SARM1 modulators, their preparation, and use

Abstract

The present disclosure provides a compound of formula (1), a composition comprising the same, and methods of using the same, including the modulation of SARM1 and use in the treatment of various diseases and conditions, such as diseases and conditions caused by axonal degeneration. JPEG2025519407000441.jpg35128

Description

Technical Field

[0001] (Cross - reference to Related Applications) This application claims the benefit of priority of International Application PCT / CN2022 / 097337 filed on July 7, 2022, and International Application PCT / CN2023 / 083360 filed on March 23, 2023. The content of both applications is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to compounds that modulate SARM1, compositions containing such compounds, methods of preparing such compounds, and methods of using such compounds for treating various diseases or conditions, such as diseases or conditions caused by axonal degeneration.

Background Art

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

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

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

[0006] Certain SARM1 inhibitors are disclosed in Bosanac 2021, Hughes 2021, Sporny 2020 (M. Sporny et al, Structural basis for SARM1 inhibition and activation under energetic stress. Elife. 2020 Nov 13;9:e62021.doi:10.7554 / eLife.62021.PMID:33185189;PMCID:PMC7688312.), International Publication No. 2018 / 057989 (Al), International Publication No. 2020 / 081923 (A1), International Publication No. 2021 / 142006 (Al), International Publication No. 2021207302 (Al), and International Publication No. 2021207308 (Al). Certain dipeptidyl peptidase inhibitors (e.g., biphenyl or phenylbenzimidazole derivatives) are disclosed in US Patent Application Publication No. 2005 / 0272765 (A1). Certain benzyl benzoxazole derivatives as Met kinase inhibitors are disclosed in International Publication No. 2008 / 148449 (A1). Certain dihydroisoquinolinone derivatives and their combinatorial libraries are described in International Publication No. 01 / 14879. Certain compositions for promoting readthrough of premature termination codons and methods of using the same are described in International Publication No. 2017 / 049409. Certain nitrogen-containing heterocyclic ring compounds having nematicidal properties, their preparation and use are described in Chinese Patent Application Publication No. 108276352.

[0007] The present disclosure describes SARM1 inhibitors that can be used to prevent axonal degeneration in peripheral and central axonal injuries and to provide modified treatment of degenerative diseases for related diseases or conditions.

Summary of the Invention

[0008] In one aspect of the present disclosure, provided are compounds selected from the compounds of Formulas 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 (e.g., Compounds 1 to 391), their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing. For example, in the present specification, the following Structural Formula 1: [Chemical Formula] [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 heterocyclyl 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 optionally substituted with 1 to 3 groups selected from halogen, -OH, cyclopropyl, oxetanyl, and azetidinyl, R b is =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, [Chemical formula] C1-C4 alkyl optionally substituted with 1 to 3 groups selected from 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- or 6-membered heteroaryl optionally substituted with 1 or 2 groups selected from C1-C3 alkyl, =O, -NH2, -CN, -CONH2, and halogen, and selected from 4- to 6-membered heterocyclyl optionally substituted with 1 or 2 groups selected from =O, -OH, -NH2, -CN, -CONH2, halogen, and C1-C3 alkyl, or two Rs attached to the same position on ring B b are attached to form C3-C6 cycloalkyl, R4 and R5 are each independently selected from H and C1-C3 alkyl, or R4 and R5 are attached to form 3- to 5-membered cycloalkyl, L is

Chemical formula

[0009] In one aspect of the present disclosure, the compounds of the formulas disclosed herein are selected from Compounds 1 to 391 shown in Table 1, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing.

[0010] In some embodiments, the present disclosure provides a pharmaceutical composition comprising 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, 16-2a, 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, 34-5, 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 1-391) and Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can comprise a compound selected from Compounds 1-391 and Compounds 1A-121A shown below, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, and a pharmaceutically acceptable carrier. These compositions may further comprise an additional active pharmaceutical ingredient.

[0011] In another aspect of the present disclosure, a method of treating a disease or condition is provided, the method 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, 16-2a, 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 1-391) and Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer and pharmaceutically acceptable salt, wherein the disease or condition is 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 Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), but not limited thereto, glaucoma, optic nerve disorders such as retinal ganglion degeneration, colitis, diabetic neuropathy, metabolic diseases or disorders such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathies such as CIPN induced by various drugs.

[0012] In a further aspect of the present disclosure, there is provided a method of treating a disease or condition caused by axonal degeneration or nerve damage mediated by SARM1, the method 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, 16-2a, 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 1-391) and Compounds 1A-121A, tautomers thereof, solvates or stereoisomers of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0013] In some embodiments, the treatment method comprises administering to a subject in need a compound selected from Compounds 1 to 391 and Compounds 1A to 121A shown below, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0014] In some embodiments, the treatment method comprises administering an additional active pharmaceutical in the same pharmaceutical composition as, or in a separate composition from, any of the compounds 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 (e.g., Compounds 1-391) and Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or in an additional active pharmaceutical in a separate composition. In some embodiments, the treatment method comprises administering a compound selected from Compounds 1-391 and Compounds 1A-121A shown below, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, together with an additional active pharmaceutical in the same pharmaceutical composition as, or in a separate composition from, any of the foregoing.When administered as a separate composition, the additional therapeutic agent can be administered before, simultaneously with, or after the administration of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt disclosed herein.

[0015] Also, this specification discloses a method of modulating, e.g., inhibiting, SARM1 in a subject in need thereof, the method comprising contacting the subject with a pharmaceutical composition comprising 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, 16-2a, 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 1-391) and Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.In some embodiments, a method of modulating, e.g., inhibiting, SARM1 in a subject in need thereof comprises contacting the subject with a compound selected from Compounds 1-391 and Compounds 1A-121A shown below, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0016] This specification also discloses a method of inhibiting or preventing axonal degeneration in a subject in need thereof, the method comprising contacting the subject with a pharmaceutical composition comprising 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, 16-2a, 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 1-391) and Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.In some embodiments, a method of inhibiting or preventing axonal degeneration or nerve injury mediated by SARM1 in a subject in need thereof comprises contacting the subject with a compound selected from Compounds 1-391 and Compounds 1A-121A shown below, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

Mode for Carrying Out the Invention

[0017] I. Definitions As used herein, the term "a" or "an" when referring to a noun includes the expression "at least one" and thus includes both singular and plural units of the noun. For example, "an additional pharmaceutical" means a single or two or more additional pharmaceuticals.

[0018] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched-chain saturated hydrocarbon groups containing 1 to 20 carbon atoms, for example, 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Examples of alkyl groups include methyl group, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. Lower alkyl contains 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, and even more preferably 1 to 3 carbon atoms.

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

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

[0021] The term "heteroalkyl" refers to an alkyl group as defined herein in which one or more of the constituent carbon atoms are replaced by a heteroatom, for example, nitrogen, oxygen, or sulfur, such as CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5, etc. In some embodiments, in addition to the replacement of one or more of the constituent carbon atoms by nitrogen, oxygen, or sulfur, the heteroalkyl group is further optionally substituted as defined herein.

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

[0023] The terms "heterocyclic ring", "heterocyclyl ring", or "heterocyclyl" refer to rings selected from monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated rings having 3 to 12 members, such as 3 to 6 members, 3 to 5 members, 4 to 5 members, or 5 to 6 members, containing at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms selected from, for example, oxygen, sulfur, nitrogen, and silicon. "Heterocyclyl ring" also refers to a 5- to 7-membered heterocyclyl ring containing at least one heteroatom selected from N, O, and S fused to a 5-membered, 6-membered, and / or 7-membered cycloalkyl ring, an aromatic carbocyclic ring, or a heteroaromatic ring, provided that when the heterocyclyl ring is fused to an aromatic carbocyclic ring or a heteroaromatic ring, the point of attachment is on the heterocyclyl ring, and when the heterocyclyl ring is fused to a cycloalkyl, the point of attachment may be on the cycloalkyl or the heterocyclyl ring.

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

[0025] Examples of heterocyclic rings include, as numbers from the linking position assigned the highest priority (1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, thietanyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl, but are not limited thereto. Substituted heterocyclic rings include ring systems substituted with one or more oxo moieties such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0026] As used herein, the term "fused ring" refers to a polycyclic ring system in which two rings share only two common ring atoms and one bond, such as a bicyclic or tricyclic ring system. Examples of fused rings include fused bicyclic cycloalkyl rings having 7 to 12 ring atoms arranged as a bicyclic ring selected from the above-mentioned [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems, etc., fused bicyclic aryl rings such as the above-mentioned 7- to 12-membered bicyclic aryl ring systems, etc., fused tricyclic aryl rings such as the above-mentioned 10- to 15-membered tricyclic aryl ring systems, etc., fused bicyclic heteroaryl rings such as the above-mentioned 8- to 12-membered bicyclic heteroaryl rings, etc., fused tricyclic heteroaryl rings such as the above-mentioned 11- to 14-membered tricyclic heteroaryl rings, and the above-mentioned fused bicyclic or tricyclic heterocyclyl rings.

[0027] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, and silicon, and all oxidation forms of nitrogen or sulfur, all basic nitrogens of heterocyclyl rings or quaternized forms of substitutable nitrogens, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + [wherein R is, for example, an optionally substituted alkyl group) (as in N-substituted pyrrolidinyl).

[0028] As used herein, the term "unsaturated" means that a moiety has one or more unsaturated units or degrees of unsaturation. Unsaturation means that not all of the available valence bonds in a compound are filled by substituents, and thus the compound is in a state containing one or more double bonds or triple bonds. A double bond can be

Chemical formula

Chemical formula

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

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

[0031] As used herein, the "CN", "cyano" or "nitrile" group

Chem.

[0032] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring containing a conjugated planar ring system having a delocalized π - electron orbital composed of [4n + 2] p - orbital electrons, where n is an integer from 0 to 6. "Non - aromatic" ring refers to a carbocyclic or heterocyclic ring formula that does not meet the requirements described above for aromatic rings and may be either fully or partially saturated. Non - limiting examples of aromatic rings include aryl and heteroaryl rings, which are further defined as follows. "Aromatic ring"

Chem.

Chem.

[0033] As used herein, the term "aryl" refers to a group selected from a monocyclic aromatic carbocyclic ring, such as phenyl, a bicyclic ring system having 7 to 12 members, such as 9 to 10 members, in which at least one ring is a carbocyclic ring and an aromatic ring, such as naphthalene, indane, and 1,2,3,4-tetrahydroquinoline, and a tricyclic ring system having 10 to 15 members, such as fluorene, in which at least one ring is a carbocyclic ring and an aromatic ring.

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

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

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

[0037] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocyclic ring is 1 or less.

[0038] Examples of heteroaryl groups include, as the number from the linking position assigned priority 1, pyridyl (such as 2 - pyridyl, 3 - pyridyl, or 4 - pyridyl), cinnolinyl, pyrazinyl, 2,4 - pyrimidinyl, 3,5 - pyrimidinyl, 2,4 - imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H - pyrrolo[2,3 - b]pyridin - 5 - yl), pyrazolopyridinyl (for example, 1H - pyrazolo[3,4 - b]pyridin - 5 - yl), benzoxazolyl (such as benz[d]oxazol - 6 - yl), pteridinyl, purinyl, 1 - oxa - 2,3 - diazolyl, 1 - oxa - 2,4 - diazolyl, 1 - oxa - 2,5 - diazolyl, 1 - oxa - 3,4 - diazolyl, 1 - thia - 2,3 - diazolyl, 1 - thia - 2,4 - diazolyl, 1 - thia - 2,5 - diazolyl, 1 - thia - 3,4 - diazolyl, phthalazinyl, benzophthalazinyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (such as benz[d]thiazol - 6 - yl), indazolyl (such as 1H - indazol - 5 - yl) and 5,6,7,8 - tetrahydroisoquinolinyl, but are not limited thereto.

[0039] The term "acyl" refers to a substituent in which 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’, where R’ and R’’ in the formula are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl, any of which may be further substituted by one or more substituents.

[0040] Among the compounds, there are also those with different hydrogen bonding points called "tautomers". For example, a compound containing a carbonyl-CH2C(O)- group (keto form) can tautomerize to form a hydroxyl-CH=C(OH)- group (enol form). Both the keto form and the enol form are intended to be included, either alone or as a mixture thereof, where applicable.

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

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

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

[0044] The term "substantially pure" in the context of stereoisomers means that the desired stereoisomer contains no more than 35% by weight, for example no more than 30% by weight, more particularly no more than 25% by weight, and even more particularly no more than 20% by weight of any other stereoisomer. In some embodiments, the term "substantially pure" means that the desired stereoisomer contains no more than 10% by weight, for example no more than 5% by weight, for example no more than 1% by weight of any other stereoisomer.

[0045] Unless otherwise indicated, the structures shown herein are meant to include all isomeric forms of the structure, for example, geometric (or conformational) isomers such as racemic mixtures, cis / trans isomers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, geometric and conformational mixtures of the compounds disclosed herein are within the scope of the present disclosure. Unless otherwise specifically noted, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0046] The present disclosure provides pharmaceutically acceptable salts of the disclosed compounds, tautomers, solvates, and stereoisomers. The salts of the compounds are formed between an acid and a basic group of the compound such as an amino functional group or between a base and an acidic group of the compound such as a carboxyl functional group.

[0047] As used herein, the term "pharmaceutically acceptable" refers to components that are suitable for use in contact with the tissues of humans and other mammals within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. "Pharmaceutically acceptable salts" mean any non-toxic salts that can provide the compounds of the present disclosure either directly or indirectly upon administration to a recipient.

[0048] Examples of "pharmaceutically acceptable salts" include salts with inorganic acids selected from, for example, hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, and nitrate, and salts with organic acids selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, acetate, etc., and salts with HOOC-(CH2)n-COOH where n is selected from 0 to 4, but are not limited thereto. 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 those disclosed, for example, in S.M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1-19.

[0049] Examples of acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as bisulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, decanoate (i.e., caprinate), caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed using mineral acids such as hydrochloric acid and hydrobromic acid, and those formed using organic acids such as maleic acid.

[0050] Pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Examples of the (alkyl)4 salts include. The present disclosure also contemplates the quaternization of any basic nitrogen-containing group 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. Further non-limiting examples of pharmaceutically acceptable salts include ammonium, quaternary ammonium, and amine cation salts formed using counterions such as halide salts, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate salts and glucosamine salts.

[0051] When the compound is obtained as an acid addition salt, the free base can be obtained by basifying the solution of the acid addition salt. Conversely, when the product is a free base, an addition salt such as a pharmaceutically acceptable addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0052] The compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts of the present disclosure may also contain atom isotopes different from the natural proportions in one or more atoms constituting such compounds. For example, -CD3, -CD2H, or -CDH2 contains one or more deuteriums in place of hydrogen. For example, the compound can be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotope variants of the compounds of the present disclosure are intended to be included within the scope of the present disclosure, whether radioactive or not.

[0053] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted". Generally, the term "substituted" refers to replacing a hydrogen radical in a given structure with a radical of a particular substituent. Unless otherwise indicated, an "optionally substituted" group may have a substituent at each substitutable position of the group, and if two or more positions in any given structure may be substituted with two or more substituents selected from a particular group, the substituents may be the same or different at all positions.

[0054] The chemical components contemplated by the present disclosure, such as combinations of substituents, ring structures, linkers, and / or heteroatoms, form stable or chemically realizable compounds.

[0055] In some embodiments, the substituents are independently selected from optionally substituted heteroatoms and optionally substituted, optionally hetero-, optionally cyclic C1-C 18 hydrocarbyls, and in particular, optionally substituted, optionally hetero-, optionally cyclic C1-C 18 hydrocarbyls are optionally substituted, optionally hetero-, optionally cyclic alkyl, alkenyl or alkynyl, or optionally substituted, optionally hetero-, optionally aryl, and / or optionally substituted heteroatoms are halogen, optionally substituted hydroxyl (alkoxy, aryloxy, etc.), optionally substituted acyl (formyl, alkanoyl, carbamoyl, carboxyl, amide, etc.), optionally substituted amino (amino, alkylamino, dialkylamino, amide, sulfamidyl, etc.), optionally substituted thiol (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyl (alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, etc.), nitro, or cyano.

[0056] In some embodiments, the substituent is independently selected from zero to three numbers of halogen, -R’, -OR’, =O, =NR’, =N-OR’, -NR’R’’, -SR’, -SiR’R’’R’’’, -OC(=O)R’, -C(=O)R’, -CO2R’, -C(=O)NR’R’’, -OC(=O)NR’R’’, -NR’’C(=O)R’, -NR’-C(=O)NR’’R’’’, -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, and a group having zero, one or two substituents is particularly preferred. R’, R’’ and R’’’ each independently refer to hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted with one to three halogens, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy group, or aryl-(C1-C4)alkyl group. When R’ and R’’ are bonded to the same nitrogen atom, they can together form a 5-, 6- or 7-membered ring with the nitrogen atom. Accordingly, -NR’R’’ includes 1-pyrrolidinyl and 4-morpholinyl. When the aryl group is 1,2,3,4-tetrahydronaphthalenyl, it may be substituted with a substituted or unsubstituted C3-C7 spirocycloalkyl group. The C3-C7 spirocycloalkyl group may be substituted in the same manner as defined herein for “cycloalkyl”.

[0057] In some embodiments, the substituent is selected from halogen, -R’, -OR’, =O, -NR’R’’, -SR’, -SiR’R’’R’’’, -OC(=O)R’, -C(=O)R’, -CO2R’, -C(=O)NR’R’’, -OC(=O)NR’R’’, -NR’’C(=O)R’, -NR’’CO2R’, -NR’-SO2NR’’R’’’, -S(=O)R’, -SO2R’, -SO2NR’R’’, -NR’’SO2R, -CN, -NO2, perfluoro C1-C4 alkoxy and perfluoro C1-C4 alkyl, and R’ and R’’ are as defined above.

[0058] In some embodiments, the substituent is an optionally substituted heteroatom, C1-C6 alkyl containing 0-3 optionally substituted heteroatoms (e.g., C1-C3 alkyl or C1-C2 alkyl), C2-C6 alkenyl containing 0-3 optionally substituted heteroatoms (e.g., C2-C4 alkenyl), C2-C6 alkynyl containing 0-3 optionally substituted heteroatoms (e.g., C2-C4 alkynyl), or optionally substituted C6-C 14 aryl (e.g., C5-C6 aryl), independently selected, and each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0059] In some embodiments, the substituents are independently selected from aldehyde group, aldimine group, alkanoyloxy group, alkoxy group, alkoxycarbonyl group, alkyloxy group, alkyl group, alkenyl group, alkynyl group, amine group, azo group, halogen group, carbamoyl group, carbonyl group, carboxamide group, carboxyl group, cyanilyl group, ester group, halocarbonyl group, hydroperoxyl group, hydroxyl group, imine group, isocyanide group, isocyanate group, N-tert-butoxycarbonyl group, nitrate group, nitrile group, nitrite group, nitro group, nitroso group, phosphate group, phosphono group, sulfide group, sulfonyl group, sulfo group, sulfhydryl group, thiol group, thiocyanilyl group, trifluoromethyl group, and trifluoromethyl ether group (OCF3).

[0060] Preferred substituents are disclosed herein, exemplified in tables, structures, examples, and claims, and can be applied across the various compounds of the present disclosure. For example, the substituents of a given compound may be used in combination with other compounds.

[0061] It may be beneficial to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated and / or purified (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separation includes multistage extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography includes, for example, reverse and normal phase, size exclusion, ion exchange, high pressure, medium pressure, and low pressure liquid chromatography methods and apparatuses, small scale analysis, simulated moving bed ("SMB") and preparative thin layer chromatography or preparative thick layer chromatography, and many methods including techniques of small scale thin layer chromatography and flash chromatography. One of ordinary skill in the art can apply such techniques to achieve the desired separation.

[0062] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-Me THF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0063] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N, TEA), diisopropyl-ethylamine (i-Pr2EtN, DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0064] The term "subject" refers to an animal including a human.

[0065] The term "therapeutically effective amount" refers to the amount of a compound that produces a desired effect (e.g., improvement of a disease or condition, reduction in the severity of a disease or condition, and / or reduction in the progression of a disease or condition such as ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN) when administered. The disease or condition can be caused by axonal degeneration. The exact amount of the therapeutically effective amount will vary depending on the purpose of the treatment and can be determined by one of ordinary skill in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

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

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

[0068] II. Compounds and Compositions In a first embodiment, a compound of the present disclosure has the following structural formula 1:

Chemical formula

Chemical formula

Chemical formula

[0069] The combinations of substituents disclosed herein result in the formation of stable or chemically realizable compounds. In the case of abbreviations, or according to convention, a particular hydrogen atom bonded to a particular atom (e.g., carbon atom C or nitrogen atom N) is not specifically shown in the chemical structure, formula, or symbol, and the hydrogen atom is considered to be present to the extent that the valence of the particular atom (e.g., C or N) is satisfied.

[0070] In some embodiments, the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the present disclosure are not any of Compounds 1A-121A.

[0071] In one embodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the present disclosure, Ring A is phenyl, pyridinyl, a 5-membered heteroaryl ring containing 1 or 2 heteroatoms selected from O, S, and N, or a 6- to 10-membered heterocyclyl ring containing 1 or 2 heteroatoms selected from N and O, and all other variable elements not specifically defined herein are as defined in the preceding embodiments.

[0072] In one embodiment, in the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts thereof of the present disclosure, ring B is phenyl, a 9- to 11-membered aryl, a 9- to 11-membered heteroaryl ring containing one or two heteroatoms selected from N, S and O, or a 9- to 11-membered heterocyclyl ring containing one or two heteroatoms selected from N, S and O, and all other variable elements not specifically defined herein are as defined in any one of the preceding embodiments.

[0073] In one embodiment, the compound of the present disclosure has the following structural formula 2:

Chemical formula

[0074] In one embodiment, the compound of the present disclosure has the following structural formula 2a:

Chemical formula

[0075] In one embodiment, the compounds of the present disclosure have the following structural formula 2b:

Chemical formula

[0076] In one embodiment, the compounds of the present disclosure have the following structural formula 2c:

Chemical formula

[0077] In one embodiment, the compounds of the present disclosure have the following structural formula 2d:

Chemical formula

[0078] In one embodiment, the compound of the present disclosure has the following structural formula 2e: [Chemical formula] [wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0079] In one embodiment, the compound of the present disclosure has the following structural formula 2f: [Chemical formula] [wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0080] In one embodiment, the compound of the present disclosure has the following structural formula 2g: [Chemical formula] [wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0081] In one embodiment, the compound of the present disclosure has the following structural formula 2h:

Chemical formula

[0082] In one embodiment, the compound of the present disclosure has the following structural formula 2i:

Chemical formula

[0083] In one embodiment, the compound of the present disclosure has the following structural formula 2j:

Chemical formula

[0084] In one embodiment, the compounds of the present disclosure have the following structural formula 2k:

Chemical formula

[0085] In one embodiment, the compounds of the present disclosure have the following structural formula 2L:

Chemical formula

[0086] In one embodiment, the compounds of the present disclosure have the following structural formula 2m:

Chemical formula

[0087] In one embodiment, the compound of the present disclosure has the following structural formula 3: [Chemical formula] [wherein one or two of X1, X2, and X3 are N, and the remaining X1, X2, and X3 are C, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0088] In one embodiment, the compound of the present disclosure has the following structural formula 3a: [Chemical formula] [wherein one or two of X1, X2, and X3 are N, and the remaining X1, X2, and X3 are C, and R a1 , R a2 , R a3 , R a4 and R a5 are independently selected from 0, 1, 2, or 3 of F, Cl, Br, methyl, CF3, CF2H, ethyl, cyclopropyl, and OCH3, provided that the point of attachment on ring A is not N, and the remaining R a1 , R a2 , R a3 , R a4 and R a5is H, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0089] In one embodiment, a compound of the present disclosure has the following structural formula 3b:

Chemical formula

[0090] In one embodiment, a compound of the present disclosure has the following structural formula 3c:

Chemical formula

[0091] In one embodiment, a compound of the present disclosure has the following structural formula 3d:

Chemical formula

[0092] In one embodiment, a compound of the present disclosure has the following structural formula 3e:

Chemical formula

[0093] In one embodiment, a compound of the present disclosure has the following structural formula 3f:

Chemical formula

[0094] In one embodiment, a compound of the present disclosure has the following structural formula 3g:

Chemical formula

[0095] In one embodiment, the compound of the present disclosure has the following structural formula 3h: [Chemical formula] [wherein, R a1 , R a2 , and R a3 are independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0096] In one embodiment, the compound of the present disclosure has the following structural formula 3i: [Chemical formula] [wherein, R a1 , R a2 , and R a3 are independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0097] In one embodiment, the compound of the present disclosure has the following structural formula 3j: [Chemical formula] [In the formula, one of R a1 , R a2 , and R a3 is selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, and the rest are H, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0098] In one embodiment, the compound of the present disclosure has the following structural formula 3k: [Chemical formula] [In the formula, one of R a1 , R a2 , and R a3 is selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, and OCH3, and the rest are H, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0099] In one embodiment, the compound of the present disclosure has the following structural formula 3L: [Chemical formula] [In the formula, 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 variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0100] In one embodiment, a compound of the present disclosure has the following structural formula 4:

Chemical formula

[0101] In one embodiment, a compound of the present disclosure has the following structural formula 5:

Chemical formula

[0102] In one embodiment, a compound of the present disclosure has the following structural formula 6:

Chemical formula

[0103] In one embodiment, the compound of the present disclosure has the following structural formula 7:

Chemical formula

[0104] In one embodiment, the compound of the present disclosure has the following structural formula 7a:

Chemical formula

[0105] In one embodiment, the compound of the present disclosure has the following structural formula 7b:

Chemical formula

[0106] In one embodiment, the compound of the present disclosure has the following structural formula 8:

Chemical formula

[0107] In one embodiment, the compound of the present disclosure has the following structural formula 8a: [Chemical formula] [wherein, Y2 is selected from N, O and C, x is 0, 1 and 2, and R b1 is selected from H, =O, OH, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0108] In one embodiment, the compound of the present disclosure has the following structural formula 9: [Chemical formula] [wherein, 0 or 1 of Y1, Y2, Y3, and Y4 is N, and the remaining Y1, Y2, Y3, and Y4 are C, 0 or 1 of Z1 and Z2 is N, and the others are C, and 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 optionally substituted with 1-2 groups selected from halogen, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2 and phenyl, n is 0, 1, and 2, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0109] In one embodiment, the compound of the present disclosure has the following structural formula 9a: [Chemical formula] [Wherein, 0 or 1 of Y1, Y2, Y3, and Y4 is N, and the remaining Y1, Y2, Y3, and Y4 are C, 0 or 1 of Z1 and Z2 is N, and the others are C, and R b1 is selected from H, halogen, and C1-C3, provided that when R b1 is not H, Y2 is C, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments]. The compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0110] In one embodiment, the compound of the present disclosure has the following structural formula 10:

Chemical formula

[0111] In one embodiment, the compound of the present disclosure has the following structural formula 11:

Chemical formula

[0112] In one embodiment, the compound of the present disclosure has the following structural formula 12:

Chemical formula

[0113] In one embodiment, the compound of the present disclosure has the following structural formula 13:

Chemical formula

[0114] In one embodiment, a compound of the present disclosure has the following structural formula 13a:

Chemical formula

[0115] In one embodiment, a compound of the present disclosure has the following structural formula 13b:

Chemical formula

[0116] In one embodiment, the compound of the present disclosure has the following structural formula 14:

Chemical formula

[0117] In a second embodiment, the compound of the present disclosure has the following structural formula 14a: [Chemical formula] [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 [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0118] In a third embodiment, the compound of the present disclosure has the following structural formula 14b: [Chemical formula] [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 [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0119] In a fourth embodiment, the compound of the present disclosure has the following structural formula 14c: [Chemical formula] [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 optionally substituted with C3-C4 cycloalkyl, R b2 is selected from H, halogen and C1-C3 alkyl, and L is [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0120] In a fifth embodiment, the compound of the present disclosure has the following structural formula 14d: [Chemical formula] [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 [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0121] In a sixth embodiment, the compound of the present disclosure has the following structural formula 14e: [Chemical formula] [wherein, R a1 and R a2is independently selected from F, Cl, Br, methyl and OCH3, Y2 is selected from N and O, and L is [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0122] In a seventh embodiment, the compound of the present disclosure has the following structural formula 14f: [Chemical formula] [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 [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0123] In an eighth embodiment, the compound of the present disclosure has the following structural formula 14g: [Chemical formula] [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 [Chemical formula] Compounds selected from and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], tautomers thereof, solvates or stereoisomers of the compound or tautomers, or pharmaceutically acceptable salts of the foregoing.

[0124] In a ninth embodiment, the compound of the present disclosure has the following structural formula 14h-1 or 14h-2: [Table 1] [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 [Chemical formula] Compounds selected from and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], tautomers thereof, solvates or stereoisomers of the compound or tautomers, or pharmaceutically acceptable salts of the foregoing.

[0125] In a tenth embodiment, the compound of the present disclosure has the following structural formula 14i: [Chemical formula] [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 [Chemical formula] A compound selected from and otherwise all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0126] In the eleventh embodiment, the compound of the present disclosure has the following structural formula 14j: [Chemical formula] [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 [Chemical formula] selected from and otherwise all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0127] In one embodiment, the compound of the present disclosure has the following structural formula 15: [Chemical formula] [wherein, R a1 , R a2 , R a3 , R a4 , and R a5 of 0, 1, 2, or 3 are independently selected from F, Cl, Br, methyl, and OCH3, and the remaining R a1 , R a2 , R a3 , R a4 , and R a5is H, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0128] In a twelfth embodiment, a compound of the present disclosure has the following structural formula 15a: [Chemical formula] [wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, and L is [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0129] In a thirteenth embodiment, a compound of the present disclosure has the following structural formulas 16-1 and 16-2: [Table 2] [wherein R a1 , R a2 , R a3 , R a4 , and R a5 0, 1, 2, or 3 of are independently selected from F, Cl, Br, methyl, and OCH3, and the remaining R a1 , R a2 , R a3 , R a4 , and R a5is H, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0130] In a fourteenth embodiment, the compounds of the present disclosure have the following structural formulas 16-1a and 16-2a: [Table 3] [wherein R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, and L is [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0131] In a fifteenth embodiment, the compounds of the present disclosure have the following structural formula 17: [Chemical formula] [wherein R a1 , R a2 , R a3 , R a4 , and R a5 of 0, 1, 2, or 3 are independently selected from F, Cl, Br, methyl, and OCH3, and the remaining R a1 , R a2 , R a3 , R a4 , and R a5 are H, R b1 is selected from H and C1-C2 alkyl, R b2is selected from H and C1-C4 alkyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0132] In the 16th embodiment, the compound of the present disclosure has the following structural formula 17a: [Chemical formula] [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 [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0133] In the 17th embodiment, the compound of the present disclosure has the following structural formula 18: [Chemical formula] [wherein, R a1 , R a2 , R a3 , R a4 , and R a5 of 0, 1, 2, or 3 are independently selected from F, Cl, Br, methyl, and OCH3, and the remaining R a1 , R a2 , R a3 , R a4 , and R a5 are H, and R b1is =O, -NHCOCH3, and OH, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0134] In the 18th embodiment, the compound of the present disclosure has the following structural formula 18a:

Chemical formula

Chemical formula

[0135] In one embodiment, the compound of the present disclosure has the following structural formula 19:

Chemical formula

[0136] In a nineteenth embodiment, the compound of the present disclosure has the following structural formula 20: [Chemical formula] [wherein, 0 or 1 of Y1 and Y2 is N and the others are C, and 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 is absent, R b2 is selected from H, CN, C1-C2 alkyl, and -C(=O)NH2, and when Y1 is N, R b2 is absent, R b3 is selected from H and C1-C2 alkyl, R b4 is selected from H and C1-C2 alkyl, and L is [Chemical formula] selected from] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0137] In one embodiment, the compound of the present disclosure has the following structural formula 21: [Chemical formula] [wherein, 0, 1, 2, or 3 of R a1 , R a2 , R a3 , R a4 , and R a5 are independently selected from F, Cl, Br, methyl, and OCH3, and the remaining R a1 , R a2, R a3 , R a4 , and R a5 is H, and R b is selected from -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), 5-6 membered heteroaryl, and 5-6 membered heterocyclyl optionally substituted with 1-2 groups selected from =O and C1-C3 alkyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments. A compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0138] In the 20th embodiment, the compound of the present disclosure has the following structural formula 21a:

Chemical formula

Chemical formula

[0139] In the 21st embodiment, the compound of the present disclosure has the following structural formula 21b:

Chemical formula

[0140] In one embodiment, the compound of the present disclosure has the following structural formula 22: [Chemical formula] [wherein, R a1 , R a2 , R a3 , R a4 , and R a5 0, 1, 2, or 3 of are independently selected from F, Cl, Br, methyl, and OCH3, and the remaining R a1 , R a2 , R a3 , R a4 , and R a5 are H, 0, 1, or 2 of Y1, Y2, and Y3 are N, and the remaining Y1, Y2, and Y3 are C, and R b is selected from C1-C2 alkyl, C3-C4 cycloalkyl, and halogen, n is 0, 1, or 2, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0141] In the 22nd embodiment, the compound of the present disclosure has the following structural formula 22a: [Chemical formula] [wherein, R a1 and R a2 are independently selected from F, Cl, Br, methyl, and OCH3, 0, 1, or 2 of Y1, Y2, and Y3 are N, and the remaining Y1, Y2, and Y3 are C, and R bis selected from C1-C2 alkyl, C3-C5 cycloalkyl, CN, C(O)NH2 and halogen, n is 0, 1, or 2, and L is [Chemical formula] selected from], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0142] In one embodiment, the compound of the present disclosure has the following structural formula 23: [Chemical formula] [wherein R a1 , R a2 , R a3 , R a4 , and R a5 0, 1, 2, or 3 of are independently selected from F, Cl, Br, methyl, and OCH3, and the remaining R a1 , R a2 , R a3 , R a4 , and R a5 are H, one of Y2 and Y3 is S or O, the other is C, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0143] In the 23rd embodiment, the compound of the present disclosure has the following structural formula 23a: [Chemical formula] [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 b1does not exist, one of Y2 and Y3 is S or O, the other is C, and L is [Chemical formula] a compound selected from], its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0144] In the 24th embodiment, the compound of the present disclosure has the following structural formula 24: [Chemical formula] [wherein, one of X1, X2, and X3 is N, the other two 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 variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, L is [Chemical formula] is.

[0145] In one embodiment, the compound of the present disclosure has the following structural formula 25: [Chemical formula] [wherein, X1 is selected from C, N, and O, 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 variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0146] In one embodiment, the compound of the present disclosure has the following structural formula 26:

Chemical formula

[0147] In one embodiment, the compound of the present disclosure has the following structural formula 27:

Chemical formula

[0148] In the 25th embodiment, the compound of the present disclosure has the following structural formula 28-1 or 28-2:

Table 4

[0149] In a 26th embodiment, a compound of the present disclosure has the following structural formula 29-1 or 29-2: [Table 5] [wherein X1, X2, and Z1 are independently selected from C and N, and R a1 is selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl and cyclopropyl, and R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, CH2OH, cyclopropyl, and OCH3, and when linked to N in ring B, R b1 is absent or is C1-C4 alkyl, and R c is H, halogen, CN, or methyl, p is 1, 2, or 3, q is 0, 1, or 2, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0150] In a 27th embodiment, a compound of the present disclosure has the following structural formula 30-1, 30-2, 30-3, 30-4, or 30-5: [Table 6] [wherein, X1, X2, Y1, Y2, and Z1 are each independently selected from C and N, and R a1 and R a2 are each independently selected from F, Cl, Br, methyl, CF3, CF2H, ethyl, CN, CONH2, CH2NH2, and cyclopropyl, and R b1 and R b2 are independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3; when linked to N in ring B, R b1 and R b2 are absent, R b3 is C1-C4 alkyl optionally substituted with -C(=O)NH2, 3- to 5-membered cycloalkyl optionally substituted with OH, 5- to 6-membered heteroaryl optionally substituted with 1 to 2 groups independently selected from F, Cl, Br, Me, CF3, CF2H, CN, CONH2, and NH2, and R c is H, halogen, CN, or methyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0151] In a 28th embodiment, the compound of the present disclosure has the following structural formula 31-1 or 31-2:

Table 7

[0152] In the 29th embodiment, the compounds of the present disclosure have the following structural formulas 32-1, 32-2, 32-3, 32-4, or 32-5: [Table 8] [wherein X1, X2, Y1, Y2, and Z1 are each independently selected from C and N, and R a1 , R a2 and R a3 are each independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl, cyclopropyl, and OCH3, and R b1 and R b2 are independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and when linked to N in ring B, R b1 and R b2 are absent, and R b3 is selected from H, C1-C4 alkyl optionally substituted with -C(=O)NH2, 3-5 membered cycloalkyl optionally substituted with OH, and 5-6 membered heteroaryl optionally substituted with 1-2 groups selected from F, Cl, Br, Me, CF3, CF2H, CN, CONH2, and NH2, and R c is H, halogen, CN, or methyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0153] In the 30th embodiment, the compound of the present disclosure has the following structural formulas 33-1, 33-2, or 33-3: [Table 9] [wherein, X1, X2, and Z1 are each independently selected from C and N, and R a1 , R a2 and R a3 are each independently selected from F, Cl, Br, methyl, CF3, CF2H, CN, CONH2, CH2NH2, ethyl, cyclopropyl, and OCH3, and R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and when linked to N in ring B, R b1 is absent or is C1-C4 alkyl, R c is H, halogen, CN, or methyl, p is 1, 2, or 3, q is 0, 1, or 2, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0154] In the 31st embodiment, the compound of the present disclosure has the following structural formulas 34-1, 34-2, 34-3, 34-4, 34-5, or 34-6: [Table 10] [wherein, X1 and X2 are each independently selected from N, O, and S, Y1, Y2, and Z1 are each independently selected from C and N, and R a1 and R a2 and R a4 are each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2, and OCH3, R a3 is C1-C4 alkyl, and R b1 and R b2is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and when linked to N in ring B, R b1 and R b2 are absent, R b3 is selected from H, a 5- to 6-membered heteroaryl optionally substituted with one or two groups independently selected from F, Cl, Br, Me, CF3, CF2H, CN, CONH2, and NH2, and a C1-C4 alkyl optionally substituted with -C(=O)NH2, R c is H, halogen, CN, or methyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments] a compound, its tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0155] In a 32nd embodiment, the compounds of the present disclosure have the following structural formulas 35-1, 35-2, 35-3, or 35-4:

Table 11

[0156] In a 33rd embodiment, the compound of the present disclosure has the following structural formulas 36-1, 36-2, or 36-3: [Table 12] [wherein X1 and X2 are independently selected from N, O, and S, Y1, Y2, and Z1 are independently selected from C and N, and R a1 and R a2 are each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2, and OCH3, R a3 is C1-C4 alkyl, R b1 and R b2 are independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and when linked to N in ring B, R b1 and R b2 are absent, and R c is H, halogen, CN, or methyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0157] In a 34th embodiment, the compound of the present disclosure has the following structural formulas 37-1, 37-2, 37-3, 37-4, 37-5, or 37-6: [Table 13] [wherein X1 and X2 are independently selected from N, O, and S, Y1, Y2, and Z1 are independently selected from C and N, and Ra1 and R a2 is independently selected from F, Cl, Br, C1-C4 alkyl optionally substituted with 1-3 halogens, C3-C4 cycloalkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, and R a3 is selected from C3-C4 cycloalkyl and C1-C4 alkyl optionally substituted with 1-3 groups independently selected from halogen and cyclopropyl, and 4-5 membered heterocyclyl, and R b1 and R b2 is independently selected from H, F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and when linked to N in ring B, R b1 and R b2 is absent, and R b3 is selected from 5-6 membered heteroaryl substituted with 1-2 groups selected from F, Cl, Br, Me, CF3, CF2H, CN, CONH2 and NH2, and C1-C4 alkyl optionally substituted with -OH or -C(=O)NH2, and R c is H, halogen, CN, or methyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0158] In a 35th embodiment, the compounds of the present disclosure have the following structural formulas 38-1, 38-2, or 38-3:

Table 14

[0159] In a 36th embodiment, a compound of the present disclosure has the following structural formulas 39-1, 39-2, 39-3, or 39-4: [Table 15] [wherein X1 and X2 are independently selected from N, O, and S, Z1 is selected from C and N, R a1 and R a2 are each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2, and OCH3, R a3 is C1-C4 alkyl, 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 variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0160] In a 37th embodiment, a compound of the present disclosure has the following structural formulas 40-1, 40-2, or 40-3: [Table 16] [wherein, X1 and X2 are independently selected from N, O, and S, Z1 is selected from C and N, R a1 and R a2 are each independently selected from F, Cl, Br, C1-C4 alkyl, CF3, CF2H, CN, CONH2, CH2NH2 and OCH3, R a3 is C1-C4 alkyl, 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 variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0161] In a 38th embodiment, the compounds of the present disclosure have the following structural formulas 41-1, 41-2, 41-3, 41-4, or 41-5:

Table 17

[0162] In a 39th embodiment, a compound of the present disclosure has the following structural formulas 42-1, 42-2, or 42-3: [Table 18] [wherein X1, X2, X3, and X4 are independently selected from C, N, and S; X5 is selected from C and N; r is an integer selected from 0, 1, and 2; and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0163] In a 40th embodiment, a compound of the present disclosure has the following structural formulas 43-1, 43-2, 43-3, or 43-4: [Table 19] [wherein Z, Z1, Z2, and Z3 are independently selected from C, S, and N; r is an integer selected from 0, 1, and 2; and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

[0164] In the 41st embodiment, the compounds of the present disclosure have the following structural formulas 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:

Table 20

Chemical formula

[0165] In a 42nd embodiment, the compounds of the present disclosure have the following structural formulas 45-1, or 45-2:

Table 21

[0166] In a 43rd embodiment, the compounds of the present disclosure have the following structural formulas 46-1, 46-2, or 46-3: [Table 22] [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 with 1 to 3 halogen groups, R’ a1 、R’ a2 、R’ a3 、R’ a4 and R’ a5 are each independently selected from H and halogen, two, three, or four of R’ a1 、R’ a2 、R’ a3 、R’ a4 and R’ a5 are halogen and the remainder are H, R b is selected from H and 5- to 6-membered heteroaryl containing 2 to 3 heteroatoms selected from N and S, and the 5- to 6-membered heteroaryl of R b is optionally substituted by 1 to 3 groups selected from halogen and C1-C4 alkyl, R b1 is selected from H and C1-C4 alkyl optionally substituted with -C(=O)NH2, R b2is selected from H, halogen, -O(C1-C4 alkyl), and C1-C4 alkyl optionally substituted with 1 to 3 halogen groups, R c is selected from H, halogen, and C1-C2 alkyl, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments], a compound, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0167] In the 44th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, m R a groups substituted ring A is

Chemical formula

[0168] In the 45th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, m R a groups substituted ring A is

Chemical formula

[0169] In the 46th embodiment, in the compound of the present disclosure, a tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt, ring A is, [Chemical formula] [wherein ring A is substituted with m R a groups, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments.] is selected from.]

[0170] In the 47th embodiment, in the compound of the present disclosure, a tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt, ring A substituted with m R a groups is, [Chemical formula] [Chemical formula] [wherein all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments.] is selected from.]

[0171] In the 48th embodiment, in the compound of the present disclosure, a tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt, ring A substituted with m R a groups is, [Chemical formula] Selected from [[All other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments]].

[0172] In the 49th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, n R b groups substituted ring B is

Chemical formula

Chemical formula

[0173] In the 50th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, n R b groups substituted ring B is

Chemical formula

[0174] In the 51st embodiment, in the compound of the present disclosure, a tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt, n R b groups substituted ring B is

Chemical formula

[0175] In the 52nd embodiment, in the compound of the present disclosure, a tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt, n R b groups substituted ring B is

Chemical formula

[0176] In the 53rd embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, n R's b Ring B substituted with a group is

Chemical formula

[0177] In the 54th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, n R's b Ring B substituted with a group is

Chemical formula

[0178] In the 55th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, n Rs b Ring B substituted with a group is [Chemical formula] [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, and R c is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, and OCH3, and R b1 is selected from H, halogen, CN, and methyl, p is 1 or 2, q is 0, 1, or 2, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments].

[0179] In the 56th embodiment, in the compound of the present disclosure, a tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt, n Rs b Ring B substituted with a group is [Chemical formula] [wherein Z is selected from C and N, Y1, Y2 and Y3 are independently selected from C, N, S, and O, and R b1 is selected from F, Cl, Br, methyl, CN, CF3, CF2H, ethyl, cyclopropyl, CONH2, OCH3, CH2CONH2, [Chemical formula] is selected from, and R c is selected from H, halogen, CN, and methyl, p is 0, 1, or 2, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments].

[0180] In the 57th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, n R b groups substituted ring B is

Chemical formula

[0181] In the 58th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, n R b groups substituted ring B is

Chemical formula

[0182] In the 59th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, ring B is,

Chemical formula

[0183] In the 60th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, ring B substituted with n Rb groups is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0184] In the 61st embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, ring B substituted with n R b groups is

Chemical formula

[0185] In the 62nd embodiment, in the compound of the present disclosure, the tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt, R a is 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), halogen, and C1-C2 alkyl optionally substituted with 1 to 3 groups selected from halogen, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0186] In the 63rd embodiment, in the compound of the present disclosure, the tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt, 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 variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0187] In the 64th embodiment, in the compound of the present disclosure, the tautomer, the solvate or stereoisomer of the compound or the tautomer, or the pharmaceutically acceptable salt, R b is =O, OH, halogen, CN, -C(=O)NH(C1-C4 alkyl), -C(=O)O(C1-C4 alkyl), -C(=O)NH2, C3-C4 cycloalkyl optionally substituted with OH, O(C1-C3 alkyl), -C(=O)(C1-C2 alkyl), -C(=O)(C3-C6 cycloalkyl), -C(=O)(4-6 membered heterocyclyl optionally substituted with =O), -C(=O)(5-6 membered heteroaryl optionally substituted with 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,

Chem.

[0188] In Embodiment 65, in the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the present disclosure, R b is =O,

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0189] where

Chem.

[0190] In the 67th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, L is, [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0191] In the 68th embodiment, in the compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, L is, [Chemical formula] selected from, and all other variable elements not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0192] In certain embodiments, the compounds of the present disclosure are selected from Compounds 1-391 shown in Table 1, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing. [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] [Table 23-5] [Table 23-6] [Table 23-7] [Table 23-8] [Table 23-9] [Table 23-10] [Table 23-11] [Table 23-12] [Table 23-13] [Table 23-14] [Table 23-15]

Table 23-16

Table 23-17

Table 23-18

Table 23-19

[0193] When used in the chemical structures of this specification, the notations “or1” or “or2” mean that the configuration of the chiral center labeled by “or1” or “or2” is either the R configuration or the S configuration. For example, Compounds 194A and 194B have “or1” located on the stereocenter bonded to a methyl group and a hydrogen atom (the hydrogen atom is not shown). This means that the configuration of the chiral carbon in Compounds 194A and 194B labeled with “or1” is either R or S, and a single stereoisomer, that is, a compound having the R configuration and a compound having the S configuration are separately obtained and characterized by NMR, MS, and retention time, but the configuration of the chiral center was not determined. In other words, the compound

Chem.

[0194] In another example, compounds 302, 302A, 302B, and 302C have "or1" located on one stereocenter and "or2" located on another stereocenter. This means that the configurations of the two chiral carbons in these compounds labeled by "or1" and "or2" are each either R or S. Single stereoisomers, for example, compounds having the (S,S) configuration, compounds having the (R,S) configuration, compounds having the (R,R) configuration, and compounds having the (S,R) configuration were obtained separately and characterized by NMR, MS, and retention time, but the configurations of the chiral centers were not determined. In other words, each of the compounds

Chemical formula

[0195] In certain embodiments, for example, in various use and method embodiments, the compounds of the present disclosure are selected from Compounds 1A - 121A shown in Table 2, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing.

Table 24 - 1

Table 24 - 2

Table 24 - 3

Table 24 - 4

Table 24 - 5

Table 24 - 6

[0196] In another aspect of the present disclosure, at least one compound selected from the compounds of Formulas 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 (e.g., Compounds 1 to 391), and Compounds 1A to 121A in Table 2, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, and at least one pharmaceutically acceptable carrier are provided.

[0197] In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

[0198] It is also understood that the pharmaceutical compositions of the present disclosure can be used in combination therapies, i.e., the pharmaceutical compositions described herein may further comprise an additional active agent. Alternatively, the compounds of Formulas 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 (e.g., Compounds 1-391), and Compounds 1A-121A of Table 2, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, as a separate composition, may be administered simultaneously with, before, or after a composition comprising an additional active agent.

[0199] In some embodiments, the pharmaceutically acceptable carrier can be selected from adjuvants and vehicles. As used herein, the pharmaceutically acceptable carrier can be, for example, any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants suitable for the particular dosage form desired. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988 to 1999, Marcel Dekker, New York disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. For example, the use of all conventional carriers is considered to be within the scope of the present disclosure, except when they produce any undesirable biological effects or are otherwise incompatible with the compounds of the present disclosure by interacting in a detrimental manner with any other component of the pharmaceutical composition.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene block polymer, lanolin, sugars (such as lactose, glucose, and sucrose), starches (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol and polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), coloring agents, release agents, coating agents, sweetening agents, flavoring agents, fragrances, preservatives, and antioxidants.

[0200] The compounds of Formulas 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 (e.g., Compounds 1 to 391), and Compounds 1A to 121A in Table 2, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or the pharmaceutical compositions disclosed herein can be administered orally in solid dosage forms such as capsules, tablets, troches, dragees, granules and powders, or in liquid formulations such as elixirs, syrups, emulsions, dispersions and suspensions. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can also be administered parenterally in sterile liquid dosage forms such as dispersions, suspensions or solutions.For administering the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein, other dosage forms can also be used, such as ointments, creams, drops, transdermal patches, or powders for topical administration, ophthalmic solutions or suspension formulations for intraocular administration, for example, eye drops, aerosol sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration.

[0201] Gelatin capsules containing the compounds disclosed herein, their tautomers, solvates or stereoisomers of the compounds or tautomers, and / or pharmaceutically acceptable salts of the foregoing, and powder carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc. can also be used. Compressed tablets can be manufactured using similar diluents. Both tablets and capsules can be manufactured as sustained-release products and can continuously release the pharmaceutical over a certain period. Compressed tablets can be sugar-coated or film-coated to mask unpleasant tastes and protect the tablets from the atmosphere, or enteric-coated to selectively disintegrate in the gastrointestinal tract.

[0202] Liquid dosage forms for oral administration may further contain at least one agent selected from coloring agents and flavoring agents to enhance patient acceptability.

[0203] Generally, water, suitable oils, physiological saline, dextrose (glucose) aqueous solutions, and related sugar solutions, as well as glycols such as propylene glycol or polyethylene glycol, can be examples of carriers suitable for parenteral solutions. Solutions for parenteral administration can contain water-soluble salts of at least one compound described herein, at least one suitable stabilizer, and optionally at least one buffering substance. 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. Further, the parenteral solution may further contain at least one preservative selected from, for example, benzalkonium chloride, methylparaben and propylparaben, and chlorobutanol.

[0204] Pharmaceutically acceptable carriers are selected from carriers that are, for example, compatible with the active ingredient of the composition (and in some embodiments can stabilize the active ingredient) and not harmful to the subject being treated. For example, solubilizing agents such as cyclodextrin (which can form specific and more soluble complexes with at least one compound and / or at least one pharmaceutically acceptable salt disclosed herein) can be utilized as pharmaceutical excipients for active ingredient delivery. 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.

[0205] For administration by inhalation, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can be conveniently delivered in the form of an aerosol spray from a pressurized pack or a nebulizer. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can also be delivered as a formulated powder, and the powder composition can be inhaled using a powder insufflation device. One exemplary delivery system for inhalation may be a metered dose inhaler (MDI), which can be formulated as a suspension or solution of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein in at least one suitable propellant selected, for example, from fluorocarbons and hydrocarbons.

[0206] For intraocular administration, a solution or suspension of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein in a suitable ophthalmic vehicle at a suitable weight percent is used to formulate an ophthalmic preparation such that the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein are maintained in contact with the surface of the eye for a time sufficient to penetrate the cornea and internal regions of the eye.

[0207] Pharmaceutical dosage forms useful for the administration of 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.

[0208] The term "unit dosage form" refers to physically discrete units suitable as a single dosage form for human and other mammalian subjects, each unit containing a predetermined amount of an active substance calculated to provide the desired therapeutic effect in combination with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes in the case of liquid compositions, or pills, tablets, capsules, drops, etc. in the case of solid compositions. In such compositions, the active substance is usually a component in the range of about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight, the remainder being the vehicle or carrier and various processing aids useful for forming the desired dosage form. Unit dosage formulations are preferably about 5, 10, 25, 50, 100, 250, 500, or 1,000 mg per unit. In certain embodiments, the unit dosage form is packaged in a multi-pack adapted for continuous use, such as a blister pack containing at least 6, 9 or 12 sheets of unit dosage forms.

[0209] In some embodiments, unit capsules can be prepared by filling each of standard two-piece hard gelatin capsules with, for example, 100 milligrams of a powder of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

[0210] In some embodiments, a mixture of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein with a digestible oil such as soybean oil, cottonseed oil, or olive oil is prepared and injected into gelatin by a volumetric pump to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

[0211] In some embodiments, tablets can be prepared by conventional procedures such that the dosage unit contains, for example, 100 milligrams of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.8 milligrams of lactose. Suitable coatings can be applied to enhance taste or delay absorption.

[0212] In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of the compounds disclosed herein and / or at least one of its enantiomers, diastereoisomers, or pharmaceutically acceptable salts in 10% by volume of propylene glycol. The solution is prepared to the intended volume with water for injection and sterilized.

[0213] In some embodiments, an aqueous suspension can be prepared for oral administration. For example, an aqueous suspension of 5 milliliters each containing 100 milligrams of micronized compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 gram of a sorbitol solution (U.S.P.), and 0.025 milliliters of vanillin can be used.

[0214] When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein are administered in sequence or simultaneously with at least one other therapeutic agent, generally the same dosage form can be used. When the drugs are administered in a physically combined form, it is necessary to select the dosage form and route of administration according to the compatibility of the drugs to be combined. Thus, the term co-administration is understood to include administering at least two agents simultaneously or sequentially, or administering as a fixed-dose combination of at least two active ingredients.

[0215] The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts disclosed herein can be administered as a single active ingredient or in combination with at least one second active ingredient.

[0216] The compounds, tautomers, solvates, or stereoisomers described herein can be used in the above forms or in the form of their pharmaceutically acceptable salts, such as hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, trifluoroacetate, etc. When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein contain relatively acidic functional groups, the salts can be obtained as such or by adding the desired base 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 as such or by adding the desired acid in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonic acid, phosphoric acid, monohydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, monohydrogen sulfuric acid, hydroiodic acid, or phosphorous acid, and relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginate, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1~19).

[0217] The neutral form of the pharmaceutically acceptable salts described herein can be regenerated by contacting the salt with a base or an acid and isolating the parent compound by conventional methods.

[0218] The present disclosure provides prodrugs. The prodrugs of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein readily undergo chemical change under physiological conditions to provide the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure. Further, the prodrugs can be converted to the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure by chemical or biochemical means in an ex vivo environment. For example, when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent, the prodrug can be slowly converted to the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of the present disclosure. Prodrugs are often useful because they can be easier to administer than the parent drug in some situations. For example, oral administration may result in higher bioavailability than the parent drug. Prodrugs may also have improved solubility in a pharmaceutical composition compared to the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. Examples of prodrugs include, but are not limited to, compounds of the present disclosure that are administered as esters ("prodrugs") but are subsequently metabolically hydrolyzed to carboxylic acids, i.e., the active forms.

[0219] Certain compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts of the present disclosure may exist in unsolvated forms as well as solvated forms including hydrated forms. Certain compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure may exist in multiple crystalline or amorphous forms.

[0220] Certain compounds, tautomers, solvates, or pharmaceutically acceptable salts in the present disclosure have asymmetric carbon atoms (optical centers) or double bonds, and racemates, enantiomers, diastereoisomers, geometric isomers, and individual isomers are all intended to be encompassed within the scope of the present disclosure.

[0221] III. Treatments and Methods of Use In the present disclosure, a treatment and method of use are provided that utilize a compound described in any one of Section II (Compounds and Compositions) and the various embodiments of Tables 1 and 2, for example, 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, 16-2a, 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, as well as Compounds 1 to 391 of Table 1 and Compounds 1A to 121A of Table 2, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0222] In one aspect of the present disclosure, a therapeutically effective amount of the compounds 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 (e.g., Compounds 1 to 391), and Compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt is administered to a subject in need thereof to provide a method for treating a disease or condition, which 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 the PNS, including but not limited to genetic neuropathies such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), glaucoma, optic nerve disorders such as retinal ganglion degeneration, colitis, diabetic neuropathy, metabolic diseases or disorders such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathies such as CIPN induced by various drugs, for example, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage.,

[0223] In another aspect, as used herein, the compounds 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 disclosed herein (e.g., Compounds 1 to 391), and Compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, are disclosed herein. Also disclosed are pharmaceutical compositions comprising any of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts thereof.

[0224] In another aspect, as used herein, the compounds of Formulas 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 (e.g., Compounds 1-391), and Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts disclosed herein, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt for use in the manufacture 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 the PNS, including but not limited to genetic neuropathies such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), glaucoma, and optic nerve disorders such as retinal ganglion degeneration, colitis, diabetic neuropathy, metabolic diseases or disorders such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathies such as CIPN induced by various drugs, for example, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage.

[0225] In a further aspect of the present disclosure, the compounds of Formulas 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 (e.g., Compounds 1 to 391), and Compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts disclosed herein, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt is used for the treatment of a disease or condition, and 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 the PNS, including but not limited to genetic neuropathies such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), glaucoma, and optic nerve disorders such as retinal ganglion degeneration, colitis, diabetic neuropathy, metabolic diseases or disorders such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathies such as CIPN induced by various drugs, for example, but not limited to, taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage.,

[0226] In another aspect of the present disclosure, 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-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 1-391), Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt is provided.

[0227] In another aspect, the present specification discloses the use of the compounds of Formulas 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 (e.g., Compounds 1 to 391), Compounds 1A to 121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, the tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, or a pharmaceutical composition comprising any of the compound, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts for the manufacture of a medicament for inhibiting or preventing axonal degeneration or neuronal damage.

[0228] In a further aspect of the present disclosure, the compounds of Formulas 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 (e.g., Compounds 1-391), Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein, or a pharmaceutical composition comprising any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts are used to inhibit or prevent axonal degeneration or neuronal damage.

[0229] In another aspect of the present disclosure, a method of modulating, e.g., inhibiting, SARM1 in a subject in need thereof, the method 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, 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 (e.g., Compounds 1-391), Compounds 1A-121A, tautomers thereof, solvates or stereoisomers of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt is provided.

[0230] In another aspect, as used herein, the compounds of Formulas 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 (e.g., Compounds 1-391), Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts described herein, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt for use in modulating, e.g., inhibiting, SARM1 in a subject in need thereof is disclosed.

[0231] In another aspect of the present disclosure, the compounds of Formulas 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 (e.g., Compounds 1-391), Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt are used to modulate, e.g., inhibit, SARM1 in a subject in need by contacting the subject with the compound, tautomer, solvate, stereoisomer, pharmaceutically acceptable salt, or pharmaceutical composition.

[0232] The compounds 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 (e.g., Compounds 1-391), Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts can be administered, for example, once a day, twice a day, or three times a day for treating a disease or condition, and 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 the PNS, including but not limited to genetic neuropathies such as Charcot-Marie-Tooth disease and chronic inflammatory demyelinating polyneuropathy (CIDP), glaucoma, optic nerve disorders such as retinal ganglion degeneration, colitis, diabetic neuropathy, metabolic diseases or disorders such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), and peripheral neuropathies such as CIPN induced by various drugs, such as but not limited to taxanes, vinca alkaloids, and proteasome inhibitors. In some embodiments, the disease or condition is caused by axonal degeneration or neuronal damage.

[0233] The compounds 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 (e.g., Compounds 1-391), Compounds 1A-121A, their tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt, in all given cases the most appropriate route depends on the specific host and the nature and severity of the condition in which the active ingredient is administered, but can be administered in various ways, for example, orally, topically, rectally, parenterally, by inhalation spray, or by implanted reservoir, etc.As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intramedullary, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein are provided in convenient unit dosage forms and can be prepared by any of the methods 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 as described in International Publications WO2013 / 075083, WO2013 / 075084, WO2013 / 078320, WO2013 / 120104, WO2014 / 124418, WO2014 / 151142, and WO2015 / 023915.

[0234] Generally, contact is effected by administering to the subject an effective amount of one or more of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts disclosed herein. Generally, administration is adjusted to achieve a therapeutic dosage of about 0.1 to 50, preferably 0.5 to 10, more preferably 1 to 10 mg / kg, although the optimal dosage varies for each compound and is generally determined empirically for each compound.

[0235] The dosage will vary depending on factors such as the age, health and weight of the recipient, the degree of the disease, the type of concurrent treatment if any, the frequency of treatment, and the nature of the desired effect. Generally, the daily dosage of the active ingredient can vary, for example, from 0.1 to 2000 milligrams per day. For example, to obtain the desired result, 10 to 500 milligrams once or multiple times a day may be effective.

[0236] In some embodiments, 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, 16-2a, 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 disclosed herein (e.g., Compounds 1-391), Compounds 1A-121A, its tautomers, solvates or stereoisomers of the compound or tautomer, or pharmaceutically acceptable salts of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt 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 the morning / daytime and discontinued at night.

[0237] A. Examples To better understand the disclosure described herein, the following examples are disclosed in this specification. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the present disclosure in any way.

[0238] Example I. Synthesis of Exemplary Compounds The compounds of the present disclosure selected from compounds of the formulas shown herein, their tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing can be synthesized according to standard chemical procedures or as exemplified herein, which include the following general synthetic procedures and specific synthetic schemes for Compounds 1 - 354 and Compounds 1A - 15A as representative examples of Formula 1. 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

Chemical Structure

Table 25-1

Table 25-2

Table 25-3

Table 25-4

Table 25-5

Table 25-6

Table 25-7

Table 25-8

Table 25-9

Table 25-10

Table 25-11

Table 25-12

Table 25-13

Table 25-14

Table 25-15

Table 25-16

Table 25-17

Table 25-18

Table 25-19

Table 25-20

Table 25-21

Table 25-22

Table 25-23

Table 25-24

Chem.

Table 26 - 1

Table 26-2

Table 26-3

Table 26-4

Table 26-5

Table 26-6

Table 26-7

Table 26-8

Table 26-9

Table 26-10

Table 26-11

Table 26-12

Table 26-13

Table 26-14

Table 26-15

Table 26-16

Table 26-17

Table 26-18

Table 26-19

Table 26-20

Table 26-21

Chem.

Chem.

Table 28

Table 29-1

Table 29-2

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Table 30

Chem.

Chemical Structure

Table 31-1

Table 31-2

Table 31-3

Table 31-4

Table 31-5

Table 31-6

Table 31-7

Table 31-8

Table 31-9

Table 31-10

Table 31-11

Table 31-12

Table 31-13

Table 31-14

Table 31-15

Chemical formula

Table 32

Chem.

Table 33 - 1

Table 33 - 2

Table 33 - 3

Table 33 - 4

Chemical formula

Table 34-1

Table 34-2

Table 34-3

Table 34-4

Table 34-5

Table 34-6

Table 34-7

Table 34-8

Table 34-9

Table 34-10

Table 34-11

Table 34-12

Chemical formula

Chemical Structure

Table 35-1

Table 35-2

Table 35-3

Table 35-4

Chem.

Chemical Structure

Chemical Structure

Table 36

Chem.

Chemical Structure

Table 38

Chem.

Table 39 - 1

Table 39 - 2

Chemical formula

Table 40-1

Table 40-2

Table 40-3

[0239] Example II. SAMR1 (50-724) Enzyme Assay The enzyme assay was performed in a 384-well plate using Dulbecco's phosphate buffered saline (PBS) as the reaction buffer. Purified SARM1 (50-724) at a final concentration of 2 nM was pre-incubated with the test compound at a final assay concentration of 1% DMSO for 15 min at room temperature. 200 μM nicotinamide mononucleotide (NMN) as an activator and 100 μM NAD as a substrate +The mixture was added to initiate the reaction. After incubating at room temperature for 1 hour, the reaction was stopped with 10 volumes of 70% acetonitrile and then centrifuged at 3800 rpm for 10 minutes. The sample was diluted to an appropriate concentration with 10 mM ammonium acetate (pH 9.75) and then analyzed using LC-MS / MS.

[0240] The SARM1 inhibitory activities of Compounds 1 to 391 and Compounds 1A to 15A are summarized in Table 3. In Table 3, the activities are shown as follows: A = IC 50 ≦ 100 nM; B = 100 nM < IC 50 ≦ 500 nM; C = 500 nM < IC 50 ≦ 1000 nM; D = IC 50 > 1000 nM.

Table 41-1

Table 41-2

Table 41-3

Table 41-4

[0241] All publications, including but not limited to the disclosures and patent applications cited herein, are hereby incorporated by reference as if fully set forth herein. If the specific content of the publications cited herein conflicts with or is inconsistent with the present disclosure, the present disclosure shall prevail.

[0242] Those skilled in the art will readily recognize that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the present disclosure as defined in the following claims from the present disclosure and the claims.

Claims

1. The following structural formula 1: 【Chemistry 1】 [In the formula, Ring A is a phenyl ring, a 5-10 membered heteroaryl ring, a 5-10 membered carbocykyl ring, or a 5-10 membered heterocycline ring. Ring B is a phenyl ring, a 9-11 membered aryl ring, a 9-11 membered heteroaryl ring, or a 9-11 membered heterocyclyl ring. R ａ is =O, C ３ -C ６ cycloalkyl, -O(C １ -C ４ alkyl), COOH, CN, CONH ２ , -C(=O)NH(C １ -C ４ alkyl), -C(=O)N(C １ -C ４ alkyl) ２ , -C(=O)O(C １ -C ４ alkyl), halogen, and optionally C １ -C ４ alkyl selected from alkyl substituted with 1 to 3 groups selected from halogen, -OH, cyclopropyl, oxetanyl, and azetidinyl R ｂ is =O, OH, halogen, CN, -C(=O)NH ２ , -C(=O)NH(C １ ~C ４ Alkyl), -C(=O)O(C １ ~C ４ Alkyl), optionally substituted C ３ ~C ６ Cycloalkyl, optionally substituted C ３ ~C ６ Heterocyclyl, arbitrarily substituted C ５ ~C ６ Heteroaryl, -O(C) １ ~C ４ Alkyl), -C (=O) (C １ ~C ４ Alkyl), -C (=O) (arbitrarily substituted C) ３ ~C ６ Cycloalkyl), -C(=O)(arbitrarily substituted 5-6 member heterocyclyl), -C(=O)(arbitrarily substituted 5-6 member heteroaryl), -C(=O)(CH ２ ) pC(=O)NH ２ , -NHC(=O)(C １ ~C ４ Alkyl), -C(=O)N(C １ ~C ４ Alkyl) ２ , -C(=O)NH(CH ２ )pOH, -S(=O) ２ NH ２ , 【Chemistry 2】 Halogen, NH (optional) ２ OH, OCH ３ , -C(=O)NH(C １ ~C ４ Alkyl), -C(=O)O(C １ ~C ４ Alkyl), -C(=O)N(C １ ~C ４ Alkyl) ２ , -COOH, -C(=O)NH ２ , CN, C ３ ~C ５ Cycloalkyl, phenyl, -C(=O)(C １ ~C ４ Alkyl), -C (=O) (C ３ ~C ６ Cycloalkyl), -C(=O)(5-6 member heterocyclyl), -C(=O)(arbitrarily substituted 5-6 member heteroaryl), C(=O)NH(CH ２ ) pOH and C substituted with 1 to 3 groups selected from 5-6 member heteroaryl groups １ ~C ４ Alkyl, C at will １ ~C ３ Alkyl, =O, -NH ２ , -CN, -CONH ２ , 5-6 membered heteroaryls substituted with 1-2 groups selected from halogens, and Optionally =O, -OH, -NH ２ , -CN, -CONH ２ , halogen and C １ ~C ３ Selected from 4-6 membered heterocyclines substituted with 1-2 groups selected from alkyl groups, or Two Rs bonded at the same position on ring B ｂ They combine to form C ３ ~C ６ Forming a cycloalkyl group, R ４ and R ５ H and C are independent of each other. １ ~C ３ Selected from alkyl groups, or R ４ and R ５ These combine to form a 3-5 membered cycloalkyl group, L is 【Transformation 3】 Selected from, R １ is H, D, or C １ ~C ６ It is alkyl, R ２ , CN, C １ ~C ６ Alkenil, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Heterocyclyl, 5- or 6-membered heteroaryl, Optionally C １ ~C ４ phenyl substituted with 1 to 3 groups selected from alkyl and halogen, and Optionally substituted with 1 to 3 groups selected from halogen, OH, CN, -SO ２ CH ３ , -NHSO ２ CH ３、 -CONH ２ , OCH ３ and phenyl, or selected from C １ to C ６ alkyl, or R １ and R ２ These combine to form a 3-6 membered carbocyclyl or a 3-6 membered heterocyclyl, R ３ is optionally a halogen, O(C) １ ~C ３ Alkyl), OH, and NH ２ C substituted with 1 to 3 groups selected from １ ~C ４ It is alkyl, m is an integer selected from 0, 1, 2, 3, and 4. n is an integer selected from 0, 1, 2, 3, and 4. p is an integer selected from 0, 1, 2, 3, and 4. A compound, provided that it is not any of compounds 1A to 121A, a tautomer thereof, a solvate or stereoisomer of the compound or its tautomer, or a pharmaceutically acceptable salt thereof.

2. The aforementioned compound has the following structural formula 14a: 【Chemistry 4】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ｂ１ H, CH ２ CN, and C １ ~C ２ Selected from alkyl groups, R ｂ２ H, halogen, CN, OCH ３ , C １ ~C ３ Alkyl and C ３ ~C ５ Selected from cycloalkyl, L is 【Transformation 5】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

3. The aforementioned compound has the following structural formula 14b: 【Transformation 6】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ｂ１ H and C １ ~C ２ Selected from alkyl groups, R ｂ２ H, halogen, CN, OCH ３ , C １ ~C ３ Alkyl and C ３ ~C ５ Selected from cycloalkyl, L is 【Transformation 7】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound has the following structural formula 14c: 【Transformation 8】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, R ｂ１ is H and optionally C ３ ~C ４ Cycloalkyl-substituted C １ ~C ２ Selected from alkyl groups, R ｂ２ H, halogen and C １ ~C ３ Selected from alkyl, L is 【Chemistry 9】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

5. The aforementioned compound has the following structural formula 14d: 【Chemistry 10】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, Y ２ is selected from N and O, and L is 【Chemistry 11】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

6. The aforementioned compound has the following structural formula 14e: 【Chemistry 12】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, Y ２ is selected from N and O, and L is 【Chemistry 13】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

7. The aforementioned compound has the following structural formula 14f: 【Chemistry 14】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, Y ２ is selected from N and O, and L is 【Chemistry 15】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

8. The above compound has the following structural formula: 14 g 【Chemistry 16】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, Y ２ is selected from N and O, and L is 【Chemistry 17】 A compound according to claim 1 having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

9. The aforementioned compound has the following structural formula 14h-1 or 14h-2: Table 1 [In the formula, R ａ１ , R ａ２ , and R ａ３ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, Y ２ is selected from N and O, and L is [Chemistry 18] A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

10. The aforementioned compound has the following structural formula 14i: 【Chemistry 19】 [In the formula, R ａ１ , R ａ２ and R ａ３ These are independently F, Cl, Br, methyl and OCH ３ Selected from, Y ２ is selected from N and O, and L is 【Chemistry 20】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

11. The aforementioned compound has the following structural formula 14j: 【Chemistry 21】 [In the formula, R ａ１ , R ａ２ and R ａ３ These are independently F, Cl, Br, methyl and OCH ３ Selected from, Y ２ is selected from N and O, and L is 【Chemistry 22】 A compound of claim 1 having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

12. The aforementioned compound has the following structural formula 15a: 【Chemistry 23】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, L is 【Chemistry 24】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

13. The aforementioned compound is defined by the following structural formula 16-1 or 16-2: Table 2 [In the formula, R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ 0, 1, 2, or 3 of these are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ａ１ , R ａ２ , R ａ３ , R ａ４ , and R ａ５ The compound according to claim 1, the tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the remainder is H.

14. The aforementioned compound has the following structural formula 16-1a or 16-2a: Table 3 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, L is 【Chemistry 25】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

15. The aforementioned compound has the following structural formula 17: 【Chemistry 26】 [In the formula, R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ 0, 1, 2, or 3 of these are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ａ１ , R ａ２ , R ａ３ , R ａ４ and R ａ５ The remaining part is H, and R ｂ１ H and C １ ~C ２ Selected from alkyl groups, R ｂ２ H and C １ ~C ４ A compound according to claim 1, having [selected from alkyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. The aforementioned compound has the following structural formula 17a: 【Chemistry 27】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl and OCH ３ Selected from, R ｂ１ H and C １ ~C ２ Selected from alkyl groups, R ｂ２ H and C １ ~C ４ Selected from alkyl, L is 【Chemistry 28】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

17. The aforementioned compound has the following structural formula 18: 【Chemistry 29】 [In the formula, R ａ１ , R ａ２ , R ａ３ , R ａ４ , and R ａ５ 0, 1, 2, or 3 of these are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ａ１ , R ａ２ , R ａ３ , R ａ４ , and R ａ５ The remaining part is H, and R ｂ１ ha = O, -NHCOCH ３ A compound according to claim 1, having [selected from , and OH], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof.

18. The aforementioned compound has the following structural formula 18a: 【Transformation 30】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ｂ１ H = O, OH, and -NHCOCH ３ Selected from, L is 【Chemistry 31】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

19. The aforementioned compound has the following structural formula 20: 【Chemistry 32】 [In the formula, Y １ and Y ２ 0 or 1 of them are N, the others are C, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ｂ１ H and C １ ~C ２ Selected from alkyl, however, Y ２ If R is N, ｂ１ It does not exist, R ｂ２ H, CN, C １ ~C ２ Alkyl and -C(=O)NH ２ Selected from, however, Y １ If R is N, ｂ２ It does not exist, R ｂ３ H and C １ ~C ２ Selected from alkyl groups, R ｂ４ H and C １ ~C ２ Selected from alkyl, L is 【Transformation 33】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

20. The aforementioned compound has the following structural formula 21a: 【Transformation 34】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ｂ１ , arbitrarily = O and C １ ~C ３ Selected from 5-6 membered heteroaryls and 5-6 membered heterocyclines substituted with one or two groups selected from alkyls, L is 【Chemistry 35】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

21. The aforementioned compound has the following structural formula 21b: 【Transformation 36】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ｂ１ is -C(=O)NH(C １ ~C ４ Alkyl), OCH ３ , and -C(=O)O(C １ ~C ４ Selected from alkyl, R ｂ２ H and -C(=O)NH ２ Selected from, L is 【Chemistry 37】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

22. The aforementioned compound has the following structural formula 22a: 【Transformation 38】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, Y １ , Y ２ and Y ３ 0, 1, or 2 of these is N, and Y １ , Y ２ and Y ３ The remainder is C, and R ｂ is C １ ~C ２ Alkyl, C ３ ~C ５ Cycloalkyl, CN, CONH ２ and selected from halogen, where n is 0, 1, or 2, and L is 【Chemistry 39】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

23. The aforementioned compound has the following structural formula 23a: 【Chemistry 40】 [In the formula, R ａ１ and R ａ２ These are independently F, Cl, Br, methyl, and OCH ３ Selected from, R ｂ１ H, C １ ~C ３ Alkyl, halogen, C ３ ~C ５ Cycloalkyl, CN, and CONH ２ Selected from, however, Y ２ If S or O, R ｂ１ Y does not exist. ２ and Y ３ One of them is S or O, the other is C, and L is 【Chemistry 41】 A compound according to claim 1, having [selected from], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

24. The aforementioned compound has the following structural formula 24: 【Chemistry 42】 [In the formula, X １ , X ２ , and X ３ One of them is N, and the other two are C, Y ２ is selected from C, N, and O, R ｂ１ is C １ ~C alkyl, C ３ ~C ５ Cycloalkyl, O(C) １ ~C ３ Selected from alkyl, and halogen, L is 【Chemistry 43】 A compound according to claim 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof.

25. The aforementioned compound has the following structural formula 28-1 or 28-2: Table 4 [In the formula, X １ , X ２ , Y １ , Y ２ and Z １ R is independently selected from C and N. ａ１ F, Cl, Br, methyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ Selected from ethyl and cyclopropyl, R ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

26. The aforementioned compound has the following structural formula 29-1 or 29-2: Table 5 [In the formula, X １ , X ２ and Z １ R is independently selected from C and N. ａ１ F, Cl, Br, methyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ Selected from ethyl and cyclopropyl, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, CH ２ OH, cyclopropyl, and OCH ３ Selected from, R ｂ１ If it is connected to N in ring B, then it does not exist, or C １ ~C ４ It is alkyl, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl, p is 1, 2, or 3, and q is 0, 1, or 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

27. The aforementioned compound has the following structural formulas 30-1, 30-2, 30-3, 30-4, or 30-5: Table 6 [In the formula, X １ , X ２ , Y １ , Y ２ and Z １ R is independently selected from C and N. ａ１ and R ａ２ Each of them is independently F, Cl, Br, methyl, CF ３ CF ２ H, ethyl, CN, CONH ２ ,CH ２ NH ２ Selected from and cyclopropyl, R ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｂ３ is arbitrarily -C(=O)NH ２ C replaced by １ ~C ４ Alkyl, optionally 3- to 5-membered cycloalkyl groups substituted with OH, and optionally F, Cl, Br, Me, CF ３ CF ２ H, CN, CONH ２ and NH ２ Selected from a 5-6 member heteroaryl substituted with 1-2 groups selected from R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

28. The aforementioned compound has the following structural formula 31-1 or 31-2: Table 7 [In the formula, X １ , X ２ and Z １ R is independently selected from C and N. ａ１ and R ａ２ Each of them is independently F, Cl, Br, methyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ Selected from ethyl and cyclopropyl, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ If it is connected to N in ring B, then it does not exist, or C １ ~C ４ It is alkyl, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl, p is 1, 2, or 3, and q is 0, 1, or 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

29. The aforementioned compound has the following structural formulas 32-1, 32-2, 32-3, 32-4, or 32-5: Table 8 [In the formula, X １ , X ２ , Y １ , Y ２ and Z １ R is independently selected from C and N. ａ１ , R ａ２ and R ａ３ Each of them is independently F, Cl, Br, methyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｂ３ H, arbitrarily -C(=O)NH ２ C replaced by １ ~C ４ Alkyl, optionally 3- to 5-membered cycloalkyl groups substituted with OH, and optionally F, Cl, Br, Me, CF ３ CF ２ H, CN, CONH ２ and NH ２ Selected from a 5-6 member heteroaryl substituted with 1-2 groups selected from R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

30. The aforementioned compound has the following structural formulas 33-1, 33-2, or 33-3: Table 9 [In the formula, X １ , X ２ and Z １ R is independently selected from C and N. ａ１ , R ａ２ and R ａ３ Each of them is independently F, Cl, Br, methyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ If it is connected to N in ring B, then it does not exist, or C １ ~C ４ It is alkyl, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl, p is 1, 2, or 3, and q is 0, 1, or 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

31. The aforementioned compound has the following structural formulas 34-1, 34-2, 34-3, 34-4, 34-5, or 34-6: Table 10 [In the formula, X １ and X ２ It is independently selected from N, O, and S, and Y １ , Y ２ and Z １ R is independently selected from C and N. ａ１ and R ａ２ and R ａ４ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ａ３ is C １ ~C ４ It is alkyl, R ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｂ３ H, and optionally F, Cl, Br, Me, CF ３ CF ２ H, CN, CONH ２ and NH ２ Five- to six-membered heteroaryls substituted with one or two groups selected from, and optionally -C(=O)NH ２ C replaced by １ ~C ４ Selected from alkyl groups, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

32. The aforementioned compound has the following structural formulas 35-1, 35-2, 35-3, or 35-4: Table 11 [In the formula, X １ and X ２ It is independently selected from N, O, and S, and Y １ , Y ２ and Z １ R is independently selected from C and N. ａ１ and R ａ２ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, and OCH ３ Selected from, R ａ３ is C １ ~C ４ It is alkyl, R ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

33. The aforementioned compound has the following structural formulas 36-1, 36-2, or 36-3: Table 12 [In the formula, X １ and X ２ It is independently selected from N, O, and S, and Y １ , Y ２ and Z １ R is independently selected from C and N. ａ１ and R ａ２ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ａ３ is C １ ~C ４ It is alkyl, R ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

34. The aforementioned compound has the following structural formulas 37-1, 37-2, 37-3, 37-4, 37-5, or 37-6: Table 13 [In the formula, X １ and X ２ It is independently selected from N, O, and S, and Y １ , Y ２ and Z １ R is independently selected from C and N. ａ１ and R ａ２ Each of these is independently F, Cl, Br, and C, which is substituted with any one to three halogen groups. １ ~C ４ Alkyl, C ３ ~C ４ Cycloalkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ａ３ C is optionally substituted with 1 to 3 groups selected from halogens, cyclopropyls, and 4-5 membered heterocyclines. ３ ~C ４ Cycloalkyl and C １ ~C ４ Selected from alkyl groups, R ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｂ３ F, Cl, Br, Me, CF ３ CF ２ H, CN, CONH ２ and NH ２ Five- to six-membered heteroaryls substituted with one or two groups selected from, and optionally -OH or -C(=O)NH ２ C replaced by １ ~C ４ Selected from alkyl groups, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

35. The aforementioned compound has the following structural formulas 38-1, 38-2, or 38-3: Table 14 [In the formula, X １ and X ２ The elements are independently selected from N, O, and S, and Z １ is selected from C and N, R ａ１ and R ａ２ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ａ３ is C １ ~C ４ It is alkyl, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl, p is 1, 2, or 3, and q is 0, 1, or 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

36. The aforementioned compound has the following structural formulas 39-1, 39-2, 39-3, or 39-4: Table 15 [In the formula, X １ and X ２ The elements are independently selected from N, O, and S, and Z １ is selected from C and N, R ａ１ and R ａ２ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ａ３ is C １ ~C ４ It is alkyl, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl, p is 1, 2, or 3, and q is 0, 1, or 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

37. The aforementioned compound has the following structural formulas 40-1, 40-2, or 40-3: Table 16 [In the formula, X １ and X ２ The elements are independently selected from N, O, and S, and Z １ is selected from C and N, R ａ１ and R ａ２ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ａ３ is C １ ~C ４ It is alkyl, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN or methyl, p is 1, 2 or 3, and q is 0, 1 or 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

38. The aforementioned compound has the following structural formulas 41-1, 41-2, 41-3, 41-4, or 41-5: Table 17 [In the formula, X １ and X ２ The elements are independently selected from N, O, and S, and Z １ is selected from C and N, R ａ１ and R ａ２ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ａ３ is C １ ~C ４ It is alkyl, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ３ This can be any -OH or -C(=O)NH ２ C replaced by １ ~C ４ Selected from alkyl groups, R ｃ The compound according to claim 1, wherein [ is H, halogen, CN, or methyl, p is 1, 2, or 3, and q is 0, 1, or 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

39. The aforementioned compound has the following structural formulas 42-1, 42-2, or 42-3: Table 18 [In the formula, X １ , X ２ , X ３ , and X ４ Independently, C, N, and S are selected, and X ５ The compound according to claim 1, wherein [ is selected from C and N, and r is an integer selected from 0, 1, and 2], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

40. The aforementioned compound has the following structural formulas 43-1, 43-2, 43-3, or 43-4: Table 19 [In the formula, Z １ Z １ , and Z ３ The compound according to claim 1, wherein [ is independently selected from C, S, and N, and r is an integer selected from 0, 1, and 2], its tautomer, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

41. The aforementioned compound has the following structural formulas 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: Table 20 [In the formula, X １ is selected from C, S, O, and N, X ２ is selected from C, N, S, and O, Z １ and Z ２ These are independently selected from C, N, and S. R ａ１ , R ａ２ and R ａ３ Each of them is independent of F, Cl, Br, and C. １ ~C ４ Alkyl, CF ３ CF ２ H, CN, CONH ２ ,CH ２ NH ２ and OCH ３ Selected from, R ｂ１ H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, OCH ３ , -C(=O)CH ２ C(=O)NH ２ , -C (=O) (C １ ~C ４ Alkyl), -C (=O) (C ３ ~C ５ Cycloalkyl), -C(=O)(5-6 member heteroaryl), -C(=O)(4-6 member heterocyclyl optionally substituted with =O or OH), -C(=O)OH, OH, 【Chemistry 44】 -C(=O)NH ２ , optionally substituted with OH, 3- to 5-membered cycloalkyl groups, and optionally OH or -C(=O)NH ２ C replaced by １ ~C ４ Selected from alkyl groups, R ｂ２ and R ｂ３ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, -C(=O)NH ２ , and OCH ３ Selected from or R ｂ２ and R ｂ３ and combine, C ３ ~C ５ Forming a cycloalkyl group, R ｂ４ is either = O or does not exist. R ｂ５ H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, OCH ３ , -C(=O)CH ２ C(=O)NH ２ , -C (=O) (C １ ~C ４ Alkyl), -C (=O) (C ３ ~C ５ Cycloalkyl), -C(=O)(5-6 member heteroaryl), -C(=O)(5-6 member heterocyclyl optionally substituted with =O), -C(=O)OH, OH, optionally -OH or -C(=O)NH ２ C replaced by １ ~C ４ Alkyl and optionally OH-substituted C ３ ~C ５ Selected from cycloalkyl, and R ｃ is H, halogen, CN, or methyl, R ４ and R ５ The compound according to claim 1, having [a bond with a 3-4 membered cycloalkyl group], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt thereof.

42. The aforementioned compound has the following structural formula 45-1 or 45-2: Table 21 [In the formula, R ａ１ and R ａ２ Each of these is independently a halogen, and C is optionally substituted with 1 to 3 halogen groups. １ ~C ２ Selected from alkyl groups, R' ａ１ , R' ａ２ , R' ａ３ , R' ａ４ and R' ａ５ Each is independently selected from H and halogen, and R' ａ１ , R' ａ２ , R' ａ３ , R' ａ４ and R' ａ５ Two, three, or four of them are halogens, and the rest are H. R ｂ１ is H, and optionally -C(=O)NH ２ C replaced by １ ~C ４ Selected from alkyl groups, R ｂ２ C is substituted with H and optionally 1 to 3 halogen groups. １ ~C ４ Selected from alkyl groups, R ｃ H, halogen and C １ ~C ２ A compound according to claim 1, having [selected from alkyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof.

43. The aforementioned compound has the following structural formulas 46-1, 46-2, or 46-3: Table 22 [In the formula, Z １ is selected from C and N, R ａ１ and R ａ２ Each of these is independently a halogen, and C is optionally substituted with 1 to 3 halogen groups. １ ~C ２ Selected from alkyl groups, R' ａ１ , R' ａ２ , R' ａ３ , R' ａ４ and R' ａ５ Each is independently selected from H and halogen, and R' ａ１ , R' ａ２ , R' ａ３ , R' ａ４ and R' ａ５ Two, three, or four of them are halogens, and the rest are H. R ｂ is selected from a 5-6 membered heteroaryl compound containing H and 2-3 heteroatoms selected from N and S, and the R ｂ The 5-6 member heteroaryl group can optionally contain halogens and C １ ~C ４ Substituted with 1 to 3 groups selected from alkyl groups, R ｂ１ is H, and optionally -C(=O)NH ２ C replaced by １ ~C ４ Selected from alkyl groups, R ｂ２ H, halogen, -O(C) １ ~C ４ C(alkyl) and optionally substituted with 1 to 3 halogen groups １ ~C ４ Selected from alkyl groups, R ｃ H, halogen and C １ ~C ２ A compound according to claim 1, having [selected from alkyl], a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof.

44. m R ａ Ring A substituted with the group, 【Chemistry 45】 [In the formula, R ａ１ , R ａ２ , and R ａ３ These are independently F, Cl, Br, methyl, CF ３ CF ２ Selected from H and cyclopropyl, X １ and X ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein [ is independently selected from C and N].

45. m R ａ Ring A substituted with the group, 【Chemistry 46】 [In the formula, R ａ１ and R ａ２ These are independently H, CN, F, Cl, Br, C １ ~C ４ Alkyl, CF ３ CF ２ H, and OCH ３ Selected from, R ａ３ is H, or C １ ~C ４ It is alkyl, R ａ４ These are H, F, Cl, Br, and C １ ~C ４ Selected from alkyl groups, X １ and X ２ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein [ is independently selected from N, O, and S].

46. Ring A is 【Chemistry 47】 Selected from, ring A has m R ａ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, substituted with a group.

47. m R ａ Ring A substituted with the group, 【Chemistry 48】 【Chemistry 49】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1.

48. m R ａ Ring A substituted with the group, [Transformation 50] A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1.

49. n R ｂ Ring B substituted with the group, 【Chemistry 51】 [In the formula, Z is selected from C and N, and Y １ and Y ２ R is independently selected from C and N. ｂ１ and R ｂ２ These are independently H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｂ１ and R ｂ２ In ring B, there is no case where it is connected to N, and R ｂ３ H, methyl, ethyl, 【Chemistry 52】 and selected from 5-membered heteroaryls, the R ｂ３ The five-membered heteroaryl contains two to three heteroatoms selected from N and S, and the five-membered heteroaryl optionally contains halogens and C １ ~C ４ Substituted with one or two groups selected from alkyl groups, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein [ is selected from H, halogen, CN, and methyl].

50. n R ｂ Ring B substituted with the group, 【Chemistry 53】 [In the formula, Z is selected from C and N, R ｂ１ H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl and OCH ３ Selected from, R ｂ２ H, F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl and OCH ３ Selected from, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein is selected from H, halogen, CN, and methyl.

51. n R ｂ Ring B substituted with the group, 【Chemistry 54】 [In the formula, Z is selected from C and N, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl and OCH ３ Selected from, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein p is selected from H, halogen, CN, and methyl, p is 1, 2, or 3, and q is 0, 1, or 2.

52. n R ｂ Ring B substituted with the group, 【Transformation 55】 [In the formula, Z is selected from C and N, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl and OCH ３ Selected from, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein is selected from H, halogen, CN, and methyl, and q is selected from 0, 1, or 2.

53. n R ｂ Ring B substituted with the group, 【Transformation 56】 [In the formula, Z is selected from C and N, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ Selected from, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein [ is H, halogen, CN, or methyl, p is 1, 2, or 3, and q is 0, 1, or 2].

54. n R ｂ Ring B substituted with the group, 【Chemistry 57】 [In the formula, Z is selected from C and N, R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, and OCH ３ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, selected from [where q is 0, 1, or 2].

55. n R ｂ Ring B substituted with the group, 【Chemistry 58】 [In the formula, Y is selected from C and N, E is selected from C, N and O, R ｄ１ and R ｄ２ R is independently selected from H, methyl, ethyl, and cyclopropyl. ｃ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl and OCH ３ Selected from, R ｂ１ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein p is selected from H, halogen, CN, and methyl, p is 1 or 2, and q is 0, 1, or 2.

56. n R ｂ Ring B substituted with the group, 【Chemistry 59】 [In the formula, Z is selected from C and N, and Y １ , Y ２ and Y ３ The following are independently selected from C, N, S, and O, and R ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, CONH ２ , OCH ３ ,CH ２ CONH ２ , 【Transformation 60】 Selected from, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein p is selected from H, halogen, CN, and methyl, and p is 0, 1, or 2.

57. n R ｂ Ring B substituted with the group, 【Chemistry 61】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1.

58. n R ｂ Ring B substituted with the group, 【Transformation 62】 [In the formula, Z is selected from C and N, and Y １ , Y ２ , Y ３ and Y ４ R is independently selected from C and N. ｂ１ F, Cl, Br, methyl, CN, CF ３ CF ２ H, ethyl, cyclopropyl, CONH ２ and OCH ３ Selected from, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein p is H, halogen, CN, or methyl, and p is 0, 1, or 2.

59. Ring B is 【Transformation 63】 Selected from, ring B has n R ｂ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, substituted with a group.

60. n R ｂ Ring B substituted with the group, 【Chemistry 64】 【Transformation 65】 【Chemical Formula 66】 【Transformation 67】 【Transformation 68】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1.

61. n R ｂ Ring B substituted with the group, 【Transformation 69】 [In the formula, q1 is an integer selected from 0, 1, 2, and 3, and q2 is an integer selected from 0, 1, and 2, R ｃ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein is selected from F, Cl, Br, and Me.

62. R ａ is C ３ to C ５ cycloalkyl, -O(C １ to C ２ alkyl), COOH, CN, CONH ２ , -C(=O)NH(C １ to C ２ alkyl), -C(=O)N(C １ to C ２ alkyl), ２ , -C(=O)O(C １ to C ２ alkyl), halogen, and optionally C １ to C ２ alkyl selected and substituted with 1 to 3 groups selected from halogen, the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1.

63. R ａ is CH ３ , CH ２ CH ３ , CH ２ CF ３ , F, Cl, Br, C ３ ~C ４ cycloalkyl, COOH, CN, CONH ２ , -C(=O)NHCH ３ , -C(=O)NCH ３ , -OC(=O)N(CH ３ ) ３ and OCH ３ The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt according to claim 1, selected from

64. R ｂ However, =O, OH, halogen, CN, -C(=O)NH(C １ ~C ４ Alkyl), -C(=O)O(C １ ~C ４ Alkyl), -C(=O)NH ２ , C arbitrarily substituted with OH ３ ~C ４ Cycloalkyl, O(C) １ ~C ３ Alkyl), -C (=O) (C １ ~C ２ Alkyl), -C (=O) (C ３ ~C ６ Cycloalkyl), -C(=O)(4-6 member heterocyclyl optionally substituted with =O), -C(=O)(optionally C １ ~C ２ Alkyl or NH ２ (5-6 member heteroaryl substituted with)-C(=O)(CH ２ ) pC(=O)NH ２ , -NHC(=O)(C １ ~C ２ Alkyl), -C(=O)N(C １ ~C ２ Alkyl) ２ , -C(=O)NH(CH ２ )pOH, -S(=O) ２ NH ２ , 【Transformation 70】 Halogen, NH (optional) ２ OH, OCH ３ , -C(=O)NH(C １ ~C ４ Alkyl), -C(=O)O(C １ ~C ４ Alkyl), -C(=O)N(C １ ~C ４ Alkyl) ２ , -COOH, -C(=O)NH ２ , CN, C ３ ~C ４ Cycloalkyl, phenyl, -C(=O)(C １ ~C ２ Alkyl), -C (=O) (C ３ ~C ６ Cycloalkyl), -C(=O)(5-6 member heterocyclyl), -C(=O)(arbitrarily C １ ~C ２ (Alkyl-substituted 5-6 member heteroaryls), C(=O)NH(CH ２ ) pOH and C substituted with 1 to 3 groups selected from 5-6 member heteroaryl groups １ ~C ３ Alkyl, C at will １ ~C ２ Five- to six-membered heteroaryls substituted with one or two groups selected from alkyls, and Arbitrarily = O and C １ ~C ２ Selected from 5-6 membered heterocyclines substituted with 1-2 groups selected from alkyl groups, or Two Rs attached to the same position on ring B ｂ are attached to form C ３ to C ５ to form cycloalkyl, p is an integer selected from 1 and 2. R ４ and R ５ H and C are independent of each other. １ ~C ３ Selected from alkyl groups, or R ４ and R ５ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein the two are bonded to form a 3-5 membered cycloalkyl group.

65. R ｂ However, = O, 【Chemistry 71】 CH ３ 、CHF ２ 、CF ３ 、OH、F、Cl、Br、CN、CH (CH ３ ) ２ 、CH ２ CN、OCH ３ 、-C(=O)NH ２ 、-C(=O)OCH ３ 、 【Chemistry 72】 CH ２ CH ２ OH、CH ２ CH ２ CH ２ OH、CH ２ C(=O)OH、CH ２ C(=O)NH ２ 、CH ２ C(=O)NHCH ２ CH ２ OH、CH ２ CH ２ CH ２ C(=O)NH ２ 、 【Transformation 73】 -C(=O)CH ３ 、 【Chemistry 74】 -NHC(=0)CH ３ 、-C(=O)N(CH ３ ) ２ 、-C(=O)NCH ３ ,NH ２ 、-C(=O)NHCH ２ CH ２ OH, 【Chemistry 75】 CH ２ OH、 【Transformation 76】 Select from, or two Rs bonded at the same position on ring B ｂ The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, wherein the compounds are bonded to form a three-membered or five-membered cycloalkyl group.

66. L, 【Chemical 77】 [In the formula, R １ is H, D, or C １ ~C ４ It is alkyl, R ２ CN, C １ ~C ４ Alkenil, C ３ ~C ５ Cycloalkyl, 5-6 member heteroaryl, C at will １ ~C ３ Phenyls substituted with one or two groups selected from alkyl and halogen, and C is substituted with 1 to 3 groups arbitrarily selected from halo, OH, and phenyl. １ ~C ４ Selected from alkyl groups, or R １ and R ２ These combine to form a 3-4 member heterocycline, R ３ C is substituted with 1 to 3 groups arbitrarily selected from halogens and OH groups. １ ~C ４ A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to claim 1, selected from [being alkyl].

67. L, 【Transformation 78】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1.

68. L, 【Transformation 79】 A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt selected from the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described in claim 1.

69. The aforementioned compound is the following compound Table 23-1 Table 23-2 Table 23-3 Table 23-4 Table 23-5 Table 23-6 Table 23-7 Table 23-8 Table 23-9 Table 23-10 Table 23-11 Table 23-12 Table 23-13 Table 23-14 Table 23-15 Table 23-16 Table 23-17 Table 23-18 Table 23-19 Table 23-20 Table 23-21 A compound according to claim 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer thereof, or a pharmaceutically acceptable salt thereof, selected from the above.

70. A pharmaceutical composition comprising a compound according to any one of claims 1 to 69 and a compound selected from the group consisting of compounds 1A to 121A, tautomers thereof, solvates or stereoisomers of the compound or the tautomer, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

71. A pharmaceutical composition for treating a disease or condition, wherein the disease or condition is selected from ALS, Parkinson's disease, multiple sclerosis, traumatic brain injury, diabetic neuropathy, and CIPN, according to claim 70.

72. A pharmaceutical composition according to claim 70 for treating a disease or condition caused by axonal degeneration.

73. A pharmaceutical composition according to claim 70 for adjusting SARM1.

74. A pharmaceutical composition according to claim 70 for inhibiting or preventing axonal degeneration.

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