SARM1 modulators, preparation and use thereof

Abstract

The present disclosure provides compounds of Formula 1, compositions comprising the same, and methods of using the same, including use in modulating SARM1 and treating various diseases and disorders, such as those caused by axial degeneration. # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to International Application No. PCT / CN2022 / 097337 filed on June 7, 2022 and International Application No. PCT / CN2023 / 083360 filed on March 23, 2023. The contents of both applications are incorporated herein by reference in their entirety.

[0003] Public domain

[0004] The present disclosure relates to compounds that modulate SARM1, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds to treat various diseases or disorders, such as those caused by axonal degeneration.

[0005] Public background

[0006] Axon degeneration leads to disease progression and defect accumulation 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 Allow Recovery of a Metastable Pool of Axons Fated to Degenerate, Cell Rep. 2021 Jan 5; 34 (1): 108588.); Bosanac 2021 (T. Bosanac et al., Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy, Brain, Vol. 144, Issue 10, 2021, pp. 3226-3238)). Therefore, axonal protection is an important neuroprotective approach for the treatment of chronic and acute CNS and PNS neurodegenerative disorders (Hughes 2021; Bosanac 2021).

[0007] SARM1 (sterile alpha and TIR motif-containing 1) is a unique member of the Myd88 adaptor protein family and is considered a major driver of an evolutionarily conserved program of axon degeneration downstream of chemical, inflammatory, mechanical, or metabolic insults to axons. (Hughes 2021; Bosanac 2021). SARM1 has been implicated as a central mediator of axonal degeneration in many diseases or conditions, including ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, and diabetic neuropathy, as well as chemotherapy-induced peripheral neuropathy (CIPN), a major cause of morbidity and a leading cause of dose reduction and cessation of cancer therapy. (Hughes 2021; Bosanac 2021). SARM1 is an attractive target for the treatment of neurodegenerative diseases characterized by axonal lesions in the peripheral and central nervous system.

[0008] SARM1 contains a mitochondrial targeting sequence, an N-terminal domain with an armadillo repeat motif (ARM), two sterile α-motif (SAM) domains and a Toll / interleukin-1 receptor (TIR) ​​domain (Gerdts 2013 (J. Gerdts et al., Sarm1-mediated axon degeneration requires both SAM and TIR interactions. J Neurosci. 2013 Aug 14; 33 (33): 13569-80.)). The SARM1 TIR domain is a NAD+ hydrolase (NADase) that converts 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 NADase activity is essential for its axonal degeneration function. (Bosanac 2021). The activity of SARM1 also depends on oligomerization through the SAM domain (Sporny 2019) and autoinhibition through the ARM domain (Chen (2021) (C. Shen et al., Multiple domain interfaces mediate SARM1 autoinhibition. Proc Natl Acad Sci US A. 2021 Jan 26; 118 (4).)).

[0009] 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, WO2020 / 081923A1, WO 2021 / 142006 Al, WO2021207302A1 and WO2021207308A1 disclose certain SARM1 inhibitors. US2005 / 0272765 Al discloses certain dipeptidyl peptidase inhibitors (such as biphenyl or phenylbenzimidazole derivatives). WO 2008 / 148449 Al discloses certain benzylbenzoxazole derivatives as Met-kinase inhibitors. WO 01 / 14879 describes certain dihydroisoquinolinone derivatives and combinatorial libraries thereof. WO 2017 / 049409 describes certain compositions for promoting premature stop codon read-through and methods of use thereof. CN 108276352 describes certain nitrogen-containing heterocyclic compounds with nematicidal properties and methods of preparation and use thereof.

[0010] The present disclosure describes SARM1 inhibitors that can be used to prevent axonal degeneration in peripheral and central axonopathies and provide transformational disease-modifying treatments for related diseases or disorders.

[0011] Public Overview

[0012] One aspect of the present disclosure provides a compound, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, which can be used to treat various diseases or conditions, such as diseases or conditions caused by axonal degeneration, wherein the compound is selected from Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 1 6-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 3 0-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3 , 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391). For example, disclosed herein is a compound having the following structural formula 1:

[0013]

[0014] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein:

[0015] Ring A is phenyl, a 5- to 10-membered heteroaryl ring, a 5- to 10-membered carbocyclic ring, or a 5- to 10-membered heterocyclic ring;

[0016] Ring B is phenyl, a 9- to 11-membered aryl ring, a 9- to 11-membered heteroaryl ring, or a 9- to 11-membered heterocyclic ring;

[0017] R a is selected from =O, C3-C6 cycloalkyl, -O(C1-C4 alkyl), COOH, CN, CONH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -C(=O)O(C1-C4 alkyl), halogen and C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, -OH, cyclopropyl, oxetanyl and azetidine;

[0018] R b is selected from the group consisting of =O, OH, halogen, CN, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C5-C6 heteroaryl, -O(C1-C4 alkyl), -C(=O)(C1-C4 alkyl), -C(=O)(optionally substituted C3-C6 cycloalkyl), -C(=O)(optionally substituted 5- to 6-membered heterocyclyl), -C(=O)(optionally substituted 5- to 6-membered heteroaryl), -C(=O)(CH2)pC(=O)NH2, -NHC(=O)(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -C(=O)NH(CH2)pOH, -S(=O)2NH2,

[0019] C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, NH2, OH, OCH3, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -COOH, -C(=O)NH2, CN, C3-C5 cycloalkyl, phenyl, -C(=O)(C1-C4 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(5- to 6-membered heterocyclyl), -C(=O)(optionally substituted 5- to 6-membered heteroaryl), C(=O)NH(CH2)pOH, and 5- to 6-membered heteroaryl,

[0020] 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C3 alkyl, =O, -NH2, -CN, -CONH2, halogen, and

[0021] 4 to 6 membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O, -OH, -NH2, -CN, -CONH2, halogen and C1-C3 alkyl, or

[0022] Two R connected to the same position of ring B b Together they form a C3-C6 cycloalkyl group,

[0023] wherein R4 and R5 are each independently selected from H and C1-C3 alkyl or R4 and R5 together form a 3 to 5 membered cycloalkyl;

[0024] L is selected from in

[0025] R1 is H, D or C1-C6 alkyl, and R2 is selected from CN, C1-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, 5- or 6-membered heteroaryl,

[0026] Phenyl, which is optionally substituted by 1-3 groups selected from the group consisting of C1-C4 alkyl and

[0027] Halogens, and

[0028] C1-C6 alkyl, which is optionally substituted by 1-3 groups selected from the group consisting of halogen, OH, CN, -SO2CH3, -NHSO2CH3, -CONH2, OCH3 and phenyl, or

[0029] R1 and R2 together form a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group;

[0030] R3 is C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the group consisting of halogen, O(C1-C3 alkyl), OH and NH2;

[0031] m is an integer selected from 0, 1, 2, 3 and 4;

[0032] n is an integer selected from 0, 1, 2, 3 and 4, and

[0033] p is an integer selected from 1, 2, 3 and 4.

[0034] Provided that the compound is not any of Compound 1A to Compound 121A.

[0035] In one aspect of the present disclosure, the compound of formula disclosed herein is selected from compounds 1 to 391 as shown in the following table, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0036] In some embodiments, the disclosure provides pharmaceutical compositions comprising an amine, amine-containing compound of formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14h-1, 14h-2, 14h-3, 14h-4, 14h-5, 14h-6, 14h-7, 14h-8, 14h-9, 14h-10, 14h-11, 14h-12, 14h-13, 14h-14 h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27 ,28-1,28-2,29-1,29-2,29-3,30-1,30-2,30-3,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32-4,32-5,33-1,33-2,33 -3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43 -2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. In some embodiments, the pharmaceutical composition may include a compound selected from compounds 1 to 391 and compounds 1A to 121A as shown below, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. These compositions may also contain additional active agents.

[0037] Another aspect of the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2, 16-1b, 16-3, 16-4, 16-5, 16-6, 16-7, 16-8, 16-9, 16-10, 16-11, 16-12, 16-13, 16-14 6-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32 -1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37 -5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their interconversions isomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, wherein the disease or condition is selected from 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 diseases of the PNS including hereditary neuropathies such as, but not limited to, Charcot-Marie-Tooth disease 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 various drug-induced peripheral neuropathy (such as CIPN).

[0038] Another aspect of the present disclosure provides a method of treating a disease or condition caused by SARM1-mediated axonal degeneration or neuronal damage, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14f, 14g, 14h, 14i, 14i, 14j, 14k, 14l, 14i, 14i, 14j, 14i ... 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 2 4, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 3 3-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.

[0039] In some embodiments, the method of treatment comprises administering to a subject in need thereof a compound selected from Compounds 1 to 391 and Compounds 1A to 121A as 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 one of the compound, tautomer, solvate, stereoisomer and pharmaceutically acceptable salt.

[0040] In some embodiments, the method of treatment comprises administering to a subject in need thereof an additional active agent which may be administered in combination with an active pharmaceutical ingredient of Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g disclosed herein , 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25 ,26,27,28-1,28-2,29-1,29-2,29-3,30-1,30-2,30-3,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32-4,32-5,33-1,33-2 , 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2 , 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing are in the same pharmaceutical composition, or in separate compositions. In some embodiments, the method of treatment comprises administering a compound selected from Compounds 1 to 391 and Compounds 1A to 121A as shown below, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt thereof with another active agent in the same pharmaceutical composition or in a separate composition. When administered as a separate composition, the additional therapeutic agent may be administered before, simultaneously with, or after the administration of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt disclosed herein.

[0041] Also disclosed herein are methods of modulating (e.g., inhibiting) SARM1 in a subject in need thereof, comprising contacting the subject with an agent of Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1 disclosed herein , 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28- 1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34 -2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts. In some embodiments, the method of modulating (e.g., inhibiting) SARM1 in a subject in need thereof comprises contacting the subject with a compound selected from Compounds 1 to 391 and Compounds 1A to 121A as shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts.

[0042] Also disclosed herein are methods of inhibiting or preventing axonal degeneration in a subject in need thereof, comprising contacting the subject with a drug of Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14h-1, 14h-2, 14h-3, 14h-4, 14h-5, 14h-6, 14h-7, 14h-8, 14h-9, 14h-10, 14h-11, 14h-12, 14h-13, 14h-14 h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2 , 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3 4-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.In some embodiments, the method of inhibiting or preventing axonal degeneration or neuronal damage mediated by SARM1 in a subject in need thereof comprises contacting the subject with a compound selected from Compounds 1 to 391 and Compounds 1A to 121A as shown below, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts. DETAILED DESCRIPTION

[0043] definition

[0044] The terms "a" or "an" when referring to a noun used herein encompass the expression "at least one," thus encompassing both the singular and plural members of the noun. For example, "an additional agent" means a single or two or more additional agents.

[0045] The term "alkyl" refers to a hydrocarbon group selected from straight and branched saturated hydrocarbon groups containing 1-20, such as 1-18, 1-12, 1-10, 1-8, 1-6, 1-4 or 1-3 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. Lower alkyl groups contain 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms.

[0046] The term "alkenyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C=C double bond and 2-20, such as 2-18, 2-12, 2-10, 2-8, 2-6 or 2-4 carbon atoms. Examples of alkenyl 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-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl. Lower alkenyl contains 2-8, preferably 2-6, and more preferably 2-4 carbon atoms.

[0047] The term "alkynyl" refers to a hydrocarbon group selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and 2-20, such as 2-18, 2-12, 2-10, 2-8, 2-6 or 2-4 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl and 3-butynyl. Lower alkynyl groups contain 2-8, preferably 2-6, and more preferably 2-4 carbon atoms.

[0048] The term "heteroalkyl" refers to an alkyl group as defined herein in which one or more constituent carbon atoms have been replaced by a heteroatom such as nitrogen, oxygen or sulfur, for example, CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5, etc. In some embodiments, the heteroalkyl group is optionally substituted as defined herein in addition to replacement of one or more constituent carbon atoms with nitrogen, oxygen or sulfur.

[0049] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, such as monocycles and polycyclic (such as bicyclic and tricyclic) groups. For example, cycloalkyl can have 3-12, 3-10, 3-8, 3-6, 3-4 or 5-6 carbon atoms. Even further, for example, cycloalkyl can be a monocyclic group with 3-12, 3-8, 3-6, 3-4 or 5-6 carbon atoms. The example of monocyclic cycloalkyl includes 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. Examples of bicyclic cycloalkyls include those having 7-12 ring atoms 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 arrangement selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated), but is not fully conjugated and is not an aromatic ring, as "aromatic ring" is defined herein.

[0050] The term "heterocyclic" or "heterocycle" or "heterocyclyl" refers to 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, e.g., oxygen, sulfur, nitrogen and silicon. "Heterocyclic" also refers to a 5 to 7 membered heterocyclic ring 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 heterocyclic ring is fused to the carbocyclic aromatic or heteroaromatic ring, the point of attachment is at the heterocyclic ring, and when the heterocyclic ring is fused to a cycloalkyl ring, the point of attachment may be at the cycloalkyl ring or the heterocyclic ring.

[0051] "Heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O and S, provided that the point of attachment is at the heterocycle. The ring may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle may be oxo-substituted. The point of attachment may be a carbon or heteroatom in the heterocycle. The heterocycle is not a heteroaryl as defined herein.

[0052] Examples of heterocycles include, but are not limited to (numbering from the designated preferred attachment position 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, aziridine, thiol, azetidinyl, oxetanyl, thietane 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thiooxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathietanyl, 1,4-dioxepanyl, 1,4-oxathietanyl, 1,4-oxazepanyl, 1,4-dithietanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-oxathianyl, oxazepine, diazepine, thiazepine, dihydrothiophenyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl In some embodiments, the substituted heterocycles include 1,4-dioxane, 1,3-dioxolane, ...

[0053] The term "fused ring" as used herein refers to a polycyclic ring system, such as a bicyclic or tricyclic ring system, in which the two rings share only two ring atoms and one bond in common. Examples of fused rings may include fused bicyclic cycloalkyl rings, such as those having 7 to 12 ring atoms in a bicyclic arrangement selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems as described above; fused bicyclic aromatic rings, such as 7 to 12 membered bicyclic aromatic ring systems as described above, fused tricyclic aromatic rings, such as 10 to 15 membered tricyclic aromatic ring systems as described above; fused bicyclic heteroaromatic rings, such as 8 to 12 membered bicyclic heteroaromatic rings as described above, fused tricyclic heteroaromatic rings, such as 11 to 14 membered tricyclic heteroaromatic rings as described above; and fused bicyclic or tricyclic heterocyclic rings as described above.

[0054] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus and silicon, including any oxidized form of nitrogen or sulfur; any basic nitrogen or quaternized form of a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (wherein R is, for example, optionally substituted alkyl) (as in N-substituted pyrrolidinyl).

[0055] As used herein, the term "unsaturated" refers to a group having one or more unsaturated units or degrees of unsaturation. Unsaturation is a condition in which not all available valence bonds in a compound are satisfied by substituents, so the compound contains one or more double or triple bonds. Double bonds can be represented by (Two solid lines). The narrative used in this paper (one solid line and one dashed line) represent bonds that can be double or single bonds.

[0056] The term "alkoxy" as used herein refers to an alkyl group as defined above wherein one of the carbons of the alkyl group is replaced by an oxygen atom, provided that the oxygen atom is attached between two carbon atoms.

[0057] The term "halogen" includes F, Cl, Br and I, ie fluorine, chlorine, bromine and iodine, respectively.

[0058] As used herein, a "CN," "cyano," or "nitrile" group refers to C=N.

[0059] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system having a delocalized π electron orbital consisting of [4n+2]p orbital electrons, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring, and may be fully or partially saturated. Non-limiting examples of aromatic rings include aromatic rings and heteroaromatic rings, which are further defined below. An "aromatic ring" may be described as a ring having conjugated double bonds, such as or described as a ring with an inner ring, e.g.

[0060] The term "aryl" as used herein refers to a group selected from: a monocyclic carbocyclic aromatic ring, such as phenyl; a bicyclic ring system, such as a 7-12 membered, such as a 9-10 membered bicyclic ring system, wherein at least one ring is carbocyclic and aromatic, selected from, for example, naphthalene, indane and 1,2,3,4-tetrahydroquinoline; and a tricyclic ring system, such as a 10-15 membered tricyclic ring system, wherein at least one ring is carbocyclic and aromatic, such as fluorene.

[0061] For example, the aryl group can be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycle optionally containing at least one heteroatom selected from N, O and S, provided that when the carbocyclic aromatic ring is fused to the heterocycle, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to the cycloalkyl, the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl. Divalent groups formed by substituted benzene derivatives and having free valences on ring atoms are called substituted phenylene groups. Divalent groups derived from monovalent polycyclic hydrocarbon groups (whose names end with "-yl" by removing a hydrogen atom from a carbon atom having a free valence) are named by adding "-subunit" to the name of the corresponding monovalent group, for example, naphthyl with two points of attachment is called naphthylene.

[0062] The term "heteroaryl" refers to a group selected from the following: a 5- to 7-membered, e.g. 5- to 6-membered aromatic monocyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon; an 8- to 12-membered bicyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; and an 11- to 14-membered tricyclic ring comprising 1, 2, 3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0063] For example, the 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 heteroaromatic 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.

[0064] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1.

[0065] Examples of heteroaryl groups include, but are not limited to (numbering from the designated preferred attachment position 1), pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4

[0013] In some embodiments, the present invention includes 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinolinyl.

[0066] The term "acyl" refers to a substituent wherein the point of attachment in the substituent is a carbonyl. Exemplary acyl groups include, but are not limited to, -C(=O)R', -C(=O)NR'R" or -C(=O)OR', wherein R' and R" are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, any of which may be further substituted with one or more substituents.

[0067] Some compounds may exist with different points of hydrogen attachment, known as "tautomers." For example, a compound containing a carbonyl CH2C(O)- group (keto form) may tautomerize to form a hydroxyl -CH=C(OH)- group (enol form). Keto and enol forms, both individually and in mixtures thereof, are also intended to be included, where applicable.

[0068] The compounds, tautomers, solvates or pharmaceutically acceptable salts of the present disclosure may contain asymmetric centers and therefore may exist as enantiomers. For example, when a compound has two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a wider class of stereoisomers. All these possible stereoisomers, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers are intended to be included in the present disclosure. All stereoisomers of compounds, tautomers, solvates and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, a reference to an isomer is applicable to any possible isomer. When the isomer composition is not clear, all possible isomers are included.

[0069] Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) each diastereomer to the corresponding pure enantiomer. Enantiomers can also be separated by using a chiral HPLC column.

[0070] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolving racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents. Racemic mixtures of chiral compounds of the disclosure can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts using chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds using chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions.

[0071] In the context of stereoisomers, the term "substantially pure" means that the target stereoisomer contains no more than 35%, 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 by weight. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10%, such as no more than 5%, such as no more than 1% of any other stereoisomer by weight.

[0072] Unless otherwise stated, structures described herein are intended to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, geometric and conformational mixtures of the compounds disclosed herein are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0073] The present disclosure provides pharmaceutically acceptable salts of disclosed compounds, tautomers, solvates and stereoisomers. Salts of compounds are formed between acids and basic groups (e.g., amino functional groups) of compounds, or between bases and acidic groups (e.g., carboxyl functional groups) of compounds.

[0074] The term "pharmaceutically acceptable" as used herein refers to compositions that are suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and are commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salt" refers to any non-toxic salt that is capable of providing, directly or indirectly, a compound of the present disclosure upon administration to a recipient.

[0075] "Pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids, selected from, for example, hydrochlorides, phosphates, diphosphates, hydrobromides, sulfates, sulfites / sulfinates and nitrates; and salts formed with organic acids, selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoates such as acetate, and salts formed with HOOC-(CH2)n-COOH, wherein n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, magnesium, aluminum, lithium and ammonium. Suitable pharmaceutically acceptable salts are, for example, those disclosed in SM Berge et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.

[0076] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogenbisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, and 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-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, succinates ... Pharmaceutically acceptable acid addition salts include salts such as 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, etc. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with inorganic acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0077] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N+(C 1-4 The present disclosure also contemplates the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, and magnesium salts. Other non-limiting examples of pharmaceutically acceptable salts include salts of ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include benzenesulfonates and glucosamine salts.

[0078] If the compound is obtained in the form of an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional methods for preparing acid addition salts from base compounds. Those skilled in the art will recognize a variety of synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0079] The compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, -CD3, -CD2H or -CDH2 contains one or more deuterium in place of hydrogen. For example, the compounds may be substituted with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or carbon 14 ( 14 C) Radiolabeled. All isotopic variations of the disclosed compounds, whether radioactive or not, are intended to be encompassed within the scope of the disclosure.

[0080] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise specified, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position.

[0081] Combinations of chemical components, such as substituents, ring structures, linkers, and / or heteroatoms, envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0082] In some embodiments, the substituents are independently selected from optionally substituted heteroatoms and optionally substituted, optionally hybridized, optionally cyclic C1-C 18 Hydrocarbyl, in particular optionally substituted, optionally hybridized, optionally cyclic C1-C 18The hydrocarbon group is an optionally substituted, optionally heterocyclic alkyl, alkenyl or alkynyl group, or an optionally substituted, optionally heterocyclic aryl group; and / or the optionally substituted heteroatom is a halogen, an optionally substituted hydroxyl group (e.g., alkoxy, aryloxy), an optionally substituted acyl group (e.g., formyl, alkanoyl, carbamoyl, carboxyl, amide), an optionally substituted amino group (e.g., amino, alkylamino, dialkylamino, amide, sulfonamide), an optionally substituted thiol group (e.g., mercapto, alkylthiol, arylthiol), an optionally substituted sulfinyl or sulfonyl group (e.g., alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl), a nitro group or a cyano group.

[0083] In some embodiments, the substituents are independently selected from halogen, -R', -OR', =O, =NR', =N-OR', -NR'R", -SR', -SiR'R"R'", -OC(=O)R', -C(=O)R', -C02R', -C(=O)NR'R", -OC(=O)NR'R", -NR"C(=O)R', -NR'-C(=O)NR"R'", -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -SO2R', -SO2NR' R", -NR"SO2R, -CN, -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy and perfluoro(C1-C4)alkyl, the number is 0 to 3, among which those groups with 0, 1 or 2 substituents are particularly preferred. R', R" and R'" each independently represent hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted by 1-3 halogens, unsubstituted aryl, aryl substituted by 1-3 halogens, unsubstituted alkyl, alkoxy, or thioalkoxy, or aryl-(C1-C4)alkyl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6- or 7-membered ring. Thus, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. When aryl is 1,2,3,4-tetrahydronaphthyl, it may be substituted with a substituted or unsubstituted C3-C7 spirocycloalkyl. The C3-C7 spirocycloalkyl may be substituted in the same manner as defined herein for "cycloalkyl".

[0084] In some embodiments, the substituents are selected from halogen, -R', -OR', =O, -NR'R", -SR', -SiR'R"R'", -OC(=O)R', -C(=O)R', -C02R', -C(=O)NR'R", -OC(=O)NR'R", -NR"C(=O)R', -NR"C02R', -NR'-SO2NR"R'", -S(=O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN, -NO2, perfluoroC1-C4 alkoxy, and perfluoroC1-C4 alkyl, wherein R' and R" are as defined above.

[0085] In some embodiments, the substituents are independently selected from substituted or unsubstituted heteroatoms, substituted or unsubstituted C1-C6 alkyl containing 0-3 heteroatoms (e.g., C1-C3 alkyl or C1-C2 alkyl), substituted or unsubstituted C2-C6 alkenyl containing 0-3 heteroatoms (e.g., C2-C4 alkenyl), substituted or unsubstituted C2-C6 alkynyl containing 0-3 heteroatoms (e.g., C2-C4 alkynyl), or substituted or unsubstituted C6-C6 alkynyl containing 0-3 heteroatoms. 14 Aryl (eg, C5-C6 aryl), wherein each heteroatom is independently oxygen, phosphorus, sulfur or nitrogen.

[0086] In some embodiments, the substituents are independently selected from aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkoxy, alkyl, alkenyl, alkynyl, amine, azo, halogen, carbamoyl, carbonyl, carboxyl, cyano, ester, haloformyl, hydroperoxy, hydroxyl, imine, isocyanide, isocyanate, N-tert-butoxycarbonyl, nitrate, nitrile, nitrite, nitro, nitroso, phosphate, phosphonyl, sulfide, sulfonyl, sulfo, mercapto, thiol, thiocyano, trifluoromethyl and trifluoromethyl ether (OCF3) groups.

[0087] Preferred substituents are disclosed herein and exemplified in the tables, structures, examples and claims, and can be applied to different compounds of the present disclosure. For example, substituents of a given compound can be used in combination with other compounds.

[0088] 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 separated) to the desired homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve a variety of methods, including, for example, reverse phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography (chromatography) methods and apparatus; small-scale analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art can apply such techniques to achieve the desired separation.

[0089] Non-limiting examples of suitable bases that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropanol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0090] Non-limiting examples of suitable solvents that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropylethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0091] The term "subject" refers to animals including humans.

[0092] The term "therapeutically effective amount" refers to the amount of the compound that produces the desired effect of the administration (e.g., improving the disease or condition, reducing the severity of the disease or condition, and / or slowing the progression of the disease or condition, such as ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN). The disease or condition may be caused by axonal degeneration. The exact amount of the therapeutically effective amount will depend on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0093] As used herein, the term "treat" and its cognates refer to slowing or stopping the progression of a disease. "Treatment" and its cognates as used herein include, but are not limited to, the following: complete or partial relief, cure of a disease or condition or its symptoms, reduction of 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 may be caused by axonal degeneration. The improvement or reduction of the severity of any of these symptoms can be assessed according to methods and techniques known in the art.

[0094] When used in conjunction with a number such as a percentage, the terms "about" and "approximately" include the specified number and ranges of numbers (eg, percentage ranges, such as a range of ±10% relative to a particular point value) as recognized by one of ordinary skill in the art.

[0095] II. Compounds and Compositions

[0096] In the first embodiment, the compound of the present disclosure is a compound of the following structural formula 1:

[0097]

[0098] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein:

[0099] Ring A is phenyl, a 5- to 10-membered heteroaryl ring, a 5- to 10-membered carbocyclic ring, or a 5- to 10-membered heterocyclic ring;

[0100] Ring B is phenyl, a 9- to 11-membered aryl ring, a 9- to 11-membered heteroaryl ring, or a 9- to 11-membered heterocyclic ring;

[0101] R ais selected from =O, C3-C6 cycloalkyl, -O(C1-C4 alkyl), COOH, CN, CONH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -C(=O)O(C1-C4 alkyl), halogen and C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, -OH, cyclopropyl, oxetanyl and azetidine;

[0102] R b is selected from the group consisting of =O, OH, halogen, CN, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C5-C6 heteroaryl, -O(C1-C4 alkyl), -C(=O)(C1-C4 alkyl), -C(=O)(optionally substituted C3-C6 cycloalkyl), -C(=O)(optionally substituted 5- to 6-membered heterocyclyl), -C(=O)(optionally substituted 5- to 6-membered heteroaryl), -C(=O)(CH2)pC(=O)NH2, -NHC(=O)(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -C(=O)NH(CH2)pOH, -S(=O)2NH2,

[0103] C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, NH2, OH, OCH3, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -COOH, -C(=O)NH2, CN, C3-C5 cycloalkyl, phenyl, -C(=O)(C1-C4 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(5- to 6-membered heterocyclyl), -C(=O)(optionally substituted 5- to 6-membered heteroaryl), C(=O)NH(CH2)pOH, and 5- to 6-membered heteroaryl,

[0104] 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C3 alkyl, =O, -NH2, -CN, -CONH2, halogen, and

[0105] 4 to 6 membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O, -OH, -NH2, -CN, -CONH2, halogen and C1-C3 alkyl, or

[0106] Two R connected to the same position of ring B b Together they form a C3-C6 cycloalkyl group,

[0107] wherein R4 and R5 are each independently selected from H and C1-C3 alkyl or R4 and R5 together form a 3 to 5 membered cycloalkyl;

[0108] L is selected from in

[0109] R1 is H, D or C1-C6 alkyl, and R2 is selected from CN, C1-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, 5- or 6-membered heteroaryl,

[0110] Phenyl, which is optionally substituted by 1-3 groups selected from the group consisting of C1-C4 alkyl and

[0111] Halogens, and

[0112] C1-C6 alkyl, which is optionally substituted by 1-3 groups selected from halogen, OH, and phenyl, or

[0113] R1 and R2 together form a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group;

[0114] R3 is C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the group consisting of halogen, O(C1-C3 alkyl), OH and NH2;

[0115] m is an integer selected from 0, 1, 2, 3 and 4;

[0116] n is an integer selected from 0, 1, 2, 3 and 4, and

[0117] p is an integer selected from 1, 2, 3 and 4.

[0118] The combination of substituents disclosed herein is those that result in the formation of stable or chemically feasible compounds. For abbreviation or according to convention, some hydrogen atoms connected to a particular atom (e.g., a carbon atom C or a nitrogen atom N) are not specifically described in a chemical structure, formula or symbol; Hydrogen atoms are considered to be present to the extent that the valence of a particular atom (e.g., C or N) is complete.

[0119] In some embodiments, the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure is not any of Compounds 1A to 121A.

[0120] In one embodiment, in a compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the present disclosure, ring A is phenyl, pyridyl, a 5-membered heteroaryl ring including 1 or 2 heteroatoms selected from O, S and N, or a 6- to 10-membered heterocyclic ring including 1 or 2 heteroatoms selected from N and O; and all other variants not specifically defined herein are as defined in the preceding embodiments.

[0121] In one embodiment, in a compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, Ring B is phenyl, a 9- to 11-membered aryl, a 9- to 11-membered heteroaryl ring including 1 or 2 heteroatoms selected from N, S and O, or a 9- to 11-membered heterocyclyl ring including 1 or 2 heteroatoms selected from N, S and O; and all other variants not specifically defined herein are as defined in any of the preceding embodiments.

[0122] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2:

[0123]

[0124] its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing; and all other variants not specifically defined herein are as defined in any of the preceding embodiments.

[0125] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2a:

[0126]

[0127] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two, three or four of are independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, cyclopropyl and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The remainder of is H; and all other variants not specifically defined herein are as defined in any of the preceding embodiments.

[0128] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2b:

[0129]

[0130] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0131] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2c:

[0132]

[0133] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0134] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2d:

[0135]

[0136] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0137] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2e:

[0138]

[0139] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0140] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2f:

[0141]

[0142] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0143] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2g:

[0144]

[0145] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0146] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2h:

[0147]

[0148] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0149] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2i:

[0150]

[0151] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , Ra2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0152] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2j:

[0153]

[0154] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0155] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2k:

[0156]

[0157] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0158] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2L:

[0159]

[0160] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0161] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 2m:

[0162]

[0163] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0164] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3:

[0165]

[0166] A tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein one or two of X1, X2 and X3 are N and the rest of X1, X2 and X3 are C; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0167] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3a:

[0168]

[0169] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein one or two of X1, X2 and X3 are N and the rest of X1, X2 and X3 are C, R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, cyclopropyl and OCH3, provided that the point of attachment on ring A is not N, and R a1 , R a2 , R a3 , R a4 and R a5 The remainder of is H; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0170] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3b:

[0171]

[0172] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0173] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3c:

[0174]

[0175] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0176] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3d:

[0177]

[0178] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0179] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3e:

[0180]

[0181] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X3 are independently selected from C and N, R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0182] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3f:

[0183]

[0184] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X2 and X3 are independently selected from C and N, R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0185] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3g:

[0186]

[0187] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X2 and X3 are independently selected from C and N, R a1 and R a2 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0188] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3h:

[0189]

[0190] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0191] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3i:

[0192]

[0193] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0194] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3j:

[0195]

[0196] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 one of which is selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, the rest of which are H; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0197] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3k:

[0198]

[0199] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 one of which is selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, the rest of which are H; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0200] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 3L:

[0201]

[0202] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X3 are independently selected from C and N, R a1 , R a2 and R a3is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0203] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 4:

[0204]

[0205] Its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein X1 is selected from C, N and O; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0206] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 5:

[0207]

[0208] A tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Ring A is an 8-membered, 9-membered or 10-membered heterocyclic ring, wherein the heterocyclic ring is a fused or bridged ring system; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0209] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 6:

[0210]

[0211] Its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein one or two of X1, X2, X3 and X4 are selected from N, O and S, and the rest of X1, X2, X3 and X4 are C; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0212] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 7:

[0213]

[0214] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein zero, one or two of Y1, Y2, Y3 and Y4 are N and the rest of Y1, Y2, Y3 and Y4 are C, R bselected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), and C1-C4 alkyl, which is optionally substituted with 1-2 groups selected from the following groups: -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -C(=O)NH2, -COOH, and phenyl, and n is 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0215] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 7a:

[0216]

[0217] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein Y2 is C, N or O, and R b1 is selected from H, halogen, OCH3, CN, C1-C3 alkyl, and C3-C5 cycloalkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0218] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 7b:

[0219]

[0220] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein Y1 is C, N or O, and R b1 is selected from the group consisting of H, halogen, and C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0221] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 8:

[0222]

[0223] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein Y2 is selected from N, O and C, x is 0, 1 and 2, R bselected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, COOH, and C1-C4 alkyl, optionally substituted with 1-2 groups selected from -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, COOH, and phenyl, and n is 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0224] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 8a:

[0225]

[0226] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein Y2 is selected from N, O and C, x is 0, 1 and 2, and R b1 is selected from H, OH, and =0; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0227] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 9:

[0228]

[0229] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein zero or one of Y1, Y2, Y3 and Y4 is N and the rest of Y1, Y2, Y3 and Y4 are C, zero or one of Z1 and Z2 is N and the rest are C, R b is selected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, OCH3, and C1-C4 alkyl, which is optionally substituted with 1-2 groups selected from the following groups: halogen, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, and phenyl, and n is 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0230] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 9a:

[0231]

[0232] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein zero or one of Y1, Y2, Y3 and Y4 is N and the rest of Y1, Y2, Y3 and Y4 are C, zero or one of Z1 and Z2 is N and the rest are C, R b1 is selected from H, halogen and C1-C3 alkyl, provided that when R b1 is not H, Y2 is C; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0233] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 10:

[0234]

[0235] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein zero, one or two of Y1, Y2, Y3 and Y4 are N and the rest of Y1, Y2, Y3 and Y4 are C, R b is selected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, COOH, C3-C5 cycloalkyl, and C1-C4 alkyl, which is optionally substituted with 1-2 groups selected from the following groups: -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, and phenyl, and n is 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0236] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 11:

[0237]

[0238] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein one of Y2 and Y3 is S or O, and the others are C, R bis selected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), and C1-C4 alkyl, which is optionally substituted with 1-2 groups selected from the following groups: -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, and phenyl, and n is 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0239] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 12:

[0240]

[0241] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein one of Y2 and Y4 is N and the other is C, y is 0 or 1, R b is selected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), and C1-C4 alkyl, which is optionally substituted with 1-2 groups selected from the following groups: -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, and phenyl, and n is 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0242] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 13:

[0243]

[0244] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R b Selected from:

[0245] C1-C4 alkyl, which is optionally substituted by 1-2 groups selected from: -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, and phenyl,

[0246] 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C3 alkyl, and

[0247] 5- to 6-membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O, C1-C3 alkyl, and O(C1-C3 alkyl),

[0248] and where n is 1 and 2;

[0249] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0250] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 13a:

[0251]

[0252] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R b1 Selected from:

[0253] 5 to 6 membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C3 alkyl and

[0254] 5- to 6-membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O and C1-C3 alkyl;

[0255] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0256] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 13b:

[0257]

[0258] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R b1 selected from C1-C4 alkyl, which is optionally substituted with 1-2 groups selected from the following: NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), and -C(=O)NH2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0259] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 14:

[0260]

[0261] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 is selected from N and C, Y2 is selected from N and O, wherein R a1 , R a2 , R a3 , R a4 and R a5Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, cyclopropyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The rest of the are H, provided that when X1 is N, R a1 Does not exist, R b1 is selected from H, CH2CN, and C1-C2 alkyl, which is optionally substituted with C3-C4 cycloalkyl, provided that when Y2 is O, R b1 does not exist, and R b2 is selected from H, halogen, CN, OCH3, C1-C3 alkyl, and C3-C5 cycloalkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0262] In a second embodiment, the compound of the present disclosure is a compound of the following structural formula 14a:

[0263]

[0264] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H, CH2CN, and C1-C2 alkyl, R b2 is selected from H, halogen, CN, OCH3, C1-C3 alkyl, and C3-C5 cycloalkyl, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0265] In a third embodiment, the compound of the present disclosure is a compound of the following structural formula 14b:

[0266]

[0267] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, R b2 is selected from H, halogen, CN, OCH3, C1-C3 alkyl, and C3-C5 cycloalkyl, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0268] In a fourth embodiment, the compound of the present disclosure is a compound of the following structural formula 14c:

[0269]

[0270] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, which is optionally substituted by C3-C4 cycloalkyl, R b2 is selected from H, halogen and C1-C3 alkyl, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0271] In a fifth embodiment, the compound of the present disclosure is a compound of the following structural formula 14d:

[0272]

[0273] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0274] In a sixth embodiment, the compound of the present disclosure is a compound of the following structural formula 14e:

[0275]

[0276] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0277] In a seventh embodiment, the compound of the present disclosure is a compound of the following structural formula 14f:

[0278]

[0279] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0280] In an eighth embodiment, the compound of the present disclosure is a compound of the following structural formula 14g:

[0281]

[0282] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0283] In a ninth embodiment, the compound of the present disclosure is a compound of the following structural formula 14h-1 or 14h-2:

[0284]

[0285] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0286] In the tenth embodiment, the compound of the present disclosure is a compound of the following structural formula 14i:

[0287]

[0288] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0289] In the 11th embodiment, the compound of the present disclosure is a compound of the following structural formula 14j:

[0290]

[0291] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0292] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 15:

[0293]

[0294] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The remainder of is H; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0295] In a twelfth embodiment, the compound of the present disclosure is a compound of the following structural formula 15a:

[0296]

[0297] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0298] In the 13th embodiment, the compound of the present disclosure is a compound of the following structural formula 16-1 or 16-2:

[0299]

[0300] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The remainder of is H; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0301] In the 14th embodiment, the compound of the present disclosure is a compound of the following structural formula 16-1a or 16-2a:

[0302]

[0303] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0304] In the 15th embodiment, the compound of the present disclosure is a compound of the following structural formula 17:

[0305]

[0306] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The rest are H, R b1 is selected from H and C1-C2 alkyl, and R b2 is selected from H and C1-C4 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0307] In the 16th embodiment, the compound of the present disclosure is a compound of the following structural formula 17a:

[0308]

[0309] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, R b2 is selected from H and C1-C4 alkyl, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0310] In the 17th embodiment, the compound of the present disclosure is a compound of the following structural formula 18:

[0311]

[0312] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and Ra5 The rest are H, R b1 is selected from the group consisting of =O, -NHCOCH3, and OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0313] In the 18th embodiment, the compound of the present disclosure is a compound of the following structural formula 18a:

[0314]

[0315] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from =O, OH, and -NHCOCH3, and L is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0316] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 19:

[0317]

[0318] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein neither or one of Y1 and Y2 is N and the other is C, Z1 and Z2 are independently selected from N and C, R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The remainder of is H; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0319] In the 19th embodiment, the compound of the present disclosure is a compound of the following structural formula 20:

[0320]

[0321] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein neither or one of Y1 and Y2 is N and the other is C, R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, provided that when Y2 is N, R b1 Does not exist, R b2 is selected from H, CN, C1-C2 alkyl, and -C(=O)NH2, provided that when Y1 is N, R b2 Does not exist, R b3 is selected from H and C1-C2 alkyl, R b4 is selected from H and C1-C2 alkyl, and L is selected from

[0322] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 21:

[0323]

[0324] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The rest are H, R b selected from -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl, optionally substituted with 1-2 groups selected from: =O and C1-C3 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0325] In the 20th embodiment, the compound of the present disclosure is a compound of the following structural formula 21a:

[0326]

[0327] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and Ra2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O and C1-C3 alkyl, and L is selected from

[0328] In the 21st embodiment, the compound of the present disclosure is a compound of the following structural formula 21b:

[0329]

[0330] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from -C(=O)NH(C1-C4 alkyl), OCH3, and -C(=O)O(C1-C4 alkyl), R b2 is selected from H and -C(=O)NH2, and L is selected from

[0331] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 22:

[0332]

[0333] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The rest of Y1, Y2 and Y3 are H, zero, one or two of Y1, Y2 and Y3 are N and the rest of Y1, Y2 and Y3 are C, R b is selected from C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, and n is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0334] In the 22nd embodiment, the compound of the present disclosure is a compound of the following structural formula 22a:

[0335]

[0336] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 independently selected from F, Cl, Br, methyl, and OCH3, zero, one or two of Y1, Y2 and Y3 are N and the rest of Y1, Y2 and Y3 are C, R b is selected from C1-C2 alkyl, C3-C5 cycloalkyl, CN, C(O)NH2, and halogen, n is 0, 1 or 2, and L is selected from

[0337] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 23:

[0338]

[0339] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 the remainder of Y2 and Y3 are H, one of Y2 and Y3 is S or O, and the remainder are C; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0340] In the 23rd embodiment, the compound of the present disclosure is a compound of the following structural formula 23a:

[0341]

[0342] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H, C1-C3 alkyl, halogen, C3-C5 cycloalkyl, CN, and CONH2, provided that when Y2 is S or O, R b1 not present, one of Y2 and Y3 is S or O, and the others are C, and L is selected from

[0343] In the 24th embodiment, the compound of the present disclosure is a compound of the following structural formula 24:

[0344]

[0345] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein one of X1, X2 and X3 is N and the other two of them are C, Y2 is selected from C, N and O, and R b1 is selected from C1-C2 alkyl, C3-C5 cycloalkyl, O(C1-C3 alkyl), and halogen; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments. In some embodiments, L is

[0346] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 25:

[0347]

[0348] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 is selected from C, N and O, Y2 is selected from C, N and O, and R b1 is selected from the group consisting of C1-C2 alkyl, C3-C5 cycloalkyl, O(C1-C3 alkyl), and halogen; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0349] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 26:

[0350]

[0351] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein Ring A is an 8-membered, 9-membered or 10-membered heterocyclic ring, wherein the heterocyclic ring is a fused or bridged ring system, Y2 is selected from C, N and O, and R b1 is selected from the group consisting of C1-C2 alkyl, C3-C5 cycloalkyl, O(C1-C3 alkyl), and halogen; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0352] In one embodiment, the compound of the present disclosure is a compound of the following structural formula 27:

[0353]

[0354] Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 is selected from C, O and S, X2 is selected from N and C, Y2 is selected from C, N and O, and R b1 is selected from C1-C2 alkyl and halogen; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0355] In the 25th embodiment, the compound of the present disclosure is a compound of the following structural formula 28-1 or 28-2:

[0356]

[0357] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2, Y1, Y2 and Z1 are independently selected from C and N, R a1 is selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl and cyclopropyl, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R c is H, halogen, CN or methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0358] In the 26th embodiment, the compound of the present disclosure is a compound of the following structural formula 29-1 or 29-2:

[0359]

[0360] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2 and Z1 are independently selected from C and N, R a1 is selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl and cyclopropyl, R b1 is selected from the group consisting of F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, CH2OH, cyclopropyl, and OCH3, wherein R b1 When absent or C1-C4 alkyl, when attached to N in ring B, R cis H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0361] In the 27th embodiment, the compound of the present disclosure is a compound of the following structural formula 30-1, 30-2, 30-3, 30-4 or 30-5:

[0362]

[0363] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, CN, CONH2, CH2NH2, and cyclopropyl, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from C1-C4 alkyl, which is optionally substituted by -C(=O)NH2, 3- to 5-membered cycloalkyl, which is optionally substituted by OH, and 5-6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the following: F, Cl, Br, Me, CF3, CF2H, CN, CONH2 and NH2, and R c is H, halogen, CN or methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0364] In the 28th embodiment, the compound of the present disclosure is a compound of the following structural formula 31-1 or 31-2:

[0365]

[0366] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2 and Z1 are independently selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl and cyclopropyl, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1When absent or C1-C4 alkyl, when attached to N in ring B, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0367] In the 29th embodiment, the compound of the present disclosure is a compound of the following structural formula 32-1, 32-2, 32-3, 32-4 or 32-5:

[0368]

[0369]

[0370] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2, Y1, Y2 and Z1 are independently selected from C and N, R a1 , R a2 and R a3 Each is independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl, cyclopropyl and OCH3, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from H, C1-C4 alkyl, which is optionally substituted by -C(=O)NH2, 3- to 5-membered cycloalkyl, which is optionally substituted by OH, and 5-6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the following: F, Cl, Br, Me, CF3, CF2H, CN, CONH2 and NH2, and R c is H, halogen, CN or methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0371] In the 30th embodiment, the compound of the present disclosure is a compound of the following structural formula 33-1, 33-2 or 33-3:

[0372]

[0373]

[0374] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2 and Z1 are independently selected from C and N, Ra1 , R a2 and R a3 Each is independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl, cyclopropyl and OCH3, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 is absent or is C1-C4 alkyl, when attached to N in ring B, and R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0375] In the 31st embodiment, the compound of the present disclosure is a compound of the following structural formula 34-1, 34-2, 34-3, 34-4, 34-5 or 34-6:

[0376]

[0377]

[0378] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 , and R a4 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from H, 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 substituents selected from the group consisting of F, Cl, Br, Me, CF3, CF2H, CN, CONH2, and NH2, and C1-C4 alkyl, which is optionally substituted by -C(=O)NH2, and R c is H, halogen, CN or methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0379] In the 32nd embodiment, the compound of the present disclosure is a compound of the following structural formula 35-1, 35-2, 35-3 or 35-4:

[0380]

[0381] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H and OCH3, R a3 is a C1-C4 alkyl group, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R c is H, halogen, CN or methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0382] In the 33rd embodiment, the compound of the present disclosure is a compound of the following structural formula 36-1, 36-2 or 36-3:

[0383]

[0384] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R c is H, halogen, CN or methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0385] In the 34th embodiment, the compound of the present disclosure is a compound of the following structural formula 37-1, 37-2, 37-3, 37-4, 37-5 or 37-6:

[0386]

[0387]

[0388] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each is independently selected from F, Cl, Br, C1-C4 alkyl, optionally substituted by 1-3 groups selected from halogen, C3-C4 cycloalkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is selected from C3-C4 cycloalkyl and C1-C4 alkyl, optionally substituted by 1-3 groups selected from halogen, cyclopropyl, and 4 to 5 membered heterocyclyl, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from 5- to 6-membered heteroaryl, (optionally) substituted by 1-2 groups selected from F, Cl, Br, Me, CF3, CF2H, CN, CONH2, and NH2, and C1-C4 alkyl, optionally substituted by OH or -C(=O)NH2, and R c is H, halogen, CN or methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0389] In the 35th embodiment, the compound of the present disclosure is a compound of the following structural formula 38-1, 38-2 or 38-3:

[0390]

[0391] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, Ra3 is a C1-C4 alkyl group, R b1 is selected from the group consisting of F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0392] In the 36th embodiment, the compound of the present disclosure is a compound of the following structural formula 39-1, 39-2, 39-3 or 39-4:

[0393]

[0394]

[0395] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0396] In the 37th embodiment, the compound of the present disclosure is a compound of the following structural formula 40-1, 40-2 or 40-3:

[0397]

[0398]

[0399] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0400] In the 38th embodiment, the compound of the present disclosure is a compound of the following structural formula 41-1, 41-2, 41-3, 41-4 or 41-5:

[0401]

[0402]

[0403] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R b3 is selected from C1-C4 alkyl, which is optionally substituted by OH or -C(=O)NH2, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0404] In the 39th embodiment, the compound of the present disclosure is a compound of the following structural formula 42-1, 42-2 or 42-3:

[0405]

[0406]

[0407] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt of the foregoing, wherein X1, X2, X3 and X4 are independently selected from C, N and S, and wherein X5 is selected from C and N, and R is an integer selected from 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0408] In the 40th embodiment, the compound of the present disclosure is a compound of the following structural formula 43-1, 43-2, 43-3 or 43-4:

[0409]

[0410] Its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Z, Z1, Z2 and Z3 are independently selected from C, S and N, and R is an integer selected from 0, 1 and 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0411] In the 41st embodiment, the compound of the present disclosure is a compound of the following structural formula 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13 or 44-14:

[0412]

[0413]

[0414]

[0415] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein:

[0416] X1 is selected from C, S, O and N, X2 is selected from C, N, S and O, Z1 and Z2 are independently selected from C, N and S,

[0417] R a1 , R a2 and R a3 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3,

[0418] R b1 is selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, OCH3, -C(=O)CH2C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)(C3-C5 cycloalkyl), -C(=O)(5- to 6-membered heteroaryl), -C(=O)(4- to 6-membered heterocyclyl optionally substituted with =O or OH), -C(=O)OH, OH, -C(=O)NH2, 3- to 5-membered cycloalkyl optionally substituted by OH, and C1-C4 alkyl optionally substituted by OH or -C(=O)NH2,

[0419] R b2 and R b3 independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, -C(=O)NH2 and OCH3 or R b2 and R b3 Together they form a C3-C5 cycloalkyl group,

[0420] R b4 Yes = O or does not exist,

[0421] R b5 is selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, OCH3, -C(=O)CH2C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)(C3-C5 cycloalkyl), -C(=O)(5- to 6-membered heteroaryl), -C(=O)(5- to 6-membered heterocyclyl optionally substituted by =O), -C(=O)OH, OH, C1-C4 alkyl optionally substituted by OH or -C(=O)NH2, and C3-C5 cycloalkyl optionally substituted by OH, and

[0422] R c is H, halogen, CN or methyl, and

[0423] wherein R4 and R5 are taken together to form a 3 to 4 membered cycloalkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0424] In the 42nd embodiment, the compound of the present disclosure is a compound of the following structural formula 45-1 or 45-2:

[0425]

[0426] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein:

[0427] R a1 and R a2 are each independently selected from halogen and C1-C2 alkyl optionally substituted by 1 to 3 halogen groups,

[0428] R' a1 , R' a2 , R' a3 , R' a4 , and R' a5 are each independently selected from H and halogen, wherein R' a1 , R' a2 , R' a3 , R' a4 , and R'a5 2, 3 or 4 of them are halogen and the rest are H,

[0429] R b1 is selected from H and C1-C4 alkyl optionally substituted by -C(=O)NH2,

[0430] R b2 is selected from H and C1-C4 alkyl optionally substituted by 1-3 halogen groups, and

[0431] R c is selected from the group consisting of H, halogen, and C1-C2 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0432] In the 43rd embodiment, the compound of the present disclosure is a compound of the following structural formula 46-1, 46-2 or 46-3:

[0433]

[0434] Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein:

[0435] Z1 is selected from C and N,

[0436] R a1 and R a2 are each independently selected from halogen and C1-C2 alkyl optionally substituted by 1 to 3 halogen groups,

[0437] R' a1 , R' a2 , R' a3 , R' a4 , and R' a5 are each independently selected from H and halogen, wherein R' a1 , R' a2 , R' a3 , R' a4 , and R' a5 2, 3 or 4 of them are halogen and the rest are H,

[0438] R b is selected from H and a 5- to 6-membered heteroaryl group containing 2-3 heteroatoms selected from N and S, wherein R b The 5- to 6-membered heteroaryl is optionally substituted by 1-3 groups selected from halogen and C1-C4 alkyl,

[0439] R b1 is selected from H and C1-C4 alkyl optionally substituted by -C(=O)NH2,

[0440] Rb2 is selected from H, halogen, -O(C1-C4 alkyl), and C1-C4 alkyl, optionally substituted with 1-3 groups selected from halogen, and

[0441] R c is selected from the group consisting of H, halogen, and C1-C2 alkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0442] In the 44th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, m R a The group substituted ring A is selected from:

[0443] Where R a1 , R a2 and R a3 independently selected from F, Cl, Br, methyl, CF3, CF2H and cyclopropyl, and X1 and X2 are independently selected from C and N; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0444] In the 45th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, m R a The group substituted ring A is selected from:

[0445] Where R a1 and R a2 R is independently selected from H, CN, F, Cl, Br, C1-C4 alkyl, CF3, CF2H and OCH3, a3 is H or C1-C4 alkyl, R a4 selected from H, F, Cl, Br, and C1-C4 alkyl, and X1 and X2 are independently selected from N, O and S; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0446] In the 46th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, ring A is selected from:

[0447]

[0448] The ring A is surrounded by m R aand all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0449] In the 47th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, m R a The group substituted ring A is selected from:

[0450]

[0451]

[0452] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0453] In the 48th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, m R a The group substituted ring A is selected from:

[0454]

[0455] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0456] In the 49th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, n R b The group substituted ring B is: wherein Z is selected from C and N, Y1 and Y2 are independently selected from C and N, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R b3 Selected from H, methyl, ethyl, and a 5-membered heteroaryl group, wherein R b3 The 5-membered heteroaryl contains 2-3 heteroatoms selected from N and S and the 5-membered heteroaryl is optionally substituted by 1-2 groups selected from halogen and C1-C4 alkyl, and R c is selected from the group consisting of H, halogen, CN, and methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0457] In the 50th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, n R b The group substituted ring B is selected from: Wherein Z is selected from C and N, R b1 is selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R b2 is selected from the group consisting of H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and R c is selected from the group consisting of H, halogen, CN, and methyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0458] In the 51st embodiment, in a compound, a tautomer, a solvate or stereoisomer or a pharmaceutically acceptable salt of the compound or tautomer of the present disclosure,

[0459] By n R b The group substituted ring B is: Wherein Z is selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is selected from H, halogen, CN, and methyl, p is 1, 2 or 3, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0460] In the 52nd embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, n R b The group substituted ring B is selected from: Wherein Z is selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is selected from H, halogen, CN, and methyl, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0461] In the 53rd embodiment, in a compound, a tautomer, a solvate or stereoisomer or a pharmaceutically acceptable salt of the compound or tautomer of the present disclosure,

[0462] By n R bThe group substituted ring B is: Wherein Z is selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is H, halogen, CN or methyl, p is 1, 2 or 3, q ​​is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the preceding embodiments as appropriate.

[0463] In the 54th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, n R b The group substituted ring B is selected from: Wherein Z is selected from C and N, R b1 is selected from the group consisting of F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, and q is 1 or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0464] In the 55th embodiment, in a compound, a tautomer, a solvate or stereoisomer or a pharmaceutically acceptable salt of the compound or tautomer of the present disclosure,

[0465] By n R b The group-substituted ring B is wherein Y is selected from C and N, E is selected from C, N and O, R d1 and R d2 are independently selected from H, methyl, ethyl and cyclopropyl, R c is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R b1 is selected from H, halogen, CN, and methyl, p is 1 or 2, and q is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0466] In the 56th embodiment, in a compound, a tautomer, a solvate or stereoisomer or a pharmaceutically acceptable salt of the compound or tautomer of the present disclosure,

[0467] By n R b The group-substituted ring B is wherein Z is selected from C and N, Y1, Y2, and Y3 are independently selected from C, N, S and O, R b1 Selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, CONH2, OCH3, CH2CONH2, R c is selected from H, halogen, CN, and methyl, and p is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0468] In the 57th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, n R b The group substituted ring B is selected from And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0469] In the 58th embodiment, in a compound, a tautomer, a solvate or stereoisomer or a pharmaceutically acceptable salt of the compound or tautomer of the present disclosure,

[0470] By n R b The group-substituted ring B is Z is selected from C and N, Y1, Y2, Y3 and Y4 are independently selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, CONH2 and OCH3, R c is H, halogen, CN or methyl, and p is 0, 1 or 2; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0471] In the 59th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, Ring B is selected from:

[0472]

[0473]

[0474] The ring B is surrounded by n R b and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0475] In the 60th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, n R b The group substituted ring B is selected from:

[0476]

[0477]

[0478]

[0479]

[0480]

[0481] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0482] In the 61st embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, n R b The group substituted ring B is selected from:

[0483] wherein q1 is an integer selected from 0, 1, 2 and 3, q2 is an integer selected from 0, 1 and 2, and R c is selected from the group consisting of F, Cl, Br, and Me; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0484] In the 62nd embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, wherein R a selected from C3-C5 cycloalkyl, -O(C1-C2 alkyl), COOH, CN, CONH2, -C(=O)NH(C1-C2 alkyl), -C(=O)N(C1-C2 alkyl)2, -C(=O)O(C1-C2 alkyl), halogen and C1-C2 alkyl, which are optionally substituted with 1-3 groups selected from the following: halogen; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0485] In the 63rd embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, R a is selected from CH3, CH2CH3, CH2CF3, F, Cl, Br, C3-C4 cycloalkyl, COOH, CN, CONH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -NC(=O)N(CH3)3 and OCH3; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0486] In the 64th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, R b is selected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2,

[0487] C3-C4 cycloalkyl optionally substituted by OH,

[0488] O(C1-C3 alkyl), -C(=O)(C1-C2 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(4- to 6-membered heterocyclyl optionally substituted by =O), -C(=O)(5- to 6-membered heteroaryl optionally substituted by C1-C2 alkyl or NH2), -C(=O)(CH2)pC(=O)NH2, -NHC(=O)(C1-C2 alkyl), -C(=O)N(C1-C2 alkyl)2, -C(=O)NH(CH2)pOH, -S(=O)2NH2,

[0489] C1-C3 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, NH2, OH, OCH3, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -COOH, -C(=O)NH2, CN, C3-C4 cycloalkyl, phenyl, -C(=O)(C1-C2 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(5- to 6-membered heterocyclyl), -C(=O)(5- to 6-membered heteroaryl optionally substituted by C1-C2 alkyl), C(=O)NH(CH2)pOH, and 5- to 6-membered heteroaryl,

[0490] 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C2 alkyl, and

[0491] 5 to 6 membered heterocyclic group, which is optionally substituted by 1-2 groups selected from: =O and C1-C2 alkyl, or two R attached to the same position of ring B b Together they form a C3-C5 cycloalkyl group,

[0492] wherein p is an integer selected from 1 and 2, and

[0493] wherein R4 and R5 are each independently selected from H and C1-C3 alkyl or R4 and R5 together form a 3 to 5 membered cycloalkyl;

[0494] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0495] In the 65th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, R b Selected from =O, CH3, CHF2, CF3, OH, F, Cl, Br, CN, CH(CH3)2, CH2CN, OCH3, -C(=O)NH2, -C(=O)OCH3,

[0496]

[0497] CH2CH2OH, CH2CH2CH2OH, CH2C(=O)OH, CH2C(=O)NH2,

[0498] CH2C(=O)NHCH2CH2OH, CH2CH2CH2C(=O)NH2, -

[0499] C(=O)CH3, -NHC(=O)CH3, -C(=O)N(CH3)2, -C(=O)NCH3, NH2, -C(=O)NHCH2CH2OH, CH2OH, or two R attached to the same position of ring B b taken together to form a 3- or 5-membered cycloalkyl; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0500] In the 66th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, L is selected from in

[0501] R1 is H, D or C1-C4 alkyl, and R2 is selected from CN, C1-C4 alkenyl (e.g., C2, C3 or C4 alkenyl), C3-C5 cycloalkyl, 5-6 membered heteroaryl,

[0502] Phenyl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C3 alkyl (e.g., C1, C2 or C3 alkyl) and halogen, and

[0503] C1-C4 alkyl (e.g., C1, C2, C3 or C4 alkyl), which is optionally substituted with 1-3 groups selected from halo, OH, and phenyl,

[0504] or

[0505] R1 and R2 are taken together to form a 3-4 membered heterocyclic group; and

[0506] R3 is C1-C4 alkyl (e.g., C1, C2, C3 or C4 alkyl), optionally substituted with 1-3 groups selected from halogen and OH; and all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0507] In the 67th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, L is selected from:

[0508]

[0509] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0510] In the 68th embodiment, in the compound, tautomer, solvate or stereoisomer or pharmaceutically acceptable salt of the compound or tautomer of the present disclosure, L is selected from

[0511] And all other variables not specifically defined herein are as defined in any of the appropriate preceding embodiments.

[0512] In certain embodiments, the compound of the present disclosure is selected from Compounds 1 to 391 described in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0513] Table 1: Compounds 1 to 391

[0514]

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531] The symbols "or1" or "or2" used in the chemical structures herein indicate that the stereo configuration of the chiral center marked with "or1" or "or2" is R configuration or S configuration. For example, "or1" of compounds 194A and 194B is located above the stereo center connected to a methyl group and a hydrogen atom (hydrogen atoms are not shown). This means that the stereo configuration of the chiral carbon marked with "or1" in compounds 194A and 194B is R or S. Single stereoisomers, i.e., a compound with R configuration and a compound with S configuration, were obtained separately and characterized by NMR, MS, and retention time, but the stereo configuration of the chiral center was not determined. In other words, compound Each of the compounds is obtained individually as a single stereoisomer. In this case, the compounds (e.g., compounds 194A and 194B) are represented as "single unknown stereoisomer".

[0532] For another example, compounds 302, 302A, 302B, and 302C have "or1" located above one stereocenter and "or2" located above another stereocenter. This means that the stereoconfiguration of the two chiral carbons labeled "or1" and "or2" in these compounds is R or S, respectively. Single stereoisomers, such as a compound with (S, S) configuration, a compound with (R, S) configuration, a compound with (R, R) configuration, and a compound with (S, R) configuration, were obtained separately and characterized by NMR, MS, and retention time, but the stereoconfiguration of the chiral center was not determined. In other words, the compound Each of these is obtained individually as a single stereoisomer.

[0533] In certain embodiments, for example in various uses and method embodiments, the compound of the present disclosure is selected from compounds 1A to 121A shown in Table 2, their tautomers, solvates or stereoisomers of the compound or the tautomers, or pharmaceutically acceptable salts thereof.

[0534] Table 2: Compounds 1A to 121A

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] Another aspect of the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h ... -1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26 ,27,28-1,28-2,29-1,29-2,29-3,30-1,30-2,30-3,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32-4,32-5,33-1,33-2,3 3-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A in Table 2, tautomers thereof, solvates or stereoisomers of the compound or the tautomer, or pharmaceutically acceptable salts of the foregoing, and at least one pharmaceutically acceptable carrier.

[0542] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant. In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, a disintegrant, a surfactant, a binder and a lubricant.

[0543] It should also be understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy; that is, the pharmaceutical compositions described herein can also include additional active agents. Alternatively, a pharmaceutical composition comprising a compound selected from Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 2 9-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34- 3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, Compounds of 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A in Table 2, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, can be administered as separate compositions simultaneously with, before, or after a composition containing another active agent.

[0544] In some embodiments, pharmaceutically acceptable carriers can be selected from adjuvants and vehicles. Pharmaceutically acceptable carriers used herein can be selected from any and all solvents, diluents, other liquid vehicles, dispersing aids, suspension aids, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, the 21st edition, 2005, edited by DB Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, edited by J. Swarbrick and JC Boylan, 1988 to 1999, Marcel Dekker, New York discloses various carriers for preparing pharmaceutical compositions and known techniques for their preparation. Unless any conventional carrier is incompatible with the compound of the present disclosure, such as by producing any undesirable biological effect or interacting with any other component of the pharmaceutical composition in a harmful manner, its use is covered within the scope of the present disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), saturated vegetable fatty acids, water, partial glyceride mixtures of salts and electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), 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 solution, nontoxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives and antioxidants.

[0545] A compound selected from Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14f, 14g, 14h, 14i, 14j, 14k, 14h, 14i, 14j, 14i, 14j, 14k, 14h, 14i, 14i, 14j, 14i ... , 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b ,22,22a,23,23a,24,25,26,27,28-1,28-2,29-1,29-2,29-3,30-1,30-2,30-3,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32 -4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A in Table 2, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition disclosed herein. The compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts described herein can also be administered parenterally in a sterile liquid dosage form such as a dispersion, suspension or solution.Other dosage forms that can be used to administer a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein are also available as ointments, creams, drops, transdermal patches, or powders for topical administration, as ophthalmic solutions or suspensions, e.g., eye drops for ocular administration, as aerosol sprays or powder compositions for inhalation or intranasal administration, or as creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0546] It is also possible to use a pharmaceutically acceptable salt and powdered carrier containing a compound disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, and / or the foregoing, such as a gelatin capsule containing lactose, starch, a cellulose derivative, magnesium stearate, stearic acid, etc. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained-release products to continuously release the drug over a period of time. Compressed tablets can be coated with sugar or film to cover any unpleasant taste and protect the tablet from atmospheric influences, or can be enteric-coated to selectively disintegrate in the gastrointestinal tract.

[0547] Liquid dosage forms for oral administration may also contain at least one agent selected from coloring agents and flavoring agents to increase patient acceptance.

[0548] In general, water, suitable oil, saline, aqueous dextrose (glucose) and related sugar solutions and glycols such as propylene glycol or polyethylene glycol can be examples of suitable carriers for parenteral solutions. The solution for parenteral administration can include a water-soluble salt of at least one compound described herein, at least one suitable stabilizer and at least one buffer substance if necessary. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, can be examples of suitable stabilizers. Citric acid and its salts and sodium EDTA can also be used as examples of suitable stabilizers. In addition, parenteral solutions can also include at least one preservative selected from, for example, benzalkonium chloride, methyl parahydroxybenzoate and propyl parahydroxybenzoate and chlorobutanol.

[0549] Pharmaceutically acceptable carriers are, for example, selected from carriers that are compatible with the active ingredient of the composition (and in some embodiments, capable of stabilizing the active ingredient) and harmless to the subject to be treated. 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 silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C yellow #10. Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol.

[0550] For administration by inhalation, compound as herein described, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt can be conveniently delivered in the form presented by aerosol spray from a pressurized bag or aerosol. Compound as herein described, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt can also be delivered in powder form, which can be prepared, and powder composition can be inhaled by blowing into a powder inhaler device. An exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol, which can be formulated as a suspension or solution of compound as herein described, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt in at least one suitable propellant, the propellant being for example selected from fluorocarbon and hydrocarbon.

[0551] For ocular administration, ophthalmic preparations can be formulated with an appropriate weight percentage of a solution or suspension of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in an appropriate ophthalmic vehicle 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 areas of the eye.

[0552] 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.

[0553] 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 material calculated to produce the desired therapeutic effect and a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, lozenges, etc. in the case of solid compositions. In such compositions, the active material is generally about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight of the component, and the rest are various vehicles or carriers and processing aids that help form the desired dosage form. The unit dose formulation is preferably about 5, 10, 25, 50, 100, 250, 500 or 1,000 mg per unit. In a specific embodiment, the unit dosage form is packaged in a multipack suitable for sequential use, such as a blister package containing at least 6, 9 or 12 sheets of unit dosage forms.

[0554] In some embodiments, unit capsules can be prepared by filling standard two-piece hard gelatin capsules, each with, for example, 100 mg of a powdered compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein, 150 mg of lactose, 50 mg of cellulose, and 6 mg of magnesium stearate.

[0555] In some embodiments, a mixture of a compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt described herein and a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected into gelatin by a positive displacement pump to form soft gelatin capsules containing 100 mg of active ingredient. The capsules are washed and dried.

[0556] In some embodiments, tablets can be prepared by conventional procedures so that the dosage unit contains, for example, 100 mg of the compound, its stereoisomer or a pharmaceutically acceptable salt thereof, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

[0557] In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of a compound disclosed herein and / or at least one enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof in 10% by volume of propylene glycol. The solution is made up to the desired volume with water for injection and sterilized.

[0558] In some embodiments, an aqueous suspension for oral administration may be prepared. For example, an aqueous suspension may be used that contains 100 mg of the finely divided compound, its stereoisomers, or a pharmaceutically acceptable salt thereof, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, USP, and 0.025 ml of vanillin per 5 ml of aqueous suspension.

[0559] 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 the drugs are physically combined for administration, 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 simultaneous or sequential administration of at least two agents, or as a fixed dose combination of at least two active ingredients.

[0560] 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.

[0561] The compounds, tautomers, solvates or stereoisomers described herein can be used in the aforementioned form or in the form of their pharmaceutically acceptable salts, such as hydrochlorides, hydrobromides, 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 the desired base in pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts or magnesium salts, etc. When the compounds, tautomers, solvates or stereoisomers described herein contain relatively basic functional groups, the salts can be obtained by adding the desired acid in pure or in 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, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like, and salts derived from relatively nontoxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are amino acid salts such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid, and the like (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0562] The neutral forms of the pharmaceutically acceptable salts described herein can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0563] The present disclosure provides prodrugs. Compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts described herein are prone to chemical changes under physiological conditions to provide compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts of the present disclosure. In addition, prodrugs can be converted into compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, when placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent, prodrugs can be slowly converted into compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts of the present disclosure. Prodrugs are usually very useful because in some cases, they may be easier to use than the parent drug. For example, they may have higher bioavailability than the parent drug by oral administration. Compared with the parent drug, prodrugs can also have improved solubility in pharmacological compositions. Various prodrug derivatives are known in the art, such as those that rely on the hydrolytic cleavage or oxidative activation of prodrugs. A non-limiting example of a prodrug is a compound of the disclosure that is administered as an ester (the "prodrug") but is subsequently metabolically hydrolyzed to the carboxylic acid, the active entity.

[0564] Certain compounds, tautomers, stereoisomers or pharmaceutically acceptable salts of the present disclosure may exist in unsolvated forms as well as solvated forms, including hydrate forms. Certain compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts of the present disclosure may exist in multiple crystalline or amorphous forms.

[0565] Certain compounds, tautomers, solvates or pharmaceutically acceptable salts in the present disclosure possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and various isomers are intended to be encompassed within the scope of the present disclosure.

[0566] III. Methods of treatment and use

[0567] The present disclosure provides methods of treatment and uses utilizing compounds described in any of the various embodiments of Section II (Compounds and Compositions) and in Tables 1 and 2, such as Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f , 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26 ,27,28-1,28-2,29-1,29-2,29-3,30-1,30-2,30-3,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32-4,32-5,33-1,33-2,33-3,34- 1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3 The invention relates to a compound of the invention comprising: 4-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3, as well as compounds 1 to 391 in Table 1 and compounds 1A to 121A in Table 2, tautomers thereof, solvates or stereoisomers of the compound or the tautomer, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.

[0568] One aspect of the present disclosure provides a method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of an agent of Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22 a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30 -3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36- 1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, wherein the 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 diseases of PNS including hereditary neuropathy,For example, but not limited to Charcot-Marie-Tooth disease 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 neuropathies such as CIPN, caused by various drugs (such as, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors). In certain embodiments, the disease or disorder is caused by axonal degeneration or neuronal cell damage. ,

[0569] In another aspect, disclosed herein are compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts thereof as described herein, including formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14d, 14e, 14h, 14i, 14j, 14k, 14l, 14g, 14h, 14i, 14i, 14j, 14k, 14l, 14i ... 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 3 4-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44 -3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for use as a drug.

[0570] In another aspect, disclosed herein are compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts as described herein, including Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 15b, 15c, 15d, 15e, 15f, 15g, 15h-2, 15h-3, 15h-4, 15h-5, 15h-6, 15h-7, 15h-8, 15h-9, 15h-10, 15h-11, 15h-12, 15h-13 ,16-1,16-2,16-1a,16-2a,17,17a,18,18a,19,20,21,21a,21b,22,22 a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3 ,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32-4,32-5,33-1,33-2,33- 3. 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36- 2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 47-2 The use of compounds of 6-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts for the preparation of a medicament for treating a disease or condition, the 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 diseases of PNS including hereditary neuropathy,For example, but not limited to Charcot-Marie-Tooth disease 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 neuropathies such as CIPN, caused by various drugs (such as, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors). In certain embodiments, the disease or disorder is caused by axonal degeneration or neuronal cell damage. ,

[0571] In another aspect of the present disclosure, a compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt as described herein includes Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 14h-3, 14h-4, 14h-5, 14h-6, 14h-7, 14h-8, 14h-9, 14h-10, 14h-11, 14h-22, 14h-12 5, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b ,22,22a,23,23a,24,25,26,27,28-1,28-2,29-1,29-2,29-3,30-1,30 -2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 3 3-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1 , 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for treating 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 diseases of PNS including hereditary neuropathy,For example, but not limited to Charcot-Marie-Tooth disease 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 neuropathies such as CIPN, caused by various drugs (such as, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors). In certain embodiments, the disease or disorder is caused by axonal degeneration or neuronal cell damage. ,

[0572] Another aspect of the present disclosure provides a method of inhibiting or preventing axonal degeneration, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14d, 14e, 14f, 14g, 14h, 14i, 14i, 14j, 14k, 14l, 14i ... h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2 , 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.

[0573] In another aspect, disclosed herein are compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts thereof as described herein, including formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14h-3, 14h-4, 14h-5, 14h-6, 14h-7, 14h-8, 14h-9, 14h-10, 14h-11, 14h-12 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2 ,29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34- 4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, The compounds of 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts for the preparation of a medicament for inhibiting or preventing axonal degeneration or neuronal cell damage.

[0574] In another aspect of the present disclosure, a compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt as described herein includes Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14d, 14e, 14f, 14g, 14h, 14i, 14j, 14k ... h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1 ,28-2,29-1,29-2,29-3,30-1,30-2,30-3,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32-4,32-5,33-1,33-2,33-3,34-1,34-2,34 -3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44- 5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts, for inhibiting or preventing axonal degeneration or neuronal cell damage.

[0575] Another aspect of the present disclosure provides a method of modulating, e.g., inhibiting SARM1 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f ... 4g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26 ,27,28-1,28-2,29-1,29-2,29-3,30-1,30-2,30-3,30-4,30-5,31-1,31-2,32-1,32-2,32-3,32-4,32-5,33-1,33-2,33-3,34 -1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44- 2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts.

[0576] In another aspect, disclosed herein are compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts thereof as described herein, including formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14h-1 disclosed herein. , 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28 -2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 3 4-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44 -6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts for use in modulating, for example, inhibiting SARM1 in a subject in need thereof.

[0577] In another aspect of the disclosure, the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts described herein include Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14h-1, 14h-2, 14h-3, 14h-4, 14h-5, 14h-6, 14h-7, 14h-8, 14h-9, 14h-10, 14h-11, 14h-12 -2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20 ,21,21a,21b,22,22a,23,23a,24,25,26,27,28-1,28-2,29-1,29-2,2 9-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2 , 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14 The compounds of 4-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or the tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts is used to modulate (e.g., inhibit) SARM1 in a subject in need thereof by contacting the subject with the compound, tautomer, solvate or stereoisomer of the compound or the tautomer, pharmaceutically acceptable salt, or pharmaceutical composition.

[0578] The formulas disclosed herein 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 18 9, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 3 2-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., Compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts can be administered once a day, twice a day or three times a day, for example, for the treatment of diseases or conditions 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 diseases of PNS including hereditary neuropathy,For example, but not limited to Charcot-Marie-Tooth disease 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 neuropathies such as CIPN, caused by various drugs (such as, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors). In certain embodiments, the disease or disorder is caused by axonal degeneration or neuronal cell damage. ,

[0579] Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2 a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 3 0-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36 -1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12 Compounds of 4-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 (e.g., compounds 1 to 391) and compounds 1A to 121A, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts can be administered, for example, in various forms, such as orally, topically, rectally, parenterally, by inhalation spray or by implanted reservoirs, although the most appropriate route in any given case will depend on the nature and severity of the particular host and the condition for which the active ingredient is administered. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compositions disclosed herein may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art.Parenteral administration may be by continuous infusion over a selected period of time.Other administration forms contemplated in the present disclosure are described in International Patent Application Nos. WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142 and WO 2015 / 023915.

[0580] The contact is usually achieved by administering to the subject an effective amount of one or more compounds disclosed herein, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts. In general, 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, but the optimal dose is compound-specific and is usually determined empirically for each compound.

[0581] The dosage administered will depend on a variety of factors, such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment (if any), the frequency of treatment, and the nature of the desired effect. In general, the daily dose of the active ingredient may vary, for example, from 0.1 to 2000 mg per day. For example, 10-500 mg once or more per day may be effective to obtain the desired result.

[0582] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of Formula 1, 2, 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2L, 2m, 3, 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k, 3L, 4, 5, 6, 7, 7a, 7b, 8, 8a, 9, 9a, 10, 11, 12, 13, 13a, 13b, 14, 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h-1, 14h-2, 14i, 14j, 15, 15a, 16-1, 16-2, 16-1a, 16-2a, 17, 17a, 18, 18a, 19, 20, 21, 21a, 21b, 22, 22a, 23, 23a, 24, 25, 26, 27, 28-1, 28-2, 29-1, 29-2, 29-3, 30-1, 30-2, 30-3, 30-4, 30-5, 31-1, 31-2, 32-1, 32-2, 32-3, 32-4, 32-5, 33-1, 33-2, 33-3, 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 35-1, 35-2, 35-3, 35-4, 36-1, 36-2, 36-3, 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 38-1, 38-2, 38-3, 39-1, 39-2, 39-3, 39-4, 40-1, 40-2, 40-3, 41-1, 41-2, 41-3, 41-4, 41-5, 42-1, 42-2, 42-3, 43-1, 43-2, 43-3, 43-4, 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13, 44-14, 45-1, 45-2, 46-1, 46-2 and 46-3 compounds (e.g., compounds 1 to 391) and compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising any one of the compounds, tautomers, solvates, stereoisomers and pharmaceutically acceptable salts is administered once a day, twice a day or three times a day. The compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts described herein are administered in a morning / daytime dosing manner, with a rest period at night.

[0583] Example

[0584] In order to more fully understand the disclosure described herein, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the disclosure in any way.

[0585] Example 1. Synthesis of Exemplary Compounds

[0586] The compounds of the present disclosure, selected from the compounds of the various formulas shown herein, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, can be prepared according to standard chemical practices or as shown herein, including the following general synthetic procedures and specific synthetic schemes with compounds 1 to 354 and compounds 1A to 15A as representative examples of Formula 1.

[0587] Preparation of (5-(3,5-difluorophenyl)-4,5-dihydro-1H-pyrazol-1-yl)(3-((6-fluoropyridin-3-yl)oxy)azetidin-1-yl)methanone (1) Method 1

[0588]

[0589] To a solution of 7-amino-3,4-dihydroisoquinolin-1(2H)-one 1-01 (150 mg, 0.92 mmol) in DCM (10 mL) was added 3-fluoro-2-methylbenzenesulfonyl chloride 1-02 (192 mg, 0.92 mmol) and pyridine (219 mg, 2.7 mmol). The mixture was stirred at 25 °C for 2 hours. Water was added and the resulting mixture was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. Compound 1 (90 mg, 27.6%) was purified by silica gel chromatography as a white solid. Mass (m / z): 335.40 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.68(s,1H),7.90(d,J=3.0Hz,1H),7.70(dd,J=7.6,1.6Hz,1H),7.57(d,J= 2.0Hz,1H),7.49-7.34(m,2H),7.16(d,J=2.0Hz,2H),3.28(td,J=6.4,2.8Hz,2H),2.76(,t,J=6.4Hz 2H), 2.48 (d, J = 2.4Hz, 3H).

[0590] Using a method similar to that used in Example 1, Examples (Compounds) 2-91, 191, 196-197, 204, and 206, 208-209, 211-212, 217, 219, 220, 224-225, 227, 251, 265-265, 268-270, 270A, 274, 283, 298, 304, 304A and 304B were synthesized.

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611] Preparation of 6-(5-(pyridazin-3-ylamino)pyridin-3-yl)benzo[d]oxazol-2(3H)-one (1A) Method 2

[0612]

[0613] Step 1: A mixture of 1A-01 (500 mg, 5.33 mmol), 1A-02 (270 mg, 5.33 mmol), HOBt (720 mg, 5.33 mmol), EDCI (1.023 g, 5.33 mmol) and DIEA (2.07 g, 16 mmol) was stirred in DMF (10 mL) under N at 25 ° C for 12 hours. The reaction mixture was diluted with water. The aqueous phase was extracted with EA. The combined organic extracts were washed with brine and dried over Na2SO4. The solvent was removed under vacuum to give 600 mg of crude product 1A-03, which was used directly in the next step.

[0614] Step 2: 1A-03 (600 mg, 5.33 mmol) was dissolved in 10 mL of anhydrous THF, methylmagnesium bromide (2M THF solution, 6 mL, 12 mmol) was added to the above solution at 0 ° C, and the mixture was stirred at room temperature for 12 hours. The mixture was quenched with saturated ammonium chloride solution, extracted with EA, washed with brine, dried over Na2SO4, and concentrated in vacuo. Compound 1A-04 (300 mg, 49%) was obtained by silica gel chromatography.

[0615] Step 3: 1A-04 (90 mg, 0.5 mmol) was dissolved in 5 mL of anhydrous MeOH, 1A-05 (240 mg, 1.5 mmol), NaBH3CN (0.28 g, 4.5 mmol) and a drop of AcOH were added to the above solution, and the mixture was stirred at room temperature for 12 hours. The mixture was quenched with water and extracted with EA, washed with brine, and washed with Na2SO 4干燥 The residue was concentrated in vacuo and purified by silica gel chromatography to give the title compound 1A (14 mg, 8.1%).

[0616] 1 H NMR (400MHz, DMSO-d6) δ8.12(d,J=2.4Hz,1H),7.87(d,J=2.4Hz,1H),7.71(s,1H),7.05(s,1H),6.95(d,J=8.0Hz,1H),6.66(d,J=8. 0Hz,1H),6.22(s,1H),4.56(d,J=6.8Hz,1H),3.89(s,3H),3.25(td,J=6.4,2.8Hz,2H),2.67(t,J=6.4Hz,2H),1.41(d,J=6.8Hz,3H).

[0617] preparation

[0618] (S)-7-((1-(3-chlorophenyl)ethyl)amino)isoquinolin-1-ol (92)

[0619]

[0620] Step 1: Under argon, Pd2(dba)3 (590 mg, 0.64 mmol), Xant-phos (373 mg, 0.64 mmol), 92-02 (455 mg, 1.28 mmol) and Cs2CO3 (1300 mg, 3.99 mmol) were added to a solution of 92-01 (200 mg, 1.29 mmol) in toluene (5 mL), and the mixture was degassed with argon. The mixture was heated at 110 °C for 16 hours. After completion, the mixture was diluted with EtOAc, filtered through celite and concentrated in vacuo. The crude product was purified by flash column chromatography to give the product 92-03. MS (m / z): 429.1 (M+H+).

[0621] Step 2: Compound 92-03 (200 mg, 0.46 mmol) was dissolved in DCM (4 mL), stirred at room temperature, and then TFA (1 mL) was added. The reaction mixture was stirred at 25 ° C for 2 hours, and LCMS showed that the reaction was complete. The solvent was removed in vacuo and NH3.H2O (2 mL) was added. The mixture was stirred at room temperature for 2 hours. The residue was concentrated in vacuo and purified by preparative HPLC to give 92 (45 mg, yield 32.6) as a light yellow solid. MS (m / z): 299.0 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ7.44(t,J=1.9Hz,1H),7.41(d,J=8.6Hz,1H),7.37(dt,J=7.6,1.6Hz,1H),7.29(t,J=7.8Hz,1H),7.24-7.1 7(m,2H),7.13(dd,J=8.6,2.5Hz,1H),6.89(d,J=7.0Hz,1H),6.55(d,J=7.0Hz,1H),4.62(q,J=6.8Hz,1H),1.55(d,J=6.9Hz,3H).

[0622] Examples (Compounds) 93-157, 192-195, 198-201A, 203, 205, 210, 213, 221-223, 237-237A, 239A-239B, 244 and 254 were synthesized using a similar procedure as in Example 1A.

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651] Preparation of N-(3-fluoro-2-methylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-sulfenamide (158)

[0652]

[0653] 158-02 (126 mg, 0.604 mmol), pyridine (143 mg, 1.81 mmol) and triphenylphosphine (242 mg, 0.925 mmol) were added to a solution of 158-01 (150 mg, 0.604 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo. Compound 158 (30 mg, 9.68%) was purified by preparative HPLC as a white solid. Mass (m / z): 318.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.27(s,1H),7.92(s,1H),7.77(d,J=8.4Hz,1H),7.61(d,J=2.4Hz,1H),7.55(d,J=5.6,8.0Hz,1H),7.42(dd,J=1. 2,9.6Hz,1H),7.21(d,J=8.0Hz,1H),7.18(dd,J=2.4,8.0Hz,1H)3.35(dd,J=6.4,2.8Hz,2H),2.81(t,J=6.4Hz,2H),2.24(d,J=1.6Hz,3H).

[0654] Preparation of 3-fluoro-2-methyl-N-(3-(thiazol-4-yl)phenyl)benzenesulfonamide (159) Method 3

[0655]

[0656] Step 1: To a solution of 3-bromoaniline 159-01 (5.00 g, 29.4 mmol) in pyridine (100 mL) was added 3-fluoro-2-methylbenzene-1-sulfonyl chloride 1-02 (7.30 g, 35.2 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over (Na2SO4), and concentrated in vacuo to give the desired product 159-03. MS (m / z): 344.0 [M+H] + .

[0657] Step 2: To a solution of 159-03 (5.00 g, 14.5 mmol) in dioxane (100 mL) was added 4,4,5,5,4',4',5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)-159-04 (7.40 g, 29.1 mmol), Pd(dppf)Cl2 (1.10 g, 1.5 mmol) and KOAc (4.30 g, 43.5 mmol) at room temperature under N2. The mixture was stirred at 100 °C for 3 hours under N2. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over (Na2SO4) and concentrated under vacuum. The desired product 159-05 was obtained by purification by silica gel chromatography. MS (m / z): 392.1 [M+H] + .

[0658] Step 3: To a suspension of 159-05 (619 mg, 14.5 mmol) in dioxane (20 mL) and H2O (5 mL) at room temperature under N2 was added 4-bromothiazole 159-06 (200 mg, 1.21 mmol), Cs2CO3 (786 mg, 2.21 mmol) and Pd(dppf)Cl2 (88 mg, 0.12 mmol). The mixture was stirred at 100°C under N2 for 2 hours. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried (Na2SO4) and concentrated under vacuum. Purification by preparative HPLC gave the title compound 159 (164.3 mg, 38.7%) as a white solid. MS (m / z): 348.9 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.01 (d, J = 2.0 Hz, 1H), 7.81-7.76 (m, 2H), 7.66 (d, J = 2.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.28-7.24 (m, 3H), 7.07 (d, J = 6.4 Hz, 1H), 2.54 (d, J = 2.0 Hz, 3H).

[0659] Compounds 160-162 were synthesized in a similar manner to Example 159.

[0660]

[0661]

[0662] Preparation of 7-((1-(3-fluoro-5-methylphenyl)-2-hydroxyethyl)amino)-3,4-dihydroisoquinolin-1(2H)-one (163)

[0663]

[0664] Step 1: Prepare a suspension of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (509 mg, 2.12 mmol) and 1-bromo-3-fluoro-5-methylbenzene 163-01 (1.00 g, 5.29 mmol) in 1,4-dioxane (20 mL) / water (4 mL) and pass argon for 10 minutes. Add Pd(dppf)2Cl2 (193 mg, 0.265 mmol) and K3PO4 (3.36 g, 15.9 mmol). Heat the mixture to 100°C under argon for 16 hours. Concentrate the reaction to dryness and dissolve the residue in EtOAc (20 mLx2). Wash the organics with 2x20 mL of water and then with 20 mL of saturated brine solution. The organics are then separated and dried (MgSO4) and then concentrated to dryness. The crude product was then purified by flash column chromatography eluting with 10% EtOAc / PE. The desired fractions were concentrated to dryness in vacuo to afford 1-fluoro-3-methyl-5-vinyl-benzene 163-02 (530 mg, 3.81 mmol, 72.1% yield) as a white oil.

[0665] Step 2: 3-chloroperoxybenzoic acid (190 mg, 1.10 mmol) was added to a DCM (10 mL) solution of 163-02 (150 mg, 1.10 mmol). The reaction was stirred overnight at 25 ° C. The mixture was extracted with DCM (10 mL x 3). The combined organic layer was washed with NaHSO3 aq (10 mL x 3), dried with Na2SO4 and concentrated to give a crude product, which was purified by silica gel chromatography (EA / PE = 1: 5) to give the desired product 2- (3-fluoro-5-methyl-phenyl) oxirane 163-03 (103 mg, 0.51 mmol, yield 46.1%), as a yellow oil. MS (m / z): 153.2 [M + H] + .

[0666] Step 3: To a solution of 163-03 (100 mg, 0.657 mmol) in acetic acid (5 mL) was added 7-amino-3,4-dihydro-2H-isoquinolin-1-one 1-01 (107 mg, 0.657 mmol). The solution was stirred at room temperature for 12 hours. The mixture was extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4 and concentrated, and purified by preparative HPLC to give the desired product 7-[[1-(3-fluoro-5-methyl-phenyl)-2-hydroxy-ethyl]amino]-3,4-dihydro-2H-isoquinolin-1-one 163 (15 mg, 0.0466 mmol, 7.0% yield) as a yellow solid. MS (m / z): 315.1 [M+H]+ . 1 HNMR (400MHz, DMSO-d6) δ7.73(d,J=2.8Hz,1H),7.04(s,1H),7.00(d,J=2.4Hz,1H),6.98-6.90(m,2H),6.84(d,J=9.7,1H),6.66(dd,J=8.0,2. 4Hz,1H),6.25(d,J=6.4Hz,1H),5.14(s,1H),4.33(q,J=6.0Hz,1H),3.6 2-3.50(m,2H),3.25(t,J=6.8,2H),2.66(t,J=6.8Hz,2H),2.28(s,3H).

[0667] Compounds 238 and 250 were synthesized using a method similar to that in Example 163.

[0668]

[0669] Preparation of 4-methyl-N-(1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)piperidine-1-sulfonamide (164) Method 4

[0670]

[0671] Step 1: A mixed solution of 7-amino-3,4-dihydroisoquinolin-1(2H)-one 164-01 (3 g, 0.019 mol), 1-(fluorosulfonyl)-2,3-dimethyl-1H-imidazol-3-ium trifluoromethanesulfonate 164-02 (6.073 g, 0.019 mol) and DCM (30 mL) was stirred at 0°C for 16 hours. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (EA / PE=1:1) to give (1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)sulfamoyl fluoride 164-03 (2.5 g, 55.56% yield) as a white solid. MS (ESI) m / z 245.1 [M+H] + .

[0672] Step 2: A mixture of (1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)sulfamoyl fluoride (90 mg, 0.37 mmol), 4-methylpiperidine 164-04 (73 mg, 0.74 mmol) and DIEA (238 mg, 1.85 mmol) was stirred in ACN (3 mL) at 80 °C for 16 hours. After the reaction was completed, the solvent was removed in vacuo and the residue was purified by perp-HPLC (column - Gemini-C 18150x21.2mm, 5um; mobile phase: ACN-H2O (0.1% FA), 30%-50%), to obtain the desired product 164 (7.7 mg) as a white solid. MS (ESI) m / z 324.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.90 (s, 1H), 7.93 (s, 1H), 7.68 (d, J = 2.2Hz, 1H), 7.25 (dt, J = 16.8, 5.4Hz, 2H), 3.55 (d, J = 12.2Hz, 2H), 3.35 (d, J = 3. 0Hz,2H),2.82(t,J=6.6Hz,2H),2.68-2.61(m,2H),1.58(d,J=10.6Hz,2H),1.36(s,1H),0.95(dt,J=12.0,8.6Hz,2H),0.82(d,J=6.6Hz,3H).

[0673] Compounds 165-172 were synthesized in a similar manner to Example 164.

[0674]

[0675]

[0676]

[0677] Preparation of 2-(3-fluoro-5-methylphenyl)-2-((1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)acetonitrile (173)

[0678]

[0679] To a solution of 3-fluoro-5-methylbenzaldehyde 173-01 (100 mg, 0.72 mmol) and 7-amino-3,4-dihydro-2H-isoquinolin-1-one 1-01 solution (117 mg, 0.724 mmol) and trimethylsilane nitrile 173-02 (79 mg, 0.796 mmol) in MeCN (10 mL), tetrabutylammonium bromide (257 mg, 0.80 mmol) and IBX (223 mg, 0.80 mmol) were added. The mixture was stirred at room temperature for 16 hours. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (35 mL x 3), dried over Na2SO4 and concentrated to give a crude product, which was purified by preparative HPLC to give the desired product, 2-(3-fluoro-5-methyl-phenyl)-2-[(1-oxo-3,4-dihydro-2H-isoquinolin-7-yl)amino]acetonitrile 173 (14 mg, 0.043 mmol, 6.0% yield) as a white solid. MS (m / z): 357.3 [M+H] + ,1H NMR (400MHz, DMSO-d6) δ7.85(d,J=2.8Hz,1H),7.34(d,J=2.4Hz,1H),7.28(s,1H),7.19(d,J=9.6,1H),7.15-7.08(m,2H),6.94 (dd,J=8.0,2.8Hz,1H),6.78(d,J=9.6Hz,1H),6.04(d,J=9.6Hz,1H),3.30(d,J=2.8Hz,2H),2.77(t,J=6.4Hz,2H),2.37(s,3H).

[0680] Preparation of 7-((2,2,2-trifluoro-1-(3-fluoro-5-methylphenyl)ethyl)amino)-3,4-dihydroisoquinolin-1(2H)-one (174)

[0681]

[0682] Step 1: To a solution of 174-01 (200 mg, 1.45 mmol) and TMS-CF3 (618 mg, 4.34 mmol) in DMF (5 mL) was added potassium carbonate (20 mg, 0.145 mmol), and the reaction mixture was stirred at 25 ° C overnight. The reaction progress was monitored by TLC. After completion, water (10 mL) was slowly added to the mixture to quench the reaction. The reaction mixture was extracted with DCM, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 10: 1) to give the product (292 mg, 97%). 1H NMR (400 MHz, chloroform-d) δ 7.05 (qd, J = 1.7, 0.9 Hz, 1H), 7.02-6.95 (m, 1H), 6.91 (dddd, J = 9.5, 2.4, 1.6, 0.8 Hz, 1H), 4.94 (q, J = 6.7 Hz, 1H), 3.37 (bs, 1H).

[0683] Step 2: 2,6-dimethylpyridine (0.42 mL, 2.40 mmol) and trifluoromethylsulfonic anhydride (0.12 mL, 1.80 mmol) were added to a solution of 174-02 (250 mg, 1.20 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was then stirred at 25 °C for 2 hours. The progress of the reaction was monitored by TLC. SM disappeared and new spots appeared. The solvent was removed under reduced pressure and the crude product was used directly in the next step.

[0684] Step 3: To a solution of 174-03 (408 mg, 1.20 mmol) in DMF (5 mL) were added 1-01 (584 mg, 3.60 mmol) and cesium carbonate (1.17 g, 3.60 mmol). The reaction mixture was then stirred at 25 °C over the weekend. The progress of the reaction was monitored by LC / MS. A small peak was found for the desired mass. The mixture was diluted with water and extracted with EA. The organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product 174 (1 mg, 0.2%). MS (m / z): 353.02 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 7.78 (s, 1H), 7.34 (d, J = 2.4 Hz, 1H), 7.31-7.27 (m, 2H), 7.04-7.01 (m, 2H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 6.73 (d, J = 10.4 Hz, 1H), 5.74-5.44 (m, 1H), 3.28-3.26 (m, 2H), 2.70 (t, J = 6.4 Hz, 2H), 2.30 (m, 2H).

[0685] Preparation of 7-((3-(3-fluoro-5-methylphenyl)oxetan-3-yl)amino)-2-methyl-3,4-dihydroisoquinolin-1(2H)-one (175)

[0686]

[0687] Step 1: n-BuLi (2.4M hexane solution, 1.2 mL, 2.91 mmol) was added to a solution of 175-01 (500 mg, 2.65 mmol) in THF (15 mL) at -70 ° C, and the reaction mixture was stirred for 20 minutes. Then 2-methyl-N-(oxetane-3-ylidene) propane-2-sulfinamide (5.00 eq, 2.3 g, 13.2 mmol) was added at -70 ° C, and the mixture was warmed to room temperature and stirred for another 2 hours. The progress of the reaction was monitored by LC / MS. The desired mass was found in the main peak. The reaction mixture was diluted with water (50 mL) and extracted with DCM (100 mL, 2 times). The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 5: 1) to give the product 175-02 (480 mg, 64%). MS (m / z) 286.24 [M+H] +

[0688] Step 2: To a solution of 175-02 (220 mg, 0.77 mmol) in methanol (1.5 mL) was added HCl (4 M in dioxane, 0.35 mL, 1.16 mmol) at 0°C and the reaction mixture was stirred for 10 minutes. The progress of the reaction was monitored by LC / MS. The product was identified. The solvent was then removed and the solid was washed with MTBE and dried to give the product (52 mg, 37%). 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 2H), 7.32-7.18 (m, 2H), 7.17-7.05 (m, 1H), 4.97 (d, J = 7.5Hz, 2H), 4.88 (d, J = 7.5Hz, 2H), 2.37 (s, 3H).

[0689] Step 3: To a mixture of 175-03 (5.7 mg, 0.0316 mmol) and 175-04 (7.6 mg, 0.0316 mmol) were added t-BuONa (9.1 mg, 0.0948 mmol), tBuXPhos (1.3 mg, 0.0032 mmol), [Pd(cinnamyl)Cl]2 (0.82 mg, 0.0016 mmol) and TPGS-750-M (1.0 mL). The mixture was then stirred at 50 °C overnight. The progress of the reaction was monitored by LC-MS. The desired mass was found. The reaction mixture was then diluted with water (10 mL) and extracted with DCM (15 mL, 2 times). The organic layer was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the product 175 (5 mg, 46%). MS (m / z) 315.29 [M+H] +.1H NMR (400MHz, DMSO-d6) δ7.34 (s, 1H), 7.10-7.04 (m, 2H), 6.96-6.90 (m, 2H), 6.80 (d, J = 2.4Hz, 1H), 6.26 (dd, J = 8.4, 2.4Hz, 1H), 4.83 (d, J = 6.0Hz, 2H), 4.75 (d, J = 6.0Hz, 2H), 3.43 (t, J = 6.4Hz, 2H), 2.95 (s, 3H), 2.75 (t, J = 6.4Hz, 2H), 2.33 (s, 3H).

[0690] Preparation of 7-(1-(3-fluoro-5-methylphenyl)-2-hydroxyethoxy)-3,4-dihydroisoquinolin-1(2H)-one (176)

[0691]

[0692] Step 1: To a solution of 2-(3-fluoro-5-methyl-phenyl)oxirane 163-03 (100 mg, 0.657 mmol) in aqueous NaOH (5 mL) was added 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one 176-01 (107 mg, 0.66 mmol). The reaction was stirred at 100 °C overnight. The mixture was extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to give the desired product 7-[1-(3-fluoro-5-methyl-phenyl)-2-hydroxy-ethoxy]-3,4-dihydro-2H-isoquinolin-1-one 176 (11 mg, 0.034 mmol, 5.1% yield) as a white solid. MS (m / z): 316.3 [M+H] + ,1H NMR (400MHz, DMSO-d6) δ7.90(d,J=2.8Hz,1H),7.32(d,J=2.8Hz,1H),7.16(d,J=8.4Hz,1H),7.08-7.02(m,2H),7.00(d,J=9.6,1H),6.92(d,J=10.0 1H),5.30-5.25(m,1H),5.14(t,J=6.0Hz,1H),3.77-3.55(m,2H),3.31-3.27(m,2H),2.77(t,J=6.5Hz,2H),2.29(s,3H).

[0693] Preparation of 7-(((3-fluoro-5-methylphenyl)(pyridin-4-yl)methyl)amino)-3,4-dihydroisoquinolin-1(2H)-one (177) Method 5

[0694]

[0695] Step 1: To a solution of (3-fluoro-5-methyl-phenyl)boronic acid 177-01 (532 mg, 3.46 mmol) and pyridine-4-carbonitrile 177-02 (300 mg, 2.88 mmol) in water (9 mL) and TfOH (3 mL) were added 2-(2-pyridyl)pyridine (23 mg, 0.144 mmol) and Pd(OAc)2 (32 mg, 0.144 mmol). The mixture was stirred at 80 °C for 16 hours. The mixture was extracted with EA (25 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried over Na2SO4 and concentrated to give a crude product, which was purified by TLC (MeOH / DCM = 1 / 25) to give the desired product (3-fluoro-5-methyl-phenyl)-(4-pyridyl)methanone 177-03 (285 mg, 1.26 mmol, 43.6% yield) as a yellow oil. MS (m / z): 216.2 [M+H] + .

[0696] Step 2: A solution of 177-03 (50 mg, 0.23 mmol), 7-amino-3,4-dihydro-2H-isoquinolin-1-one 1-01 (38 mg, 0.23 mmol), p-toluenesulfonic acid (4.0 mg, 0.023 mmol) in toluene (5 mL) was stirred at 160 ° C. for 5 hours under microwave. The reaction was filtered and concentrated under vacuum to give the desired product 7-[(E)-[(3-fluoro-5-methyl-phenyl)-(4-pyridyl)methylene]amino]-3,4-dihydro-2H-isoquinolin-1-one 177-04 (45 mg, 0.075 mmol, yield 32.34%) as a yellow oil. MS (m / z): 360.3 [M+H] + .

[0697] Step 3: NaBH4 (9.5 mg, 0.25 mmol) was added to a solution of 177-04 (45 mg, 0.125 mmol) in methanol (5 mL). The solution was stirred at 25 ° C for 1 hour. The reaction was quenched with water (10 mL) and extracted with DCM (15 ml x 3). The combined organic layers were washed with brine (15 mL x 3), dried over sodium sulfate and concentrated to give a crude product, which was purified by preparative HPLC to give the desired product 7-[[(3-fluoro-5-methyl-phenyl)-(4-pyridyl)methyl]amino]-3,4-dihydro-2H-isoquinolin-1-one 177 (6.0 mg, 0.016 mmol, 13.1% yield) as a white solid. MS (m / z): 362.1 [M+H] +.1HNMR(400MHz,DMSO-d6)δ8.51(d,J=5.2Hz,2H),7.74(d,J=2.8Hz,1H),7.47-7 .41(m,2H),7.18(d,J=2.8Hz,1H),7.13(s,1H),7.10(d,J=9.8Hz,1H),6.98(d,J= 8.0Hz,1H),6.91(d,J=9.6,1H),6.81(dd,J=8.2,2.6Hz,1H),6.64(d,J=8.0Hz,1 H),5.73(d,J=7.6Hz,1H),3.28-3.25(m,2H),2.69(t,J=6.8Hz,2H),2.28(s,3H).

[0698] The synthesis method of compound 178 is similar to that of compound 177.

[0699]

[0700]

[0701] Preparation of N-(cyclobutyl(2,3-dichlorophenyl)methyl)quinolin-7-amine (179)

[0702]

[0703] A mixture of quinolin-7-amine (1.00 equiv., 150 mg, 1.04 mmol), (Ir[dF(CF3)ppy]2(dtbpy))PF6 (0.0500 equiv., 58 mg, 0.0520 mmol), cyclobutylboronic acid (2.00 equiv., 208 mg, 2.08 mmol), NaHSO4 (0.200 equiv., 25 mg, 0.208 mmol) and 2,3-dichlorobenzaldehyde (1.00 equiv., 182 mg, 1.04 mmol) was stirred in anhydrous DMF (10 mL) under nitrogen at 45 ° C under blue light for 2 days. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane / methanol 10 / 1) and then by Prep-HPLC to give N-[cyclobutyl-(2,3-dichlorophenyl)methyl]quinolin-7-amine (13 mg, 0.0353 mmol, yield 3.3%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.55(dd,J=4.3,1.8Hz,1H),7.98(dd,J=8.0,1.8Hz,1H),7.60(d ,J=8.9Hz,1H),7.53-7.42(m,2H),7.30(t,J=7.8Hz,1H),7.19-7.11(m,1H),7.07(dd,J=8 .0,4.3Hz,1H),6.94(d,J=7.4Hz,1H),6.55(d,J=2.3Hz,1H),4.92(t,J=8.1Hz,1H),2.78- 2.66(m,1H),2.17-2.06(m,1H),2.02-1.90(m,2H),1.86-1.79(m,2H),1.78-1.70(m,1H).

[0704] Preparation of N-(cyclopropyl(2,3-dichlorophenyl)methyl)quinolin-7-amine (180)

[0705]

[0706] A mixture of quinolin-7-amine (1.00 equiv., 144 mg, 0.999 mmol) and 2,3-dichlorobenzaldehyde (1.00 equiv., 175 mg, 0.999 mmol) was stirred in THF (10 mL) at 65 ° C for 2 hours. The reaction mixture was cooled, and bromo(cyclopropyl)magnesium (0.5M, THF) (3.00 equiv., 6.0 mL, 3.00 mmol) was added. The reaction was stirred at room temperature overnight and then quenched with water. The resulting mixture was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative thin layer chromatography (dichloromethane / methanol 15 / 1) and preparative high performance liquid chromatography (Prep-HPLC) to give N-[cyclopropyl-(2,3-dichlorophenyl)methyl]quinolin-7-amine (19 mg, 0.0548 mmol, 5.4% yield) as a yellow solid. LCMS (ESI, m / z) 343.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.53 (dd, J=4.3, 1.8Hz, 1H), 7.98 (dd, J=8.0, 1.8Hz, 1H), 7.60 (d,J=8.9Hz,1H),7.57-7.49(m,2H),7.32(t,J=7.9Hz,1H),7.22(d,J=6.9Hz,1H),7.15 (dd,J=8.9,2.4Hz,1H),7.07(dd,J=8.0,4.3Hz,1H),6.44(d,J=2.2Hz,1H),4.48(t,J=7 .5Hz,1H),1.33-1.23(m,1H),0.68-0.56(m,1H),0.56-0.45(m,2H),0.41-0.29(m,1H).

[0707] Preparation of 7-((1-(2,3-dichlorophenyl)ethyl)amino)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one (181) Method 6

[0708] 181-1 (100 mg, 0.61 mmol), 181-02 (307 mg, 1.22 mmol) and CsF (185 mg, 1.21 mmol) were dissolved in DMF (5 mL) and stirred at 30 °C for 4 hours. The mixture was extracted with EA, washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by preparative HPLC gave the title compound 181 (4.7 mg, 2.3%) as a light green solid. MS (m / z): 337.0 (M+H + ), 1 H NMR (400MHz, methanol-d4) δ10.71(s,1H),8.31(dd,J=7.8,1.8Hz,1H),8.19(dd,J=7.8,1.8Hz,1H),8.11(t,J=7.8Hz,1H),7.62(d,J=8.1Hz,1 H),7.43(d,J=7.0Hz,1H),6.86(dd,J=8.2,2.2Hz,1H),6.79(d,J=2.2Hz,1H),5.84(s,2H),5.55(p,J=6.8Hz,1H),2.22(d,J=6.6Hz,3H).

[0709] Compounds 182-186, 215, 229-231, 233-234A, 236, 245-246, 249, 257-263, 266-267, 271, 275, 277-278, 282, 288, 302-302C, 310-311, 314-316, 318, 321-322, 324-325, 330, 342, 349, 350-354, 382-388 were synthesized using a method similar to compound 181.

[0710] Depending on the substrate, some other substitution conditions are also used:

[0711] 2)DMF,H2O(1 / 1),KI,CaCO3; 3)DMF,KI,CaCO3; or 4)DMF,KI,CsCO3

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726] Preparation of 2,3-dichloro-N-(4-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)benzenesulfonamide (188) Method 7

[0727]

[0728] Step 1: A mixture of 188-1, 188-2 (470.36 mg, 3.747 mmol), K2CO3 (517.87 mg, 3.747 mmol) and Pd(dppf)Cl2 (91.39 mg, 0.1249 mmol) was stirred in 1,4-dioxane / H2O (10:2 mL) under N2 at 100°C for 16 hours. After cooling, the reaction mixture was diluted with water (60 mL) and extracted three times with ethyl acetate (20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE / EA=3:1) to give 188-3 (245 mg, 58.48% yield) as a yellow solid. MS (ESI) m / z 335.0 [M+H] + .

[0729] Step 2: A mixed solution of 188-3 (125 mg, 0.3726 mmol), Fe (104.05 mg, 1.863 mmol), NH4Cl (99.65 mg, 1.863 mmol) and EtOH / H2O (10:10 mL) was stirred at 80°C for 2 hours. After cooling, the reaction mixture was diluted with water (60 mL) and extracted three times with ethyl acetate (20 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE / EA=4:1) to give 188-4 (102 mg, 89.61% yield) as an oil. MS (ESI) m / z 305.0 [M+H] + .

[0730] Step 3: A mixed solution of 188-4 (92 mg, 0.3012 mmol), 2,3-dichlorobenzenesulfonyl chloride (73.95 mg, 0.3012 mmol), pyridine (71.47 mg, 0.9036 mmol) and DCM (10 mL) was stirred at 25 ° C for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (60 mL) and extracted three times with ethyl acetate (20 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA=5:1) to obtain 188-5 (129 mg, 83.23% yield) as an oil. MS (ESI) m / z 512.9 [M+H] + .

[0731] Step 4: 188-5 (119 mg, 0.2313 mmol) was dissolved in TFA (10 mL) and stirred at 80 °C for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (60 mL) and extracted three times with DCM (20 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by perp-HPLC (column-Gemini-C 18 150x21.2mm, 5um; mobile phase: ACN-H2O (0.1% FA, 40%-60%) to give the desired product 188 (31.2 mg) as a white solid. MS (ESI) m / z 382.8 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ11.16-11.03(m,2H),8.05(dd,J=8.0,1.6Hz,1H),7.97 -7.88(m,2H),7.59-7.50(m,3H),6.90(d,J=4.8Hz,1H),2.13(d,J=0.7Hz,3H).

[0732] Compound 189 was synthesized using a method similar to that of compound 188.

[0733]

[0734] Preparation of 6-((1-(4,5-dichlorothiazol-2-yl)ethyl)amino)quinazolin-4(3H)-one (202) Method 8

[0735]

[0736] Step 1: To a solution of 6-aminoquinazolin-4(3H)-one (88 mg, 0.54 mmol) in MeOH (5 mL) was added 202-1 (100 mg, 0.55 mmol) and AcOH (0.5 ml). The mixture was stirred at 80 °C for 1 hour. Water was added and the resulting mixture was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo to give (E)-6-(((4,5-dichlorothiazol-2-yl)methylene)amino)quinazolin-4(3H)-one 202-2 (100 mg, crude) as a yellow solid without purification. Mass (m / z): 325.40 [M+H] + .

[0737] Step 2: Methyl lithium (0.4 mL, 1.6 M) was added dropwise to a solution of 203-2 (100 mg, 0.30 mmol) in THF (10 ml) at 0°C. The mixture was stirred at 0°C for 10 minutes. Water was added, and the resulting mixture was extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative HPLC (H2O:ACN=30:70-100:0; the product was collected under 60% ACN) to give 202 (13.5 mg, yield 14.7%) as a white solid. Mass (m / z): 341.40 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ11.97(brs,1H),7.83(s,1H),7.48(d,J=8.8Hz,1H),7.22(d d,J=8.8,2.8Hz,1H),7.10-7.04(m,2H),4.86(p,J=6.4Hz,1H),1.57(d,J=6.8Hz,3H).

[0738] Compounds 187, 190, 207, 214, 216, 226A-226B, 232, 247-248, 256, 272, 308, 328, 338 and 344-346 were synthesized using a method similar to compound 202.

[0739]

[0740]

[0741]

[0742]

[0743]

[0744] Preparation of 2,3-dichloro-N-(1-(2-hydroxyethyl)-3,3-dimethyl-2-oxoindolyl-6-yl)benzenesulfonamide (240) Method 9

[0745]

[0746] Step 1: To a solution of methyl 2-bromoacetate (1.00 equiv., 153 mg, 0.999 mmol) in DMF (2 mL) at 0 °C was added sodium hydride (60%; 1.00 equiv., 40 mg, 0.999 mmol) followed by methyl 2-bromoacetate (1.00 equiv., 153 mg, 0.999 mmol). The reaction was stirred at the same temperature for 2 hours. The reaction was then quenched with 0.5 N HCl and extracted twice with ethyl acetate. The combined organic layers were washed twice with brine, dried over sodium sulfate and concentrated under vacuum to give methyl 2-(6-amino-3,3-dimethyl-2-oxo-indol-1-yl)acetate (240 mg, 0.97 mmol, 96.8% yield) as a yellow oil. Mass (m / z): 249.2 [M+H] + .

[0747] Step 2: Method 1 was used to obtain ethyl 2-[6-[(2,3-dichlorophenyl)sulfonylamino]-3,3-dimethyl-2-oxo-indolin-1-yl]acetate (400 mg, 0.875 mmol, 87.56% yield) as a brown solid. 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.05(dd,J=8.0,1.5Hz,1H),7.94(dd,J=8.1,1.5Hz,1H),7.55(t,J=8.0Hz,1H ),7.22(d,J=8.0Hz,1H),6.73(dd,J=7.9,1.9Hz,1H),6.64(d,J=1.9Hz,1H),4.47(s,2H),3.67(s,3H),1.21(s,6H).

[0748] Step 3: To a solution of methyl 2-[6-[(2,3-dichlorophenyl)sulfonylamino]-3,3-dimethyl-2-oxo-indol-1-yl]acetate (1.00 equiv., 70 mg, 0.15 mmol) in methanol (5 mL) was added NaBH4 (3.00 equiv., 17 mg, 0.459 mmol) and stirred at 60 °C overnight. The reaction was quenched with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under vacuum. The residue was purified by preparative HPLC to give 2,3-dichloro-N-[1-(2-hydroxyethyl)-3,3-dimethyl-2-oxo-indol-6-yl]benzenesulfonamide (11 mg, 0.025 mmol, 16.1% yield) as a white solid. Mass (m / z): 429.3 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.07(dd,J=7.9,1.5Hz,1H),7.90(dd,J=8.1,1.5Hz,1H),7.53(t,J=8.0Hz,1H),7.13(d,J=8. 0Hz,1H),6.78(d,J=2.0Hz,1H),6.67(dd,J=8.0,1.9Hz,1H),4.84(s,1H),3.60(t,J=6.0Hz,2H),3.49(t,J=4.9Hz,2H),1.17(s,6H).

[0749] Compounds 273, 289-290, 297, 300-301, 303, 305-307, 312, 312A, 312B, 317, 320, 320A, 323, 323A, 327, 329, 331-332, 334-337, 339-341, 341A, 341B, 343, 347-348, 347A, 355, 355A, 355B, 357-358, 361-368, 376-381 and 389-391 were synthesized using a method similar to compound 240.

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763] Preparation of 2-[6-[(2,3-dichlorophenyl)sulfonylamino]-3,3-dimethyl-2-oxo-indolyl-1-yl]acetic acid (241)

[0764]

[0765] A solution of methyl 2-[6-[(2,3-dichlorophenyl)sulfonylamino]-3,3-dimethyl-2-oxo-indol-1-yl]acetate (1.00 equiv., 40 mg, 0.088 mmol) in methanol (1 mL) was added to lithium hydroxide (2.00 equiv., 4.2 mg, 0.175 mmol) in water (0.2 mL) and then stirred at room temperature for 2 hours. The reaction was acidified to pH ~5 with 1N HCl and concentrated under vacuum. The residue was purified by preparative HPLC to give the desired product 241 (2.8 mg, 0.0062 mmol, 7.08% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.05(dd,J=7.9,1.6Hz,1H),7.88(dd,J=8.1,1.5Hz,1H),7.52(t,J=8.0Hz,1H),7.18(d,J =8.0Hz,1H),6.69(dd,J=8.0,1.9Hz,1H),6.64(d,J=1.9Hz,1H),4.25(s,2H),1.19(s,6H).Mass(m / z):443.3[M+H] + .

[0766] Preparation of 6-((2,3-dichlorophenyl)sulfonylamino)-3,3-dimethylindoline-1-carboxamide (242) Method 10

[0767]

[0768] Step 1: To a solution of 2,3-dichlorobenzenesulfonyl chloride 242-1 (1.00 eq, 454 mg, 1.849 mmol) and pyridine (3.00 eq, 438 mg, 5.548 mmol) in THF (10 mL) was added 3,3-dimethylindol-6-amine 242-2 (1.00 eq, 300 mg, 1.85 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hours. H2O (20 mL) was added and extracted with EtOAc. The combined organic layers were washed with HCl solution (1 mol / L) (25 mL x 3) and dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column to give 2,3-dichloro-N-(2-oxoindole-6-yl)benzenesulfonamide 242-3 (380 mg, 0.97 mmol, 52.6% yield) as a white solid. Mass(m / z):371 / 373[M+H] + .

[0769] Step 2: To a solution of 2,3-dichloro-N-(3,3-dimethylindol-6-yl)benzenesulfonamide 242-3 (1.00 equiv., 50 mg, 0.135 mmol) in DMF (10 mL) was added 1,1'-carbonyldiimidazole (3.00 equiv., 66 mg, 0.404 mmol). The reaction was stirred at 25 °C overnight. Ammonium hydroxide (5.00 equiv., 24 mg, 0.673 mmol) was added and the mixture was stirred at 25 °C for 5 min. The mixture was then extracted with EA (25 mLx3). The combined organic layers were washed with brine (15 mLx3), dried over Na2SO4 and concentrated to give the crude product, which was purified by preparative HPLC to give the desired product 242 (5.6 mg, 0.0134 mmol, 9.94% yield) as a white solid. Mass (m / z): 414.1 / 416.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.61(s,1H),7.99(dd,J=8.0,1.6Hz,1H),7.90(dd,J=8.0,1.6Hz,1H),7.66(d,J=2.0Hz,1H ),7.52(t,J=8.0Hz,1H),6.97(d,J=8.0Hz,1H),6.59(dd,J=8.0,2.0Hz,1H),6.24(s,2H),3.57(s,2H),1.18(s,6H).

[0770] Compounds 243, 276, 279-281, 284-285, 295-296, 299, 309, 313, 319, 326, and 333 were synthesized in a similar manner to compound 242.

[0771]

[0772]

[0773]

[0774]

[0775] Preparation of 7-((1-(2,3-dichlorophenyl)-3-hydroxypropyl)amino)isoquinolin-1(2H)-one (252) (mixture of stereoisomers)

[0776]

[0777] Step 1: A mixture of 3-amino-3-(2,3-dichlorophenyl)propanoate 252-1 (400 mg, 1.6122 mmol), 7-bromo-1-methoxy-1,2-dihydroisoquinoline (387 mg, 1.61 mmol), RuPhosPdG2 (250 mg, 0.32 mmol) and Cs2CO3 (1576 mg, 4.84 mmol) was dissolved in 1,4-dioxane (10 mL) and stirred at 100 ° C for 16 hours under N2 protection. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (EA:PE=1:1) to obtain compound 252-2 (300 mg, yield 45.6%) as an oil. MS (m / z) 405.1 [M+H] + .

[0778] Step 2: A mixture of 252-2 (300 mg, 0.74 mmol) and LiOH (156 mg, 3.71 mmol) was stirred in THF:H2O (5 mL) under nitrogen at 25 ° C for 2 hours. The reaction mixture was extracted with EA (30 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (MeOH:CH2Cl2=1:10) to give 3-(2,3-dichlorophenyl)-3-((1-methoxyisoquinolin-7-yl)amino)propanoic acid (200 mg, 68.9% yield) as an oil. MS (ESI) m / z 391.1 [M+H] + .

[0779] Step 3: A mixture of 3-(2,3-dichlorophenyl)-3-((1-methoxyisoquinolin-7-yl)amino)propanoic acid (200 mg, 0.5128 mmol) and BH3 in THF (5 mL) was stirred at 50 ° C for 16 hours. The reaction was quenched with water and extracted with EA (50 mL). The organic layers were combined and concentrated under vacuum to give oily compound 252-3 (110 mg, yield 56.9%). MS (m / z) 377.1 [M+H] + .

[0780] Step 4: A mixed solution of 252-3 (110 mg, 0.28 mmol), TMSCl (61 mg, 0.5648 mmol), and LiCl (24 mg, 0.5714 mmol) was stirred in DMF (3 mL) at 80 °C. 18 The reaction mixture was diluted with water (20 mL) and extracted three times with EA (30 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by full chromatography HPLC (column-Gemini-C 18 150x21.2mm, 5um; mobile phase: ACN-H2O (0.1% TFA, 30%-70%) to obtain the desired product (31.6 mg) as a white solid. MS (m / z) 362.9 [M+H] + .1H NMR (400MHz, DMSO-d6) δ10.83(d,J=5.0Hz,1H),7.45(dd,J=8.0,1.6Hz,1H),7.39(dd,J=8.0,1.5Hz,1H),7.32-7.23(m,2H),6.99-6.94(m,2H),6. 79-6.73(m,2H),6.27(d,J=7.0Hz,1H),4.96(dd,J=13.0,7.6Hz,1H),4.6 4(t,J=5.0Hz,1H),3.56(ddd,J=14.8,9.4,5.5Hz,2H),1.91-1.73(m,2H).

[0781] Preparation of 7-((1-(2,3-dichlorophenyl)-2-hydroxy-2-methylpropyl)amino)isoquinolin-1(2H)-one (253) (mixture of stereoisomers)

[0782]

[0783] Step 1: A mixture of 253-1 (180 mg, 1.035 mmol) and MeLi (0.9 mL) was stirred in THF (5 mL) under nitrogen at -78 ° C for 30 minutes. The reaction was quenched with water (20 mL) and extracted with EA (30 mL), and the organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (MeOH: CH2Cl2 = 1: 10) to give 253-2 (50 mg, yield 27.7%) as a yellow solid. MS (m / z) 391.1 [M+H] + .

[0784] Step 2: A mixture of 253-2 (50 mg, 0.13 mmol), TMSCl (28 mg, 0.26 mmol) and LiCl (11 mg, 0.26 mmol) was stirred in DMF (2 mL) at 80 ° C for 18 hours. The reaction was diluted with water (20 mL) and extracted three times with EA (30 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude product, which was purified by high performance liquid chromatography (column-Gemini-C 18 150x21.2mm, 5um; mobile phase: ACN-H2O (0.1% FA), 40%-60%) to give the desired product 253 (10.5 mg) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ10.79(d,J=5.6Hz,1H),7.50(dd,J=8.0,1.5Hz,1H),7.4 4(dd,J=8.0,1.5Hz,1H),7.29-7.21(m,2H),7.13(d,J=2.0Hz,1H),7.09(dd,J=8. 6,2.5Hz,1H),6.75(dd,J=7.0,5.8Hz,1H),6.45(d,J=8.8Hz,1H),6.26(d,J=6.6 Hz,1H),4.82(s,1H),4.79(s,1H),1.31(s,3H),1.02(s,3H).MS(m / z)377.0[M+H] + .

[0785] Preparation of 2-[6-[(2,3-dichlorophenyl)sulfonylamino]-3,3-dimethyl-2-oxo-indolyl-1-yl]acetamide (255) Method 11

[0786]

[0787] A mixture of 241 (1.00 equiv, 120 mg, 0.27 mmol), ammonium chloride (6.00 equiv, 87 mg, 1.62 mmol), N-ethyl-N-isopropyl-propan-2-amine (10.0 equiv, 350 mg, 2.71 mmol) and HATU (2.00 equiv, 206 mg, 0.541 mmol) was stirred in DMF (1 mL) at room temperature overnight. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to afford 255 as a yellow solid (7.3 mg, 0.016 mmol, 5.97% yield). 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.06(dd,J=7.9,1.5Hz,1H),7.93(dd,J=8.1,1.5Hz,1H),7.65(s,1H),7.57(t,J=8.1Hz,1H),7. 24(s,1H),7.18(d,J=8.0Hz,1H),6.70(dd,J=8.0,2.0Hz,1H),6.61(d,J=1.9Hz,1H),4.15(s,2H),1.20(s,6H).Mass(m / z):442.3[M+H] + .

[0788] Compounds 286-287 and 291 were synthesized using a method similar to compound 255.

[0789]

[0790]

[0791] Preparation of 2,3-dichloro-N-(2'-oxospiro[cyclobutane-1,3'-indoline]-6'-yl)benzenesulfonamide (218) Method 13

[0792]

[0793] Step 1: To a solution of 2,3-dichlorobenzenesulfonyl chloride 242-1 (1.00 eq, 300 mg, 1.22 mmol) and pyridine (3.00 eq, 0.29 mL, 3.67 mmol) in THF (10 mL) was added 6-aminoindolin-2-one 218-1 (1.00 eq, 181 mg, 1.22 mmol) at 25 °C. The mixture was stirred at 25 °C for 12 hours. H2O (20 mL) was added and the organic phase was extracted with EtOAc. The combined organic layers were washed with HCl solution (1 mol / L) (25 mLx3), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column to give 218-2 (415 mg, 1.07 mmol, 87.5% yield) as a red solid. Mass (m / z): 357 / 359 [M+H] + .

[0794] Step 2: n-BuLi (4.00 eq., 0.5 mL, 1.12 mmol) was added dropwise to a stirred and cooled (-70 ° C) suspension of 218-2 (1.00 eq., 100 mg, 0.28 mmol) and N-isopropylpropan-2-amine 218-4 (4 eq., 113 mg, 1.12 mmol) in anhydrous THF (20 mL) under Ar2. The temperature was kept below -70 ° C during the addition. After the addition was completed, the temperature was raised to 0 ° C, and then a solution of 1,3-dibromopropane 218-3 (1.1 eq., 62 mg, 0.308 mmol) in anhydrous THF (10 mL) was added dropwise while keeping the temperature below -70 ° C. After the addition was completed, the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure to a smaller volume. The residue was diluted with EtOAc (20 mL) and brine (20 mL). The biphasic mixture was then stirred vigorously. The pH was adjusted to 5 by slowly adding 4M aqueous hydrochloric acid. The biphasic system was filtered through a glass filter to remove the solids present in the biphasic system. The solids were rinsed with EtOAc, collected and dried in air to give the first batch of 218 (1.7 mg, 0.0042 mmol, 1.51% yield) as a white solid. Mass (m / z): 397.2 / 399.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ9.97(s,1H),8.34(s,1H),7.94(dd,J=8.0,1.6Hz,1H),7.78(d,J=8.0Hz,1H),7.44(t,J=8 .0Hz,1H),7.23(d,J=8.0Hz,1H),6.61-6.46(m,2H),2.31(d,J=7.2Hz,2H),2.19-2.11(m,2H),2.08-1.98(m,2H).

[0795] 235 was synthesized using a similar method to 218.

[0796]

[0797] Preparation of 7-(1-(2,3-dichlorophenyl)-2-hydroxyethoxy)isoquinolin-1(2H)-one (228) (mixture of stereoisomers)

[0798]

[0799] Step 1: Add NBS (1.62 g, 9.10 mmol) to a stirred solution of 228-1 (2.00 g, 9.10 mmol) and BPO (0.22 g, 0.91 mmol) in CCl4 (20 mL). Stir the mixture at 70 °C for 16 hours. LCMS showed the reaction was complete. Filter the mixture. Concentrate the filtrate to give 228-2 (2.3 g, 84.4%) as a yellow oil.

[0800] Step 2: Solution 228-2 (90 mg, 0.30 mmol) and 1-methoxyisoquinolin-7-ol TBAB (9.7 mg, 0.03 mmol) (53 mg, 0.30 mmol) was dissolved in DCM (5 mL) and a solution of NaOH (13 mg, 0.33 mmol) in H2O (0.5 mL) was added. The mixture was stirred at 25 °C for 16 hours. The mixture was treated with H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative thin layer chromatography (PE / EA=3:1) to give 228-3 (80 mg, 67.5%) as a yellow solid.

[0801] Step 3: To the solution 228-3 (70 mg, 0.18 mmol) was dissolved in MeOH (5 mL) and NaBH4 (20 mg, 0.54 mmol) was added. The mixture was stirred at 25 ° C for 4 hours. The mixture was quenched with H2O (20 mL) and extracted with EA (20 mLx3). The combined organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated. The residue was purified by preparative thin layer chromatography (PE / EA=1:1) to 228-4 (48 mg, 73.6%) as a white solid.

[0802] Step 4: 228-4 (40 mg, 0.11 mmol) solution The mixture was stirred in dioxane (2 mL) and 6N HCl (2 mL) at 100 ° C for 4 hours. LCMS showed that the reaction was complete. The mixture was concentrated and the residue was purified by preparative HPLC (sunfire5um19-150mm, mobile phase: MeCN-H2O (0.1% FA), gradient: 25-75-8 minutes, flow rate: 20 mL / minute) to give 228 (26 mg, 67.4%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ11.17(d,J=4.8Hz,1H),7.63-7.54(m,2H),7.46-7.40(m,2H),7.37-7.30(m,2H),7.01(dd,J=6.8Hz ,5.6Hz,1H),6.47(d,J=6.8Hz,1H),5.71(t,J=4.8Hz,1H),5.37(t,J=6.0Hz,1H),3.75(t,J=5.2Hz,2H).Mass(m / z):349.9[M+H] + .

[0803] Preparation of 6-((1-(4,5-dichlorothiazol-2-yl)-3-hydroxypropyl)amino)-3,3-dimethylindolin-2-one (292) (mixture of stereoisomers) Method 14

[0804]

[0805] Step 1: Dissolve 4,5-dichlorothiazole-2-carboxaldehyde (1.00 eq, 500 mg, 2.75 mmol) in THF (10 mL), add 6-amino-3,3-dimethyl-indolin-2-one (1.00 eq, 484 mg, 2.75 mmol), heat to 60 ° C, and concentrate after the reaction to obtain 292-1 (880 mg, 2.59 mmol, yield 94.2%) as a yellow solid.

[0806] Step 2: n-BuLi (2.4M, 10.0eq, 7.3mL, 17.8mmol) in n-hexane was added to a solution of diisopropylamine (10.0eq, 2.5mL, 17.8mmol) in distilled THF (30mL) at -40°C. After stirring for 1 hour, the solution was cooled to -78°C and dry methyl acetate (10.0eq, 1.4mL, 17.8mmol) was slowly added. After stirring for 1 hour, a solution of 292-1 (1.00eq, 604mg, 1.78mmol) in distilled THF (15.0mL) was added to the reaction mixture. The reaction mixture was stirred at -78°C for 10 minutes and then NH4Cl solution was added at the same temperature to terminate the reaction. The reaction mixture was extracted with EA and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EA:Hex=0-1:1) to give yellow solid 3-(4,5-dichlorothiazol-2-yl)-3-[(3,3-dimethyl-2-oxo-indolyl-6-yl)amino]propionic acid methyl ester (180 mg, 0.434 mmol, yield 24.5%). Mass (m / z): 414.2 [M+H] +

[0807] Step 3: To a solution of 292-2 (1.00 equiv., 60 mg, 0.145 mmol) in methanol (15 mL) was added NaBH4 (10.0 equiv., 55 mg, 1.45 mmol). The mixture was stirred at room temperature for 5 hours, and then 20 mL of water was added. The resulting solution was extracted with EA and concentrated in vacuo. The residue was subjected to flash column chromatography using silica gel (EA: Hex = 0-1) to obtain the final product 292 (25 mg, 0.065 mmol, yield 44.5%) as a white solid. Mass (m / z): 386.2 [M+H] +1 H NMR (400 MHz, methanol-d4) δ 10.87 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 7.03-6.93 (m, 2H), 5.56-5.45 (m, 2H), 4.37 (s, 2H), 2.90-2.71 (m, 2H), 1.97 (s, 6H).

[0808] Compounds 293 and 294 were synthesized using a similar method to 292.

[0809]

[0810]

[0811] Preparation of 6-((1-(4,5-dichlorothiazol-2-yl)ethyl)amino)-8-fluoro-3-(1H-pyrazol-5-yl)quinazolin-4(3H)-one (356-rac), rel-(S)-6-((1-(4,5-dichlorothiazol-2-yl)ethyl)amino)-8-fluoro-3-(1H-pyrazol-5-yl)quinazolin-4(3H)-one (356) and Rel-(R)-6-((1-(4,5-dichlorothiazol-2-yl)ethyl)amino)-8-fluoro-3-(1H-pyrazol-5-yl)quinazolin-4(3H)-one (356A) Method 15

[0812]

[0813] Step 1: Under nitrogen, cesium carbonate (172.9 g, 0.53 mol) and p-methoxybenzoyl chloride (33.12 g, 0.21 mol) were added to a solution of 356-01 (20.0 g, 0.1769 mol) in ACN (200 mL) at 0 ° C. Under nitrogen, the reaction mixture was stirred at 60 ° C for 16 hours. The mixture was poured into water (100 mL) and extracted with EA (100 mLx3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product 356-02 (15.0 g, 36.4%) as an off-white solid. MS (m / z): 234.1 [M+H] + .

[0814] Step 2: To a solution of 356-02 (12.0 g, 0.0515 mol) in THF (120 mL) and NH4Cl aqueous solution (96 mL) was added Fe (17.26 g, 0.3090 mol) at 25°C. The mixture was stirred at 60°C for 4 hours. The reaction mixture was poured into water (100 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give 356-03 (8.9 g, 85.1%) as a yellow solid. MS (m / z): 204.1 [M+H] + .

[0815] Step 3: Under nitrogen, HATU (9.86 g, 0.02 mol) and 2-amino-5-bromo-3-fluorobenzoic acid (6.07 g, 0.026 mol) were added to a solution of DMF (40 mL) at 0 ° C. DIEA (8.37 g, 0.0648 mol) was added at 0 ° C. The reaction mixture was stirred at 25 ° C. for 3 hours under nitrogen. The reaction mixture was poured into water (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude product 356-04 (20.0 g, 50%) as a yellow solid. MS (m / z): 419.0 [M+H] + .

[0816] Step 4: At 20 ° C, triethyl orthoformate (35.4 g, 0.2390 mol) and TsOH (4.11 g, 0.0239 mol) were added to a solution of 356-04 (10.0 g, 0.0239 mol) in toluene (100 mL) at 20 ° C. The reaction mixture was stirred at 120 ° C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EA (50 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by silica gel (PE / EA=20 / 1-5 / 1) to give 356-05 (2.9 g, 28.32%) as a brown solid. MS (m / z): 429.0 [M+H] + .

[0817] Step 5: Xantphos (0.39 g, 0.0007 mol) and Pd2(dba)3 (0.31 g) were added to a solution of 356-04 (2.9 g, 0.0068 mol), Boc-NH2 (0.96 g, 0.0081 mol) and cesium carbonate (6.65 g, 0.0204 mol) in 1,4-dioxane (30 mL) under nitrogen at 20°C. The reaction mixture was stirred at 85°C for 8 hours under nitrogen. The reaction mixture was poured into water (50 mL x 3) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a crude product. The crude product was purified on silica gel (PE / EA = 20 / 1-3 / 1) to give 356-06 (1.4 g, 44.5%) as a yellow solid. MS (m / z): 466.2 [M+H] + .

[0818] Step 6: 356-06 (1.3 g, 0.0028 mol) was dissolved in DCM (10 mL) and 4N HCl / dioxane (5 mL) and stirred at 25°C for 3 hours. The reaction solution was concentrated and dried in vacuo to give crude 356-07 (1.0 g, 98.0%) as a yellow solid. MS (m / z): 366.1 [M+H] + .

[0819] Step 7: 4,5-dichloro-2-(1-chloroethyl)-1,3-thiazole (355.6 mg, 1.6422 mmol), calcium carbonate (410.9 mg, 4.1055 mmol) and potassium iodide (68.2 mg, 0.4105 mmol) were added to a solution of 356-07 (300.0 mg, 0.8211 mmol) in DMF / H2O=1 / 1 (3 mL) at 20°C. The reaction mixture was stirred at 100°C for 16 hours. The mixture was poured into water (20 mL) and extracted with EA (20 mLx3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product 356-08 (150 mg, 33.5%) as a yellow solid. MS (m / z): 545.1 [M+H] + .

[0820] Step 8: 356-08 (150.0 mg, 0.2750 mmol) was dissolved in a solution of DCM: TFA: TfOH = 3: 1: 0.5 (4.5 mL) and stirred at 30 ° C for 16 hours. The mixture was poured into water (20 mL) and extracted with EA (20 mL x 3). The combined organic layer was washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC to give the product 356-rac (47 mg, 40.2%) as a yellow solid. MS (m / z): 425.0 [M + H] + .356-rac (40 mg) was purified by preparative chiral HPLC (preparative chiral HPLC conditions: chromatographic column: IG; mobile phase: Hex (0.1% TFA)-EtOH; gradient: HEX75 (0.1% TFA): EtOH 25-30 min-500 VL) to give 356 (13.20 mg, 33.0% yield, RT = 16.628 min, single unknown stereoisomer) and 356A (10.02 mg, 25.05% yield, RT = 23.211 min, single unknown stereoisomer) as off-white solids. 356-rac: 1H NMR(400MHz,DMSO-d6)δ13.12(s,1H),8.32(s,1H),7.90(s,1H),7.50-7.26(m ,1H),7.26-7.00(m,2H),6.64(s,1H),4.98(m,1H),1.58(d,J=6.1Hz,3H); 356: 1 H NMR (400MHz, DMSO-d6) δ13.12(s,1H),8.32(s,1H),7.90(s,1H),7.50-7.26(m,1H),7. 26-7.00(m,2H),6.64(s,1H),4.98(m,1H),1.58(d,J=6.1Hz,3H).MS(m / z):425.2[M+H] + .356A: 1 H NMR (400MHz, DMSO-d6) δ13.12(s,1H),8.32(s,1H),7.90(s,1H),7.50-7.26(m,1H),7. 26-7.00(m,2H),6.64(s,1H),4.98(m,1H),1.58(d,J=6.1Hz,3H).MS(m / z):425.2[M+H] + .

[0821] Compounds 359 and 369-375 were synthesized using a method similar to that of 356.

[0822]

[0823]

[0824] Preparation of 2-(6-((2-(4,5-dichlorothiazol-2-yl)propan-2-yl)amino)-3-methyl-2H-indazol-2-yl)acetamide (360)

[0825]

[0826] Step 1: To a solution of 360-01 (200.0 mg, 0.943 mmol), ethyl 2-{3-methyl-6-[(4-nitro-1-sulfonylphenyl)amino]indazol-2-yl}acetate (395.5 mg, 0.943 mmol) and PPh3 (371.0 mg, 1.4145 mmol) in THF (5 mL) was added DIAD (286.0 mg, 1.4145 mmol) at 0 ° C and N2 atmosphere. The mixture was stirred at 50 ° C for 16 hours. The mixture was poured into water (20 mL) and extracted with EA (10 mLx3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative thin layer chromatography (PE / EA=1 / 1) to give the product 360-02 (120.0 mg, 20.78%) as a yellow solid. MS (m / z): 612.1, 614.1 [M+H] + .

[0827] Step 2: A mixture of 360-02 (100.0 mg, 0.163 mmol) and NH3 was stirred in MeOH (2 mL, 7 mol / L) at 25 °C for 4 hours. The mixture was concentrated to give a crude product. The crude product was purified by preparative HPLC to give product 360-03 (11.0 mg, 11.55%) as a white solid. MS (m / z): 583.1, 585.1 [M+H] + .

[0828] Step 3: To a solution of 360-03 (9 mg, 0.015 mmol) in CH3CN (8 ml) was added benzenethiol (3.3 mg, 0.03 mmol), K2CO3 (8.5 mg, 0.06 mmol). The mixture was stirred at 25°C for 2 hours, water (30 ml) was added and extracted with EtOAc (1 mL×3). The solution was washed with water (2x5 ml) and saturated brine solution (30 ml). The organics were then separated and dried (MgSO4) and then concentrated to dryness. The crude product was purified by preparative HPLC to give the desired product as a white solid (2 mg), yield: 30.92%. 1 H NMR (400MHz, DMSO-d6) δ7.54(m,1H),7.39(dd,J=8.8,2.0Hz,1H),7.25(m,1H),6.57(dd,J=9.0,2.1 Hz,1H),6.38(s,1H),5.82(s,1H),4.83(m,2H),2.42(s,3H),1.65(s,6H).Mass(m / z):398.31[M+H] + .

[0829] Compounds 1A-15A were prepared and characterized as follows.

[0830]

[0831]

[0832]

[0833]

[0834]

[0835] Example II. SAMR1 (50-724) enzyme assay

[0836] Enzyme assays were performed in 384-well plates using Dulbecco's phosphate buffered saline (PBS) as reaction buffer. Purified SARM1 (50-724) at a final concentration of 2 nM was pre-incubated with test compounds at a final assay concentration of 1% DMSO for 15 minutes at room temperature. The activator was activated by adding 200 μM nicotinamide mononucleotide (NMN) as an activator and 100 μM NAD + The reaction was initiated with 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 an appropriate concentration with 10 mM ammonium acetate (pH 9.75) and analyzed using LC-MS / MS.

[0837] The SARM1 inhibitory activities of compounds 1-391 and compounds 1A-15A are summarized in Table 3. In Table 3, the activities are provided as follows: A = IC 50 ≤100nM; B=100nM <IC 50 ≤500nM; C=500nM <IC 50 ≤1000nM; D=IC 50 >1000nM.

[0838] Table 3

[0839]

[0840]

[0841]

[0842]

[0843] All publications cited in this specification, including but not limited to published texts and published applications, are incorporated herein by reference as if fully set forth. If some of the contents of the publications cited herein contradict or are inconsistent with the present disclosure, the present disclosure shall prevail.

[0844] One skilled in the art will readily recognize from the present disclosure and claims that various changes, modifications and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.

Claims

1. The compound of the following structural formula 1: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl, a 5- to 10-membered heteroaryl ring, a 5- to 10-membered carbocyclic ring, or a 5- to 10-membered heterocyclic ring; Ring B is phenyl, a 9- to 11-membered aryl ring, a 9- to 11-membered heteroaryl ring, or a 9- to 11-membered heterocyclic ring; R a is selected from =O, C3-C6 cycloalkyl, -O(C1-C4 alkyl), COOH, CN, CONH2, -C(=O)NH(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -C(=O)O(C1-C4 alkyl), halogen and C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, -OH, cyclopropyl, oxetanyl and azetidine; R b is selected from the group consisting of =O, OH, halogen, CN, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), optionally substituted C3-C6 cycloalkyl, optionally substituted C3-C6 heterocyclyl, optionally substituted C5-C6 heteroaryl, -O(C1-C4 alkyl), -C(=O)(C1-C4 alkyl), -C(=O)(optionally substituted C3-C6 cycloalkyl), -C(=O)(optionally substituted 5- to 6-membered heterocyclyl), -C(=O)(optionally substituted 5- to 6-membered heteroaryl), -C(=O)(CH2)pC(=O)NH2, -NHC(=O)(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -C(=O)NH(CH2)pOH, -S(=O)2NH2, C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, NH2, OH, OCH3, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -COOH, -C(=O)NH2, CN, C3-C5 cycloalkyl, phenyl, -C(=O)(C1-C4 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(5- to 6-membered heterocyclyl), -C(=O)(optionally substituted 5- to 6-membered heteroaryl), C(=O)NH(CH2)pOH, and 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C3 alkyl, =O, -NH2, -CN, -CONH2, halogen, and 4 to 6 membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O, -OH, -NH2, -CN, -CONH2, halogen and C1-C3 alkyl, or Two R connected to the same position of ring B b Together they form a C3-C6 cycloalkyl group, wherein R4 and R5 are each independently selected from H and C1-C3 alkyl or R4 and R5 together form a 3 to 5 membered cycloalkyl; L is selected from in R1 is H, D or C1-C6 alkyl, and R2 is selected from CN, C1-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, 5- or 6-membered heteroaryl, Phenyl, which is optionally substituted by 1-3 groups selected from the group consisting of C1-C4 alkyl and Halogens, and C1-C6 alkyl, which is optionally substituted by 1-3 groups selected from the group consisting of halogen, OH, CN, -SO2CH3, -NHSO2CH3, -CONH2, OCH3 and phenyl, or R1 and R2 together form a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group; R3 is C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from the group consisting of halogen, O(C1-C3 alkyl), OH, and NH2; m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3 and 4, and p is an integer selected from 1, 2, 3 and 4; Provided that the compound is not any of Compound 1A to Compound 121A.

2. The compound of claim 1, wherein the compound has the following structural formula 14a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H, CH2CN, and C1-C2 alkyl, R b2 is selected from H, halogen, CN, OCH3, C1-C3 alkyl, and C3-C5 cycloalkyl, and L is selected from 3. The compound of claim 1, wherein the compound has the following structural formula 14b: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, R b2 is selected from H, halogen, CN, OCH3, C1-C3 alkyl, and C3-C5 cycloalkyl, and L is selected from 4. The compound of claim 1, wherein the compound has the following structural formula 14c: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, which is optionally substituted by C3-C4 cycloalkyl, R b2 is selected from H, halogen and C1-C3 alkyl, and L is selected from 5. The compound of claim 1, wherein the compound has the following structural formula 14d: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from 6. The compound of claim 1, wherein the compound has the following structural formula 14e: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from 7. The compound of claim 1, wherein the compound has the following structural formula 14f: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from 8. The compound of claim 1, wherein the compound has the following structural formula 14g: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from 9. The compound of claim 1, wherein the compound has the following structural formula 14h-1 or 14h-2: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 and R a3 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from 10. The compound of claim 1, wherein the compound has the following structural formula 14i: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 ,R a2 and R a3 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from 11. The compound of claim 1, wherein the compound has the following structural formula 14j: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 ,R a2 and R a3 are independently selected from F, Cl, Br, methyl, and OCH3, Y2 is selected from N and O, and L is selected from 12. The compound of claim 1, wherein the compound has the following structural formula 15a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, and L is selected from 13. The compound of claim 1, wherein the compound has the following structural formula 16-1 or 16-2: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The rest is H.

14. The compound of any one of claims 1 and 13, wherein the compound has the following structural formula 16-1a or 16-2a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, and L is selected from 15. The compound of claim 1, wherein the compound has the following structural formula 17: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The rest are H, R b1 is selected from H and C1-C2 alkyl, and R b2 Selected from H and C1-C4 alkyl.

16. The compound of any one of claims 1 and 15, wherein the compound has the following structural formula 17a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, R b2 is selected from H and C1-C4 alkyl, and L is selected from 17. The compound of claim 1, wherein the compound has the following structural formula 18: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 , R a2 , R a3 , R a4 and R a5 Zero, one, two or three of them are independently selected from F, Cl, Br, methyl, and OCH3, and R a1 , R a2 , R a3 , R a4 and R a5 The rest are H, R b1 Selected from =O, -NHCOCH3, and OH.

18. The compound of any one of claims 1 and 17, wherein the compound has the following structural formula 18a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from =O, OH, and -NHCOCH3, and L is selected from 19. The compound of claim 1, wherein the compound has the following structural formula 20: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein neither or one of Y1 and Y2 is N and the other is C, R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H and C1-C2 alkyl, provided that when Y2 is N, R b1 Does not exist, R b2 is selected from H, CN, C1-C2 alkyl, and -C(=O)NH2, provided that when Y1 is N, R b2 Does not exist, R b3 is selected from H and C1-C2 alkyl, R b4 is selected from H and C1-C2 alkyl, and L is selected from 20. The compound of claim 1, wherein the compound has the following structural formula 21a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from 5- to 6-membered heteroaryl and 5- to 6-membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O and C1-C3 alkyl, and L is selected from 21. The compound of claim 1, wherein the compound has the following structural formula 21b: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from -C(=O)NH(C1-C4 alkyl), OCH3, and -C(=O)O(C1-C4 alkyl), R b2 is selected from H and -C(=O)NH2, and L is selected from 22. The compound of claim 1, wherein the compound has the following structural formula 22a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 independently selected from F, Cl, Br, methyl, and OCH3, zero, one or two of Y1, Y2 and Y3 are N and the rest of Y1, Y2 and Y3 are C, R b is selected from C1-C2 alkyl, C3-C5 cycloalkyl, CN, CONH2, and halogen, n is 0, 1 or 2, and L is selected from 23. The compound of claim 1, wherein the compound has the following structural formula 23a: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, R b1 is selected from H, C1-C3 alkyl, halogen, C3-C5 cycloalkyl, CN, and CONH2, provided that when Y is S or O, R b1 does not exist, one of Y2 and Y3 is S or O, and the others are C, and L is selected from 24. The compound of claim 1, wherein the compound has the following structural formula 24: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein one of X1, X2 and X3 is N and the other two of them are C, Y2 is selected from C, N and O, and R b1 is selected from C1-C2 alkyl, C3-C5 cycloalkyl, O(C1-C3 alkyl), and halogen, and wherein L is 25. The compound of claim 1, wherein the compound has the following structural formula 28-1 or 28-2: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2, Y1, Y2 and Z1 are independently selected from C and N, R a1 is selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl and cyclopropyl, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R c is H, halogen, CN or methyl.

26. The compound of claim 1, wherein the compound has the following structural formula 29-1 or 29-2: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2 and Z1 are independently selected from C and N, R a1 is selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl and cyclopropyl, R b1 is selected from the group consisting of F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, CH2OH, cyclopropyl, and OCH3, wherein R b1 When absent or C1-C4 alkyl, when attached to N in ring B, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

27. The compound of claim 1, wherein the compound has the following structural formula 30-1, 30-2, 30-3, 30-4 or 30-5: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each is independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, CN, CONH2, CH2NH2, and cyclopropyl, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from C1-C4 alkyl, which is optionally substituted by -C(=O)NH2, 3- to 5-membered cycloalkyl, which is optionally substituted by OH, and 5-6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the following: F, Cl, Br, Me, CF3, CF2H, CN, CONH2 and NH2, and R c is H, halogen, CN or methyl.

28. The compound of claim 1, wherein the compound has the following structural formula 31-1 or 31-2: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2 and Z1 are independently selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl and cyclopropyl, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 When absent or C1-C4 alkyl, when attached to N in ring B, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

29. The compound of claim 1, wherein the compound has the following structural formula 32-1, 32-2, 32-3, 32-4 or 32-5: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2, Y1, Y2 and Z1 are independently selected from C and N, R a1 , R a2 and R a3 each independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl, cyclopropyl and OCH3, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, Where R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from H, C1-C4 alkyl, which is optionally substituted by -C(=O)NH2, 3- to 5-membered cycloalkyl, which is optionally substituted by OH, and 5-6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of F, Cl, Br, Me, CF3, CF2H, CN, CONH2 and NH2, and R c is H, halogen, CN or methyl.

30. The compound of claim 1, wherein the compound has the following structural formula 33-1, 33-2 or 33-3: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2 and Z1 are independently selected from C and N, R a1 , R a2 and R a3 Each is independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl, cyclopropyl and OCH3, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 is absent or is C1-C4 alkyl, when attached to N in ring B, and R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

31. The compound of claim 1, wherein the compound has the following structural formula 34-1, 34-2, 34-3, 34-4, 34-5 or 34-6: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 , R a2 and R a4 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from H, 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 substituents selected from the group consisting of F, Cl, Br, Me, CF3, CF2H, CN, CONH2, and NH2, and C1-C4 alkyl, which is optionally substituted by -C(=O)NH2, and R c is H, halogen, CN or methyl.

32. The compound of claim 1, wherein the compound has the following structural formula 35-1, 35-2, 35-3 or 35-4: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H and OCH3, R a3 is a C1-C4 alkyl group, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R c is H, halogen, CN or methyl.

33. The compound of claim 1, wherein the compound has the following structural formula 36-1, 36-2 or 36-3: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R c is H, halogen, CN or methyl.

34. The compound of claim 1, wherein the compound has the following structural formula 37-1, 37-2, 37-3, 37-4, 37-5 or 37-6: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Y1, Y2 and Z1 are independently selected from C and N, R a1 and R a2 Each is independently selected from F, Cl, Br, C1-C4 alkyl, optionally substituted by 1-3 groups selected from halogen, C3-C4 cycloalkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is selected from C3-C4 cycloalkyl and C1-C4 alkyl, optionally substituted by 1-3 groups selected from halogen, cyclopropyl, and 4 to 5 membered heterocyclyl, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, R b3 is selected from 5- to 6-membered heteroaryl, (optionally) substituted by 1-2 groups selected from F, Cl, Br, Me, CF3, CF2H, CN, CONH2, and NH2, and C1-C4 alkyl, optionally substituted by OH or -C(=O)NH2, and R c is H, halogen, CN or methyl.

35. The compound of claim 1, wherein the compound has the following structural formula 38-1, 38-2 or 38-3: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 is selected from the group consisting of F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

36. The compound of claim 1, wherein the compound has the following structural formula 39-1, 39-2, 39-3 or 39-4: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

37. The compound of claim 1, wherein the compound has the following structural formula 40-1, 40-2 or 40-3: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

38. The compound of claim 1, wherein the compound has the following structural formula 41-1, 41-2, 41-3, 41-4 or 41-5: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1 and X2 are independently selected from N, O and S, Z1 is selected from C and N, R a1 and R a2 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is a C1-C4 alkyl group, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R b3 is selected from C1-C4 alkyl optionally substituted by OH or -C(=O)NH2, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

39. The compound of claim 1, wherein the compound has the following structural formula 42-1, 42-2 or 42-3: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein X1, X2, X3 and X4 are independently selected from C, N and S, and wherein X5 is selected from C and N, and R is an integer selected from 0, 1 and 2.

40. The compound of claim 1, wherein the compound has the following structural formula 43-1, 43-2, 43-3 or 43-4: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein Z, Z1, Z2 and Z3 are independently selected from C, S and N, and R is an integer selected from 0, 1 and 2.

41. The compound of claim 1, wherein the compound has the following structural formula 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10, 44-11, 44-12, 44-13 or 44-14: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein: X1 is selected from C, S, O and N, X2 is selected from C, N, S and O, Z1 and Z2 are independently selected from C, N and S, R a1 , R a2 and R a3 Each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R b1 is selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, OCH3, -C(=O)CH2C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)(C3-C5 cycloalkyl), -C(=O)(5- to 6-membered heteroaryl), -C(=O)(4- to 6-membered heterocyclyl optionally substituted with =O or OH), -C(=O)OH, OH, -C(=O)NH2, 3- to 5-membered cycloalkyl optionally substituted by OH, and C1-C4 alkyl optionally substituted by OH or -C(=O)NH2, R b2 and R b3 independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, -C(=O)NH2 and OCH3 or R b2 and R b3 Together they form a C3-C5 cycloalkyl group, R b4 Yes = O or does not exist, R b5 is selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, OCH3, -C(=O)CH2C(=O)NH2, -C(=O)(C1-C4 alkyl), -C(=O)(C3-C5 cycloalkyl), -C(=O)(5- to 6-membered heteroaryl), -C(=O)(5- to 6-membered heterocyclyl optionally substituted by =O), -C(=O)OH, OH, C1-C4 alkyl optionally substituted by OH or -C(=O)NH2, and C3-C5 cycloalkyl optionally substituted by OH, and R c is H, halogen, CN or methyl, and wherein R4 and R5 are taken together to form a 3- to 4-membered cycloalkyl group.

42. The compound of claim 1, wherein the compound has the following structural formula 45-1 or 45-2: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof, wherein R a1 and R a2 are each independently selected from halogen and C1-C2 alkyl optionally substituted by 1 to 3 halogen groups, R' a1 , R' a2 , R' a3 , R' a4 , and R' a5 are each independently selected from H and halogen, wherein R' a1 , R' a2 , R' a3 , R' a4 , and R' a5 2, 3 or 4 of them are halogen and the rest are H, R b1 is selected from H and C1-C4 alkyl optionally substituted by -C(=O)NH2, R b2 is selected from H and C1-C4 alkyl optionally substituted by 1-3 halogen groups, and R c Selected from H, halogen and C1-C2 alkyl.

43. The compound of claim 1, wherein the compound has the following structural formula 46-1, 46-2 or 46-3: Its tautomer, the compound or the solvate or stereoisomer of the tautomer, or the pharmaceutically acceptable salt thereof, wherein Z1 is selected from C and N, R a1 and R a2 are each independently selected from halogen and C1-C2 alkyl optionally substituted by 1 to 3 halogen groups, R' a1 , R' a2 , R' a3 , R' a4 , and R' a5 are each independently selected from H and halogen, wherein R' a1 , R' a2 , R' a3 , R' a4 , and R' a5 2, 3 or 4 of them are halogen and the rest are H, R b is selected from H and a 5- to 6-membered heteroaryl group containing 2-3 heteroatoms selected from N and S, wherein R b The 5- to 6-membered heteroaryl is optionally substituted by 1-3 groups selected from halogen and C1-C4 alkyl, R b1 is selected from H and C1-C4 alkyl optionally substituted by -C(=O)NH2, R b2 is selected from H, halogen, -O(C1-C4 alkyl), and C1-C4 alkyl, optionally substituted with 1-3 groups selected from halogen, and R c Selected from H, halogen and C1-C2 alkyl.

44. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1 and 40, wherein m R a The group substituted ring A is selected from: Where R a1 , R a2 and R a3 are independently selected from F, Cl, Br, methyl, CF3, CF2H and cyclopropyl, and X1 and X2 are independently selected from C and N.

45. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1 and 40, wherein m R a The group substituted ring A is selected from: Where R a1 and R a2 R is independently selected from H, CN, F, Cl, Br, C1-C4 alkyl, CF3, CF2H and OCH3, a3 is H or C1-C4 alkyl, R a4 is selected from H, F, Cl, Br, and C1-C4 alkyl, and X1 and X2 are independently selected from N, O and S.

46. ​​The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1 and 40, wherein Ring A is selected from: The ring A is surrounded by m R a Group substitution.

47. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 40 and 46, wherein m R a The group substituted ring A is selected from:

48. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 40 and 46-47, wherein m R a The group substituted ring A is selected from:

49. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-48, wherein n R b The group substituted ring B is: wherein Z is selected from C and N, Y1 and Y2 are independently selected from C and N, R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, wherein R b1 and R b2 does not exist, when connected to N in ring B, and R b3 Selected from H, methyl, ethyl, and a 5-membered heteroaryl group, wherein R b3 The 5-membered heteroaryl contains 2-3 heteroatoms selected from N and S and the 5-membered heteroaryl is optionally substituted by 1-2 groups selected from halogen and C1-C4 alkyl, and R c is selected from H, halogen, CN, and methyl.

50. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-49, wherein n R b The group substituted ring B is selected from: Wherein Z is selected from C and N, R b1 is selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R b2 is selected from the group consisting of H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and R c is selected from H, halogen, CN, and methyl.

51. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-48, wherein n R b The group substituted ring B is: Wherein Z is selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is selected from H, halogen, CN, and methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

52. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 44-48 and 51, wherein n R b The group substituted ring B is selected from: Wherein Z is selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is selected from H, halogen, CN, and methyl, and q is 0, 1 or 2.

53. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-48, wherein n R b The group substituted ring B is: Wherein Z is selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R c is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2.

54. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 44-48 and 53, wherein n R b The group substituted ring B is selected from: Wherein Z is selected from C and N, R b1 is selected from the group consisting of F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, and q is 0, 1 or 2.

55. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-48, wherein n R b The group-substituted ring B is wherein Y is selected from C and N, E is selected from C, N and O, Rd1 and Rd2 are independently selected from H, methyl, ethyl and cyclopropyl, R c is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl and OCH3, R b1 is selected from H, halogen, CN, and methyl, p is 1 or 2, and q is 0, 1 or 2.

56. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-48, wherein n R b The group-substituted ring B is wherein Z is selected from C and N, Y1, Y2, and Y3 are independently selected from C, N, S and O, R b1 Selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, CONH2, OCH3, CH2CONH2, R c is selected from H, halogen, CN, and methyl, and p is 0, 1 or 2.

57. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 44-48 and 56, wherein n R b The group substituted ring B is selected from 58. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-48, wherein n R b The group-substituted ring B is Z is selected from C and N, Y1, Y2, Y3 and Y4 are independently selected from C and N, R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, CONH2 and OCH3, R c is H, halogen, CN or methyl, and p is 0, 1 or 2.

59. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39 and 44-48, wherein Ring B is selected from: The ring B is surrounded by n R b Group substitution.

60. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 44-48 and 59, wherein n R b The group substituted ring B is selected from:

61. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 44-48 and 59, wherein n R b The group substituted ring B is selected from: wherein q1 is an integer selected from 0, 1, 2 and 3, q2 is an integer selected from 0, 1 and 2, and R c Selected from F, Cl, Br and Me.

62. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 40 and 46, wherein R a Selected from C3-C5 cycloalkyl, -O(C1-C2 alkyl), COOH, CN, CONH2, -C(=O)NH(C1-C2 alkyl), -C(=O)N(C1-C2 alkyl)2, -C(=O)O(C1-C2 alkyl), halogen and C1-C2 alkyl, which are optionally substituted by 1-3 groups selected from the following: halogen.

63. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 40, 46 and 62, wherein R a Selected from CH3, CH2CH3, CH2CF3, F, Cl, Br, C3-C4 cycloalkyl, COOH, CN, CONH2, -C(=O)NHCH3, -C(=O)NCH3, -OC(=O)N(CH3)3, and OCH3.

64. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 40, 44-48, 59 and 62-63, wherein R b is selected from =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, C3-C4 cycloalkyl optionally substituted by OH, O(C1-C3 alkyl), -C(=O)(C1-C2 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(4- to 6-membered heterocyclyl optionally substituted by =O), -C(=O)(5- to 6-membered heteroaryl optionally substituted by C1-C2 alkyl or NH2), -C(=O)(CH2)pC(=O)NH2, -NHC(=O)(C1-C2 alkyl), -C(=O)N(C1-C2 alkyl)2, -C(=O)NH(CH2)pOH, -S(=O)2NH2, C1-C3 alkyl, which is optionally substituted by 1-3 groups selected from the following: halogen, NH2, OH, OCH3, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)N(C1-C4 alkyl)2, -COOH, -C(=O)NH2, CN, C3-C4 cycloalkyl, phenyl, -C(=O)(C1-C2 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(5- to 6-membered heterocyclyl), -C(=O)(5- to 6-membered heteroaryl optionally substituted by C1-C2 alkyl), C(=O)NH(CH2)pOH, and 5- to 6-membered heteroaryl, 5- to 6-membered heteroaryl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C2 alkyl, and 5 to 6 membered heterocyclyl, which is optionally substituted by 1-2 groups selected from: =O and C1-C2 alkyl, or Two R connected to the same position of ring B b Together they form a C3-C5 cycloalkyl group, wherein p is an integer selected from 1 and 2, and wherein R4 and R5 are each independently selected from H and C1-C3 alkyl or R4 and R5 are taken together to form a 3 to 5 membered cycloalkyl.

65. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 39, 40, 44-48, 59 and 62-64, wherein R b Selected from =O, CH3, CHF2, CF3, OH, F, Cl, Br, CN, CH(CH3)2, CH2CN, OCH3, -C(=O)NH2, -C(=O)OCH3, CH2CH2OH, CH2CH2CH2OH, CH2C(=O)OH, CH2C(=O)NH2, CH2C(=O)NHCH2CH2OH, CH2CH2CH2C(=O)NH2, C(=O)CH3, -NHC(=O)CH3, -C(=O)N(CH3)2, -C(=O)NCH3, NH2, -C(=O)NHCH2CH2OH, CH2OH, or two R attached to the same position of ring B b Together they form a 3- or 5-membered cycloalkyl group.

66. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 13, 15, 17 and 25-65, wherein L is selected from and in R1 is H, D or C1-C4 alkyl, and R2 is selected from CN, C1-C4 alkenyl, C3-C5 cycloalkyl, 5-6 membered heteroaryl, phenyl, which is optionally substituted by 1-2 groups selected from the group consisting of C1-C3 alkyl and halogen, and C1-C4 alkyl, which is optionally substituted by 1-3 groups selected from halogen, OH, and phenyl, or R1 and R2 are taken together to form a 3-4 membered heterocyclic group; and R3 is C1-C4 alkyl, which is optionally substituted with 1-3 groups selected from halogen and OH.

67. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 13, 15, 17 and 25-66, wherein L is selected from 68. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1, 13, 15, 17 and 25-67, wherein L is selected from 69. The compound according to claim 1, wherein the compound is selected from the group consisting of: Its tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt thereof.

70. A pharmaceutical composition comprising a compound according to any one of claims 1 to 69, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

71. A method for treating a disease or condition, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-69 and compounds 1A to 121A, 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 according to claim 70 or a pharmaceutical composition comprising any one of compounds 1A to 121A, wherein the disease or condition is selected from ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN.

72. A method for treating a disease or condition caused by axonal degeneration, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1-69 and compounds 1A to 121A, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 70 or a pharmaceutical composition comprising any one of compounds 1A to 121A.

73. A method of modulating SARM1, comprising contacting a subject in need thereof with a compound according to any one of claims 1-69 and compounds 1A to 121A, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 70 or a pharmaceutical composition comprising any one of compounds 1A to 121A.

74. A method for inhibiting or preventing axonal degeneration, comprising contacting a subject in need thereof with a compound according to any one of claims 1-69 and compounds 1A to 121A, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 70 or a pharmaceutical composition comprising any one of compounds 1A to 121A.

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