionally substituted with 1-3 groups selected from halogens, -C(=O)NH2, R...) m and OR m ),and Where R m and R n Each occurrence is independently selected from H, C1-C6 alkyl groups, and -S (=O). p (C1-C4 alkyl), phenyl, 3- to 8-membered cycloalkyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl, wherein R m The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from D, -C(=O)NH2, -OH, -OMe, -S(=O)2CH3 and halogens; R 2 Selected from H, halogens, 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 (C1-C4 alkyl), -CN, 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 10-membered heterocyclic (containing 1 to 3 heteroatoms independently selected from S, O, and N), wherein: R 2 The C1-C6 alkyl or C1-C6 alkenyl group is optionally substituted with 1-3 groups selected from halogens, CN, and -C(=O)O (C1-C6 alkyl). R 2 The 3- to 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 the -O (C1-C6 alkyl) is optionally substituted with 1-3 groups selected from halogens and CN, and R 2 The 3- to 10-membered heterocyclic group is optionally substituted with 1-3 groups selected from OH, CN, and halogens; or R 1 and R 2 Connect to form ; R 3 and R 4 Each is independently selected from H, halogen, C1-C6 alkyl (optionally substituted by 1-3 groups selected from OH and halogen) and -O (C1-C6 alkyl); R 5 Selected from non-existent, H, -CN, halogen, -C(=O)NH2, -S(=O)p (C1-C4 alkyl), -OR p , phenyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic, 3- to 8-membered cycloalkyl and C1-C6 alkyl, wherein: R 5 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from OH, -NHR, etc. p -OR p and -S(=O)p(C1-C4 alkyl), R 5 The 4- to 6-membered heterocyclic group is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl, CN, halogen, and =O. R 5 The 3- to 8-membered cycloalkyl group is optionally substituted with 1 to 3 groups selected from C1-C3 alkyl, CN, and halogens, wherein: R p Selected from C1-C6 alkyl, 3- to 6-membered cycloalkyl and 5- to 6-membered heteroaryl, wherein R p The C1-C6 alkyl, 3- to 6-membered cycloalkyl or 5- to 6-membered heteroaryl groups are optionally substituted by 1 to 3 groups selected from CN, OH and halogens; R 6 Each occurrence is independently selected from 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 , 4- to 6-membered heterocyclic groups and C1-C6 alkyl groups, wherein: R 6 The C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from halogens, -OR s =O, -S (=O) p R t -NHS(=O) p R t -S(=O)(=NH)R t , -NHS(=O) p (C1-C4 alkyl), -CN, -C(=O)NR t R o -NR t R o Halogen, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl (optionally substituted with 1 to 3 groups selected from halogen, OH and R) t ) and 4- to 10-membered heterocyclic groups (optionally substituted with 1 to 3 groups selected from halogens, OH and R) t ),in: R 6 The 4- to 8-membered heterocyclic group of the C1-C6 alkyl group is optionally substituted with 1 to 3 groups selected from halogens, OH, C1-C3 alkyl groups and =O; R s Selected from H, C1-C6 alkyl, 4- to 6-membered heterocyclic and 3- to 6-membered cycloalkyl, wherein: R s The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from -OH, -OMe, and halogens, and R s The 3- to 6-membered cycloalkyl group is optionally replaced by -OH or -OMe; R t and R o Each of the following groups is independently selected from H, C1-C6 alkyl, 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic, and 3- to 5-membered cycloalkyl, wherein R t and R o The C1-C6 alkyl group is optionally substituted with 1-3 groups selected from D, halogen, -OH, CN, C(=O)NH2, -O (C1-C3 alkyl) and -S(=O)2CH3; R 7 Each time it appears, it is independently selected from 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 ynyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl, wherein: R 7 The C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl groups are optionally substituted with one to three groups selected from halogens, -OH, CN, and -S (=O). p (C1-C4 alkyl), -C(=O)2NH2 and 3- to 6-membered heterocyclic groups, R 7 The 4- to 6-membered heterocyclic group is optionally substituted by 1 to 3 groups selected from O, halogens, and R. b , R a Selected from H, C1-C8 alkyl, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclic, phenyl, and 5- to 6-membered heteroaryl, wherein R a The C1-C8 alkyl group is optionally substituted with 1 to 4 groups selected from D, halogens, OH, CN, -S (=O). p (C1-C4 alkyl), -C(=O)NH2, 3- to 6-membered cycloalkyl, 4- to 6-membered heterocyclic and 5- to 6-membered heteroaryl R b and R c Each of the following groups, when appearing independently, is selected from H, C1-C8 alkyl, 4- to 6-membered heterocyclic, phenyl, 5- to 6-membered heteroaryl, and 3- to 6-membered cycloalkyl, wherein R b and R c The C1-C8 alkyl group is optionally substituted with 1 to 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; and p is an integer selected from 0, 1, and 2.

2. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein X1, X2, X3, and X4 are C.

3. The compound according to any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 2: 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.

4. The compound of any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 3-1, 3-2 or 3-3: 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.

5. The compound of any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 4: Z1, Z2, and Z3 are each independently selected from N and C.

6. The compound of any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 5: Z1, Z2, and Z3 are each independently selected from N, S, and C.

7. The compound of any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 6-1 or 6-2: Y3, Y4, and Y5 are each independently selected from N, S, O, and C, Y2 is selected from N and C, Z1, Z2, and Z3 in Equation 6-1 are each independently selected from N and C, and Z1, Z2, and Z3 in Equation 6-2 are each independently selected from N, S, and C.

8. The compound of any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 7-1 or 7-2: 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. Z1, Z2 and Z3 of Equation 7-1 are each independently selected from N and C, and Z1, Z2 and Z3 of Equation 7-2 are each independently selected from N, S and C.

9. The compound of any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 8-1, 8-2, 8-3, 8-4, 8-5 or 8-6: in: 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. In Equation 8-1, Y5 is selected from N, S, and C. Z1, Z2, and Z3 are each independently selected from N and C.

10. The compound of any one of claims 1-2, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing substances, wherein the compound has the following structural formula 9-1, 9-2, 9-3 or 9-4: in: 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; in Equation 9-1, Y5 is selected from S and C. Z1 and Z2 are each independently selected from N and S, Z3 is selected from N and C, and at least one of Z1, Z2 and Z3 is a heteroatom.

11. The compound of claim 1, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein the compound has the following structural formula 10⁻¹, 10⁻², 10⁻³, 10⁻⁴, 10⁻⁵, or 10⁻⁶: in: In formulas 10-1 to 10-5, 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; In 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.

12. The compound of claim 1, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein the compound has the following structural formula 11-1, 11-2, 11-3, 11-4, 11-5, 11-6 or 11-7: in: In Equations 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, 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 Equations 11-6 to 11-7, 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.

13. The compound of claim 1, its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein the compound has the following structural formula 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7 or 12-8: in: In Equations 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, 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 Equations 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.

14. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2, wherein: Selected from: Selected from: Selected from: 。 15. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 14, wherein... Selected from: in: R 8 Selected from: H, F, Cl, Me, CHF2, CF3, CN, SO2Me, SMe, CH2CF3, CH2SO2Me and R 9 Selected from: Me, CF3, CHF2, CH2CF3, acetyl (-C(=O)CH3), SO2Me, .

16. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein: Selected from: Selected from: and Selected from: T1, T2, and T3 are each independently selected from N and C.

17. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein ring A is selected from: Among them, ring A is R 1 R 2 R 3 R 4 and R 5 replace.

18. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2 and 17, wherein... Selected from: Where L is -NH- or -O-, q is 1, 2, or 3, and R p It is selected from C1-C4 alkyl, 3- to 6-membered cycloalkyl and 5- to 7-membered heteroaryl.

19. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 and 17, wherein... Selected from: 。 20. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2, 5-6, and 17-19, wherein ring B is selected from: Among them, ring B is R 6 The m groups are substituted.

21. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2, 5-6, and 17-19, wherein ring B is selected from: Among them, ring B is R 6 The m groups are substituted.

22. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-2, 5-6, and 17-21, wherein... Selected from: 。 23. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-4, 11, and 17-22, wherein ring C is selected from: Among them, ring C is R 7 The n groups are substituted.

24. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-4, 11, and 17-22, wherein... Selected from in: R 8 Each time it appears, it is independently selected from H, F, Cl, Me, CHF2, CF3, CN, SO2Me, SMe, CH2CF3, CH2SO2Me. and R 9 Each time it appears, it is independently selected from Me, CF3, CHF2, CH2CF3, acetyl, SO2Me, .

25. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-4, 11, and 17-23, wherein... Selected from: 。 26. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-18 and 20-25, wherein R 1 Selected from: H, Me, Cl, F, Br, OMe, CF3, OCF3, CHF2, SO2Me, CN, OH, CH2OH, COOH, CONH2 , where R 10 Each occurrence is independently selected from H, Me, Cl, F, CF3, and CN.

27. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-18 and 20-25, wherein R 1 Selected from: H, -CH3, -CF3, -CHF2, -OCF3, -C(CH3)2OH, Br, Cl, -S(=O)2CH3, -SF5, 。 28. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-18 and 20-25, wherein R 1 Selected from: Halogen, -C(=O)R f -OR f -NR f R g -SF5 C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from F, -CN, -OR) f , phenyl, -NR f R g and 5- to 6-membered heteroaryl), C1-C6 alkenyl groups (optionally substituted with 1 to 3 groups selected from F, -CN, -OR) f , phenyl, -NR f R g and 5- to 6-membered heteroaryl), 3- to 6-membered cycloalkyl groups (optionally substituted with 1-2 groups selected from D, halogens, -CN, R) f -OR f CH2OR f -C(=O)NR f R g and 5- to 6-membered heteroaryl), 4- to 8-membered heterocyclic groups (optionally substituted by 1-2 groups selected from R) f -OR f , halogens and -CN), and 5- to 6-membered heteroaryl (optionally substituted by 1-2 groups selected from R) f -OR f , halogens and -CN), in: R f and R g Each of the groups is independently selected from H, 5- to 6-membered heteroaryl, 3- to 6-membered cycloalkyl and C1-C3 alkyl (optionally substituted by 1 to 3 groups selected from D, halogen, -OH, -OCH3, -C(=O)NH2 and -CN).

29. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-18 and 20-28, wherein R 1 Selected from: CF3, F, Cl, C1-C3 alkyl and C3-C5 cycloalkyl.

30. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17 and 20-29, wherein R 2 Selected from: H, Me, Cl, F, Br, -OMe, CF3, -CN, -CONH2, -SO2Me, -S(=O)CH3, -SCH3 。 31. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17 and 20-30, wherein R 2 Selected from: -CH3, -S(=O)CH3, -SCH3, -CN and -S(=O)2CH3.

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

33. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17 and 20-31, wherein R 3 and R 4 Each is independently selected from H, Me, Cl, F, Br, OMe, CF3 and .

34. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17 and 20-33, wherein R 4 Selected from F and Cl.

35. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-13, 17, and 20-34, wherein R 5 Selected from: -CN and -CH2OH.

36. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17 and 20-34, wherein R 5 Selected from: Nonexistent, H, -CN, -CH2OH 。 37. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17 and 20-34, wherein R 5 Selected from: None, H, CN, halogen, -S(=O)2CH3, -CH2S(=O)2CH3, 3- to 4-membered cycloalkyl, 5- to 6-membered heterocyclic, 5- to 6-membered heteroaryl, CH2OH and CH2CH2OH.

38. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-21 and 23-37, wherein R 6 Selected from: Where R t and R o Each is independently selected from H and C1-C6 alkyl groups, wherein R t and R o The C1-C6 alkyl group is optionally replaced by 1-3 groups selected from halogens.

39. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-21 and 23-37, wherein R 6 Selected from: -CN, =O, -CH3, -CH2S(=O)2CH3, -CH2OH, -CH2CH2OH, -C(=O)NH2, -O(CH2)2OH, -OCH3, -SH, -SCH3, 。 40. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-21 and 23-37, wherein R 6 Selected from 。 41. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-21 and 23-37, wherein R 6 Selected from D, halogens, -S(=O)2R h -NR h R i -C(=O)NR h R i and C1-C4 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens, -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 , , 5- to 6-membered heteroaryl, 3- to 5-membered cycloalkyl (optionally substituted with 1 to 3 groups selected from halogens and R) h ) and optionally 1 to 3 selected from halogens and R h (3- to 8-membered heterocyclic groups substituted with radicals), in: R h and R i Each of the groups is independently selected from H, C1-C3 alkyl (optionally substituted by 1 to 3 groups selected from halogens, -OH, -O (C1-C3 alkyl) and -S (=O)2CH3) and 3- to 5-membered cycloalkyl.

42. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-14, 16-23, and 26-41, wherein R 7 Selected from F, Cl, Me, CHF2, CF3, CN, -SO2Me, -SMe, CH2CF3, CH2SO2Me, acetyl And n is 0, 1, 2 or 3.

43. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-14, 16-23, and 26-42, wherein R 7 Selected from: Cl, F, -CF3, -OCF3, -CN, -S(=O)2CH3, -CH3, -OCH3 and -OH.

44. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-14, 16-23, and 26-41, wherein R 7 Selected from: 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- to 5-membered cycloalkyl, 5- to 6-membered heteroaryl, C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens, -OH, -S(=O)2CH3, and 4- to 6-membered heterocyclic groups) and 4- to 6-membered heterocyclic groups (optionally substituted with 1 to 2 groups selected from =O and R) k ), in: R j and R k Each time it appears, it is independently selected from H, C1-C6 alkyl (optionally substituted by 1 to 3 groups selected from halogens, OH, -C(=O)NH2 and -S(=O)2CH3), 4- to 6-membered heterocyclic groups and 3- to 5-membered cycloalkyl groups.

45. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17, 20-21, and 23, wherein: R 1 Selected from R 2 Selected from H, CN and S(=O)2CH3, R 3 R 4 and R 5 It's H. R 6 Selected from =O, CH3, Cl, -C(=O)NH2, -CH2CH2OH, -CH2OH and -CH2S(=O)2CH3, where m is 0, 1 or 2. R 7 The components are selected from CH3, Cl, F, CN, OCH3, and OH, and n is 0, 1, 2, or 3.

46. ​​The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-17, 20-21, and 23, wherein: R 1 Selected from C1-C6 alkyl groups (optionally substituted with 1 to 3 groups selected from halogens, -OH, CN, -OCH3, -NR) d R e phenyl, 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S and 6-membered heteroaryl containing 1 to 3 nitrogen atoms, C2-C4 alkenyl (optionally substituted with 1 to 3 groups selected from halogen, -OH, -CN and -OCH3), -OR d -NR d R e , -S(=O) p CH3, -SF5, halogen, -C(=O)CH3 A 5-membered heteroaryl group containing 1 to 2 heteroatoms selected from N and S (optionally substituted by 1 to 2 groups selected from C1-C3 alkyl groups) and a 6-membered heteroaryl group containing 1 to 2 nitrogen atoms (optionally substituted by 1 to 2 groups selected from C1-C3 alkyl groups); R 2 Selected from H, CN, CH3, F and S(=O)2CH3; R 3 It is H; R 4 Selected from F, Cl and H; R 5 The group is selected from the absence of, H, F, -CN, -C(=O)NH2, 3- to 4-membered cycloalkyl (optionally substituted with 1 to 3 groups selected from CN and halogens), C1-C4 alkyl (optionally substituted with 1 to 3 groups selected from halogens, -S(=O)2CH3 and -OH), 5- to 6-membered heterocyclic groups, -S(=O)2CH3, 5-membered heteroaryl containing 1 to 3 heteroatoms selected from N and O and 6-membered heteroaryl containing 1 to 3 nitrogen atoms; R 6 Selected from absent, D, C1-C4 alkyl (optionally substituted with 1-3 groups selected from halogens, -S(=O)CH3, -S(=O)2CH3, -C(=O)NHCH3, -OH, -C(=O)NH2, -NR d R e -NR d OR e and -NHS(=O)2CH3), =O, Cl and -C(=O)NH2; R 7 Selected from 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 C1-C6 (optionally substituted with 1-3 groups selected from halogens, -OH, -S(=O)2CH3, -C(=O)2NH2 and 3- to 6-membered heterocyclic groups), 5- to 6-membered heteroaryl, 3- to 5-membered cycloalkyl and 4- to 6-membered heterocyclic groups (optionally substituted with 1 to 3 groups selected from =O and C1-C3 alkyl groups); in: R d and R e Each of the groups is independently selected from H, C1-C4 alkyl (optionally substituted by 1 to 3 groups selected from D, halogen, -OH, CN, -C(=O)NH2, -S(=O)2CH3 and -OCH3), 5- to 6-membered heteroaryl, 4- to 6-membered heterocyclic and 3- to 5-membered cycloalkyl; q is 0, 1, 2, or 3; U1 and U2 are independently selected from O and C.

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

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, or a pharmaceutically acceptable salt of the foregoing substances, and at least one pharmaceutically acceptable carrier.

49. A method of treating a disease or condition, comprising administering to a subject in need 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 of the aforementioned substances, 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 of treating a disease or condition associated with axonal degeneration, comprising administering to a subject in need 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 of the aforementioned substances, or a pharmaceutical composition according to claim 48.

51. A method for regulating SARM1, comprising contacting the object to which this is desired 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, or a pharmaceutically acceptable salt of the aforementioned substances, or a pharmaceutical composition according to claim 48.

52. A method for inhibiting or preventing axonal degeneration, comprising contacting the object in need 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, or a pharmaceutically acceptable salt of the aforementioned substances, or a pharmaceutical composition according to claim 48.

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